CN101088564A - Intravenous medicine carrier material and its prepn process - Google Patents
Intravenous medicine carrier material and its prepn process Download PDFInfo
- Publication number
- CN101088564A CN101088564A CNA2006100872547A CN200610087254A CN101088564A CN 101088564 A CN101088564 A CN 101088564A CN A2006100872547 A CNA2006100872547 A CN A2006100872547A CN 200610087254 A CN200610087254 A CN 200610087254A CN 101088564 A CN101088564 A CN 101088564A
- Authority
- CN
- China
- Prior art keywords
- gelatin
- cross
- medicine carrier
- carrier material
- intravenous medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 47
- 238000001990 intravenous administration Methods 0.000 title claims abstract description 33
- 239000012876 carrier material Substances 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims description 15
- 230000008569 process Effects 0.000 title description 2
- 108010010803 Gelatin Proteins 0.000 claims abstract description 30
- 229920000159 gelatin Polymers 0.000 claims abstract description 30
- 239000008273 gelatin Substances 0.000 claims abstract description 30
- 235000019322 gelatine Nutrition 0.000 claims abstract description 30
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 30
- 239000000463 material Substances 0.000 claims abstract description 20
- 238000004132 cross linking Methods 0.000 claims abstract description 12
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 12
- 102000004190 Enzymes Human genes 0.000 claims abstract description 4
- 108090000790 Enzymes Proteins 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 15
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000004365 Protease Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000006731 degradation reaction Methods 0.000 claims description 5
- 108091005804 Peptidases Proteins 0.000 claims description 4
- 150000001718 carbodiimides Chemical class 0.000 claims description 4
- 235000019419 proteases Nutrition 0.000 claims description 4
- 108090000145 Bacillolysin Proteins 0.000 claims description 3
- 102000035092 Neutral proteases Human genes 0.000 claims description 3
- 108091005507 Neutral proteases Proteins 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 3
- 229940088598 enzyme Drugs 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000017854 proteolysis Effects 0.000 claims description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 2
- 108010004032 Bromelains Proteins 0.000 claims description 2
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 2
- 108090000526 Papain Proteins 0.000 claims description 2
- 235000019835 bromelain Nutrition 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 235000013305 food Nutrition 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 235000019834 papain Nutrition 0.000 claims description 2
- 229940055729 papain Drugs 0.000 claims description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims 2
- 239000008280 blood Substances 0.000 abstract description 12
- 210000004369 blood Anatomy 0.000 abstract description 12
- 238000002360 preparation method Methods 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
- 230000001276 controlling effect Effects 0.000 abstract 2
- 230000000593 degrading effect Effects 0.000 abstract 1
- 231100000956 nontoxicity Toxicity 0.000 abstract 1
- 230000003480 fibrinolytic effect Effects 0.000 description 24
- 239000003527 fibrinolytic agent Substances 0.000 description 23
- 229960005356 urokinase Drugs 0.000 description 18
- 238000012360 testing method Methods 0.000 description 14
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 12
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 12
- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000002798 spectrophotometry method Methods 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 2
- 208000007536 Thrombosis Diseases 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- BHTJEPVNHUUIPV-UHFFFAOYSA-N pentanedial;hydrate Chemical compound O.O=CCCCC=O BHTJEPVNHUUIPV-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Images
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to intravenous medicine carrier material and its preparation process. The intravenous medicine carrier material is medicine release controlling material to avoid the fast removing of medicine from blood, and has itself no pharmacological effect. It is prepared with gelatin as base material, and through degrading gelatin in enzyme solution, cross-linking with cross-linking agent, purifying and drying. It has intravenous medicine release controlling effect, no toxicity, and other advantages.
Description
(1) technical field
The present invention relates to the excipient substance material, belong to the no pharmacological action of material self, can slow down drug carrier material and manufacture method thereof that protein drug is removed fast from blood.
(2) technical background
Some intravenous drug has sure therapeutical effect, but owing to medicine blood concentration after administration rises fast and reduces, it is of short duration to cause medicine to hold time at the treatment concentration level, and therapeutic effect is limited; Simultaneously, the risk that causes side effect but increases therefrom because blood concentration raises.The dynamic characteristic of this class medicine has hindered its clinical practice significantly.
In order to reduce the too high risk that causes of medicine blood concentration, the main preventive measure in clinical treatment is the control dosage at present, reduces but its cost is a therapeutic effect.
The new drug that development has good pharmacological action and good dynamic characteristic simultaneously needs considerable time.
As another solution, this class medicine can be combined with specific pharmaceutical carrier, thereby the concentration change of medicine in blood controlled by pharmaceutical carrier, can improve the therapeutic effect of medicine and reduce side effects of pharmaceutical drugs.Obtained successful experience by pharmaceutical carrier to change pharmacokinetics, and become developing tendency in future at drug research and the clinical drug two big fields of using.
Clinical existing drug carrier material is mainly synthetic by polyester material at present.People such as N.Kumar have introduced the application of polyester material as pharmaceutical carrier in the article of " Advanced drug delivery reviews 53 (2001) 23-44, Biodegradable blockcopolymers ".Because still among research, thereby range of application is restricted in its safety.
Adopting the gelatin catabolite is that self is nontoxic because gelatin is made of natural amino acid as intravenous medicine carrier material, and its catabolite is also nontoxic, and wide material sources processs easyly, and existing secular medical science use history is easily generally accepted for the public.The intravenous medicine carrier material that the gelatin catabolite is made is convenient to be convenient to control drug release with the medicine combination.
(3) summary of the invention
The objective of the invention is to develop a kind of novel intravenous medicine carrier material, overcome the deficiency of above-mentioned existing material.
Another object of the present invention is the preparation method of this intravenous medicine carrier material of research.
A kind of intravenous medicine carrier material of the present invention is carried out crosslinkedly after degraded by gelatin, form material.
Said gelatin be categorized as in the state food drug additive gelatin quality standard rigid, in rigid, neutral and soft wherein a kind of.
The method for making of a kind of intravenous medicine carrier material of the present invention is:
1) gelatin is mixed with aqueous solution according to 0.1%～30% percetage by weight.
2) part by weight according to gelatin and protein degradation enzyme is 100: 0.1～10, protease is added gelatin solution degrade.
3) cross-linking agent is mixed with aqueous solution according to 0.1%～30% percetage by weight.Part by weight according to gelatin and cross-linking agent is 100: 0.1～20, cross-linking agent aqueous solution is added the gelatin degradation solution carry out cross-linking reaction.
4) cross-linking reaction thing drying and form material.
Said protease can be one or more the combination wherein of papain, bromelain or neutral protease;
Said cross-linking agent can be wherein a kind of of glutaraldehyde, epoxychloropropane or carbodiimides.
Degradation reaction was carried out 1-24 hour at 10～60 ℃.
Cross-linking reaction was carried out 1-24 hour at-20～30 ℃.
Cross-linking products carries out 6-48 hour drying at-80～30 ℃, forms material.
The advantage of a kind of intravenous medicine carrier material of the present invention and method for making thereof is:
1) intravenous medicine carrier material of the present invention has the medicine controlled releasing effect, sees Fig. 1.
2) the no haemolysis of intravenous medicine carrier material of the present invention self, no blood coagulation, no fibrinolysis.
3) intravenous medicine carrier material of the present invention is made of natural amino acid, and self is nontoxic, and catabolite is also nontoxic.
4) intravenous medicine carrier material wide material sources of the present invention are easy to get, and with low cost, preparation technology is simple and clear, and equipment code is easy to grasp.
(4) description of drawings
Fig. 1 intravenous medicine carrier material of the present invention is to the influence of urokinase fibrinolytic effect.
Among the figure, vertical coordinate is that (unit: %), abscissa is a time (unit: min) to the fibrinolytic rate.
Curve 1 is the dynamic fibrinolytic rate of simple urokinase.
Curve 2 is the dynamic fibrinolytic rate of carrier-urokinase complex.
Fig. 2 is the intravenous medicine carrier controlled-release effect figure of the embodiment of the invention 2.
Among the figure, vertical coordinate is that (unit: %), abscissa is a time (unit: min) to the fibrinolytic rate.
Curve 1 is the dynamic fibrinolytic rate of simple urokinase.
Curve 2 is the dynamic fibrinolytic rate of carrier-urokinase complex.
Fig. 3 is the intravenous medicine carrier controlled-release effect figure of the embodiment of the invention 3.
Among the figure, vertical coordinate is that (unit: %), abscissa is a time (unit: min) to the fibrinolytic rate.
Curve 1 is the dynamic fibrinolytic rate of simple urokinase.
Curve 2 is the dynamic fibrinolytic rate of carrier-urokinase complex.
Dynamically the mensuration of fibrinolytic rate is according to medical apparatus and instruments biological assessment standard test guide (chief editor Hao peace, China Standard Press, 2000) the described basic skills of 92-93 page or leaf, and adjusts accordingly.
1 measures used material
1) experimental animal is a rabbit, body weight 2～2.5kg
2) calcium chloride (CaCl
2) 0.025mol/L solution
3) distilled water
4) urokinase (UK) 800 units/ml solution
5) carrier-urokinase (CGUK) 3% solution
2 experimental procedures
1) get blood with the syringe that contains the ACD anticoagulant from rabbit vein, ACD and blood volume ratio are 1: 4.Blood sampling 0.2ml adds test tube, adds distilled water 50ml, carries out spectrophotometric determination in the 540nm wavelength, as positive value.
2) get blood with the syringe that contains the ACD anticoagulant from rabbit vein, blood sample 0.2ml adds test tube, adds calcium chloride 0.2ml, leaves standstill 20min, forms thrombosis.Add distilled water 50ml, carry out spectrophotometric determination in the 540nm wavelength, as the feminine gender value.
3) through vein UK is injected the matched group rabbit,, get blood with the syringe that contains the ACD anticoagulant from vein at 5min, 30min, 60min and 120min respectively, add test tube, every test tube 0.2ml CGUK injection testing group rabbit.In test tube, add calcium chloride 0.2ml, leave standstill 20min, form thrombosis.In test tube, add distilled water 50ml, carry out spectrophotometric determination, draw matched group UK test value and test group CGUK test value respectively in the 540nm wavelength.
3 date processing
1) calculates the fibrinolytic rate: fibrinolytic rate=(test value-feminine gender value)/(positive value-feminine gender value) * 100%.
2) draw dynamic fibrinolytic rate curve figure: with the fibrinolytic rate as vertical coordinate, with the time as abscissa curve plotting figure.
(5) specific embodiment
With following indefiniteness embodiment intravenous medicine carrier material of the present invention and preparation method thereof is further described, can helps the present invention and effect thereof are had a better understanding.Protection scope of the present invention is decided by claims.
Embodiment 1
The intravenous medicine carrier material of present embodiment is made for base material by commercially available gelatin (the precious gelatin company limited of Wenzhou China).
Its preparation method is:
1) gelatin is mixed with aqueous solution according to 3% percetage by weight;
2) part by weight according to gelatin and protein degradation enzyme is 100: 1, and neutral protease is added gelatin solution, at 50 ℃ of 60min that degrade;
3) part by weight according to gelatin and cross-linking agent is 100: 2, and glutaraldehyde water solution is added the gelatin degradation solution, carries out cross-linking reaction 20h at 25 ℃;
4) the cross-linking reaction product forms material at 45 ℃ of dry 20h after filtering.
With the material of method for preparing and urokinase mixed preparing solution as the test group injection, organize injection in contrast with simple urokinase obtain solution, through vein difference injection testing group rabbit and matched group rabbit, and get blood from vein in 5min, 30min, 60min and 120min, measure dynamic fibrinolytic rate.Measurement result is seen curve 1 and the curve 2 of Fig. 1.
As can be seen from the figure the intravenous medicine carrier material of present embodiment has good controlled-release function.
Embodiment 2
Its method and apparatus is substantially with embodiment 1, and the gelatin of only different is present embodiment is mixed with aqueous solution according to 5% percetage by weight; Cross-linking agent adopts carbodiimides solution, carries out cross-linking reaction 12h at 5 ℃.Dynamically fibrinolytic rate measurement result is seen curve 1 and the curve 2 of Fig. 2.
The dynamic fibrinolytic rate of Fig. 2
Curve 1 is the dynamic fibrinolytic rate of simple urokinase.
Curve 2 is the dynamic fibrinolytic rate of carrier-urokinase complex.
As can be seen from the figure the intravenous medicine carrier material of present embodiment has good controlled-release function.
Embodiment 3
Its method and apparatus is substantially with embodiment 1, and the gelatin of only different is present embodiment is mixed with aqueous solution according to 5% percetage by weight; Cross-linking agent adopts carbodiimides solution, carries out cross-linking reaction 18h at 15 ℃.Dynamically fibrinolytic rate measurement result is seen curve 1 and the curve 2 of Fig. 3.
The dynamic fibrinolytic rate of Fig. 3
Curve 1 is the dynamic fibrinolytic rate of simple urokinase.
Curve 2 is the dynamic fibrinolytic rate of carrier-urokinase complex.
As can be seen from the figure the intravenous medicine carrier material of present embodiment has good controlled-release function.
Claims (8)
1 one kinds of intravenous medicine carrier materials is characterized in that, gelatin carries out crosslinked after degraded, form material.
The 2 a kind of intravenous medicine carrier materials according to claim 1 is characterized in that, said gelatin be categorized as in the state food drug additive gelatin quality standard rigid, in rigid, neutral and soft wherein a kind of.
The method for making of 3 one kinds of intravenous medicine carrier materials is characterized in that,
3.1 gelatin is mixed with aqueous solution according to 0.1%～30% percetage by weight;
3.2 the part by weight according to gelatin and protein degradation enzyme is 100: 0.1～10, protease is added gelatin solution degrade;
3.3 cross-linking agent is mixed with aqueous solution according to 0.1%～30% percetage by weight.Part by weight according to gelatin and cross-linking agent is 100: 0.1～20, cross-linking agent aqueous solution is added the gelatin degradation solution carry out cross-linking reaction;
3.4 cross-linking reaction product drying and form material.
4 method for makings according to a kind of intravenous medicine carrier material of claim 3 is characterized in that, said protease can be one or more the combination wherein of papain, bromelain or neutral protease;
5 method for makings according to a kind of intravenous medicine carrier material of claim 3 is characterized in that, said cross-linking agent can be wherein a kind of of glutaraldehyde, epoxychloropropane or carbodiimides.
6 method for makings according to a kind of intravenous medicine carrier material of claim 3 is characterized in that degradation reaction was carried out 1-24 hour at 10～60 ℃.
7 method for makings according to a kind of intravenous medicine carrier material of claim 3 is characterized in that cross-linking reaction was carried out 1-24 hour at-20～30 ℃.
8 method for makings according to a kind of intravenous medicine carrier material of claim 3 is characterized in that, dryly carry out 6-48 hour at-80～30 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100872547A CN101088564A (en) | 2006-06-15 | 2006-06-15 | Intravenous medicine carrier material and its prepn process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100872547A CN101088564A (en) | 2006-06-15 | 2006-06-15 | Intravenous medicine carrier material and its prepn process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101088564A true CN101088564A (en) | 2007-12-19 |
Family
ID=38942164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100872547A Pending CN101088564A (en) | 2006-06-15 | 2006-06-15 | Intravenous medicine carrier material and its prepn process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101088564A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108495709A (en) * | 2016-01-25 | 2018-09-04 | 三得利控股株式会社 | Capsule containing functional substance and manufacturing method thereof |
-
2006
- 2006-06-15 CN CNA2006100872547A patent/CN101088564A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108495709A (en) * | 2016-01-25 | 2018-09-04 | 三得利控股株式会社 | Capsule containing functional substance and manufacturing method thereof |
| CN108495709B (en) * | 2016-01-25 | 2021-09-03 | 三得利控股株式会社 | Capsule containing functional substance and method for producing same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kang et al. | Oxygen-supplying syringe to create hyperoxia-inducible hydrogels for in situ tissue regeneration | |
| US20090081753A1 (en) | Method for formulating and immobilizing a matrix protein and a matrix protein for use in a sensor | |
| AU2015206597B2 (en) | Thermosensitive hydrogel collagenase formulations | |
| PT84188A (en) | PROCESS FOR PREPARING A PHARMACEUTICAL COMPOSITION FOR THE OBTENTION OF AN HYDROGEL OR AN HIGHLY VISCOSE SUSPENSION | |
| Urban et al. | Effect of the association of nystatin with a tissue conditioner on its ultimate tensile strength | |
| DE69804974D1 (en) | OPIOID CONJUGATES WITH ENDOGENIC CARRIER PROTEINS | |
| Zaugg-Vesti et al. | Lymphatic capillary pressure in patients with primary lymphedema | |
| White et al. | Intravenous valproate associated with significant hypotension in the treatment of status epilepticus | |
| Zhuang et al. | A poly (γ‐glutamic acid)‐based hydrogel loaded with superoxide dismutase for wound healing | |
| Dubber et al. | In vitro and in vivo studies with Trasylol, an anticoagulant and a fibrinolytic inhibitor | |
| Ambros et al. | Pharmacokinetics and pharmacodynamics of a constant rate infusion of fentanyl (5 μg/kg/h) in awake cats | |
| Taylor et al. | Studies with crystalline trypsin: results and hazards of intravenous administration and its postulated role in blood coagulation | |
| O'Shea et al. | Laboratory control of heparin therapy | |
| CN101088564A (en) | Intravenous medicine carrier material and its prepn process | |
| Dupe et al. | The evaluation of plasmin and streptokinase activator complexes in a new rabbit model of venous thrombosis | |
| Plate et al. | On the mechanism of enhanced thromboresistance of polymeric materials in the presence of heparin | |
| EP4125997A1 (en) | New method to treat the hepatotoxicity induced by amanitins | |
| Jensen et al. | Allergic intolerance to tetracosactrin | |
| Westerink et al. | Effect of choline administration on the release of acetylcholine from the striatum as determined by microdialysis in awake rats | |
| JPS58500610A (en) | A novel drug consisting of an aprotinin-plasmin complex and a method for producing the novel complex | |
| Svendsen | Intramuscular injections and local muscle damage: an experimental study of the effect of injection speed | |
| TW513307B (en) | Pharmaceutical composition for treating vascular disorders comprising activated protein C | |
| US3639626A (en) | Suppressing the activity of plasmin in humans and animals with trans-4-(aminomethyl)-cyclohexane - 1 - carboxylic acid | |
| US3876774A (en) | Method of using a simple protein derived from liver | |
| Joyia et al. | 1. Isolation, purification and functional characterization of fibrinolytic Protease from an Earthworm Eisenia foetida |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20071219 |