WO2000031098A1 - Injectable anthelmintic formulation - Google Patents
Injectable anthelmintic formulation Download PDFInfo
- Publication number
- WO2000031098A1 WO2000031098A1 PCT/KR1999/000704 KR9900704W WO0031098A1 WO 2000031098 A1 WO2000031098 A1 WO 2000031098A1 KR 9900704 W KR9900704 W KR 9900704W WO 0031098 A1 WO0031098 A1 WO 0031098A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation
- present
- ivermectin
- ivomec
- pigs
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
Definitions
- the present invention relates to an injectable anthelmintic formulation, and more particularly, to an injectable antheliminitic formulation with increased water solubility and bioavailibility of an active substance.
- ivermectin or avermectin
- avermectin is highly effective against both internal and external parasites located in a variety of mammals including cows, pigs, horses, etc.
- ivermectin dissolves in water using a non-ionic surfactant such as polysorbate 80 (Tween 80), and the resulting mixture is stabilized with a cosolvent such as glycerol formal, propylene glycol, glycerine, or polyethylene glycol, and a substrate such as benzyl alcohol, lidocaine, parabens, or choline.
- a cosolvent such as glycerol formal, propylene glycol, glycerine, or polyethylene glycol
- a substrate such as benzyl alcohol, lidocaine, parabens, or choline.
- ivermectin is able to be stabilized in an aqueous solution.
- no description of the pharmacokinetics and efficiency of the invermectin formulation in animal body are given in this application.
- non-aqueous solution is used as injectable
- stability and solubility problems of ivermectin may be solved but following problems can be encountered: high viscosity; poor injectability; possibility of tissue damage or irritation where the injection is administered; precipitation of active components at the area of injection.
- the injectable anthelmintic formulation includes a water-insoluble anthelmintic, a surfactant, a cosolvent and a water-soluble solvent.
- the formulation may further include additives such as an antioxidant and a preservative.
- the surfactant includes a block copolymer of ethylene oxide and propylene oxide.
- FIG. 1 is a graph of comparing pharmacokinetics in swine between the formulation of the present invention and the commercially available Ivomec formulation (Merck & Co. INC. of the United States).
- the present invention provides a novel injectable anthelmintic formulation.
- the formulation includes a water-insoluble anthelimintic, a surfactant, a cosolvent and a water-soluble solvent.
- the formulation may further include additives such as an antioxidant and a preservative.
- the insoluble anthelmintic in the formulation of the present invention it is possible to use ivermectin or avermectin, or derivatives thereof.
- the formulation includes from 0.5 to 2.0%(w/v) of ivermectin or avermectin, or derivatives thereof.
- the surfactant and the cosolvent act as solubilizer.
- the surfactant and the cosolvent facilitate the water-insoluble anthelmintic to be dissolved in the water-soluble solvent.
- the surfactant may be a water-soluble copolymer that is listed in the pharmacopoeia.
- the water-soluble copolymer has both hydrophilic and hydrophobic properties.
- the water-soluble copolymer includes a block copolymer of propylene oxide (PO) and ethylene oxide (EO).
- the block copolymer has (EO) x (PO) y (EO) x as a unit, where the ratio of x to y is between 0.75 and 2.0.
- the copolymer which average molecular weight is between 9000 Da and 20000 Da, is presolubilized in water before use.
- the concentration of copolymer in water is between 5 and 25%. If the concentration of the copolymer is more than 25%, the viscosity of the mixed solution is increased and the solubility may be reduced. Whereas, the concentration thereof is less than 5%, the stability of the resulting injectable formulation is not guaranteed.
- the cosolvent may be alcohol, and more preferably, ethanol.
- the concentration of cosolvent is from 1 to 50 % (w/v) in the formulation of the present invention. If the amount of the cosolvent is more than 50 %(w/v), the animals may feel a pain and stability of the resulting injectable formulation is reduced. Whereas, the amount thereof is less than 1 % (w/v), it is difficult to facilitate the water-insolube anthelmintic to dissolve in the water-soluble solvent.
- the water-soluble solvent may be water.
- the formulation of the present invention may contain a variety of additives such as an antioxidant and a preservative.
- BHT butylated hydroxytoluene
- benzyl alcohol as the preservative agent ranging from 0.5 to 10 %(w/v).
- ivermectin or avermectin is immediately dissolved in the solvent with additives. This solution is then added to another solution in which the surfactant is pre-dissolved in water, thereby producing the injectable formulation of the present invention.
- the direct mixing method all components of the formulation are simultaneously mixed together to produce the injectable formulation of the present invention.
- the stepwise mixing method is preferable because the anthelmintic agent can be completely dissolved in the solvent for a short period of time, while the other direct mixing method needs more than 24 h to solubilize the anthelmintic agent completely.
- the pH of the solution is adjusted to 6.8 to 7.4 while the concentration of components in the injectable formulation is properly adjusted with water for injection. Finally, the prepared solution is sterilized by filtration.
- the injectable formulation of the present invention prepared according to the above mentioned process remains stable for more than one year at both 4 ° C and room temperature without any phase separation or precipitation.
- the parasite egg positive rate in growing & finishing pigs (swine) was reduced to 0% in 2 weeks after the treatment of Ivomec, while it took just 1 week using the formulation of the present invention.
- the parasite egg positive rates in one week after anthelmintic treatment started were as follows: 86% for Ascaris suum and 57% for Trichuris suis in no treatment groups; 80% for Ascaris suum and 0.0% for Trichuris suis in Ivomec group; 50% for Ascaris suum and 20% for Trichuris suis in the test group with the formulation of the present invention. These percentages decreased to 0.0% in two weeks in both treatment groups.
- the dead parasites were excreted between 1 and 3 days after the treatment with formulation of the present invention, while the killed parasites were observed between 1 and 8 days with Ivomec treatment. This is another good example showing the superior characteristics of the present invention for the removal of endo-parasites.
- the rate of pathological change for skin ailment in no treatment group was increased from 0.58 to 1.67 in 1 week and further augmented to 4.20 in 3 weeks after test started.
- the rate of pathological change for skin ailment was sharply decreased from 1.82 to 0.07 in 1 week and maintained at 0.13 after three weeks, which changes are quite similar to those rates of 1.06, 0.13 and 0.07 in case of the Ivomec treatment.
- the formulation of the present invention is at least equivalent or superior to Ivomec with respect to the pharmacokinetics and the efficacy as anthelmintic agent. Moreover, as described above, the present formulation is stable in aqueous phase for a considerable period of time without any physical changes such as phase separation or precipitation.
- Ivermectin injectable solution was prepared by the same procedure in
- Example 1 except that 1 % (w/v) of ivermectin, 10.0 % (w/v) of poloxamer 407, 20.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Ivermectin injectable solution was prepared by the same procedure in
- Example 1 except that 0.5 % (w/v) of ivermectin, 10.0 % (w/v) of poloxamer 407, 15.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Avermectin injectable solution was prepared by the same procedure in
- Example 1 except that 1 % (w/v) of avermectin, 10.0 % (w/v) of poloxamer 407, 15.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Avermectin injectable solution was prepared by the same procedure in Example 1 except that 0.5 % (w/v) of avermectin, 10.0 % (w/v) of poloxamer 407, 15.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Second step Approximately 30 min later after the above first step of mixing process, a second mixing process was performed. Adding 2 ml of benzyl alcohol (Korean Pharmacopoeia grade) in a 25 ml flask which was pre- sterilized for 30 min at 121 ° C , 0.01g of BHT (Korean Pharmacopoeia grade), 10 ml of ethanol (Korean Pharmacopoeia grade), and 1.17 g of ivermectin were transferred to the flask. Next, a 5 cm magnetic bar was transferred to the flask and stirred at 300 to 400 rpm. Mixing continued approximately 10 min until all the contents in the flask were dissolved, thereby producing a clear second mixed solution. The second mixed solution was then filtered using a 0.2 ⁇ filter.
- Third step The first mixed solution and the second mixed solution were then transferred to a sterilized container and mixed for approximately 10 min to give a final mixed solution. Next, small amount of water was added to the final solution (at an amount to result in a desired final volume of the solution) to complete the mixing process, thereby producing a fully sterilized ivermectin injectable solution of 1%(w/v).
- Example 7 Ivermectin injectable solution was prepared by the same procedure in Example 6 except that 1.0 % (w/v) of ivermectin, 10.0 % (w/v) of poloxamer 407, 5.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Example 8 Ivermectin injectable solution was prepared by the same procedure in Example 6 except that 0.5 % (w/v) of ivermectin, 20.0 % (w/v) of poloxamer 407, 10.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Example 9 Avermectin injectable solution was prepared by the same procedure in Example 6 except that 1.0 % (w/v) of avermectin, 10.0 % (w/v) of poloxamer 407, 15.0 % (w/v) of ethanol, 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Example 10 Avermectin injectable solution was prepared by the same procedure in Example 6 except that 0.5 % (w/v) of avermectin, 10.0 % (w/v) of poloxamer 407, 15.0 % (w/v) of ethanol 0.01 % (w/v) of BHT, 2.0 % (w/v) of benzyl alcohol, and balance of water were used.
- Ivomec (Merck & Co. INC. of the United States)
- the injectable formulation was manufactured according to the method of Example 6. It consists of 1.0% of ivermectin, 10.0% of Poloxamer 407, 15.0% of ethanol, 2.0% of benzyl alcohol, 0.01 % of BHT, and sterilized water making up the remaining portion of the solution.
- the formulation of the present invention and Ivomec were injected in two separate test groups of growing & finishing pigs (swine) at an amount of 300 ⁇ g per kilogram body weight. Next, blood samples were taken at every predetermined time. The blood samples were then centrifuged for 20 min at 3000 rpm to separate the plasma from the blood, after which the plasma was stored at -20°C.
- each dried sample was dissolved with 100 ⁇ l of 1- methylimidazole: acetonitrile mixture (1:2, v/v) and 150 ⁇ l of trifluroacetic anhydride: acetonitrile mixture (1 :2, v/v) was added thereto such that the ivermectin isolated was derivatized for better measurement.
- 100 ⁇ l of this derivatized solution was then analyzed with HPLC (TSO P1000, U.S.A) with a fluorescence detector (TSP F3000, U.S.A.). Peak measurement was done under a 374 nm excitation wavelength and a 475 nm emission wavelength conditions.
- a concentration of the ivermectin in the samples was determined by comparing HPLC peak area of the plasma samples from the pigs injected by the present formulation and Ivomec, with standard curve prepared by addition of 0.5, 5, and 50 ng of ivermectin (Sigma, U.S.A.) to 1 ml of plasma taken from the pigs not treated with any anthelmintic. The treatment and measurement of the samples were simultaneously performed without any delay and blood samples taken from one pig were analyzed all at once. To reduce variation errors in pre- treatment of samples, standard samples were simultaneously prepared and used every time of analysis. At this time the peak of derivatized ivermectin B1a derivative appeared at about 10 min retention time in HPLC. Also a small peak appeared at about 8 min, which represents ivermectin B1 b derivative.
- the concentration of ivermectin in blood samples was determined by comparing combined areas of two peaks with those of ivermectin peak areas in the standard curve. Everytime the analysis was performed, standard blood sera were prepared by adding different concentrations of ivermectin and treated with the same method as for the test sample treatment. These newly prepared standards were used to determine the concentration of the test samples.
- the maximum concentration of ivermectin in plasma samples from pigs injected with the formulation manufactured according to Example 6 is twice higher than that of Ivomec. However, 4 or 5 days later after injection, concentrations of ivermectin for both the present formulation and Ivomec are substantially reduced to equal levels.
- Such a different pharmacokinetics of ivermectin is because of the composition difference between Ivomec and the formulation of the present invention. Compared with the Ivomec, the formulation of the present invention is more quickly absorbed in the blood and shows superior pharmacodynamic property. This suggests that, when identical amounts of ivermection are used, the ability of the formulation of the present invention to kill parasites is significantly better than that of Ivomec.
- An injectability comparison test was performed using the injectable formulation of the present invention (I), Ivomec (Merck Co.) (II), Ivomec-F (Merck Co.) (Ill), Baymec (Bayel Co.) (IV), Abamec (Daesung, Korea) (V), and Dectomax (Pfizer) (VI).
- the formulation of the present invention manufactured according to Example 6 and Ivomec were injected to two separate test groups of growing & finishing pigs (swine) at an amount of 300 ⁇ g per kilogram of body weight. Blood samples were taken at predetermined time intervals after the injection and using the method described in [Test 1], ivermectin concentration changes in the blood were measured. The results are shown in Table 3 below. As shown in the table, average maximum concentrations of ivermectin in the blood are ranged from 1.7 to 2.1 -times of that for Ivomec and the time for Ivomec to reach its peak is 36 h, while the formulation of the present invention takes 2 to 5 h depending on the amount of ethanol in the present formulation.
- a parasitic egg reduction was 100% for the pigs treated with either Ivomec or the present formulation, while it was 0% for the untreated control group of pigs.
- An excretion of dead parasites was 0% for the control group of pigs, while it was between 23.3 and 26.7% for the pigs treated with Ivomec or the formulation of the present invention.
- no abnormalities in the area of injection e.g., fever, inflammation
- unusual behavior were observed.
- Injection amount of the present formulation X 2 0.6 mg/kg body weight (5-3) Efficacy test in growing & fiinishing pigs artificially infected with the endo-parasite, Ascaris suum
- Trichuris suis eggs per 1g EPG; egg/gram
- Trichuris suis eggs were detected in the feces of the control group of pigs, while the number of Trichuris suis eggs in feces of the groups treated with the present formulation or Ivomec decreased significantly after one week and no eggs being detected after two weeks.
- Table 9 The results are shown in Table 9 below.
- Piglets were used to conduct the efficacy test of the present formulation against the ecto-parasite, Sarcoptes scabiei.
- the rate of skin pathological change at the start of test was 0.58, and increased to 1.67 after one week and further increased to 4.20 after three weeks.
- the rate of skin pathological change was reduced from 1.82 to 0.7 after one week and further decreased to 0.13 after three weeks.
- the rate of skin pathological change was reduced from 1.06 to 0.13 after one week and 0.07 after three weeks. Test results are shown in Table 10. Table 10
- Sows were used to conduct the efficacy test of the present formulation against the endo and ecto-parasites. No diarrhea was seen among the sows tested at 1 , 2 and 3 weeks. Dead parasites were detected in the feces of the sows injected with the formulation of the present invention after two days and no more parasites were found after 7 days. In the case where the sows were treated with Ivomec, the parasites begun to be excreted after three days and were no longer detected after 8 days. Further, with regard to ecto-parasites, all the parasites were removed in the sows treated with either the present formulation or Ivomec, whereas no significant improvement was detected in the untreated control group of sows.
- the formulations of the present invention as described above are extremely stable in aqueous phase and do not undergo phase separation. Further, as shown in a number of clinical tests, the formulations of the present invention have a better pharmacokinetic property and an equivalent or better efficacy against both endo and ecto-parasites than the prior art. Other physicochemical properties of the formulations of the present invention include their long stability, similar viscosity, and injectability compared to the prior art. Finally, no physical damage or other side effects were observed in the area of injection with the use of the present formulation.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15844/00A AU753532B2 (en) | 1998-11-23 | 1999-11-22 | Injectable anthelmintic formulation |
MXPA01005123A MXPA01005123A (en) | 1998-11-23 | 1999-11-22 | Injectable anthelmintic formulation. |
NZ511852A NZ511852A (en) | 1998-11-23 | 1999-11-22 | Injectable anthelmintic formulation |
BR9915559-1A BR9915559A (en) | 1998-11-23 | 1999-11-22 | Anthelmintically injectable formulation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1019980050135A KR100315465B1 (en) | 1998-11-23 | 1998-11-23 | Animal Insect Repellent Compositions Containing Water Soluble Polymer and Alcohol |
KR98/50135 | 1998-11-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000031098A1 true WO2000031098A1 (en) | 2000-06-02 |
Family
ID=19559247
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/KR1999/000704 WO2000031098A1 (en) | 1998-11-23 | 1999-11-22 | Injectable anthelmintic formulation |
Country Status (7)
Country | Link |
---|---|
KR (1) | KR100315465B1 (en) |
CN (1) | CN1166676C (en) |
AU (1) | AU753532B2 (en) |
BR (1) | BR9915559A (en) |
MX (1) | MXPA01005123A (en) |
NZ (1) | NZ511852A (en) |
WO (1) | WO2000031098A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1294375A2 (en) * | 2000-06-29 | 2003-03-26 | L. Dean Parks | Method of treatment of seborrheic dermatitis |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103720652B (en) * | 2014-01-07 | 2016-09-28 | 王玉万 | Prepare containing Avermectins medicine injection with poloxamer and oil medium |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01135717A (en) * | 1987-11-09 | 1989-05-29 | Alza Corp | Improved drug percataneous supply apparatus |
JPH07173017A (en) * | 1993-12-17 | 1995-07-11 | Toshio Suzuki | Composition for preventing pines from being damaged by death and method for prevention |
US5439924A (en) * | 1991-12-23 | 1995-08-08 | Virbac, Inc. | Systemic control of parasites |
US5593683A (en) * | 1990-05-01 | 1997-01-14 | Mdv Technologies, Inc. | Method of making thermoreversible polyoxyalkylene gels |
-
1998
- 1998-11-23 KR KR1019980050135A patent/KR100315465B1/en not_active IP Right Cessation
-
1999
- 1999-11-22 CN CNB998153664A patent/CN1166676C/en not_active Expired - Fee Related
- 1999-11-22 MX MXPA01005123A patent/MXPA01005123A/en unknown
- 1999-11-22 WO PCT/KR1999/000704 patent/WO2000031098A1/en active IP Right Grant
- 1999-11-22 BR BR9915559-1A patent/BR9915559A/en not_active IP Right Cessation
- 1999-11-22 AU AU15844/00A patent/AU753532B2/en not_active Ceased
- 1999-11-22 NZ NZ511852A patent/NZ511852A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01135717A (en) * | 1987-11-09 | 1989-05-29 | Alza Corp | Improved drug percataneous supply apparatus |
US5593683A (en) * | 1990-05-01 | 1997-01-14 | Mdv Technologies, Inc. | Method of making thermoreversible polyoxyalkylene gels |
US5439924A (en) * | 1991-12-23 | 1995-08-08 | Virbac, Inc. | Systemic control of parasites |
JPH07173017A (en) * | 1993-12-17 | 1995-07-11 | Toshio Suzuki | Composition for preventing pines from being damaged by death and method for prevention |
Non-Patent Citations (2)
Title |
---|
DATABASE WPI Week 198927, Derwent World Patents Index; AN 1989-197150 * |
DATABASE WPI Week 199536, Derwent World Patents Index; AN 1995-272810 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1294375A2 (en) * | 2000-06-29 | 2003-03-26 | L. Dean Parks | Method of treatment of seborrheic dermatitis |
EP1294375A4 (en) * | 2000-06-29 | 2004-06-09 | L Dean Parks | Method of treatment of seborrheic dermatitis |
Also Published As
Publication number | Publication date |
---|---|
NZ511852A (en) | 2003-08-29 |
BR9915559A (en) | 2001-11-20 |
AU753532B2 (en) | 2002-10-17 |
CN1354754A (en) | 2002-06-19 |
MXPA01005123A (en) | 2002-06-04 |
AU1584400A (en) | 2000-06-13 |
KR100315465B1 (en) | 2002-02-19 |
CN1166676C (en) | 2004-09-15 |
KR20000033304A (en) | 2000-06-15 |
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