WO1998041458A1 - Multi-compartment rehydrating container - Google Patents
Multi-compartment rehydrating container Download PDFInfo
- Publication number
- WO1998041458A1 WO1998041458A1 PCT/BE1998/000035 BE9800035W WO9841458A1 WO 1998041458 A1 WO1998041458 A1 WO 1998041458A1 BE 9800035 W BE9800035 W BE 9800035W WO 9841458 A1 WO9841458 A1 WO 9841458A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compartment
- container
- self
- water
- rehydrating
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2093—Containers having several compartments for products to be mixed
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
- B65D81/32—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents for packaging two or more different materials which must be maintained separate prior to use in admixture
- B65D81/3261—Flexible containers having several compartments
- B65D81/3266—Flexible containers having several compartments separated by a common rupturable seal, a clip or other removable fastening device
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
- A61J1/10—Bag-type containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
- A61J1/202—Separating means
- A61J1/2024—Separating means having peelable seals
Definitions
- the invention is related to a new self-rehydrating container having at least two separated compartments containing solutes, drugs, insoluble materials or mixtures thereof.
- the invention concerns also methods of using such a container to prepare rehydrated solutions or suspensions.
- Cellulose films are known to be relatively inert semi-permeable strong membranes capable of separating compounds with different molecular weight by osmosis or dialysis for example. According to EP 360,612 or USP 4,920,105, such films are efficiently used as membrane for the manufacture of self-rehydrating container wherein the membrane constitutes at least a portion of the walls of the container and wherein an osmotically active solute is retained within the container. When this container is placed into water, osmosis takes place and fills it with water which is purified by filtration through the membrane.
- osmotically active solute means a substantially water-soluble solute or a concentrated solution thereof able to sustain osmosis through the semi-permeable membrane.
- Another problem resides in the fact that when containers having semi-permeable membranes are used to produce nutritional solute solutions such as milk powder solutions or fruit juice preparations, the dried food may contain residual bacte ⁇ a, usually m a dormant form.
- the container is put into water of about 30°C, such as in tropical areas, and the rehydrated solution is consumed directly after preparation, no significant bacterial problem arises.
- the container is left in the 30°C water after preparation, the contaminating bacte ⁇ a can proliferate and become a se ⁇ ous threat to health.
- a self-rehydrating container having an osmotically active compartment and at least a separate watertight compartment containing a solute, a liquid, a drug, nut ⁇ tional mate ⁇ als, insoluble mate ⁇ als, etc (generally a water- soluble or -suspendible product) and which could be easily manufactured and especially easily used.
- osmotically active compartment means a compartment having at least a portion of its walls of semi-permeable material, such that when an osmotically active solute is retained withm this compartment and when the compartment is placed into water, osmosis can take place.
- Another object of the present invention is to provide a self-rehydrating container allowing the preparation of accurately dosed solutions
- Yet another object of the invention is to provide a self-rehydrating container for the preparation of solutions comprising labile mate ⁇ als or low molecular weight mate ⁇ als, these solutions being substantially free of micro-organisms coming from the outside water
- a further aim of the present invention is also to provide a self-rehydrating container for the production of nutritional solutions or suspension substantially free of undesirable micro-organisms having grown within the container.
- Another object of this invention is to provide a self-rehydrating container which fulfils these requirements but which is also easy to use and easy to manufacture.
- the invention is firstly concerned with a self-rehydrating container for the production of solutions or suspensions substantially free of undesirable micro-organisms, characte ⁇ sed in that the container is divided into at least two compartments by at least a non- permanent seal bonding the opposite walls of said container, the walls of the container surrounding at least a first compartment being watertight, the walls of the container surrounding at least one portion of at least a second compartment being semi-permeable, an osmotically active solute being retained in said second compartment and a solute, a drug, a nutritional suspension or powder to be put into solution or suspension is retained in said first watertight compartment.
- a non-permanent seal means a seal which may be peeled or broken by seal anchorage failure or external manipulation or by the effect of water pressure.
- the container is constituted of a rectangular sheet of semi- permeable mate ⁇ al folded over itself to form a tube, a waterproof longitudinal seal bonding the overlapping portions of said tube, said tube being flattened and closure means closing the top and bottom extremities of the tube.
- the semi-permeable mate ⁇ al constituting the membrane can be selected from a wide variety of mate ⁇ als including cellulose, regenerated cellulose (CELLOPHANE®, cuprammonium cellulose, ..), benzoylated cellulose, and collagen
- the prefe ⁇ ed mate ⁇ al is regenerated cellulose.
- This membrane may be produced by one or several known manufactu ⁇ ng methods, such as xanthate, cuprammonium, carbamate or organic solvent (e g NMMO) processes when a regenerated cellulose mate ⁇ al is used.
- this membrane may serve as a support layer for a thin second layer
- the second layer can be composed of cellulose derivatives (e g ethers, esters, nitro-cellulose, etc.), synthetic organic polymers (e g polyacryhc ester, polyvinyl acetate copolymers, polyurethanes, aliphatic polyamides such as a nylon 6, nylon 6 6, nylon 4 6 and the like), modified or unmodified naturally occur ⁇ ng polymers (e g starches, proteins, etc )
- the second layer consists of a thm layer of an hydrophihc polyurethane such as those conventionally used for covering textile with a protective waterproof but water vapour permeable coating
- the overall thickness of the membrane is from 20 to 50 ⁇ m
- the sheet of semi permeable mate ⁇ al advantageously possesses a st ⁇ p of adhesive material coated therein in a direction perpendicular to the axis of the tube to be formed. Therefore, when the tube is flattened, the opposite walls of the container possess a strip of adhesive material into register with one another and when pressure is applied, with or without heat, a seal is created between the opposite walls of the container.
- Suitable material which can be used as adhesive material to form the seal bonding the opposite walls of the container are heat sealable adhesive compositions such as polyvinylidene chloride, polyethylene, thermoplastic polyurethane, ethylene-vinyl acetate copolymer, acrylic resins, and the like, alone or in admixture. Additives such as waxes may also be added to these components. Cold sealable adhesive compositions such as natural or modified rubber, neoprene and the like are also suitable.
- the longitudinal seal closing the tube according to this embodiment may also advantageously possess some particular features.
- the seal geometry itself is of importance. It is indeed necessary that the seal withstands quite high water pressure without opening.
- the inventors have observed that a seal between two different portions of a semi-permeable material sheet in overlap position will withstand quite high water pressure without opening. It has indeed been observed that an overlap seal resists high water pressure without opening due to the fact the adhesive shear plane no longer lays in line with the water pressure.
- An overlap seal according to this embodiment is a seal where, in the zone of adherence, the opposite walls of the two semi-permeable materials are positioned in a parallel relationship, both respective membrane endings pointing in the opposite direction and made adherent to one another by means of an adhesive layer in such a manner that the water pressure no longer lays in line the adhesive shear surface of the adhesive layer.
- Suitable materials which can be used as adhesive material to form the longitudinal seal are heat sealable adhesive compositions such as polyvinylidene chloride, polyethylene, thermoplastic polyurethane, ethylene-vinyl acetate copolymer, acrylic resins, and the like, alone or in admixture. Additives such as waxes may also be added to these components. Cold sealable adhesive compositions such as natural or modified rubber, neoprene and the like are also suitable.
- This kind of overlap seal may also be used as closure means at the top and bottom extremities of the container.
- closure means at the top and bottom extremities of the container are therefore constituted of waterproof seals between the opposite walls of the container.
- a double folded seal according to this embodiment is a composed seal where, in the zone of adherence, the two semi-permeable sheets are positioned in a parallel relationship, both respective membrane endings pointing in the same direction, in the zone of adherence the parallel laying sheet extremities are being folded back over such that the outer surface parts of the semi-permeable material sheet are pointing to one another.
- the said extremities are made adherent to one another by means of an adhesive in a manner such that the water pressure which can be exerted on the longitudinal seal lays in line with the adhesive shear plane of the adhesive coating.
- the adhesive coating adheres the two outer surface parts of the sheet and remains unopened even under considerable water pressure in the container.
- Suitable materials which can be used as adhesive material for the top and bottom seals are heat sealable adhesive compositions such as polyvinylidene chloride, polyethylene, thermoplastic polyurethane, ethylene-vinyl acetate copolymer, acrylic resins, and the like, alone or in admixture. Additives such as waxes may also be added to these components. Cold sealable adhesive compositions such as natural or modified rubber, neoprene and the like are also suitable.
- a suitable water- or air-barrier composition for example by coating from a solution, lamination, extrusion coating or in-situ polymerisation into either or both surfaces of the membrane.
- Suitable materials to this end are: for the watertight only walls polyvinyl chloride copolymer with vinyl acetate or vinyl maleate and the like and for the water- and air-tight walls polyvinylidene chloride and the like.
- a self-rehydrating container can be used to prepare a water solution of a water soluble or suspendible product having a molecular weight well below the molecular weight cut-off of the membrane.
- the low molecular weight water soluble or suspendible product must be retained in the watertight compartment while an osmotically active solute (eventually the same) is retained in the osmotically active compartment.
- a self-rehydrating container is the preparation of accurately dosed solutions of labile water soluble or suspendible product.
- the labile water soluble or suspendible product is retained in the watertight compartment while an osmotically active solute is retained in the osmotically active compartment.
- the osmotically active compartment should also possess a mark allowing to determine the volume of water in said container. Once this mark has been reached by the internal water, the container is removed from the external water, the non-permanent seal is broken and the final accurately dosed solution or suspension is prepared.
- a self-rehydrating container can also be used to prevent products such as vitamins, fats or drugs to be affected by oxidation or hydrolysis because they are only contacted with water (and air if the compartment is also air-tight) just before consumption after substantially sterile water has been prepared in the osmotically active compartment and the non-permanent seal is peeled (broken).
- food grade rehydrated solutions or suspensions can be prepared using a container according to the invention, the shelf life thereof can be extended. Indeed, the dried food powder is kept in the watertight compartment, and is only mixed with water, just before consumption once sterile water is prepared. Deprived from water, the food powder contaminating bacteria, if any, will not proliferate. Once the solution prepared with the container is ready, it can directly be consumed or refrigerated.
- a typical use of the new self-rehydrating container with a watertight and oxygen proof compartment is to protect the components of Infant Formulae Milk and High Energy Therapeutic Milks which are subjected to dialysis and oxidation and may contain dormant bacteria or bacterial spores which would proliferate to dangerous levels with time when mixed with water.
- Carbohydrates are used as the water soluble osmotically active solutes in the osmotically active compartment.
- compositions may be distributed into the two compartments of the container according to the invention in the following way: 38 g/1 sucrose and 2.9 g/1 trisodium citrate in the osmotically active compartment and 3.5 g/1 sodium chloride and 1.5 g/1 potassium chloride in the watertight compartment.
- the container containing thus a sodium and potassium chloride mix in the watertight compartment and an osmotically active sucrose/citrate blend in the other compartment is immersed into water with a "ready-to-use" mark pointing up.
- the osmotically active compartment is allowed to fill by osmosis up to the ready-to-use mark while the watertight compartment floats on top of the water. Once filled, the pack is gently removed from the external water.
- the container is inverted and the non-permanent seal is allowed to gently break open.
- the salt content is mixed with the water and an ORS solution is obtained.
- Example 1 Preparation of the container.
- the mixture is heated at 90°C while stirring and 0.15 g of tin 2- ethylhexanoate (DABCO T9 (AIR PRODUCTS)) as catalyst, is introduced.
- DABCO T9 AIR PRODUCTS
- the reaction mixture is maintained at 90°C for 2 hours and then cooled. 120 g of methylethylketone are then introduced into the reaction vessel.
- a solution of 133.02 g of polyethylene glycol (PEG 600 (HOECHST)) having a molecular weight of about 600 and 79.00 g of 1 , 1 '-methylenebis(4- isocyanatocyclohexane) in 342.00 g of toluene is introduced into a 2-liter four necked round bottomed flask equipped with a mechanical stirrer, a thermometer, an air condenser, a nitrogen inlet and a dropping funnel. The mixture is heated at 90°C while stirring and 25 mg of dibutyltinlaurate (DABCO T12 (AIR
- PRODUCTS PRODUCTS
- the reaction mixture is maintained at
- a solution of 13.68 g of isophorone diamine in 350.00 g of isopropyl alcohol is introduced in a second 2-liter four necked round bottomed flask equipped with a mechanical stirrer, a thermometer, an air condenser, a nitrogen inlet and a dropping funnel.
- the content of the first flask is cooled at room temperature and is then added slowly to the mixture alcohol/amine (second flask). Chain extension is complete after about 3 hours.
- a solution of 114.40 g of polyethylene glycol having a molecular weight of about 400 PEG 400 (HOESCHT)
- 20.60 g of poly(tetramethylene glycol) having a molecular weight of about 1000 TERATHANE 1000 (DUPONT)
- 106.80 g of l, l '-methylenebis(4-isocyanatocyclohexane) in 342.00 g of toluene is introduced into a 2 -liter four necked round bottomed flask equipped with a mechanical stirrer, a thermometer, an air condenser, a nitrogen inlet and a dropping funnel.
- VOCLAN VR 545 from ZENECA
- Containers without any seal dividing the inner space into two compartments has been prepared by way of comparison.
- a solid composition comprising sucrose (27 g), trisodium citrate (1.7 g), sodium chloride (14 g) and potassium chloride (6 g) is retained in the unique compartment of the container prepared at point 1.4.0, and the container is placed in a vessel containing 4 litres of water. After around 9.5 hours, 496.4 ml of solution is produced which contains the equivalent of 42 g of sucrose, 3 g of trisodium citrate, 3.5 g of sodium chloride and 1.5 g of potassium chloride per litter. Around 20% of sucrose and trisodium citrate is effectively lost through dialysis.
- a solid composition containing sucrose (27 g) and trisodium citrate (1.7 g) is placed in the osmotically active compartment of the container prepared at point 1.4.1 and sodium chloride (1.75 g) and potassium chloride (0.75 g) are retained in the wate ⁇ ight compartment.
- the container is placed into 4 litres of water. After 9.5 hours, 498 ml of solution is produced which contains the equivalent of 42 g of sucrose and 3 g of trisodium citrate per litter.
- the watertight compartment remains intact and floats on the surface.
- the container is inverted and in less than 1 minute, the water enters the watertight compartment.
- the solution is mixed with resulting concentration of 42 g of sucrose, 3 g trisodium citrate, 3.5 g of sodium chloride and 1.5 g of potassium chloride per litter solution.
- the resulting milk initially had low total viable count (TVC) for bacteria but within 1-2 hours the TVC increases to levels which become unacceptable for human consumption.
- TVC total viable count
- Using the container prepared at point 1.4.1 above the osmotically active compartment contains sucrose (10 g) only.
- the watertight compartment contains dried skim milk, fat, vitamins and minerals (32 g).
- the container is placed in 4 litres of water, after around 8 hours, 200 g of sterile sucrose solution is prepared. Approximately, 20% of the sugar has diaiysed. At this point, the container is inverted and in less than 1 minute the water enters the watertight compartment.
- the milk is thoroughly mixed. By this technique all vitamins and minerals are present, little oxidation of fats or vitamins has occurred and the fresh milk is sterile and has a greatly extended shelf life.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP53995998A JP2001516238A (en) | 1997-03-17 | 1998-03-13 | Rehydration multi-compartment container |
CA002282520A CA2282520A1 (en) | 1997-03-17 | 1998-03-13 | Multi-compartment rehydrating container |
DE69807207T DE69807207D1 (en) | 1997-03-17 | 1998-03-13 | MULTI-CHAMBER REHYDRATION TANK |
EP98909237A EP0975532B1 (en) | 1997-03-17 | 1998-03-13 | Multi-compartment rehydrating container |
NZ337564A NZ337564A (en) | 1997-03-17 | 1998-03-13 | A two compartment rehydrating container for production of osmotically driven filtration of oral, accurately dosed rehydration solutions for delivery of medicinal or nutritional supplements substantially free of microorganisms |
AU63875/98A AU735473B2 (en) | 1997-03-17 | 1998-03-13 | Multi-compartment rehydrating container |
AT98909237T ATE222204T1 (en) | 1997-03-17 | 1998-03-13 | MULTI-CHAMBER REHYDRATION TANK |
BR9808361-9A BR9808361A (en) | 1997-03-17 | 1998-03-13 | Self-rehydrating container for the production of solutions or suspensions substantially free of undesirable microorganisms, process for the preparation of a solution or a suspension of at least one suspensive or water-soluble product, substantially free of undesirable microorganisms, dairy product, and, solution oral rehydration. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9705455A GB9705455D0 (en) | 1997-03-17 | 1997-03-17 | Self-rehydrating container |
GB9705455.5 | 1997-03-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998041458A1 true WO1998041458A1 (en) | 1998-09-24 |
Family
ID=10809344
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BE1998/000035 WO1998041458A1 (en) | 1997-03-17 | 1998-03-13 | Multi-compartment rehydrating container |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP0975532B1 (en) |
JP (1) | JP2001516238A (en) |
CN (1) | CN1251075A (en) |
AT (1) | ATE222204T1 (en) |
AU (1) | AU735473B2 (en) |
BR (1) | BR9808361A (en) |
CA (1) | CA2282520A1 (en) |
DE (1) | DE69807207D1 (en) |
GB (1) | GB9705455D0 (en) |
IN (1) | IN190381B (en) |
NZ (1) | NZ337564A (en) |
PE (1) | PE63899A1 (en) |
WO (1) | WO1998041458A1 (en) |
ZA (1) | ZA982201B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2096570A (en) * | 1981-03-18 | 1982-10-20 | Maloney John | Bag and bag making apparatus |
EP0360612A1 (en) * | 1988-09-23 | 1990-03-28 | Hampshire Advisory And Technical Services Limited | Water purifying system |
US4920105A (en) * | 1987-07-09 | 1990-04-24 | Rensselaer Polytechnic Insitute | Membrane pouch |
US5287961A (en) * | 1992-10-23 | 1994-02-22 | W.R. Grace & Co.-Conn. | Multi-compartment package having improved partition strip |
EP0639364A1 (en) * | 1992-05-03 | 1995-02-22 | Otsuka Pharmaceutical Factory, Inc. | Vessel having a plurality of chambers |
-
1997
- 1997-03-17 GB GB9705455A patent/GB9705455D0/en active Pending
-
1998
- 1998-03-13 WO PCT/BE1998/000035 patent/WO1998041458A1/en active IP Right Grant
- 1998-03-13 CA CA002282520A patent/CA2282520A1/en not_active Abandoned
- 1998-03-13 NZ NZ337564A patent/NZ337564A/en unknown
- 1998-03-13 JP JP53995998A patent/JP2001516238A/en active Pending
- 1998-03-13 AU AU63875/98A patent/AU735473B2/en not_active Ceased
- 1998-03-13 BR BR9808361-9A patent/BR9808361A/en unknown
- 1998-03-13 EP EP98909237A patent/EP0975532B1/en not_active Expired - Lifetime
- 1998-03-13 DE DE69807207T patent/DE69807207D1/en not_active Expired - Lifetime
- 1998-03-13 CN CN98803463A patent/CN1251075A/en active Pending
- 1998-03-13 AT AT98909237T patent/ATE222204T1/en not_active IP Right Cessation
- 1998-03-16 PE PE00018498A patent/PE63899A1/en not_active Application Discontinuation
- 1998-03-16 IN IN653DE1998 patent/IN190381B/en unknown
- 1998-03-16 ZA ZA982201A patent/ZA982201B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2096570A (en) * | 1981-03-18 | 1982-10-20 | Maloney John | Bag and bag making apparatus |
US4920105A (en) * | 1987-07-09 | 1990-04-24 | Rensselaer Polytechnic Insitute | Membrane pouch |
EP0360612A1 (en) * | 1988-09-23 | 1990-03-28 | Hampshire Advisory And Technical Services Limited | Water purifying system |
EP0639364A1 (en) * | 1992-05-03 | 1995-02-22 | Otsuka Pharmaceutical Factory, Inc. | Vessel having a plurality of chambers |
US5287961A (en) * | 1992-10-23 | 1994-02-22 | W.R. Grace & Co.-Conn. | Multi-compartment package having improved partition strip |
Also Published As
Publication number | Publication date |
---|---|
EP0975532B1 (en) | 2002-08-14 |
ZA982201B (en) | 1998-09-17 |
AU6387598A (en) | 1998-10-12 |
IN190381B (en) | 2003-07-26 |
CN1251075A (en) | 2000-04-19 |
EP0975532A1 (en) | 2000-02-02 |
NZ337564A (en) | 2001-03-30 |
DE69807207D1 (en) | 2002-09-19 |
BR9808361A (en) | 2000-05-23 |
AU735473B2 (en) | 2001-07-12 |
GB9705455D0 (en) | 1997-05-07 |
PE63899A1 (en) | 1999-07-03 |
ATE222204T1 (en) | 2002-08-15 |
CA2282520A1 (en) | 1998-09-24 |
JP2001516238A (en) | 2001-09-25 |
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