CN1347346A - Dosing and delivering system - Google Patents
Dosing and delivering system Download PDFInfo
- Publication number
- CN1347346A CN1347346A CN00802613A CN00802613A CN1347346A CN 1347346 A CN1347346 A CN 1347346A CN 00802613 A CN00802613 A CN 00802613A CN 00802613 A CN00802613 A CN 00802613A CN 1347346 A CN1347346 A CN 1347346A
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- Prior art keywords
- piston
- damper
- fluid
- valve
- storage tank
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
- B05B5/025—Discharge apparatus, e.g. electrostatic spray guns
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/02—Membranes or pistons acting on the contents inside the container, e.g. follower pistons
- B05B11/028—Pistons separating the content remaining in the container from the atmospheric air to compensate underpressure inside the container
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
- B05B11/1001—Piston pumps
- B05B11/1015—Piston pumps actuated without substantial movement of the nozzle in the direction of the pressure stroke
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
- B05B11/1042—Components or details
- B05B11/1052—Actuation means
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B11/00—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use
- B05B11/01—Single-unit hand-held apparatus in which flow of contents is produced by the muscular force of the operator at the moment of use characterised by the means producing the flow
- B05B11/10—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle
- B05B11/1094—Pump arrangements for transferring the contents from the container to a pump chamber by a sucking effect and forcing the contents out through the dispensing nozzle having inlet or outlet valves not being actuated by pressure or having no inlet or outlet valve
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
- B05B5/00—Electrostatic spraying apparatus; Spraying apparatus with means for charging the spray electrically; Apparatus for spraying liquids or other fluent materials by other electric means
- B05B5/16—Arrangements for supplying liquids or other fluent material
- B05B5/1691—Apparatus to be carried on or by a person or with a container fixed to the discharge device
Abstract
The present invention relates to a dispensing device (1) for a fluid (10), the dispensing device (1) comprising a reservoir (11), a shaft (12), a back seal (13), a damper (14), a piston (151) and a one-way valve (16), the back seal (13) sealing a first end of the reservoir and being displaceable along the shaft, the valve being on the second end of the reservoir, the piston being fixed to one end of the shaft, the piston being located between the valve and the damper, the damper being also fixed to the shaft, the damper being located between the piston and the back seal, whereby the piston has an opened position (151) and a closed position (152), the open position allowing fluid communication between the valve and the part of the reservoir between the piston and the back seal, the displacement of the piston between the opened and the closed position being induced by a displacement of the shaft along its own axis, the pressure in the area comprised between the valve and the piston reducing when the piston is moved from its closed position towards its opened position, the damper collapsing when the piston is moved from its closed position towards its opened position, the only fluid flow from the part of the reservoir situated between the damper and the back seal and the part of the reservoir situated on the other side of the damper being a connecting passage (140) situated in the damper (14) when the piston is moved from its opened position towards its closed position.
Description
Technical field
The present invention relates to a kind of mechanical component that is used for quantitatively and supplies with fluid.
Background of invention
The device that is used for fluid quantitative and supply is widely used for the consumer goods or is used for medical industry.The supply that this device that is used for fluid quantitative and supply should be able to be controlled the amount of dosed fluid well and control this dosed fluid well.Especially at medical industry, it is very important accurately controlling dosage and administration.And, but need produce this device with duplication of production and economic mode.Purpose of the present invention just is to realize by a kind of quantitative and feed system of economy the accurate quantification and the supply of convection cell.
According to the present invention, this purpose realizes by a kind of like this fluid distributing apparatus, this distributor comprises a storage tank, one, one back of the body seal, one damper, one piston and a check valve, described back of the body seal seals first end of described storage tank, and can move along described axle, described check valve is positioned at second end of described storage tank, described piston is fixed in an end of described axle, described piston is arranged between described check valve and the described damper, described damper also is fixed in described axle, described damper is arranged between described piston and the described back of the body seal, thereby described piston has an open position and a closed position, described open position allows described check valve to be communicated with the part phase fluid of described storage tank between described piston and described back of the body seal, described axle causes described piston mobile between described open position and described closed position along himself the mobile of axis, when described piston from its closed position when its open position moves, pressure in the zone that constitutes between described check valve and described piston reduces, when described piston from its closed position when its open position moves, described damper draws in, described piston from its open position when move its closed position, from described storage tank between described damper and described back of the body seal part and the fluid that only has that is positioned at the part of described damper opposite side from described storage tank flow, be a connection channel that is arranged in described damper.
Have many advantages according to the formed device of the present invention.Because device comprises a piston, this piston has an open position and a closed position, permission is communicated with fluid between the storage tank at check valve, Fluid Volume to be allocated can move to the check valve part from storage tank by the fluid that piston is moved to open position from the closed position, make aequum and be subjected to accurate control, directly link to each other between storage tank and the check valve, this is avoided storage tank to pass through check valve uncontrolled emptying takes place.And, along with the pressure in the zone that is constituted between check valve and the piston reduces when its open position moves from its closed position at piston, piston towards open position move with needs apply one be enough to overcome or at least equalizing pressure reduce and the minimum force of built-in system frictional force, thereby can avoid piston undesirable mobile.Dosage is supplied with and also is subjected to accurate control by being used in combination check valve, piston, damper and back of the body seal.Certainly, check valve only just allows to supply with fluid at piston when check valve moves forward, the translational speed of piston is subjected to the control of size and the fluid viscosity and the mechanical force (for example spring force) that is applied of interface channel in the damper, thereby allows the fluid feed speed by check valve is controlled.
Detailed description of the Invention
The present invention is described with reference to the accompanying drawings, in the accompanying drawing:
Fig. 1 is the cutaway view of distributor of the present invention, and wherein piston is shown in an open position;
Fig. 2 is the cutaway view of distributor of the present invention, and wherein piston is in the closed position.
The present invention relates to a kind of distributor 1 or 2 that is used for fluid 10.Fluid is construed as it and comprises the liquid with different viscosities.Preferably fluid in a preferred embodiment of the present invention is a medical fluid, but also can be other application scenario, such as air freshener.
Distributor also comprises one 12, this axle is a slender member normally, its long direction is as main shaft, this generally also comprises a part that constant cross-section is arranged on the plane perpendicular to main shaft, be used to allow a back of the body seal 13 translations, perhaps be shaped on screw thread, move as spiral along axle 12 to allow a back of the body seal 13.
Device also comprises a back of the body seal 13, and this back of the body seal 13 all can make storage tank 11 sealings basically no matter how many amounts of contained fluid 10 has in the storage tank 11.This for example can be achieved like this, make storage tank 11 have a main portion, it has constant cross-section on the plane perpendicular to the main shaft of axle 12, back of the body seal 13 has essentially identical cross section, the cross section of back of the body seal 13 is preferably slightly greater than the constant cross-section of storage tank 11, to reach sealing, thereby back of the body seal 13 in any position makes storage tank 11 sealings along constant cross-section along the mobile permission of axle 12 in the main portion of the storage tank 11 with constant cross-section, thereby allows to seal different volumes in airtight mode.In a preferred embodiment, back of the body seal 13 by one flexible and elastomeric material make, it is umbrella, or even preferably be pair umbrellas, seal just is pressed against on the cross-sectional perimeter of storage tank 11 consistently like this.
Also comprise a piston 151 or 152 in the device of the present invention.Piston 151 or 152 is a part that has constant cross-section on the plane perpendicular to its main shaft normally, this piston 151 or 152 is elongate along main shaft, piston 151 or 152 moves in the part of storage tank 11, this part is equaling perpendicular to the cross section on the plane of piston 151 or 152 main shafts but substantially preferably slightly less than the cross section of piston 151 or 152, to realize good sealing.Generally, piston 151 or 152 main shaft are parallel to or even align with the main shaft of axle 12.Device also comprises a check valve 16.Check valve is interpreted as, and during normal use, valve 16 allows fluid only to pass through along a direction.In a preferred embodiment, check valve 16 is one " self sealss " valves, for example at EP-A-0597601, and big volume description among EP-A-0395380 or the EP-A-0160336.
An essential feature of device of the present invention is, first end of back of the body seal 13 sealing storage tanks 11.This allow to use an airtight storage tank 11, this storage tank to can be used for making fluid product 10 to keep stable, and also is essential, as will be described below for the work of device.
Back of the body seal 13 also should move along axle 12, and this moving for example comprises that straight line moves or spiral moves.
Piston 151 or 152 is fixed in an end of axle 12.In fact, piston 151 or 152 is to be used for the product 100 of doses is pushed away towards check valve 16 in device 1 of the present invention or 2.For this reason, piston 151 or 152 is arranged between check valve 16 and the damper 14.
For device of the present invention can be worked, piston 151 or 152 has an open position 151 and a closed position 152, and open position 151 allows check valve 16 and the part of storage tank 11 between piston 151 and back of the body seal 13 that fluid passage 153 is arranged.This fluid passage 153 allows to make the product 100 of doses to be located between piston 151 and the check valve 16 before distributing.
Piston mobile between open position 151 and closed position 152 be by axle 12 along himself axis, just main shaft move cause.When piston from its closed position 152 when its open position 151 moves, the pressure in the zone that is constituted between check valve 16 and piston reduces, thereby produces partial vacuum.This makes the product 100 of the doses in the part between the seal at the piston and the back of the body of storage tank 11 part 100 between " suction " check valve and the piston when piston moves to open position 151.
When piston from its closed position 152 when its open position 151 moves, damper 14 draws in.This is convenient to carry out with regard to the preparation that makes distribution, and when operator's drive unit, avoid producing excessive counteragent, thereby motion or mobile will make storage tank part and storage tank the fluid passage 153 part check valve and piston between 100 between piston and back of the body seal between of piston from its closed position towards its open position opened, in order to make fluid charge into a back part 100 by above-mentioned pressure reduction or partial vacuum, the fluid 100 of doses reduces by " suction " this part because of pressure by path 153, and can be for distributing by check valve when being subjected to the piston pushing.
Since from storage tank damper and the back of the body between the seal part and be positioned at from storage tank the damper opposite side part only have fluid mobile, be when move its closed position, to be arranged in a connection channel 140 of damper from its open position, thereby this motion that causes waiting supplying with the supply of fluid is subjected to being arranged in the obstruction of the interface channel 140 fluid flow restriction of damper 14 at piston.Certainly, in order to supply with the dosage 100 between piston and check valve 16, piston must move towards its closed position 152 from its open position 151, thereby be fixed in axle at damper 14 and piston and damper 14 moved at 12 o'clock, damper 14 moves through fluid 10, thereby storage tank 11 damper 14 and the back of the body between the seal 13 part and between the part between damper 14 and the piston, produce uneven, this imbalance is compensated by the flowing of interface channel 140 that is arranged in damper 14, thereby utilizes moving of control piston to control the supply velocity of discharge of preparation by the dosage 100 of check valve 16 distribution.In fact, the maximal rate of piston more or less depends on compressibility, and depends primarily on the geometry and/or the mechanical property of fluid viscosity and device.For example, interface channel 140 is big more or to put on axle 12 propulsive force high more, and maximal rate is just big more.
In a preferred embodiment, axle is made by conductive material, such as metal.In a better embodiment, fluid was recharged before distributing.Device of the present invention is particularly useful for this occasion because by control flow can so that convection cell charge.Specifically, have a maximal rate, exceed this speed, convection cell charges and just becomes comparatively difficult or even unfeasible, therefore, is subjected to the supply of damping can realize good charging.Preferably, charge rate and fluid flow rate are complementary, and realize the atomizing of effective electricity-flow power with convection cell.
In a preferred embodiment, the volume that is constituted between the piston of open position and the check valve is less than 100 μ l.
In another preferred embodiment, make the fluid displacement variation that each batch operation distributed be lower than 10% to the control of supplying with.More preferably, volume-variation is lower than 5%.
In another preferred embodiment, be provided with a compression spring at the other end that is fixed with piston one end of axle, on the direction of the axis that is basically parallel to axle, axle is applied a power.
In another preferred embodiment, the single opening that interface channel is in the damper to be provided, even be more preferably a circular open.
A most preferred embodiment of the present invention can obtain by device of the present invention being incorporated into the sprayer unit that is disclosed among await the reply patent application GB9806937.0 and the GB9806939.6.
This sprayer unit is particularly suitable for treating the disease that influences the nasal region, the hyperemia that causes such as Hay Fever or because of flu.Recently, it has been recognized that nasal membrane can be as convenient the give snack made with traditional Chinese medicines of drug effect at other regional medicament of health.For example referring to WO92/11049, it has disclosed a kind of pen shaped arrangement that is used for nasal region administration (especially insulin).Sprayable for this treatment normally comparatively easily.Treatment to eyes also can be undertaken by sprayer unit easily.For this occasion, preferable volume dosage is generally lower, low reaching below the 10 μ l.Usually, give full play to effectiveness, need dosed administration repeatedly in order to make treatment.It may be comparatively difficult realizing the stopping-starting mobile completely of sprayer unit and supply with this lower volume.Usually the problem that is run into comprises: the residue water clock takes place in valve after using, this may cause inverse contamination; And valve blocks.
Use elastomer valve, especially use slit valve, can provide completely to stop-starting flowing, even the spraying fluid comprises the granular solids of segmentation, also can not cause obstruction, this especially realizes by valve (fully start) with because of the combination of unloading the pressure drop (stopping fully) that nip causes.
Best, sprayer unit is suitable for providing the fluid dosage of one or more unit, the volume of each dosage is in the scope of 1 to 100 μ l, device comprises an elastomeric self-sealing valve, this valve has a fluid side and a supply side, and when when the fluid side convection cell is exerted pressure, valve is opened and allowed fluid to pass through, and when removing this pressure, valve seal.
Best, sprayer unit is an electrostatic atomizer, and it charged to it before spraying enters the nostril.
Fluid
Device of the present invention preferably includes a fluid storage tank, it accommodates a kind of at pharmaceutically qualified fluid, this fluid comprises a kind of in pharmaceutically qualified treatment matter agent, and this matter agent is chosen from medicine, flavor enhancement, salt, surfactant and their mixture.This fluid comprises that selectively dissolving or disperse are in assistant agent wherein.This fluid can be that water becomes, and also can be that non-water becomes.Suitable water becomes fluid to comprise the mixture of water and water and water-soluble solvent, such as glycerine, propane diols or alcohol (as ethanol or isopropyl alcohol).Also can use aqueous emulsion, or water-in-oil emulsion, or O/w emulsion.Fluid is the aqueous solution, aqueous dispersion or O/w emulsion preferably.Suitable non-water becomes fluid to comprise polyethylene glycol, glycerine, propane diols, Isosorbide dimethyl ether, silicone oil, ketone, ether and their mixture.
Though the scope to resistivity is unqualified, the present invention is applied to the liquid of low-resistivity especially, and particularly specific insulation is lower than 1 * 10
8Ohm.cm, preferred resistivity is lower than 1 * 10
4Ohm.cm more preferably is lower than 1 * 10
3Ohm.cm.When needing, liquid can comprise the resistivity dressing agent, as pharmaceutically qualified salt, so that specific insulation is in the required scope.
Use carrier in the preferably pharmaceutically qualified nose of described fluid.Preferably, nasal composition etc. ooze, and promptly it is identical with the osmotic pressure of blood and tear.The required isotonicity of the present composition can be used the sodium chloride that has existed, or other pharmaceutically qualified reagent, inorganic or organic solute reaches as dextrose, boric acid, citric acid, sodium tartrate, natrium citricum, sodium phosphate, potassium phosphate, propane diols or other.Sodium chloride is particularly preferred for the buffer solution that contains sodium ion.Remington ' sPharmaceutical Sciences (Alfonso Gennaro the 18th edition, 1990) 1491-1497 page or leaf has disclosed the example of sodium chloride equivalent, incorporates into for reference at this.
Medicine
Described fluid can comprise various medicines." medicine " expression is to the medicative medicine of body or other material.The proper level of medicine is 0.001-20%, preferably 0.01-5%, more preferably 0.1-5%.The level that should be understood that certain drug is decided according to many factors such as the easiness of the effectiveness that comprises medicine, safety curve, solubility/dispersion and effects rapidly.Medicine can be, in use to applying the effective material in position, and as decongestant, antihistamine or anti-inflammatory drug, or the medicine that supplies whole body to absorb, as antiviral agent, antidepressants, emesis medicine, alexipyretic or hormone or similar medicine.Medicinal soluble in or be insoluble to described fluid, or be dispersed in the fine dispersion particle liquid or solid in the described fluid.
Suitable decongestant comprises first azoles quinoline, Tramazoline, Xylometazoline, Naphazoline, tetrahydrazoline, pseudoephedrine, ephedrine, phenylephrine, their pharmaceutically qualified salt, example hydrochloric acid salt and their mixture.Preferred decongestant is selected from first azoles quinoline, Xylometazoline, their pharmaceutically qualified salt and their mixture.The hydrochloric acid that particularly preferably is that the present invention uses removes first azoles quinoline, and it is water-soluble.When being used for the present composition, going congested agent preferably to have concentration is about 0.01%-3.0%, more preferably about 0.01-1%.
Be used for antihistamine of the present invention and include, but not limited to quick-acting histamine H-1 receptor antagonist.This class H-1 acceptor antihistamine is selected from following antihistaminic: alkyl alkane, monoethanolamine, ethylene diamine, piperazine, phenthazine, piperidines.Useful quick-acting antihistamine examples comprise Acrivastine, carbinoxamine, diphenhydramine, chlorphenamine, Brompheniramine, dexchlorpheniramine, many Xi Namin, clemastine, fenazil, alimemazine, first ground piperazine, hydroxyzine, mepyramine, Tripelennamine, meclozine, triprolidine, azatadine, cyproheptadine, rocastine, phenindamine or its pharmaceutically qualified salt and their mixture.Other useful antihistaminic comprises RMI 9918, nitrogen Si spit of fland, cetirizine, astemizole, Ebastine, Ketotifen, lodoxamide, Loratadine, histimet, mequitazine, Oxatomide, setastine, tazifylline, temelastine or its pharmaceutically qualified salt and their mixture.When being used for combination ingredient of the present invention, the preferred concentration of antihistamine component is about 0.01-3.0%, more preferably about 0.01-1%.
Also can use anti-inflammatory drug, as corticosteroid.Particularly preferably be glucocorticoid in such, be selected from betamethasone, 9-and go fluorine fluocinolone acetonide, fluorine for Mi Song, memetasone, budesonide, the salt that it is pharmaceutically qualified and their mixture.When being used for combination ingredient of the present invention, the preferred concentration of anti-inflammatory agent is about 0.001%-0.1%, more preferably about 0.01%-0.1%.
At this xanthine derivative usefully also, as caffeine and methyl xanthine etc.; Anti-allergic drug; Mucolytic agent; Anticholinergic agent; Non-opium class anodyne, as paracetamol, acetylsalicylic acid, brufen, Etodolac, fenbuprofen, fenoprofen, ketorolac, Flurbiprofen, Indomethacin, Ketoprofen, naproxen, salt that it is pharmaceutically qualified and their mixture; Opium class anodyne such as butorphanol; LTRA; Mast cell (mast cell) stabilizing agent is as nasmil, nedocromil and lodoxamide; Lipoxygenase suppresses compound; And nicotine, insulin and Ka Xinuoding (calcinotin).
At WO97/46243, EP-A-780127, US-A-5, can find other example of suitable drug in 656,255 and US-A-5,705,490.
Flavor enhancement
Various seasonings and/or aromatised fraction (as, aldehyde and ester) can be used for fluid of the present invention.These comprise, as methyl alcohol, camphor, eucalyptus brain, benzaldehyde (cherry, almond); Citral (lemon, bitter orange); Neral; Capraldehyde (orange, lemon); C-8 aldehyde, C-9 aldehyde and C-12 aldehyde (citrus fruit); Tolyl aldehyde (cherry, almond); 2,6-dimethyl octanal (green fruit); 2-dodecylene aldehyde (oranges and tangerines, mandarin orange); With the herbaceous plant component, as musk deer hay-scented, rosemary, and sage oil.Be applicable to that other aromatised fraction of the present invention comprises United States Patent (USP) 4,136,163 (authorizing Watson etc.), United States Patent (USP) 4,459,425 (authorizing Amano etc.) and United States Patent (USP) 4, the aromatised fraction that is disclosed in 230,688 (the authorizing Rowsell etc.), it is for reference that all these patent documentations are incorporated this paper into.Also can use the mixture of these aromatic substances.
Surfactant
Described fluid also can comprise one or more pharmaceutically qualified surfactants.This class surfactant can be used for disperseing or emulsification medicine or flavor enhancement, the absorption of passing through the nose film with increase, or with performance itself as therapeutic agent, as for softening earwax.Surfactant can be anion, nonionic, cation or amphoteric ion type, preferably nonionic.Being used for typical ionic surfactant pack of the present invention draws together: the polyoxyethylene deriv of the fatty acid partial ester of sorbierite acid anhydrides, as Tween 80; The polyoxyethylene deriv of aliphatic acid, as polyoxyethylene 50 stearate, and tert-octyl phenol yuban of oxyethylation (Sterling organics sells, trade name Tyloxapol) or their mixture.Common concentration is 0.1-3 weight %.
Salt
Described fluid also can comprise one or more pharmaceutically qualified salt.This salt can be inorganic salts, as sodium chloride, or organic salt, as natrium citricum.
Other assistant agent
Described fluid can further comprise other component, as thickener, wetting agent, suspension aids, formation capsule auxiliary agent, chelating agent and preservative agent.
Make the viscosity of composition remain on selected level with pharmaceutically qualified thickener.Suitable thickening comprises, as bassora gum, methylcellulose, microcrystalline cellulose, carboxymethyl cellulose, chitosan, hydroxypropyl cellulose, hydroxypropyl methylcellulose, CMC, hydroxyethylcellulose, carboxyl vinyl polymer, carbomer etc. or its pharmaceutically qualified salt.Also can use this class mixtures of thickening agents.The preferred concentration of thickener depends on selected reagent.Importantly use the consumption that can reach selected viscosity.Usually the composition that from solution, prepares thickness by adding this class adhesion agent.
Be used for fluid of the present invention and also can comprise about 0.01%-5% wetting agent,, and prevent to stimulate with inhibition mucous membrane drying.Also can use various pharmaceutically qualified wetting agents, comprise, as sorbierite, propane diols, polyethylene glycol, glycerine or their mixture.The viscosity of thickener can become with selected reagent, but the existence of these reagent whether, or their concentration is not essential feature of the present invention.
Usually use pharmaceutically qualified preservative agent to increase the shelf life of the present composition.Can use various preservative agents, comprise, as benzyl alcohol, metagin class, phenethyl alcohol, thimerosal, methaform, glucose chlohexidine or Benasept.Be used for most preferred preservative agent of the present invention system and be Benasept, chlorhexidine gluconate and as the combination of the EDTA disodium of chelating agent.Though change to some extent according to selected reagent, the concentration that preservative agent is suitable based on gross weight, is 0.001%-2%.
Device is suitable for providing one or more unit fluid dosage, preferably a plurality of fluid dosage, the preferred solvents of each dosage in the scope of 1 to 100 μ l, better 1 to 20 μ l, best 5 to the 15 μ l that are about of being about.Dosage volume preferably preestablishes, but also can be adjusted to required volume by the user.Preferably, device is a filled again unit, and this unit is the part than bigger device, and can change.
This device preferably is suitable for producing the spraying with fluid straight line portion, and this straight line portion extends from shower nozzle, and has a shower nozzle end and a transmitting terminal, and this spraying also comprises a spraying tapering part, and it scatters from the transmitting terminal of straight line portion.So-called " shower nozzle end " is a bit, and perpendicular to the plane of the axis of straight line portion (below be called " shower nozzle plane "), this plane just in time contacts with the outside of shower nozzle, and intersects with the center of straight line portion at this some place picture one.This straight line portion preferably has from about 1 to about 20mm from the shower nozzle end to transmitting terminal, more preferably from about 1 to about 10mm, best be from about 2 to about 8mm, particularly from about length of 3 to about 6mm.
In preferred embodiment, the spraying tapering part have from about 10 to about 90 °, preferably from about 20 to about 50 °, more preferably from about 30 to about 40 ° bevel angle.In electrostatic equipment, the length of straight line portion and spraying bevel angle can be regulated in the following manner, promptly change the viscosity or the surface tension of fluid, change rate of flow of fluid or output speed, or change valve slit characteristic or valve material property, or by applying voltage, electric potential gradient or using and strengthen electric field electrode change electric-field intensity.
The total length of straight line portion can greater than, preferably greater than length from the shower nozzle end to transmitting terminal because straight line portion preferably from device one side on shower nozzle plane a bit, such as taking place from flexible self-sealing valve described here, and passing through a passage in this shower nozzle.Distance from the origination point of straight line portion to the shower nozzle plane is from about 2 to about 15mm, preferably from about 3 to about 10mm, more preferably in about scope of 5 to about 9mm.Like this, shower nozzle can be used as the reinforcement electric field, thereby helps to control the length of straight line portion.For this reason, shower nozzle is non-conducting material, the plastics such as polypropylene preferably, but preferably soft thermoplastic elastomer (TPE), it can provide bigger comfortableness when supporting nose.The elastomer that is used for self-sealing valve described here also is applicable to shower nozzle.
International patent application WO96/40441 number, European patent EP-A-501, No. 725 and the application of awaiting the reply have been introduced for PCT/GB97/02746 number can be with the electrostatic equipment of linear fashion spraying.This device is preferably a kind of according to European patent EP-A-501, the device of No. 725 or the embodiment of application among the PCT/GB97/02746 that await the reply, wherein, produce to spray by mechanical device, and applied high voltage will make and spray or straight line portion is shattered into the spraying tapering part.Suitable injection rate is about 0.5 to 0.8, preferably is about 1 to 3ms
-1
Suitable high voltage in the scope of 1kV to 15kV, the preferable 2kV to 10kV that is about, the better 2kV to 5kV that is about.This voltage can more easily add that by a low-voltage (1.5V is just enough) battery a step-up transformer offers fluid, even in small hand-held formula device.This battery is durable type preferably, but and recharge.Generator can be started by external switch by the user, and this switch can also make the pump starting.This switch preferably comprises a metal part, and the user can utilize this metal partly to realize earth-return circuit to high-voltage circuit.PCT/GB97/02746 has introduced a kind of suitable layout of whole apparatus structure.Like this, the user can not obtain net charge.Also can use alternating current equipment that alternating voltage is provided, gather thereby prevent to produce electric charge.
Best, start this device and produce spraying.The straight line portion of spraying extends through the nostril opening before the formation spraying tapering part that scatters, enter vestibular, preferably in the short distance of nose lobe (nasal valve) opening.
Cut off in order to provide completely when hanging down unit volume, this device preferably includes a flexible self sealss delivery valve, and this valve has a fluid side and a conveyor side, when the fluid on convection current side is exerted pressure, this valve is opened to allow fluid to pass through, and when pressure disappeared, valve cut out.Preferably, stop fully by making moving forward of piston end to realize that this causes pressure at once to reduce, and causes valve to close in the release chamber (the big zone of diameter)." delivery valve " described here is meant that this feather valve is last distributing valve, and this device does not have other element mechanically to retrain or the fluid that changes in the downstream of this valve flows.In preferred embodiment, this valve is a slit valve.This valve can comprise a slit or the slit that intersects more than two, so that form the shape of for example intersecting.Yet preferably, this valve comprises a slit.Though this valve can be flat, preferably a dome-shaped this means that it is a non-flat valve with groove, such as having hemispheric or Frusto-conical circular arch.In preferred embodiment, this valve is hemispheric circular arch basically, has along its peripheral flange, and like this, an available collar is fixed on this valve on this device.The diameter of valve (comprising flange) is generally from about 2 to 6mm, and circular arch partly has from about 1 to about 4mm, the diameter of about 2.5mm usually, and have from inside to outside about 0.5 to about 1.5mm, the preferably thickness of about 1mm.This valve does not need homogeneous thickness.In preferred embodiment, the outer surface of the dome-shaped of this valve is hemispheric, but inner surface at dome-shaped top place, promptly forming the ground of slit can be slightly smooth.Suitable slit width from about 50 to about 400 μ m, preferably from about 150 to about 250 μ m.Longest dimension when the width that should be understood that slit relates to slit and forms for the first time.Here employed term " elastomer " relates to a kind of material, but its both elastic compression, but elastic elongation again.Spendable elastomeric scope includes, but is not limited to polyurethane, chlorobutadiene, butyl, butadiene and SBR styrene butadiene rubbers, and silicone elastomer, such as 2 parts of room temperature vulcanizations (RTV) silicones.Here preferably use 2 parts of silicones RTVs.The trade mark of suitable silicones RTVs is Nusil, and it has from about 30 to about 80 Xiao A hardness, preferably from about 40 to 70 Xiao A hardness.This elastomer can be selectively mixes with suitable plasticizer or blowing agent, so that they have better compressibility.This elastomer also can have other wherein the material of being distributed in, so that change its performance, such as its electric conductivity.If use the elastomer of low tearing strength, the width of slit may increase when slit stays open a long period.This slit valve can have elastic sealing element that needle-penetration one injection moulding of sharp-pointed end or compression molding are shaped, that have with required valve same size and shape and forms by using one.The width of slit is roughly proportional with the width of pin.This pin can be a flat blade, also can have polygon or circular cross section.This pin preferably has polygon, the particularly cross section of circle.Have been found that when otch that pin taper, sharp edges produces uses more as if a flat seam, rather than a hole.This may cause spraying be not straight or even produce plural injection, thereby may cause insecure and unpredictable injection.The suitable diameter of pin from about 100 to about 350, preferably from 150 to 250 μ m.When using silicone elastomer, preferably thorn is threaded a needle and is withdrawed from rapidly after forming slit, unnecessarily enlarges to avoid slit.Find that also the geometry of elastic sealing element and the method that pierces through have remarkable influence to efficient and the repeatability that slit forms.If piercing through of seal is to carry out from the inboard of circular arch rather than from the outside, can form slit more reliably.
Under the normal condition, when when the fluid side convection cell is exerted pressure, valve is opened, and when pressure disappeared, valve cut out.As previously described, can exert pressure by the dosing device convection cell such as syringe pump.Institute's applied pressure is suitable for from about 200 to the scope of about 5000mbar (20 to 500kPa), preferably from about 500 to the scope of about 3000mbar (50 to 300kPa).Flow rate by valve is general and institute's applied pressure is proportional, be suitable for from about 5 to about 50, preferably from about 5 to the scope of about 30 μ ls-1.Under this pressure, and when having described valve-type and slit sizes, can obtain output speed from about 0.5 to about 8, preferably from about 1 straight fluid straight line portion to about 3ms-1 scope.
The diameter parts ground of the straight line portion that is sprayed is determined by flow rate, and is generally less than the width of slit valve.According to described flow rate,, also can obtain straight line portion diameter less than 50 μ m even be 200 μ m at the slit width of valve.The diameter of straight line portion influences significantly and is sprayed at the particle size that is shattered into the spraying behind the tapering part, and the particle size major part is similar to the diameter of straight line portion.The characteristics of the electrostatic spray of linear fashion described here are, can obtain tight distribution, almost single spraying of scattering.Like this, might obtain to be about 20 to 80, preferable be about 30 to 70, the better middle droplet size that is about 40 to 60 μ m, particle size distribution has less than 5 usually, be generally less than 2 μ m, preferably less than the standard deviation of 1 μ m.General common recognition is, for the nose internal spraying, 10 μ m or littler particle size are undesirable, and like this, particulate can not be carried in the lung.Yet, it is believed that electrostatic charge that spray particles has will make them unlikelyly be carried into the nose back, because charged corpuscle trends towards at a good pace arriving earthed surface.
The performance that stops fully of bottom valve can be by being further improved in valve rear portion importing pressure relief feature.When piston enters this zone and when finishing it to front travel, this zone can provide a pressure drop, and shut off valve at once and reliably, do not have drippage at the end of full dosage.
Method
Sprayer unit described here is suitable for to body cavity, particularly people's nose, face or ear spraying.Low capacity and gentle spraying also make it be suitable for for example medicament for the eyes spraying.Preferably, this device is a nose inner sprayer unit.Enforcement provides the preferred approach of fluid to comprise from sprayer unit to nasal cavity, fluid is sprayed into nasal cavity, and do not need this device to enter the nostril basically.Here so-called " not needing to enter the nostril basically " is meant, neither one nozzle or similar thing insert the nose vestibular.During use, the shower nozzle of this device preferably contacts with the nostril opening, thereby obtains whole benefits of described here, relevant with shower nozzle reinforcement electric field effect.If provide pressure,, the nostril is opened or overlapping with the barrier film cartilage slightly, but in any case, shower nozzle will can not surrounded fully by the nostril for guaranteeing contact or helping its orientation by the user.
Claims (8)
1. distributor (1 that is used for fluid (10), 2), this distributor (1,2) comprise a storage tank (11), one (12), one back of the body seal (13), one damper (14), one piston (151,152) and a check valve (16), described back of the body seal (13) seals first end of described storage tank (11), and can move along described axle (12), described check valve (16) is positioned at second end of described storage tank (11), described piston (151,152) be fixed in an end of described axle (12), described piston (151,152) be arranged between described check valve (16) and the described damper, described damper (14) also is fixed in described axle (12), described damper (14) is arranged between described piston and the described back of the body seal (13), thereby described piston (151,152) have an open position (151) and a closed position (152), described open position allows described check valve (16) and described storage tank (11) to be positioned at described piston (151,152) and the part phase fluid between the described back of the body seal (13) be communicated with, described axle (12) causes described piston (151 along himself axis mobile, 152) between described open position and described closed position, move, when described piston from its closed position when its open position moves, at described check valve (16) and described piston (151,152) pressure in the zone that constitutes between reduces, when described piston from its closed position when its open position moves, described damper (14) draws in, the fluid that only has that is positioned at the part between described damper (14) and the described back of the body seal (13) and is positioned at the part of described damper (14) opposite side from described storage tank (11) from described storage tank (11) flows, be when move its closed position, to be arranged in a connection channel (140) of described damper (14) from its open position at described piston (151,152).
2. distributor as claimed in claim 1 is characterized in that, described axle (12) is made by conductive material.
3. distributor as claimed in claim 2 is characterized in that, described fluid was recharged before distributing.
4. distributor as claimed in claim 1 is characterized in that, the volume that is constituted between described piston that is in described open position and described check valve (16) is less than 100 μ l.
5. distributor as claimed in claim 1 is characterized in that, the fluid volume variation that each batch operation is distributed is lower than 10%.
6. distributor as claimed in claim 1, it is characterized in that, the other end that is fixed with described piston (151, a 152) end at described axle (12) is provided with a compression spring, and it applies a power to described axle (12) on the direction of the axis that is basically parallel to described axle (12).
7. distributor as claimed in claim 1 is characterized in that, described check valve (16) is a self-sealing valve.
8. distributor as claimed in claim 1 is characterized in that, described interface channel (140) is a single opening that is provided in the described damper (14).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP99870004A EP1020233A1 (en) | 1999-01-13 | 1999-01-13 | Dosing and delivering system |
| EP99870004.1 | 1999-01-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1347346A true CN1347346A (en) | 2002-05-01 |
Family
ID=8243788
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00802613A Pending CN1347346A (en) | 1999-01-13 | 2000-01-12 | Dosing and delivering system |
Country Status (23)
| Country | Link |
|---|---|
| EP (2) | EP1020233A1 (en) |
| JP (1) | JP4295437B2 (en) |
| KR (1) | KR20020004944A (en) |
| CN (1) | CN1347346A (en) |
| AT (1) | ATE248030T1 (en) |
| AU (1) | AU748289B2 (en) |
| BR (1) | BR0007526A (en) |
| CA (1) | CA2360411A1 (en) |
| CO (1) | CO5231171A1 (en) |
| CZ (1) | CZ20012506A3 (en) |
| DE (1) | DE60004780T2 (en) |
| EG (1) | EG22672A (en) |
| HU (1) | HUP0105057A3 (en) |
| IL (1) | IL144092A0 (en) |
| MA (1) | MA25341A1 (en) |
| NO (1) | NO20013508L (en) |
| NZ (1) | NZ512600A (en) |
| PE (1) | PE20001192A1 (en) |
| PL (1) | PL349767A1 (en) |
| RU (1) | RU2198740C1 (en) |
| SK (1) | SK10062001A3 (en) |
| WO (1) | WO2000041816A1 (en) |
| ZA (1) | ZA200105289B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104797347A (en) * | 2012-10-25 | 2015-07-22 | 雀艾斯达有限公司 | Pump apparatus |
| CN108144168A (en) * | 2015-05-16 | 2018-06-12 | 苏州汉方医药有限公司 | A kind for the treatment of medicine box of manual microactuator suspension particle generator and chemicals medicine composition |
| CN110709565A (en) * | 2017-06-27 | 2020-01-17 | 柯勒米拉有限公司 | Additive dispenser |
| US11666931B2 (en) | 2019-05-14 | 2023-06-06 | Kohler Co. | Inline shower device |
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| GB2389530B (en) | 2002-06-14 | 2007-01-10 | Cipla Ltd | Pharmaceutical compositions |
| FR2893090A1 (en) * | 2005-11-09 | 2007-05-11 | Claude Jaunay | FLUID PUMPING AND DISPENSING ASSEMBLY |
| NL1030992C2 (en) | 2006-01-24 | 2007-07-26 | Airspray Nv | Squeeze foamer. |
| GB0602980D0 (en) * | 2006-02-14 | 2006-03-29 | Optinose As | Delivery device and method |
| WO2010045186A2 (en) * | 2008-10-16 | 2010-04-22 | Automatic Bar Controls, Inc. | Apparatus and method and turntable for on-demand distributing of a food product |
| EP2201977A1 (en) * | 2008-12-23 | 2010-06-30 | Siegfried Generics International AG | Metering device for creating a gas flow with an active agent |
| RU2452585C2 (en) * | 2009-06-03 | 2012-06-10 | Макнейл Аб | Pocket distributor |
| AU2010303985B2 (en) * | 2009-10-08 | 2012-09-13 | Shl Group Ab | Metered liquid droplet inhaler |
| RU2529397C2 (en) * | 2012-10-04 | 2014-09-27 | Ирина Леонидовна Лисовская | Medicinal electrophoresis device for eye tissues |
| JP5992321B2 (en) * | 2012-12-27 | 2016-09-14 | 株式会社吉野工業所 | Syringe type ejection container |
| US11554229B2 (en) | 2013-03-26 | 2023-01-17 | OptiNose Inc. | Nasal administration |
| DE102013013530A1 (en) * | 2013-08-13 | 2015-03-12 | Dürr Systems GmbH | Application system with cable-guided handling device for moving an application device |
| KR101498220B1 (en) * | 2013-08-30 | 2015-03-03 | 삼성중공업 주식회사 | Sealing apparatus for anti-corrosion |
| DE102018121513B4 (en) * | 2018-09-04 | 2020-04-02 | Prof. Reymond & Hetzel GbR (vertretungsberechtigter Gesellschafter: Alexander Hetzel, 78667 Villingendorf) | Medical instrument for the directed introduction of a substance into a cavity of a body and tool therefor |
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| FR920943A (en) * | 1946-01-30 | 1947-04-22 | ejector for liquids | |
| DE3339180C2 (en) * | 1983-10-28 | 1993-10-14 | Pfeiffer Erich Gmbh & Co Kg | Discharge device for media |
| US4728006A (en) | 1984-04-27 | 1988-03-01 | The Procter & Gamble Company | Flexible container including self-sealing dispensing valve to provide automatic shut-off and leak resistant inverted storage |
| US4991745A (en) | 1989-04-25 | 1991-02-12 | Liquid Molding Systems, Inc. | Dispensing valve with trampoline-like construction |
| WO1993002729A1 (en) * | 1990-07-12 | 1993-02-18 | Habley Medical Technology Corporation | Super atomizing nonchlorinated fluorocarbon medication inhaler |
| DK302890D0 (en) | 1990-12-21 | 1990-12-21 | Novo Nordisk As | DISPENSER |
| EP0597601A1 (en) | 1992-11-13 | 1994-05-18 | National Semiconductor Corporation | Reflexively sizing memory bus interface |
| EP0780127A1 (en) | 1995-12-19 | 1997-06-25 | The Procter & Gamble Company | A nasal spray containing a steroid and a antihistamine |
| BR9709650A (en) | 1996-06-04 | 1999-08-10 | Procter & Gamble | Nasal aerosol containing an intransal steroid and an antihistamine |
| GB9619445D0 (en) * | 1996-09-18 | 1996-10-30 | Boots Co Plc | Fluid dispenser |
-
1999
- 1999-01-13 EP EP99870004A patent/EP1020233A1/en not_active Withdrawn
-
2000
- 2000-01-12 NZ NZ512600A patent/NZ512600A/en unknown
- 2000-01-12 KR KR1020017008745A patent/KR20020004944A/en not_active Application Discontinuation
- 2000-01-12 BR BR0007526-4A patent/BR0007526A/en not_active IP Right Cessation
- 2000-01-12 PE PE2000000022A patent/PE20001192A1/en not_active Application Discontinuation
- 2000-01-12 EG EG20000030A patent/EG22672A/en active
- 2000-01-12 CA CA002360411A patent/CA2360411A1/en not_active Abandoned
- 2000-01-12 JP JP2000593418A patent/JP4295437B2/en not_active Expired - Lifetime
- 2000-01-12 AT AT00903272T patent/ATE248030T1/en not_active IP Right Cessation
- 2000-01-12 HU HU0105057A patent/HUP0105057A3/en unknown
- 2000-01-12 RU RU2001122593/12A patent/RU2198740C1/en not_active IP Right Cessation
- 2000-01-12 PL PL00349767A patent/PL349767A1/en unknown
- 2000-01-12 CN CN00802613A patent/CN1347346A/en active Pending
- 2000-01-12 CZ CZ20012506A patent/CZ20012506A3/en unknown
- 2000-01-12 IL IL14409200A patent/IL144092A0/en unknown
- 2000-01-12 SK SK1006-2001A patent/SK10062001A3/en unknown
- 2000-01-12 EP EP00903272A patent/EP1140368B1/en not_active Expired - Lifetime
- 2000-01-12 CO CO00001231A patent/CO5231171A1/en not_active Application Discontinuation
- 2000-01-12 DE DE60004780T patent/DE60004780T2/en not_active Expired - Lifetime
- 2000-01-12 AU AU25046/00A patent/AU748289B2/en not_active Ceased
- 2000-01-12 WO PCT/US2000/000834 patent/WO2000041816A1/en not_active Application Discontinuation
-
2001
- 2001-06-27 ZA ZA200105289A patent/ZA200105289B/en unknown
- 2001-07-11 MA MA26264A patent/MA25341A1/en unknown
- 2001-07-13 NO NO20013508A patent/NO20013508L/en not_active Application Discontinuation
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104797347A (en) * | 2012-10-25 | 2015-07-22 | 雀艾斯达有限公司 | Pump apparatus |
| CN108144168A (en) * | 2015-05-16 | 2018-06-12 | 苏州汉方医药有限公司 | A kind for the treatment of medicine box of manual microactuator suspension particle generator and chemicals medicine composition |
| CN108498913A (en) * | 2015-05-16 | 2018-09-07 | 苏州汉方医药有限公司 | A kind of medicine box for treating diabetes that medicine instrument is combined into |
| CN108525090A (en) * | 2015-05-16 | 2018-09-14 | 苏州汉方医药有限公司 | A kind of medicine box for treating anaemia that medicine instrument is combined into |
| CN108525089A (en) * | 2015-05-16 | 2018-09-14 | 苏州汉方医药有限公司 | A kind of medicine instrument be combined into for treating underfed medicine box |
| CN110709565A (en) * | 2017-06-27 | 2020-01-17 | 柯勒米拉有限公司 | Additive dispenser |
| US11230833B2 (en) | 2017-06-27 | 2022-01-25 | Kohler Mira Limited | Additive dispenser |
| US11773577B2 (en) | 2017-06-27 | 2023-10-03 | Kohler Mira Limited | Additive dispenser |
| US11666931B2 (en) | 2019-05-14 | 2023-06-06 | Kohler Co. | Inline shower device |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2360411A1 (en) | 2000-07-20 |
| MA25341A1 (en) | 2001-12-31 |
| ZA200105289B (en) | 2002-03-06 |
| IL144092A0 (en) | 2002-05-23 |
| NZ512600A (en) | 2002-12-20 |
| PL349767A1 (en) | 2002-09-09 |
| KR20020004944A (en) | 2002-01-16 |
| RU2198740C1 (en) | 2003-02-20 |
| BR0007526A (en) | 2001-11-27 |
| HUP0105057A3 (en) | 2002-06-28 |
| EP1140368B1 (en) | 2003-08-27 |
| ATE248030T1 (en) | 2003-09-15 |
| EP1140368A1 (en) | 2001-10-10 |
| JP4295437B2 (en) | 2009-07-15 |
| EG22672A (en) | 2003-06-30 |
| HUP0105057A2 (en) | 2002-04-29 |
| JP2002534331A (en) | 2002-10-15 |
| AU2504600A (en) | 2000-08-01 |
| NO20013508D0 (en) | 2001-07-13 |
| CO5231171A1 (en) | 2002-12-27 |
| WO2000041816A1 (en) | 2000-07-20 |
| DE60004780T2 (en) | 2004-06-17 |
| PE20001192A1 (en) | 2000-12-04 |
| CZ20012506A3 (en) | 2002-03-13 |
| AU748289B2 (en) | 2002-05-30 |
| EP1020233A1 (en) | 2000-07-19 |
| RU2001122593A (en) | 2004-02-20 |
| NO20013508L (en) | 2001-07-13 |
| DE60004780D1 (en) | 2003-10-02 |
| SK10062001A3 (en) | 2002-03-05 |
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