WO2003000300A2 - A system for microbial control of a fluid - Google Patents
A system for microbial control of a fluid Download PDFInfo
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- WO2003000300A2 WO2003000300A2 PCT/SE2002/000991 SE0200991W WO03000300A2 WO 2003000300 A2 WO2003000300 A2 WO 2003000300A2 SE 0200991 W SE0200991 W SE 0200991W WO 03000300 A2 WO03000300 A2 WO 03000300A2
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- zeolite
- fluid
- agent
- pores
- arrangement
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/24—Apparatus using programmed or automatic operation
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/23—Solid substances, e.g. granules, powders, blocks, tablets
- A61L2/235—Solid substances, e.g. granules, powders, blocks, tablets cellular, porous or foamed
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L9/00—Disinfection, sterilisation or deodorisation of air
Definitions
- the present invention relates to an arrangement for controlling microbial content or growth in a fluid.
- the arrangement comprises a) a zeolite with micro-pores charged with an agent having affinity to the zeolite micro-pores and having properties and b) the fluid, the zeolite and the fluid being at least partially in contact, or being arranged for being brought at least partially in contact.
- the invention also relates to a suitable zeolite for the arrangement and methods for use thereof.
- antiseptic agents for control of microbial content or growth is common for various purposes such as cleaning and sterilizing the fluid and as preservative additives to the fluid.
- a general problem is that the agents tend to be toxic or hazardous not only to the mi- crobes but to other life forms as well, including humans and animals, and it is desirable to limit the amounts of agents to a minimum.
- the antiseptics frequently have to be used in excess, corresponding to the worst microbial exposure foreseen for the fluid in its contemplated use. The problems are exacerbated when the fluid is intended for body exposure, e.g. as breathing air or preparations for body treatment.
- the ion exchange system proposed limits the absorbed agents to certain metal ions. Similar problems are encountered when using a zeolite as absorbent for a medical to be administered orally, as exemplified by EP 240169, where peak concentrations can be avoided but no control is available for obtaining low and uniform concentrations.
- the WO 97/15391 reference suggests use of zeolite to absorb preservatives from pharmaceutical preparations in connection with ejection to reduce the amount of preservatives delivered to the body.
- the zeolite can be arranged in the front of a syringe type device to be passed by the preparation in connection with ejection.
- the position of the zeolite between the preparation and an exit opening for the preparation means that necessarily there is a low content of preservative at the most probable infection path, i.e. through the exit opening, and if this part is infected enough preservative is not available for control of its growth.
- the problem will be more pronounced in multi-dose arrangements since the liquid in dead spaces in front of the zeolite absorbent has passed the zeolite and is subject to uncontrolled microbial growth.
- WO 87/05592 A similar problem is presented in WO 87/05592 with respect to wastewater treatment.
- the recipient to be protected is the biological bed used for breakdown of the waste content in the water.
- a zeolite bed is inserted in the influx line before the bed and is able to absorb occasional bursts of toxic components in the incoming water.
- the concentration of toxic substances is thus kept low and not higher than the biological bed is able to degrade. Since this system simply absorbs random toxic components in the incoming wastewater there is no use at all, and still less an efficient use, of the toxic component for antiseptic purposes and no control means are provided for such purposes.
- a main object of the present invention is to provide a system for controlling microbial growth in fluids avoiding the disadvantages and shortcomings of hitherto used technologies!
- a more specific object is to provide such a system based on controlled and efficient use of an antiseptic agent.
- Another object is provide a system allowing reduced amounts of agent with maintained antiseptic action or improved antiseptic action with maintained agent amounts.
- Still another object is to offer a system exposing the fluid to agent amounts adapted to its current microbial charge and to reduce the need for surplus agent amounts for worst case purposes.
- a further object is to offer a system providing an antiseptic barrier between a confined fluid and the environment, independent of the fluid content of agent.
- Yet another object is to provide a system giving treated fluid of sufficiently low agent content to permit its exposure to human and animals, including injection into the body, and compatible with fluids being pharmaceutical preparations.
- a further object is to offer a system applicable to both small and large volumes of fluid in static as well as intermittent or continuous movement or dosing.
- Yet another object is to offer a system allowing use of a broad range of antiseptic agents.
- a fur- ther object is to offer a system usable for both gas and liquid fluids.
- Still another object is to provide a system allowing devices and arrangements of flexible design.
- a zeolite is used for absorption of the antiseptic agent.
- zeolites are generally highly inert and structurally rigid, can be shaped into structures of very flexible form and varying bulk porosity, and are selective and efficient absorbents due to the high pore contents and uniform pore sizes, yet with a possibility to vary the pore size for adaptation to specific target molecules. Additional advantages of importance in the present context are obtained with hydrophobic zeolites, i.e. zeolites with high silicon and " low aluminum content in the crystal lattice backbone. These zeolites are still more inert and stable, of particular importance where the fluid is to be exposed to human or animals. They have no or low tendency to release particles and aluminum ions, of importance for example when the fluid is a pharmaceutical preparation.
- hydrophobic zeolites broaden the range of possible antiseptics by being compatible also with hydrophobic and non-ionic compounds, which is of importance these classes of compounds cover many antiseptics permitted for hu- man exposure and which operates particularly well with the principles of the present invention.
- the invention utilizes a zeolite pre-charged with an antiseptic agent to such a level that fluid in contact with the pre-charged zeolite will attain an antiseptic level of the agent by controlled release from the zeolite.
- the invention utilizes a hitherto not exploited property of the zeolites, namely their ability to absorb such quantities of an agent that a fluid in contact with the zeolite increases its content of agent to an antiseptic level.
- This in contrast e.g. with zeolite applications for filtering where the fluid will have its agent content reduced from antiseptic level to lower than antiseptic levels under concurrent increase of agent to moderate levels in the zeolite filter.
- This new way of using the zeolite meets several objects of the invention.
- the levels of antiseptic agent in the fluid can be kept low and need not be raised to excess levels for worst case situations since the charged zeolite acts as a buffer, providing additional release of agent when needed, e.g.
- the fluid and zeolite can be contacted statically with a zeolite body or powder, by passing the fluid past a zeolite surface or coating or through a bed or column of the zeolite.
- the system is compatible with static, intermittent and continuous arrangements and with equilibrium establishment by diffusion, mixing or forced streaming.
- the charged zeolite has excellent barrier properties in its neighborhood, preventing infection at its surfaces, through its pores and at possible fissures, imperfections and dead spaces.
- the barrier properties can be employed to position the zeolite where the infection risks are highest, e.g.
- the charged zeolites of the present system allow reversible controlled release of the agents both when the fluid is a gas an when the fluid is a liquid and the combined flexibility of the system permits the invention to be adapted for numerous different applications to be exemplified.
- system shall be understood to refer to the principles of the invention generally, whether described, claimed, exemplified or implemented as one or more devices/arrangements, methods, uses or combinations thereof.
- composition compounds/components in any physical or chemical aggregation or mixture with possible intervening compounds/components, or state of aggregation as well as method steps in any time sequence.
- microbes shall be understood to mean any organism able to survive as single cells in the presence of nutrients or a host organism, e.g. protozoa such as amoebas etc. More narrowly the concept shall have the common meaning of "microorganisms”, i.e. bacteria and fungi of mould or yeast type.
- antiseptic conditions like "antiseptic conditions”, “antiseptic concentration”, “antiseptic level”, antiseptically effective” and similar terminology shall be understood to refer to conditions adapted and suitable for at least retarding growth of, preferably stopping growth of and most preferably killing at least one living microbe, if and when in contact with any component able to act as a nutrient for the microbe, although the expressions shall not be understood to require presence of such a nutrient. Nor shall the expressions be understood to require presence of microbes but include pre- cautionary situations as well. The expressions shall, however, be understood to exclude situations and conditions where the contact or residence time is insufficient for any significant action between the antiseptic and the microbe.
- the system antiseptic action sufficiency against a single microbe shall be seen in light of the possibility according to the invention to use the charged zeolite as buffer, to release additional antiseptic agent and restore fluid con- tent of agent when the microbe absorbs or otherwise interacts with the agent, and shall not exclude the option that the fluid has an amount or concentration sufficient for being active against more than one or against numerous microbes.
- the agent amounts necessary may vary for different agent types, e.g. low for antibiotics having precise metabolic action and high for agents of more bold oxidizing or poisonous action. Accordingly conditions com- monly referred to as for example bactericide and bacteristatic are included in the meaning of the expressions.
- the zeolite Zeolites can in general be described as crystal frameworks of aluminum silicates or tectosilicates, which can be characterized by their chemical composition and crystal structure.
- the chemical composition is generally expressed in terms of the Si/Al ratio.
- High silica zeolites carry less framework charge and are commonly referred to as hydrophobic.
- high alumina zeolites which are labeled hydrophilic.
- Zeolites suitable for the present purposes can be said to have the general structure formula (AlO2)x(SiO2)y wherein 5 the ratio y/x can have different values, to be described.
- other ions like P, B, Fe, Ga, Ge etc.
- Zeolites may be substituted for Al and Si to a certain degree and can also be used for the purposes of the invention.
- Zeolites may contain more or less water. 10
- the crystal lattice provides a pore system where the pores are highly uniform in size although the size is somewhat different between different zeolite types. In general the pores comprises a main cavity and entrance openings. The size of the main cavity varies between about 3 to 11 A in diameter between different zeolites and the entrances may be about 1 to 3 A smaller.
- micro-pores These uniform pores are responsible for the high and selective absorbency of the 15 zeolites and will be referred to as micro-pores herein.
- the zeolite crystal may in addition have micro-fissures, resulting from their chemical and physical manufacturing and treatment history, which fissures are not uniform and for the present purposes it is preferred to use zeolites with low or no fissures.
- zeolite crystals are normally of limited size, forming a powder or particulate mass. Such a mass can be used as such, e.g. to be suspended in a fluid for 20 absorption. By sintering or by adding a gluing component, e.g.
- the mass can be consolidated into forms of any shape and size. In doing so macro-pores may be left between the particles.
- macro-pores between the crystal particle will be referred to as bulk porosity and expressed as the total macro-pore volume to total bulk volume of the zeolite mass or shape respectively.
- a 25 bulk porosity may serve the purpose of allowing the fluid to enter the macro-pores and contact the individual particle and even allowing the fluid to pass through the zeolite mass or shape.
- a suitable bulk porosity for such purposes can be at least 20 percent, preferably at least 30 percent and most preferably at least 35 percent and for among others stability reasons the bulk porosity may be at most 90 percent, preferably at most 80 percent and most preferably at most 30 75 percent. It is certainly possible to use, alternatively or in combination, other known means than pore porosity for creating permeability and/or increasing contact surface between fluid and zeolite, e.g. thin channels through a zeolite bed or body, layers of zeolite etc. For the present purposes zeolites having y/x ratios of 15 and below will be regarded as hydrophilic whereas zeolites with y/x ratios higher than 15 will be regarded as hydrophobic.
- Hydrophilic zeolites may for example be used when the antiseptic agent is also hydrophilic. If the agent is ionic it is also possible to • utilize the well-known possibility of affecting its affinity to- the zeolite by change of the surrounding ionic properties, e.g. pH, lowering the affinity in environments where the agent be- comes non-ionic. This may be of interest to fine-tune the release of agent, making self- regulating systems or to make the same charged zeolite useful for the requirements of different fluids. Hydrophilic zeolites may have y/x ratios lower than 15, e.g. lower than 5 and even lower than 1.
- hydrophobic zeolites also referred to as de-aluminized or ultra-stable zeolites, e.g. due to their high stability, the possibility to use also the large class of hydrophobic antiseptic agents and non-ionic agents, the latter giving stable affinity properties independent of fluid ionic properties.
- the hydrophobic zeolites preferably have y/x ratios higher than 100, more preferably higher than 200 and most preferably higher than 1000.
- Suitable zeolite types may be e.g. silicalite, mordenit and especially zeolite Y.
- the zeolite Y and mordenite types belong to the largest known today with pore diameters of about 7 A and 7.5 A respectively whereas silicalite has two different pore sizes around 5.5 A.
- Silicalite and zeolite Y have three-dimensional pore systems whereas mordenite has two-dimensional pore systems and hence somewhat less accessible.
- the hydrophobic zeolites can for example be manufactures through direct synthesis (e.g. silicalite) or by post-synthetic manipulations (e.g. mordenite, zeolite Y), for example by alternating the treatment of zeolite Y with alkali, e.g. ammonia, and acid e.g.
- hydrochloric acid USY
- zeolite Y zeolite Y
- silicon tertrachloride DAY
- the alkali/acid treated have been found faster in its adsorption and release but with a high tendency for adsorption of high-weight proteins on the surface of the particles, whereas the opposite has been found for the silicon tetrachloride treated zeolites.
- the zeolite may be used as such or may be treated modify its properties. It is for example possible to coat with e.g. dextran or polyethyleneglycol to reduce the risk for clogging the micro-pore system with larger molecules contained in the fluid.
- the antiseptic agent Generally the antiseptic agents useful for the present purposes should have a size suit- able for accommodation in the zeolite micro-pore system. Atoms and atomic ions such as Ag or Cu are easily accommodated and can be used.
- the agent comprises molecules, among which a much broader range of suitable agent compounds are available, and such molecules should be possible to accommodate in the micro-pores, at least partially in case of elongated or branched molecules, but preferably the entire molecule should be accommo- dated. This puts certain limits to the size of suitable molecules and roughly the molecules should have mole weights below 3000, preferably below 2000 and most preferably below 1500.
- the agent shall have sufficient affinity to at least one zeolite type to allow absorption in an amount sufficient to give antiseptic conditions in a fluid, at least in a small volume relative to the zeolite, in contact therewith. As indicated, se- lecting the agent in relation to the zeolite type in general controls this.
- Any low-molecular antiseptic agent fulfilling the above requirements can be used according to the invention.
- Purely oxidizing substances, such as chlorine, hydrogen peroxide etc. can be used as well as purely toxic substances like cyanide although it is preferred to use agents with a more selective action.
- a suitable class of agents is antibiotics able to inhibit growth or kill microbes at low concentration levels, e.g. Clindamycin or penicillin. Preferred are those not or only moderately toxic against animals or humans, allowing medical use.
- Antibiotics can be used belonging to different groups with respect to their biological mechanism, such as those affecting synthesis of cell walls, synthesis of proteins, metabolism of folic acid, synthesis of nucleic acid etc.
- Suitable class of agents is what broadly is referred to as preservatives, e.g. halogenated compounds like DDT, triclosan etc. or aromates or polyaro- mates.
- preservatives e.g. halogenated compounds like DDT, triclosan etc. or aromates or polyaro- mates.
- preservatives approved for such use may include benzyl alcohol, bensalconium chloride, cetri- mid, chorbutol, chlorohexidine, chlorocresol, hydroxy benzoates, phenyl alcohol, phenoxi alcohol, phenyl mercury nitrate, chlororamphenicol etc. Good results have been obtained with phenol and cresol, especially m-cresol.
- the zeolite can be charged with the agent by any known method, e.g. by being contacted with the agent in pure form or in mixture, suspension, emulsion etc. of a media in liquid or gaseous form.
- the contacting procedure can take place for example by letting the zeolite and agent reside in contact, being agitated together or by passing the agent past or through the zeolite, the latter allowing for a gradient of the agent in the zeolite to be created.
- Contacting can take place at different temperatures, e.g. elevated temperature to speed up the procedure.
- the zeolite can be submitted to various after-treatments, e.g.
- any zeolite present can be subjected to the same treatment.
- some agent may be lost from the charged zeolite but can be compensated by a corresponding initial overcharging.
- the charged zeolite by subjecting the charged zeolite to a short washing or eluation step to remove to loosely bound agent or by inserting a non-charged or less charged zeolite downstream of the charged zeolite, whereby the first released agent will be captured in the micro-pores of the downstream zeolite until it will have the same saturation degree as the main charged zeolite.
- the minimum requirement on the agent and zeolite in the charged zeolite is that a small volume of the fluid, for which the charged zeolite is intended, when contacted with the charged zeolite will reach a minimum antiseptic level of the agent in the fluid, after that the concentration or distribution of the agent between the fluid and the zeolite substantially has reached an equilibrium.
- These minimum conditions may be useful, for example when in contact with air or a no more than moistened charged zeolite is used as an antiseptic barrier.
- agent amounts can be provided either by increasing the volume of zeolite, having low concentration of agent, or preferably by increasing the concentration of agent in the zeolite, e.g. to minimize the amount of zeolite necessary.
- volumes of fluid it is preferred to maintain minimum or buffer levels in the zeo- lite by continuous or batch replenishment of the agent in the zeolite, either by adding new agent or by separating out agent form already treated fluid and feeding it back to the zeolite, directly or to the fluid to be contacted with the zeolite. It is also preferred to increase the amount of agent in the zeolite above the minimum requirement to a buffer level in the zeolite, i.e.
- the agent has a fairly high affinity to the zeolite type selected.
- the affinity shall here be expressed as the amount of agent in the zeolite, weight percent agent in zeolite, at the maximum saturation degree, i.e. the saturation degree obtained with the zeolite in contact with pure agent after sufficient contact time for stabilization.
- the maximum saturation degree can be at least 10%, preferably at least 25% and most preferably at least 50%.
- the maximum saturation degree should be regarded as a gauge value only and shall not necessarily be the degree to which the zeolite is charged for use.
- a zeolite When a zeolite is charged to a highly saturated degree, and provided no substantial column effect is present at contact to be described, it will release substantially higher amounts initially than later when the saturation degree has been lowered.
- the fall off of concentration in the fluid, at continuous or repeated " contact with the fluid; is quite rapid and can be approximated with ah inverted linear, polynomial or exponential function.
- High saturation degrees can be used if this concentration pattern is desired, e.g. for a high cleaning burst follow by lower maintaining concentrations.
- the agent charged to the zeolite should be lower than at the maximum saturation degree and preferably so much lower that the fall off curve has reached an approximately constant behavior.
- the agent amount in the zeolite should be less than 50% of the amount corresponding to the maximum saturation degree, preferably less than 30% and most preferably less than 10%.
- the amounts can be still lower.
- this ratio of actual agent amount to the agent amount corresponding to maximum saturation degree is higher than 0.01%, preferably higher than 0.1% and most preferably higher than 1%.
- a column effect is present at the contacting these conditions are less stringent.
- the charged column is long enough to provide substantially equilibrium agent concentration in the fluid after only partial passage of the column no changes in fluid or zeolite agent amounts will take place during passage of the last parts of the column and the conditions at exit will be highly constant.
- a parameter of great concern for the present purposes is the concentration of agent in the fluid in equilibrium with the charged zeolite. This concentration can be lower than when not utilizing the principles of the invention, e.g.
- the present system can be used for control of microbial growth in broad ranges of fluids.
- the fluid may be a pure substance or a mixture of components of the same or different states of aggregation.
- a gas as continuous phase may contain liquid drops or solid particles.
- a liquid as continuous phase may contain particles of solids or droplets of liquids and the mix- tures may be suspensions, emulsions etc.
- the fluids may be simple mixtures, such as air or water solutions or mixtures, or may be complex mixtures of even unknown content, e.g. a contaminated stream or a body fluid. It is preferred to use the system for fluids that not too strongly interfere with the release mechanism described.
- the fluid should only contain small amounts of compounds or compositions able to precipitate on or adhere to the zeolite to such an extent as to block micro-pores or the macro-pores.
- the fluid has a not too high viscosity, e.g. below 10000 cP, preferably below 1000 cP and most preferably below 100 cP.
- the fluid may contain compounds that compete with the agent for zeolite affinity, e.g. to create a control means for release of varying agent amounts depending on presence or added amounts of such a competing compound.
- the competing compound may then have an affinity, as defined, to the zeolite similar to the agent or even larger than the agent, e.g.
- Such compound shall also be understood to include typical eluating media, e.g. media that affects the absorbed agent to a state of less affinity to the zeolite, e.g. by reducing or increasing its ionic character for hydrophilic and hydrophobic zeolites respectively.
- typical eluating media e.g. media that affects the absorbed agent to a state of less affinity to the zeolite, e.g. by reducing or increasing its ionic character for hydrophilic and hydrophobic zeolites respectively.
- the controlled release of agent means a substantially constant level of agent in the fluid.
- the liquid have only small amounts of compounds that compete with the agent for zeolite affinity, i.e. compound that are both low-molecular in the above discussed sense and have high affinity to the zeolite.
- the fluid may contain large amounts of low-molecular compounds provided these have lower affinity to the zeolite than the agent, e.g. an affinity, as defined, of at most 0.5 times that of the agent, preferably at most 0.1 times and most preferably at most 0.05 times that of the agent.
- Such compounds may be air or water molecules, having low affinity to hydrophobic zeolites, or small non-ionic compounds, having low affinity to hydrophilic zeolites.
- the fluid may well contain large amounts of high-molecular compounds, as defined, since these do not tend to be absorbed by the zeolite independent of their hydrophobic or hydrophilic properties respectively. It is often preferred to use the invention in connection with fluids containing such compounds, e.g.
- the compounds can be for example proteins, polypeptides, carbohydrate compounds, nucleic acid sequences etc., hereby utilizing the zeolite property of not absorbing these kind of large molecules.
- large amounts in the above sense can be above 0.01 mg/ml, preferably above 0.1 and most preferably above 1 mg/ml.
- small amounts may refer to less than these values.
- the advantages of the present invention are especially pronounced when the fluid contains components serving as nutrients for the microbes and especially when such nutrients are present in large amounts. Further, when using the invention it is not necessary to include preservatives in the fluid and it is accordingly preferred that the fluid contains no or only small amounts of preservatives of either the agent or preferably any other preservative.
- Fluid/zeolite contact As indicated the fluid and the zeolite can be brought into contact in different ways.
- the contact can be made by keeping the fluid static with respect to the zeolite, typically relying on a diffusion of agent from the zeolite to the fluid, resulting in concentration gradients in at least the fluid before saturation has been achieved throughout the fluid volume.
- Contacting can also be made by relative movement between the fluid and the zeolite, e.g. by agitating the fluid or forcing it to stream past or through the zeolite, typically resulting in less concentration gradients in the fluid.
- the zeolite may be in particulate form suspended in the fluid, typically giving small agent concentration gradients in the zeolite.
- the zeolite may be present in the form of a coating on a surface in contact with the fluid or a bed or column past or through which the fluid is moved, typically resulting in a concentration gradient for the agent in the zeolite, with increasing amounts when moving from the upstream to the downstream side of the zeolite.
- a bed or column also has the advantages of facilitating contact with all fluid, providing an additional barrier effect and providing bulk porosity or interstices for the fluid to occupy and improving contact.
- a column of not insignificant length may also serve the pur- pose of maintaining highly constant agent concentrations at column exit by saturating the fluid already at the entrance or intermediate parts of the column while maintaining substantially constant agent amounts in the zeolite at the exit.
- the agent concentration in the fluid typically increases at contact with the zeolite, at least initially and provided that equilibrium has not already been reached by earlier contact or pre-charging. It is advanta- geous to reach equilibrium or almost equilibrium and this may be obtained, e.g. when storing the fluid for sufficient time in contact with the charged zeolite.
- the contact may take place by a batch operation, by intermittent operation or by continuous contact.
- batch or intermittent operations there are some advantages, at least for smaller fluid volumes, to use a zeolite bed or column having sufficient bulk porosity to accommodate much, preferably most and most preferably all of the fluid in the macro-pores, i.e. so that the bed contains the fluid volume. Among others this optimizes contact conditions during the available residence time.
- fluid volume accommodated corresponds at least to the volume of the doses to be repeated or, in case of varying doses, to the largest dose considered.
- the charged zeolite may have utility as such, e.g. due to its excellent barrier properties, and may then just be adapted to the specific application where it is intended to be applied as barrier, e.g. formed or inserted into a sealing part or being designed as a patch for attachment on a part to be protected, e.g. a wound.
- a preferred arrangement is to have at least a chamber for the fluid in combination with the zeolite.
- a chamber may be open, e.g. an open vessel where, or closed, like a vial or other enclosure, or being part of a conduit, like in a transport channel for the fluid up to the zeolite.
- the charged zeolite may serve to maintain the content sterile, to act as a barrier e.g. over an opening to prevent contamination or to raise the agent concentration in the fluid when the fluid is passed from the chamber past or preferably through the zeolite out from the chamber.
- Another preferred arrangement is to have a first, upstream chamber, a second, downstream, chamber and the charged zeolite arranged so as to allow the fluid to come into contact with the zeolite at least when passing from the upstream chamber to the downstream chamber in such a way that the fluid content of agent increases.
- Such an arrangement may for example be a growth control part of a fluid transport channel for any purpose or be part of a fluid delivery arrangement.
- the arrangements are intended for interaction with the fluid, the arrangements shall be regarded as a part of the present system when useful or adapted for the pur- poses of the invention.
- the arrangements may be useful also when the fluid does not necessarily come into contact with the zeolite, for example when the zeolite is " used as a " precautionary measure, e.g. to be activated in case a sealing is inadvertently broken or becomes defect.
- precautionary measure e.g. to be activated in case a sealing is inadvertently broken or becomes defect.
- such limitations are intentionally introduced, e.g. when valves, rupturable, pierceable or removable membranes or other sealings are inserted in the arrangement to allow creation of fluid contact at a controlled moment, e.g. in connection with activation or opening of a pre-filled device.
- Figure 1 illustrates schematically in box form the contemplated equilibrium system of the invention under idealized conditions.
- Figure 2 illustrates schematically an eluation curve for a zeolite initially charged to a high saturation degree.
- Figure 3 illustrates schematically a zeolite bed in the form of a column of sufficient length to allow for gradients of agent amounts in the zeolite to form.
- Figure 4 illustrates schematically various zeolite arrangements in connection with a single chamber.
- Figure 5 illustrates schematically various zeolite arrangements in connection with an upstream chamber and a downstream chamber.
- Figure 6 illustrates a diagram in relation to Example 1.
- Figure 7 illustrates a diagram in relation to Example 2.
- Figure 8 illustrates a diagram in relation to Example 5.
- Figure 9 illustrates a diagram in relation to Example 6.
- Figure 10 illustrates a diagram in relation to Example 7.
- Figure 1 illustrates schematically in box form the contemplated equilibrium system of the invention under idealized conditions.
- the left box illustrates the charged zeolite 1
- the middle box illustrates the fluid 2 being in contact with the zeolite 1
- the right box illustrates microbes 3 present in the fluid.
- the zeolite and the fluid are in reversible equilibrium with each other, which is illustrated with arrows 4 and 5.
- the microbes and the fluid are in reversible equilibrium, which is illustrated by arrows 6 and 7.
- Arrow 4 indicates the flow of agent from the zeolite to the fluid, e.g.
- Arrow 5 indicatesrthe opposite flow of agent from the fluid to the zeolite if or when the fluid becomes over- saturated with agent, for example if liquid fluid is evaporated or if the microbes release the agent when destroyed. In most uses the back-flow of agent according to arrow 5 is less im- portant than the arrow 4 flow. Arrow 6 indicates the flow of agent from the fluid to the microbes, here assumed to be present.
- the system illustrated is highly resilient against any form of disturbances or any form of agent consumption.
- the speed with which the system moves towards a new equilibrium at a disturbance may vary. In general terms can be said that the equilibrium between the zeolite and the fluid is quite fast at their interface but slower where diffusion is necessary for fluid volumes not in contact with the zeolite.
- agitation or 10 fluid flow may be used to remedy diffusion delays.
- the equilibrium between the fluid and the microbes is highly dependent on the antiseptic mechanism but may be slower, although this is typically less important for the system overall performance.
- Figure 2 illustrates schematically an eluation curve 20 for a zeolite initially charged to a high saturation degree.
- the vertical axis 21 represents the concentration of agent in the fluid 15 having been in contact with the zeolite and the horizontal axis 22 represents the volume of fluid or number of re-suspensions.
- the solid curve 23 can be said to represent the pattern obtained when contacting the fluid continuously with the zeolite and the discrete values 24 can be said to represent the concentrations achieved at repeated batch contacting.
- the curve illustrates that an initially high concentration 25 is obtained in the fluid, which concentration rap- 0 idly falls off to a state where further volumes or further re-suspensions give substantially con- — stant concentration of agent in the fluid.
- Dotted lines 26 and 27 indicate roughly upper arid “ "'” " ' •' lower charging degrees respectively that can be selected to give substantially constant agent concentrations in the treated fluid.
- Suitable initial zeolite charge can be obtained by overcharging it followed by eluation or evaporation of agent until the level of line 26 is reached or 5 preferably by initially charging the zeolite to a level corresponding to line 26, e.g. by use of a diluted charging fluid. It should be noted that the curve represents the agent amount in the fluid and not in the zeolite.
- the zeolite may comprise enormous amounts of the agent in spite of the fact that the concentration in the fluid is low, allowing large volumes of fluid or numerous contact repetitions with substantially con- 0 stant agent concentration in the outgoing fluid.
- the curve illustrated in Figure 2 is typical for contact patterns where no substantial agent amount variations or gradients results in the zeolite, for example no column effects. Such an equalized state may result e.g. when the zeolite is mixed or agitated randomly with the fluid or when a bed of zeolite is thin or shallow.
- Figure 3 illustrates schematically an arrangement, generally designated 30, with a zeolite bed in the form of a column 31 of sufficient length to allow for gradients of agent amounts in the zeolite to form. If the fluid residence time is sufficient in relation to the speed of the equilibrium system, the fluid will typically become saturated with the agent during pas- sage if an early fraction of the column height after which the fluid will pass the remainder of the column without further exchange of agent between zeolite and fluid, i.e. with both fluid and zeolite remaining unchanged. This will allow highly constant fluid exit concentrations for large volumes of fluid until the column has been depleted of agent to such a degree that passage of the entire column will not any longer give the target concentration.
- the column 31 has an entrance end 32 and an exit end 33.
- the column is assumed to have an over its length constant charge of agent. Fluid is then passed from the entrance 32 end of the column, as illustrated by arrow 34, to the exit end 33, as illustrated by arrow 35. After a certain time of operation the conditions illustrated will be reached. Typically a dynamic borderline, illustrated with dotted line 36, will form, separating a lower part 37 of the column, with unaffected agent amounts, from an upper part 38 of the column, with reduced agent amounts. The fluid will reach saturation concentration of the agent during passage of the upper part 38 of the column, between the entrance 32 and the borderline 36, and in this part the column will have a gradient of agent amount increasing from the entrance to the borderline.
- FIG. 4 illustrates schematically various zeolite arrangements, generally designated 40, in connection with a single chamber 41, here comprising a liquid fluid 42.
- the chamber may be closed or may be a part of a conduit or larger system as indicated by dotted line 43.
- the chamber is also shown with an opening 44, which opening is sealed with a charged zeolite in the form of a fixed disc 45, e.g. of particulate zeolite arranged between retaining sieves or preferably a sintered. self-supporting body.
- the charged zeolite in the opening 44 is here exposed to the surrounding and may act as an antiseptic barrier against microbial infection of 5 the chamber.
- the liquid 42 is not in contact with the zeolite disc 45 and the zeolite can be regarded as a safety mean and the liquid need not necessarily have an antiseptic level of agent. Still the opening may allow access to the liquid, e.g. pouring or forcing it through the porous disc.
- another fixed arrangement of the zeolite as a coating 46 on the chamber interior surface Due to the possibility of charging a zeolite 10 with high amounts of agent to give low concentrations in the fluid it is often possible to use fairly small amounts of charged zeolite and a partial coating can be fully sufficient.
- non-fixed amount of zeolite 47 in particulate or powder form which can be residing in the chamber or agitated to be suspended. The arrangements shown can be used for protection of chambers for various purposes or sizes, e.g. enclosures for fluids to large manu- 15 facturing plants for example in connection with shut down and preservation of the plant.
- FIG. 5 illustrates schematically various zeolite arrangements, generally designated 50, in connection with an upstream chamber 51 and a downstream chamber 52 for a streaming fluid fed to the upstream chamber, as illustrated by arrow 53, and extracted from the downstream chamber, as illustrated by arrow 54.
- a charged 20 zeolite either as coatings 55 on the walls or preferably by a bed 56 thought which the fluid is - - f orCec ⁇ to pass:
- Also schematically " illustrated is the possibility to suspend " a zeolite in particulate or powder form 57 in the incoming fluid stream 53, e.g. through a zeolite feeding line 58, and collecting it further downstream with for example a filter for possible removal, e.g.
- zeolite extraction line 59 possibly for repeated feeding to the zeolite feeding line 25 58.
- zeolite feeding line 25 58 Such an arrangement gives an additional control degree in that the charged zeolite fed into line 58 can be externally manipulated to optimize its condition, e.g. with agent re-charging to minimize the amount of zeolite or to adapt its agent amount or agent type to varying conditions in the incoming fluid 53.
- the arrangement shown in this figure can be adapted for numerous applications with streaming fluids and arrangement sizes, e.g. from a small syringe 0 to a large manufacturing or fluid cleaning plant.
- Example 1 This example illustrates release of m-cresol from zeolite with adsorbed m-cresol and is described with reference to the diagram in Figure 6.
- the zeolite was allowed to sediment and the supernatant was removed. Then the zeolite was suspended in PBS (phosphate buffer salin) so that an amount corresponding to 20 mg dry.
- zeolite per ml was suspended and after 30 - 60 minutes of incubation on a rocker table the concentration of cresol in the supernatant was measured by absorption at 276 nm, after which the zeolite was suspended in a new portion of PBS. The concentration of cresol was again determined in the supernatant and the zeolite was again suspended in PBS.
- Example 2 This example illustrates release of m-cresol from zeolite containing adsorbed m-cresol and is described with reference to the diagram in Figure 7.
- This example illustrates growth inhibition of Staphylococcus aureus (ATCC 6538), CFU ml-1) after incubation with m-cresol adsorbed on zeolite. Test according to Eur. Pharm. 2nd Ed. VIII 14 (1992). Efficacy of antimicrobial preservation.
- Ultra-stable zeolite Y (USY, 63 - 125 ⁇ m particles) was incubated with m-cresol 5 mg/ml after which the zeolite was. sucked dry and further dried in warm closet overnight. Zeolite with adsorbed m-cresol was then suspended in PBS and was incubated with Staphylococcus aureus at 37°C. The concentration of m-cresol in the solution after the suspension of zeolite was 0,14 mg/ml.
- Blank zeolite without any adsorbed m-cresol (25 mg/ml). b 5mg m-cresol / ml dissolved in water as positive control
- Example 4 This example illustrates growth inhibition of Staphylococcus aureus (ATCC 6538), CFU ml-1) after treatment with m-cresol adsorbed to zeolite.
- the zeolite was then suspended in phosphate buffer (0,3336 mg/ml mono-sodium phosphate, 0,7064 mg/ml di-sodium phosphate) with 0,2 mg glycine / ml and 41 mg mannitol /ml with and without addition of growth hormone (GH) after which the zeolite was incubated with Staphylococcus aureus at 37°C.
- phosphate buffer 0.3336 mg/ml mono-sodium phosphate, 0,7064 mg/ml di-sodium phosphate
- GH growth hormone
- Blank 3 30 mg/ml 30 mg/ml z. 30 mg/ml z. 50 mg /ml z.
- Example 5 This example illustrates adsorption of benzalkonium chloride to ultra-stable zeolite Y (US Y) and is described with reference to the. diagram, in Figure 8.
- Benzalkonium chloride (156 - 20 mg / ml) was incubated 60 minutes on a rocker table with 25 mg ultra-stable zeolite Y per ml (USY particles 63-125 ⁇ m). The amount of free benzalkonium chloride was determined by absorbency 263 nm and the amount of benzalkonium chloride adsorbed to the zeolite was calculated.
- Example 6 This example illustrates release of benzalkonium chloride from ultra-stable zeolite Y
- Ultra-stable zeolite Y (USY particles 63-125 ⁇ m) was incubated with benzalkonium chloride 5 mg / ml after which the zeolite was sucked dry and further dried in warm closet overnight. Zeolite with adsorbed benzalkonium chloride was repeatedly suspended to 20 mg/ml, first in PBS ( ⁇ ) and then in 95 % ethanol (•). The concentration of benzalkonium chloride in the solutions was determined by absorbency at 263 nm.
- Example 7 This example illustrates release of cephalothin from ultra-stable zeolite Y (USY) and is described with reference to the diagram in Figure 10.
- Ultra-stable zeolite Y (USY) was incubated with the antibiotic cephalothin 5mg/ml after which the zeolite was sucked dry and further dried in warm closet.
- Zeolite with adsorbed cephalothin was suspended repeatedly to 20 mg/ml in 10 mM glycin pH 2,5 ( ⁇ ) and the concentration of cephalothin in the solutions was determined by absorbency measurement at 260 nm. Then the zeolite was suspended in 10 mM phosphate buffer pH 8,0 (•). The change in pH makes the cephalothin de-protonized and the charge introduced results in an increased release of cephalothin from the zeolite.
- Ultra-stable zeolite Y USY
- USY Ultra-stable zeolite Y
- Tetracyclin 0,09 mg 1,8 mg/ml 220 ⁇ g / ml
- Dealuminated zeolite (DAY; 63-125 microns) was charged with m-cresol (10 mg/ml) at a zeolite content of 40 mg DAY per ml m-cresol solution.
- An E. Coli (CU1867, ATCC# 47092) suspension was mixed with uncharged zeolite and zeolite charged with m-cresol and was allowed to sediment for 5 minutes. The supernatant was removed from the zeolite sediment and the zeolite with remaining confined bacterial suspension (8x10 6 colony forming units, CFU) was incubated at room temperature. After 18 hours the sediment was re- suspended and the number of CFU was determined after coating on LB-agar.
- the test were made both in buffer (0.3336 mg/ml mono- sodium phosphate, 0.7064 mg/ml di-sodium phosphate, 2 mg/ml glycin and 41 mg/ml mannitol) and in buffer containing growth hormone (GH, 5.5 mg/ml). The distribution from two tests are given below in CFU. 5
- Example 10 5 Dealuminated zeolite (DAY; 63-125 microns) was charged with m-cresol (10 mg/ml) at a zeolite content of 40 mg DAY per ml m-cresol solution.
- An E. Coli (GUI 867, ATCC# 47092) suspension was mixed with uncharged zeolite and zeolite charged with m-cresol and the mixtures were allowed to sediment for 5 minutes. The supernatant was removed from the zeolite sediment and the zeolite with remaining confined bacterial suspension (8xl0 6 colony forming units, CFU) was incubated at room temperature and at +8°C respectively.
- the test - were made in LB-medium and after 18 hours at room temperature and after 2.5 days at ' +8°C ⁇ " respectively the sediments were re-suspended and the number of CFU was determined after coating on LB-agar. The results are given below in CFU.
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Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA03011597A MXPA03011597A (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid. |
JP2003506942A JP2004533470A (en) | 2001-06-26 | 2002-05-23 | Fluid microbe control system |
CA002450418A CA2450418A1 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
HU0400400A HUP0400400A2 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
PL02367770A PL367770A1 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
IL15919402A IL159194A0 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
BR0210641-8A BR0210641A (en) | 2001-06-26 | 2002-05-23 | System for microbial control of a fluid |
EP02733738A EP1404381A2 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
KR10-2003-7016841A KR20040014578A (en) | 2001-06-26 | 2002-05-23 | A system for microbial of a fluid |
NO20035727A NO20035727D0 (en) | 2001-06-26 | 2003-12-19 | A system for microbial control of a fluid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE0102265A SE0102265D0 (en) | 2001-06-26 | 2001-06-26 | A system for microbial control of a fluid |
SE0102265-6 | 2001-06-26 |
Publications (2)
Publication Number | Publication Date |
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WO2003000300A2 true WO2003000300A2 (en) | 2003-01-03 |
WO2003000300A3 WO2003000300A3 (en) | 2003-02-13 |
Family
ID=20284616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/SE2002/000991 WO2003000300A2 (en) | 2001-06-26 | 2002-05-23 | A system for microbial control of a fluid |
Country Status (16)
Country | Link |
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EP (1) | EP1404381A2 (en) |
JP (1) | JP2004533470A (en) |
KR (1) | KR20040014578A (en) |
CN (1) | CN1520316A (en) |
BR (1) | BR0210641A (en) |
CA (1) | CA2450418A1 (en) |
CZ (1) | CZ20033468A3 (en) |
HU (1) | HUP0400400A2 (en) |
IL (1) | IL159194A0 (en) |
MX (1) | MXPA03011597A (en) |
NO (1) | NO20035727D0 (en) |
PL (1) | PL367770A1 (en) |
RU (1) | RU2004101970A (en) |
SE (1) | SE0102265D0 (en) |
TW (1) | TW527199B (en) |
WO (1) | WO2003000300A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012084900A1 (en) * | 2010-12-20 | 2012-06-28 | Universite De Poitiers | Zeolite-based phytosanitary composition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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MX2022015445A (en) * | 2020-06-08 | 2023-04-04 | Chorus Llc | Systems, methods, and apparatuses for disinfection and decontamination. |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB810196A (en) * | 1955-02-02 | 1959-03-11 | Nat Res Dev | Cephalosporin c |
EP0240169A1 (en) * | 1986-03-15 | 1987-10-07 | Fermenta Asc Europe Limited | The preparation of therapeutic compositions for veterinary use |
EP0288063A2 (en) * | 1987-04-22 | 1988-10-26 | Shinagawa Fuel Co., Ltd. | Antibiotic resin composition |
EP0301717A1 (en) * | 1987-07-09 | 1989-02-01 | Karo Maeda | Medical tubes for placement into the body of a patient |
-
2001
- 2001-06-26 SE SE0102265A patent/SE0102265D0/en unknown
- 2001-08-02 TW TW090118886A patent/TW527199B/en not_active IP Right Cessation
-
2002
- 2002-05-23 WO PCT/SE2002/000991 patent/WO2003000300A2/en not_active Application Discontinuation
- 2002-05-23 CN CNA028128796A patent/CN1520316A/en active Pending
- 2002-05-23 RU RU2004101970/15A patent/RU2004101970A/en not_active Application Discontinuation
- 2002-05-23 PL PL02367770A patent/PL367770A1/en not_active Application Discontinuation
- 2002-05-23 EP EP02733738A patent/EP1404381A2/en not_active Withdrawn
- 2002-05-23 CZ CZ20033468A patent/CZ20033468A3/en unknown
- 2002-05-23 KR KR10-2003-7016841A patent/KR20040014578A/en not_active Application Discontinuation
- 2002-05-23 HU HU0400400A patent/HUP0400400A2/en unknown
- 2002-05-23 BR BR0210641-8A patent/BR0210641A/en not_active IP Right Cessation
- 2002-05-23 JP JP2003506942A patent/JP2004533470A/en not_active Withdrawn
- 2002-05-23 CA CA002450418A patent/CA2450418A1/en not_active Abandoned
- 2002-05-23 MX MXPA03011597A patent/MXPA03011597A/en not_active Application Discontinuation
- 2002-05-23 IL IL15919402A patent/IL159194A0/en unknown
-
2003
- 2003-12-19 NO NO20035727A patent/NO20035727D0/en not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB810196A (en) * | 1955-02-02 | 1959-03-11 | Nat Res Dev | Cephalosporin c |
EP0240169A1 (en) * | 1986-03-15 | 1987-10-07 | Fermenta Asc Europe Limited | The preparation of therapeutic compositions for veterinary use |
EP0288063A2 (en) * | 1987-04-22 | 1988-10-26 | Shinagawa Fuel Co., Ltd. | Antibiotic resin composition |
EP0301717A1 (en) * | 1987-07-09 | 1989-02-01 | Karo Maeda | Medical tubes for placement into the body of a patient |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012084900A1 (en) * | 2010-12-20 | 2012-06-28 | Universite De Poitiers | Zeolite-based phytosanitary composition |
Also Published As
Publication number | Publication date |
---|---|
TW527199B (en) | 2003-04-11 |
MXPA03011597A (en) | 2005-03-07 |
KR20040014578A (en) | 2004-02-14 |
HUP0400400A2 (en) | 2004-08-30 |
SE0102265D0 (en) | 2001-06-26 |
JP2004533470A (en) | 2004-11-04 |
RU2004101970A (en) | 2005-04-10 |
BR0210641A (en) | 2004-07-27 |
EP1404381A2 (en) | 2004-04-07 |
CA2450418A1 (en) | 2003-01-03 |
CN1520316A (en) | 2004-08-11 |
IL159194A0 (en) | 2004-06-01 |
CZ20033468A3 (en) | 2005-01-12 |
WO2003000300A3 (en) | 2003-02-13 |
PL367770A1 (en) | 2005-03-07 |
NO20035727D0 (en) | 2003-12-19 |
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