CZ20033468A3 - System for microbial control of a fluid - Google Patents

Abstract

An arrangement for controlling microbial content or growth in a fluid, comprising a) a zeolite with micro-pores charged with an agent having affinity to the zeolite micro-pores and having antiseptic properties and b) the fluid, the zeolite and the fluid being enclosed by, at least partially in contact, or being arranged for being brought at least partially in contact. The fluid contains molecules being larger than the micro-pores of the zeolite and having less affinity, as defined, to the zeolite than the agent. The fluid may contain a therapeutically active compound or composition in a therapeutically effective amount and concentration and that the total amount of agent in the zeolite is larger than an amount corresponding to an antiseptic level for the fluid. Also disclosed are methods, uses and zeolites for control of microbial content or growth in a fluid.

Description

Microbial fluid control system

Technical field

The invention relates to a composition for controlling microbial content or growth in a fluid. The composition comprises a) zeolite with micropores filled with an agent having an affinity for zeolite micropores and antiseptic properties, and b) a fluid wherein the zeolite and the fluid are at least partially in contact or in an arrangement that allows them to achieve at least partial contact. The invention also relates to a suitable zeolite for the composition and methods of use thereof.

BACKGROUND OF THE INVENTION

Antiseptic agents are generally used for a variety of purposes in which microbial content or growth needs to be controlled, for example, for cleaning, sterilizing fluid, and also used as preservative additives to the fluid. The general problem is that these agents are toxic or dangerous, not only for microbes but also for other living forms, including humans and animals, and it is desirable to minimize the amount of these agents. On the other hand, antiseptic agents must often be used in excess, corresponding to the assumption that the fluid is exposed to the worst possible microbial exposure in the use for which it is intended. These problems are all the more significant when the fluid is to be used to expose the body of the animal, for example, as air to breathe or to treat the body of the animal.

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These are mostly injectable preparations where the antiseptic type and amount are greatly limited but still have unavoidable side effects, the limitation of which is at the expense of the therapeutic value of the treatment using such preparations.

Some attempts have been made to control the amount of antiseptic agent and improve the exposure pattern. One suggestion is the absorption of an antiseptic agent in a carrier that regulates the rate of release of the antiseptic agent. EP 301 717 proposes to wrap medical tubes with zeolite filled with metal ions, such as Ag, Cu or Zn, as antibacterial agents to provide long-term prevention of body tissues that encapsulate the introduced tube from infection. However, the degree of control obtained is limited. This release is completely dictated by diffusion and cannot be altered or positively controlled. The desired effect can only be achieved in a thin layer and the zeolite, if it is to be used effectively, must be used only in a thin layer. The proposed ion exchange system limits the absorbed reagents to certain metal ions only. Similar problems are to be expected when the zeolite is used as an absorbent for a drug intended for oral administration, see for example EP 240 169 where maximum concentrations can be avoided but no means of control is available to achieve a low and uniform concentration.

WO 97/15391 proposes the use of zeolite for the absorption of preservatives from pharmaceutical preparations in connection with expulsion, which is intended to limit the amount of preservatives delivered to the body. The zeolite can be arranged in front of the syringe type device so that the pharmaceutical preparation has to pass through the zeolite when ejecting from the device. However, the position of the zeolite between the specimen and the outlet for the specimen means

01-2697-03-Ma · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · That, while passing, it is probably the most infectious pathway, ie. when passing through the exit orifice, the preservative content of the preparation is low, and if this portion is infected, then there is insufficient preservative to control the growth of the infection. This problem is exacerbated in multi-dose compositions, since the liquid at the dead spots inside the face of the zeolite absorbent passes through the zeolite and is exposed to uncontrolled microbial growth.

A similar problem is outlined in WO 87/05592 in connection with wastewater treatment. Here, the subject to be protected is a biological bed used to decompose waste products in water. The zeolite bed is inserted into the inlet manifold in front of the bed and is capable of absorbing occasional doses of toxic components in the inflow water. Consequently, the concentration of toxic substances is kept at a low level and is not higher than the level that the biological bed is capable of decomposing. Because this system simply absorbs accidental toxic components in the inflow effluent, it does not provide any utility, and no longer an effective utility, in the control of the toxic component intended for antiseptic purposes or any control means for this purpose.

Accordingly, there remains a need to improve methods and compositions for controlling microbial content or growth in a fluid.

SUMMARY OF THE INVENTION

The main object of the invention is to provide a system for controlling microbial growth in fluids, which would eliminate the disadvantages and drawbacks of the hitherto used

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4444 44994 44 4 technologies. A more specific object is to provide a system based on the controlled and efficient use of an antiseptic agent. Another object is to provide a system that allows to reduce the amount of agent while maintaining the antiseptic effect or to improve the antiseptic effect while maintaining the amount of the agent. Yet another object of the invention is to provide a system that exposes the fluid to an amount of reagent that adapts to the current microbial content of the fluid and thereby reduces the amount of sulfur reagent that would be required in the event of the most severe microbial contamination. Another object of the invention is to provide a system that provides an antiseptic barrier between the fluid under consideration and the environment independently of the reagent content of the fluid. It is yet another object of the present invention to provide a system by which a treated fluid having a sufficiently low reagent content is capable of being exposed to humans and other animals, including injection into the body of animals, which system must be compatible with fluids that are pharmaceuticals. . It is a further object of the invention to provide a system that can be applied to both small and large volumes of fluid in a static state, as well as intermittent or continuous movement or dosing. Yet another object of the invention is to provide a system that allows the use of a wide variety of antiseptic agents. Another object of the invention is to provide a system that will be applicable to both gaseous and liquid fluids. Yet another object of the invention is to provide a system that allows flexible design of devices and assemblies.

These objects are achieved by using the features of the appended claims.

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In the system of the invention, zeolite is used to absorb the antiseptic agent. Compared to other absorbents, zeolites are generally highly inert and structurally rigid, and their shape and structures are very easy to deliver the desired form and the desired porosity, while being selective and effective absorbents due to their high pore content and uniform pore size, yet vary the pore size to accommodate the dimensions of the specific target molecules. Further important advantages can be obtained in the context of the invention by the use of hydrophobic zeolites, i. zeolites with high silicon content and low aluminum content in the crystalline lattice. These zeolites are even more inert and stable, which is particularly important when the fluid is to be applied to humans or other animals. They have no or only limited tendency to release aluminum particles and ions, which is important, for example, when the fluid is a pharmaceutical formulation. They withstand high temperatures and long-term exposure to water without degradation, which is important, for example, for sterilization and long-term storage of pre-filled equipment or for repeated operation or regeneration of continuous cleaning kits. Finally, hydrophobic zeolites broaden the range of possible antiseptic agents by being compatible with hydrophobic and non-ionic compounds, which is important because these classes of compounds cover many antiseptic agents that are approved for human use and particularly good when used using pre-filled zeolites antiseptic with an agent to the extent that the fluid in contact with the pre-filled zeolite reaches the antiseptic level of the agent by controlled release from the zeolite. Thus, the invention utilizes unexploited properties whose effectiveness is the invention. Invention

01-2697-03-Ma zeolite, in particular their ability to absorb such amounts of agent that allow the fluid in contact with the zeolite to increase its agent content to an antiseptic level. This represents a contrast, for example using zeolite in filtration, where the agent content in the fluid is reduced from an antiseptic level to a level lower than the antiseptic level while increasing the agent in the zeolite filter to a medium level. This novel use of zeolite fulfills several objectives of the invention. The levels of antiseptic agent in the fluid can be kept low and do not need to be increased to excess levels even in the most severe of contamination because the filled zeolite acts as a buffer and releases the agent if necessary, for example when a new volume of fluid is contacted with the zeolite; if the agent is consumed by microbes, etc. Without wishing to be bound by theory, it is assumed that the fluid-zeolite system attempts to balance certain levels of the agent in the fluid or zeolite respectively, and any distortion leads to an attempt to rebalance, which in practice the zeolite releases or absorbs said agent. Thus, the consumption of a low regulated and always appropriate level of agent in the fluid can be maintained, regardless of the large amount of absorbed substances in the zeolite, which also allows rebalancing with at least quasi-static agent concentrations in the fluid. The fluid and zeolite may be contacted in a static manner when the zeolite is to form body or powder, or the fluid may be passed over the surface of the zeolite or through a bed, optionally a column formed by zeolite. Thus, this system is compatible with static, intermittent and continuous alignment and equilibrium by diffusion, mixing or forced flow. Moreover, because the zeolite has a relatively high reagent content and microbes tend to

01-2697-03-Ma ································· * Fluid and environment, agent, growth predominantly on the surface and not inside the fluid, filled with zeolite has an excellent ability to prevent infection from penetrating into its surface, through its pores and into possible cracks, imperfections and dead spots. These barrier properties can be utilized in that the zeolite can be placed at the highest risk of infection, for example, between an opening that connects the fluid to the environment, either as an additional measure or as allowing the amount of agent in the main volume of fluid to be reduced. Nothing prevents the system of the invention from combining with a final filtration step in which the low reagent content in the fluid is further reduced. This combination can be used either when the agent is to be recovered for disposal or returned to the zeolite to form a static antiseptic system that allows continuous processing of the fluid. The filled zeolites of the invention allow reversible controlled release of agents both when the fluid is a gas and when the fluid is a liquid, and the combined flexibility of the system allows adaptation of the invention to a variety of different applications, which will be indicated in the examples.

Other objects and advantages of the invention will become more apparent from the following description.

Definition

The term "system" should be understood in the context of the invention as one or more devices and / or compositions, methods, uses or combinations thereof. The terms "comprising," including, "having a" s, and similar terms should not be used in the case

01-2697-03-Ma in the absence of explicit determinations or in cases of obvious contradiction, it is understood that they are exclusively limited to the cited elements of the device, the compound and / or the components of the composition or the process steps, but should be understood to allow the presence of other elements, compounds and / or components, respectively, further steps. Similarly, the terms "interconnected," attached, "ordered," used, "between and similar terms should not be construed as covering exclusively direct contact between the cited elements but should be construed as permitting the presence of one or more intervening elements or structures . The same applies to similar terms when used to describe action or effect. Similarly, in the absence of explicit delineation or in the case of manifestly contradictory conditions, such terms should be understood to include compounds and / or components of the composition in any physical or chemical aggregation or mixture, optionally with intervening compounds and / or components, or aggregation status, as well. and operating steps in any time sequence.

Also, the term "microbes should be understood in the context of the invention as any organism capable of surviving in the form of individual cells in the presence of a nutrient or host organism, such as a protozoa such as amoeba, etc. In a narrower context, this term should be understood as" microorganisms , ie. bacteria and fungi of the fungal or yeast type.

For the purposes of the invention, terms such as "antiseptic conditions," antiseptic concentration, "antiseptic level," antiseptic efficacy and the like should be understood to refer to conditions adapted and suitable for at least slowing growth, preferably arresting growth and most preferably killing at least one living microbe. ,

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·· 9 9 9 99 9 when in contact with any ingredient that may act as a nutrient for a microbe, however, these terms should not be construed as requiring the presence of such nutrition. Nor can these terms be construed as

required but the presence of microbes that include preventive situation. However, these expressions by should be understood as that they exclude situations and conditions, when is contact

or a residence time insufficient for any significant action between the antiseptic agent and the microbe. Sufficiency of antiseptic agent action against a single microbe should be seen in the possibility of using the filled zeolite as a buffer to release another antiseptic agent and in the repositioning of the liquid agent when the microbe absorbs or reacts with it in another way rather than having a liquid. an amount or concentration that allows it to effectively counter more than one or many microbes. Of course, the necessary amount of agent may vary depending on the use of different types of agents, for example, it may be low for antibiotics having a precise metabolic effect and high for agents having a more pronounced oxidative or deleterious effect. It follows from the foregoing that the terms defined above also include conditions commonly referred to, for example, as bacteriocidal and bacteriostatic.

Zeolite

Zeolites can be In general describe as crystalline forms aluminosilicate or of silicates with spatial by binding

tetrahedrons, which can be characterized by their chemical composition and crystalline structure. The chemical composition is usually expressed using the Si / Al ratio. High zeolites

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4 • 44 4 4 4 4 silica carry less charge and are generally referred to as hydrophobic. The opposite is true for zeolites with high alumina content, which are referred to as hydrophilic. It can be said that zeolites suitable for the purposes of the invention have the general structural formula (AlO ₂ ) _x (SiO ₂ ) _y , where the y / x ratio may have different values. Other ions, such as P, B, Fe, Ga, Ge, etc., may also be present in the crystalline lattice of the zeolite, which may to some extent replace the Al and Si ions, and these zeolites may also be used for the purposes of the invention. In this zeolite lattice, the cation is bonded to each aluminum atom or other atom with a maximum valency less than 4 and the anion is bonded to each atom with a maximum valency greater than 4. Zeolites may contain lower or higher amounts of water.

The crystalline lattice provides a porous system whose pores are highly uniform in size, but the pore size of the different types of zeolites may be somewhat different. The pores generally comprise a main cavity and inlet openings. The diameter of the main cavity ranges from about 0.3 nm to 1.1 nm for various zeolites, and the diameter of the inlet openings may be about 0.1 nm to 0.3 nm. These uniform pores are responsible for the high and selective absorbance of the zeolites and will be referred to herein as micropores. Furthermore, the zeolite crystal may have various micro-cracks due to its chemical and physical manufacturing and processing history, and these defects are not uniform and the use of zeolites with a low incidence or total absence of such defects is preferred for the purposes of the invention. Finally, the zeolite crystals are generally of limited size so as to form a powder or particulate matter. This mass can be used as such, for example, it can be suspended in a liquid to be absorbed. Sintering or ·

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01-2697-03-Ma by adding adhesive components such as benton; Phosphate glass can form the mass shape and size. In this process, macropores can be left between the particles. In the case of non-compacted powder and compact shapes, the macropores between the crystalline particles will be referred to as bulk porosity and expressed as the total volume of macropores to the total bulk volume of the zeolite mass. The bulk porosity can serve to allow the fluid to enter the macropores and contact the individual particles, while allowing the fluid to pass through the zeolite mass. A suitable volume porosity for these purposes may be at least 20%, preferably at least 30% and most preferably at least 35%, and inter alia for reasons of stability, the volume porosity should be at most 90%, preferably at most 80% and most preferably at most 75%. Of course, alternatively or in combination, other known means, for example thin channels passing through the bed or body of the zeolite, layers of zeolite, etc. may be used to create permeability and / or increase the contact surface between the fluid and the zeolite. / x 15 and below, will be considered hydrophilic, while zeolites with y / x ratios higher than 15 will be considered hydrophobic. Both types of zeolites can be used to achieve the objects of the invention. Hydrophilic zeolites can be used, for example, when the antiseptic agent is also hydrophilic. In the case of an ionic agent, the known possibility of affecting the affinity of the agent for the zeolite by altering the surrounding ionic properties, e.g., pH, by reducing the environmental affinity when the agent becomes non-ionic can also be used. This may be of interest in fine-tuning agent release, manufacturing self-regulating systems, or making equally loaded zeolite useful

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444 for various fluids. The hydrophilic zeolites may have y / x ratios of less than 15, for example less than 5, and even less than 1.

For the reasons outlined, it is often preferred to use hydrophobic zeolites, also referred to as dealuminized or ultra-stable zeolites, for example due to their high stability, the possibility of using a wide range of hydrophobic antiseptic agents and nonionic agents, the latter providing stable affinity properties independent of the ionic properties of fluids. Hydrophobic zeolites preferably have y / x ratios of greater than 100, more preferably greater than 200 and most preferably greater than 1000. Suitable types of zeolites may be, for example, silicalite, mordenite, and especially zeolite Y. With regard to micropore sizes, zeolite Y and mordenite are currently the largest known group with a pore diameter of approximately 0.7 nm and 0.75 nm, respectively, while silicalite has two different pore sizes of about 0.55 nm. Silicalite and zeolite Y have a three-dimensional porous system, while mordenite has a two-dimensional porous system and is therefore somewhat less accessible. Hydrophobic zeolites can be produced in a known manner, for example by direct synthesis (e.g. silicalite) or by manipulations following the completion of the synthesis (e.g. mordenite, zeolite Y), for example by alternating treatment with zeolite Y with a base such as ammonia and an acid such as hydrochloric acid (USY), or the zeolite Y is treated with silica chloride (DAY). In the case of zeolites obtained after post-synthesis manipulations, it has been found that alkali / acid treated zeolites exhibit faster adsorption and release but have a high tendency to adsorb high-mass proteins on the surface of particles, while the opposite properties have been found for silica treated zeolites.

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The zeolite by clogging can be used to modify the microporous as such or its desirable properties. For example, the risk of a system with larger molecules contained in a fluid can be reduced by coating the zeolite with a coating such as dextran or polyethylene glycol.

Antiseptic agent

In general, antiseptic agents useful for the purpose of the invention should be of a size that allows them to adapt in a microporous zeolite system. Atoms and ions such as Ag or Cu are readily adaptable and can therefore be used. Preferably, the agent comprises molecules that should be able to adapt in micropores, at least partially, in the case of long or branched molecules, but preferably the entire molecule should adapt. This imposes some limitations on the size of suitable molecules, so that the molecules should have roughly molecular weights of less than 3000, preferably less than 2000, and most preferably less than 1500. Compounds lying within these ranges, which can adapt in micropores, should be referred to as "low-mass," while larger molecules that are incapable of adaptation should be referred to as "high-mass molecules." Compounds and molecules should be understood to include aggregates, chelates, etc., as long as they are sufficiently stable to act as a unit against the micropores. According to a second general requirement, the agent should have sufficient affinity for at least one type of zeolite to be capable of being absorbed in a fluid in sufficient quantity for a given antiseptic condition, and at least in a small volume based on

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01-2697-03-Ma zeolite when in contact with liquid. As indicated above, compliance with this second requirement is generally controlled by the choice of the respective agent-zeolite pair.

Any low molecular weight antiseptic agent that meets the requirements outlined above may be used in the present invention. Purely oxidizing agents such as chlorine, hydrogen peroxide, etc., as well as completely toxic agents such as cyanide may be used, although it is preferred to use agents with a more selective effect. A suitable class of agents are antibiotics which, at low concentrations, inhibit the growth of microorganisms or kill microorganisms, for example clindamycin or penicillin. Preferred agents are those which are non-toxic to animals or humans or whose toxicity is only moderate and thus allow medical use. Antibiotics can be used which, depending on their biological mechanism, are divided into different groups, for example antibiotics which affect cell wall synthesis, protein synthesis, folic acid metabolism, nucleic acid synthesis, etc. Another suitable class of agents are so-called preservatives, e.g. halogenated compounds such as DDT, triclosan etc., or aromatic or polyaromatic compounds. For medical use, it is preferable to use preservatives whose use for these purposes is approved. Suitable compounds of this type may include benzyl alcohol, benzalkonium chloride, cetrimide, chorbutol, chlorhexidine, chlorocresol, hydroxybenzoates, phenylalcohol, phenoxyalcohol, phenylmercuronate, chloramphenicol etc. Good results were obtained with phenol and cresol, especially m-cresol.

The above breakdown and classification of reagents can be considered as indicative and not restrictive

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999 99 9 provided that all functional requirements are met. At the same time, mixtures and combinations of agents belonging to the same class or different classes and / or hydrophilic agents and hydrophobic agents may be used.

Filled zeolite

The zeolite may be loaded with the agent in any known manner, for example by contacting the agent in pure form or in a mixture, suspension, emulsion, etc. of the medium in liquid or gaseous form. For example, the contacting may be accomplished by static contacting the zeolite and the agent, mixing with each other or passing the agent through the zeolite, whereby the zeolite allows the agent to form a gradient in the zeolite. The contacting can be carried out at different temperatures, for example at elevated temperature, which speeds up the process. The zeolite may be subjected to various post-treatments such as sterilization by irradiation, chemical treatment, heating, etc., drying to provide a stable product for storage, or introduction into a device to prevent contact with the fluid, or various other processing steps to modify its Properties. All these operations are facilitated by the stability of the zeolite. Certain losses of reagent can be observed, for example, during heating or vacuum treatment, and such losses can be compensated, for example, by adding an appropriate amount of reagent before or after the start of these steps. For example, syringes pre-filled with the preparations may require a sterilization step, and if zeolite is present in these preparations, it will be subjected to the same treatment. Likewise, some preparations are subjected to freeze-drying or vacuum-drying

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And any zeolite present may be subjected to the same treatment. During these steps, some agent may be lost from the loaded zeolite, but this loss can be compensated by the corresponding initial overdose. It is also sometimes observed, especially at a high degree of filling, that part of the reagent is absorbed more freely than the main part of the reagent, possibly due to some absorption outside the micropores, for example on external surfaces or in micro cracks. It is advantageous to avoid inconsistency introduced by these factors, for example by subjecting the filled zeolite to a short rinse or elution step to remove the loosely bound reagent, or by introducing unfilled or less filled zeolite into the filled zeolite, This means that the agent released from the loaded zeolite is retained in the micropores of the subsequent zeolite and this process is repeated until the second zeolite reaches the same degree of loading as the main loaded zeolite.

The minimum requirement for reagent and zeolite in the filled zeolite is that the small volume of fluid for which the filled zeolite is intended to contact the filled zeolite reaches the minimum antiseptic level of the agent in the fluid after the concentration or distribution of the agent between the liquid and zeolite it basically reached equilibrium. These minimum conditions may be useful, for example, when the filled zeolite is used in contact with air, or maximally humidified air, as an antiseptic barrier. In general, it is preferred that there are more than a minimum of conditions, for example, when determining the amount of agent that must be present to achieve antiseptic levels in large volumes of fluid, for example, when volumes are predetermined.

01-2697-03-Ma ·················· 4 · 4 ··· Surrounding or passing through the zeolite, which will be sufficient for one or more doses of the formulation. These large amounts of agent can be provided either by increasing the volume of the zeolite having a low agent concentration, or preferably by increasing the concentration of the agent in the zeolite, for example to minimize the necessary amount of zeolite. For very large or unlimited volumes of fluid, it is preferable to maintain a minimum or limited level in the zeolite by continuous or batch exchange of the agent in the zeolite, either by adding a new agent or by isolating the agent from the already treated fluid and reintroducing it directly into the zeolite or be contacted with zeolite. It is also advantageous to increase the amount of agent in the zeolite above the minimum amount required, i.e. the amount of the zeolite required. above levels that ensure that the agent is present in an amount sufficient to provide a safe antiseptic concentration at minimum microbial exposure but at the same time sufficient antiseptic concentration at the worst expected bacterial infestation in the case. As already indicated, this can be achieved according to the invention without losing any significant increase in reagent concentration in the fluid, since the equilibrium between zeolite and fluid will allow repeated and consumption-regulating adjustment of antiseptic levels in the fluid to approximately the same reagent concentration. For best performance, it is preferred that the agent has a high affinity for the selected zeolite type. Affinity should be expressed herein as the amount of agent in the zeolite, the weight percent of the agent in the zeolite, at the maximum degree of saturation, i.e., the degree of saturation, where the zeolite is in contact with the pure agent for a time sufficient to stabilize. Expressed in this way, the maximum degree of saturation may be at least 10%, preferably at least 25%, and most preferably at least 50%. The maximum degree of saturation should be considered only as a calibration value and

01-2697-03-Ma * · · · · not to the degree to which zeolite must necessarily be filled when used. If the zeolite is filled to a high degree of saturation and provides substantially no columnar effect when it is in the contact described above, then a much higher amount will initially be released than later when the degree of saturation is reduced. The decrease in fluid concentration upon continuous or repeated fluid contact is relatively rapid and can be approximated by inverse linear, polynomial, or exponential function. High levels of saturation can be used where this concentration pattern is desired, for example, when a high initial cleaning concentration is required, followed by lower maintenance concentrations. However, in many cases, it is desirable to maintain a substantially constant concentration of the agent in the fluid upon contact with the filled zeolite, for example upon contact with large volumes of fluid or repeated dosing. To achieve this, the agent should be introduced into the zeolite such that the degree of saturation is less than the maximum degree of saturation, and preferably so low that the concentration drop curve achieves approximately constant behavior. By way of example, the amount of agent in the zeolite should be less than 50% of the amount corresponding to the maximum degree of saturation, preferably less than 30% and most preferably less than 10%. In the case of a combination of agent and zeolite with high affinity, this amount may be even lower. Generally, the ratio of the actual amount of agent to the amount of agent corresponding to a maximum degree of saturation is greater than 0.01%, more preferably greater than 0.1% and most preferably greater 1%. If there is a column effect on contact, then these conditions are less stringent. Assuming that the packed column is long enough to provide a substantially equilibrium concentration of reagent in the fluid, after the fluid passes through only a portion of the 01-2697-03-Ma column, there will be no passage of the last portions of the column no changes in the amount of agent in the zeolite or in the fluid and the outlet conditions will be constant. A highly important parameter for the purposes of the invention is the concentration of the agent in the fluid after equilibration with the filled zeolite. This concentration may be less than the concentration required when the principles of the invention are not applied, for example it may be less than 0.25 such a concentration, preferably less than 0.1 and most preferably less than 0.05 such a concentration. Absolute concentration values are difficult to obtain due to, for example, different antiseptic efficacy, different classes of agents and differences between technical and therapeutic applications. Typical applications are body injection fluids, where the concentrations of preservatives approved by the competent authorities reach approximately 2 mg / l to 3 mg / l where the above-mentioned general reduction is possible. Values of up to 0.01 mg / ml have been found to be still effective. It is equally difficult to obtain an absolute value for the zeolite loading, although the weight / weight loading ratios can be used as an indicator. agents to a zeolite greater than 0.1%, preferably greater than 1% and most preferably greater than 5% or even greater than 10% or greater than 20%.

The paragraph described above can only be considered as a guide. Adjustments to higher amounts of reagent may be necessary when the contact time between zeolite and liquid is too short to equilibrate, or when the combination of agent and zeolite reaches equilibrium too slowly. Similarly, temperature should be considered. Generally, the equilibrium concentration of the agent in the fluid that is in contact with a given filled zeolite will increase with temperature. At higher temperatures they may be • 4 4 4 · 4 4 • 4 4 4 4 4 · 4 4 4 • ·· 4 «4 · 4444

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01-2697-03-Ma more active and microbes. Although most often temperatures dictated by the use of constraints, the fluid / zeolite may be somewhat self-regulating.

Fluid

The system of the invention can be used for microbial growth in a wide variety of ways, it can be a pure substance or a mixture of ingredients of the same or different degree of aggregation. The gas may comprise liquid droplets or solid particles as a continuous phase. The liquid may comprise solid particles or liquid droplets as a continuous phase, and the compositions may be in the form of suspensions, emulsions, etc. The fluids may be free mixtures, for example air or aqueous solutions or mixtures, or complex mixtures whose content may even be unknown, or body fluid. It is preferred to use a system for fluids that do not interfere too strongly with the release mechanism described herein. The fluid should not contain only small amounts of compounds or compositions that tend to precipitate or adhere to the zeolite to the extent that they block micropores or macropores. The fluid should preferably not have too high a viscosity, for example, should have a viscosity of less than 10,000 mPa · ^e s, preferably lower than 1000 mPa.s and most preferably lower than 10 mPa · s. The fluid may contain compounds that compete with the agent in terms of affinity for the zeolite, for example, in providing a control means for releasing varying amounts of the agent, depending on the amount of such a competing compound present or delivered. The competing compound may then have a similar affinity for the zeolite as the agent, or even a higher affinity than the agent, for example greater than twice, preferably, more preferably twice as high, preferably. • · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

01-2697-03-Ma is greater than 10 times, and most preferably greater than 20 times the affinity of the agent. Such agents should also be understood to include typical elution media, for example, media that affect the absorbed agent to a degree of lower affinity for the zeolite, for example, by reducing or increasing its ionic character in the case of hydrophilic and hydrophilic, respectively. hydrophobic zeolites. However, for the reasons outlined, it is often preferred that constant agent release means a substantially constant level of agent in the fluid. For these reasons, it is preferred that the liquid contains only a small amount of compounds that compete with the agent in terms of affinity for zeolite, i.e., compounds that are low molecular weight in the sense discussed above and have a high affinity for zeolite. The fluid may contain a high amount of low molecular weight compounds, provided that the compounds have a lower affinity for the zeolite than the agent, for example an affinity that is at most 0.5 times the affinity of the agent, preferably at most 0.1 times and most preferably at most 0.05 times the affinity of the agent. These compounds may be air or water molecules having low affinity for hydrophobic zeolites or small nonionic molecules having low affinity for hydrophilic zeolites. Equally well, the fluid may contain large amounts of high molecular weight compounds, since they do not tend to be absorbed by the zeolite, regardless of their hydrophobic or hydrophobic properties. hydrophilic properties. It is often advantageous to use the invention in conjunction with fluids containing such compounds, for example in conjunction with medical preparations, where the compounds may be, for example, proteins, polypeptides, sugars, nucleic acid sequences, etc., where the zeolite properties do not absorb these large species. of molecules. As a rough guide we can use the definition of "large

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9 99 99 999 9 * 99

99,999 ·

The amount may be greater than 0.01 mg / ml, preferably greater than 0.1 mg / ml, and most preferably greater than 1 mg / ml. Similarly, the term "small amount" may denote an amount less than that defined by these values. The advantages of the invention are particularly noticeable when the fluid contains nutrient components for microbes, and in particular when the nutrients are present in large quantities.

It is further advantageous in the application of the invention that there is no need to include preservatives in the fluid and that, therefore, the fluid contains no preservative at all or only a small amount in addition to the antiseptic, and preferably contains no other preservative.

Contact of liquid and zeolite

As indicated, the fluid and zeolite can be contacted in various ways. Contact can be made by maintaining a static fluid connection with the zeolite, which generally depends on the diffusion of the agent from the zeolite into the fluid, whereby concentration gradients are achieved throughout the fluid volume before saturation of the fluid. Contact can also be made by the relative movement between the fluid and the zeolite, for example by stirring the fluid or forcing the fluid stream to pass through the zeolite, which generally results in a lower concentration gradient in the fluid. The zeolite may be present in the form of particles suspended in a liquid which generally provides a small concentration gradient of the agent in the zeolite. The zeolite may be present as a coating on the surface in contact with the fluid or in the form of a bed or column through which fluid flows, in which case the result is a concentration gradient of the agent in the zeolite increasing as it passes from the front of the zeolite to the back. The advantage of the bed or column is also ease

01-2697-03-Ma • 9 9 9 9 9

9 9 9 9 9 9

99 9 99 99 9 9 9 9 contact with the entire fluid, providing an additional barrier effect and providing bulk porosity that can be filled with the fluid, thereby improving contact between the fluid and the zeolite. A column that is not insignificant in length may also serve to maintain highly constant concentrations of agent at the outlet of the column by already saturating the inlet or in the middle portions of the column and maintaining a substantially constant amount of agent in the zeolite at the outlet. In all embodiments, the concentration of the agent in the fluid upon contact with the zeolite generally increases, at least initially and provided that no equilibrium has been reached upon earlier contact or prior filling. It is preferred that equilibrium is reached or nearly equilibrium is achieved, for example, when storing a liquid for a sufficiently long time in contact with the filled zeolite. However, achieving this equilibrium may not always be necessary, and it may be sufficient to achieve an acceptable antiseptic concentration level, for example to avoid too long contact times due to the rate of reagent / zeolite combination, for example, in flowing fluid systems. This may also be possible and advantageous to obtain static conditions at a suitable antiseptic level. Generally, contact can be achieved in batch operation, intermittent operation, or continuous contact. The batch or intermittent operation has certain advantages, at least in the case of smaller fluid volumes, when using a zeolite bed or column having sufficient bulk porosity to accommodate most of the fluid in the macropores, and most preferably the entire volume of fluid in the macropores, the entire volume of fluid. This, among other things, optimizes contact conditions during the available residence time. During intermittent operations, it is preferred that the volume of fluid

01-2697-03-Ma · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · the dose or, in the case of varying doses, corresponds to the highest dose considered.

Composition

As already mentioned, the filled zeolite is, due to its excellent barrier properties, usable as such and can subsequently only be adapted for specific applications where it is to be used as a barrier, for example processed into a sealing part or inserted into a sealing part or designed as a patch the part to be protected, for example to cover the wound. A preferred composition has at least a fluid chamber in combination with a zeolite. The chamber may be open, for example an open container, or closed, for example a vial, or may be part of a pipeline such as a transport channel through which fluid is led into the zeolite. In such compositions, the filled zeolite may serve to maintain a sterile content, act as a barrier, for example, during opening of the container to prevent contamination, or serve to increase the concentration of the agent in the fluid when the fluid passes through the zeolite or preferably through the zeolite. . A further preferred composition is to have a first chamber, a second chamber, and a filled zeolite arranged so that the fluid comes into contact with the zeolite at least as it passes from the first chamber to the second chamber to increase the reagent content of the fluid. Such a composition may, for example, be part of a fluid transport channel to control microbial growth or part of a fluid transport assembly. For these reasons, it is preferable to use zeolite in the form of a bed or column that allows fluid to pass through the bed.

01-2697-03-Ma

4 · 44

4 «4 4 4 4 4 4« 4 4 4 4 4 4 4 4 · 4 • 4 4 4 4 4 4 4 444

4 4 4 4

443 4 «4 44 4 44 ·

Although the compositions are intended to interact with a fluid, they should be considered as part of the system of the invention when applicable or adapted to the purposes of the invention. The compositions may also be useful when the fluid does not necessarily come into contact with the zeolite, for example when the zeolite is used as a safety measure, which, for example, is activated only when the seal is unwanted or otherwise destroyed. In some cases, these constraints are intentionally introduced, for example, in assemblies that contain valves, rupture, puncturable or removable membranes or other sealing elements that allow fluid contact at a controlled time, for example in the case of activation or opening of a pre-filled device.

The generally indicated compositions can be adapted to a variety of applications, and these specific applications can affect the detailed execution of the compositions. In addition to the applications already indicated, other applications are contemplated, some of which will be illustrated by way of example in the following description and in the accompanying drawings.

Brief description of the pictures

Giant. 1 schematically illustrates a flow diagram of a contemplated equilibrium system according to the invention under idealized conditions.

Giant. 2 schematically shows the elution curve of a zeolite after loading to a high degree of saturation.

01-2697-03-Ma ··· 9 · 9 · 9 · 9

9 9 9 9 9 9 9 9 9 9 9

Giant. 3 schematically shows a zeolite bed in the form of a column having a length sufficient to create gradients of the amount of agent in the zeolite.

Giant. 4 schematically illustrates various zeolite compositions in conjunction with a single chamber.

Giant. 5 schematically illustrates various zeolite compositions in conjunction with a pre-chamber and a subsequent chamber.

Giant. 6 is a graph showing the results of Example 1.

Giant. 7 is a graph showing the results of Example 2;

Giant. 8 is a graph showing the results of Example 5

Giant. 9 is a graph showing the results of Example 6

Giant. 10 is a graph showing the results of Example 7.

Giant. 1 schematically illustrates a flow diagram of a contemplated equilibrium system according to the invention under idealized conditions. The left square illustrates the filled zeolite 1, the middle square illustrates the fluid 2 that is in contact with the filled zeolite 1, and the right square illustrates the microbes 3 present in the fluid. The zeolite and the fluid are in a reciprocal equilibrium state as illustrated by arrows 4 and 5. Similarly, microbes and fluid are in the equilibrium state, as indicated by arrows 6 and 7. Arrow 4 indicates the flow of reagent from zeolite to the fluid, for example, initially when the fluid contains less than the equilibrium concentration or in any situation where the reagent content in the fluid it will fall below saturation, for example in conjunction with microbial reagent consumption or when new fluid is added. Arrow 5 indicates upstream • 4 4444 »4 4» 4 4 4 4 • 4 4 4 4

4 * 44

01-2697-03-Ma reagents from the fluid to the zeolite that occur when the fluid becomes supersaturated, for example, when the liquid fluid evaporates or if the microbes release the agent upon its disappearance. In most applications, the reverse flow of the reagent indicated by arrow 5 is less important than the flow indicated by arrow 4. Arrow 6 indicates the flow of reagent from the fluid to the microbes, provided that the microbes are present. The consumption of the reagent indicated by the arrow 6 may result in a decrease in the concentration of the reagent in the fluid 2 and a restoration of the flow of the reagent from the zeolite 7 to the fluid 2 as indicated by the arrow 4. The arrow naznač indicates the theoretical possibility of releasing the microbes into the fluid 2. death and decomposition, which in turn may result in an adequate equalizing flow of the agent back into the zeolite in the direction of arrow 5. The flow indicated by arrow 7 is highly dependent on the mechanism running between the agent and microbes and may not occur in every situation. This is not the case, for example, when dead microbes are removed from the system. It should be noted that the right square may also illustrate any component or disorder, other than microbes, that destroys or consumes the agent from the fluid 2, for example an impurity in the fluid or a compound in a complex liquid preparation to which the agent may bind, which may be absorbed, etc. It is clear from the above that the illustrated system is highly resistant to any form of failure or any form of reagent consumption. For purposes of the invention, it is desirable to maintain the concentration of the agent in the fluid 2 at an antiseptic level and generally at a relatively low level, which makes the fluid much less harmful than if the buffering capacity of the filled zeolite is not used. The rate at which the system approaches the moment of disruption to create a new equilibrium state may vary. In general, the equilibrium between zeolite and liquid occurs in the liquid. ···· · · · · · · · · · · · ·

01-2697-03-Ma relatively quickly at their interface but slower in cases where diffusion is required to bring the volume of fluid that is not in contact with the zeolite into contact with the zeolite. Mixing or fluid flow can be used to accelerate this process if diffusion is necessary. The equilibrium between fluid and microbes is highly dependent on the antiseptic mechanism and may be slower, but this is generally not more relevant to the overall performance of the system.

Giant. 2 schematically shows an elution curve 20 for a zeolite which is initially filled to a high degree of saturation. The vertical axis 21 represents the concentration of the agent in contact with the zeolite, and the horizontal axis 22 represents the fluid volume or the number of resuspensions. It can be said that the continuous curve 23 represents the pattern that is obtained when continuous contact of the fluid with the zeolite is made, and the discrete values 24 represent the concentrations achieved when the repeated batch contact is made. The curve shows that a high initial concentration of agent in the fluid, as represented by point 25, is obtained and this concentration decreases rapidly until additional volumes of fluid or resuspension provide a substantially constant concentration of agent in the fluid. The dashed lines 26 and 27 represent roughly the top and bottom respectively. a bottom loading stage that will provide a substantially constant concentration of agent in the treated fluid. A suitable initial charge of the zeolite may be obtained by overfilling it and subsequently washing or evaporating the reagent up to the dashed line 26 level, or preferably by filling the zeolite to a level corresponding to the dashed line 26, for example using a diluted filler fluid. It should be noted that the curve represents the amount of agent in the fluid and not in the zeolite. If the agent has a high affinity for zeolite, 111

9111 ·

120 9 11

1111 1 111

I 1 19 11111

II 119 1

1912 11 1

01-2697-03-Ma then the zeolite may contain an enormous amount of reagent despite the fact that the concentration in the fluid is low, allowing large volumes of fluid to be contacted or innumerable repetitions of contact while maintaining a substantially constant concentration of agent in the effluent. It should further be emphasized that the curve shown in Fig. 2 is typical of contact patterns where no significant deviations or gradients of the reagent amount occur in the zeolites, for example in the absence of column effects. Such an equilibrium state can be achieved, for example, when the zeolite is mixed or randomly mixed with the liquid or when the zeolite bed is thin or shallow.

Giant. 3 schematically illustrates a zeolite bed composition 30 in the form of a column 31 with a length sufficient to create gradients of the amount of agent in the zeolites. If the residence time of the fluid is sufficient relative to the speed of the equilibrium system, then the fluid will typically be saturated with the reagent during the passage of the upper fraction of the column height and pass through the remainder of the column without further reagent exchange between zeolite and liquid. . This will allow a highly constant concentration of the agent in the outlet fluid in the case of large volumes of fluid until the column releases the agent to such an extent that passage through the entire column is sufficient to provide the target concentration. The column 31 shown in FIG. 3 has an inlet end 32 and an outlet end 33. Initially, prior to contact with the fluid, it is assumed that the column has a constant reagent load over its entire length. The fluid is then routed from the inlet end 32 of the column 31 as shown by the arrow 34 to the outlet end 33 as shown by the arrow 35. After some

01-2697-03-Ma · «·· ·

• 9 9 9 9 9 • 9 9 99

9 9 9 999 9 99

9 9 9 9 9 9 ·· · «» 99 9 The operating conditions are as shown. Generally, a dynamic boundary line is shown, represented by the dashed line 36, which separates the lower portion 37 of the unchanged reagent column from the upper portion 38 of the reduced reagent column. The fluid reaches a saturated concentration of reagent during the passage of the top 38 of the column, i.e. in the portion between the inlet end 32 and the boundary line defined by the dashed line 36, and in this portion of the column a gradient of the amount of reagent increasing from the inlet to the boundary line is formed. During the passage through the remaining bottom portion 37 of the column, i.e. from the boundary line shown by the dashed line 36 to the outlet end 33, there will be no substantial changes in the fluid or column and the column will have essentially its initial reagent content and no gradient will be formed. the fluid will have a constant outlet concentration. With the continuous introduction of fluid into the column, the boundary line defined by the dashed line 36 will gradually shift downward until it reaches the outlet end 33. The entire column will now have a gradient of agent amount decreasing towards the outlet end and the agent concentration in the fluid will begin to decrease. Unlike the situation shown in Fig. 2, it is no longer necessary to limit the degree of saturation from the beginning to obtain stable outlet concentrations. Instead, the column effect ensures a constant output concentration, independent of the initial degree of saturation. Very high or maximum saturation levels may also be used, although in the case where similar exit concentrations are to be achieved as in the system shown in Fig. 2, a combination of zeolite and a reagent with a stronger reagent to zeolite coupling should be selected.

Giant. 4 schematically depicts various compositions 40 in conjunction with a single chamber 41 containing a liquid therein

01-2697-03-Ma

Fluid 42. This chamber may be enclosed or may be part of a pipeline or larger system. as indicated by dashed line 43. The chamber has an opening 44 which is closed by a filled zeolite in the form of a fixed disc 45, for example consisting of zeolite particles arranged between the grids or preferably a sintered self-supporting body. The filled zeolite is exposed to the environment in the aperture 44 and may act as an antiseptic barrier to the chamber against microbial infection. In the position shown in Fig. 4, the liquid fluid 42 is not in contact with the zeolite disc 45 and the zeolite may be considered as a safety device, the liquid not necessarily having an antiseptic level of the agent. The aperture 44 also allows fluid to enter, for example by pouring or pumping, through the porous disk. The figure further illustrates another fixed zeolite composition having the form of a sheath 46 on the inner surface of the chamber. Due to the possibility of filling the zeolite with a high amount of reagent to achieve low concentrations in the fluid, it is often possible to use a relatively small amount of filled zeolite and thus only a partial sheath may be sufficient. The figure further shows an unfixed amount of zeolite 47, which is in the form of particles or powder and which can be stored in the chamber or stirred to suspend it. The illustrated compositions can be used to protect chambers designed for various purposes or chambers of different sizes, for example, fluid storage tanks for large-scale production plants, in the event of interruption of operation of said apparatus.

Giant. 5 schematically illustrates various zeolite compositions 50 in conjunction with an anterior chamber 51 and a posterior chamber 52 for introducing a fluid flow into the anterior chamber as shown by arrow 53 and for extracting flowing fluid from the posterior chamber as shown by arrow 54. Between the chambers is

4

4 4 4 4 4

4,444 4 4 4 4

4,444 44,444

4 4 4 4 4

445 44 4

4444

01-2697-03-Ma is provided with filled zeolite either in the form of shells 55 on the walls or preferably in the form of a bed 56 through which the fluid is guided. The possibility of suspending the zeolite in particulate or powder form 57 in the inlet fluid stream indicated by the arrow 53 is also schematically indicated, whereby the zeolite in this form can be introduced into the inlet fluid stream through, for example, an inlet pipe 58 and collected e.g. This composition provides an additional control step in the sense that the filled zeolite that is fed to the feed line 58 can be externally manipulated to optimize its condition. , for example, by repeatedly replenishing the agent in an attempt to minimize the amount of zeolite required, or by adjusting the amount of agent or type of agent to varying conditions in the flowing fluid stream. The composition shown in this figure can also be adapted to a variety of fluid flow applications and to various sizes of compositions, for example, ranging from a small syringe to a large-scale or liquid purification plant.

The following examples are illustrative only and are not intended to limit the scope of the invention as set forth in the appended claims.

01-2697-03-Ma * · · φ φ φ φ φ φ φ • • • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

DETAILED DESCRIPTION OF THE INVENTION

Example 1

This example illustrates the release of m-cresol from zeolite with adsorbed m-cresol and is described with reference to the diagram shown in Figure 6.

After incubation with various concentrations of m-cresol, the zeolite was allowed to sediment and the supernatant was discarded.

Then, the zeolite was suspended in PBS (phosphate buffered saline) by suspending an amount corresponding to 20 mg of dry zeolite per ml and after 30 min to 60 min of incubation on a rocking table, the concentration of cresol in the supernatant was measured by absorption at 276 nm. the zeolite was suspended in a new portion of PBS. Again, the concentration of cresol in the supernatant was determined and the zeolite was resuspended in PBS.

Example 2

This example illustrates the release of m-cresol from zeolite containing adsorbed m-cresol and is described with reference to the diagram shown in Figure 7.

After incubation with 23.1 mmol of m-cresol, the zeolite was dried on a glass filter and repeatedly suspended in an amount of PBS corresponding to 5 mg to 20 mg of dry zeolite per ml. Between each suspension, the zeolite was incubated on a rocking table. Cresol concentrations in the supernatants were analyzed by absorption at 276 nm.

01-2697-03-Ma φ φ φ φ φ • • • · · · · φ φ

Example 3

This example illustrates growth inhibition of Staphylococcus aureus (ATCC 6538, CFU ml -1) after incubation with m-cresol adsorbed on zeolite. The test was performed according to Eur. Pharm. 2nd Ed. VIII 14 (1992), Efficacy of antimicrobial preservation.

The ultrastable zeolite Y (USY, 63 µm to 125 µm particles) was incubated with m-cresol 5 mg / ml, after which the zeolite was aspirated to dryness and further dried in a heated cabinet overnight. The adsorbed m-cresol zeolite was then suspended in PBS and incubated with Staphylococcus aureus at 37 ° C. The concentration of m-cresol in the zeolite suspension was 0.14 mg / ml.

Incubation time (h) Clean ^and Zeolite 50 mg / ml Free m-cresol ^b CFU / ml CFU / ml CFU / ml 0 5.8 x 10 ⁶ 5.8 x 10 ⁶ 5.9 x 10 ⁶ 2 5.4 x 10 ^δ 132 1.2 x 10 ² 4 6.3 x 10 ⁶ 25 24 8 7.9 x 10 ⁶ 13 3 24 5.5 x 10 ⁶ 6 0 48 9.1 x 10 ⁶ 0 0

^a Pure: zeolite without adsorbed m-cresol (25 mg / ml) ^b 5 mg of m-cresol / ml dissolved in water as a positive control

01-2697-03-Ma ···· »· · · · · · · ·

9 9 »· * · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 4

This example illustrates the growth of inhibition of Staphylococcus aureus (ATCC 6538, CFU ml-1) after treatment with m-cresol adsorbed on zeolite.

The test according to Eur. Pharm. 2nd Ed. VIII 14 (1992), Efficacy of antimicrobial preservation. Dealuminated zeolite Y (DAY, 63 µm to 125 µτη particles) was incubated with 5 mg / ml m-cresol, after which the zeolite was aspirated to dryness and further dried in a heated cabinet overnight. The zeolite was then suspended in phosphate buffer (0.3336 mg / ml monosodium phosphate, 0.7064 mg / ml disodium phosphate) with 0.2 mg glycine / ml and 41 mg mannitol / ml with and without the addition of growth hormone (GH). whereupon the zeolite was incubated with Staphylococcus aureus at 37 ° C.

Incub. time Net* 30 mg / ml zeolite (z ·) 30 mg / ml z + GH 5 mg / ml 30 mg / ml z + GH 1 mg / ml 50 mg / ml z + GH 5 mg / ml (h) CFU / ml CFU / ml CFU / ml CFU / ml CFU / ml 0 6.2 x 10 ⁶ 6.4 x 10 ⁶ 6.4 x 10 ⁶ 6.4 x 10 ⁶ 6.4 x 10 ⁶ 1 6.3 x 10 ⁶ 5.9 x 10 ⁴ 8.1 x 10 ⁴ 7.2 x 10 ⁴ 8.7 x 10 ³ 4 6.1 x 10 ⁶ 3.3 x 10 ⁴ 3.2 x 10 ⁴ 6.9 X 10 ⁴ 3.3 x 10 ³ 8 5.8 X 10 ⁶ 1.2 x 10 ⁴ 8.5 x 10 ³ 5.7 x 10 ⁴ 1.6 x 10 ³ 24 4.9 x 10 ⁶ 7.9 x 10 ³ 1.8 x 10 ³ 2.2 x 10 ⁴ 7.4 x 10 ² 48 4.7 x 10 ⁶ 3.6 x 10 ³ 1.6 x 10 ² 6.7 x 10 ³ 73

^and Pure: only phosphate, glycine, mannitol

01-2697-03-Ma

49 »4 • 4 4 ·· 4 4 4 4 9 · 4 • 4 4 4 4 4 4 4 4

4,444 4,444 4,494

44 4 4 4 4 · «« 9 ·· 443 44 ·

Example 5

This example illustrates the adsorption of benzalkonium chloride to ultra-stable zeolite Y (USY) and is described with reference to the diagram shown in Figure 8.

Benzalkonium chloride (156 mg / ml to 20 mg / ml) was incubated for 60 min on a rocking table with 25 mg of ultrastable zeolite Y per ml (USY 63μτη to 125 µm particles). The amount of free benzalkonium chloride was determined by absorption at 263 nm and the amount of benzalkonium chloride adsorbed on the zeolite was calculated.

Example 6

This example illustrates the release of benzalkonium chloride from ultra-stable zeolite Y (USY) and is described with reference to the diagram shown in Figure 9.

The ultra-stable zeolite Y (USY 63pm to 125pm particles) was incubated with 5 mg / ml benzalkonium chloride, then the zeolite was aspirated to dryness and further dried in a heated cabinet overnight. The adsorbed benzalkonium chloride zeolite was repeatedly suspended to 20 mg / ml, first in PBS () and then in 95% ethanol (4). The concentration of benzalkonium chloride in the solutions was determined based on absorption at 263 nm.

Example 7

This example illustrates the release of cephalothin from ultra-stable zeolite Y (USY) and is described with reference to the diagram shown in Figure 10.

01-2697-03-Ma • 9 * 9 · 9 ····· · 9 · 9 · 9 · 9 999

9 9 9 9999 999 9 9 9 9 9

9 · · 99 ·· ·

The ultrastable zeolite Y (USY) was incubated with the antibiotic cephalothin 5 mg / ml, after which the zeolite was aspirated to dryness and further dried in a heated cabinet. The zeolite with adsorbed cephalothin was repeatedly suspended to 20 mg / ml in 10 mmol of glycine pH 2.5 () and the concentration of cephalothin in the solutions was determined by measuring absorption at 260 nm. Then the zeolite was suspended in 10 mmol of phosphate buffer pH 8.0 (9). The pH change caused the deprotonation of cephalothin and the loading introduced resulted in increased release of cephalothin from the zeolite.

Example 8

This example illustrates the adsorption and release of various antibiotics. Ultrastable zeolite Y (USY) was incubated with various antibiotics and the amount absorbed on the zeolite was calculated. Then the zeolite was dried and suspended to 20 mg / ml in buffer and the concentrations of the released antibiotics in the solution were determined.

Antibiotic Amount adsorbed antibiotics / mg zeolite Antibiotic amount in 20 mg zeolite / ml Concentration relaxed antibiotics Ampicillin 0.14 mg 2.8 mg / ml 400 pg / ml Cephalothin 0.21 mg 4.2 mg / ml 4.6 pg / ml Chloramphenicol 0.125 mg 2.5 mg / ml 7 pg / ml Gentamycin 0.18 mg 3.6 mg / ml nezj ištěno Streptomycin 0.48 mg 9.6 mg / ml 4800 pg / ml Tetracycline 0.09 mg 1.8 mg / ml 220 pg / ml

01-2697-03-Ma ··· «· <· · • • • • • • -2 -2 -2 • -2 -2 -2 -2 -2 • 9 9 9 9 9 • 9

Example 9

Dealuminated zeolite (DAY; 63 µm to 125 µm) was loaded with m-cresol (10 mg / ml) at a zeolite content of 40 mg DAY per ml of m-cresol solution. E. Coli suspension (CU1867, ATCC 47092) was mixed with unfilled zeolite and the zeolite was filled with m-cresol and allowed to sediment for 5 min. The supernatant was discarded and the settled zeolite with the remaining limited bacterial suspension (8 x 10 ⁶ colony forming units, CFU) was incubated at room temperature. After 18 h, the sediment was resuspended and the CFU count was determined after loading on LB-agar. The assay was performed in buffer (0.3336 mg / ml monosodium phosphate, 0.7064 mg / ml disodium phosphate, 2 mg / ml glycine and 41 mg / ml mannitol) and in a buffer containing growth hormone (GH, 5.5 mg / ml). ml). The distribution obtained from both assays is shown below in CFU.

Zeolite Y containing cresol Control zeolite Y (without m-cresol) Zeolite in buffer 2.2 x 10 ⁶ +/- 0.1 x 10 ⁶ 67.5 x 10 ⁶ + / 38.9 x 10 ⁶ Zeolite in buffer and growth hormone 2.1 x 10 ⁶ +/- 0.4 x 10 ⁶ 122.5 x 10 ⁶ +/- 17.7 x 10 ⁶

Example 10

Dealuminated zeolite (DAY; 63 µm to 125 µm) was loaded with m-cresol (10 mg / ml) at a zeolite content of 40 mg DAY per ml of m-cresol solution. E. coli suspension (CU1867, ATCC 47092) was filled with zeolite, mixed with m-cresol, unfilled zeolite and allowed to sediment for 5 min. The supernatant was discarded and the settled zeolite with the remaining limited bacterial suspension (8 x 10 ⁶ colony forming units, CFU) was incubated at room temperature and at room temperature, respectively. at ·· ···· · ·

01-2697-03-Ma +7 ° C. The assay was performed in LB-medium and after 18 h at room temperature and after 2.5 days at +8 ° C, the sediments were resuspended and the CFU count was determined after loading on LB-agar. The results are shown below in CFU.

Zeolite Y containing cresol Control zeolite Y (without m-cresol) Zeolite at room temperature 4.1 x 10 ⁴ 10,000 x 10 ⁴ Zeolite at 8 ° C 16.3 x 10 ⁴ 14.7 x 10 ⁴

Claims (72)

A composition for controlling microbial content or growth in a fluid comprising a) a zeolite with micropores filled with an agent having an affinity for zeolite micropores and antiseptic properties, and b) a fluid wherein the fluid is enclosed in the zeolite or at least partially in contact with the zeolite and fluid; or the zeolite and the fluid are arranged to come into at least partial contact, characterized in that the fluid comprises the therapeutically active compound or composition in a therapeutically effective amount and concentration, wherein the total amount of agent in the zeolite is greater than the amount corresponding to the antiseptic level for the fluid . Composition according to claim 1, characterized in that the zeolite micropores have main cavities of uniform size ranging from 0.3 nm to 1.1 nm. Composition according to claim 1, characterized in that the zeolite comprises a powder or particulate matter. The composition of claim 1, wherein the zeolite comprises a bonded particulate or particulate mass structure. Composition according to claim 4, characterized in that the bulk porosity of the structure is at least 20%, preferably at least 30% and most preferably at least 35% and preferably 01-2697-03-Ma • ···· ··· 4 ··· 44 4 44 4,444 444 4 4 4444 4444 4 44 44 4444 4444 4444 44444 44 4 at most 80%, more preferably at most 70% and most preferably at most 65%. The composition of claim 1, wherein the zeolite comprises a hydrophobic zeolite, the zeolite having the general structural formula (AlO ₂ ) _x (SiO ₂ ) _y , wherein the y / x ratio is at least 15, preferably greater than 100, more preferably greater than 200 and most preferably greater than 1000. The composition of claim 1, wherein the agent comprises, consists essentially of, or consists of molecules having molecular weights of less than 3000, preferably less than 2000, and most preferably less than 1500. The composition of claim 1, wherein the agent comprises at least one antibiotic. The composition of claim 1, wherein the agent comprises at least one preservative. Composition according to claim 9, characterized in that the preservative comprises a substance selected from benzyl alcohol, benzalkonium chloride, chorbutol, chlorhexidine, chlorocresol, hydroxybenzoates, phenylalcohol, phenoxyalcohol, phenylrtuenitrate, chloramphenicol, phenol, cresol, especially m-cresol, and combinations thereof. consisting of cetrimide, 01-2697-03-Ma Composition according to claim 1, characterized in that the affinity of the zeolite agent, expressed as w / w. the amount of agent in the zeolite at the maximum degree of saturation is at least 10%, preferably at least 25%, and most preferably at least 50%. Composition according to claim 1, characterized in that the weight / weight of the composition of the composition of the composition of the composition of the composition of the composition of the present invention is 12%. the amount of agent in the zeolite is less than 100% that corresponds to the maximum degree of saturation, preferably less than 50%, more preferably less than 30% and most preferably less than 10%. Composition according to claim 1, characterized in that the weight / weight of the composition of the composition of the composition of the composition of the composition of the composition of the composition of the composition. the amount of agent in the zeolite is greater than 0.01% of the amount corresponding to the maximum degree of saturation, preferably greater than 0.1%, and most preferably greater than 1%. The composition of claim 1, wherein the amount of agent introduced into the zeolite is adapted to be released into the fluid at an antiseptic concentration upon contact with the fluid. The composition of claim 1, wherein the zeolite forms a column having a length sufficient to provide a substantially equilibrium concentration of the agent to the fluid upon partial passage through the column. The composition of claim 1, wherein the fluid comprises a gas. • · · · · · · · · · · · 01-2697-03-Ma 17. The composition of claim 1, wherein the fluid comprises a liquid. The composition of claim 1, wherein the fluid comprises low weight molecules having a lower affinity for zeolite than the agent. The composition of claim 18, wherein the affinity of the low weight molecules is at most 0.5 times _; preferably at most 0.1 times, and most preferably 0.05 times the affinity of the agent. The composition of claim 1, wherein the fluid comprises high-weight molecules. Composition according to claim 20, characterized in that the amount of high-weight molecules is greater than 0.01 mg / ml, preferably greater than 0.1 mg / ml and most preferably greater than 1 mg / ml. 22. The composition of claim 20, wherein the high weight molecules comprise a molecule selected from the group consisting of proteins, polypeptides, sugars, nucleic acid sequences, lipids, or mixtures thereof. . 23. The composition of claim 20, wherein the high weight molecules comprise at least one therapeutically active compound or composition. • · · · ·· 01-2697-03-Ma • • • < 24. The composition of claim 1, wherein the fluid comprises nutrient components for microbes. A composition for controlling microbial content or growth in a fluid comprising a) a zeolite with micropores filled with an agent having an affinity for zeolite micropores and antiseptic properties; and b) a fluid wherein the fluid is enclosed in the zeolite or at least partially in contact with the zeolite and fluid; or the zeolite and the fluid are arranged to come into at least partial contact, characterized in that the fluid comprises molecules that are larger than the zeolite micropores and have less affinity for the zeolite than said agent. 26. The composition of claim 25, wherein the molecules form a therapeutically active compound or composition or form part of a therapeutically active compound or composition. The composition of claim 26, wherein the therapeutically active compound or composition is present in the fluid at a therapeutically effective concentration. 28. The composition of claim 25, comprising any feature of claims 1 to 24. 29. A method for controlling microbial content or growth in a fluid comprising a therapeutically active compound or composition in a therapeutically effective amount and / or concentration, wherein at least a portion of the composition comprises a therapeutically effective amount and / or concentration. 01-2697-03-Ma. í í * · *. . í • 9 · · · · The fluid is contacted with zeolite with micropores that are filled with an agent having affinity for zeolite micropores and antiseptic properties, thereby releasing the agent from the zeolite and increasing its content in at least a portion of the fluid. 30. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises maintaining the fluid in a substantially static relationship to the zeolite. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises moving the fluid relative to the zeolite. The method of claim 31, wherein moving the fluid comprises mixing the fluid and / or zeolite. The method of claim 31, wherein moving the fluid comprises conducting the fluid through the zeolite. 34. The method of claim 31, wherein moving the fluid comprises passing the fluid through the macropores in the zeolite. 35. The method of claim 34 wherein conducting fluid through a zeolite column of sufficient length provides a substantially equilibrium concentration of agent in the fluid before or at the end of the column. 01-2697-03-Ma 4 4 4 4 4 4 · 4 4 4 4 · 36. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises maintaining the fluid in a static relationship with the macropores in the zeolite. 37. The method of claim 36, wherein the antiseptic level of the agent in the fluid is substantially maintained during the static relationship. 38. The method of claim 29, wherein the agent content of the fluid is increased to an antiseptic level. 39. The method of claim 29, wherein the reagent content of the fluid is increased to a substantially equilibrium level relative to the reagent content of the filled zeolite. 40. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises batch contact between the fluid and the zeolite. 41. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises intermittent contact between more than one fluid dose and the zeolite. 42. The method of claim 41, wherein the intermittent contact comprises maintaining at least a portion of the fluid dose, and preferably the entire fluid dose, in a static relationship with the macropores in the zeolite. 01-2697-03-Ma • · <··· 4 · 4 4 4 4 4 4 4 4 _t 4,444 «4,444« 4,444 4444 4 4 4 4 # 44 444 ·· * 43. The method of claim 29, wherein contacting at least a portion of the fluid with the zeolite comprises continuous contact between the fluid and the zeolite. 44. The method of claim 43, wherein the agent in the zeolite is fed continuously or batchwise. 45. The method of claim 44, wherein the replenishment comprises introducing the agent into the fluid prior to contacting the zeolite. 46. The method of claim 44, wherein the replenishment comprises separating the agent from the fluid upon termination of contact with the zeolite and introducing it into the zeolite. 47. The method of claim 46, wherein the separation comprises extracting the reagent by contacting the fluid with a second reagent-free zeolite or which is loaded with less reagent than the zeolite. 48. The method of claim 29, including any feature of the preceding claims. 49. A method of controlling microbial content or growth in a fluid, comprising contacting at least a portion of the fluid with zeolite with micropores filled with an agent having an affinity for zeolite micropores and antiseptic properties, releasing the agent from the zeolite and increasing the agent content in at least a portion of the fluid, wherein 01-2697-03-Ma 444 · ·· 4 4 4 4 4 4 444 · 444 4,444 «444 4 4 4 4 4 The fluid contains molecules that are larger than the zeolite micropores and which have less affinity for the zeolite than the reagent. 50. The method of claim 49, wherein the fluid is a therapeutically active compound or composition in a therapeutically effective amount and / or concentration. 51. The method of claim 49, including any feature of the preceding claims. 52. A composition for controlling microbial content or growth in a fluid comprising a) a front chamber or duct, b) a back chamber or duct, c) a bed disposed between the anterior chamber and a back chamber in a manner that permits fluid passage from at least the anterior chamber through the bed and wherein the bed comprises zeolite with micropores filled with an agent having an affinity for zeolite micropores and antiseptic properties; and d) the fluid is present in at least the anterior chamber, the bed or the posterior chamber, characterized in that by which the zeolite is filled is adapted to said release of the agent to an antiseptic concentration of the agent in the fluid when the fluid comes into contact with the bed. 53. The composition of claim 52, comprising any feature of the preceding claims. 54. A composition for controlling microbial content or growth in a fluid comprising a) an anterior chamber or duct, b) a posterior chamber or duct, c) a bed disposed between 01-2697-03-Ma φ · · · · · · přední přední φ * přední * přední * přední * přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední přední and (d) the fluid is present in at least the anterior chamber, the bed or the posterior chamber, characterized in that the improvement is that at least the volume of fluid behind the bed contains the antiseptic concentration of the agent. 55. The composition of claim 54, comprising any feature of the preceding claims. 56. A method of controlling microbial content or growth in a fluid, comprising: a) providing a bed of zeolite with micropores filled with an agent having affinity for zeolite micropores and antiseptic properties, and macropores that allow fluid to pass through the bed; and b) at least a portion of the fluid is passed through the bed in a manner that allows release of the agent from the zeolite and increasing the agent content in at least a portion of the fluid to an antiseptic concentration of the agent. 57. The method of claim 56, including any feature of the preceding claims. 58. A hydrophobic zeolite with micro-pores having the general structural formula (A1O _{2) x} (SiO _{2) y} wherein the ratio y / x is at least 15, characterized in that the improvement consists in the fact that the zeolite micro-pores are filled with an antiseptic agent in 01-2697-03-Ma • φ φ φ φ φ ΦΦΦ Φ Φ Φ 9 9 9 9 99 999 Φ Φ Φ Φ Φ Φ ΦΦΦ ΦΦΦ Φ Φ ΦΦΦ Φ Φ Φ * An amount corresponding to more than 10% of the amount of the agent at maximum zeolite saturation, the absolute amount of the antiseptic agent being greater than 1% w / w based on the weight of the zeolite. Zeolite according to claim 58, characterized in that it is filled with an antiseptic agent in an amount corresponding to more than 25% and preferably more than 35% of the amount of the agent at maximum saturation of the zeolite. 60. The zeolite of claim 58, wherein the zeolite is filled with an absolute amount of an antiseptic agent greater than 5% w / w based on the weight of the zeolite. 61. The zeolite of claim 58 wherein said improvement is that the zeolite is dry. 62. The zeolite of claim 58, comprising any feature of the preceding claims. 63. Use of a hydrophobic zeolite with micro-pores having the general structural formula (A1O _{2) x} (SiO _{2) y} wherein the ratio y / x is at least 15, wherein the zeolite micro-pores are filled with an antiseptic agent for controlling microbial content or growth in a fluid, wherein the fluid and the filled zeolite are brought into contact with each other, thereby increasing the concentration of the antiseptic agent in the fluid to an antiseptic effective concentration. 01-2697-03-Ma · <·· ·· ··························· 9 9 99 ·· · * ··· ·· * Use according to claim 63, wherein the feature according to the preceding claims. includes any 65. A method of controlling microbial content or growth in a fluid, characterized in that a) providing a hydrophobic zeolite with micro-pores having the structural formula (A1O _{2) x} (SiO _{2) y} wherein the ratio y / x is at least 15, and micropores filled with an antiseptic agent and b) the fluid is contacted with the zeolite, thereby increasing the antiseptic agent in at least a portion of the antiseptic effective concentration. concentration of liquid to 66. The method of claim 65, wherein the fluid is maintained in contact with the zeolite for a time sufficient to produce an antiseptic effect against the microbes. 67. The method of claim 65, wherein the fluid is removed and a new portion of the fluid is contacted with the zeolite. 68. The method of claim 65, comprising any feature of the preceding claims. 69. A method for controlling microbial content or growth in a fluid, comprising: a) contacting the first portion of the fluid with zeolite with micropores filled with an agent having affinity for zeolite micropores and antiseptic properties, thereby releasing the agent from zeolite and increasing the zeolite agent; b) the first portion of the fluid is kept static 01-2697-03-Ma · ··· • · * · * · ··· «« «· 1 · «• · ·· ♦ 1 · * 9 · 1 11 119 11 9 1 11 1 111 11 1 911 C) contacting the zeolite under antiseptic conditions, c) contacting the first portion of the fluid with contact with the zeolite having a limited reagent content, and d) contacting the second portion of the fluid with the zeolite having said limited reagent content. 70. The method of claim 69, comprising any feature of the preceding claims. 71. A method of controlling microbial content or growth in a fluid, comprising: (a) contacting the first fluid portion with zeolite with micropores filled with an agent having affinity for zeolite micropores and antiseptic properties, thereby releasing the agent from the zeolites and increasing the zeolite; b) a first portion of the fluid is brought out of contact with the zeolite, c) at least a portion of the agent is separated from the first portion of the fluid, d) at least said portion of the agent is added to the second portion of the fluid, and e) said second portion of the fluid is contacted with zeolite. 72. The method of claim 71, comprising any feature of the preceding claims.