System, method and process for self-sterilization of an iodine-containing device

Abstract

A method and system for sterilizing an iodine disinfectant solution are disclosed. The iodine disinfectant solution can contain crystalline iodine and / or povidone iodine (PVP-I). The method includes supplying the iodine disinfectant solution to a sealed container. During the sterilization cycle, the method further includes heating the iodine preservative solution within the sealed container to a sterilization temperature sufficient to produce free elemental iodine within the sealed container. The method further includes applying a positive pressure within the sealed container to pressurize the free elemental iodine to produce sterilized iodine within the sealed container.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 345,383, filed May 24, 2022. This application is hereby incorporated by reference in its entirety.

Background Art

[0002] Regulations regarding the sterilization requirements of disinfectants vary widely around the world. In some jurisdictions, such as most of the countries in the European Union (EU), a certain degree of sterilization is mandatory. However, currently in the United States, there are no regulations regarding the sterilization of disinfectants, so disinfectants currently sold in the United States generally do not undergo a sterilization process. For example, currently, the pre - treatment of the skin before a patient's surgery is not required to be sterile.

[0003] In December 2012, the U.S. Food and Drug Administration (FDA) solicited opinions on how to address microbial contamination of the skin pre - treatment before a patient's surgery. In July 2021, the FDA advised manufacturers of aqueous pharmaceutical products that do not undergo sterilization that the Burkholderia cepacia complex (BCC or "B.cepacia") continues to pose a significant contamination risk to such products. At that time, in particular, there were numerous incidents of disinfectants such as chlorhexidine gluconate, povidone - iodine, and chloroxylenol being contaminated by bacteria. Bacteria can contaminate these products during manufacturing, storage, or use. Contaminated skin pre - treatment before a patient's surgery is associated with clinical infections and adverse outcomes. Therefore, it is necessary to sterilize disinfectants.

[0004] Currently, the disinfectants used in hospitals include the following known ones. That is, those containing 2-4% weight / volume of chlorhexidine gluconate in water or in water containing 70% volume / volume of alcohol, povidone iodine solution, where povidone iodine is contained in water in the range of 0.5% - 10%, or in water containing 70% alcohol, and 3%-4% chloroxylenol (PCMX) containing a surfactant in water. Conventional methods for sterilizing disinfectant products include heat sterilization (i.e., by autoclave), ethylene oxide sterilization, and gamma-ray sterilization, etc.

[0005] Regardless of which method is used to sterilize the disinfectant product, the antimicrobial molecules are degraded by the method, producing undesirable impurities and reducing the overall concentration of the components of the active drug. High concentrations of impurities can be toxic for human use and may be carcinogenic. Even when the concentration of the active ingredient is low, the product may be subject to recall because it does not meet the label display standards. At least in the regulations of the United States and EU countries, the amount of impurities that may be present in the disinfectant solution after sterilization is particularly restricted.

[0006] Electron beam (E-beam) sterilization is a form of radiation sterilization that uses beta particles to inactivate or kill microorganisms. Gamma rays, another form of radiation sterilization, utilize the self-decay of cobalt 60 (60Co) or cesium 137 to inactivate or kill microorganisms. Sterilization by gamma rays and electron beams is known as an effective sterilization process, but it is also known to be extremely inappropriate for most disinfection products. For example, gamma rays decompose the polymers, chemical components, and active ingredients (such as chlorhexidine, povidone iodine, and chloroxylenol) of some products, generating many impurities. In the United States, disinfection products sterilized by gamma rays are required to submit an application to the FDA and obtain approval before marketing these products. This regulatory process is known as a New Drug Application (NDA). The NDA process takes 5 to 10 years to obtain FDA approval, and companies must invest a huge amount of capital to conduct all the tests required for each NDA. Therefore, the industry avoids gamma ray sterilization of disinfectant products.

[0007] Ethylene oxide (ETO) sterilization is almost exclusively used for the sterilization of medical devices, which are packaged in breathable packaging. ETO gas cannot penetrate thick plastic packaging or hard, airtight containers. However, ETO sterilization is not suitable for disinfectant solutions filled in plastic chambers, glass ampoules, syringes, and integrated airtight containers using form-fill-seal technology.

[0008] Another sterilizer called an "autoclave" sterilizes using saturated steam at 121 - 132 °C inside a carbon steel container. Typical criteria for steam sterilization are achieved after 15 - 30 minutes under a pressure of 106 kPa (1 atmosphere) after all surfaces reach a temperature of 121 °C. The process by autoclave utilizes the phenomenon that the boiling point of water (or steam) rises under high pressure, as seen in Figure 1. However, the autoclave system and process are applicable only to small-scale mixtures of the solution to be sterilized and are not suitable for mass production. There are also some notable drawbacks such as residual moisture, and some of its effects are described below.

[0009] Carbon steel can be damaged by exposure to moisture, chemical components, certain polymers, and other active ingredients, and can also deteriorate under high temperature and high pressure. Only stainless steel instruments and heat-resistant plastics can be sterilized using an autoclave. Some plastic parts of equipment containers and packaging materials, such as pre-filled syringes containing drugs sensitive to high temperatures, cannot withstand such high temperatures. Some currently commercially available iodine products are not stable at high temperatures due to poor formulation. Therefore, high-temperature sterilization using an autoclave is not suitable as deterioration is expected.

[0010] Free elemental iodine (I2) is a well-known antibacterial agent with the activity of a wide range of disinfectants with bactericidal, fungicidal, sporicidal, and virucidal properties. To kill bacteria and viruses, a few parts per million (ppm) in solution is sufficient. Currently used iodine-based products rely on free elemental iodine as the main antibacterial component. These products may be formulated with cationic, anionic, non-ionic surfactants, and emollients for the purpose of topical application to the skin.

[0011] Elemental iodine (I2) was first isolated as an antibacterial agent. It is a crystalline solid with a dark purple luster at room temperature. When heated, it melts at 113.5 °C to form a liquid and boils at 184.4 °C to become a pinkish purple vapor, but under certain conditions, it may also sublime directly from the solid to vapor. Iodine dissolves easily in ethanol or ether to form a brown solution, or in chloroform or benzene to form a purple solution. Iodine dissolves slightly in water (0.29 g / l at 20 °C, 0.33 g / l or 1.2 mM at 25 °C, 0.78 g / l at 50 °C, 1.25 g / l at 80 °C) to form a yellowish brown solution. The solubility of elemental iodine increases in iodide ions such as potassium iodide, and iodine reacts to form triiodide ions.

[0012] One of the most widely used iodine-containing solutions in hospitals, or iodophors, is povidone iodine (PVP-I), which is commonly used in iodophors as a bactericide. It has also been used as a pretreatment for a patient's skin before surgery or for handwashing before surgery. Aqueous iodophors such as povidone iodine contain iodine complexed with a solubilizer and can release free iodine in solution. Iodine exerts a sterilizing effect by destroying the proteins and DNA of microorganisms. Products containing iodophors are widely used due to their broad antibacterial properties, effectiveness, and safety on almost all skin surfaces regardless of the patient's age.

[0013] Regarding the mechanism of action and antibacterial spectrum of iodine, since iodine is a low-molecular substance, it rapidly penetrates microorganisms, oxidizes major proteins, nucleotides, and fatty acids, and ultimately leads to cell death. PVP-I shows activity against Gram-positive bacteria and Gram-negative bacteria, fungi, and protozoa, including antibiotic-resistant strains and sterilant-resistant strains, and has a broad antibacterial spectrum. It is also effective against viruses with a wide range of envelopes and non-enveloped viruses, and furthermore, against some bacterial spores by increasing the exposure time. Additionally, PVP-I has shown activity against biofilms of mature bacteria and fungi in vitro and ex-vivo.

[0014] However, there is a need for a heat sterilization method that enables sterilization at a lower temperature for a shorter time, has a more efficient processing time, maintains the purity of the iodine solution sufficient to comply with regulatory requirements, and does not generate additional impurities.

[0015] The activity of an antimicrobial agent is always affected by the pH, temperature, concentration, contact time, presence of organic matter, electrolyte, microbial strain, and neutralizing agent used. For iodine solutions after production or on the market, these products are already fixed by being formulated, and the concentration of the active ingredient is established. However, due to contamination of the final solution by bacteria during mixing, production, or in the raw material components, these products are regarded as non-sterilized products.

[0016] Many types of plastics have different melting points. A wide variety of common plastics begin to melt at 100 °C (212 °F). For example, polyethylene (PE) is a soft polymer, and there are two main types: low-density PE (LDPE) and high-density PE (HDPE). When heated, PE loses its rigidity and begins to melt. LDPE already begins to melt at 105 °C, and HDPE begins to melt at 125 °C. Polypropylene (PP) is slightly harder and more rigid than HDPE, so its melting point is higher at 165 °C. Polystyrene (PS) is a hard polymer used in the production of well-known expanded polystyrene. Since PS does not require a high melting point, it melts around 90 °C.

[0017] Plastic materials exposed to high temperatures for a long time lose strength and toughness, and cracks, chips, and breakages are likely to occur at a rate proportional to the temperature and time of exposure. Materials exposed to higher temperatures for a longer time deteriorate at a significantly faster rate than materials exposed to lower temperatures and shorter exposure times. Summary of the Invention Problems to be Solved by the Invention

[0018] Therefore, in order to prevent HAI when using these products, there is a further requirement to sterilize the final device or container containing the iodine solution before using these devices in medical procedures.

Means for Solving the Problems

[0019] Summary of the Invention This document describes a system, method, and process for the self-sterilization of iodine-containing solutions and devices containing such solutions. The systems and methods described herein focus on the effects of pressure and temperature, thereby enhancing the antibacterial activity of iodine without antibacterial agents in the iodine solution and converting the device into a sterile product through a process called the self-sterilization process. The systems and methods described herein are applicable to all iodine solutions.

[0020] According to the embodiments described herein, the sterilization process heats a sealed container system at a low temperature (60 - 100 °C) to generate free elemental iodine under high pressure (i.e., above atmospheric pressure), and further utilizes the high diffusibility of elemental iodine in water, air, and lipids and its reactivity as an oxidizing agent against bacteria and viruses. Elemental iodine is used as an antibacterial agent, particularly when heating a container containing an iodine solution in the range of 60 - 100 °C, to remove contamination by bacteria in the iodine solution. At higher temperatures, more free elemental iodine is generated by chemical reactions, and the free iodine generated by heating kills all bacteria in the solution and on the container surface. Therefore, this is a self-sterilization process. This self-sterilization process uses heat within a short time, i.e., 5 - 30 minutes, in the range of 60 - 100 °C, and does not generate new impurities in the iodine solution.

[0021] In one aspect, in accordance with the disclosure herein, a method for sterilizing an iodine disinfectant solution is described. The iodine disinfectant solution contains crystalline iodine and / or povidone iodine (PVP-I). This method includes the step of supplying the iodine disinfectant solution to a sealed container. This method further includes, during a sterilization cycle, heating the iodine disinfectant solution in the sealed container to a sterilization temperature sufficient to generate free elemental iodine, and applying a positive pressure within the sealed container to pressurize the free elemental iodine to produce sterilized iodine within the sealed container.

[0022] In another aspect in accordance with the disclosure herein, a system for disinfecting an epithelium of a living body is described. This system includes a device having a surface configured to be disposed proximate to the epithelium of the living body. This system further includes a container in contact with the device, the container containing sterilized iodine and being pressurized to a positive pressure. The container releases the sterilized iodine under positive pressure to disinfect the surface of the device before or while the surface is disposed proximate to the epithelium of the living body, thereby disinfecting the nearby epithelium.

[0023] In yet another aspect in accordance with the disclosure herein, a sterilization system for sterilizing an iodine disinfectant solution is described. This system includes a plurality of containers, each of the plurality of sealed containers containing a portion of the iodine disinfectant solution. This system further includes a chamber configured to house the plurality of containers, the chamber being further configured to perform a sterilization cycle to sterilize a portion of the iodine disinfectant solution within each of the plurality of closed containers. As described herein, this sterilization cycle includes heating the iodine disinfectant solution within each of the plurality of containers to a sterilization temperature sufficient to generate free elemental iodine within each container, and applying a positive pressure within each of the plurality of containers to pressurize the free elemental iodine to produce sterilized iodine within each container.

[0024] Details of one or more embodiments are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0025] For these and other aspects, a detailed description will be given here with reference to the following drawings.

Brief Description of the Drawings

[0026]

Figure 1

Figure 2

Figure 3

Embodiments for Carrying Out the Invention

[0027] Like reference numerals in the various drawings indicate like elements.

[0028] This document describes systems, methods, and processes for the self-sterilization of iodine-containing solutions, as well as devices or systems that contain or utilize such solutions.

[0029] An aqueous solution of iodine is not stable, and depending on the conditions, there may be many different iodine solution species. Among the solution species, molecular iodine (I2) may have the highest antibacterial power. Stability is affected by pH, and activities such as antibacterial activity decrease with an increase in alkalinity and storage time. How iodine acts chemically is described below in terms of reactions in water. The iodine present in an aqueous solution exists in seven types: I2, HOI, OI−, H2OI+, I3−, I−, and IO3−, and among these, only hydrated iodine (I2), hypoiodous acid (HOI), and iodine cation (H2OI+) have bactericidal activity. At physiologically compatible pH levels and low concentrations, the important species for a disinfectant solution are only I−, I2, and I3−.

[0030] According to the embodiments described in this specification, the sterilization system and process utilize heating a closed container system at a low temperature (60 - 100 °C) to generate free elemental iodine under high pressure exceeding atmospheric pressure. The fact that elemental iodine passes through water, air, and lipids with high diffusibility and its reactivity as an oxidizing agent against bacteria and viruses are utilized. Especially when heating a container containing an iodine solution in the range of 60 - 100 °C, elemental iodine is used as an antibacterial agent to kill contaminated bacteria in the iodine solution. At higher temperatures, more free elemental iodine is generated by chemical reactions, and the free elemental iodine generated by heating this iodine solution kills all bacteria in the solution and on the container surface. Therefore, this is called an "autosterilization" process. This autosterilization process, which is carried out in a short time of 5 - 30 minutes in the range of 60 - 100 °C, does not generate new impurities in the iodine solution.

[0031] At temperatures above 65 °C (149 °F), viruses and bacteria can be almost completely inactivated by exposure for more than 3 minutes. When the temperature is 55 - 60 °C (131 - 140 °F), heating needs to continue for 5 minutes or more. However, in the range of 50 - 55 °C (122 - 131 °F), exposure for 20 minutes or more is required. At these levels, the concentration of the virus is expected to decrease logarithmically by 5 - 7 and be near or below the detectable limit. Since current virus and bacterial infections are serious, in order to ensure the safety rate of product sterility, the above temperature can be raised by 10 °C (about 18 °F), and the sterilization temperature can be set to 75 °C. The sterilization temperature is in the range of 60 - 100 °C, preferably 70 - 80 °C, and the sterilization time is in the range of 3 minutes to 24 hours, preferably 10 - 30 minutes.

[0032] Figure 1 is a phase diagram of water and shows the effects of heat and temperature on an aqueous solution such as an aqueous solution that may contain an iodine solution. Each sterilization process includes one or more stages, for example, as follows. 1) Stage I, the conditioning stage. In this stage, the temperature and pressure of the sterilizer are gradually raised to the desired temperature and pressure. 2) Stage II, the sterilization stage. This stage is also known as the holding time stage, and the sterilizer is maintained at a specific temperature and pressure. And 3) Stage III, the stage of returning the sterilizer to a state where it can be safely opened. In this stage, the temperature and pressure of the sterilizer are returned to room temperature and atmospheric pressure.

[0033] According to the embodiments described herein, several carriers for iodine can be used. For example, in certain embodiments, the following four types can be used as carriers for iodine: poloxamer iodine, cationic surfactant iodine, nonionic surfactant iodine, and polyvinylpyrrolidone iodine (also known as polyvinylpyrrolidine iodine, povidone iodine, or PVP-I). In most of these agents, iodine is retained within aggregates (or micelles) of the surfactant, which functions as a reservoir for iodine. Upon dilution, these micelles gradually disperse, releasing free elemental iodine into the aqueous solution, so that the concentration of the active ingredient gradually increases without reaching the undesirable concentrations associated with conventional products. This free iodine is known as available iodine, and the activity of the iodine carrier is related to the amount of iodine released.

[0034] Iodophors are solutions containing povidone-iodine (PVP-I), a stable chemical complex of polyvinylpyrrolidone (povidone, PVP) and elemental iodine. In these solutions, small amounts of iodine are gradually released into the solution under certain environmental constraints and factors. They are usually used at concentrations in the range of 6 - 75 ppm depending on the formulation. Iodophors penetrate the cell walls and cell membranes of microorganisms and inhibit DNA synthesis. Iodophors also bind to proteins and inactivate them. Conventional aqueous iodophors such as povidone iodine are one of the few products that can be safely used on the mucosal surfaces of animals. The equilibrium concentrations of I2 and I3- in an aqueous povidone iodine solution (0.001 - 20.0%, pH 4, 25 °C) have been evaluated from the redox potential and the iodide concentration measured by an iodide electrode (under the selected conditions, HOI, OI-, H2O+I and IO3- can be ignored).

[0035] The values obtained for [I-], [I2], [I3-] and Cox (i.e., iodine-titratable iodine solution) indicate that the amount of iodine complexed in the povidone matrix is composed of HI3 and I2 groups. Below 1% concentration, it represents almost all of the oxidizing ability, but is negligible below 0.01%. In some embodiments, the concentration of free molecular iodine (I2) remains at only 4.5×10 -m / l (1.1 ppm) in a 20% solution and increases to a maximum of about 10-4 m / l (25.4 ppm) in a 0.1% solution.

[0036] The iodide ions (I-) present in the PVP-I solution are converted to iodine (I2), and this free iodine molecule acts as an antibacterial agent, killing the bacteria it contacts. Furthermore, this iodine molecule can penetrate into any substance to which it is exposed or comes into contact with, and can make these substances themselves antibacterial. Therefore, when these materials are integrated with medical devices, they can have one or more antibacterial functions, such as killing bacteria that come into contact with the surface of the medical device. In addition, this antibacterial material prevents bacteria from adhering to the surface such as a biofilm on the surface of a medical device or the material forming it. Not all PVP-I formulations are the same, and the release rate of free iodine depends on the components of the formulation. For example, some components of the formulation may increase the solubility of free iodine in the solution, while other components may slow down the release rate of free iodine into the solution.

[0037] Figure 2 is a flowchart showing a self-sterilization method for a container containing iodine, such as a syringe, pouch, or bottle or other container. At 202, a solution containing povidone iodine is supplied to the container. Preferably, the solution occupies the entire volume of the container so that no space or air remains in the container. At 204, a solubilizer is added to the solution as described herein. At 206, free iodine is released from povidone iodine in the solution by the chemical reaction described herein. At 208, the free iodine is supplied as an antibacterial agent inside or in the vicinity of the container, for example, supplied throughout the container and / or outside the container by penetration or other chemical processes (especially when the container includes an iodine-permeable membrane).

[0038] The self-sterilization method described herein is sufficient to accommodate any iodine-containing solution. The activity of the antibacterial agent is always affected by, but not limited to, pH, temperature, concentration, contact time, the presence of organic matter, electrolytes used in a particular solution, microbial strains, and / or neutralizing agents. Iodine-containing solutions currently on the market, that is, after manufacture, have their formulation and active ingredients fixed, but during the final stage of mixing of the material components and the manufacture of the device containing the solution, due to either post-manufacture contamination or contamination of one or more raw material components during mixing or during the manufacturing process, bacteria may be mixed in, and thus they are considered not to be in a sterile state.

[0039] Accordingly, embodiments related to the present case include a self-sterilization method or process for sterilizing devices or containers containing iodine-containing solutions, which is carried out before these solutions can be used in medical treatments and aims to prevent healthcare-associated infections (HAIs) during their use. In some specific embodiments, one or more of pressure and / or temperature, and / or other parameters are used to enhance the antibacterial activity as an antibacterial agent against free iodine in the iodine solution and sterilize the device or container.

[0040] In some embodiments, the potential reaction of molecular iodine (I2) in water is utilized. The main iodine species found in aqueous solutions include I2, HOI, OI-, H2OI+, I3-, I-, and IO3-.

Chemical formula

[0041] Free iodine can directly sublime from liquid iodine to vapor under stress conditions. These stress conditions can be made consistent with Le Chatelier's principle, which states that when stress is applied to a reaction mixture in equilibrium, the overall reaction proceeds in the direction that relieves that stress. One way to apply stress to a reaction in equilibrium is to change the concentration of reactants or products. Another way is to increase the temperature and pressure. Accordingly, free iodine gradually penetrates through the liquid and evaporates against the surface of iodine until all chemicals reach equilibrium.

[0042] In an embodiment of the present subject matter, when the container of the device containing the iodine solution is heated to a desired temperature, the concentration of free iodine molecules gradually increases. When the concentration of free iodine exceeds the solubility of iodine in water, the free iodine escapes from the water. By increasing the concentration of free iodine in the water and on the surface of the iodine solution, the amount of free iodine available to kill all bacteria that may be present in the solution, within the device, or in the vicinity of the device increases. This process can include heating the device in a moist heat medium or a dry heat medium to generate more free iodine within the device container. This iodine kills all bacteria within the device container and enables the device to reach a sterilization assurance level of 10-6.

[0043] In some preferred exemplary embodiments, the method for self-sterilizing an iodine-containing solution involves the volatilization of free iodine and includes several steps. The first step (1) involves the oxidation reaction of I3- to I2 and I- for each reaction, the second step (2) involves the oxidation reaction of I- to I2 for each reaction, and the third step (3) involves the step of evaporating dissolved I2 to gaseous I2. When predicting the volatilization of iodine under various environmental conditions, it is beneficial to individually evaluate the influence of environmental factors on each step. For example, temperature may be one of the main factors affecting these three steps. As the temperature increases, the oxidation rates of I3- and I- decrease, while the evaporation rate of I2 increases.

[0044] In an open and well-ventilated space, the effects of temperature, I2 concentration, and the presence of I- on the evaporation of I2 in a mixed solution of I2 and I- were investigated. Experiments confirmed that as the temperature of the solution increases, the evaporation rate of I2 increases exponentially, showing a trend similar to the temperature dependence of the saturated vapor pressure of I2. The evaporation rate constants of I2 at temperatures of 26°C and 80°C in an open system are shown in the following table.

Table 1

[0045] When the temperature increased, the concentration of I2 in the solution decreased very rapidly, while the concentration of I2 in the vapor increased. When the initial I2 concentration was 0.99 mm, it was observed that the time until it decreased to less than 10% of the initial concentration was about 700 minutes (11.67 hours) at 26 °C, 30 minutes at 50 °C, and 7 minutes at 80 °C. This result shows that the evaporation rate of I2 is greatly affected by temperature. The phenomenon that I2 evaporation is promoted at higher temperatures can be explained by the temperature dependence of the evaporation enthalpy and the saturated vapor pressure. In the case of an open system, the vapor pressure of elemental iodine increases by about 14 torr, i.e., 0.27 psi.

Table 2

[0046] However, in a closed system at a constant temperature, when the system is in an equilibrium state, the free energy of I2 dissolved in water is equal to the free energy of I2 evaporated into the gas phase. I2 (dissolved in water) = I2 in the gas phase (3)

[0047] As shown in Table 4, the densitometer uses the formula p = m / V, and the density (p) is equal to the value obtained by dividing the mass (m) by the volume (V). Therefore, if the density is constant, the pressure increases as the temperature rises.

Table 3

[0048] In the case of a closed container system as shown in FIGS. 3A to 3C, since the volume of the closed system does not change, the total mass is also the same and remains within the system, the density is constant. Therefore, when the temperature of the closed container rises, the pressure rises dramatically.

[0049] Therefore, in a preferred embodiment, the iodine solution is contained within a closed container (i.e., inside). At room temperature, the free elemental iodine I2 dissolved in water is the same as the free elemental iodine I2 in the gas portion of the closed container. When heated air, steam, or water is introduced into the process in the sterilization chamber, these gradually heat the iodine solution within the closed container. This is called the "heating-up" step of the sterilization process. During this step, the temperature of the iodine solution rises from 25°C to 80°C, and at the same time, the concentration of free elemental iodine I2 gradually increases. The pressure within the closed container rises due to the increase in iodine molecules evaporating from water to gas and the increase in molecules of liquid water vapor migrating to gas. The pressure within the closed container system exceeds 1 atmosphere.

[0050] When the temperature reaches 80°C, the sterilization process maintains the iodine solution at 80°C and holds it for 3 to 30 minutes (depending on the set preferred sterilization time). This step is called the sterilization time step. During this step, the free elemental iodine I2 dissolved in water at 80°C reaches equilibrium with the free elemental iodine I2 in the gas portion of the closed container. The free iodine dissolved in water is 290 ppm at 20°C, 1,100 ppm at 70°C, and increases to 1,250 ppm at 80°C.

[0051] In one example, in the case of a closed container containing 10 ml of iodine solution, the free elemental iodine dissolved within the container is approximately 2.9 ppm. When the iodine solution in this container is heated to 80°C, this solution will contain approximately 12.5 - 13 ppm of free elemental iodine within the container. Since this container is a closed system and the volume is fixed, the pressure of the free iodine rises dramatically in proportion to the concentration of the free iodine and reaches a concentration far exceeding 13 ppm. Due to this high concentration of free iodine within the container, all bacteria and viruses within the container are killed. Therefore, all bacteria and viruses are completely killed in this step.

[0052] During the manufacturing process, bacteria and viruses that contaminated the iodine solution are all killed by the free elemental iodine itself, so this is called a self-sterilization method and process. In this sterilization process, other chemicals such as ETO - ethylene oxide, hydrogen peroxide, and formaldehyde are not used. Since this sterilization treatment is carried out at a low temperature, it does not damage the components of the equipment containers. This self-sterilization process does not generate new impurities from the iodine solution.

[0053] After sterilizing a closed container containing an iodine solution at 80 °C for a predetermined time (10 - 30 minutes), the vapor pressure of free iodine I2 in the container / equipment becomes very high (after the holding stage of the sterilization process). In stage III of the sterilization process, the sterilizer is returned to normal room temperature and pressure. All the vapors of the elements / chemical components in the closed container return to the liquid state to satisfy the equilibrium of the system as predicted by Le Chatelier's principle. This principle states that when the dynamic equilibrium is disturbed by a change in conditions, the position of the equilibrium moves in a direction that counteracts that change to reconstruct the equilibrium. When a chemical reaction is in equilibrium and the pressure, temperature, or the concentration of the products or reactants changes, the equilibrium moves in the opposite direction to counteract that change.

[0054] Since the system of the closed container / device needs to be in an equilibrium state at room temperature, all the elements and chemical components in the sealed container return to the liquid state. However, since elemental iodine is solid at room temperature, not all of the free iodine in the vapor state can condense into the liquid state, and the free iodine remains in the vapor state, generating a high pressure of about 0.027 kPa (0.2 mmHg) I2 in the device within the closed container. Therefore, when the container / equipment is unsealed, opened, injected, or applied, the iodine vapor escapes (sublimes) and disinfects the contact surfaces such as the surface of the needleless valve and the luer lock of the catheter medical device adapter, killing all the bacteria that may contaminate those surfaces. This function is called self-decontamination.

[0055] Therefore, at equilibrium, the change in free energy represented by equation (4) should be zero.

Number

[0056] When the temperature of the system rises, since it is the latent heat required for evaporation, the evaporation enthalpy (ΔH evaporation) with a positive value decreases. Furthermore, since evaporation is a phase change reaction from liquid to gas, the entropy change (ΔS evaporation) should be positive. Therefore, by increasing the temperature, the values of both the enthalpy (ΔH evaporation) and the entropy term (TΔS evaporation) in Equation (4) decrease. Therefore, the value of the free energy change (ΔG evaporation) becomes negative.

[0057] In summary, as the temperature rises, the equilibrium equation (4) shifts to the right, more free elemental iodine is generated, and accordingly, the saturation vapor pressure of free elemental I2 increases. Therefore, in the container containing the iodine solution, the free elemental iodine available to kill all bacteria present in the container increases, and the iodine solution in the container becomes sterile. It was confirmed that the evaporation reaction of I2 follows the first-order kinetics depending on the concentration of I2 dissolved in the solution. When the temperature rises (between 26°C and 80°C), the evaporation rate constant of free elemental iodine I2 increases rapidly.

[0058] In some embodiments, a method for sterilizing an iodine disinfectant solution includes supplying the iodine disinfectant solution to a closed container and heating the iodine disinfectant solution in the closed container during a sterilization cycle to reach a sterilization temperature that generates a sufficient amount of free elemental iodine in the sealed container. This method further includes applying a positive pressure in the closed container to pressurize the free elemental iodine to produce sterilized iodine in the sealed container. In a preferred embodiment, the iodine disinfectant solution contains iodine crystals and / or povidone iodine (PVP-I).

[0059] In other embodiments, a system for disinfecting a living body's epithelium includes a device having a surface configured to be disposed proximate to the living body's epithelium. The device may be an indwelling urinary catheter such as a Foley catheter. The system further includes a container in contact with the device, the container containing sterilized iodine and being pressurized to a positive pressure. The container releases the sterilized iodine under positive pressure to disinfect the surface of the device before or while the surface is disposed proximate to the living body's epithelium, thereby disinfecting the nearby epithelium.

[0060] In yet another embodiment, a sterilization system for sterilizing an iodine disinfectant solution includes a plurality of containers. Each of the plurality of closed containers contains a portion of the iodine disinfectant solution. The system further includes a chamber configured to house or carry the containers. The chamber is further configured to execute or receive a sterilization cycle for sterilizing a portion of the iodine disinfectant solution in each of the plurality of closed containers. As described herein, the sterilization cycle includes heating the iodine disinfectant solution in each of the plurality of containers to a sterilization temperature sufficient to produce free elemental iodine in the solution within each container, and applying a positive pressure within each of the plurality of containers to pressurize the free elemental iodine to produce sterilized iodine within each container.

[0061] The chamber can be a container or a stable room of any size capable of controlling the internal temperature, for example, the temperature can be controlled by introducing heated air, heated liquid, steam, or a combination thereof. For example, the chamber can include an air circulation mechanism to ensure that the heated air, liquid, and / or steam continuously and uniformly contacts each container. Alternatively, the chamber can include a mechanism for supplying heated air, heated liquid, and / or steam directly to a portion of the iodine disinfectant solution in each container to heat the solution from room temperature to the desired sterilization temperature.

[0062] One or more containers can be closed, i.e., sealed. The containers can be formed of plastic, glass, metal, etc. The iodine disinfectant solution can be placed in the form of an iodophor in a glass ampoule or formed and filled into a plastic container or a sealed pouch and sealed, and placed or supplied in each container.

[0063] The containers can be housed or placed in trays, buckets, racks, and can also be supplied through chambers in conveyor belts or similar moving mechanisms, enabling continuous heating and / or pressurization. By automating the heating and pressurization of the containers in the chamber, the number of containers supplying sterilized iodine can be increased. In some alternative embodiments, the heating and pressurization of the containers can be performed in two or more separate chambers or positions on an automatic sterilization line.

[0064] Although several embodiments have been described in detail above, other modifications are possible. Other embodiments may fall within the scope of the following claims.

Claims

1. A method for sterilizing an iodine disinfectant solution, wherein the iodine disinfectant solution contains crystalline iodine and / or povidone iodine (PVP-I), and the method comprises: supplying the iodine disinfectant solution to a sealed container; during a sterilization cycle; heating the iodine disinfectant solution in the sealed container to a sterilization temperature sufficient to produce free elemental iodine in the sealed container; applying a positive pressure within the sealed container to pressurize the free elemental iodine to produce sterilized iodine in the sealed container. A method.

2. The method according to claim 1, wherein the sterilization temperature is from about 60°C to about 100°C.

3. The method according to claim 2, wherein the sterilization temperature is from about 70°C to about 80°C.

4. The method according to claim 1, wherein the positive pressure applied within the sealed container exceeds 1013 millibars.

5. The method according to claim 1, wherein the sterilization cycle is from about 3 minutes to about 24 hours.

6. The method according to claim 5, wherein the sterilization cycle is from about 10 minutes to about 30 minutes.

7. The method according to claim 1, further comprising maintaining the sealed container containing the sterilized iodine at or near the positive pressure applied to the sealed container.

8. The method according to claim 1, wherein heating the iodine disinfectant solution further comprises exposing the sealed container to one or more of hot air, hot liquid, and steam.

9. The method according to claim 1, wherein heating the iodine disinfectant solution further comprises exposing the iodine disinfectant solution in the sealed container to one or more of hot air, hot liquid, and steam.

10. The method according to claim 1, further comprising simultaneously sterilizing iodine disinfectant solutions in a plurality of sealed containers.

11. A system for disinfecting an epithelium of a living body, the system comprising: a device having a surface configured to be disposed proximate to the epithelium of the living body; a container in contact with the device, the container containing sterilized iodine and being pressurized to a positive pressure, the container being configured to release the sterilized iodine under the positive pressure to disinfect the surface of the device before or while the surface is disposed proximate to the epithelium of the living body for disinfecting the epithelium in the vicinity thereof. A system.

12. The sterilized iodine is obtained by: supplying an iodine disinfectant solution to a container; during a sterilization cycle; heating the iodine disinfectant solution in the container to a sterilization temperature sufficient to generate free elemental iodine in the container; applying a positive pressure to the inside of the container to pressurize the free elemental iodine and generate the sterilized iodine in the container; The system according to claim 11, which is manufactured by the above.

13. The system according to claim 12, wherein the sterilization temperature is about 60°C to about 100°C.

14. The system according to claim 13, wherein the sterilization temperature is about 70°C to about 80°C.

15. The system according to claim 12, wherein the positive pressure applied to the inside of the sealed container exceeds 1013 millibars.

16. The system according to claim 12, wherein the sterilization time cycle is about 3 minutes to about 24 hours.

17. The system according to claim 16, wherein the sterilization time cycle is about 10 minutes to about 30 minutes.

18. A sterilization system for sterilizing an iodine disinfectant solution, wherein the iodine disinfectant solution contains crystalline iodine and / or povidone iodine (PVP-I), and the system includes: a plurality of containers, each of the plurality of sealed containers containing a portion of the iodine disinfectant solution; a chamber configured to accommodate the plurality of containers, the chamber being further configured to execute a sterilization cycle for sterilizing a portion of the iodine disinfectant solution in each of the plurality of sealed containers, the sterilization cycle including: heating the iodine disinfectant solution in each of the plurality of containers to a sterilization temperature sufficient to generate free elemental iodine in each container; applying a positive pressure to each of the plurality of containers to pressurize the free elemental iodine and generate sterilized iodine in each container. A system.

19. The sterilization system according to claim 18, wherein the chamber further includes a heating source for heating the iodine disinfectant solution in each of the plurality of containers, and the heating source includes one or more of hot air, hot liquid, and hot steam.

20. The sterilization system according to claim 18, wherein the chamber further includes a pressurizing source configured to apply a positive pressure to each of the plurality of containers.

21. The sterilization system according to claim 18, wherein each of the plurality of containers is a sealed container, the chamber further includes a receptacle configured to accommodate the plurality of containers, and the receptacle positions the plurality of containers for the sterilization cycle.

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