CN1153668A - Vapor sterilization using inorganic hydrogen peroxide complexes - Google Patents

Abstract

An apparatus and process for hydrogen peroxide vapor sterilization of medical instruments and similar devices make use of hydrogen peroxide vapor released from an inorganic hydrogen peroxide complex. The peroxide vapor can be released at room temperature and atmospheric pressure; however, the pressure used can be less than 50 torr and the temperature greater than 86 DEG C to facilitate the release of hydrogen peroxide vapor. Preferred hydrogen peroxide complexes for use in the invention include Na4P2O7.3H2O2 and KH2PO4.H2O2. The heating rate can be greater than 5 DEG C. Optionally, a plasma can be used in conjunction with the vapor.

Description

Steam sterilization using inorganic hydrogen peroxide complexes

The present application is a continuation of a portion of the 08/369,786u.s. patent application, filed 1995.1.6, and 08/369,786 is a continuation of a portion of the 1994.4.28 application, filed 08/234,738.

The present invention relates to an apparatus and method for sterilizing articles, such as medical devices, with hydrogen peroxide vapor, and in particular to the use of inorganic hydrogen peroxide complexes in such processes.

Medical instrument sterilization has traditionally used heat, such as that provided by steam, or chemicals, such as formaldehyde or ethylene oxide in gaseous or vaporous form. Each of these methods has drawbacks. Many medical instruments, such as fiber optic instruments, endoscopes, power processes, and the like, are sensitive to heat, moisture, or both. Both formaldehyde and ethylene oxide are toxic gases that pose potential hazards to worker health. The problem with ethylene oxide is particularly acute because its use requires long aeration times to remove the gas from the items being sterilized. This makes the disinfection cycle time undesirably long. In addition, formaldehyde and ethylene oxide require a large amount of moisture to be present in the system. Thus, the device to be sterilized must be humidified before the chemicals are added, or the chemicals and moisture must be added simultaneously. In addition to ethylene oxide and formaldehyde, moisture also functions in disinfection with other various chemicals in gaseous or vapor state as shown in table 1, as shown in table 1.

TABLE 1 relative humidity references required for optimal Effect of chemicals ethylene oxide 25-50% propylene oxide 25-50% 1 ozone 75-90% 2 formaldehyde>75% 1 glutaraldehyde 80-90% 3 chlorine Dioxide 60-80% 4 methyl bromide 40-70% 1 β -propiolactone>75% 1 peracetic acid 40-80% 51.Bruch, C.W.Gaseous Sterilation, Ann.Rev.Microbiolo qy15: 245-262(1961)2. Jansen, D.W.and Schneider, P.M.overlay of ethylene oxide assisted gradient Sterilation technologies, Zentrals gradient 1: 16-32(1993) 3. Bovallisus, A.and Dias, P.Suzufa (e-degassing activation gradient amplification carbohydrate Phase) 32. media and 32. Bovallisi, A.and D.S.S.P.Suzu-D.7. application viscosity modifier J.52. application of calcium chloride (K.178. application of calcium chloride, K.7. application of calcium chloride, 2. 9. application

Steam sterilization using hydrogen peroxide has been shown to have some advantages over other chemical sterilization methods (see, e.g., U.S. patent nos. 4,169,123 and 4,169,124), while hydrogen peroxide in combination with plasma provides other advantages, as disclosed in U.S. patent No.4,643,876. In these publications, the hydrogen peroxide vapor is generated from an aqueous hydrogen peroxide solution, which ensures that moisture is present in the system. These publications, together with the information summarized in table 1, indicate that: moisture is required in order for the hydrogen peroxide to be effective or exhibit its maximum sporicidal activity in the vapor phase. However, the use of aqueous hydrogen peroxide to generate hydrogen peroxide vapor for sterilization may cause problems. At higher pressures, such as atmospheric pressure, excess water in the system may condense. Therefore, the relative humidity in the sterilization chamber must be reduced prior to introducing the aqueous hydrogen peroxide vapor.

Sterilizing articles containing a diffusion-limiting zone, such as long narrow chambers, presents particular difficulties with respect to the hydrogen peroxide vapor generated by aqueous hydrogen peroxide solutions, because:

1. water has a higher vapor pressure than hydrogen peroxide and evaporates from an aqueous solution faster than hydrogen peroxide.

2. Water has a lower molecular weight than hydrogen peroxide and diffuses faster than hydrogen peroxide in the vapor state.

For these reasons, when evaporating the aqueous hydrogen peroxide solution, the water reaches the sterilized article first and in a higher concentration. The water vapor thus acts as a barrier to the penetration of the hydrogen peroxide vapor into diffusion-restricted areas such as small slits and long narrow chambers. The removal of water from aqueous solutions and the use of more concentrated hydrogen peroxide does not solve the problem, since concentrated hydrogen peroxide solutions, i.e. more than 65% by weight, can be dangerous due to the oxidizing properties of the solution.

Us patents 4,642,165 and 4,744,951 attempt to solve this problem. The former discloses measuring small increments of hydrogen peroxide solution on a heated surface to ensure that each increment is evaporated before the next increment is added. While this helps to eliminate the difference in vapor pressure and volatility between hydrogen peroxide and water, the fact that water diffuses faster than hydrogen peroxide in the vapor state cannot be negated.

The latter patent describes a method of concentrating hydrogen peroxide from a relatively dilute solution of hydrogen peroxide and water and supplying the concentrated hydrogen peroxide to the sterilization chamber as a vapor. The method includes evaporating a substantial portion of the water from the solution and removing the resulting water vapor prior to spraying the concentrated hydrogen oxide vapor into the sterilization chamber. For this concentrated hydrogen peroxide solution, the preferred range is 50-80% by weight. The disadvantage of this process is that it operates with a hydrogen peroxide solution in the hazardous range, i.e. greater than 65%, and does not remove all the water in the vapour state. Since water is also present in the solution, it will evaporate first, diffuse faster and reach the items to be disinfected first. This effect will be particularly pronounced in long and narrow lumens.

Us patent 4943414 discloses a method in which a container containing a small quantity of a vaporizable liquid disinfectant solution is connected to a chamber, the disinfectant is then vaporized and caused to flow directly into the chamber of the article as a result of the pressure being reduced during the sterilization cycle. This system has the advantage of increasing the speed of sterilization of the chamber by allowing water and hydrogen peroxide vapour to be forced through the chamber by the presence of a pressure differential, buthas the disadvantage that the container needs to be attached to each chamber to be sterilized. In addition, water evaporates faster and enters the chamber before the hydrogen peroxide.

U.S. patent No.5008106 discloses: substantially anhydrous PVP and H₂O₂The complexes of (a) are useful for reducing the microbial content of a material surface. The complex is used in the form of white fine powder to form antibacterial solution, gel, ointment, etc. It can also be applied to gauze, cotton drug , sponge, etc. It is released by contact with water present on the surface containing the microorganism. Therefore, this method cannot be sterilized because of the excessive presence of moisture.

Several inorganic hydrogen peroxide complexes have been reported, including examples in the following categories: alkali metal and ammonium carbonates, alkali metal oxalates, alkali metal phosphates, alkali metal pyrophosphates, fluorides, and hydroxides. U.S. s.r patent document No. su1681860(Nikolskaya et al) discloses: the use of ammonium fluoride peroxyhydrate also decontaminates the surface, although no disinfection is required. However, the inorganic peroxide complexes only produce decontamination in a narrow temperature range, 70-86 ℃. Even in this rangeThe time of formation is also quite long, requiring at least two hours. Furthermore, ammonium fluoride is known to decompose to ammonia and hydrofluoric acid at temperatures above 40 ℃. Hydrofluoric acid is undesirable in most disinfection systems due to its toxicity and reactivity. Further, Nikolskaya et al disclose: NH although its hydrogen peroxide was released 90% at 60 deg.C₄F·H₂O₂Is ineffective at this temperature in surface decontamination. Thus, it is clear that factors other than hydrogen peroxide are decisive for the decontamination.

Hydrogen peroxide can form complexes with organic and inorganic compounds, and the bonding in these complexes results from the bonding of an electron-rich functional group in the compound being complexed with hydrogen between the hydrogen peroxide. These complexes have been used in commercial and industrial applications such as bleaching agents, disinfectants, sterilants, oxidizing agents in organic synthesis and catalysts for induced radical polymerization.

In general, these classes of compounds are prepared by crystallizing the complex from an aqueous solution. The urea hydrogen peroxide complex is prepared, for example, by Lu et al (J.Am.chem.Soc.63 (1): 1507-1513(1941)) in liquid phase by adding a urea solution to a hydrogen peroxide solution and allowing the complex to crystallize under suitable conditions. U.S. Pat. No.2,986,448 describes the use of a catalyst containing 50-90% H at 0-5 ℃ in a closed circulation system₂O₂The solution of (2) will be saturated with Na₂CO₃Treating the aqueous solution for 4-12 hours to prepare the sodium carbonate hydrogen peroxide complex. More recently, U.S. Pat. No.3,870,783 disclosesSodium carbonate hydroperoxide complexes are prepared by reacting aqueous hydrogen peroxide with sodium carbonate in a batch or continuous crystallizer. The crystals are separated by filtration or centrifugation and the mother liquor is used to regenerate the sodium carbonate solution. Titova et al (Zhumal Neorg. Khim., 30: 2222-2227, 1985) describe the synthesis of potassium carbonate peroxyhydrate (K-peroxohydrate) by reacting solid potassium carbonate with aqueous hydrogen peroxide at low temperatures followed by crystallization of the complex from ethanol₂CO₃·3H₂O). These processes yield well stabilized, crystallized, bulk, from aqueous solutionsThe peroxide complex product of (a).

U.S. Pat. Nos. 3,376,110 and 3,480,557 disclose the preparation of complexes of hydrogen peroxide with polymeric N-vinyl heterocyclic compounds (PVP) from aqueous solutions. The resulting complex contains variable amounts of hydrogen peroxide and large amounts of water. U.S. patent No.5,008,093 teaches: by contacting PVP suspension with H₂O₂Solution reaction in an anhydrous organic solvent such as ethyl acetate yields bulk, stable, substantially anhydrous PVP and H₂O₂More recently, U.S. Pat. No.5,077,047 describes an industrial process for preparing a PVP-hydrogen peroxide product by adding 30-80% by weight of an aqueous solution of hydrogen peroxide divided into fine droplets to a fluidized bed of PVP maintained at a temperature of room temperature to 60 ℃. The product obtained is known to be a stable, essentially anhydrous, loose powder with a hydrogen peroxide concentration of 15-24%.

U.S. patent No.5,030,380 describes the preparation of solid electrolytic complexes polymerized with hydrogen peroxide by first forming the complex in an aqueous solution and then drying the reaction product under vacuum or spray drying it at a temperature sufficiently low to avoid thermal degradation of the product.

All of the above-described processes for preparing hydrogen peroxide complexes use solutions of hydrogen peroxide. Either the complex may be formed in a hydrogen peroxide-containing solution or droplets of the hydrogen peroxide solution may be sprayed onto a fluidized bed of reagent material.

Vapor and gas phase reactions are well known syntheses. For example, U.S. patent No.2,812,244 discloses a solid-gas dehydrogenation, thermal cracking, and demethanization process. Fujimoto et al (J.catalysis, 133: 370-382(1992)) describe the carboxylation of methanol in the vapor phase. Zellers et al (anal. chem., 62: 1222-1227(1990)) have discussed the reaction of styrene vapor with square planar organic platinum complexes. However, none of these prior art vapor-and gas-phase reactions are useful forforming hydrogen peroxide complexes.

One object of the present invention relates to a device for hydrogen peroxide disinfection of articles. The apparatus includes a vessel for holding the article to be sterilized at a pressure of less than 50 torr. Preferably, the pressure is less than 20 torr, more preferably less than 10 torr. The apparatus also includes a source of hydrogen peroxide vapor in fluid communication with the container. The vapor source comprises an inorganic hydrogen peroxide complex at a temperature greater than 86 ℃ and is configured to allow the peroxide vapor to contact the articles to be sterilized. The source may be located in the container or, alternatively, the apparatus may comprise a closed box outside the container containing the complex. And an inlet for fluid communication between the container and the cartridge, such that steam released from the formulation is introduced along the inlet and then into the container for sterilization. The inorganic hydrogen peroxide complex may be a complex of sodium carbonate, potassium pyrophosphate or potassium oxalate. Preferably, the apparatus further comprises a heater disposed in the container, whereby the compound is placed on the heater and heated to promote release of the vapour from the compound. Such heaters may be heated prior to contact with the complex. The apparatus may further comprise a vacuum pump in fluid communication with the vessel for evacuating the vessel. In certain embodiments, the apparatus comprises an electrode adapted to generate a plasma around the article. The electrode may be within the vessel or may be separate from the vessel and adapted to cause the generated plasma to flow so as to flow around the article. In a preferred embodiment, the complex is in the solid phase.

Another object of the invention relates to a method for hydrogen peroxide vapor sterilization ofarticles. The method comprises placing the article in a container, then contacting the article with hydrogen peroxide vapor released from an inorganic hydrogen peroxide complex heated at a rate of at least 5 ℃/minute, and sterilizing the article. Preferably, the heating rate is at least 10 ℃/min, more preferably at least 50 ℃/min, and most preferably at least 1000 ℃/min. The complex preferably contains less than 10% water. The complex may be heated, preferably to a temperature greater than 86 ℃ to promote the release of vapour from the complex. The vessel may be evacuated to a pressure of less than 50 torr, preferably less than 20 torr, and more preferably less than 10 torr, prior to introducing the steam into the vessel. Optionally, a plasma may be generated around the article after introducing the vapor into the vessel. The plasma may be generated inside or outside the vessel. The invention also includes a method of hydrogen peroxide vapor sterilization of articles wherein the inorganic hydrogen peroxide complex used is one which does not decompose, thereby releasing hydrohalic acid.

Yet another object of the present invention relates to a method of hydrogen peroxide sterilization of articles using a self-sterilizing cassette. In this way, the article is placed in a capsule containing an inorganic hydrogen peroxide complex, the capsule is sealed, and the capsule is then left at a temperature below 70 ℃ for a time sufficient to allow hydrogen peroxide vapour to be released from the complex and to complete the sterilization of the article. Although not required, the cassette may be placed under a pressure less than atmospheric pressure or at a temperature above room temperature (23 ℃). Thus, the cartridge may be subjected to a temperature of less than about 40 deg.CAnd (5) degree (b). Any of a variety of cassettes may be used, such as bags, containers, compartments, or chambers. Preferably, the hydrogen peroxide complex is in the form of a powder or flakes. The sealing step may include using a gas permeable material, such as TYVEK^TMCSR wrap, and/or paper to seal the case.

The invention also relates to a sealed capsule containing a sterile product and an inorganic hydrogen peroxide complex capable of releasing hydrogen peroxide vapour.

Also included in the present invention are potassium pyrophosphate hydroperoxide complexes.

Yet another object of the present invention relates to a method of hydrogen peroxide sterilization of articles having exterior and interior cavities therein. The method comprises connecting a vessel containing an inorganic peroxide complex to a chamber of the article, placing the article in a container, thereby maintaining the vessel in connection with the chamber, reducing the pressure in the container, and contacting the chamber of the article with hydrogen peroxide vapor released from the inorganic peroxide complex at a temperature of less than 70 ℃.

Fig. 1 is a schematic view of a steam sterilizing apparatus of the present invention.

Fig. 2 is a schematic view of a steam sterilizing apparatus of the present invention including electrodes optionally used to generate plasma.

Fig. 3A is a schematic of an apparatus that can be used to heat the peroxide complex.

Figure 3B is a schematic view of a preferred container for containing a source of peroxide for sterilization in accordance with the present invention.

Figure 4 is a graph depicting the release of hydrogen peroxide vapor from a vacuum unstable, water-free hydrogen peroxide complex.

Fig. 5 is a schematic diagram of a pressure control system of a Differential Scanning Calorimeter (DSC) for determining the hydrogen peroxide-releasing or decomposition characteristics of an inorganic peroxide complex according to the present invention.

Figure 6 is a graph showing the effect of pressure on the release of hydrogen peroxide from a potassium oxalate peroxide complex.

Figure 7A is a schematic view of a hose for introducing peroxide vapor into a chamber, in accordance with the present invention, prior to spraying the peroxide.

Fig. 7B is a schematic view of the hose of fig. 7A showing the heated plate in contact with the peroxide complex upon spraying.

Hydrogen peroxide sterilizers that have been used in the past always use an aqueous hydrogen peroxide solution as the source of the sterilizing agent. These sterilizers have disadvantages in the system due to the presence of water. At high pressure, such as at atmospheric pressure, the water in the system causes condensation. This requires an additional step to be performed in order to reduce the relative humidity in the atmosphere in the cassette to be sterilized to an acceptable level before introducing this aqueous hydrogen peroxide vapour. These sterilisers also have drawbacks due to the fact that: water having a high vapor pressure evaporates more rapidly from an aqueous solution than hydrogen peroxide; and water with a low molecular weight diffuses faster than hydrogen peroxide. When transferring medical devices and the like into a sterilizer, the initial sterilant reaching the device from the source of hydrogen peroxide is dilute compared to the concentration of the source, which may be an obstacle to the sterilant reaching afterwards, especially if the device to be sterilized is an item having a narrow lumen, such as an endoscope. The use of concentrated hydrogen peroxide solutions like this source is unsatisfactory in an attempt to overcome these disadvantages, since such solutions are hazardous.

In the present invention, the disadvantages of prior art hydrogen peroxide sterilizers are overcome by using a source of hydrogen peroxide that is substantially non-aqueous (i.e., substantially anhydrous) and releases substantially anhydrous hydrogen peroxide vapor. In a preferred embodiment, the substantially anhydrous hydrogen peroxide vapour is generated directly from a substantially anhydrous hydrogen peroxide complex. However, the substantially anhydrous hydrogen peroxide vapor may also originate from an aqueous complex which is treated during evaporation, e.g., under vacuum, to remove water. Thus, where an aqueous hydrogen peroxide complex is used, the aqueous complex may be converted to a substantially anhydrous hydrogen peroxide complex while the process of the present invention is carried out. Preferably, the substantially anhydrous hydrogen peroxide complex contains less than about 20% water, preferably no more than about 10% water, more preferably no more than about 5% water, and most preferably no more than about 2% water.

As is clear from the preferred percentage of water in the substantially anhydrous hydrogen peroxide complexes as described above for use in the present invention, the most preferred hydrogen peroxide complexes and the peroxide vapors generated therefrom are substantially anhydrous. Nevertheless, it is clear from these data that some water may be present in this system. Some of this water may result from the decomposition of hydrogen peroxide to form water and oxygen as by-products, and some hydrogen incorporation of this water into the complex may also occur.

In a series of tests, the effect of water was measured with a disinfection chamber maintained at different relative humidities. The test conditions were as described in example 1 below, and the spores were loaded on Stainless Steel (SS) plates of 3mmX50 cm stainless steel tubes. As shown in table 2, under the test conditions, 5% relative humidity had no effect, but 10% relative humidity decreased the sterilization rate. This example shows that small amounts of water may be allowed to be present in the system together with the hydrogen peroxide generated from the anhydrous peroxide complex, and the presence of water in the system may be overcome by increasing the exposure time.

TABLE 2

Effect of relative humidity on the Effect of SS discs in 3mm X50 cm SS Chambers diffusion time Sterilization results (Positive volume/sample)

1% relative humidity 5% relative humidity 10% relative humidity 50/30/33/3100/30/32/3150/30/30/3300/30/30/3

The main criterion for the composition of the hydrogen peroxide source is the relationship between its stability and the rate of evaporation of hydrogen peroxide as a function of temperature and pressure. Depending on the parameters of the sterilization process, such as pressure, temperature, etc., a higher or lower peroxide evaporation rate may be preferred, while heating the peroxide source may or may not be required. The need to heat the peroxide complex depends on the vapor pressure of the complex. Certain peroxide complexes have sufficiently high vapor pressures that significant amounts of hydrogen peroxide vapor can be released without heating the complex. Generally, heating the complex increases the vapor pressure of the hydrogen peroxide, thereby accelerating the release of peroxide from the complex.

To provide a desirably high evaporation rate, the source preferably has a large surface area. Thus, the source may be a fine powder or a coating on a material with a large surface area. Of course, the safety, availability and cost of the material are also important criteria. The release of hydrogen peroxidefrom complexes of hydrogen peroxide with urea, polyvinylpyrrolidone, nylon-6, glycine anhydride and 1, 3 dimethyl urea was evaluated. This complex of hydrogen peroxide with urea, polyvinylpyrrolidone, nylon-6 and glycine anhydride is a solid. The 1, 3 dimethyl urea peroxide complex is a liquid. The glycine anhydride hydrogen peroxide complex was less stable under reduced pressure than the other complexes evaluated, whereas under vacuum conditions most of the hydrogen peroxide could be released from the complex without additional heating.

The urea hydrogen peroxide complex is available in tablet form from Fluka Chemical corp., ronkonkonkoma, NY, and in powder form from aldrich Chemical co., Milwaukee, w1. The complex can be used as carbamide peroxide, carbamide hydroperoxide complex, carbamide peroxide adduct, carbamide peroxide, carbamide hydroperoxide and carbamide peroxide. The term "carbamide peroxide" as used herein includes all of the above terms.

Polyvinylpyrrolidone-hydrogen peroxide complexes (PVP-H)₂O₂) Can be prepared according to the method disclosed in International application publication No. WO92/17158. Alternatively, complexes containing PVP, nylon-6, 1, 3-dimethyl urea and glycine anhydride, as well as other organic and inorganic compounds, may be prepared as disclosed in detail below.

Achieving a suitable rate of evaporation of the anhydrous peroxide from the source may be facilitated by increasing the temperature and/or decreasing the pressure. Therefore, a heater for heating the peroxide source and/or a vacuum pump for evacuating the sterilization chamber are suitable components of the sterilizer. Preferably, the source is made of a layer of breathable material, such as TYVEK^TMNon-woven polyethylene fabrics, non-woven polypropylene, e.g. SPUNGUARD^TMOr similar material that allows the peroxide vapor to pass through but does not allow the peroxide complex material to pass through. Porous aluminum or other suitable porous materials may also be used as the cover layer.

Fig. 3A shows an apparatus 80 that can be used to measure the release of hydrogen peroxide from a hydrogen peroxide complex under various temperature conditions. In this arrangement, the aluminum plate 90 is provided with a gas permeable layer 92, such as medical grade TYVEK^TMIs covered with the layer(s). The plate 90 is placed on top of a heating base 94, and the heating base 94 is placed within a heat resistant glass plate 96. A thermocouple thermometer 98 is placed on the outside face of the plate 90 approximately 1cm from its bottom.

A preferred container 99 for the peroxide source is illustrated in fig. 3B. The container 99 comprises a metal plate 100E.g., aluminum plate, optionally connected to a heater for heating the solid peroxide complex, a temperature monitor 101, e.g., a thermometer, may be placed on the plate 100 to monitor the temperature. The peroxide complex is placed directly on the plate 100. Alternatively, to provide uniform heating of all the peroxide complex, the peroxide complex may be placed between one or more aluminum meshes 102, 104 placed on top of the plate 100. The aluminum meshes 102, 104 provide a greater surface area and, when a large amount of peroxide complex is used, a uniform heating of the complex. Then passing the oxide complex, orGas-permeable layer 106 for one or more of the barriers 102, 104, e.g. medical grade TYVEK^TMOr SPUNGUARD^TMSuch that hydrogen peroxide released from the complex passes through the cover layer 106 before diffusing into the remainder of the chamber. A porous aluminum plate 108 optionally placed in the TYVEK^TMOr SPUNGUARD^TMOn top of layer 106 to provide pressure to keep the complex in contact with heater plate 100 and to ensure uniform heating of the peroxide.

The device just described provides uniform heating of the complex, resulting in an increase in the amount of hydrogen peroxide vapour released from the peroxide complex.

Fig. 1 is a schematic diagram depicting a hydrogen peroxide vapor sterilization device of the present invention. The chamber 10 contains items 12 to be disinfected, which are conveniently placed on shelves 14. Door 16 provides access to the interior of chamber 10. The anhydrous source 18 of hydrogen peroxide is depicted on an optional heater 20, the heater 20 being controlled by a temperature controller 22. The peroxide concentration may be monitored by an optional monitor 24. If desired, chamber 10 can be evacuated with pump 26; however, sterilization can also be accomplished at atmospheric pressure.

The container containing the goods to be sterilised may be a conventional evacuated sterilisation chamber, or it may be an atmospheric container (or a room).

The time required for sterilization of the articles depends on the nature, quantity, packaging and placement in the chamber of the articles. Alternatively, it may be the sterilization of the chamber itself (or of a complete room). In any case, the optimal sterilization time can be determined experimentally.

The use of pressure pulses to enhance the penetration and bactericidal activity of the sterilant gas is well known in the art of sterilization and may also be used in the anhydrous hydrogen peroxide process. As described in additional detail below, plasma may also be used to further enhance activity.

At the end of the sterilization process, excess hydrogen peroxide may be removed from the peroxide-compatible device by replacing the air in contact with the device. This can be done by circulating hot air throughout the device for a sustained period of time or by evacuating the chamber.

Articles that have been previously sterilized by constant exposure to hydrogen peroxide vapor may also be exposed to a plasma to remove residual hydrogen peroxide that may remain on the article. Since hydrogen peroxide is decomposed into non-toxic products during plasma treatment, the sterilized article can be used without any other steps.

It may be desirable to isolate the peroxide source from the sterilizer after the peroxide vapor is released in order to avoid re-absorption of the vapor, or, when a plasma is used, to avoid exposing the source to the plasma. Isolation is also advantageous when the complexes used are unstable under vacuum. Isolation may be accomplished using valves or other isolation devices known in the art.

Fig. 2 depicts a schematic of a hydrogen peroxide plasma sterilization system of the present invention. Sterilization may be achieved with or without the use of plasma. The use of plasma can enhance the sporicidal activity of the peroxide vapor and/or remove residual hydrogen peroxide left on the sterilized article.

Sterilization takes place in a chamber 30, which chamber 30 comprises a door or opening 32 through which the items to be sterilized can be introduced. The chamber 30 includes an outlet 34 to a vacuum pump 36 through which the chamber can be evacuated. The outlet 34 includes a valve 38 that isolates the chamber from the vacuum pump 36. The chamber 30 also includes an inlet 40 connected to a cartridge 42, the cartridge 42 containing the hydrogen peroxide complex. The inlet 40 includes a valve 44 that isolates the cartridge 42 from the chamber. The sterilization system also includes an inlet 41 connecting the cassette 42 to the vacuum pump 36, which includes a valve 43. The system may have cassette 42 and chamber 30 evacuated simultaneously, or cassette 42 or chamber 30 evacuated separately. Evacuation is controlled by opening and closing valves 38, 44 and 43. As will be clear to those skilled in the art, two pumps, one for each chamber, may also be employed in the system.

The cartridge 42 contains an optional heater 49 which is connected to a temperature controller 46 which controls the temperature of the hydrogen peroxide complex. The concentration of the hydrogen peroxide complex in the vapor state may be monitored by an optional peroxide monitor 48. The chamber interior includes a Radio Frequency (RF) electrode 50 that is connected to a matching electrical network 52 and an RF power source 54. A suitable electrode form is a perforated cylinder which surrounds the sample and is open at both ends. The general operation of the process is as follows:

1. items 56 to be sterilized are placed in chamber 30.

2. The chamber 30 may be at atmospheric pressure or, alternatively, may be evacuated to facilitate permeation of the hydrogen peroxide. Evacuation is accomplished by opening valve 38 and activating vacuum pump 36. On the other hand, chamber 30 and cartridge 42 may be evacuated by opening valves 38 and 44 and/or 43.

3. Valves 38 and 43 are closed to isolate vacuum pump 36 and chamber 30 from cassette 42, and valve 44 is then opened. Hydrogen peroxide vapor is fed into chamber 30 from a source of hydrogen peroxide, which may be heated to facilitate the release of the hydrogen peroxide vapor. Air or an inert gas may also optionally be added.

4. The items to be sterilized 56 are either treated with peroxide vapor in the chamber until sterilization is complete, or pre-treated with peroxide vapor before generating a plasma having sufficient power to effect sterilization. The chamber 30 may then be evacuated to facilitate plasma generation, if desired. The pre-plasma duration depends on the type of assembly used, the nature and number of items to be sterilized, and the placement of the items in the chamber. The optimum time can be determined experimentally.

5. An article 56 is subjected to plasma by supplying power from an RF power source 54 to the RF electrode 50. The RF energy used to generate the plasma may be pulsed or continuous. The articles 56 are in the plasma for a period of time to completely sterilize and/or remove residual hydrogen peroxide. In some embodiments, plasma is used for 5-30 minutes. However, the optimum time can be determined experimentally.

As used in the specification and claims of this application, the term "plasma" is intended to include any portion of an atom or molecule containing electrons, ions, free radicals, dissociated and/or excited as a result of an applied electric field, including any accompanying radiation that may be generated. The applied electric field can cover a wide range of frequencies; however, radio frequency or microwave is generally used.

The anhydrous hydrogen peroxide delivery system disclosed in the present invention may also function with the plasma generated by the method disclosed in the above-mentioned U.S. patent 4643876. In addition, it may be used with a plasma as described in U.S. patent 5,115,166 or 5,087,418, wherein the items to be sterilized are placed in a chamber isolated from the plasma source.

The apparatus just described is particularly advantageous when peroxide complexes which are unstable under vacuum are used. There are at least two possible ways to minimize the loss of hydrogen peroxide during the vacuum phase. First, the chamber can be separately evacuated. Second, if a sufficiently small chamber is used, there is no need to evacuate the chamber at all.

One unstable anhydrous peroxide complex is glycine anhydride peroxide. When this compound is placed under vacuum, it releases hydrogen peroxide vapor. Figure 4 is a graph illustrating the releaseof hydrogen peroxide vapor from glycine anhydride peroxide under vacuum. The procedure for liberating hydrogen peroxide from glycine anhydride complex is as follows: (1) closing valves 43 and 44 evacuates main chamber 30. (2) Closing valves 38 and 44 and opening valve 43 evacuates the chamber containing hydrogen peroxide complex 42. (3) Valve 43 is closed and valve 44 is opened to allow the hydrogen peroxide vapor to diffuse into chamber 30.

As shown by this graph, when the pressure is reduced, hydrogen peroxide vapor is released from the complex even without additional heating. By heating this complex to higher temperatures, the release of peroxide vapour can be significantly enhanced, as illustrated in figure 4. Thus, even unstable peroxide complexes are useful in the present sterilization method.

The present invention has at least four advantages over previous hydrogen peroxide disinfection systems:

1 avoiding the use of concentrated, potentially dangerous hydrogen peroxide solutions

2 eliminates the need to lower the relative humidity of the area to be disinfected beforehand in order to prevent condensation.

3 substantially removes water in the system, thereby leaving little competition between water and hydrogen peroxide for diffusion into the long narrow chamber.

4 often eliminates the need to connect a special container for delivering sterilizing gas to a long system.

The ability to sterilize using hydrogen peroxide vapor in the substantial absence of moisture is one of the surprising discoveries of the present invention. The prior art teaches that the presence of water is required to accomplish disinfection in a chemical gaseous or steam disinfection process. Advantageously, the present invention substantially eliminates water from the system, which results in faster, more efficient disinfection.

The disinfecting efficacy of various anhydrous hydrogen peroxide complexes was determined according to the following examples 1-4.

Example 1

With hydrogen peroxide vapour released from substantially anhydrous carbamide peroxide complex, with metal and TEFLON^TMBacillus Subtilis Var (Niger) spores in plastic tubes were used as biological targets to obtain efficacy data. A. Test procedure

1 apparatus

As shown in FIG. 3A, a 4 gram piece of comminuted urea hydrogen peroxide adduct (Fluka chemical Corp, Ronkon koma, NY) was placed on aluminum plate 90. On top of the plate 90, a medical grade TYVEK is laid^TM92 (a breathable spun (spun) polyethylene fiber) so that any hydrogen peroxide released from the complex must pass through the TYVEK before diffusing into the remainder of the chamber^TMAnd (4) a covering layer.The aluminum plate 90 is placed on a heated base 94 in a heat resistant glass plate 96, the heat resistant glass plate 96 being placed at the bottom of the aluminum sterilization chamber (see fig. 1). The sterilization chamber having a volume of about 173 liters further comprises:

a hydrogen peroxide monitor that measures the concentration of hydrogen peroxide in the vapor phase.

A temperature controller for controlling the temperature of the heating susceptor.

An injection port through which liquid hydrogen peroxide can be injected into the chamber.

A metal stand on which the plastic disk of the chamber-containing device for the test is placed.

Resistance heaters outside the chamber walls, which maintained the chamber temperature at 45 ℃during the efficacy test.

2 biological test object and test

To evaluate the efficacy of the anhydrous peroxide delivery system, the system was constructed from 1.04X 10 on stainless steel surgical blades⁶Subtilis Var (niger) spore composition biological test subjects were placed equidistantly from the end of each stainless steel chamber measuring 3mm id x 40cm long, 3mm id x 50cm long and 1mm id x 50cm long. These inner diameters and lengths are typical for metal lumens for medical devicesAnd (4) carrying out the following steps. The dimension of the area containing the biological test piece in the middle portion of each chamber was 13mm in inner diameter × 7.6cm long. In the biological test using the metal chamber, a total of 9 chambers were evaluated in each test. These 9 lumens included 3 lumens from each of 3 different sets of inner diameters and lengths.

With 4.1X 10 bands on a paper strip (6mm X4 mm Whatman 1' chromatography paper)⁵Similar tests were carried out on biological test subjects consisting of (niger) spores, made from TEFLON^TMThe ends of the lumen are equidistantly spaced and have the dimensions 1mm id x 1m long, 1mm id x 2m long, 1mm id x 3m long, and 1mm id x 4m long. The central portion of these chambers contained biological test strips, the dimensions of which were 15mm inner diameter x 7.6cm long. Under-use TEFLON^TMIn the chamber bioassay, a total of 12 chambers were evaluated for each test, and 3 chambers were taken from each group of 4 different lengths.

The chamber containing the biological test sample is placed on a plastic tray, which is then placed on a rack in a sterilization chamber. The chamber door was closed and the chamber was evacuated to a pressure of 0.2 torr using a vacuum pump. The aluminum plate containing the urea hydrogen peroxide adduct was then heated to 80-81 c for 5minutes as measured with a thermocouple thermometer mounted on the side wall of the aluminum plate about 1cm from the bottom of the aluminum plate. The hydrogen peroxide concentration in this chamber, measured by the peroxide monitor at this time, increased to 6 mg/L. The biological test specimens were exposed to hydrogen peroxide vapor for 5, 10, 15, 20, and 25 minutes. After exposure to hydrogen peroxide vapor, the biological test samples were aseptically transferred to 15mL of trypsin (trypticase) soy medium containing 277 units of catalase to neutralize any hydrogen peroxide residue that may remain on the test samples. All samples were incubated at 32 ℃ for 7 days and observed for growth.

A comparative study was also conducted in which a 50% aqueous solution of hydrogen peroxide was injected into the sterilization chamber and then evaporated from a heated injector (heated metal surface). The hydrogen peroxide solution introduced in large amounts produced a hydrogen peroxide vapor phase with a concentration of 6 mg/L. The test chamber and biological sample used in these tests were the same as used in the anhydrous hydrogen peroxide test. The treatment of the biological sample after exposure to hydrogen peroxide is also the same. Test results of B

Stainless steels and TEFLON for these^TMThe results of the tests, listed in tables 3 and 4, respectively, illustrate the advantages of the anhydrous peroxide delivery system for disinfecting metal and non-metal cavities. Sterilization with the anhydrous peroxide delivery system within 5 minutes of the smallest inner diameter and longest lumen evaluated killed all bacterial spores. At the same time, complete kill cannot be achieved with a 50% hydrogen peroxide solution even after a diffusion time of 25 minutesDeath.

TABLE 3

Comparison of Water/Water free efficacy

Disinfection results (positive/sample) with SS blade peroxide source diffusion time (minutes) in SS chamber

3mm×40cm 3mm×50cm 1mm×50cm

5 3/3 3/3 3/3

100/32/33/350% solution 151/31/31/3

20 0/3 0/3 1/3

25 0/3 0/3 1/3

5 0/3 0/3 0/3

100/30/30/3 Urea peroxide 150/30/30/3

20 0/3 0/3 0/3

25 0/3 0/3 0/3

TABLE 4

Comparison of Water/Water free efficacy

In TEFLON^TM6mm 4mm paper tape in cavity

Disinfection results (Positive quantity/sample) peroxide Source diffusion time (minutes) 1 mm. times.1 m.times.2 m.times.1 m.times.3 m.times.1 mm. times.4 m

5 3/3 3/3 3/3 3/3

103/33/33/33/350% solution 150/31/31/32/3

20 0/3 0/3 1/3 1/3

25 0/3 0/3 0/3 1/3

5 0/3 0/3 0/3 0/3

100/30/30/30/3 Urea peroxide 150/30/30/30/3

20 0/3 0/3 0/3 0/3

25 0/3 0/3 0/3 0/3

The fact that sterilization can be accomplished quickly in the substantial absence of water is unexpected in view of the fact that moisture is generally always present during chemical gas/vapor phase sterilization with various sterilizing agents other than hydrogen peroxide. Since vapor phase hydrogen peroxide sterilization systems have been using aqueous hydrogen peroxide, moisture has also been present in these systems.

To test the disinfecting efficacy of various other peroxide complexes, the following tests were performed.

Examples 2, 3 and 4

The apparatus of example 1 was used to test the efficacy of polyvinylpyrrolidone-hydrogen peroxide complex (example 2), nylon 6-hydrogen peroxide complex (example 3) and 1, 3 dimethyl urea hydrogen peroxide complex (example 4). These compounds were synthesized according to the methods described in examples 12 and 13 below. The test parameters were as follows:

examples

Temperature of 234 Chambers 45 deg.C initial pressure 0.2 torr 1.0 torr% weight of peroxide 17% 10.5% 26.6% peroxide concentration 6 mg/L6 mg/L6 mg/L6 g weight of peroxide used for each process temperature 110 deg.C 80 deg.C

In each case, the spore carriers were a 6mm by 4mm paper substrate in a plastic chamber and a stainless steel blade in a stainless steel chamber. The end of the efficacy test is shown in table 5 below.

TABLE 5

Efficacy Chamber size Disinfection results (positive volume/sample) for PVP, Nylon 6 and 1, 3 dimethyl Urea Complex

Example 2 example 3 example 4

1mm×1m 0/3 0/3 0/3

1mm×2m 0/3 0/3 0/3TEFLON^TM

1mm×3m 0/3 0/3 0/3

1mm×4m 0/3 0/3 0/3

3mm X40 cm 0/30/30/3 stainless steel 3mm X50 cm 0/30/30/3

1mm×50cm 0/3 0/3 0/3

The results shown in table 5 indicate that each of the hydrogen peroxide complexes tested produced peroxide vapor providing effective disinfection after 5 minutes exposure.

As indicated above, the temperature required to release the hydrogen peroxide vapor from the solid complex was the temperature measured by a thermocouple thermometer positioned outside the aluminum plate at about 1cm from the bottom of the aluminum plate. As described in example 5 below, another test with a thermometer, such as a fluorotic thermometer, mounted on the inside of the bottom of the aluminum plate showed a temperature at the bottom of the aluminum plate that was about 30-35 deg.C higher. Thus, in the above embodiment, the temperature at the bottom of the aluminum plate was approximately 110 ℃ and 115 ℃ when the thermocouple thermometer read 80 ℃ and approximately 140 ℃ and 145 ℃ when the thermocouple thermometer read 110 ℃.

Example 5

To determine the temperature of the bottom of the aluminum plate used to hold the solid peroxide complex, a fluorogenic thermometer was placed inside the bottom of the aluminum plate. Will be one Omega^TMA thermocouple thermometer was mounted about 1cm from the bottom of the aluminum plate, on the outside of the aluminum plate. Three different thermometer readings were taken. Each time the aluminum plate was heated to the desired temperature as indicated by a thermometer mounted on the side of the aluminum plate, then cooled, and then reheated to the desired temperature. The temperatures recorded are listed below:

temperature on side of aluminum plate bottom temperature (. degree. C.)

First second third average

80℃ 110.9 110.6 110.6 110.7

These results, 100 ℃ 131.5132.6132132, show that: the temperature at the bottom of the aluminum plate was 30-35 c higher than that indicated by a thermocouple thermometer mounted on the side of the aluminum plate.

Another experiment was conducted to compare the efficacy data obtained using aqueous and anhydrous peroxide sources in an open system (non-luminal). The experiments are detailed below.

Example 6

Using the apparatus of example 1, biological test subjects were prepared by coating TYVEK with^TM/MYLAR^TMWhatman 1 in the housing^#6.8X 10 on 6mm X4 mm bands of chromatography paper⁵B. subtilis Var (niger) spore composition. (TYVEK)^TMIs a breathable fabric made of polyethylene. MYLAR^TMIs an air impermeable polyester material). The strips of the encapsulated biological test subjects were placed in front, in the middle and in the back of a polybenzoxy disk containing a bendable fiber optic sigmoidoscope. The tray was placed in a polyphenylene oxide container with one port on the top and two ports on the bottom for diffusion. Breathable polypropylene sealing material (SPUNGUARD) for 4 inch diameter port^TMHeavydty Sterilation Wrap, Kimberly-Clark, Dallas, TX) to keep the contents of the container sterile after Sterilization. The vessel was placed in the apparatus of example 1 and the pressure in the chamber was then reduced to 0.2 torr. 2 grams of urea hydrogen peroxide adduct (Fluka Chemical Corp) were then chargedThe aluminum plate was heated to 80-81 c for 5 minutes as measured by a thermocouple thermometer on the outside of the aluminum plate about 1cm from the bottom of the aluminum plate to provide 3mg/L of hydrogen peroxide vapor in the chamber. The biological sample is exposed to this hydrogen peroxide vapor for a period of 5 and 10 minutes. After exposure, the experimental samples were treated in the same manner as in example 1.

A comparative study was also conducted in which a 50% aqueous hydrogen peroxide solution was injected into the sterilization chamber and then evaporated from the heated injector. The large amount of hydrogen peroxide solution injected produced a vapor phase with a concentration of 3 mg/L. The composition of the test, the composition of the biological sample and the treatment of the biological sample after exposure are the same as those used in the anhydrous hydrogen peroxide test. The structures of these tests are shown in table 6.

TABLE 6

Comparison of aqueous/Anhydrous efficacy in open System (non-Chamber test) peroxide Source diffusion time (minutes) Disinfection results (Positive amount/sample)

53/350% solution

10 3/3

51/3 Urea peroxide

10 0/3

These test results demonstrate that in an "open" system where the biological sample is not placed in the chamber, the efficacy of anhydrous peroxide is greater when compared to the aqueous hydrogen peroxide method. Furthermore, the surprising findings are: even though hydrogen peroxide does not need to diffuse in long and narrow cavities, the anhydrous system provides superior efficacy. This suggests that: the mode of action of hydrogen peroxide is different for aqueous and anhydrous systems.

Additional tests were conducted to determine the efficacy of anhydrous peroxide vapor at atmospheric, non-reduced pressure. The assay is described in detail below.

Example 7

In an open system at atmospheric pressure with hydrogen peroxide vapour released from the urea hydrogen peroxide complexAnd (4) efficacy test. In this test, 1.04X 10 on a stainless steel scalpel⁶SubtilisVar. (niger) spore bioassay subjects TYVEK^TM/MYLAR^TMPackaging in a sealed envelope, and placing the packaged biological test object blades at the front, middle and rear parts of a polyphenylene oxide disc. The tray was placed in the apparatus of example 1 and the door was closed. An aluminum plate containing 4.0gm of carbamide peroxide (Fluka Chemical Corp) was heated to 80-81 ℃ during the test, as measured by a thermocouple thermometer mounted on the side of the aluminum plate approximately 1cm from the bottom of the plate. The biological sample is exposed to this hydrogen peroxide vapor for 5, 10, 20 and 30 minutes. After exposure, the sample was treated in the same manner as in example 1. The test results are shown in table 7 and illustrate the efficacy of the anhydrous peroxide process in an open system at atmospheric pressure.

TABLE 7

Efficacy of the Anhydrous peroxide Process in an open System at atmospheric pressure, peroxide source diffusion time (minutes) Disinfection results (Positive/sample)

5 3/3

101/3 Urea peroxide 200/3

30 0/3

Another test was conducted to determine the approximate amount of peroxide released from the urea hydrogen peroxide complex at different temperatures. This test will be described in example 8.

Example 8

The powder obtained from the crushed commercial urea peroxide flake (Fluka Chemical Corp) was placed between two aluminum plates in the apparatus of FIG. 3B, the size of the plates being 12.7cm by 12.7 cm. The aluminum plate was then heated and the temperature monitored with a thermometer located near the corner of the aluminum plate. Table 8 lists the approximate percentages of peroxide released at different temperatures over 5 minutes after heating. The data show that: approximately 100% of the peroxide is released from the complex at a temperature of 140 ℃. A smaller percentage of peroxide is released at lower temperatures.

TABLE 8

Release of anhydrous peroxide at different temperatures

Peroxide released at heating temperature%

80℃ ～25％

100℃ ～65％

120℃ ～80％

130℃ ～90％

140℃ ～100％

Peroxide complexes having the ability to release hydrogen peroxide vapour at room temperature and pressure, such as carbamide peroxide complexes, are effective for use in different sterilization applications, not only in the above-described sterilization device of the present invention, but the compounds of the present invention may also be used in part as self-sterilizing packaging materials, or applied to carriers such as gauze, sponges, cotton, and the like. The compounds provide for the sterilization of sealed packages at room temperature or elevated temperatures, and are particularly useful for the sterilization of packaged medical or surgical products.

Specific uses of the compounds of the invention are described in the examples below. The peroxide complex used in the following examples is in the form of a tablet (Fluka Chemical Corp) or urea peroxide in powder form obtained by crushing the tablet.

Example 9

The self-sterilizing pouch is assembled as follows: one carrying 3.8X 10 on its surface⁵B. sutilis var. niger spores knives were placed in sterile petri dishes. The dish was placed in a larger petri dish together with 1gm of the carbamide peroxide complex in the form of a tablet or powder. The petri dish was then placed in TYVEK^TM/MYLAR^TM(breathable, table 9), MYLAR^TM/MYLAR^TM(gas impermeable watch 10) or Paper/MYLAR^TM(breathable, table 10). The bag is then sealed.

Each bag was exposed to different temperatures and different times as shown in tables 9 and 10. The biological test samples were evaluated for sterilization as described in example 1. The results are shown in tables 9 and 10, with the "+" sign indicating bacterial growth.

TABLE 9

Self-eliminating vegetable bag (TYVEK) on air-permeable partition^TM/MYLAR^TM)

Temperature of	Peroxide type	1 hour	2 hours	3 hours	4 hours
						23℃	Powder	+	-	-	-
Sheet	+	+	-	-
					40℃		Powder	-	-	-	-
Sheet	-	-	-	-
						60℃	Powder	-	-	-	-
Sheet	-	-	-	-

Table 10 lists the results obtained with (Daper/MYLAR)^TM) While not used (MYLAR)^TM) Efficacy data for self-disinfecting bags for breathable barriers. These bags are assembled as described above, however, the source of peroxide vapor is simply urea peroxide in powder form.

Watch 10

Self-disinfecting pouch with and without air-permeable barrier

Temperature of	Type of package	2 hours	4 hours
				23℃	MYLAR/MYLAR	-	-
Paper/MYLAR	+	-
			40℃		MYLAR/MYLAR	-	-
Paper/MYLAR	-	-
				60℃	MYLAR/MYLAR	-	-
Paper/MYLAR	-	-

The results of this test show that: the carbamide peroxide of the present invention, packaged in bags with and without breathable barrier, is effective in sterilizing the contents of the bag after only 2-3 hours in the absence of moisture at room temperature and pressure. At higher temperatures, the sterilization is completed in only 1 hour.

The efficacy of the sterilization system of the present invention in a sealed container was determined and the following experiments were conducted.

Example 10

The self-sterilizing container is assembled as follows: having a surface of 3.8X 10⁵Subtilis var niger spores (Table 11) or 9.2X 10 on their surface⁵A stainless steel carrier of subtilis Var niger spores (table 12) was placed in a Polyethylene (PE) vial having 20 holes (size 3/16 ") in its surface. This vial was placed in a larger PE vial using either an airtight cap or a SPUNGGARD^RThe gas permeable layer of (CSR Wrap) was capped. Also included in the larger vial is aTwo PE vials also had 20 wells (size 3/16 ") in their surface. The vial contains 1gm of carbamide peroxide in powder or tablet form and is treated with SPUNGUARD^TM(CSR wrappers) or TYVEK^TMThe bag is sealed.

Each container was exposed to different temperatures for different times as shown in tables 11 and 12 below. The sterilization of biological samples was evaluated as described in example 1. The results are shown in tables 11 and 12, with the "+" sign indicating bacterial growth.

TABLE 11

Self-sterilizing container without air vent

Temperature of	Type of package	2 hours	6 hours
				23℃	Non-packaging sheet	+	-
C/C packaging sheet	+	-
			C/C packaging powder		+	-
40℃	Non-packaging sheet	-					-
			C/C packaging sheet	-	-
	C/C packaging powder	-				-
			60℃	Non-packaging sheet	-		-
C/C packaging sheet	-	-
				C/C packaging powder	-	-

Bag made of CSR wrap

TABLE 12

Self-sterilizing container with CSR ventilation port

Temperature of	Type of package	0.5 hour	1.0 hour	1.5 hours	2.0 hour	3.0 hours	4.0 hours
								23℃	Non-packaging sheet		+	+	+	-	-
Unpackaged powder		+	+	+	-	-
							T/T packaging sheet			+	+	+	+	-
T/T packaging powder		+	+	+	-	-
							C/C packaging sheet			+	+	+	-	-
C/C bagCharging powder		+	+	+	-	-
							40℃		Non-packaging sheet	-	-	-	-
Unpackaged powder	-	-	-	-
								T/T packaging sheet	+	-	-	-
T/T packaging powder	-	-	-	-
								C/C packaging sheet	-	-	-	-
C/C packaging powder	-	-	-	-
								60℃	Non-packaging sheet	-	-	-	-
Unpackaged powder	-	-	-	-
							T/T packaging sheet		-	-	-	-
T/T packaging powder	-	-	-	-
							C/C packaging sheet			-	-	-
C/C packaging powder	-	-	-	-

*TYVEK^TMBag made of CSR wrap

The results of this test show that: the anhydrous carbamide peroxide complex contained in the container with and without the air-permeable barrier provides effective disinfection after only 3-4 hours at room temperature. At higher temperatures, sterilization is completed in as little as one and a half hours.

It has been found that anhydrous peroxide complexes that release peroxide vapor are useful for disinfecting articles at room temperature, but are more effective at higher temperatures. These compounds can be placed in bags, containers, chambers, rooms or any sealable area where they release peroxide vapor for effective sterilization of the article. These compositions can be heated to promote vapor release and require less time to sterilize than at room temperature. Therefore, the compounds of the present invention are useful in a variety of applications where disinfection is desired. In short, sterilization is accomplished by placing the composition in a sealed area containing the item to be sterilized. Unlike prior art methods, hydrogen peroxide activity is provided without the need for moisture exposure.

To further confirm that sterilization can be accomplished with the anhydrous peroxide complex at low pressure in less time, the following experiment was conducted.

Example 11

A self-sterilizing container is assembled as follows: one carrying 9.2X 10 on its surface⁵B. subtilis var. niger spores are placed in PE vials with 20 wells (size 3/16 ") on the surface. The vial is placed in a CSR bagWrapping material (SPVNGVARD)^TM) In larger PE bottles covered with a gas permeable layer. Also contained in this larger bottle was a second PE bottle also having 20 holes (size 3/16 ") in its surface. This bottle contained 1gm of carbamide peroxide in powder or tablet form. The bottles were then coated with CSR wrap or TYVEK^TMThe bag is sealed.

The large bottle was placed in a 4.5L sterilization chamber or a 173L sterilization chamber. As shown in Table 13, each vessel was exposed to a pressure of 100 torr and a temperature of 23 ℃ for 2 hours. The sterilization of biological samples was evaluated as described in example 1. The results are shown in Table 13.

Watch 13

Self-sterilizing container with venting port under reduced pressure

Temperature of	Type of package	4.5L Chamber	173L chamber
				23℃	Unpackaged powder	-	-
T/T packaging powder	-	-
			C/C packaging powder		-	-

These results show that: the anhydrous carbamide peroxide complex contained in the container with the air-permeable barrier can provide effective disinfection after only 2 hours at 100 torr and room temperature. When compared to the results in table 12, these results demonstrate that: the peroxide complexes of the present invention provide disinfection under reduced pressure in less time than is required to accomplish disinfection at atmospheric pressure.

In this way, the hydrogen peroxide complexes of the present invention can provide effective disinfection in a significantly short period of time. In addition, as noted above, plasma may also be used to enhance the disinfecting activity of the hydrogen peroxide vapor. The articles to be sterilized are subjected to the plasma after exposure to the peroxide vapor and left in the plasma for a sufficient time to complete sterilization.

An article that has been sterilized by exposure to hydrogen peroxide vapor may be exposed to a plasma to remove any residual hydrogen peroxide remaining on the article. Since the residual hydrogen peroxide is decomposed into non-toxic products during the plasma treatment, the sterilized article can be quickly used for subsequent treatment without any additional steps.

The anhydrous peroxide complexes are useful in a variety of applications, including self-sterilizing packaging components. In addition, the complexes are suitable for use in various methods of steam sterilization of articles, such as the method disclosed in U.S. patent No.4,943,414. This patent discloses a method in which a container containing a small quantity of a vaporizable fluid disinfectant solution is connected to a chamber and the disinfectant is vaporized and then allowed to flow directly into the chamber of the article as the pressure is reduced during sterilization. The process disclosed in this patent can be modified to employ anhydrous peroxide compounds. The compound is placed in a container and connected to the chamber of the item to be sterilized. The article is then placed in a container and the container is evacuated. The cavity of the article and the exterior of the article are contacted with hydrogen peroxide vapor released from the anhydrous compound. A plasma may optionally be generated and used to enhance the sterilization and/or to remove any residual hydrogen peroxide from the article.

As previously mentioned, the use of an anhydrous peroxide complex in the present system overcomes the disadvantage of water in the aqueous solution evaporating more rapidly and into the chamber before the hydrogen peroxide vapor. Thus, a more efficient sterilization is achieved, requiring less time to complete the sterilization. Hydrogen peroxide complexes, such as those of glycine anhydride, are particularly advantageous because they release large amounts of hydrogen peroxide under reduced pressure without the need for additional heating of the complex. Synthesis of anhydrous Hydrogen peroxide complexes

The present invention further provides a process for preparing an anhydrous hydrogen peroxide complex, which, as described above, can be used as a source of hydrogen peroxide in a hydrogen peroxide vapor sterilizer, or as a component of a self-sterilizing package. Of course, the hydrogen peroxide complexes may also be used in other applications, such as bleaching agents, contact lens solutions, catalysts and others, as is well known to those of ordinary skill in the art.

The general procedure for preparing the hydrogen peroxide complexes of the invention is as follows: (1) placing a reactant material in the chamber

The material to be reacted with the hydrogen peroxide may be in the form of a solid (e.g., powder, crystal, film, etc., preferably having a high surface area to increase the reaction rate). The reactive material may also be present as an aqueous or other reagent solution if sufficient time is available to allow thereagent to evaporate after depressurization in the chamber. The material may also be a liquid with a boiling point higher than that of hydrogen peroxide (150 c). Because of the relatively fast reaction rate at high temperatures, it is desirable to heat the chamber either before or after introduction of the reaction components. However, the temperature should not be so high as to cause boiling or evaporation of the reactants.

The reaction components can be contained in any container that provides a passage for peroxide vapor. If it is in powder form or otherwise, and may be in a form that is blown around when the chamber is evacuated, the reactant may be left in a gas permeable container, which allows the hydrogen peroxide to diffuse into the container. (2) Evacuating the chamber

The chamber is preferably evacuated to a pressure below the vapor pressure of the hydrogen peroxide (depending on its concentration and temperature) to ensure that all the peroxide is in the vapor phase. The vapor pressure increases with increasing temperature and decreases with increasing peroxide concentration. For most experiments, the chamber may be evacuated to about 0.2 Torr at room temperature or above. (3) Generating hydrogen peroxide vapor

The hydrogen peroxide vapor may be generated from a hydrogen peroxide solution or from a substantially anhydrous hydrogen peroxide complex.The latter produces dry hydrogen peroxide in the vapour state, which is an advantage if the starting material to be reacted with the vapour, or the complex to be formed, is hygroscopic. Another advantage of generating hydrogen peroxide vapor from a substantially anhydrous complex is: the percentage of hydrogen peroxide in the complex being formed is higher than if the vapor originated from H₂O₂The percentage of aqueous solution of (a) is high. This may be due to the generation of H when using aqueous solutions₂O₂Water molecule and H in steam₂O₂The molecules compete for binding sites on the complex.

The peroxide vapor may be generated in the same chamber that holds the reactive material or in another chamber separated by a vacuum valve. (4) Reacting a reactant material with hydrogen peroxide

The time required for the reaction will, of course, depend on the rate of reaction of the reactants with the hydrogen peroxide. It can be determined experimentally by monitoring the pressure which is reduced during the time the peroxide is bound to the reactive material. Generally, the reaction time is about 5 to 30 minutes. The concentration of hydrogen peroxide that is vaporized and the weight of the starting materials determine the weight percent of peroxide in the final reaction product. As the weight ratio of reactants to hydrogen peroxide increases, the weight percent of hydrogen peroxide in the complex decreases. The reaction is repeated a number of times in order to increase the concentration of hydrogen peroxide in the complex. (5) The chamber is then evacuated

At the end of the reaction, the chamber is further evacuated to about 2 torr to remove any unreacted hydrogen peroxide. (6) Venting the chamber and recovering the peroxide complex

The mechanism by which hydrogen peroxide forms complexes with reactive materials is not fully understood. The formation of the complex is believed to be associated with the formation of hydrogen bonds between the hydrogen peroxide and the electron rich functional groups containing oxygen and/or fluorine on the reactive material. It is not known whether this is the only way to bind; however, it has been found that materials having a wide range of functional groups form complexes with hydrogen peroxide.

Advantages of the vapor phase reaction over the earlier methods of formingperoxide complexes include:

1. the ratio of hydrogen peroxide to reactant material can be accurately controlled by varying the amount of hydrogen peroxide present in the vapor state or the amount of reactant material exposed to the vapor.

2. Eliminating the need to remove the solvent from the reaction product.

3. The peroxide complexes may be formed as liquids or solids, such as powders, crystals, flakes, and the like.

4. Peroxide complexes of hygroscopic materials can be prepared.

The synthesis of anhydrous peroxide complexes according to the present invention is further illustrated in the following examples. Many of these compounds have utility as catalysts in addition to those described in more detail herein, as will be readily understood by those of ordinary skill in the art. These examples illustrate embodiments of the compositions and methods of the present invention, but are not intended to limit the scope of the invention in any way.

Example 12

The hydrogen peroxide complex of glycine anhydride was prepared as follows: a1.0 gm sample of glycine anhydride (Aldrich chemical Co., Milwaukee, W1) was placed in an aluminum pan in a 173 liter chamber maintained at a temperature of 45 ℃. TYVEK for the Top of an aluminum dish^TMA non-woven fabric covering which prevents glycine anhydride from escaping from the tray when the pressure in the chamber is reduced, but which is breathable and does not absorb hydrogen peroxide. The chamber door was closed and the chamber was evacuated by a vacuum pump to reduce the pressure in the chamber to 0.2 torr. A hydrogen peroxide concentration of 10 mg/liter was achieved by evaporating an appropriate amount of 70% aqueous hydrogen peroxide (FCM corp., philiadelphia, PA) into the chamber. The hydrogen peroxide vapor was kept in contact with glycine anhydride for 20 minutes. At the end of the reaction, the pressure in the chamber was reduced to 2 torr and then raised back to atmospheric pressure. The reaction product was removed from the chamber and then analyzed for weight percent hydrogen peroxide by iodometric titration as described below.

A starch indicator was used in the iodine-sodium thiosulfate titration reaction to enhance the color change of the endpoint. The weight percent hydrogen peroxide is calculated by the following equation:

Wt％H₂O₂＝[(Na₂S₂O₃ml)*(Na₂S₂O₃equivalent concentration) 1.7]V (sample weight gm)

The weight percent of hydrogen peroxide in the glycine anhydride complex was found to be 24.3%.

Example 13

The procedure of example 12 was used to prepare hydrogen peroxide complexes of various organic and inorganic complexes. In each case, the reaction conditions were the same as in example 12, but 1.0gm of each compound listed in table 14 was used instead of glycine anhydride.

TABLE 14

In the compounds to be evaluated and complexes formed by vapour phase synthesis

Weight percent chemical name of Hydrogen peroxide chemical Structure the wt% class poly (vinyl alcohol) [ -CH after peroxide treatment₂CH(OH)-]_n18.9% alcoholic poly (vinyl methyl ether) [ -CH₂CH(OCH₃)-]_n22.0% Ether poly (vinyl methyl ketone) [ -CH₂CH(COCH₃)-]_n13.9% Ketone Poly (acrylic acid) [ -CH₂CH(COOH)-]_n5.1% acid Glycine H₂C(NH₂) (COOH) 20.7% amino acid L-histidine14.1% amino acid poly (vinyl acetate) [ -CH₂CH(OCOCH₃)-]_n9.1% cellulose acetate ester 10.9% sodium alginate 27.7% cellulose sulfate organic salt18.2% sodium salt of organic salt Poly (4-vinylpyridine) [ -CH₂CH(P-C₅H₄N)-]_n21.8% of an aromatic amineHistamine

13.2% Aminopropionamide (C)₂H₅)CONH₂31.8% amide Urea (H)₂N)₂CO 17.9% Urea 1, 3-dimethylurea (H)₃C)HNCONH(CH₃) 31.7% Urea biuret (H)₂N)CO(NH)CO(NH₂) 13.7% biuret polyacrylamide [ -CH₂CH(CONH₂)-]_n30.1% of polyamide polyvinylpyrrolidone

29.9% Polyamide Nylon 6 [ -NH (CH)₂)₅CO-]_n17.1% Polyamide Nylon 6, 6 film [ -NH (CH)₂)₆NHCO(CH₂)₄CO-]_n16.6% of a polyamide polyether polyurethane [ -RHNCOOR-]_n9.5% polyurethane sodium carbonate Na₂CO₃14.3% inorganic Potassium carbonate K₂CO₃33.9% of inorganic substanceRb carbonate₂CO₃37.0% inorganic calcium hydroxide Ca (OH)₂23.4% inorganic sodium bicarbonate NaHCO₃10.7% of inorganic substanceTetrasodium pyrophosphate Na₄P₂O₇18.9% of inorganic matter

These organic complexes formed include functional groups capable of forming hydrogen bonds with hydrogen peroxide in the following ranges: alcohols, ethers, ketones, acids, amino acids, esters, organic salts, amines, amides, polyamides, polyurethanes, ureas, and biurets. Inorganic complexes include carbonates of sodium, potassium and sodium cations, and sodium bicarbonate. In addition, hydrogen peroxide complexes of calcium hydroxide and tetrasodium pyrophosphate may be prepared. The starting material was finely ground or a slightly larger crystalline material, except for nylon 6, which was processed into a film having a thickness of 0.12mm and except for polyvinyl methyl ether, which was a 50% by weight aqueous solution.

The hydrogen peroxide complexes obtained with these materials under the test conditions were solid except for polyvinylpyrrolidone, histamine, poly (vinyl methyl ether), poly (vinyl methyl ketone), propionamide and 1, 3-dimethylurea. The 1, 3-dimethylurea and propionamide hydroperoxide complexes are free flowing liquids which are easily handled in a vapor phase synthesis process because no solvent removal is required to obtain the final product. Histamine, polyvinylpyrrolidone, poly (vinyl methyl ether) and poly (vinyl methyl ketone) complexes are colloidal materials that are not easily handled.

Examples 14 and 15 describe additional studies with polyvinylpyrrolidone under different process conditions, resulting in a peroxide complex as a free-flowing solid product.

Example 14

Hydrogen peroxide complexes of polyvinylpyrrolidone are prepared in which the percentage of hydrogen peroxide in the polyvinylpyrrolidone complex varies as a function of the ratio of the weight of polyvinylpyrrolidone to the concentration of hydrogen peroxide in the vapor state. The conditions in these tests were the same as in example 12, except that the weight of polyvinylpyrrolidone was increased from 1.0 to 3.0 to 5.0 grams. The hydrogen peroxide concentration was kept constant at 10.0 mg/liter of chamber volume in all tests. The results of these tests are shown in Table 15.

Example 15

Preparing a hydrogen peroxide complex of PVP, wherein the hydrogen peroxide is provided from a urea hydrogen peroxide complex. When hydrogen peroxide is provided in this manner, it is substantially anhydrous. In this test, 5 grams of PVP was placed in a reaction chamber and passed through a reactor containing about 7 grams of 35% urea H₂O₂The complex is heated to a temperature of about 110 ℃ for about 5 minutes to obtain a temperature of 10mgH₂O₂The reaction chamber is supplied with/liter of chamber volume.The remaining conditions in this test were the same as in example 12. The percentage of hydrogen peroxide in the PVP complex and the physical state of the complex are shown in table 15.

Watch 15

In a complex of polyvinylpyrrolidone and vaporized hydrogen peroxide

Effect of% Hydrogen peroxide and physical State of the product

Weight (g) of PVP H in Complex₂O₂Physical State of the weight% products example 14129.9 Soft gel product

323.5 hard gum products

517.7 self-flowing solid example 15519.7 self-flowing solid

These test results demonstrate that: by controlling the ratio of PVP to vaporized hydrogen peroxide, a free flowing solid can be obtained with a PVP hydrogen peroxide complex, in other words, by using a substantially anhydrous source of hydrogen peroxide vapor. Inorganic hydrogen peroxide complexes

Inorganic hydrogen peroxide complexes are also suitable for use as disinfectants as described in detail above for organic hydrogen peroxide complexes. Peroxide vapors can be released from these inorganic complexes at atmospheric pressure and room temperature. However, as described in more detail below, a large amount of hydrogen peroxide vapor may be released from the inorganic peroxide complex under reduced pressure with rapid heating to a specific release temperature. For successful release of hydrogen peroxide from the inorganic complex, the heating rate of the inorganic peroxide complex is preferably at least 5 ℃/min; more preferably at least 10 ℃/min, still more preferably at least 50 ℃/min; and preferably at least 1000 c/min.

A representative list of these inorganic peroxide complexes and the weight percent hydrogen peroxide are shown in table 16. For determining H in the complex₂O₂The titration method for weight percent was the same as described in example 12. Sodium carbonate H₂O₂The complexes were purchased from Fluka chemical Corp. The vapor phase synthesis method for synthesizing the inorganic peroxide complex was the same as that disclosed in example 12 except that 10g of the solid inorganic sample was used instead of 1-5g and both were reactedThe cycle is changed to one reaction cycle.

Example 16

The procedure for the liquid phase synthesis of inorganic hydrogen peroxide complexes is essentially as described by Jones et al (Jchem Soc., Dalton, 12: 2526-2532, 1980). Briefly, first, an inorganic solid was dissolved in a 30% aqueous hydrogen peroxide solution to prepare a saturated solution, followed by dropwise addition of ethanol. For the potassium oxalate and rubidium carbonate complexes, white peroxide precipitates formed with increasing amounts of ethanol added. For potassium carbonate, potassium pyrophosphate and sodium pyrophosphate, the saturated solution was incubated at-10 ℃ for several hours to promote the formation of crystalline peroxide complexes. The complex was separated from the liquid by vacuum filtration, washed at least three times with ethanol and dried in vacuo.

TABLE 16

Weight percent hydrogen peroxide present in Compounds and complexes evaluated¹Middle H₂O₂wt％

Purchased²Steam generating device³Liquid, method for producing the same and use thereof³Sodium carbonate Na₂CO₃27.35 Potassium carbonate K₂CO₃7.4322.70 Rb carbonate₂CO₃20.3126.78 Potassium oxalate K₂C₂O₄16.1316.42 sodium pyrophosphate Na₄P₂O₇11.4823.49 Potassium pyrophosphate K₄P₂O₇20.9032.76 sodium orthophosphate Na₃PO₄15.67 Potassium orthophosphate K₃PO₄16.111. For determining H in the complex₂O₂The titration method of weight percent is the same as described in the above-mentioned patent application. 2. Sodium carbonate hydrogen peroxide complex was purchased from Fluka Chemical Corp. 3. The vapor and liquid phase procedures are used to synthesize the inorganic peroxide.

A Differential Scanning Calorimeter (DSC) (Model PDSC2920, TAinstinstruments) was used to determine the H2O2 release or decomposition performance of the inorganic peroxide complex. The DSC was run at a ramp rate of 10 ℃/min, at a temperature range between 30 ℃ and 200 ℃ and under atmospheric and variable vacuum pressure conditions. Referring now to fig. 5, the DSC includes a sample chamber 110, a heating plate 112, and a pressure control system. The pressure control system includes a pressure sensor 114 coupled to a pressure gauge 116. The pressure gauge 116 is connected to a controller 118, which in turn is connected to a pressure control valve 120. Pressure sensor 114 is in fluid communication with a pressure control valve 120 and a pump 122.

The potassium oxalate hydrogen peroxide complex synthesized as described above was placed in a DSC and subjected to a specific vacuum pressure throughout the temperature range of 50-170 ℃. As can be seen in FIG. 6, there is more H₂O₂Liberation, endothermic processes take place at low pressure, while exothermic H₂O₂Decomposition is promoted at high pressure. The partial vacuum pressure is preferably less than 20 torr, and more preferably less than 10 torr. The actual pressure in the sample chamber is slightly higher than the pressure measured in this device, while the actual temperature of the chamber is slightly lower than the measured temperature of the metal or aluminum plate. Without wishing to be bound by any particular theory of operation, it is believed that the actual pressure used in the sterilization device should be less than the vapor pressure of the inorganic peroxide complex at the actual temperature of the chamber in order to ensure that the complex releases hydrogen peroxide without substantially decomposing. However, in general, the pressure used is preferably less than 50 Torr, more preferably less than 10 Torr. In certain embodiments of the invention in which the peroxide complex has a low vapor pressure, the pressure is preferably less than 5 torr.

The stability of the inorganic peroxide complex due to rapid heating during sterilization using the complex is limiting, and can be affected by preheating the aluminum plate prior to contact with the inorganic peroxide component. Temperatures above 86 ℃ are also suitable when using the inorganic peroxide compound.

As mentioned above, it is desirable for the inorganic hydrogen peroxide complex to be heated rapidly, i.e., as fast as 1000 deg.C/minute or faster. This can be done by contacting the peroxide with a preheated hot plate. A preferred embodiment for accomplishing this rapid heating is shown in fig. 7A and 7B. Referring to fig. 7A,there is shown a device 125 for injecting peroxide vapor into the sterilization chamber 131 in a closed position. The inorganic hydrogen peroxide complex is added to the peroxide tray 132. The disc 132 includes 5 layers: 3 layers of CSR wrap, peroxide complex powder and aluminum foil coated with polypropylene. The tray 132 is heat sealed around its edges to retain the peroxide complex powder. The peroxide disk 132 is placed under a porous aluminum plate 130 which is attached to the housing 150 by an aluminum connector block 142. The disc 132 is loosely captured between the 0-ring 151. The heated aluminum plate 134 was separated from the peroxide disk 132 and attached to an aluminum plate 136 prior to introducing the peroxide vapor into the chamber. A spring (not shown) inside the hose 138 holds the plate 136 down in the closed position. When chamber 131 is evacuated, hose 138 is also evacuated. The plate 136 is positioned against the 0-ring 148 to isolate the peroxide release chamber 152 from the channel 158. The device is secured in place and connected to the sterilization chamber 131 by bolts 144, 146, 154 and 156.

Referring to fig. 7B, to bring plate 134 up into contact with peroxide tray 132, hose 138 is vented. Upon pressure increase, hose 138 moves upward, thereby pushing heated aluminum plate 134 against peroxide disk 132. In a preferred embodiment, aluminum plate 134 is preheated to 175 ℃; however, other temperatures may be used. The peroxide vapor from this powder is then released through the CSP layer, through the perforations 160 in the porous aluminum plate 130, and into the peroxide release chamber 152. The upward movement of the heated aluminum plate 134 also opens the peroxide release chamber 152, allowing peroxide vapor to enter the channel 158, which is in fluid communication with the sterilization chamber.

The inorganic peroxide complex used to determine peroxide delivery and disinfecting efficacy in the two examples belowis potassium pyrophosphate (K)₄P₂O₇·3H₂O₂: PP), potassium oxalate (K)₂C₂O₄·1H₂O₂: PO) and sodium carbonate (Na)₂CO₃·1.5H₂O₂·SC)。

Example 17

Release of peroxides from SC, PO and PP

Release of H from SC, PO and PP₂O₂The ideal temperature of (b) was determined by DSC. From 2g of each of these complexes was determined at different temperatures using a 75 liter chamber and the apparatus of FIGS. 7A and 7BIn released H₂O₂The actual amount. H liberated from PP at 175 ℃₂O₂The amount is greater than the amount released from SC and PO. Although SC releases a minimal amount of H at 175 deg.C₂O₂But as the sample size increased, a significant release was seen.

TABLE 17

Release of peroxide in 75 liter Chamber Release H₂O₂Temperature SC PO PP (by DSC) 170 ℃ 150 ℃ 130 ℃ 0.3 mg/L0.8 mg/L1.0 mg/L125 ℃ 0.3 mg/L2.0 mg/L150 ℃ 1.2 mg/L2.0 mg/L1.5 mg/L175 ℃ 1.8 mg/L2.5 mg/L3.4 mg/L3 g sample 175 ℃ 2.3 mg/L4 g sample 175 ℃ 2.9 mg/L175 DEG C

Example 18

Efficacy tests with SC, PO and PP

2X 10 incubation on SS blades⁶A subtilis Var niger spore. The three-piece incubated blade was first placed in the front, middle and back of a 10 "21" 3.5 "poly-phenoxy dish in a SPUnguard package. The packaged disc was then placed in a 75 liter vacuum chamber having an initial vacuum pressure of 0.2 torr. A 5.5 peroxide dish was made by heat sealing SC, O or PP inorganic peroxide powder between three layers of spurguard and an aluminum foil coated with apolypropylene film. The peroxide was released by contacting the dish with an aluminum plate that had been preheated to 175 ℃ for 2 minutes, followed by an additional diffusion time of 8 minutes, resulting in a total exposure time of 10 minutes. After treatment, the three blades were placed in trypsin (Trypticase) soy broth (TSB) at 32 ℃ for 7 days, and bacterial growth was recorded. The results are summarized in table 18.

Watch 18

Results of efficacy tests results peroxide Complex weight Complex concentration Disinfection (+/Total) PP 2g 3.4mg/l 0/3 PO 2g 2.5mg/l 0/3 SC 2g 1.8mg/l 1/3 SC 3g 2.3mg/l 0/3 SC 4g 2.9mg/l 0/3

As can be seen from this table, no spore growth was observed except for 2gSC (1/3). However, when the amount of SC subjected to evaporation was increased to 3g, no bacterial growth was observed. These results highlight the disinfection efficacy with inorganic hydrogen peroxide compounds.

The inorganic hydrogen peroxide complexes can be readily incorporated into the disinfection processes described above in connection with the organic peroxide complexes. For example, the inorganic complexes may be used in methods associated with plasma sterilization or in applications associated with self-sterilizing cassettes in which peroxide is slowly released from the complex. Similarly, the inorganic complex may also be used to disinfect articles having a narrow chamber, whereby a container containing the inorganic peroxide complex is connected to the chamber. Furthermore, pressure pulses of the vapor released from the inorganic peroxide complex may also be employed. Other examples of sterilization using inorganic complexes will be apparent to those of ordinary skill in the art having reference to this specification.

Claims (41)

1. An apparatus for sterilizing articles with hydrogen peroxide, comprising:

   a container for the items to be sterilized at a pressure of less than 50 torr, and

   a source of hydrogen peroxide vapor in fluid communication with said container, said source comprising an inorganic hydrogen peroxide complex at a temperature greater than 86 ℃, said source being constructed such that said vapor is contactable with said articles for sterilization.
2. The apparatus of claim 1, wherein said pressure is less than 20 torr.
3. The apparatus of claim 1, wherein said pressure is less than 10 torr.
4. The apparatus of claim 1, wherein said source is disposed in said container.
5. The apparatus of claim 1, further comprising a cartridge disposed outside said container, said cartridge having said composition disposed therein, and an inlet for providing fluid communication between said container and said cartridge, whereby steam released from said composition is transported along the inlet and into said container for sterilization.
6. The device of claim 1, wherein the inorganic hydrogen peroxide complex is a complex of sodium carbonate, potassium pyrophosphate, or potassium oxalate.
7. The apparatus of claim 1 further comprising a heater disposed in said container, whereby said compound is placed on said heater and heated to facilitate release of said vapor from said compound.
8. The apparatus of claim 7 wherein theheater is heated prior to contacting the complex.
9. The apparatus of claim 1, further comprising a vacuum pump in fluid communication with said vessel for evacuating the vessel.
10. The apparatus of claim 1, further comprising an electrode adapted to generate a plasma around said article.
11. The device of claim 10, wherein the electrodes are inside the container.
12. The apparatus of claim 10, wherein said electrode is spaced from said container and adapted to flow the generated plasma, thereby flowing toward and around said article.
13. The device of claim 1, wherein said complex is in the solid state.
14. A method of hydrogen peroxide vapor sterilizing an article comprising:

    placing said article in a container; and

    contacting the article with hydrogen peroxide vapor released from the inorganic hydrogen peroxide complex by heating the complex at a rate of at least 5 ℃/minute to contact and sterilize the article.
15. The method of claim 14, wherein the heating rate is at least 10 ℃/min.
16. The method of claim 14, wherein the heating rate is at least 50 ℃/min.
17. The method of claim 14, wherein the heating rate is at least 1000 ℃/min.
18. The method of claim 14 wherein the complex has less than 10% water.
19. The method of claim 14 further comprising heating said complex to facilitate release of said vapor from said complex.
20. The method of claim 19, wherein the heating step comprises contacting the complex with a preheated heater.
21. The process of claim 19 wherein said complex is heated to a temperature greater than 86 ℃.
22. The method of claim 14 further comprising evacuating the vessel at a pressure of less than 50 torr prior to introducing said steam into said vessel.
23. The method of claim 22, wherein said pressure is less than 20 torr.
24. The method of claim 22, wherein said pressure is less than 10 torr.
25. The method of claim 14, further comprising generating a plasma around said article after introducing said vapor into said product.
26. The method of claim 25 wherein said plasma is generated within said container.
27. The method of claim 25 wherein said plasma is generated outside said container and flows into the interior of said container and around said article.
28. The method of claim 14, wherein the contacting step comprises pressure pulsing of said steam.
29. A method of hydrogenperoxide sterilization of an article comprising:

    placing the article in a container containing an inorganic hydrogen peroxide complex;

    sealing the cartridge; and

    the combination is allowed to stand at a temperature below 70 ℃ for a time sufficient to effect sterilization of the article by the release of hydrogen peroxide vapour from said combination.
30. The method of claim 29, wherein the cassette is at a pressure less than atmospheric pressure.
31. The method of claim 29, wherein the cassette is subjected to a temperature of less than about 40 ℃.
32. The method of claim 29, wherein said cartridge is heated to a temperature greater than 23 ℃ to facilitate release of said vapor.
33. The method of claim 29, wherein said cartridge is selected from the group consisting of a bag, a container, a chamber, and a house.
34. The method of claim 29, wherein said hydrogen peroxide complex is in the form of a powder.
35. The method of claim 29, wherein the hydrogen peroxide complex is in the form of a tablet.
36. The method of claim 29, wherein said sealing step comprises sealing said capsule with a gas permeable material.
37. The method of claim 36, wherein said gas permeable material is selected from the group consisting of TYVEK^TMCSR wrapper and paper.
38. A sealed container containing a sterilant and an inorganic hydrogen peroxide complex capable of releasing hydrogen peroxide vapor.
39. 39 a potassium pyrophosphate hydrogen peroxide complex.
40. A method of hydrogen peroxide vapor sterilizing an article comprising:

    placing said article in a container; and

    contacting said article with hydrogen peroxide vapor to contact and sterilize the article, said vapor being released from the inorganic hydrogen peroxide complex which does not decompose to release hydrohalic acid.
41. A method of hydrogen peroxide sterilization of an article having an outer and an inner cavity, the method comprising:

    connecting a vessel containing an inorganic peroxide complex to the chamber of the article;

    placing the item in a container whereby said vessel remains connected to the chamber;

    reducing the pressure in the vessel; and

    contacting said hydrogen peroxide vapour released from the inorganic peroxide complex with the cavity of the article at a temperature of less than 70 ℃.

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