CA2188742A1 - Vapor sterilization using inorganic hydrogen peroxide complexes - Google Patents

Vapor sterilization using inorganic hydrogen peroxide complexes

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Publication number
CA2188742A1
CA2188742A1 CA002188742A CA2188742A CA2188742A1 CA 2188742 A1 CA2188742 A1 CA 2188742A1 CA 002188742 A CA002188742 A CA 002188742A CA 2188742 A CA2188742 A CA 2188742A CA 2188742 A1 CA2188742 A1 CA 2188742A1
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Prior art keywords
hydrogen peroxide
complex
vapor
container
article
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CA002188742A
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French (fr)
Inventor
Paul Taylor Jacobs
Szu-Min Lin
Xiaolan Chen
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Ethicon Inc
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Johnson and Johnson Medical Inc
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Publication of CA2188742A1 publication Critical patent/CA2188742A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20Gaseous substances, e.g. vapours
    • A61L2/208Hydrogen peroxide
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N59/00Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/08Radiation
    • A61L2/10Ultra-violet radiation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/02Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
    • A61L2/14Plasma, i.e. ionised gases
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/16Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
    • A61L2/20Gaseous substances, e.g. vapours
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • A61L2/26Accessories or devices or components used for biocidal treatment
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/01Hydrogen peroxide
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/01Hydrogen peroxide
    • C01B15/03Preparation from inorganic peroxy compounds, e.g. from peroxysulfates
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/01Hydrogen peroxide
    • C01B15/037Stabilisation by additives
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/055Peroxyhydrates; Peroxyacids or salts thereof
    • C01B15/06Peroxyhydrates; Peroxyacids or salts thereof containing sulfur
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/055Peroxyhydrates; Peroxyacids or salts thereof
    • C01B15/06Peroxyhydrates; Peroxyacids or salts thereof containing sulfur
    • C01B15/08Peroxysulfates
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/055Peroxyhydrates; Peroxyacids or salts thereof
    • C01B15/10Peroxyhydrates; Peroxyacids or salts thereof containing carbon
    • C01B15/103Peroxyhydrates; Peroxyacids or salts thereof containing carbon containing only alkali metals as metals
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/055Peroxyhydrates; Peroxyacids or salts thereof
    • C01B15/14Peroxyhydrates; Peroxyacids or salts thereof containing silicon
    • CCHEMISTRY; METALLURGY
    • C01INORGANIC CHEMISTRY
    • C01BNON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B15/00Peroxides; Peroxyhydrates; Peroxyacids or salts thereof; Superoxides; Ozonides
    • C01B15/055Peroxyhydrates; Peroxyacids or salts thereof
    • C01B15/16Peroxyhydrates; Peroxyacids or salts thereof containing phosphorus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/10Apparatus features
    • A61L2202/12Apparatus for isolating biocidal substances from the environment
    • A61L2202/122Chambers for sterilisation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2202/00Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
    • A61L2202/20Targets to be treated
    • A61L2202/24Medical instruments, e.g. endoscopes, catheters, sharps
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S261/00Gas and liquid contact apparatus
    • Y10S261/65Vaporizers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/13Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/13Hollow or container type article [e.g., tube, vase, etc.]
    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]
    • Y10T428/1355Elemental metal containing [e.g., substrate, foil, film, coating, etc.]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
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    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]
    • Y10T428/1355Elemental metal containing [e.g., substrate, foil, film, coating, etc.]
    • Y10T428/1359Three or more layers [continuous layer]
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
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    • Y10T428/1376Foam or porous material containing
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
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    • Y10T428/1352Polymer or resin containing [i.e., natural or synthetic]
    • Y10T428/1379Contains vapor or gas barrier, polymer derived from vinyl chloride or vinylidene chloride, or polymer containing a vinyl alcohol unit
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10T428/1379Contains vapor or gas barrier, polymer derived from vinyl chloride or vinylidene chloride, or polymer containing a vinyl alcohol unit
    • Y10T428/1383Vapor or gas barrier, polymer derived from vinyl chloride or vinylidene chloride, or polymer containing a vinyl alcohol unit is sandwiched between layers [continuous layer]

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~C to facilitate the release of hydrogen peroxide vapor. The heating rate can be greater than 5~C. Optionally, a plasma can be used in conjunction with the vapor.

Description

2 1 ~

Related A~ppliçations This application is a conffnuaffon-in-part of U.S. patent application Serial No. 08/369,786, filed January B, 1995, ~,vhich is a continuaffon-in-part of Serial No. 08/234,738, filed April 28, 19~4.
Backqround of the Invention Field of the Invention This invenffon relates to an apparatus and process for using hydrogen peroxide vapor to sterilke arffcles such as medical instruments, and more particular~y to the use of an inorganic hydrogen peroxide complex for such a process.
DescriPtion of the Related Art Medical instruments have traditionally been sterilked using either heat, such as is provided by steam, or a chemical, such as formaldehyde or ethylene oxide in the gas or vapor state. Each of these methods has drawbacks. Many medical devices, such as fiber optic devices, endosçopes, power tools, etc. are sensitive to heat, moisture, or both. Formaldehyde and ethylene oxide are both toxic gases that pose a potential hazard to healthcare workers. Problems with ethylene oxide are particularly severe, because its use requires long aeration times to remove the sas from articles that have been sterilked. This makes the sterilization cycle time undesirably lon3. In addrtion, both fomlaldehyde and ethylene oxide require the presence of a substantial amount of moisture in the system. Thu5, devices to be sterilized must be humidified before the chemical i8 introduced or the chemical and moisture must be introduced simu taneously.
Moisture plays a role in sterilkation with a variety of other chemicals in the gas 2 1 ~74~

or vapor state, in addition to ethylene oxide and formaldehyde, as shown in Table 1.

Table 1 Relative Humidity Requirements Literature Chemicalfor ODtimal Efficac~ Referenc~
Ethybne oxide 2~50%
Propybne oxide2~50%
Ozone 7~90% 2 ForrnaWehyde >75%
Glutara~dehyde8~90% 3 Chlorine dioxide6~80% 4 Methyl bromide4~70%
~-Propiolactone >75%
Peraoetic acid40 80% 5 1. Bruch, C. W. Gas~ous Sterilization, Ann. R~v. Microbiology 15:245-262 (1961).
2. Janssen, D. W. and Schneider, P.M. Overview of Ethylene Oxide AltematiYe Sterilization Technologies, Zentr~lster71~sation 1:1~32 (1993).
3. BoYallius, ~ and Anas, P. Surface Decontaminating Action of Glutaraldehyde in the Gas-Aerosol Phase. Applied and Environmental Microbiology, 129-134 (Aug. 197".
4. Knapp, J. E. et al. Chlorine Dioxide As a Gaseous Sterilant, Medical Device 8 Diagnostic Industly, 48-51 (Sept. 1986).
5. Portner, D.M. and Hoffman, R.K Sporicidal Effect of Peracetic Acid Vapor, Applied Micnobiology 16:1782-1785 (1968).

Sterilization usin~ hydro~en peroxide vapor has been shown to have some advantages over other chemical sterilization pro~sses (see, e.g., U.S.
Pat. No~. 4,169,123 and 4,169,124), and the combination of hydrogen peroxide w~th a plasma provides additional advantages, as disclosed in U.S. Pat.
4,643,876. In these disclosures the hydrogen peroxide vapor i5 generat~d from an aqueou~ solution of hydrogen peroxide, which ensures that there is moisture present in the system. These disclosures, together with those summarized in Table 1, teach that moisture i5 required for hydr~en peroxide in the vapor phase to be effective or to exhibit its ma~imum sporicidal activity. However, the 4 ~

use of aqueous solutions of hydrogen peroxide to generate hydrogen peroxide vapor for sterilkation may cause problems. At hi3her pressures, such as atmospheric pressure, exces~ water in the system can cause condensation.
Thus, one must reduce the relative humidity in a sterilization enclosure before introducing the aqueous hydrolgen peroxide vapor.
The sterilization of articl~s containing diffusion-restricted areas, such as long narrow lumens, presents a special challenge for hydrogen pteroxide vapor that has been generated from an aqueous soluffon of hydrogen peroxide, because:
1. Water has a hi~her vapor pressure than hydro~sn p~roxide and will vaporize faster than hydrogen perox~de from an aqueous solution.
2. Water has a lower molecular weight than hydrogen peroxide and will diffuse faster than hydrogen peroxide in the vapor state.
Because of this, when an aqueous solution of hydrogen peroxide is vaporized, the water reaches the items to be sterilized first and in higher concentration. The water vapor therefore becomes a barrier to the penetration of hydrogen peroxide vapor into diffusion restricted areas, such as small crevices and long narrow lumens. One cannot solve the problem by removing water from the aqueous solution and using more concentrated hydrogen peroxide, since concentrated solutions of hydrogen peroxide, i.e., grea~er than 65% by weight, can bs hazardou~, due to the oxidizin~ naturo of the solution.
U.S. Patents 4,642,165 and 4,744,551 attempt to so~ve this problem.
The former discloses metering small increments of a hydrogen peroxide solution onto a heated surface to ensuro that each increment is vaporized befor~ the next increment i5 added. Atthou~h this helps to eliminate the di~erence in tho vapor pre~sure and volaUl ty between hydrt~gen peroxide and water, it does not address the fact that water diffuses faster than hydro~en peroxide In the vap~r state.
Tho latter patent describ~s a process for conc~ntrating hydrogen peroxide from a relatively diluto solution of hydrogen peroxide and water and supplyin~ the concentrated hydrogen peroxide in vapor form to a sterilization .~

21~7~2 I

chamber. The process involves vaporizing a major portion of the water from the solu~on and removing the water vapor produced before injecting the conoentrated hydrogen peroxide vapor into the sterilization chamber. The prefe"ed range for the concentrated hydrogen peroxide solution is 50~6 to 80%
by weight. This process has the disadvantage of working with solutions that are in the hszardous range; i.e., greater than 65% hydrogen peroxide, and also doe~ not r~move all of the water fr~rn the vapor state. Sinoe water i8 still present in the solution, K will vaporize first, diffuse faster, and reach the Hems to be sterilked first. This effect will be espscial~y pronounoed in long narrow lumens.
U.S. Pat. 4,943,414 discJoses a pr~cess in which a vessel containing a small amount of a vaporizable liquid sterilant solution is attached to a lumen, and the sterilant vaporizes and flows direc~y into the lumen of the article as the pressure is reduced during the sterilization cycle. This system has the advantage that the water and hydrogen peroxide vapor are pulled through the lumen by the pressure dfflerential that exists, increasing the sterilization rate for lumens, but it has the disadvantage that the vessel needs to be attached to each lumen to be sterilized. In addition, water is vaporized faster and precedesthe hydrogen peroxide vapor into the lumen.
U.S. Pat. No. 5,008,106 discJoses that a substantially anhydrous complex of PVP and H2O2 is useful for reducing the microbial content of surfaces. The complex, in the forrn of a fine white powder, is used to form antimicrobial solutions, gels, ointments, etc. It can also be applied to gauze, cotton swab~, sponges and the like. The H2O2 is released upon contact with water present on the surfac~s containin~ the microbes. Thus, this method too requires the presence of moisture to eflect sterilization.
Certain inorganic hydrogen p~roxide complexes have been reported includin~ examples within the followin~ cl~sses: alkall metal and ammonium c~rbonates, alkali metal oxalates, alkali metal phosphates, alkali metal pyrophosphate~, fluorides and hydrox)des. U.S.S.R. patent document No. SU
1681860 (Nikolskaya et al.) discloses that surfacss can be decontaminated, 4 ~

aKhough not necessariiy sterilized, usin~ ammonium fluoride peroxohydrate (NH~F-H202). However, this inorganic peroxide complex provides decontamination only v.~ithin the very narrow temperature range of 7~86~C.
Even within this range, de~ontamination times were quite long, requiring at least two hours. Add~onally, it is known that ammonium fluoride decomposes to ammonia and hydrofluonc ac~d at temperatures above 40~C. Due to its toxicity and reac~rity, hydrofluoric ac~d is undesirab~e in most sterilkation ~ystems. Moreover, Nikolskaya et al. disclose that despite the releaso of 90%
of its hydro~en pleroxide at 60~C, NH~F-H202 is ineffe~ve at deoontamination of surfaces at this t~nperature. Thus, it appears that a factor other than hydrogen peroxide i~ responsible for the decontamination noted.
Hydrogen peroxide is capable of fomming complexes with both organic and inorganic compounds. The binding in these complexes is attributed to hydrogen bonding between el~ctron rich functional groups in the complexing compound and the peroxlde hydrogen. The complexe~ have been used in commercial and industrial applications such as bleaching agents, disinfectants, sterilking agents, oxidizing reagents in organic synthesis, and catalysts for fre~
radica~induced potym~rkation reactions.
Generally, the~e types of compounds have been prepared by the crystallizaffon of the complex from an aqueous soluffon. For example, urea hydrogen peroxide complex was prepared by Lu et al. (J. Am. Chem. Soc.
63(1):1507-1513 (1941)) in the liquid phase by adding a solution of urea to a soluffon of hydrogen perox~de and allowing the complex to cr~stallize under the proper condiffons. U.S. Pat. No. 2,986,448 describes the preparation of sodium carbonate hydrogen ~roxide complex by treating a saturated aqueous solution of Na2CO~ with a ~olution of 50 to 90% H2O2 in a closed cyclic system at 0 to 5~C for 4 to 12 hours. More recentty, U.S. Pat. No. 3,870,783 discloses the preparation of sodium carbonate hydrogen perox~de complex by reacting aqueous solution~ of hydro~en peroxide and sodium carbonate in a batch or continuous crystallker. The c ystals are separated by fittration or centrifugation and the liquors used to produc~ more sodium carbonate solution. Titova et al.

~ 1 88~42~

(Zhumal Neor~. Kt7im, 30:2222-2227, 1985) describe the synthesis of potassium carbonate peroxyhydrate (K2CO3 ~ 3H202) by reaction of solid potassium carbonate with an aqueous solution of hydro~en peroxide at low temp~rature followed by c~ystallization of the complex from ethanol. These methods work well for peroxide complexes that form stable, crystalline fre~
flowing products from aqueous solution.
U.S. Pat. Nos. 3,376,110 and 3,480,557 disclose the preparation of a complex of hydrogen peroxide with a polymeric N-vinylheterocyclic compound (PVP) fr~m aqueous solution. Tl e r~sultant complexss contained variable amounts of hydrogen peroxide and substsntial amounts of water. U.S. Pat. No.
5,008,093 teaches that free flowing, stable, substantialty anhydrous complexes of PVP and H2O2 could be obtained by reacting a suspension of PVP and a solution of H2O2 in an anhydrou~ organic sotvent like ethyl acetate. More recentty, U.S. Pat. No. 5,077,047 describes a commercial process for producing the PVP-hydrogen peroxide product by adding fine~y divided droplets of a 30%
to 80% by weight aqueous solution of hydrogen peroxide to a fluidized bed of P\/P maintained at a temperature of ambient to 60~C. The resuttant product was found to be a stable, substantially anhydrous, free flowing powder with a hydro~en peroxide conoentraUon of 15 to 24~6.
U.S. Pat No. 5,030,380 describes the preparaUon of a solid polymeric electrolytic complex with hydrogen peroxide by first forming a complex in aqueous soluUon and then dryin3 the reaction product under vacuum or by spray dryin~ at a low enough temperature to avoid therrnal degradation of the product.
PJI of these previous methods of preparing hydro~en peroxide complexes use solutions of hydrogen peroxide. Either tt~ complex is formed in a soluUon containin~ hydro~en peroxide or droplet~ of a hydrogen peroxide solution are sprayed onto a fluidked bed of the reactant material.
Vapor phase and ~a~ phas~ reactions are well known synthesis methods. For example, U.S. Pat. No. 2,812,244 discloses a solid~as process for dehydrogenaUon, thermal crsckin3, and demethanation. Fujimoto et al. (J.

21 387~

Catalysis, 133:370-382 (1992)) described a vapor-phase carboxylation ofmethanol. Zellers et al. (An~l. Chem., B2:1222-1227 (1990)) discussed the reaction of styrene vapor with a squar~plannar organoplatinum complex.
These prior art vapor- and ga~phase reacffons, however, were not used to form hydrogen p~roxide complexes.
Summary of the Invention One aspect of the present invention relates to an apparatus for hydrogen peroxide sterilization of an article. This apparatus includes a container for holding the artic~e to be sterilized at a pressure of less than 50 torr. Preferably, the pre~sure i8 les8 than 20 torr, and more preferab~y less than 10 torr. The apparatus also inc~udes a source of hydrogen peroxide vapor in fluid communication with the container. The source includes an inorganic hydrogen peroxide complex at a temperature greater than 86~C, and is configured so that the peroxide vapor can contact the article to effect sterilization. The souroe can be located within the container, or altematively, the apparatus can include an enclosure disposed outs~de of the r,ontainer in which the complex is located, and an inlet providing fluid communication betweeen the container and the enclosure, such that vapor released from the complex travels along the inlet and into the container to effect sterilization. The inorganic hydrogen peroxide complex can be a complex of sodium carbonate, potassium pyrophosphate or potassium oxalate. Preferably, the apparatus, also Includes a heater located within the container, whereby the complex is plaoed on the heater and heated to facilitate the releas~ of the vapor from the complex. Such a heater can be heated prior to contactin~ with the complex. The apparatus can also include a vacuum pump in fluid communicaffon with the container for evacuating the container. In some embodiments, the apparatus includes an electrode adapated to g~nerata a plasma around the artic~e. Such an electrode can be inside the container, or can be spaced apart from the container and adapated to flow plasrna generated thereby toward~ and around the article. In a preferred embodiment, the complex i5 in a solid phase.

74~

Another aspect of the present invention relates to a method for hydrogen peroxide vapor sterilkation of an article. This method includes placing the artide into a container, and contacting the article with a hydrogen peroxide vapor released from an inorganic hydrogen peroxide complex by heating the cornplex at a rate of at least 5~C/minute to contact and sterilke the articJe.
rlefelably, the heating rate is at hast 10~Clminute, more preferably, at least 50~~/minute, and still more preferably at least 1000~C/minute. The complex preferably has less than 10% water. The complex can be heated, preferably to a temperature greater than 88~C to facilitate the release of the vapor from tlho complex. The container can bo evacuated before introducing the vapor into the container at a pressure of le~s than 50 torr, more preferably les~ than 20 torr, and still more preferably le~ than 10 torr. Optionally, a plasma can be generated around the article after introducing the vapor into the container. Theplasma can be generated either inside or outs~e of the container. The present invention also includes a method for hydrogen peroxide vapor sterilization of an article in which the inorganic hydrogen peroxide complex used is one which does not decompose to release a hydrohalic acid.
Yet another aspect of the present invention relates to a method for hydrogen peroxide sterilization of an article using a se~f-sterilizing enclosure.
In this method, the article i8 plac~d in a enclosure containing an inorganic hydrogen peroxide complex, the enclosure i5 sealed, and the enclosure allowed to stand at a tempsrature below 70~C for a time sufficient to release hydrogen peroxide vapor from the complex and effect sterilization of the article. Although not necess~ry, the enclosure can be allowed to stand at a pressure less than atmospheric pressure or at a temperature above room temperature (23~C).
Thu~, the enclosure can be allowed to stand at a temperature below about 40~C. Any of a variety of enclo~ure~ can be used, e.g. a pouch, a container, a chamber or a room. Preferably, the hydrogen peroxide complex is in the form of a powder or tablet. The sealing step can include sealing ths enclosure with a ga~ pemmeable material, ~uch a~ lWEK~, CSR wrap, or paper.

21 ~14~

The present invention also relates to a sealed enclosure containing a sterile product and an inorganic hydrogen p~roxide complex capable of releasing hydrogen peroxide vapor.
Included w~thin the present invenbon is also a potassium pyrophosphate hydrogen peroxide complex.
A further aspect of the invenbon relates to a method for hydrogen peroxide sterilizaffon of an article having an exterior and a narrow lumen therein. This ,neU,~d invo~ves conn~ctin~ a ve~sel cont;aining an inorganic peroxide compl~x to the lumen of the article placing the article within a container whereby the v~l remains connected to tho lumen reducing the pressure within the container and contacting the lumen of the article with hydrogen psroxide vapor released from the inorganic peroxide complex at a temperature less than 70~C.
Brief Description of the Drawinqs FIGURE 1 is a schematic of a vapor sterilizaffon apparatus of the present invenffon.
FIGURE 2 iS a s~hematic of a vapor sterilization apparatus of the present invention which includes an electrode which is optionally used to generate plasma.
FIGURE 3A is a schemaffc of a device which can be used for heating peroxide com~lexes.
FIGURE 3B is a schematic of a preferred container for holding the peroxide source for sterilkation according to the present invention.
FIGURE 4 is a graph depictin~ the releas~ of hydrogen peroxide vapor from a vacuum unstabl~ non-aqueous hydrogen peroxide complex.
FIGURE 5 i~ a schematic of a pressure control system of a differential scanning calo i~"~ter (DSC) used to detemnine hydro~en peroxide release or decomposition prop~rt~s of inorganic peroxide complexes according to the present invontion.
FIGURE 6 i~ a graph showing the effect of pressure on hydrogen peroxido reloase from potassium oxalate peroxide complex.

FIGURE 7A is a schematic view of a bellows for injecting peroxide vapor into a chamber in accordance with the present invention before injection of the psrox~de vapor.
FIGURE 7B is a schemat1c view of the bellows of FlGURE 7A showing a heated plate in contact wrth a peroxide compiex during injection.
Detail~d ~riDtion of the Invention Hydro~en peroxWe sterilizers that have been used in the past invariably us~d an aqueous solution of hydrogen peroxide as their source of sterilant.
These sterilkers have disadvanta~es caused by the presence of water in the system. At higher pressure, buch as atmospheric pressure, the excess water in the system can cause condensation. This requires that an extra step be perfommed to reduce the relatrve humidity of the atmosphere in an enclosure to be sterilked to an acceptable ~evel before the aqueous hydrogen peroxide vapor is introduced. These sterilizers also have drawbacks caused by the facts that water, having a higher vapor pressure, vaporkes more quickly than hydrogen peroxide from an aqueous solution; and water, having a lower molecular weight, diffuses faster than hydrogen peroxide. When a medical device or the like is enclosed in a sterilizer, the initial sterilant that reaches the device from the hydrogen peroxide source is diluted in comparison to the concentration of the source. The dilute sterilant can be a barner to sterilant that arrives later, particularly if t1~ devic~ being sterilized is an artic~e, such as an endoscope, that has narrow lumens. Using a concentrated solution of hydrogen peroxide as tho source in an attempt to overcome these drawbacks is unsatisfactory, b~causo such solutions are hazardous.
In the present inven~on, tho shortcomings of hydrogen peroxide sterilkors of the prior art are overcomo by using a substantially non-aqueous (i.o., substantially anhydrou~) sourco of hydrogen peroxido which releas~s a substantially non-aquoous hydrogen peroxido vapor. In a preferred embodiment, tho ~ubstanffally non-aqueou~ hydrogen peroxido vap~or is produced direc~y from a substanffally nonaqueous hydro~en peroxide complex.
Howevor, the substantial~y non-aqueou~ hydrogen peroxide vapor can also be _1~

2~ 8~742 generated from an aqueous complex which. is processed durin~ vaporization to remove water, such as under vacuum. Thus, where an aqueous hydrogen peroxide complex is used, the aqueous complex can be converted to a substanffally non-aqueous hydrogen peroxide complex while carrying out the process of the pre~ent invention. Preferably, th~ substantially non-aqueous hydrogen perox~de complexss contain less than about 20% water, mors preferably no more than about 10% watsr, sbll mors prsferably no mors than about 5% watsr, and most prsfsrably no more than about 2% watsr.
A8 i8 apparsnt from the prefsrred p~rcentages of water in the suhstantially non-aqusous hydr~sn peroxide complsxes us~d in the present invention, as provided above, the most preferred hydrogen peroxide complex and the perox~ds vapor generated thersfr~m are substantial~y water-free.
Nevertheless, as is also apparent from ths~e figurss, soms water can be present in ths system. Some of this water may dsrNe from the decomposition of hydrogsn peroxide to form water and oxygen as byproducts and some hydrogen binding of this water to the complex can ocour.
The effect of water was measured in a series of tests, with a sterilization chamber maintained at various relativs humidities. Tsst conditions wers those described in Exampls 1, below, ~th spores supported on stainless stesl (SS) blades in 3mm x 50cm stainlsss steel lumens. As shown in Table 2, under the tsst conditions, 5% rslat~ve humidity has no sffect on efficacy but 10% relativehumidity decreases the sterilization rate. This exampls shows that small amounts of moisture can be allowed in the system with the hydrogen peroxide generated from the non-aqueou~ peroxide complex and the presence of water in the ~ystem can ~e overcome by increaslng t~ sxposure time.

21 ~742 T~blo 2 E~hcb of Rol~ Humldl~ on EmcJcy SS Bl~ In 3mm x 50cm SS Lum~n~
Dt~u~lon Tlm~ SbrtlltY R~utt~ (Po~lffv~/Sampl~s~
1 Y.RH 6%RH 1 0%RH

1 0 0/3 0/3 2t3 1 5 0/3 0t3 013 A primary criterion fw the composKion of the hydrogen peroxide source is the relationship between Ks stabilKy and hydrogen peroxide evaporation rate as a function of temperature and pressure. ~epending on the parameters of the sterilkation prooess- c.~. pressure, temperature, etc. a higher or lower peroxide evaporation rate may be preferred, and heatin3 the peroxide source may or may not be require~d. The need for heatin3 of the peroxide complex depends on the vapor pressure of the complex. Some peroxide complexes have a suffic~ently high vapor pressure that a significant amount of hydrogen peroxide vapor can be released without heating the complex. In general, heating the complex increases the vapor pressure of hydrogen peroxide and acc~l~rates the release of peroxide from the complex.
To provide a desirab~y h~gh evaporation rate, the souroe should preferably have a large surface area. Thus the sourc~ may be a fine powder or a coating on a material that has a lar~e surface area. Of course, safety, availability, and cost of the material are also important criteria. The release of hydrogen peroxide frorn hydrogen peroxide complexes with urea, polyvinylpyrrolidone, nylon4, ~Iycine anhydride, and 1,3 dimethyl urea were evaluated. The cornpl~xe~ of hydro~en peroxide with urea, polyvinylpyrrolidono, nylor~, and glycine anhydride are 801~s Tho 1,3 dime~yl urea peroxide cornphx i~ a li~uid. The 31ycine anhydride hydrogen peroxide c~rnplex is a IB~ stabk~ complex under reduced pressure thsn the 2~ 3~7~1~

other complexes evaluated, and under vacuum conditions, most of the hydrogen peroxide can be released from the complex without the need for additional heating.
Urea hydrogen peroxlde complex is available in tablet form from Fluka Chemical Corp., Ronkonkoma, NY and in powder fomm from AJdrich Chemical Co., Mi~vaukee, Wl. This complex is also known as urea peroxide, hydrogen peroxide urea c~mplex, peroxide urea, peroxide urea adduct, urea peroxide adduct, per~arbam~de, carbamide perhydrate, and carbamide peroxide. As used herein, th~ term ~urea peroxide~ encomp~sses all of the foregoing terms.
The poly~inylpyrrolidon~hydrogen peroxide complex (PVP-H202) can be prepared by the method disclosed in Intemational Application Pub. No. W0 92117158. A1tematNely, the complexes with PVP, with nylon4, with 1,3 dimethylurea and with g~ycine anhydride, as well as with other organic and inorganic compounds can be prepared by the method disclosed in detail below.
Achieving suitable evaporation rate~ of anhydrous peroxide vapor from the source may be facilitated by elevated temperatures and/or reduced pressure. Thus, a heater for the peroxide source and/or a vacuum pump to evacuate the sterilization chamber are preferably a part of the sterilker.
Preferab~y, the source i8 covered with a layer of gas permeable material, such as TYVEK~ nonwoven polyethylene fabric, nonwoven po~propylene such as SPUNGUARD~, or similar material, which permits the peroxide vapor to pass but not the peroxide complexing material. Perforated aluminum or other suitable perforated material could also be used as a cover.
FIGURE 3A shows a device 80 thst can be used to measure release of hydro~en psroxide from hydr~en peroxid~ complexes under various temperaturo conditions. In this device, an aluminum pan 90 is covered with a ga~ ~,c.",eabl~ layer 92, such as a layer of medical grade TYVEK~. The pan ~0 is plac~d on top of a heating pad ~ which i~ plac~d in a pyrex pan 9~. A
therrnocouplo therrnometsr ~8 i~ placed on the outside of the pan 90 approximate~y 1 cm from the bottom ther~of.

_1~

7 4 ~

A preferred container 99 for holding the peroxide source is illustrated in FIGURF 3B. The container 99 comprises a metal plate 100, e.g. an aluminum plate, with an optional attached heater used to heat the sol~d peroxide complex.A temperature monitor 101, such as a themmometer, can be plac~d on the plate 100 to monitor the temperature. The peroxide complex is placed directty on the plate 100. A~temativety, in order to provide even heatin3 of all the peroxide complex, the peroxide complex can be placed between one or more aluminum screens 102, 104 placsd on top of the plate 100. The aluminum screens 102, 104 provide ~reater surface area and even heatin~ of the complex when larger amounts of peroxid~ cornplex are ~ein3 u~d. The peroxide complex, or the screen or screens 102, 104, are then covered with a gas permeable layer 106, such as a layer of medical grade TYVEK~ or SPUNGUARD~, so that the hydro~en perox-~e r~leased from the complex passes through the covering 106 before diffusing into the rest of the chamber. A perforated aluminum plate 108 is optionalty placed on top of the TWEK~ or SPUNGUARD~ layer 106 to provide pressure to keep the complex in contact with the heated plate 100 and to ensure even heatin~ of the peroxide complex.
The device just described provides even heaUng of the complex, which resutts in an increased amount of hydro~en peroxide vapor being released from the peroxide complex.
FIGURE 1 depicts a schemaUc of a hydro~en peroxlde vapor sterilization apparatus of the present invention. Chamber 10 holds an article 12 which is to be sterilked and which, for convenience, is placed on shetf 14. Door 16 provides ~ccess to tt o interior of chamber 10. A non-aqu~ous source of hydrogsn peroxlde 18 is depicted on optional heater 20, which i8 controlled by temperature controller 22. The peroxide concentraUon can b~ monitored by optional monitor 24. If desired, chamber 10 can b~ evacuated using pump 26;
however, sterilizaUon can also be accomplished at atmosphenc pressure.
The container that hoW~ the article~ to bo sterilkeJ can be a convenUonal ~terilkaUon chamber, which is evacuated, or it can be a container (or a room) at atrnospheric pressure.

_1~

2 1 ~7$~

The time re~juired to sterilize the articles depends on the nature, number and packaging of the articles and their placement in the chamber.
Altematively, it may be the chamber itself (or an entire room) that is being sterilked. In any case, optimum sterilkation times can be determined ~",~
The use of pressure pulsing to enhance the penetration and antimicrobial activity of sterilant gases, which i8 well known in the sterilization art, can also be applied to the non-aqueous hydrogen peroxide process. As described in addi~onal detail hereinbelow, plasma can also be used to further enhance ac~ty.
At the concJusion of the sterilkation process exoess hydrogen peroxide can be removed from devices that have an affinity for peroxide by exchanging the air in contact with the devices. This can be accomplished by flowing warm air over the devices for an extended time or by evacuating the chamber.
Articles that have previously been sterilked by exposure to hydrogen peroxide vapor may also be exposed to the plasma to remove residual hydrogen peroxide that may remain on the articles. Since the hydrogen peroxide is decomposed into non-toxic products during the plasma treatment, the sterilked articles may be used without the need for any additional steps.
It may be desirable to isolate the peroxide source from the sterilizer after the peroxide vapor is rele~s~ to avoid reabsorption of the vapor or, when a plasma is used, to avoid exposing the source to the plasma. Isolation is also advantageous when the complex used i~ not stable under vacuum. Isolation can be ac~omplished usin3 valve~ or other isolating devices well known in the art.
FIGURE 2 depicts a schemstic of a hydrogen peroxide plasma sterilkation system of the present invention. Sterilization can be achieveci with or without the use of plasma. The plasma can be used to enhance the sporic~dal actrvity of the peroxide vapor, and~or to remove any residual hydro~en peroxide remaining on th~ ~terilked articles.

-1~

2~ ~74~

Sterilization is carried out in chamber 30, which includes 8 door or opening 32 through which articles 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 contains a valve 38 to isolate the chamber from the vacuum pump 3B. The chamber 30 also includes an inlet 40 attached to an enclosure 42 that contains the hydrogen perox~de complex. Inlet 40 contains a valve 44 that allows enclosure 42 to be isolated from the chamber. The sterilization ~ystem also contains an inlet 41 which connects the enclosure 42 and the vacuum pump 36, which contains a valve 43. This system allows the simultaneous evacuation of both enclosure 42 and chamber 30, or the indep~ndent evacuaUon of either enclosure 42 or chamber 30.
Evacuation is controlled by the opening and closing of the valves 38, 44, and 43. As will be apparent to one havin~ ordinary skill in the art, two pumps, one for each chamber, could also be employed in this system.
The enclosure 42 contains an optional heater 49 attached to a temperature controller 46 to control the temperature of the hydrogen peroxide complex. The hydrogen peroxide complex concentration in the vapor state can be monitored by an optional peroxide monitor 48. The interior of the chamber contains a radio frequency (RF) electrode 50, to which is attached a matching network 52 and an RF power supply 54. A convenient form for the electrode is a perforated cylinder, surrounding the samples and open at both end. The general operation of the present process is as follows:
1. The articles 56 to be sterilized are plac~d in the chamber 30.
2. The chamb~r 30 may be at atmospheric pressure or, altematively, may be evacuated to facilitate penet~ation of the hydrogen peroxide.
Evacuation i8 accoi"plished by opening valve 38 and tuming on vacuum pump 35. Altematively, both the chamber 30 and the enclosure 42 may be evacuated by opening valves 38 and 44, and/or 43.
3. The valve~ 38 and 43 are closed to isolate the vacuum pump 36 from the chamb~r 30 and enclosure 42, and the valve 44 is opened. Hydrogen peroxide vapor i~ deliver~d into chamber 30 from the hydrogen peroxide _1~

271~874~

source, which may be heated to facilitate the release of the hydrogen peroxide vapor. Optionally, air or an inert gas may also be added.
4. The srtic~es 56 to be sterilked are either treated with peroxide vapor until sterilized or pretreated wrth peroxide vapor in the chamber 30 before plasma with surfici~.)t power to sterilee is generated. If necessary, chamber 30 may be ~vacuated at thts time to facilitate generation of the plasma. T!he duration of the pre-plasma ho~ding petiod depends on the type of pac~cage used, the nature and number of items to b~ sterilized, and the placement of the items in the chamber. Opbmum bmes can be detemmined empirically.
5. Th~ arb~es 5~ are subjected to a plasma by applying power ftom the RF power supply 54 to the RF electrode 50. The RF energy used to generate the plasma msy be pulsed or continuous. The articles 56 remain in the plasma for a period to effect complete sterilization and~or to remove residual hydrogen peroxide. In certain embodiments, 5 to 30 minutes of plasma is used. However, optimum times can be determined ernpirically.
When us~d in the present spec~fication and claims, the term "plasma" is intended to incJude any portion of the gas or vapor that contains electrons, ions, free radicals, dissociated and/or excited atoms or molecules produced as a result of an applied cl~ic field, inc~uding any ac~ompanying radiation that might be produc~d. The applied field may cover a broad frequency range;
however, a radio fre~uency or microwaves are commonly used.
The non-aqueous hydrogen peroxide delivery system disclosed in the present invention can also b.e used with plasmas generated by the methoJ
di~lose~ in the previously mentioned U.S. Pat 4,643,87B. Altemative~y, it may be used with plasmas describ~d in U.S. Patent 5,115,166 or 5,087,418, in which the artic~ to bo sterilized i~ located in a chamber that is separated fromttle plasma sourco.
The device just described is particular~ advantageous when using peroxide complexes that are not stable under vacuum. There are at least two possible methods that can ~e us~d to minimke the los~ of hydro~en peroxide during the vacuum stage. First, the small chamber can be evacuated ~1 ~874~

independent~. Second, if a small enough chamber is used, there is no need to evacuate the small chamber at all.
One such unstable non-aqueous peroxide complex is glycine anhydride-peroxide. This compound releases hydrogen perox~de vapor when placed under vacuum. FIGURE 4 i8 a graph illustrating the release of hydrogen peroxide vapor from glycine anhydride-peroxide complex under vacuum. The procedure us2d to re~ease the hydrogen psroxide from the glycine anhydride complex is as follows: (1) The main chamber 30 was evacuated with valves 43 and 44 clos~d. (2) The chamber containing tl~e hydrogen peroxide complex 42 was evacuated with valves 38 and 44 closed and va~e 43 open. (3) Va~ve 43 was closed and vah~e 44 was opened and hydrogen peroxide vapor was allowed to diffuse into chambsr 30.
As shown by the graph, hydrogen peroxide vapor is released from the complex as the pressure is reduced, even without additional heating. As illusl~ated in FIGURE 4, release of peroxide vapor is significant~y increased byheating the complex to a higher temperature. Thus, even unstable peroxide complexes are useful in the sterilkation method of the present invention.
The present invenbon provides at least four advantages over earlier hydrogen peroxide sterilization systems:
1. The use of concentrated, potenbally hazardous hydrogen peroxide solutions is circumvented.
2. The n~ed to reduce beforehand the relatJv~ humidity of areas to be sterilked in order to prevent condensation is eliminated.
3. Wahr i~ substantial~y eliminated from the system, so that there is little competition between water and hydro~en peroxide for d~usion into long narrow lumen~.
4. The n~d to attach a special vessel to deliver sterilant gases into long narrow lumen~ can often ~e eliminated.
That ~terilization can be effected usin~ hydrog~n peroxide vapor in the substantial absence of moisture i5 one of the surprisin3 discoveries of the present invention. The prior art teaches that the presence of water i5 re~uired _1~

2 i ~ ~ 7 4 ~

to achieve sterilization in chemical gas or vapor state sterilkation prooesses.
Advantageous~y, the present invention substantjally eliminates water from the system, which results in faster, more efficient and effective sterilizat~on.
The sterilization efficacy of various non-aqueous hydrogen peroxide complexes was determined as described below in Examples 1~.
Ex~mplo 1 Efficacy dats was obtained with hydrogen peroxide vapor rele~se~ from sut,sta"tial~y anhydrous urea peroxide c~oplax usin3 B~cillus subblis var.
(ni~ert spore~ in metal and TEFLON~ plastic lumens as the biological challenge.
Test Pr~ç~dur~s 1. Equlpment Four grams of crushed hydrogen peroxide urea adduct tablet (Fluka Chemical Corp, Ronkonkoma, NY) were placed in an aluminum pan 90, as described in FIGURE 3A The top of the pan 90 was covered wffl medical grade TWEK~ 92 (a breathable spunbond polyethylene fabric) so that any hydrogen peroxide released from the complex would ne~d to pass through the TYVEK~ covering before diffusir~ into the rest of the chamber. The aluminum pan 90 was placed on a heating pad ~4 in a pyrex dish 96 located in the bottom of an sluminum sterilization chamber (see FIGURE 1). The sterilization chamber, which had an approximate volume of 173 liters, also contain~d:
~ A hydrogen peroxide monitor for measuring hydrogen peroxide concel,tratiol) in tho vapor phase.
~ A temperature controlhr f~r controlling the temperature of the heating pad.
~ An injection port through which liquid hydrogen peroxide could be injected into the chamber.
~ A metal shelf on which a plastic tray containing lumen devices were placed for testing.

~1 ~$742 ~ Electrical resistance heaters on the exterior of the chamber walls, which maintained the chamber temperature at 45~C during the efficacy testings.
2. Biolo~ l Challenge and Te~t To evaluate the efficacy of t~he non-aqueous peroxide dellvery system, a biological challenge consistin~ of 1.04 x 10~ B. subblis var. (niger~ spores on a stainioss steel ~calpel blade was placed equally distant frorn each end of thestaini~ss steel lumens of dimensions 3mm ID x 40cm iength, 3mm ID x 50cm ien~h, and 1mm ID x 50cm iongth. These ID's and i~ngths are typical for metal lumens us~di in medical devic~. The compartment in the middle of each lumen that contained the biological test piece had the dimensions 13mm ID x 7.6crn len~. In the biological testing with metal lumens, a total of ~ lumens were ev~lu~t~ per test. These included 3 lumens from each of the 3 different sets of ID's and lengths available.
Similar tests were conducted with a biological challenge consisting of 4.1 X 1 05 B. sub~lis var. (n~er~ spor~s on a paper strip (6mm x 4mm Whatman #1 chromatography paper) located e~ually distant from the ends of TEFLON~
lumens of dimensions 1mm ID x 1 meter len3th, 1mm ID x 2 meter length, 1mm ID x 3 meter hngth, and 1mm ID x 4 meter length. The c~nter compartment of these lumen~ that contained the biolo~ical test piece had the dimensions 15mm ID x 7.~cm iength. In the biological testing with TEFLON~
lumens, a total of 12 lumens were evaluated per test, 3 lumens from each of the 4 dfflerent ien~ths available.
The lumens containing the biolo~ical test samples were placsd in a plasffc tray that was then plac~d on the sheif in the sterilization chamber: Thechambor door wa~ th~n closed and the chamber evacuated to 0.2 Torr pressuro w~th a vacuum pump. Tho aluminum pan co"taining the hydro~en psroxide urea adduct was then heated to 80 to 81 ~C for a period of 5 minutes, as measured by a thermocouplo thermometer plac~d on the side wall of the aluminum pan approximatety 1 cm fron~l the bottom of the pan. Durin~ this time -2~

2~ ~7~

the concen~tation of hydrogen peroxide in the chamber increased to 6mglL as measured by the peroxide monitor.
The biological test samples were exposed to the hydrogen peroxide vapor for perioJs of 5, 10, 15, 20, and 25 minutes. After exposure to the hydrogsn peroxide vapor, tl~ b~ological test san ,ples were aseptically transferra~d into 15mL of trypticase soy broth containing 277 units of c~P4se to neutralke any hydrogen peroxide residuals that may remain on the test samples. AJI samples were incubated for 7 days at 32~C and observed for grow~.
Comparative studies were also conducted in which a 50% aqueous solution of hydrogen peroxide was injected into the sterilkation chamber and vaporked from a heated injector (a heated metal surface). The volume of hydr~gen peroxide solution injected produced a vapor phase conoentration of hydrogen peroxide of 5mgJL. The test lumens and biological test samples used in the~ tests were identical to those used in the non-aqueous hydrogen peroxide tests. The handling of the biological test samples after exposure to the hydrogen peroxide was also identical.
B. Test Resul~
The resuHs of these tests with stain~e~ steel and TEFLON~ lumens, which are presented in Tables 3 and 4, resp~ctively, illustrate the advantages of the non-aqueou~ peroxide delively system with both metal and non-metal lumens. Total kill of the bacterial spores was achieved within 5 minutes with the non-aqueous peroxide delivery system for the smallest ID and the longest lumens evaluated. At the same time, total kill was not achieveJ even aRer 25 minutes of d~fusion ffme with the 50% hydrogen peroxide solution.

4 ~

T-blo 3 Aqu~ou~/Non~quoou- Emc~cy Comp~ on SS Bl~do- In SS Lum n-STERILITY RESULTS
(POSITIVEISAMPLES) SOURCE OF DIFFUSION
PEROXIDE TI~IE (IIIIN) 3mm x 3mm x 1mm x ~Ocm 60cm 50cm 50 # S O LU n O N 15 1~3 1/3 113 013 0~3 1/3 0~3 0~3 0/3 0~3 013 013 UREA PEROXIDE 15 0~3 013 013 0~3 013 0/3 0~3 013 013 ~1 ~a~42 T~
Aqu~JNon Aq~ Emc~c~r Comp~on 6mm x ~mm P~p-r ~p In TEFLON" Lumon~

STERILITY RESULTS
(POSITNE/SAMPLE5) SOURCE OF DIFFUSION
PEROXIDE nllllE (I~IN) 1mm x 1m 1mm x 2rn1mm x 3m 1mm x 4m 3~3 3U3 313 3~3 3r3 313 313 3J3 ~r~ 5 0 U rll O N 15 CU3 113 1t3 213 0~3 013 1~3 113 0U3 0~3 013 1/3 6 013 0t3 0/3 0/3 URE~ 10 0~3 0/3 0/3 0/3 013 0~3 0/3 0~3 013 0/3 0/3 0~3 The fact that rapid sterilkation can be accomplished in the absence of substantial amounts of water is surprising, in light of the fact that moisture has generally been present during chernical gas/vapor phase sterilization by varioussterilants other than hydrogen peroxide. Since vapor phase hydrogen peroxide sterilkation systems have used aqueous solutions of hydrogen peroxide, there has been moisture present in those systems as well.
To test the sterilkation efficacy of various other peroxide complexes, the following experiment~ were performed.
FY~Implos 2, 3 ~nd 4 The apparatus of Example 1 was used to test the efficacy of polyvinylpyrrolidon~hydrogen p~roxide complex (Example 2), nylon ~hydrogen peroxide complex (Example 3), and 1,3 dimethylurea hydrogen peroxide complex (Example 4). Thes~ compounds wero synthesked according to the -2~

2I~74~

method disclosed below in Examples 12 and 13. Test parameters were as follows:
Ex.~mPle i~ ~ 4 Chamber Temp. 45~C 45~C 45~C
Initial Pressur~ 0.2 Torr 1.0 Torr 1.0 Torr W~ % of peroxide 17% 10.5% 26.6%
Peroxide concentration 6rn~1L 6m~/L 6m~/L
WL of complex us~d 8~ 18~ B~
psr c~
Temp to release peroxide 110~C 110~C 80~C

In each case, spore supports were 6mm x 4mm paper substrates in plastic lumens and stainless steel blad~ in stainless steel lumens. The results of this efficacy testing appear below in Table 5.
T~blo 5 Emc-cy of Complcxo~ wffl PVP, nylon 6, and 1,3-dlm-~ylur~

STERILITY RESULTS (POSITIVEISAMPLES) ~ 5 ~Inu~ Expo~ur~
TYPE OF SIZE OF
LUMEN LUMENSEx~mplc 2 E~tsmplo 3 Ex~mpl~ 4 1mm x1m 013 013 013 1mm x2m 013 013 013 TEFLON 1mm x3m 013 013 013 1mm x4m 0/3 0/3 013 3mm x40cm013 0/3 013 STAINLES~ 3mm X50cmo/3 0l3 STEEL 1mm x50cm013 013 013 ~ B~742 The results appearin~ in Table 5 show that each of the tested hydrogen peroxide complexes generate peroxide vapor which providss efficient sterilization aRer only five minutes exposure.
The tsmperature required to release the hydrogen peroxide vapor from the solid compbx which i5 shown above is the temperature measured by a thermocouple thermometsr located on the outsido of the aluminum pan approximatsly 1 -cm from the bottom of the pan. Further testing using a thsrmometer, such as a fluoroptic themmometer, placed on ths inside bottom of the pan indicated that the temp~rature at the bottom of the pan ~vas approximately 30-35~C hi~her, as described in Example 5 below. Thus, in the previous example, the tsmperatur~ at the bottom of the pan was approximately 110 -11 5~C when the thermocouple thermometer read 80~C, and the temperature at the bottom of the pan was approximate~y 140 -145~C when the thermocouple thermometer read 110~C.
Ex~mplo 5 To determine ths temperature at the bottom of the aluminum pan used to contain the solid peroxide complex, a fluoropffc thermometer was taped to the inside bottom of ths aluminum pan. An Omega~ thermocouple thermometer was placed on the out~ids of ths aluminum pan approximately 1 crn from the bottom of the pan. Three different readin~s of the thermometers were taken. Each Ume the pan was heated to the desired temperature indicated by the thermometer placed on the sids of the pan, allowed to cool, and then r~heated to the desired temperature. The recorded temperatures are listed bslow:
Tomp, ~t To~ t bottom of p~n (~C) ~ido of D~n ~ ~n~ 3rd ~VQ

80~C 110.9 110.6 110.B 110.7 100~C 131.5 132.~ 132.0 132.0 -2~

74~

The resutt~ show that the temperature at the bottom of the aluminum pan was approximat~ly 3~35~C hi~her than the temperature indicated by the thermocouplo thermometer located at the side of the pan.
Further testing wa~ perfommed to compare the efficacy data obtained usin~ an aqueous and non-aqueous source of peroxide in an open (non-lumen) system. The e~riments are described in detail below.
Ex-mpl- 6 The apparatus of Example 1 was used wi~h a biological challen~e that consi~ted of ~.8 x 104 B. svbblis var (n~r~ ~porss on a 6mm x 4mm strip of Whatman #1 ~hromatography paper pac~aged in a TYVEK~/MYLAR~
envelope. (TWEK~ is a gas pemmeable fabric made of polyethylene. MYLAR~
is a non-gas permeable polyester material). Packaged biological challenge strips were plaoed in the front, middle and back of a polyphenylene oxide tray that contained a flexible fiberopffc sigmoidoscope. The tray was placed in a potyphenyl~ne oxide container that had one port in the top and two ports in the bottom to allow for diffusion. The four-inch diameter ports were covered with a breathable polypropylene packaging material (SPUNGUARD~ Heavy Duty Sterilization Wrap, Kimberty-Clark, Dallas, TX) to maintain the sterility of thecontents of the container afler sterilization. The container was placed in the apparatus of Exampl~ 1 and the pressure in the chamb~r was reduced to 0.2 Torr. The aluminum pan containing 2 grams of hydrogen peroxide urea adduct (Fluka Chemical Corp.) wa~ then heated to 80 to 81~C, as measured by a themmocouple themmometer placed on the outs~e of the aluminum pan approximste~y 1 cm from tile bottom of the aluminum pan, for 5 minutes to provide 3rr~/L of h~dro~en peroxide vapor in th~ chamber. The biological test sampl~ were exposed to the hydro~en peroxide vapor for periods of 5 and 10 minutes. After exrosl)re the test ~amph~ were handled in the same way as were tho~ in Examph 1.
Comparat}ve studih~ were also conducted in which a 50% aqueous solution of hydr~en peroxide was inje~ted into the sterilization chamber and vaporized from a heated injector The volumc of hydrogen peroxide solution -2~

~ 1 8874~

injected produced a vapor phase concentration of 3m~tL. The test configuration, the composition of the biological test samples, and the handling of the b!ological test samples after exposure were all identical to those used in the non-aqueous hydrogen peroxicie tests. The results of these tests are presented in Table 6.
Table 6 A~ueou~/Non-Aqueou~ Efficacy C:omp~ri-on In Open Svstern ~Non~umen Te~t) Sourc- ofDlffuslon Sterill~
Peroxide Tim R~ults (min)(poslffvelsamPles) 50% soluffon 5 3/3 1 0 3~3 Urea Peroxid- 5 113 The resuits of these tests demonstrate the greater efficacy of the non-aqueous when compared with the aqueous hydrogen peroxide process in an "open" system in whieh the biological sample was not placed in a lumen.
Again, it was surprisingly discovered that a non-aqueous system provided superior st~ tion even when diffusion of hydrogen peroxide into a long and narrow lumen i~ not required. This su~gests that the mode of action of hydrogen peroxide i~ not the same for systems with and without water.
Further testing was performed to detemmine the efficacy a non-aqueous p~roxide vapor at norrnal, not reduced, pressure. Thi~ testin~ i5 detailed below.
FY~mplo 7 Efficacy t~t~ were conducted with the hydrogen peroxide vapor released from the urea peroxide complex in an open system at atmosphsric pressure.
In this test the biological challenge of 1.04 x 10~ B. subUlis var. (niger) spores on the stainless stesl surgical blades were packaged in a TYVEK~/MYLAR~

2 1 ~

envelope. Packa~ed biological challenge blades were placed on the front, m~ddle, and back of a polyphenylene oxide tray. The tray was plaoed in the apparatus of Example 1 and the chamber door was closed. The aluminum pan containing 4.0 ~m of urea peroxide (Fluka Chemical Corp.) was heated to 80~
to 81~C, as mea~ured by a thermocoupie thermometer placed on the side of the aluminum pan approximately 1 cm from the bottom of the pan, for the duration of the test. The biological test samples were exposed to the hydro~en pc.oxi~ia vapor for periods of 5, 10, 20 and 30 minutes. ARer exposure the test sampi~s were handled the same way as those in i-~ample 1. The resuHs of these t~sts are presented in Table 7 and demonstrate the efficacy of the non-aqueous peroxide process in an open system at atrnospheric pressure.
Tabl~ 7 Efficscy of non~queou~ peroxide proces~ In open sy~tem at atmo~pheric pre~ure Sourc- of Dlfh-~lon Sterillty Peroxido Tlme Re~ul~
(minut~)(Po~iffve/~ample~
Ur -Peroxide ~ 3/3 Further tests were conducteci to determine the approximate amount of peroxicie releaseci from the hydro~en peroxlde urea complex at variou~
temperatur~. This tesbn~ is described in Example 8.
FY~m~l- 8 Urea peroxide powder, obt~ir eci from crushing the commercially available tablets (Fluka Chemical Corp.), wa~ plac~ci between two aluminum ~cr~n~ in an apparatus accordin~ to flGURE 3B having dimensions 12.7 crn -2~

21 ~4~

x 12.7 cm. The aluminum plate was then heated and the temperature was monKored using a thermometer located near a comer of the aluminum plate.
Table 8 lists tho approximate percent of peroxide released at various temperatures aRer heating for five minutes. The data show that approximate~y 100% of the peroxide is rele~ed from the complex at a temperature of 140~C.
Les~er percentages of peroxide are released at lower temperatures.
T~blo 8 Relea~o of non~queou~ peroxld- at variou~ tomporatur~- -He~ffn~ TemDer~% Porox~do Rel~a~ed 80~C ~25%
1 00~C ~65%
1 20~C ~80%
1 30~C -90%
140~C ~1 00%

Peroxide complexes havin~ the ability to release hydrogen peroxide vapor at room temperature and atmospheric pressure, such as the urea peroxide complex, allows them to be effective for use in various sterilization applications. Not on~ can they be used in tho sterilization apparatus of the present invention describ~d above, the compounds of the present invention can also bs ussd as part of s~lf-sterili~ing packaging materials, or applieJ onto supports such as gauze, spon~e, cotton, and the like. The compounds allow for st~rilization of seabd packages at room temperaturo or at elevated tempsraturs~, ar~d aro parffcularty useful for the storilizaffon of packaged medical or surgical products.
Parffcular u~ of the compounds of the present invenffon are described in the example~ which follow. The peroxido complex used in the following -2~

1 4 ~

examples was urea peroxide in the form of a tablet (Fluka Chemical Corp.) or in tt e forrn of a powder obtained by crushing the tsblets.
F~nDI~ 9 A self-sterilizing pouch was assembled as follows: A surgical scalpel having 3.8 x 105 B. subblis var. ni~er spor~s on its surface was placed in a sterik p~i dish. The dish was placed in a larger petri dish, together with 1 ~m urea p~ro~de complex in either tablet or powder fomm. The lar~er petri dish was then inserted into a pouch formed of TYVEK~/MYLAR~ (gas pemmeable, Tabb ~), MYLAR~/MYlAR~ (non~as permeable, Table 10) or Paper/MYLAR~
(gas perrr~able, Table 10). The pouch was then seal~d.
Each pouch was exposed to various temperatures for various time periods, as shown in Tables 9 and 10 below. The biological test samples were evaluated for sterili~ation as described in Example 1. The results are included in Tables 9 and 10, with a "+~ sign indicating bacterial growth.
Table 9 ~;eH-Sterilizing Pouches W~th Breathable Barrier (TYVEK~/MYLAR~) TemperaturePeroxide Type 1 hr. 2 hr. 3 hr. 4 hr.
23~C powder + - - -tablet + +
40~C powder - - - -tablet 60~C powder - - - -tablet Tabb 10 lists the efficacy data for se~-sterilizina pouche~ with (Pap~r/MYLAR") and wfflout (MYLAR~JMYLAR~) a breathable barrier. The pouches wore asssmbled as described above, however th~ peroxide vapor 30urc8 W1~5 urea psroxide in powdsr foml only.

2 1 ~

T~bl~ 10 SeH-Sterilizin~ Pouches W~h & Wlthout Breath~ble Barrier Temperature Packaging Type 2 hr. 4 hr.
23~C MYLAR/MYLAR - -Papsr/MYLAR +
40~C MYIAR/~
PaperlMYLAR
60~C MYLAR~YLAR
Papsr/MYLAR

Resutts from this testing show that the urea peroxide complex of the present invention included in a pouch with and without a breathable barrier provides effective sterilization to an article inside tt~e pouch in the absence of moisture at room temperature and atmospheric pressure after only 2 to 3 hours. At higher temperatures, sterilization is effe~ted after onty one hour.
To determine the efficacy of the sterilkaffon system of the present invention in a closed container, the following experiment was performed.
E~m~lo 10 A setf-steril~ing container was as~embled as follows: A stainless steel support having either 3.8 x 106 B. subtilis var. ni~er spores on its surface (Table 11) or having ~.2 x 105 B. subtilis var. ni~r spore~ on its surfaoe (Table 12), was placed inside a small potyethylene (PE) vial having 20 holes (3/16" in size) in it~ surface. The vial was placed in a larger PE vial, which was coveredwith either an air t}~ht cap, or a gas permeabh lay~r of SPUNGUARD~ (CSR
Wrap). A150 included in the larger vial was a second PE vial, also having 20 holes (3/1~ in ~ke) in its surface. This vial contained 1 gm urea peroxide in either powder or tabht forrn, and was sea~ed in e~her a SPUNGUARD~ (CSR
wrap) or l~EK~ pouch.
Each container was exposed to various temperatures for various time periods, as shown in Tables 11 and 12 below. The biological test samples 21 ~4~

were evsluated for sterilization as described in txample 1. The results are included in Tables 11 and 12, wlth a ~+n sign indicating bacterial growth.
T~ble 11 SeH-Steriiking Container~ W~hout Breathable Wlndow TemperaturePack~ging Type 2 hr. 6 hr.
Unpackaged tablet +
23~C CIC- packa~ed tabist +
C/C packaged powder +
Unpadcaged tablet 40~C C/C packsged tablet C/C packaged powder Unpackaged tablet 60~C CIC packaged tablet - -C/C packaged powder - pouch forrned from CSR wrap ~188~4~

T~ble 12 Self-Sterilizin~ Container~ W~h Breathable CSR Window T~ Typ~ O.S ht. 1.0 ht. 1 S hr. 2.0 hr. ~.0 hr. 4.0 hr.
Ur., ~ 'u-~ ~ i bb~
U~ ~ ' ~ d p~r 23'CTJr P~d bb~ ~ 4 T/T p~d po~bt Cl~ p~d bOl t C~C p# l~d po~t U~ Id t~tht - - - -U~ d po~r - - - -40 CTIT p d~d bO~ ~ -T/T p~g-,d po~r - - - -C/C p t~d b~ - - -CIC p dc~d po~t U ~ i b~t U, ~ d p~t ~O-CT/T p-~d t-bl-t -T/T p~du~d po~r Cl~ p r~d bbl-t - - - -CIC p dug-~d Po~r ~- pou~ brrr~ld ~m TYVElC' ~ - poudl hm~d ~om CSR ~np Resu~ from this testin~ show that the non-aqueous urea peroxide compiex inciuded in a container wffl and without a breathable barrier provides effective sterilkation at room temperature after only 3 4 hours. At hi~her temperatur~, sterilizaUon is effected after as lit~ a~ one ha~f hour.
Tho non-aqueous ~roxi~io complex~ which release peroxide vapor havo b~n found to be useful in the sterilization of ar~b~ at room temperature, snd moro effec~vely, at hi~her temperatures. Th~se complexe~ can be placed in a pouch, container, chamber, room or any aroa capable of bein~ sealed, whoro thoy reba~ p~roxido vapor which eff~vo~y storilke$ the article~. The complcxes can be hoated to facil~ato the releas~ of vapor, and to provide ~1 ~874~

~leiil~tion in less time than that required for room temperature sterilization.
The compounds of the present invention are therefore useful in a variety of applications where ste~ilication is desired. Simply by placing the complex in a sealed area containing an article or articles to be sterilked, sterilizaffon can be achieved. By conb..st w~th prior art methods, there is no need for contact with moisture to provido activation of tt e hydrogen peroxide.
Toconrl~r"thatsterilka~on canb~effected using non-aqueous peroxide complexe~ in bss ffme at lower pres$ures, the followin~ experiment was ~,e, f~""eJ.
Ex~mpl~ 11 A self-sterilizing container was ass~mbled as follows: A stainless steel support having 9.2 x 105 B. stubblJs var. niger spores on its surfaoe was placedinside a small PE vial having 20 holes (3/16" in ske) in its surface. The vial was plaoed in a larger PE vial, which was covered with a gas permeable layer of CSR wrap (SPUNGUMD~). Also included in the larger vial was a second PE vial, also having 20 holes (3116~ in ske) in its surface. This vial contained1 gm urea peroxide in either powder or tablet fomm. The vial was then sealed in a CSR wrap or TWEK~ pouch.
The large vial~ were plac~d in either a 4.5 L sterilkation chamber or a 173 L sterilization chamber. Each container was exposed to 100 torr pressure and 23~C temperature for 2 hours, as shown in Table 13. The bioloyical test samples were evaluated for sterilization as described in Example 1. The results are included in Table 13.
Tablo 13 Self-Sterili2in~ Container~ W~h Breatha~le Window In Redu~d Pressure Conditions Tc.ll~.~ro r~ ~- ~ Typ~ 4.5 L ch&lllb~r 173 L ch~mb~r Ur,p~ wder - -23-C T/T p~
C/C p~d pow~l~r ~ 1 8~74~

These r~sults show that non-aqueous urea peroxide complex included in a container with a breathable barrier provides effective sterilization at 100torr and room tsmperature aRer only 2 hours. These results, when compared wffl the resutts in Table 12, demonstrate that the peroxide complexes of the present invenffon prov~de sterilizabon at r~du~d pressures in less time than that required to ef~ct sterilizabon at atmosphe~c pressure.
Thu~, the hydrogen peroxide complexes of the present invenffon can provWe eff~ve stelili~tion in significantty shorter periods of time. In addition, as discu~d above, plasrna can also be u~ed to enhance the sterilization acffvity of ~ hydro~en peroxide vapor. The articles to b~ sterilized are subjected to a plasma aft~r exposure to tt)e p{~roxi~e vapor, and remain in the plasma for a period of time sufficient to effect complete sterilization.
Ar~cles that have been sterilized by exposure to hydrogen peroxide vapor can be e~osed to a plasma to rernove any residual hydrogen peroxide remaining on the articles. Because tt~ residual hydrogen peroxide is decomposed into non-tox~c products durir~ the plasma treatment, the sterilized articles are ready for use following treatment, without the need for any additional steps.
Non-aqueous peroxide complexes are useful in a variety of applications, including as a component of self-sterili ing pac~aging. In addition, the complexes are suitable for use in various methods for vapor sterilization of articles, such as the method disclos~d in U.S. Patent No. 4,943,414. This patent disolQs~s a proc~ss in which a v~el containing a smsll amount of a vaporkabb Ibuid sterilant solution i~ attached to a lumen, and the sterilant vaporees and fk~ dir~y into the lum~n of the article as the pressure is re~ucsd during the st~.iliLatiGIl cycle. The method disclosed in the patent can b~ modified to alhw fcr us~ of 8 non~queous peroxide compound. The compound i~ plac~d in a ve85el and c~nn~cted to the lumen of the article to be sterilked. Th~ arUcle i~ then placed within a container and the container evacuated. Tho lumen of tho article and the exterior of the article are contacted by the hydro~en p~roxide vapor rcleased from the non-aqueous -3~

21 ~8~4~

compound. A plasma can optionally be ~enerated and us~d to enhançe sterilization andlor to remove any residual hydrogen peroxide form the article.
Use of non-aqueous peroxide complexes in the system just described over~omes the disadvanta~e that the water in the aqueous solubon is vaporized faster and preoedes the hydrogen peroxide vapor into the lumen.
thus, more eff~ve sterilization i8 achieved and less time i8 required to effect sterilization. Hydrogen perox~de complexes such as ~Iycine anhydride are esp~cially advantageous SH ce they release a significant amount of hydrogen peroxide at reduced pressure without the need for additional heatin~ of the complex.
Svnthesis of Non-Aqueou~ Hydrogen Peroxide Com~lexes The present invention further provides a process for preparing non-aqueous hydrogen peroxide cs~mplexes that are useful as the source in a hydrogen peroxide vapor sterilker, or as a component of self-sterilking packaging, as was descr~ed above. Of çourse, the hydrogen peroxide çomplexes can be used for other applications, such as for bleaching agents, contact lens solutions, cata~ysts, and other applications which will be well known by those havin~ ordinary skill in the art.
The general procedure for preparing the hydrogen peroxide complexes of this invention i~ as follows:
(1) Plaoe the reaçtant m~terial in th~ çhamber.
The material to be reacted with the hydrogen peroxide çan be a solid in various forms, (e.~., powder, cry~tal, film etc., preferably havin~ hi~h surfaçearea to increase the reaction rate). The reactant material can also be present a~ a solution in water or another wlvent, if sufficient time i8 allowed to evaporate the solvent after tho pressure i5 rsduced in the chamber. The material may al~o bo a liquid whoss boiling point i8 highsr than that of hydrogen peroxide (1 50~C). Sinco reaction rates ars faster at elevated temperaturo, tho chambor i- preferably hoated whethsr beforo or after the reactant composition 1~ introduced. Howsver, the hmperature should not be so high that the reactant boils or vaporizes.
-3~

The reactant composition may be contained in any container that provides access to the peroxide Yapor. If it is in the form of a powder or otherfomm that may be blown about when the chamber is evacuated, then the reactant may be retained in a permeable çontainer, which allows hydrogen peroxide to diffuse into the container.
(2) Fvaçuate ~e çhamber.
r~ererably, tt~ çhamber Is evaçuated to a pressure that is below the vapor pressure of the hydro~en peroxide (which depends on its concentration and ternperature), in order to assuro that all of the peroxide i8 in the vapor phase. The vapo~r pr~ssure inues~ with inueasin~ temperature and de~ eas3s w~th increasin~ peroxide concentration. For most of the experimentsl the çhamber was evacuated to about 0.2 Torr and the temperature was ambient or above.
(3) Generate hYdrwen peroxide vaDor.
The hydrogen peroxide vapor can be generated from a hydrogen peroxide solution or from a substantially anhydrous hydrogen peroxide complex. The latter yields dry hydrogen peroxide in the vapor state, which is an advanta~e if either the material to be reacted with the vapor or the complex to be fommed i5 hygroscopic. Another advantage of generaUn~ the hydrogen peroxide vapor from a substantially water-free complex i5 that the percent of hydrogen perox~de in the complex bein~ fommed is higher than if the vapor is ~enerated from an aqueous solution of H202. This is probably due to the compeWon between water molecules and H202 molecules for bonding sites on the complex when an aqueous solution i~ ùsed to generate the H2O2 vspor.
The peroxide vapor can be generat~d within the same chamber that hou~ the reactarlt material or in anoth~r chamber separsted from it by a vacuum valve.
(4) React tho reactant rnaterial with hYdrogen Peroxide.
The Ume required for the reaction depends, of course, on the reaction rab of the reactant with hydro~en peroxide. It can be empirically determlned by monltorin~ the pressuro, which decreabes during the binding of peroxide to 74 ~

the reactant material. Typically, the reacUon time is about ~30 minutes. The concentrabon of vaporized hydrogen peroxide and the weight of the starting material determine the weight percentage of perox~de in the final reaction product. As the weight raUo of reactant to hydrogen peroxide increases, the wei~ht percentage of hydro~en peroxide in the complex decreases. The reaction can be repeated multiple time~s to increase tt~e concentraUon of hydro~en p~roxide in the comp~ex.
(5) Fvacuate the chamber again.
At the end of the reaction p~riod, the chamber i~ further evacuated to about 2 Torr to remove any unreacted hydro,gen peroxide.
(6) Vent the chamber and retrieve the hydrogen Peroxide comPlex.
The mechanism by which the hydrogen peroxide form~ a complex with the reactant material is not completely understood. The forrnation of the complex is believed to involve hydrogen bond formation between the hydrogen peroxide and el~ctron-rich functional groups containing oxy~en andlor nitrogen on the reactant material. It is not known if this i5 the only mode of binding;
however, materials with a wide range of functional groups have been found to form complexes w~th hydrogen peroxide.
The advantages of the vapor phase reaction over ear~ier m~thods of hydrogen peroxide complex formaffon include:
1. The raffo of hydrogen peroxide to reactant material can be accurate~y controllsd by varying the amount of hydrogen peroxide present in the vapor stats or the arnount of reactant material exposed to the Yapor.
2. Tho n~d to removo so~vent from tho reaction product i8 eliminated.
3. Poroxido complexes can be formed that are liquid or solids, such a~ powder~, cry~tal~, films, etc.
4. Peroxide complexes of hygroscopic materials can be prepared.
Tho ~ynthe~i~ of the non-aqueous peroxide complexe~ according to the pressnt invention i8 further describ~d in the following e%amples. Many of these compounds have utility 88 catalysts, in addiUon to havin~ the utilities describ~d 218~4~

in greater detail herein, as will be readily appreciated by those having ordinary skill in the art. The examples represent embodiments of the compositions and processes of the invention, but they are not in any way intended to limit the scope of the invention.
F~m~l~ 12 A hydro~en peroxide complex of giycine anhydrlde was prepared as follows: A 1.0 ~ram samp~e of glycir)e anhydri~de (Aldrich Chemical Co., Milwaukee, Wl) was placed in an alurninum tray in a 173 liter chamber maintained at a temperature of 45~C. The top of the aluminum tray was cover~d with TYVEK~ nonwoven fabric, which prevented the glycine anhydride from coming out of the tray when the pressure in the chamber was reduced but was breathable and did not absorb hydrogen peroxide. The chamber door was closed and the pressure in the chamber was reduoed to 0.2 Torr by evacuating the chamber wffl a vacuum pump. A hydrogen peroxide conoer,~JdLion of 10 mg/liter was cr~ated by ovaporation of an appropriate volume of a 70~
aqueous solution of hydrogen peroxide (FMC Corp., Philadelphia, PA) into the cham~er. The hydro~en peroxide vapor was maintained in contact with the glycine anhydnde for 20 minutes. At the end of the reaction period, the chamber pressure was reduced to 2 Torr and then retumed to atmospheric pressure. The reaction product was removed from the chamber and analyzed for weight percent hydrogen peroxide by the followin3 iodometric titration reactions.
H2O2 + 2K~ + H2SO~--' 12 + K2S~4 + 2H2~
12 + 2Na2S2O~ -- > Na2S~O~ + 2Nal A st~rctl indicator wa~ uu~d in the iodine-sodium thiosuHats titration rea~;on to enhance the color change at tl~ end point. The percentage by weight of hydro~en peroxide wa~ calcubted by the following e~uation:
wt% H2O2 ~ [(ml of Na2S2O,)-(nommality of Na2S20~) ~1.7]/(sample wei~ht in grams) The wel~ht percentage of hydrogen perox~de in the glycine anhydride complex wa~ found to be 24.3%.

74 ~

FY~n~pl~ 13 The hydro~en peroxide complexes of a wide variety of or~anic and inorganic complexes were prepared usin~ the pr~cedure of Example 12. In each case, the reaction conditions were ff e sàme as those in Example 12, except 1.0 ~rarn of each one of ~e compounds presented in Table 14 was used in pl8c~ of ~Iycine anhydri~e.

2~ 8g7~2 T~
COMPO~JND5 EVALUATED AND WEI~;HT PERCENT HYDROGEN PEROXIDE
PRESENT IN COMPLEXE5 FC)RIIED Br VAPOR PHA5E 5YNTHESIS PROCESS
WtY. Atbr Ch~ "Ic-' Ch~ l P~r~a'dr Nam~ T~ l C~ry Pdy(vuT~I abo-~ [-CH2CH(OH~L 18.9% Ak~
Poly(v~yl m~yl ~r) l-CH2CH(OCH~) 1" 22.0% E~r Poly(~nyl m~ K~e) [-CH,-CH(COCH~L 13 ~%
Poly(K:ylk ~d) l-CH2CH(C~OH~L 51%
Glycln~ H2C(NH2) (COOH) 20.7% A~no AcPd L I I~W;r~ [N.CH~CH-C] C~l,CH (NE~,~ COOH 14 1% Amino Aci~
Pdy(vinyl acebh) [-cH2cH(ococH~L 91% Estor Ce J~150 ~tste 10.9% E~r Sodium al~ ab 27.7% Or~anic Satt C~Uubs~ w~, ~odium salt 18.2% Organk SaK
Pdy(~Vinylp~yndin~) l-CH2CH(p C5H~N~ 21.a% Aromat~c amine Histamir~ ~N.CHNHCH.C-l CB,CH, (NH,) 13.2% Amin~
P ~ (C2Hs)cONH2 31.8% Amid~
Ur~ (H2N)2C~ 17.~% Ur~s 1 341m~ytur~ (H,C)HNCONH(CH~) 31.7% Urea BnJr~t (H2N)CO(NH~CO(NH2) 13 7% Biur~t Polyaaybmid~ l-CH2CH(CONH,~" 30.1% Po~yamid~
Pdyvirlylp~y",'.dono [-CH,CH(-Il(C~ lo)-~, 29.5% Potyamide Nybn B l-NH(CH~,CO L. 17.1% Polyamide Nybn 5~ fflm [-NH(CH2),NHCO~CH2)~C~l,, 16.6% Po~am~o P~y~ti c.~urothane . [~HNCOOR-~ .5% Polyl"-JU,ans Sodium cubor~ N~2CO, 14.3% Ir~r~ar,-Pot3~ium c-rbon~ K2CO, 33.~% In~sn Rubidium cubo~ Ri~2CO, 37.0% In~5~ar,.c Caicium hJ~J~ io Ca(OH,~2 23.4~6 Inor~, c Sociium bicubcn-h NaHCO~ 10.7% Ir~anlc T~a~od~urn pyr~pho~ph~ Na4P207 18.~% Ino,5~ank ~1 -~1 8~74~

The organic complexes formed cover the followin~ ran3e of functional groups that are capable of forming hydrogen bonds with hydrogen peroxide:
alcohols, ethers, ketones, acids, amino aclds, esters, organic saits, amines, amide~, po~yamides, potyurethanes, ureas, and biuret. The inorganic complexe~ indude carbonates w~ sodium, potassium, and rubidium cations, as w~ll as sodium bicarbonate. In addition, the hydrogen peroxide complexes of cak~ium hydroxide and tetrasodium pyrophosphate were also prepared. The startin~ material~ wlere hnely divided powers or slightty brger crystalline materiais, except for nylon 6,~, which was proosssod as a film with a thickness of 0.12 mm, and poJyvinyl metttyl ether, which was a 50% by weight aqueous solution.
The hydro~n peroxide complexes obtained with these materials under the test conditions were solids, except for poiyvinylpyrrolidone, histamine, po~y(vinyl methyl ether), poiy(vinyi methyl ketone),propionamide, and 1,~
dimethylurea. The 1,~dimethylurea and propionamide hydrogen peroxide complexes were free flowing liquids that were easily handled in the vapor phase synthesis process, since no soivent needed to be removed to obtain the final produc~ The histamine, potyvinylpyrrolidone, poly(vinyl methyl ether), andpoiy(vinyl methyl ketone) complexes were ~ummy materials that were not as easy to handle.
Examples 14 and 15 describe additional studies with polyvinylpyrrolidone under different process conditions to obtain the peroxide complex as a free flowin~ solid produc~
FY~mD~
Hydro~en peroxiJe complexe~ with po~rinylpyrrol~one were prepared in which the percsnt hydro~en peroxido in the polyvinylpyrrolidone complex was varied by changin~ tho raffo of tho webht of polyvinylpyrrolidone to the concentration of hydro~en peroxide in the vapor state. The condition~ in these tesb were identical to thoso in Example 12, except the wei~ht of poi~vinylpyrrolidone wa~ increa~ed from 1.0 gram to 3.0 grams to 5.0 ~rams.
In all te~ts, the concsntration of hydrogen peroxide was held constant at 10.0 ~1 ~874~

m~ r of chamber volume. The results of these tests are presented in Table 15.
E~xsmDle 15 A hydro~en peroxide complex of PVP was prepared in which th~
hydro~en peroxide wa~ delivered fr~rn a complex of hydrogen peroxide with urea. When hydrogsn peroxide i~ delivered in this manner, it i8 8uLstal~ially w~hr fr~e. In this test, 5 ~rams of PVP was plaoed in th~ reaction chamber and 10 mg H202/liter of chamb~r vdume wa~ d~livered into the reaction chamb~r by heating about 7 ~rams of a 35% compl~x of H2O2 wlth urea to a temperature of about 110-C for approximately 5 minutes. Th~ rest of the conditions in this t~st were the same as those in Exampl~ 12. Th~ perc~ntag~
hydro~en peroxide in the PVP complex and t~ physical state of the complex are presented in Table 15.
Tsblo 15 EFFECT OF RATIO OF POLYVlNn,PYRROLIDONE TO HYDROGEN
PEROXIDE IN THE VAPOR ST~TE ON % HY~ROGEN PEROXIDE
IN CO~1Pl.EX AND PHYSIC~I STATE OF PRODUCT

Wel~ht Wt% H2O2 Physlc~l Stat~ ~
PVP (~ In comDlcx of Product Ex. 14 1 29.9 Soft ~ummy product 3 23.5 Hard gummy product 17.7 Free flowing solid Ex. 15 5 19.7 Free flowing solid Tho results of these test~ demonstrate that a free flowin~ solid can i~ obtainedwg~ tho PVP hydrogon peroxke compbx by controllin~ the ratio of PVP to hydro~en peroxldo in the vspor state and, aitemat~vely, by usin~ a subQtantialiywater-freo hydrogen perox-~e vapor source.
INORGANIC iHYDROGEN PERO~iDE COi~iPLEXES
Inor~anic hydrogen peroxido complexes are al~o suitable for use as sterilant~ a~ de~cribed in detail herolnabove for or~anlc hydro~en peroxkie comp-~xe~. Poroxide vapor can bo roha~ed from theso inorganic complexes 4~

2 ~ 7 i~ 2 at atmospheric pressure and room temperature. However, as described in greater detail below, substantial amounts of hydrogen peroxide vapor can be released from inor~anic peroxide complexes upon rapid heatin~ to a particular release temperature under reduced pressure. In order to s~c-4essful~y release hydro~en peroxide frorn inor~anic p~r~xide, the he~ rate of the inor~anic peroxide c~mplexes i8 preferably at least 5~C/min; more preferably it is at least 10~C per minute; still more preforably at least 50~Clmin.; and most preferably, it i8 at least 1000~C per minute.
A represontathe listing of these inorganic perox}de complexes, and the weight percent hydrogen peroxide, is pre~ented in Table 1~. The titraffon proc~dure used to determine the weight percent ~f H2O2 in the complexes wa~
as described in Example 12. Sodium carbonate H202 complex was purchased from Fluka Chemical Corp. The vapor-phase synthesis pro~edure used for synthesizing the inorganic peroxide complexes was the same as that disclosed in Example 12, with the exceptions that 10~ of the solid inorganic sample instead of 1-5~q, and two reaction cycles versus one, w~re employed.
F~t~rn~ 1 6 1 he reaction procedure for liquid-phase synthesis of inorganic hydrogen peroxide complexes wa~ essentially as describ~d by Jones et al. (J. Chem.
Soc., Dalton, 12:252~2532, 1980). Briefty, inor~anic solids were first dissolvedin a 30% aqueous solution of hydro~en perox~de to make a saturated solution, followed by dropwise addition of ethanol. For the potassium oxalate and rubidium carbonate compiexes, the white peroxide precipitat~s were forrned as the amount of ~U~anol added was ~radually increased. For potassium carbonate, potas~ium pyr~phosphate and sodium pyrophosphate, the saturated solution~ were incubated at -10~C for s~veral hour~ to facilitate crystalline peroxide complex forrnation. The complsxes were separated from the liquW by vacuum r,l~-atiGn, wash~d with ethanoJ at bs~t thrce ffmes and dried by vacuum.

21~7~' Tabl~ 1~
COMPOUNDS EVALUATED AND WEIGHT PERCENT HYDROGEN
PEROXIDE PRESENT IN COMPLEXES

Chemic~lChemic~l Wt % H,O~
Name Formul~ in Complexes' Purch~sed2 Vapor' LiquidJ
Sodium C~nate N-2CO3 27.35 Pot~ssium C~r~on~te K,CO, 7.43 22.70 Rt~bidium Carb~nateRb2COl 20.31 26.78 Pcd~iu-n Ox~l-te K2C204 16.13 16.42 Sodium PyrophosphateNa~P2O7 11.~8 23.49 Potassium Pyrophosphate K~P20, 20.gO 32.76 Sodium Onho~hosphateNa3po4 15.67 Potassium Orthophosphate KlPO4 16.11 1. The titration procedure emplo~ed to detemmine the weight percent of H2O2 in the complexff is the same as the or e st~ted in th~e p evious patent application.
2. Sociium car~onate hydrogen peroxide complex was purrhased from Fluka Chemical Corp.
3. The vapor and liquid phase procedur~s wcre used for synthesizing the inorganic peroxide.
A diff~rential scannin~ calorimetor (DSC) (Model PDSC 2920, TA
instruments) was used to determine H2O2 release or decomposition properties of the inorganic peroxide complexss. The DSC was run at a heating ramp of 10~C/min and at a temperature range of between 30~C and 200~C. under both atrnospheric and varyin~ vacuum pressure conditions. Referrin~ now to FIGURE 5, tho DSC co,np,ises a ~amph chamber 110, heating plate 112 and pres~ure control system. The pressure control system comprises a pressure transducer 114 connccted to a pres~ure ~au~o 11~. The pressure gauge 116 is connected to a controller 118 which is, in tum, connected to a pressure control valve 120. Tho prsssur~ transducer 114 i~ in fluid communication with pr~ssuro control valve 120 and wi~ pump 122.

2 ~ ~3 3 7 l~ ~

PotP~siurn oxalate hydrogen peroxide eomplex synthesized as described hereinabove was plaeed in a DSC and subjeeted to a particular vaeuum pres~ure over a t~",pe.alure ran~e of 50~C to 170~C. As ean be seen in FIGURE 6, ~reater release of H2O2, an endothemmie proeess, oeeurred at lower pressures, while the exothermie deeomposibon of H2O2 v~as favored at higher pressures. T~ e partial vaeuum pressure is preferab~y less than 20 torr and most preferably h88 than 10 torr. T~ e aetual pr~ssure in the ~ample ehamber is som~what hi~her than that measured w~hin th~ apparatus and the actual temperature of the ehamber is somewhat lower than that measured of the metal plate or aluminum platen. Wlthout wishing to be bound by any particular theory of operation, it is believed that the actual pre~sure us~d in the sterilization apparatus should be less than the vapor pressure of the inorganie peroxide complex at the actual temperature of the chamber in order to ensure that the eomplex will release hydrogen peroxide vapor w~th substantially no deeomposition. However, in general, the pressure used is preferably less than 50 torr, more preferab~y less than 10 torr. In certain embodiments of the inYention in which the vapor pressure of the peroxide complex is low, the pressure is preferably less than 5 torr.
In the use of the inor3anie peroxide e~mplexes for sterilkation, it is eritical to eornplex stability that heating oeeur rapidly which may be effeeted by preheaffng the aluminum plate prior to eontaetin~ with the inor~anie peroxide eomposiffon. In the use of the inorganie peroxide eompounds, it i8 also preferred that the temperature be higher than 8B~C.
As di~u~$e~ a~ovo, it i5 preferred that the inorganie hydrogen peroxide eomplex be heated rapidly, i.e. as rapidly as 1000~C/minute or more. This ean be accompli~hed by e~,)taclin~ the peroxide w~th a pre-heated heating plate.
A preferred embodiment for aeeomplishing sueh rapid heaffng is shown in FIGURES 7A and 7B. Referring to FIGURE 7A, there is shown an apparatus 125 for injecting peroxide vapor into a ste~il~tion ehamber 131 in a elosed position. The inorganie hydrogen peroxide complex is incorporated into a peroxide disk 132. The disk 132 eomprises five layers: three layers of CSR

21 ~'7~

wrap, peroxide complex p~wder and aluminum foil coated with polypropylene.
The disk 132 is heat sealed around its edge to retain the peroxide complex powder. The peroxide disk 132 i~ plaoed undemeath a perforated aluminum plate 130 which is attach~d to housin~ 150 by aluminum attachment pieoes 142. The disk 132 is loose~y he~d in place between O-rings 151. Prior to introductbn of pa,ux~e vapor into the chamber, a heated aluminum platen 134 is apart from the peroxide disk 132 and is attached to an aluminum plate 136.
A sprin~ (not shown) wi~hin tho bellow 138 hûlds the plate 13B dawn in the clo~d posit~on. When the chamber 131 is evacuated, the bellow 138 is also evacuatsd. The plate 13~ i~ ~ated against O-rln~s 148, thus s~parating a peroxide release chamber 152 from passageways 158. The apparatus is held in place and attached to a sterilization chamber 131 by bolts 144, 146, 154 and 156.
Referrin~ to FIGURE 7B, in order to brin3 the platen 134 up to oontact the peroxide disk 132, the bellow 138 is vented. Once the pressure is increased, the bellow 138 moves upward, thereby propeling the heated aluminum platen 134 against the peroxide disk 132. In a preferred embodiment, the aluminum platen 134 is pr~heated to 175~C; however other temperatures can be u~d. Peroxide vapor is then released from the powder through the CSP layers, pa~ses throu3h the perforations 160 in the perforated aluminum plate 130, and entsr~ tho peroxide release chamber 152. The upward movement of the heated aluminum platen 134 also opens the peroxide release chamber 152, allowing poroxide vapor to enter passageways 158 which are in fluid communication with the sterilization chamber.
Th~ inor~anic peroxids complex~ used in the following two sxamples to det~mmine amount of psroxido release and sterilization efFi~acy were potassium pyrophosphato (K4P20r-3H202: PP), potassium oxalate (K2C2O4-1H2O2: PO) and ~dium carbonate (Na2CO3-1.5 H2O2: SC).

~I8~

Example 17 R~lease of P~roxlde from SC, PO ~nd PP
Tl~e ideal temperature at which H2O2 was released from SC, PO and PP
was detemmined by DSC. The actual amount of H2O2 released from 2 g of each of ttlese complexe~ was determined at various temp~ratures using a 75 liter chamber and ~e apparatus of FIGURES 7A and 7B. The amount of H2O2 role~e~d fr~m ~e PP at 175~C was greater ~an for SC and PO. Atthou~h SC
released the least amount ~f H2O2 at 175~C, si~nificantty more release was seen when the amount of samph wa8 increa~ed.
T~ble 17 SC PO PP
Temp. to r~lea~ H2O2 (by DSC) 170~C 150~C 130~C

Wlth 2 ~ ample At 125~C 0.3 mgrL 0.8 mg/L 1.0 mg/L
At 150~C 1.2 mgtL 2.0 mg/L 1.5 mg/L
At 175~C 1.8 mg/L 2.5 mg/L 3.4 mg/L

Wl~ 3 gruT~ s~mple At 175~C 2.3 mg~L

Wl~ ~, ~rams ~ampl-At 175~C 2.~ mg/L

~ i ~g7~

FY~mplc 1B
Emc cy te~bs uslng SC, PO and PP
2 x 10~ B. subblis var. niger spores were inoculated on a SS blade.
Thr~ ino~JI~t~ blsde wsre first placsd in the front, middle and back l~oSiffGns of a Spunguard wrapped 10"x 21"x 3.5" polyphenybne ox~de tray.
The wrapped tr~y was then placed in a 75 litor vacuum chamb~r hsving an initial vacuum pre~sure of 0.2 torr. A 5.5~ peroxide disk was made by heat-sealing the SC, SO or PP inor~anic peroxide powders between t~re~ layers of Spunguard and one layer of aluminum foil c~ated with po ypropy~ne film. The peroxide was r~b~sed by co~tacting the disk for 2 minutes with an aluminum plate which had been preheated to 175~C, followed by an additional diffusion Ume of 8 minute~ for a total exposure Ume of 10 minutes. After treatment, the three blades were separateiy plac~d in Trypticase Soy Broth (TSB) at 32~C for 7 days and scored for bacterial grourth. The resuits are summarized in Table 18.

Tabl~ 18 EFFICACY TEST RESULTS
Peroxide Weight ofPeroxide Sterility ComDlex ComDlex Conc. (+/all~
PP 2 ~rams 3.4 mg/l 0/3 PO 2 grams 2.5 mgA 0/3 SC 2 grams 1.8 mg/l 1/3 SC 3 ~rams 2.3 mg/l 0/3 SC 4 ~rams 2.~ m~/l 0/3 As can be ~n in ti)o table, no growth of spores wa~ obs~ d with the exceptio" of 2 ~ SC (1t3). How~vor, when the amount of SC subjected to vaporeaffon was increa~ed to 3 grams, no bacterial ~row~ was obs~rv~d.
Those r~sul~s underscoro tho officacy of sterili~ation using inorganic hydrogen peroxide compound.

2 1 ~
( Inorganic hydrogen peroxide complexes can be readily incorporated into the stenli~tion proGedures described hereinabove in connection with organic peroxide c~"ph~xes. For example, inorganic complexes can be used in connection with 8 plasma sterilization m~od, or in connection with a seH-~terilizir~ enclosure where peroxide i~ slowly released from the complex.
Similar~y, inorganic compl~xes can also bo used in the stelil~Uon of articles having narrow lumens, whereby a vessel containing the inorganic peroxide c~llplax i5 connected to the lumen. In a~ition, pr~sure pulsin3 of the vapor relea~ed from inorganic peroxide complexes can be employed. Other example~ of the use of Inorganic complexes for sterilkation will be apparent to one having ordinary skill in the art upon reference to the present specification.

-5~

Claims (41)

1. An apparatus for hydrogen peroxide sterilization of an article, comprising:
a container for holding the article 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°C, said source configured so that said vapor can contact said article to effect 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 located within said container.
5. The apparatus of Claim 1, further comprising an enclosure disposed outside of said container in which said complex is located, and an inlet providing fluid communication between said container and said enclosure, such that vapor released from said complex travels along said inlet and into said container to effect sterilization.
6. The apparatus of Claim 1, wherein said 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 located within said container, whereby said complex is placed on said heater and heater to facilitate the release of said vapor from said complex.
8. The apparatus of Claim 7, wherein said heater is heated prior to contacting with said complex.
9. The apparatus of Claim 1, further comprising a vacuum pump in fluid communication with said container for evacuating the container.
10. The apparatus of Claim 1, further comprising an electrode adapted to generate a plasma around said article.
11. The apparatus of Claim 10, wherein said electrode is inside said container.
12. The apparatus of Claim 10, wherein said electrode is spaced apart from said container and is adapated to flow plasma generated thereby towards and around said article.
13. The apparatus of Claim 1, wherein said complex is in a solid phase.
14. A method for hydrogen peroxide vapor sterilization of an article, comprising:
placing said article into a container; and contacting the article with a hydrogen peroxide vapor released from an inorganic hydrogen peroxide complex by heating the complex at a rate of at least5°C/minute to contact and sterilize the article.
15. The method of Claim 14, wherein the heating rate is at least 10°C/minute.
16. The method of Claim 14, wherein the heating rate is at least 50°C/minute.
17. The method of Claim 14, wherein the heating rate is at least 1000°C/minute.
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 the release of said vapor from said complex.
20. The method of Claim 19, wherein the heating step comprises contacting said complex with a pre-heated heater.
21. The method of Claim 19, wherein said complex is heated to a temperature greater than 86°C.
22. The method of Claim 14, further comprising evacuating the container before introducing said vapor into said container at a pressure of less than 50 torr.
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 container.
26. The method of Claim 25, wherein said plasma is generated inside the container.
27. The method of Claim 25, wherein said plasma is generated outside the container and flowed inside the container and around said article.
28. The method of Claim 14, wherein the contacting step comprises pressure pulsing of said vapor.
29. A method for hydrogen peroxide sterilization of an article, comprising:
placing the article in a enclosure containing an inorganic hydrogen peroxide complex;
sealing said enclosure; and allowing said enclosure to stand at a temperature below 70°C for a time sufficient to release hydrogen peroxide vapor from said complex to effect sterilization of the article.
30. The method of Claim 29, wherein said enclosure is allowed to stand at a pressure less than atmospheric pressure.
31. The method of Claim 29, wherein said enclosure is allowed to stand at a temperature below about 40°C.
32. The method of Claim 29, wherein said enclosure is heated to a temperature greater than 23°C to facilitate release of said vapor.
33. The method of Claim 29, wherein said enclosure is selected from the group consisting of a pouch, a container, a chamber and a room.
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 said hydrogen peroxide complex is in the form of a tablet.
36. The method of Claim 29, wherein said sealing step comprises sealing said enclosure with a gas permeable material.
37. The method of Claim 36, wherein said gas permeable material is selected from the group consisting of TYVEK TM, CSR wrap, and paper.
38. A sealed enclosure containing a sterile product and an inorganic hydrogen peroxide complex capable of releasing hydrogen peroxide vapor.
39. A potassium pyrophosphate hydrogen peroxide complex.
40. A method for hydrogen peroxide vapor sterilization of an article, comprising:
placing said article into a container; and contacting the article with a hydrogen peroxide vapor to contact and sterilize the article, said vapor being released from an inorganic hydrogen peroxide complex which does not decompose to release a hydrohalic acid.
41. A method for hydrogen peroxide sterilization of an article having an exterior and a narrow lumen therein, comprising:
connecting a vessel containing an inorganic peroxide complex to the lumen of the article;
placing the article within a container, whereby said vessel remains connected to the lumen;
reducing the pressure within said container; and contacting the lumen of the article with hydrogen peroxide vapor released from said inorganic peroxide complex at a temperature less than 70°C.
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CA002465144A Expired - Fee Related CA2465144C (en) 1995-10-27 1996-10-28 Injection system and method for releasing gas or vapor from a solid material
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