Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Oxidoreductases
Reexamination Certificate
2000-03-06
2003-01-07
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Oxidoreductases
C435S189000, C435S190000, C435S192000, C422S028000, C514S579000, C514S042000, C514S561000, C514S564000
Reexamination Certificate
active
06503507
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for antisepsis, disinfection or sterilization. More particularly, the present invention relates to methods and compositions that remain inactive as packaged for storage, but become active on exposure to air as an antiseptic, disinfection or sterilent agent when dispensed for use.
BACKGROUND OF THE INVENTION
Antisepsis is defined as substantial reduction of microbial content whereas disinfection is the elimination of all life forms capable of causing disease. Practically, disinfection implies destruction of all viable microorganisms except spores. Sterilization means the complete elimination of all viable microorganisms including spores (Hospital Infections, 2nd Ed. (Bennett, J. V. and Brachman, P. S. eds.), Little, Brown and Co., Boston, Mass.), pp. 238-241, 1986). The acceptable methods of sterilization in current use are autoclaving (steam under pressure), dry heat, and gas sterilization (e.g., ethylene oxide). Sterilization by soaking in antiseptics is typically incomplete and is indicated only in circumstances where the sterilization methods described above are not applicable.
There are limitations to all of the sterilization methods described above. Many materials and devices are destroyed by dry heat or steam sterilization. Gas sterilization typically requires prolonged contact, e.g., exposure for greater than an hour, and a post-sterilization period for dissipation of the gas from the treated material. Lensed instruments or porous items typically require 24 to 48 hours of exposure to air before use. On the other hand, sterilization with germicidal agents, such as gluteraldehyde (2%), formaldehyde (8%)-alcohol (70%), or hydrogen peroxide (6%), requires exposure times ranging from 6 to 18 hours. These germicidal agents are also highly toxic and are indiscriminant in their toxic effect. As such, these sterilents cannot be brought in direct contact with host tissue, and have limited utility as sterilants for biomedical devices, such as contact lenses, medical and surgical instruments, and for wound cleaning. For example, an antimicrobial agent used to disinfect or sterilize a contact lens must possess a number of unique characteristics. On one hand, it must be effective against microoorganisms which may be dangerous to the eye. At the same time, it must be tolerated in the delicate ocular environment of the user, and also not damage the contact lens itself. A number of contact lens disinfecting and preserving solutions are known in the art. Typically such solutions employ either sorbic acid, thimerosal, chlorhexidine, a polyquaternary germicide, a synthetic antibiotic or a conventional quaternary germicide, such as benzalkonium chloride. However, these conventional antimicrobial agents have drawbacks that tend to restrict their use. For example, sorbic acid characteristically contains formaldehyde residues, thimerosal in some patients acts as an allergy sensitizer, and chlorhexidine is relatively toxic. Also, a problem exists in that soft contact lens materials have a tendency to bind and concentrate antimicrobial agents and other active ingredients commonly found in contact lens care solutions, in some cases to hazardous levels. For example, benzalkonium chloride is typically not used with soft contact lenses due to its tendency to be taken up into the lens matrix. In addition, many of the antimicrobial agents known to date are relatively ineffective against a number of fungi and yeasts which are problematic in the ocular environment.
U.S. Pat. No. 5,389,369 discloses an improved haloperoxidase-based system for killing bacteria, yeast or sporular microorganisms by contacting the microorganisms, in the presence of a peroxide and chloride or bromide, with a haloperoxidase and an antimicrobial activity enhancing &agr;-amino acid. Although compositions and methods of U.S. Pat. No. 5,389,369 have been found to be highly effective antimicrobials, the components must be separately stored and maintained in order to prevent haloperoxidase/peroxide interaction and depletion prior to dispensing for use.
Therefore, there exists a need for methods and compositions for disinfecting and/or sterilizing materials or devices, such as contact lenses, surgical instruments and other biomedical devices, which is effective against bacteria, fungi and yeasts, which is tolerable by the user, which does not damage the devices, and which is designed for ease and convenience of storage and use. Ideally, such disinfectant-sterilent compositions should be fast acting with minimal host toxicity and maximal germicidal action. The compositions should be easy to deliver, should not damage the material or device treated, and should not cause damage to host tissue on contact. Depending upon the strength of composition and the time interval of exposure, the compositions should produce antisepsis, disinfection or sterilization.
SUMMARY OF THE INVENTION
The present invention describes methods and compositions for producing air-activated, i.e., oxygen (O
2
) activated, disinfectant-sterilent solutions. Solutions containing a haloperoxidase (i.e., a halide:hydrogen peroxide (H
2
O
2
) oxidoreductase, such as myeloperoxidase, eosinophil peroxidase or lactoperoxidase) plus a halide or combination of halides (i.e., chloride, bromide and/or iodide) in appropriate concentrations, an oxidase (i.e., a substrate:O
2
oxidoreductase) capable of generating H
2
O
2,
and a substrate specific for that oxidase, are separately prepared under aerobic conditions, but all of the component solutions are made anaerobic prior to final combination and mixing. The anaerobic formulations are dispensed into containers capable of maintaining the anaerobic condition (e.g., pressurized canisters). At Dispensing the solution at the time of use exposes the formulation to air (i.e., O
2
) which activates its disinfectant-sterilent properties. O
2
is the rate limiting component for oxidase generation of H
2
O
2
. Under aerobic conditions the oxidase catalyzes the oxidation of its substrate and the reduction of O
2
to generate H
2
O
2
. In turn, H
2
O
2
serves as substrate for haloperoxidase which catalyzes the oxidation of halide to hypohalous acid. Hypohalous acid reacts with an additional H
2
O
2
to generate singlet molecular oxygen (
1
O
2
). Hypohalous acid (e.g., hypochlorous acid) and especially
1
O
2
are potent microbicidal agents. Both haloperoxidase generation of hypohalous acid and its reactive consumption to yield
1
O
2
are dependent on the availability of H
2
O
2
. A high rate of H
2
O
2
generation does not result in the accumulation of hypohalous acid, but instead results in a high rate of
1
O
2
production. The microbicidal capacity and toxicity of
1
O
2
are limited by the half-life of this metastable electronically excited reactant, and as such, disinfectant-sterilent activity is temporally defined by and confined to the dynamics of oxidant generation. Disinfectant-sterilent activity of a formulation requires air exposure and is dependent on the presence of the halide-haloperoxidase combination employed, the activity of the oxidase present, the availability of oxidase-specific substrate and the availability of O
2
.
For these disinfectant-sterilent formulations, O
2
is the essential and limiting component for microbicidal action. The formulation must contain sufficient haloperoxidase to produce the desired microbicidal effect. However, the relative concentrations of oxidase and its substrate can be adjusted to produce a broad spectrum of microbicidal activities ranging from rapid, high intensity microbicidal action of short duration to slow and prolonged microbicidal plus sporicidal action. By increasing the oxidase and making the oxidase substrate concentration limiting, the formulation will rapidly convert substrate to H
2
O
2
producing a highly potent but time-limited microbicidal action. Once the substrate is exhausted there is a cessation of oxidative activity. On the other hand, limiting the concentration of oxidase limits the r
ExOxEmis, Inc.
Witz Jean C.
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