Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Preservative – buffer – anticoagulant or diluent
Reexamination Certificate
2002-01-24
2004-03-16
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Preservative, buffer, anticoagulant or diluent
C436S008000, C436S010000, C436S066000, C436S130000, C436S176000, C252S408100
Reexamination Certificate
active
06706526
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to the fields of hematology and immunology and to reagents used for analyzing blood cells. More specifically, the present invention relates to an improved diluent which produces less than about 1 part per million of formaldehyde during both usage and storage.
Common medical diagnostic procedures involve the analysis of a blood sample of a patient in order to make certain clinical diagnoses. For example, complete blood counts, analyses of the white and red cell numbers and/or subpopulations, and the presence of unusual cell types as detected by a variety of flow cytometric assays provide valuable information for the physician. Regardless of the subsequent steps to be performed in any of the well-known diagnostic analytic procedures for blood samples, the first step is generally a dilution of the blood sample. Specifically, the blood sample is diluted with a diluent that may contain a mixture of salts, buffers, and preservatives, among others. See, e.g., the discussion of the contents and problems of prior art diluents in U.S. Pat. No. 5,935,857, for example.
However, the use of many commercially available blood diluents has been restricted due to the regulation of institutional and industrial, including medical, wastes. For example, regulatory agencies in the states of California and Massachusetts, for example, are increasingly requiring reduced concentrations of formaldehyde in wastewater. Unfortunately, at present, most of the commercially available blood diluents produce formaldehyde in amounts in excess of about 400 parts per million, or if there is an absence of formaldehyde producing components, the diluent contains other undesirable components, such as sodium azide, or does not have the broad biocidal protection.
There exists a need in the art for a multipurpose blood diluent which produces considerably less than about 400 parts per million of formaldehyde and does not negatively impact the analysis of samples, has broad biocidal activity and does not contain undesirable components.
SUMMARY OF THE INVENTION
The present invention is directed toward blood diluents which produce less than about 1 part per million of formaldehyde. The present invention is also directed toward such substantially formaldehyde-free diluents, which maintain good antimicrobial activity, but do not adversely affect essential parameters of blood analysis, such as mean corpuscular volume (MCV) and other blood cell parameters.
The present invention is further directed toward methods of analyzing a blood sample containing blood cells using the blood diluents of the invention.
These and other aspects of the invention will be understood to one of skill in the art upon reading of the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention resolves the problem of formaldehyde production by blood diluents by providing a novel blood diluent which contains less than about 1 part per million of formaldehyde. Further, methods for analyzing the blood samples to determine at least one physical parameter of the blood sample using the blood diluents of the invention are provided.
I. The Diluent Composition
The present invention provides a low formaldehyde-containing aqueous blood diluent containing a first component selected from specified potentiator reagents and a second component which is a combination of an effective anti-microbial amount of 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one; and 5-bromo-5-nitro-1,3-dioxane. The compositions are combined in concentrations and with other components that permit less than about 1 parts per million of formaldehyde to be produced in the diluent.
The phrase “low formaldehyde” as used herein and throughout this specification is meant to describe a solution having or producing less than about 1 part per million (ppm) of formaldehyde over a period of time of at least 1 year. In one embodiment, “low formaldehyde” describes a solution having or producing less than about 0.70 ppm of formaldehyde. In another embodiment, “low formaldehyde” describes a solution having or producing less than about 0.60 ppm of formaldehyde. In a further embodiment, “low formaldehyde” describes a solution having or producing less than about 0.50 ppm of formaldehyde. In yet another embodiment, “low formaldehyde” describes a solution having or producing less than about 0.40 ppm of formaldehyde. In another embodiment, “low of formaldehyde” describes a solution having or producing less than about 0.30 ppm of formaldehyde. In yet a further embodiment, “low formaldehyde” describes a solution having or producing less than about 0.20 ppm of formaldehyde. In another embodiment, “low formaldehyde” describes a solution having or producing less than about 0.10 ppm of formaldehyde.
The inventors have recently discovered that preservative agents contribute significantly to the production of formaldehyde in commercially available blood diluents. Specifically, the widely used preservative agent dimethylolurea (DMOU) has been found to produce greater than 1 part per million of formaldehyde both alone and in combination with other reagents. Since the blood diluents of the invention produce less than about 1 ppm formaldehyde, it is preferable for reagents that produce or contain greater than 1 ppm of formaldehyde to be omitted from the composition of the diluent of the invention. Since the inventors have discovered that dimethylolurea produces greater than 1 ppm formaldehyde, it is preferably completely excluded from the diluent composition of the invention.
As used herein and throughout this specification, an “effective amount” of a component is selected with regard to the pH, osmolality, concentration, conductivity and/or antimicrobial efficacy of the final diluent composition and with respect to the function of the particular component. One of skill in the art would readily be able to determine the effective amount of each component. While specific ranges are noted, alternate amounts may also be contemplated by one of skill in the art.
The term “aqueous” as used herein and throughout this specification is meant to describe a solution having water as its main component. The solution may additionally contain other chemical compounds and/or solvents that do not interfere with the effectiveness of the diluent. Such additional solvents may be selected by one of skill in the art and include, but are not limited to, organic solvents, inorganic solvents, and saline solutions.
A. Potentiator Reagents
As described herein, the present invention is directed toward a low formaldehyde-containing aqueous blood diluent that contains one or more potentiators as a first component. Without wishing to be bound by theory, the blood diluent potentiator is a compound that chelates ions in the cell membrane and weakens the membrane, making the cell more susceptible to biocides. In one embodiment, one potentiator may be ethylenediamine tetraacetic acid (EDTA), an EDTA derivative, or combinations thereof. In another embodiment, the potentiator is an EDTA derivative. For example, in an embodiment, the potentiator is disodium EDTA. In another embodiment, the potentiator is dipotassium EDTA. In still another embodiment, the potentiator is ethyleneglycol-bis-(2-aminoethyl ether)N,N,N′,N′-tetraacetic acid (EGTA). More preferably, the potentiator is disodium EDTA.
In another embodiment, additional potentiators other than EDTA or its derivatives may be added to the diluent. Such additional potentiators include potentiators that chelate ions as described above, which are known to those skilled in the art. Some of these potentiators include, without limitation, cyclohexanediamine-tetraacetic acid, diethylentriaminepentaacetic acid, and/or hydroxyethylethylene-diaminetriacetic acid. Still other potentiators which function via mechanisms other than chelation are known and may also be mixed with a chelating potentiator into the biocidal formulation of the diluent.
The concentration of each potentiator in the dilue
Lang Russell F.
Murza Barbara G.
Oramas Luisa C.
Payan Iris L.
Alter Mitchell E.
Coulter International Corp.
Howson and Howson
Wallenhorst Maureen M.
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