Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Preservative – buffer – anticoagulant or diluent
Reexamination Certificate
1998-12-17
2001-07-17
Warden, Jill (Department: 1609)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Preservative, buffer, anticoagulant or diluent
C436S008000, C252S380000, C252S397000, C422S040000
Reexamination Certificate
active
06261844
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a urine preservative.
In monitoring the health of patients, urine is routinely collected and analyzed for analytes such as ammonia, calcium, urea nitrogen, sodium, potassium, and chloride. If the urine must be stored prior to analysis, precautionary measures should be taken to preserve the analytes in the urine. In the absence of a preservative, many analytes such as ammonia and calcium are unstable at room temperature. Other analytes are somewhat more stable. For example, urea, sodium, potassium, and chloride are stable for approximately 28 days, 7 months, 28 days, and 4 months, respectively. Although freezing the urine is a common method for preserving urine, freezing is not always a viable option. For example, in monitoring the health of crew members on board spacecraft, or patients in geographically remote areas, the availability of cold storage space typically is limited or unavailable.
Many of the previously described methods for preserving urine analytes at ambient temperatures do not preserve a broad spectrum of analytes and/or pose health risks. For example, strong acids such as concentrated hydrochloric acid and glacial acetic acid preserve few of the analytes present in urine. In spacecraft, the use of these acids is further limited because they impose a safety hazard to crew members. Furthermore, strong acids tend to alter the pH of the urine and negatively effect the analytes in urine. Other acids, such as diluted boric acid, pose few health hazards but ammonia remains unstable after treatment of urine with boric acid. Other compounds, such as thymol and thimerosal, have been used as urine preservatives; however, these compounds require special handling in order to alleviate safety concerns. In addition, ammonia remains unstable even after treatment of urine with thymol.
SUMMARY OF THE INVENTION
The invention features a urine preservative, termed CPG, that includes (i) a 10 to 20% (wt/vol) solution of a chlorhexidine salt (such as chlorhexidine digluconate, chlorhexidine diacetate, or chlorhexidine dichloride) and (ii) a 10 to 30% (wt/vol) solution of n-propyl gallate; the ratio of the chlorhexidine salt solution to the n-propyl gallate solution is 1:2 to 2:1. Generally, the chlorhexidine salt solution is a 20% aqueous solution. Typically, the n-propyl gallate solution is a solution of n-propyl gallate in methanol. Other solvents, such as water, any alcohol, can be substituted for methanol in producing the n-propyl gallate solution. Preferably, the solution of n-propyl gallate is a 20% (wt/vol) solution, and the ratio of n-propyl gallate to chlorhexidine salt is 1:1 (vol:vol).
Included within the invention is a method for producing a urine preservative; the method includes mixing a 10 to 30% (wt/vol) solution of n-propyl gallate with a 10 to 30 % solution of chlorhexidine salt at a ratio of 1:2 to 2: 1. Typically, the n-propyl gallate solution is a 20% solution (wt/vol) of n-propyl gallate (e.g., in methanol), while the chlorhexidine salt is a 20% aqueous solution. Generally, the n-propyl gallate solution is mixed with the chlorhexidine salt solution at a ratio of 1:1.
The invention also includes a method for preserving urine (e.g., human, primate, or dog, cat, or murine urine). This method includes mixing the urine preservative of the invention with urine to a concentration of 0.4 to 1.0 mg/ml of urine preservative in urine. Typically, the urine and urine preservative are mixed to produce a concentration of 0.4 mg/ml of urine preservative in urine.
The invention offers several advantages. For example, CPG allows the urine to be stored at room temperature, thus providing a convenient method for preserving and storing urine when freezer space is unavailable. In addition, CPG can be safely handled without the need for extensive precautionary measures. Also, CPG does not substantially alter the pH of the urine.
As used herein, the term “preserving” urine means treating urine (e.g., with CPG) to increase the stability of one or more analytes normally present in urine. Examples of such analytes include urea nitrogen (UN), creatinine, ammonia, calcium, sodium, potassium, chloride, osmolality, 3-methylhistidine, aldosterone, cortisol, cGMP, melatonin, and total nitrogen.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. All references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed descriptions, and from the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preparation of CPG
The urine preservative of the invention, termed CPG (
c
hlorhexidine salt
-
p
ropyl
g
allate), can be prepared by mixing a chlorhexidine salt with n-propyl gallate. Chlorhexidine salt can be obtained from commercial suppliers. For example, chlorhexidine digluconate is available as a 20% aqueous solution (see, e.g., Sigma Chemical Company, St. Louis, Mo.; Catalog #C 9394). N-propyl gallate also is commercially available (see, e.g., Sigma Chemical Company, St. Louis, Mo.; Catalog #P 3130), and can be prepared as a 10 to 30% solution in a solvent such as absolute methanol, water, any alcohol. The chlorhexidine salt and n-propyl gallate then are mixed together at a ratio of 1:2 to 2:1. In a preferred method, CPG is produced by mixing a 20% solution of chlorhexidine digluconate (in water) with a 20% solution of n-propyl gallate (in absolute methanol) at a ratio of 1:1.
Preservation of Urine
Upon mixing CPG with urine, CPG acts as a urine preservative that inhibits decomposition of a broad spectrum of analytes in urine. Typically, CPG is mixed with urine within 2 hours, and preferably within 30 minutes, following completion of collection. For timed void periods (e.g., 24 hours), CPG is mixed with urine at the end of the collection period. When CPG is not mixed with urine immediately following urination, the urine typically will be chilled or frozen to inhibit decomposition of analytes prior to mixing the urine with CPG. Preferably, CPG and urine are mixed to yield a final concentration of 0.4 to 1.0 mg of CPG per milliliter of urine (e.g., 0.4 mg/ml). Upon mixing CPG with the urine, the urine/CPG mixture can be stored at room temperature; if desired, the urine/CPG mixture can be chilled (e.g., to 40° C.) or frozen (e.g., to −70° C.).
REFERENCES:
patent: 3887701 (1975-06-01), Nachtigal
patent: 4200651 (1980-04-01), Griffith
patent: 4258032 (1981-03-01), Mehl
patent: 4336880 (1982-06-01), Mehl
patent: 4666896 (1987-05-01), Warner, Jr. et al.
patent: 4847079 (1989-07-01), Kwan
patent: 4863989 (1989-09-01), Obayashi et al.
patent: 4972019 (1990-11-01), Obayashi et al.
“The Use of Chlorhexidine
Propyl Gallate (CPG) as a Urine Preservative”, J.L. Nillen & S.M. Smith, Clinical Chemistry, vol. 42, #6, 1996, p. S310.*
“Urine Storage During Space Flight: A Comparison of Preservatives”, J.E. Davis-Street, J. L. Nillen & S. M Smith, Clinical Chemistry, vol. 42. #6, 1996, p. S310.
Nillen Jeannie L.
Smith Scott M.
Cate James M.
Cole Monique T.
The United States of America as represented by the Administrator
Warden Jill
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