阅读说明：本技术 包含稳定氧的组合物及其形成方法 (Compositions comprising stabilized oxygen and methods of forming the same ) 是由 J.桑普罗尼 K.霍兰 M.纳拉彦 于 2018-12-19 设计创作，主要内容包括：本文公开了包含氧、糖或糖醇和氨基酸的组合物,其中所述氨基酸以足以稳定氧的量存在。还提供了水性诊断质量控制或校准试剂以及稳定液体溶液中的氧的方法。(Disclosed herein are compositions comprising oxygen, a sugar or sugar alcohol, and an amino acid, wherein the amino acid is present in an amount sufficient to stabilize the oxygen. Also provided are aqueous diagnostic quality control or calibration reagents and methods of stabilizing oxygen in liquid solutions.)

1. A composition comprising:

oxygen, a sugar or sugar alcohol, and an amino acid, wherein the amino acid is present in an amount sufficient to stabilize the oxygen.

2. The composition of claim 1, wherein the amino acid is ornithine, taurine, threonine, citrulline, histidine, lysine, arginine, tryptophan, aminoguanidine derivatives, amphotericin, or any combination thereof.

3. The composition of claim 1 or 2, wherein the amino acid is present in an amount sufficient to stabilize oxygen for extended room temperature storage.

4. The composition of any one of the preceding claims, comprising from about 0.5 mmol/l to about 11mmol/l of the amino acid.

5. The composition of any of the preceding claims comprising oxygen from about 25 mmHg to about 650 mmHg.

6. The composition of any of the preceding claims comprising from about 27 mg/dl to about 750 mg/dl glucose.

7. The composition of any of the preceding claims, further comprising Blood Urea Nitrogen (BUN) from about 4.5 mg/dl to about 200 mg/dl.

8. The composition of any one of the preceding claims, further comprising sodium, chloride, potassium, calcium, magnesium, or any combination thereof.

9. The composition of any of the preceding claims, wherein the composition has a pH of about 6.6 to about 7.7.

10. The composition of any of the preceding claims, wherein the composition is disposed in a closed system.

11. An aqueous diagnostic quality control or calibration reagent comprising the composition of any one of claims 1-10.

12. The aqueous diagnostic quality control or calibration reagent of claim 11, which is suitable for calibrating an oxygen sensor, a glucose sensor, or both an oxygen sensor and a glucose sensor of an analytical instrument.

13. A method of stabilizing oxygen in a liquid solution, the method comprising:

adding a stabilizing amount of an amino acid to the liquid solution, wherein the liquid solution contains oxygen and a sugar or sugar alcohol.

14. The method of claim 13, wherein the amino acid is ornithine, taurine, threonine, citrulline, histidine, lysine, arginine, tryptophan, aminoguanidine derivatives, amphotericin, or any combination thereof.

15. The method of claim 13 or 14, wherein the amino acid stabilizes oxygen for extended room temperature storage.

16. The method of any one of claims 13-15, wherein the liquid solution contains about 0.5 mmol/l to about 11mmol/l of the amino acid.

17. The method of any one of claims 13-16, wherein the liquid solution contains oxygen from about 25 mmHg to about 650 mmHg.

18. The process of any one of claims 13-17 wherein the liquid solution contains from about 27 mg/dl to about 750 mg/dl glucose.

19. The method of any one of claims 13-18, wherein the liquid solution is an aqueous diagnostic quality control or calibration reagent for use with a diagnostic sensor.

Technical Field

Disclosed herein are compositions comprising stabilized oxygen and methods of forming the same.

Background

Due to the instability of oxygen (pO2) at room temperature, aqueous diagnostic quality control and calibration reagents must typically be stored at 2-8 ℃. The user may need to perform the measurements without a refrigerator nearby, which preferably extends the storage temperature range to 2-30 ℃. Therefore, storage at 2-8 ℃ is often insufficient for storage of diagnostic quality control and calibration reagents.

Summary of The Invention

Disclosed herein are compositions comprising oxygen, a sugar or sugar alcohol, and an amino acid, wherein the amino acid is present in an amount sufficient to stabilize the oxygen.

Also provided are aqueous diagnostic quality control or calibration reagents comprising any of the disclosed compositions.

Further provided is a method of stabilizing oxygen in a liquid solution, the method comprising adding a stabilizing amount of an amino acid to the liquid solution, wherein the liquid solution contains oxygen and a sugar or sugar alcohol.

Brief Description of Drawings

The summary, as well as the following detailed description, is further understood when read in conjunction with the appended drawings. For the purpose of illustrating the disclosed compositions, reagents and methods, there are shown in the drawings exemplary embodiments of the compositions, reagents and methods; however, the compositions, reagents and methods are not limited to the specific embodiments disclosed. In the drawings:

FIG. 1 illustrates the percent (%) degradation of pO2 compared to the concentration of glucose in solution when stored at 45 ℃ for 2 weeks.

Figure 2 illustrates the percent oxygen recovery (%) in an amino acid containing solution stored at 25 ℃ for 12 weeks compared to time zero (baseline).

Detailed description of illustrative embodiments

The disclosed compositions, reagents and methods can be understood more readily by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure. It is to be understood that the disclosed compositions, reagents, and methods are not limited to the specific compositions, reagents, and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, reagents, and methods.

Unless specifically stated otherwise, any description of possible mechanisms or modes of action or reasons for improvement is intended to be illustrative only, and the disclosed compositions, reagents, and methods should not be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement.

Throughout this document, methods are described that relate to compositions comprising stabilized oxygen and methods of stabilizing oxygen in liquid solutions. Where the disclosure describes or claims features or embodiments relating to compositions, such features or embodiments apply equally to the disclosed methods. Likewise, where the disclosure describes or claims features or embodiments relating to the disclosed methods, such features or embodiments apply equally to the compositions.

Where a range of numerical values is stated or established herein, the range includes the endpoints thereof and all the individual integers and fractions within the range, and also includes each of the narrower ranges therein formed by all the various possible combinations of those endpoints and the internal integers and fractions forming subgroups of the larger group of values within the range, to the same extent as if each of those narrower ranges were explicitly stated. Where a range of values is specified herein as being greater than a specified value, the range is still limited and is bounded at its upper end by values operable in the context of the invention as described herein. Where a range of values is specified herein as being less than a specified value, the range is still bounded at its lower end by a non-zero value. It is not intended that the scope of the invention be limited to the specific values recited when defining a range. All ranges are inclusive and combinable.

When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise.

It is to be understood that certain features of the disclosed compositions, reagents, and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions, reagents, and methods which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

As used herein, the singular forms "a", "an" and "the" include the plural.

Various terms are used throughout the description and claims that refer to various aspects of the specification. Such terms are given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

The term "about," when used in relation to a numerical range, a cutoff value, or a specific value, is used to indicate that the recited value can vary from the recited value by up to 10%. Thus, the term "about" is intended to encompass a variation of 10% or less, a variation of 5% or less, a variation of 1% or less, a variation of 0.5% or less, or a variation of 0.1% or less, as compared to the stated value.

The term "comprising" is intended to include the examples encompassed by the term "consisting essentially of and" consisting of; similarly, the term "consisting essentially of is intended to include the examples encompassed by the term" consisting of.

In solutions containing oxygen and various sugars and sugar alcohols (such as glucose), the sugar/sugar alcohol has a tendency to destabilize the oxygen by chemical reaction. The disclosed compositions address this problem by adding an oxygen stabilizing amount of an amino acid that prevents sugar or sugar alcohol induced oxygen instability. The disclosed compositions comprise oxygen, a sugar or sugar alcohol, and an amino acid, wherein the amino acid is present in an amount sufficient to stabilize the oxygen.

Suitable sugars and sugar alcohols include, but are not limited to, glucose, maltose, lactose, maltulose, isomaltulose, or combinations thereof. In some embodiments, the sugar is glucose.

Suitable amino acids include, for example, those containing free amino, imino, or guanidino side chains, which may be ornithine, taurine, threonine, citrulline, histidine, lysine, arginine, tryptophan, aminoguanidine derivatives, amphotericin, or any combination thereof, in either the D or L form.

The amino acid is present in an amount sufficient to increase the stabilization of oxygen relative to a control composition, wherein the control composition comprises oxygen and a sugar or sugar alcohol, but does not comprise an amino acid. The increased stabilization of oxygen relative to the control composition can occur at any temperature. For example, the amino acid may be present in an amount sufficient to increase the stability of oxygen for extended storage at 4 ℃, 37 ℃, room temperature, or any temperature suitable for storage of the composition. In some embodiments, the amino acid is present in an amount sufficient to stabilize oxygen for extended room temperature storage relative to a control composition, wherein the control composition comprises oxygen and a sugar or sugar alcohol, but does not comprise an amino acid. Extended storage may last for one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or more than one year. In some embodiments, the extended room temperature storage lasts from six months to one year.

In some embodiments, the loss of pO2 is less than about 10 mmHg over a 24-week storage period at room temperature. The loss of pO2 can be about 1 mmHg, 2 mmHg, 3 mmHg, 4 mmHg, 5 mmHg, 6 mmHg, 7 mmHg, 8mmHg, 9 mmHg, or 10 mmHg over a 24-week storage period at room temperature. In some embodiments, the loss of pO2 is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to a control composition.

Suitable amino acid concentrations include from about 0.1 mmol/l to about 20 mmol/l, from about 0.5 mmol/l to about 15mmol/l, from about 1mmol/l to about 10 mmol/l, or from about 1.5 mmol/l to about 5 mmol/l. In some embodiments, the composition comprises from about 0.5 mmol/l to about 11mmol/l of amino acid.

The composition can include oxygen from about 10 mmHg to about 1000 mmHg, from about 15 mmHg to about 850 mmHg, from about 20mmHg to about 700 mmHg, from about 50 mmHg to about 500mmHg, or from about 100 mmHg to about 250 mmHg. In some embodiments, the composition comprises oxygen from about 25 mmHg to about 650 mmHg.

The composition may comprise glucose in the range of about 5 mg/dl to about 1000 mg/dl, about 15 mg/dl to about 900 mg/dl, about 20 mg/dl to about 800 mg/dl, or about 50 mg/dl to about 500 mg/dl. In some embodiments, the composition comprises glucose in the range of about 27 mg/dl to about 750 mg/dl.

In addition to oxygen, sugar or sugar alcohol and amino acid, the composition may further comprise urea (measured as Blood Urea Nitrogen (BUN)), salts, buffers, preservatives and/or surfactants. The concentration of BUN may be from about 1 mg/dl to about 200mg/dl, from about 2 mg/dl to about 175 mg/dl, from about 3 mg/dl to about 150 mg/dl, from about 4 mg/dl to about 100 mg/dl, or from about 5 mg/dl to about 50 mg/dl. In some embodiments, the composition comprises BUN from about 4.5 mg/dl to about 90 mg/dl. Suitable salts include sodium, chloride, potassium, calcium, magnesium, or any combination thereof. Suitable buffers include phosphate, MES, MOPS, MOPSO, HEPES and TRIS. Suitable surfactants include Triton, BRIJ and Surfynol. Suitable preservatives include MIT, Cl-MIT, and azide.

The composition may have a pH of about 6 to about 9, about 6.2 to about 8.5, or about 6.4 to about 8. In some embodiments, the composition may have a pH of about 6.6 to about 7.7.

The disclosed compositions may be disposed in a closed system. Suitable closure systems include, for example, flexible bags, ampoules, bottles, tubes, cartridges, and the like. The closure system may be glass or polypropylene.

Also provided herein are aqueous diagnostic quality control or calibration reagents comprising any of the compositions disclosed herein.

The disclosed aqueous diagnostic quality control and calibration reagents may be suitable for calibrating an oxygen sensor, a glucose sensor, or both an oxygen sensor and a glucose sensor in an analytical instrument. The disclosed aqueous diagnostic quality control and calibration reagents are useful in a variety of medical diagnostic applications, including, but not limited to, detection/diagnosis of disease states (such as hyperglycemia/hypoglycemia) and metabolic states (oxygen content), as well as food or beverage testing, agriculture, and drug development or testing.

Also provided is a method of stabilizing oxygen in a liquid solution, the method comprising adding a stabilizing amount of an amino acid to the liquid solution, wherein the liquid solution contains oxygen and a sugar or sugar alcohol.

Suitable amino acids include, for example, those containing free amino, imino, or guanidino side chains, which can be ornithine in the D or L form, taurine, threonine, citrulline, histidine, lysine, arginine, tryptophan, aminoguanidine derivatives, amphotericin, or any combination thereof.

The stabilizing amount of the amino acid is an amount sufficient to increase the stabilization of oxygen relative to a control composition, wherein the control composition comprises oxygen and a sugar or sugar alcohol, but does not comprise an amino acid. The increased stabilization of oxygen relative to the control composition can occur at any temperature. For example, the method can include adding the amino acid in an amount sufficient to increase the stability of oxygen for extended storage at 4 ℃, 37 ℃, room temperature, or any temperature suitable for storing liquid solutions. In some embodiments, the method comprises adding an amount of an amino acid sufficient to stabilize oxygen for extended room temperature storage relative to a control composition, wherein the control composition comprises oxygen and a sugar or sugar alcohol, but does not comprise an amino acid. Extended storage may last for one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, or more than one year. In some embodiments, the extended room temperature storage lasts from six months to one year. Suitable amino acid concentrations include from about 0.1 mmol/l to about 20 mmol/l, from about 0.5 mmol/l to about 15mmol/l, from about 1mmol/l to about 10 mmol/l, or from about 1.5 mmol/l to about 5 mmol/l. In some embodiments, the method comprises adding from about 0.5 mmol/l to about 11mmol/l of the amino acid to the liquid solution.

In some embodiments, the loss of pO2 is less than about 10 mmHg over a 24-week storage period at room temperature. The loss of pO2 can be about 1 mmHg, 2 mmHg, 3 mmHg, 4 mmHg, 5 mmHg, 6 mmHg, 7 mmHg, 8mmHg, 9 mmHg, or 10 mmHg over a 24-week storage period at room temperature. In some embodiments, the loss of pO2 is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% relative to a control composition.

The liquid solution may comprise oxygen from about 10 mmHg to about 1000 mmHg, from about 15 mmHg to about 850 mmHg, from about 20mmHg to about 700 mmHg, from about 50 mmHg to about 500mmHg, or from about 100 mmHg to about 250 mmHg. In some embodiments, the liquid solution comprises oxygen from about 25 mmHg to about 650 mmHg.

The liquid solution may comprise glucose in the range of about 5 mg/dl to about 1000 mg/dl, about 15 mg/dl to about 900 mg/dl, about 20 mg/dl to about 800 mg/dl, or about 50 mg/dl to about 500 mg/dl. In some embodiments, the liquid solution comprises glucose in the range of about 27 mg/dl to about 750 mg/dl.

In some embodiments, the liquid solution is an aqueous diagnostic quality control or calibration reagent for use with a diagnostic sensor. Diagnostic sensors include, but are not limited to, sensors for sugars or sugar alcohols and/or oxygen. In some embodiments, the sensor for a sugar or sugar alcohol is a glucose sensor.

Examples

The following examples are provided to further describe some embodiments disclosed herein. The examples are intended to illustrate, but not to limit, the disclosed embodiments.

In solutions containing oxygen and various sugars and sugar alcohols (such as glucose), the sugar/sugar alcohol has a tendency to destabilize the oxygen by chemical reaction. This example is in figure 1, which shows the loss of oxygen (% degradation of pO2) as the glucose concentration increases when stored at 45 ℃ for 2 weeks. As shown in fig. 1, the addition of glucose caused a loss of pO2, which increased as the glucose concentration increased.

Exemplary amino acids arginine and ornithine were tested for their ability to stabilize oxygen at 25 ℃. Oxygen was injected into a glucose-containing solution (table 1) containing arginine or ornithine, and then sealed in a closed system. The oxygen recovery% in samples stored at 25 ℃ for 12 weeks was analyzed and compared to time zero (baseline). As shown in table 1 and figure 2, 93.6% and 95.7% oxygen was recovered from samples containing arginine or ornithine, respectively, stored at 25 ℃ for 12 weeks, compared to time zero.

TABLE 1 oxygen recovery after 12 weeks at 25 ℃

Sample name	Amino acids	Candy	Oxygen recovery after 12 weeks at 25 ℃ compared to baseline (time = 0%)
				Reagent 1	1.94 g/L arginine	0.5 g/L glucose	93.6%
Reagent 2	2.41 g/L Ornithine	0.5 g/L glucose	95.7%

Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of this present invention.