Nitric oxide releasing compositions

Abstract

Nitric oxide (NO) generating compositions can include a nitrite component, an acidifying component, and a support material configured to carry one of the nitrite component and the acidifying agent. In some examples, the support material can minimize NO generation prior to addition of an activating amount of a suitable solvent.

Claims

1. A particulate composition, comprising: a blend of a nitrite component and an acidifying agent, wherein the acidifying agent is carried by a calcined support material, and the nitrite component is not carried by a support material.

2. The particulate composition of claim 1, wherein the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

3. The particulate composition of claim 1, wherein the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

4. The particulate composition of claim 1, wherein the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

5. The particulate composition of claim 1, wherein the support material has a surface area of at least 0.1 meters squared per gram (m.sup.2/g).

6. The particulate composition of claim 1, wherein the support material has a pore volume of at least 0.01 cubic centimeters per gram (cc/g).

7. The particulate composition of claim 1, wherein the nitrite component and the acidifying agent are present in the particulate composition at a weight ratio of from about 1:2 to about 2:1.

8. The particulate composition of claim 1, wherein the support material is present in the particulate composition at a weight ratio of from about 0.05:1 to about 10:1 with the nitrite component or the acidifying agent.

9. The particulate composition of claim 1, wherein the nitrite component is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

10. The particulate composition of claim 1, wherein the acidifying agent is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

11. The particulate composition of claim 1, wherein the support material is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

Description

EXAMPLES

(1) Certain invention embodiments are further described in detail by reference to the following experimental example. This example is provided for purposes of illustration only, and is not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following example, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

Example 1: Stability and Antimicrobial Activity of Various Nitric Oxide Releasing Compositions

(2) 20 mM NORS (50 mL), using coated citric acid, was made by mixing 20 mM sodium nitrite solution and the coated citric acid with a net weight of 0.07 g (see Table 1 for gross weight). A control of 20 mM NORS, using uncoated citric acid, was used. The pH of each NORS was measured using an Orion Star A211 pH meter and NO and NO.sub.2 production was measured using a PulmoNOx detector.

(3) TABLE-US-00001 TABLE 1 List of samples, their coating, percent citric acid, amount added to make 20 mM NORS and amount added with 7.0 g of sodium nitrite. Amount Added to Amount Volume of make Added NaNO.sub.2 + % Citric 20 mM to 7.0 g of Citric Code Carrier name Acid NORS NaNO.sub.2 Acid  6A Sipernat 2200 57.2%  0.122 g 12.24 g   30 mL  6B Sipernat 2200 66.0%  0.106 g 10.61 g 27.5 mL  6C Sipernat 2200 57.8%  0.121 g 12.11 g 32.5 mL  7A Sipernat 50 78.7%  0.089 g  8.89 g   15 mL  7B Sipernat 50 82.6%  0.083 g  8.33 g 17.5 mL  8A Sipernat 500LS 76.3%  0.092 g  9.17 g   20 mL  8B Sipernat 500LS 83.0%  0.084 g  8.43 g 17.5 mL  9A Zeofree 5161 64.0%  0.109 g 10.94 g 27.5 mL  9B Zeofree 5161 71.0%  0.099 g  9.86 g   25 mL  9C Zeofree 5161 63.8%  0.110 g 10.97 g 22.5 mL 10A Zeofree 5162 65.3%  0.107 g 10.72 g   25 mL 10B Zeofree 5162 71.0%  0.099 g  9.86 g   20 mL 10C Zeofree 5162 62.4%  0.112 g 11.22 g   25 mL 11A Hubersorb 600 71.7%  0.098 g  9.76 g   15 mL 11B Hubersorb 600 75.0%  0.093 g  9.33 g   15 mL 12 Aerosil R812 95.0%  0.074 g  7.37 g 12.5 mL 13 Aerosil R972 95.0%  0.074 g  7.37 g 12.5 mL 14 Aerosil R972 99.5% 0.0704 g 7.035 g 12.5 mL 15 Aerosil R972 99.0% 0.0707 g 7.070 g 12.5 mL 16 Aerosil R972 98.0% 0.0714 g 7.143 g 12.5 mL 17 Aerosil R972 97.0% 0.0722 g 7.216 g 12.5 mL 18 Sipernat 50 72.9% 0.0960 g 9.602 g 19 Sipernat 50 80.8% 0.0866 g 8.663 g

(4) All samples included undissolved material (e.g. solid material settling at the bottom of the container, film building up on the walls of the container and/or top of fluid, etc.) which began to appear within about a minute after mixing. In samples 11A and 11B (hubersorb coating) the pH measured was higher than normal, at 3.81 and 3.74 respectively. For the others the pH, NO and NO.sub.2 was found to be similar to the control (Table 2). Samples 6A, 6B, 7A, 7B, 10A, 10B, 10C tended to have lower NO.sub.2 release. In contrast, samples 9A, 9B, and 9C after mixing with sodium nitrite had higher NO.sub.2 than the control.

(5) TABLE-US-00002 TABLE 2 A comparison with the 20 mM NORS with silica coverings with a control. pH was measured using the Orion Star A211 pH meter and NO and NO.sub.2 was measured using the PulmoNOx. NO NO.sub.2 Sample pH (ppm) (ppm) Control 3.56 3 5.6  6A 3.56 2 3.6  6B 3.53 3 3.2  6C 3.55 1 5.3  7A 3.53 2 3.4  7B 3.53 2 3.5  8A 3.55 2 5.2  8B 3.53 3 5.7  9A 3.55 1 6.4  9B 3.55 2 6.3  9C 3.55 1 6.9 10A 3.55 3 2.9 10B 3.55 2 2.3 10C 3.57 2 2.6 11A 3.81 2 1.9 11B 3.74 1 2.2 12 3.58 0 0.6 13 3.58 0 1.2 Control 3.56 3 2.8 14 3.57 2 2.3 15 3.57 2 2.0 16 3.58 1 1.7 17 3.58 1 1.5 18 3.56 2 1.9 19 3.56 2 2.1
Stability

(6) The stability of each composition was measured by mixing 7.0 g of sodium nitrite with a net weight of 7.0 g of the coated citric acid (see Table 1 for gross weight). A control of 7.0 g of sodium nitrite and 7.0 g of citric acid was used. NO and NO.sub.2 was measured over 2 days using an electrochemical NO/NO2 analyzer (PulmoNOx IIa, Tofield, Canada).

(7) NO and NO.sub.2 generally were not detected in the samples after 24 and 48 hours of mix, except in samples 8A and 6A. (See Table 3).

(8) TABLE-US-00003 TABLE 3 Stability of dry sodium nitrite (7 g) mixed with citric acid (7 g, net weight). NO and NO.sub.2 was measured using the PulmoNOx. 0 hours 24 hours 48 hours 1 month NO NO.sub.2 NO NO.sub.2 NO NO.sub.2 NO NO.sub.2 Sample (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) (ppm) Control 200 15.6 22 12.5 8 5.8  6A 0 0 107 >21.5 48 6.7  0    0.4  6B 0 0 0 0 0 0  0    0  6C 0 0 0 0 0 0  0    0  7A 0 0 0 0 0 0  0    0  7B 0 0 0 0 0 0  0    0  8A 203 >21.5 66 >21.5 11 >21.5  0    0.4  8B 0 0 0 0 0 0  0    0  9A 0 0 0 0 0 0  0    0.1  9B 0 0 0 0 0 0  0    0  9C 0 0 0 0 0 0  0    0 10A 0 0 0 0 0 0  0    0 10B 0 0 0 0 0 0  0    0 10C 0 0 0 0 0 0  0    0 11A 0 0 0 0 0 0  0    0 11B 0 0 0 0 0 0  0    0 12 0 0 0 0 0 0  0*    0* 13 0 0 0 0 0 0  0*    0* 14 0 0 0 0 0 532 >21.5 15 0 0 0 0 0 346 >21.5 16 0 0 0 0 0 336 >21.5 17 0 0 0 0 0  0   0 18 0 0 0 0 0  0   0 19 0 0 0 0 0  0   0 *Samples 12 and 13 were measured 1 week later.
Antimicrobial Properties

(9) Antimicrobial properties were tested using 20 mM NORS solutions, as described above. 990 μL of NORS was placed into a centrifuge tube. Saline was used as a control. 10 μL of 10.sup.8 CFU/mL of Salmonella typhi was added to the tube resulting in a final concentration of 10.sup.6 CFU/mL. Exposure times of 2 and 5 minutes were used. The bacteria were plated onto BHI plates and incubated at 37° C. overnight.

(10) The coated NORS retained its antimicrobial properties against S. typhi in all the samples. In general, 2 minutes post treatment an average of 10.sup.2 was found, by 5 minutes no detectable bacteria was found. The treatments that were using samples 7A, 11A, and 11B had a higher bacterial concentration after 2 minutes (possibly due to the higher pH found after mixing the NORS in the 11 samples) but still had complete eradication after 5 min.

(11) TABLE-US-00004 TABLE 4 Antimicrobial effect of 20 mM NORS with silica covering. No detectable bacteria was found after 5 minutes. 2 min 5 min Sample Control (CFU/mL) (CFU/mL)  6A 1.13*10.sup.6 2.0*10.sup.2 0  6B 1.13*10.sup.6 6.0*10.sup.1 0  6C 1.13*10.sup.6 5.0*10.sup.1 0  7A 1.13*10.sup.6 5.8*10.sup.3 0  7B 1.13*10.sup.6 3.0*10.sup.1 0  8A 1.13*10.sup.6 4.0*10.sup.2 0  8B 1.13*10.sup.6 4.0*10.sup.1 0  9A 1.13*10.sup.6 2.0*10.sup.1 0  9B 1.13*10.sup.6 7.0*10.sup.1 0  9C 1.13*10.sup.6 2.0*10.sup.2 0 10A 1.13*10.sup.6 3.0*10.sup.2 0 10B 1.13*10.sup.6 2.0*10.sup.2 0 10C 1.13*10.sup.6 4.0*10.sup.2 0 11A 1.13*10.sup.6 3.0*10.sup.5 0 11B 1.13*10.sup.6 6.0*10.sup.4 0 12  8.9*10.sup.5 2.0*10.sup.2 0 13  8.9*10.sup.5 4.3*10.sup.2 0 14  2.6*10.sup.6 4.8*10.sup.2 0 15  2.6*10.sup.6 7.0*10.sup.1 0 16  2.6*10.sup.6 1.3*10.sup.2 0 17  2.6*10.sup.6 2.0*10.sup.2 0 18  2.6*10.sup.6 0 0 19  2.6*10.sup.6 2.0*10.sup.2 0

(12) TABLE-US-00005 TABLE 5 Antimicrobial effect of 20 mM NORS with silica covering against S. aureus and E. coli. No detectable bacteria was found after 10 minutes. S. aureus E. coli 10 min 10 min 5 min (CFU/ 5 min (CFU/ Sample Control (CFU/mL) mL) Control (CFU/mL) mL) control 1.20*10.sup.6 1.7*10.sup.3 0 2.40*10.sup.6   2*10.sup.2 0  7A 1.20*10.sup.6 3.5*10.sup.3 0 2.40*10.sup.6 2.0*10.sup.2 0  7B 1.20*10.sup.6 4.2*10.sup.3 0 2.40*10.sup.6 8.0*10.sup.1 0 12 1.20*10.sup.6 2.1*10.sup.3 0 2.40*10.sup.6 1.4*10.sup.2 0 13 1.20*10.sup.6 4.5*10.sup.3 0 2.40*10.sup.6 1.2*10.sup.2 0

Example Embodiments

(13) In one example, there is provided a particulate composition, comprising a blend of a nitrite component and an acidifying agent, wherein one, but not both, of the nitrite component and the acidifying agent is carried by a support material.

(14) In one example of a particulate composition, the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

(15) In one example of a particulate composition, the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

(16) In one example of a particulate composition, the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

(17) In one example of a particulate composition, the support material has a surface area of at least 0.1 meters squared per gram (m.sup.2/g).

(18) In one example of a particulate composition, the support material has a pore volume of at least 0.01 cubic centimeters per gram (cc/g).

(19) In one example of a particulate composition, the support material is a calcined support material.

(20) In one example of a particulate composition, the nitrite component and the acidifying agent are present in the particulate composition at a weight ratio of from about 1:2 to about 2:1.

(21) In one example of a particulate composition, the support material can be present in the particulate composition at a weight ratio of from about 0.05:1 to about 10:1 with the nitrite component or the acidifying agent.

(22) In one example of a particulate composition, the nitrite component is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(23) In one example of a particulate composition, the acidifying agent is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(24) In one example of a particulate composition, the support material is present in the particulate composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(25) In one example of a particulate composition, the nitrite component is carried by the support material.

(26) In one example of a particulate composition, the acidifying agent is carried by the support material.

(27) In one example, there is provided an inactive nitric oxide (NO) generating composition, comprising a nitrite component; and an acidifying component, said acidifying component comprising an acidifying agent carried by a support material, wherein the nitrite component and the acidifying component are mixed together in a dry form.

(28) In one example of an inactive nitric oxide (NO) generating composition, the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

(29) In one example of an inactive nitric oxide (NO) generating composition, the nitrite component is present in the composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(30) In one example of an inactive nitric oxide (NO) generating composition, the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

(31) In one example of an inactive nitric oxide (NO) generating composition, the acidifying component is present in the composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(32) In one example of an inactive nitric oxide (NO) generating composition, the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

(33) In one example of an inactive nitric oxide (NO) generating composition, the support material has a surface area of at least 0.1 meters squared per gram (m.sup.2/g).

(34) In one example of an inactive nitric oxide (NO) generating composition, the support material has a pore volume of at least 0.01 cubic centimeters per gram (cc/g).

(35) In one example of an inactive nitric oxide (NO) generating composition, the support material is a calcined support material.

(36) In one example of an inactive nitric oxide (NO) generating composition, the support material and the acidifying agent are present at a weight ratio of from about 0.05:1 to about 10:1.

(37) In one example of an inactive nitric oxide (NO) generating composition, the composition includes less than 20 wt % water.

(38) In one example there is provided a stable nitric oxide (NO) generating composition, comprising a blend of a nitrite component and an acidifying agent in a dry form, wherein less than 1 part per million (ppm) of nitric oxide is detectable by chemiluminescence upon opening a storage container within which the blend has been stored for 3 months at room temperature.

(39) In one example of a stable nitric oxide (NO) generating composition, the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

(40) In one example of a stable nitric oxide (NO) generating composition, the nitrite component is present in the composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(41) In one example of a stable nitric oxide (NO) generating composition, the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

(42) In one example of a stable nitric oxide (NO) generating composition, the acidifying agent is present in the composition in an amount of from about 0.05 wt % to about 99.5 wt %.

(43) In one example of a stable nitric oxide (NO) generating composition, the composition includes less than 20 wt % water.

(44) In one example of a stable nitric oxide (NO) generating composition, the composition further comprises a support material configured to carry the nitrite component or the acidifying agent and minimize generation of NO prior to activation.

(45) In one example of a stable nitric oxide (NO) generating composition, the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

(46) In one example, there is provided a therapeutic system, comprising a composition comprising a blend of a nitrite component and an acidifying agent in a dry form, wherein one, but not both, of the nitrite component and the acidifying agent is carried by a support material; a container within which the composition is enclosed, said container having a fill-line; and instructions directing a user to fill the container up to the fill-line with an activation solvent to activate the composition.

(47) In one example of a a therapeutic system, the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

(48) In one example of a a therapeutic system, the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

(49) In one example of a a therapeutic system, the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

(50) In one example of a a therapeutic system, the nitrite component is carried by the support material.

(51) In one example of a a therapeutic system, the acidifying agent is carried by the support material.

(52) In one example of a a therapeutic system, the container comprises one or more of glass, polyethylene, polypropylene, polycarbonate, and polyvinyl chloride.

(53) In one example, there is provided a method of minimizing NO generation prior to activation of a nitric oxide generating composition, comprising combining an acidifying agent with a support material to form an acidifying component; mixing the acidifying component with a nitrite component to form a dry composition having a water content less than 5 wt %, wherein combining the acidifying agent with a support material minimizes NO generation prior to addition of an activating amount of an aqueous solvent.

(54) In one example of a method of minimizing NO generation prior to activation of a nitric oxide generating composition, combining comprises coating the acidifying agent onto the support material.

(55) In one example of a method of minimizing NO generation prior to activation of a nitric oxide generating composition, combining comprises encapsulating the acidifying agent within the support material.

(56) In one example, there is provided a method of making an inactive nitric oxide (NO) generating composition, comprising combining an acidifying agent with a support material to form an acidifying component; mixing the acidifying component with a nitrite component in dry form, wherein combining the acidifying agent with a support material minimizes NO generation prior to addition of an activating amount of an aqueous solvent.

(57) In one example of a method of making an inactive nitric oxide (NO) generating composition, combining comprises coating the acidifying agent onto the support material.

(58) In one example of a method of making an inactive nitric oxide (NO) generating composition, combining comprises encapsulating the acidifying agent within the support material.

(59) In one example there is provided a nitric oxide releasing composition, comprising an effective amount of an acidifying agent; a nitrite component in an amount sufficient to generate a therapeutically effective amount of nitric oxide (NO) when combined with the effective amount of the acidifying agent; a support material, wherein at least a portion of the support material is dissociated from the acidifying agent or the nitrite component; and an activating amount of an activation solvent.

(60) In one example of a nitric oxide releasing composition, the acidifying agent comprises ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof.

(61) In one example of a nitric oxide releasing composition, the acidifying agent is present in the composition in an amount of from about 0.07 w/v % to about 10.0 w/v %.

(62) In one example of a nitric oxide releasing composition, the nitrite component is present in the composition in an amount of from about 0.07 w/v % to about 10.0 w/v %.

(63) In one example of a nitric oxide releasing composition, one of the acidifying agent and the nitrite component is present in an amount greater than 0.5 w/v %.

(64) In one example of a nitric oxide releasing composition, the nitrite component comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, nitrite orotate, amyl nitrite, magnesium nitrite, or a combination thereof.

(65) In one example of a nitric oxide releasing composition, the support material and the acidifying agent are present at a weight ratio of from about 0.05:1 to about 10:1.

(66) In one example of a nitric oxide releasing composition, the composition is formulated as a solution.

(67) In one example of a nitric oxide releasing composition, the support material comprises carbon black, activated carbon, a metal oxide, a silica, a silicate, a metal phosphate, or a combination thereof.

(68) In one example, there is provided a method of treating an adverse health condition, (e.g. a condition responsive to NO therapy or administration), comprising topically administering a nitric oxide releasing composition as recited herein to a treatment situs of a subject.

(69) In one example of a method of treating an adverse health condition, the adverse health condition comprises athlete's foot, onychomycosis, sinusitis, pharyngitis, a cold virus, influenza, acne, atopical dermatitis, wounds, diabetic foot ulcer, or a combination thereof.

(70) In one example of a method of treating an adverse health condition, topically administering includes immersing, wiping, soaking, covering, or spraying the treatment situs with the nitric oxide releasing composition, or a combination thereof.

(71) In one example of a method of treating an adverse health condition, topically administering includes applying the nitric oxide releasing composition to a fabric material and applying the fabric material to the treatment situs.

(72) In one example of a method of treating an adverse health condition, the treatment situs includes a nasal canal, a skin surface, or a combination thereof.

(73) In one example, there is provided a method of sanitizing a hard surface, comprising applying a nitric oxide releasing composition as recited herein to a hard surface.

(74) In one example of a method of sanitizing a hard surface, the hard surface is a countertop, a floor, a sink, a toilet, a bathtub, a shower, a doorknob, a scientific instrument, a medical instrument, or a combination thereof.

(75) While these invention embodiments and examples have been with reference particularity, it is apparent that other embodiments and variations of those provided may be devised by others skilled in the art without departing from the spirit and scope of this disclosure. The appended claims are intended to be construed to include all such embodiments and equivalent variations.