ANTIMICROBIAL COMPOSITION AND SYSTEM FOR DELIVERING AN ANTIMICROBIAL COMPOSITION

Abstract

An antimicrobial solution for a medical device having a chamber defined by a wall, the chamber being configured to be includes water, and an amount of iodine in the water sufficient to generate free elemental iodine when introduced into the chamber of the medical device. The free elemental iodine is configured to diffuse through the wall of the chamber and/or be embedded in the wall of the chamber of the medical device to form an antimicrobial polymer on the wall of the chamber.

Claims

1. An antimicrobial solution for a medical device having a chamber defined by a wall, the chamber being configured to be at least partially inserted into a patient, the antimicrobial solution comprising: water; and an amount of iodine in the water sufficient to generate free elemental iodine when introduced into the chamber of the medical device, such that the free elemental iodine diffuses through the wall of the chamber and/or is embedded in the wall of the chamber of the medical device to form an antimicrobial polymer on the wall of the chamber.

2. The antimicrobial solution in accordance with claim 1, wherein the solution comprises: 0.01% to 1% iodine by weight; and 85% to 98% water by weight.

3. The antimicrobial solution in accordance with claim 2, wherein the 0.01% to 1% iodine by weight is comprised of 0.1% to 10% povidone iodine having about 9% to 12% iodine by weight.

4. The antimicrobial solution in accordance with claim 1, further comprising: a water-soluble oxidizing agent; and water-soluble cupric salt.

5. The antimicrobial solution in accordance with claim 4, wherein the water-soluble oxidizing agent is 0.001% to 0.5% of the solution by weight, and the water-soluble cupric salt is 0.001% to 0.5% of the solution by weight.

6. The antimicrobial solution in accordance with claim 1, further comprising: a buffering agent selected from the group of buffering agents consisting of sodium acetate, ammonium acetate, sodium citrate, sodium phosphate dibasic heptahydrate, citric acid, and sodium phosphate dibasic.

7. The antimicrobial solution in accordance with claim 4, wherein the water-soluble oxidizing agent is selected from the group of oxidizing agents consisting of alkali metals nitrite, nitrate, chlorate, hydrogen peroxide and iodate.

8. The antimicrobial solution in accordance with claim 4, wherein the water-soluble cupric salt is cupric sulfate penta hydrate.

9. The antimicrobial solution in accordance with claim 1, wherein the amount of iodine by weight is provided at a volume of 2 to 20 ml.

10. An antimicrobial catheter system for a patient, the system comprising: a catheter device having a lumen and a chamber defined by a wall, the catheter device being configured for at least partial placement into the patient; and an antimicrobial solution that is introducible into the lumen and the chamber of the catheter device, the antimicrobial solution comprising iodine and water; whereupon introduction of the antimicrobial solution into the lumen and the chamber generates free elemental iodine such that the elemental iodine diffuses through the wall of the chamber and/or is embedded in the wall of the chamber and/or the lumen of the catheter device to form an antimicrobial polymer on the wall of the chamber and/or the lumen.

11. The antimicrobial catheter system in accordance with claim 10, wherein the antimicrobial solution comprises: 0.01% to 1% iodine by weight; and 85% to 98% water by weight.

12. The antimicrobial catheter system in accordance with claim 10, wherein the catheter device is a Foley catheter, and wherein the chamber is a balloon that is Tillable with the antimicrobial solution.

13. The antimicrobial catheter system in accordance with claim 11, wherein the 0.01% to 1% iodine by weight is comprised of 0.1% to 10% povidone iodine having about 9% to 12% iodine by weight.

14. The antimicrobial catheter system in accordance with claim 8, wherein the antimicrobial solution further comprises: a water-soluble oxidizing agent; and water-soluble cupric salt.

15. The antimicrobial catheter system in accordance with claim 14, wherein the water-soluble oxidizing agent is 0.001% to 0.5% of the solution by weight, and the water-soluble cupric salt is 0.001% to 0.5% of the solution by weight.

16. The antimicrobial catheter system in accordance with claim 10, wherein the antimicrobial solution further comprises: a buffering agent selected from the group of buffering agents consisting of sodium acetate, ammonium acetate, sodium citrate, sodium phosphate dibasic heptahydrate, citric acid, and sodium phosphate dibasic.

17. The antimicrobial catheter system in accordance with claim 14, wherein the water-soluble oxidizing agent is selected from the group of oxidizing agents consisting of alkali metals nitrite, nitrate, chlorate, hydrogen peroxide and iodate.

18. The antimicrobial catheter system in accordance with claim 14, wherein the water-soluble cupric salt is cupric sulfate penta hydrate.

19. The antimicrobial catheter system in accordance with claim 10, wherein the antimicrobial solution is provided to the balloon of the Foley catheter at a volume of between 2 and 20 ml.

20. A method of disinfecting a catheter that is at least partially placed into a patient, the catheter comprising a lumen and a wall, the method comprising: introducing a locking solution into the lumen of the catheter, the locking solution comprising iodine and water; generating free elemental iodine by the introduction of the locking solution into the lumen of the catheter such that the elemental iodine diffuses through the wall of the lumen and/or is embedded in the wall of the catheter to form an antimicrobial polymer on the wall of the chamber; and disinfecting an area on or around the lumen and the wall with the antimicrobial polymer formed on the lumen and/or the free elemental iodine diffused through the wall of the lumen.

21. The method in accordance with claim 20, wherein the locking solution comprises: 0.01% to 1% iodine by weight; and 85% to 98% water by weight.

22. The method in accordance with claim 21, wherein the 0.01% to 1% iodine by weight is comprised of 0.1% to 10% povidone iodine having about 9% to 12% iodine by weight.

23. The method in accordance with claim 20, wherein the locking solution further comprises: a water-soluble oxidizing agent; and water-soluble cupric salt.

24. The method in accordance with claim 23, wherein the water-soluble oxidizing agent is 0.001% to 0.5% of the locking solution by weight, and the water-soluble cupric salt is 0.001% to 0.5% of the locking solution by weight.

25. The method in accordance with claim 20, wherein the locking solution further comprises: a buffering agent selected from the group of buffering agents consisting of sodium acetate, ammonium acetate, sodium citrate, sodium phosphate dibasic heptahydrate, citric acid, and sodium phosphate dibasic.

26. The method in accordance with claim 23, wherein the water-soluble oxidizing agent is selected from the group of oxidizing agents consisting of alkali metals nitrite, nitrate, chlorate, hydrogen peroxide and iodate.

27. The method in accordance with claim 23, wherein the water-soluble cupric salt is cupric sulfate penta hydrate.

28. The method in accordance with claim 20, wherein the antimicrobial solution is provided to the balloon of the Foley catheter at a volume of between 2 and 20 ml.

29. The method in accordance with claim 20, wherein the catheter is a Foley catheter configured for intra-urinary insertion.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0037] These and other aspects will now be described in detail with reference to the following drawings.

[0038] FIG. 1 shows development of a bacterial infection and a biofilm;

[0039] FIG. 2 illustrates antimicrobial agents supplied to catheter material to impregnate the catheter material, such that the catheter material (i.e. tubing) becomes antimicrobial material to prevent the formation of a biofilm or other surface that could host bacterial growth;

[0040] FIG. 3 shows the effects of copper ions released from the solution that inflates the balloon of the urinary catheter, and how copper can kill microbes that might form in the urinary tract of a patient during use of a urinary catheter;

[0041] FIG. 4 shows a urinary catheter having an antimicrobial delivery system, in accordance with implementations described herein;

[0042] FIG. 5 illustrates the insertion and use of a urinary catheter, consistent with implementations described herein; and

[0043] FIG. 6 illustrates various delivery devices for delivering an antimicrobial solution as described herein.

[0044] Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

[0045] This document describes an antimicrobial composition and delivery system thereof, to kill or stop the growth of microorganisms, such as bacteria and viruses, and to prevent biofilm formation. In some implementations, the delivery system is configured for facilitating a chemical reaction by, or between, one or more chemical components of the composition to produce one or more new antimicrobial components.

[0046] In particular implementations, this document describes an antimicrobial solution or substance. In some implementations, the solution or substance can include a single chemical component, such as copper-containing chemical component such as copper sulfate, and/or an iodophor, and/or nitric oxide, or variants thereof.

[0047] In some implementations, a solution includes two or more chemical components that produce, via a reduction-oxidation (redox) reaction, one or more new antimicrobial components sufficient for a medical and/or pharmaceutical application. For instance, the one or more new antimicrobial components can include a gas, which is delivered by a delivery system by diffusion and/or osmosis via a surface of the delivery system. In other instances, the one or more new antimicrobial components can include a liquid, cream or gel, for topical application to an infection site, such as mucosal membranes or the like. In still yet other implementations, the one or more new antimicrobial components can be incorporated into a delivery device such as a bandage, applicator, or the like.

[0048] In some particular implementations, a free iodine-releasing solution can be used to fill a balloon/reservoir with a semiporous membrane, where the free iodine is released though the membrane to reduce any microbial attachment to the outer surface of the membrane and/or to reduce bacteria levels that may reside in a fluid surrounding the reservoir. In some implementations, the solution can be used to fill a balloon/reservoir, where the released free iodine attaches to the surfaces of the reservoir and similar or proximate surfaces to form an antimicrobial layer, therefore inhibiting the attachment and growth of bacteria on those surfaces.

[0049] Accordingly, the present invention includes a medical device fill, lock, flush, irrigation, or topical application solution that includes two or more chemical components that are combined to produce one or more new chemical components via a chemical reaction such as reduction and/or oxidation (redox), and where the one or more new chemical components includes antimicrobial properties.

[0050] In some implementations, at least one of the one or more new chemical components is a gas, while in other implementations at least one of the one or more new chemical components is a liquid, and yet in other implementations at least one of the one or more new chemical components is a solid or semi-solid, such as a powder, gel or cream. In some cases, the solution that includes two or more chemical components that are combined to produce one or more new chemical components are contained within the medical device and do not come into contact with a patient's bodily fluids, while in other cases the two or more chemical components are provided in such a way that they directly contact the patient's bodily fluids, such as vascular access or urinary catheter flushing, diffusion and/or osmosis through a selectively permeable membrane, i.e. an inflated catheter balloon, or other deliver mechanism.

[0051] Accordingly, while the initial solution may or may not be antimicrobial in its natural state, the chemical reaction is configured to produce one or more antimicrobial agents. Applications can include, without limitation, a cuffed endotracheal tube where a cuff, in the form of a balloon or the like, is filled with an antimicrobial agent such as an antimicrobial gas. Another application can include a rub or ointment. Such an application can be used in a nasal cavity, for example, or other bodily cavity for microbial decolonization. Yet another application can be a rub or ointment for a patient's skin, to inhibit colonization of a biofilm or other infection on the skin. Still yet another application includes applying an implementation of the solution described herein to a bandage or dressing, for such applications as wound care or skin decolonization.

[0052] In some implementations, the two or more chemical components and/or the one or more new antimicrobial components can include a copper sulfate fill solution, a PVP-I fill solution, or other inorganic fill solution or fill solution that produces an antimicrobial agent or new component. For instance, in some implementations, an antimicrobial device can include filling a balloon with NO gas, free iodine, or any other antimicrobial gas, or any combination thereof.

[0053] Antimicrobial Solution

[0054] In some preferred exemplary implementations, an antimicrobial solution for use in a delivery system includes: an iodophor, cupric or copper salt, and sodium nitrite, or various combinations thereof and in various proportions. The iodophor can be PVP-I USP, in powder form, which contains not less than 9% and not more than 12% of available iodine. This iodophor contains some iodide ion, preferably specified at 6.6% or less. The cupric salt can be added to the powder composition. The cupric salt can be any of a number of copper salts such as copper sulfate pentahydrate (CUSO.sub.4.5H.sub.20), copper chloride (CuCl.sub.2), or any other preferable copper(II) sulfate (CuSO.sub.4(H.sub.2O).sub.x). The sodium nitrite (NaNO.sub.2) will oxidize the cupric iodide to release nitric oxide gas (an antimicrobial agent), and the cuprous ion is oxidized back to a cupric ion, and the cupric ion oxidizes the iodide ion to free iodine 12 (another antimicrobial agent).

[0055] Iodophor

[0056] Iodine is a highly effective topical antimicrobial, with a broad spectrum of antimicrobial activity with efficacy against bacteria, mycobacteria, fungi, protozoa and viruses, but conventionally limited to topical application and treatment of both acute and chronic wounds. In a solution, iodine is generally unstable; at least seven iodine species are present in a complex equilibrium, with molecular iodine (I.sub.2) being primarily responsible for antimicrobial efficacy. For instance, or polyvinylpyrrolidone (PVP-I), has broad application for medicine as a surgical scrub, surgical skin preparation, for treatment and prevention of infection in wound, ulcers, cuts and burns. For these applications PVP-I is formulated in an liquid solution, spray, surgical scrub, ointment, and swab dosage form, and is brown in color.

[0057] Normal aging converts elemental iodine into iodide ions, thereby causing loss of efficacy. Accordingly, the implementations disclosed herein provide a stability that is adequate for various applications including, but not limited to: 1) antimicrobial balloon filling solutions for a Foley catheter to prevent CAUTI; 2) antimicrobial solutions to irrigate a patient's bladder to prevent CAUTI; and 3) antimicrobial lock solution for CVCs, hemodialysis catheters, and intermittent catheters, etc.

[0058] Povidone-iodine is a stable chemical complex of polyvinylpyrrolidone (PVP) and elemental iodine (I.sub.2), and acts as a solubilizing agent or carrier called iodophor, which in turn acts as a reservoir of the active “free” iodine. It contains from 9-12% of available iodine. This material contains some iodide ion specified to be 6.6% or less. Combining iodine with polyvinylpyrrolidone (PVP) reduces iodine vapor pressure and increases iodine solubility in water.

[0059] In some exemplary implementations, a solution can include copper sulfate and nitric oxide (NO). The color of the composition is initially brown. When all the iodide ion from the PVP-I is oxidized and all the free iodine escapes, the composition will have a blue color from the copper sulfate, since by that time all the sodium nitrite is oxidized, such as by nitric oxide gas (NO), and only copper sulfate is left in the system. The blue color can also act as an indicator that the antimicrobial solution needs to be replaced. At that time, all PVP-I and sodium nitrite have run out of the reaction, and because of this no more free iodine and/or nitric oxide gas is released.

[0060] The following is a chemical diagram of an exemplary iodophor in accordance with some implementations described herein:

##STR00001##

[0061] Nitric Oxide

[0062] With a molecular weight of 30, nitric oxide (NO) is one of the smallest biological molecular mediators. In mammalian cells, NO is produced along with 1-citrulline by the enzymatic oxidation of L-arginine. Enzymatically produced NO is important in diverse physiological processes, many of which are relevant to understanding the pathogenesis of infection. NO can contribute to the morbidity of infection by acting as a vasodilator, myocardial depressant, and cytotoxic mediator. On the other hand, microvascular, cytoprotective, immunoregulatory, and antimicrobial properties of NO have a salutary and probably essential role in the infected host.

[0063] Normally, NO is produced enzymatically by nitric oxide synthase (NOS) in the presence of oxygen from the amino acid L-arginine. NO is a transitory free radical responsible for the regulation of blood pressure, the control of platelet aggregation, and protection against vascular injury caused by tissue deposition of immune complexes, and is used as a broad spectrum antimicrobial agent by both the innate and cell-mediated immune systems. NO is a free radical that is synthesized in vivo by a family of NOSs that catalyze the oxidation of L-arginine to L-citrulline. There are three nitric oxide synthases produced by eukaryotic cells: (a) endothelial NOS (eNOS), responsible for constitutive NO synthesis in endothelial cells; (b) neuronal NOS (nNOS) responsible for NO synthesis in neural associated cells; and (c) the inducible form, (iNOS), found in epithelial, endothelial, and inflammatory cells, whose expression is upregulated by cytokines, microbes, or bacterial products. NO is synthesized at different levels based on the pathway and the intended function. Much higher levels are required, however, to elicit the bactericidal effects on NO.

[0064] NO plays an important role in human-specific and nonspecific immunity and that it is a particularly good broad spectrum antimicrobial agent. Evidence for endogenous NO production on skin, within the gut, and by the cellular immune system to protect and fight disease is growing. Furthermore, the importance of systemic nitrate, nitrite, and nitrosylated compounds in blood is becoming better understood and the implications in fighting infectious disease more apparent. Stimulation of endogenous NO or application of exogenous NO to infected human tissue can be an effective method for treating microbial infections; however, considerable hurdles with design of a commercially viable device exist.

[0065] One of the largest hurdles in bringing antimicrobial NO-producing products to the clinic is the consistency of gaseous Nitric Oxide (gNO) release at therapeutic levels while maintaining therapeutic antimicrobial levels below what is considered toxic to eukaryotic cells. The majority of adsorption release or chemical release technologies require activation by moisture, heat, light, or other factors that are difficult to control in a clinical setting. These challenges are compounded by the fact that most devices release high levels initially and weaning levels over time making it difficult to ensure bactericidal levels of gNO are sustained for sufficient duration. Consistent delivery of gNO is preferably through direct application of gNO from a tank delivered via tube and/or topical applicator, as disclosed in some implementations described herein.

[0066] Unfortunately, this renders patients non-ambulatory and bears significant cost. These hurdles can be overcome with novel gNO activation and delivery systems. In some implementations, controlled release or reaction systems, such as enzymatic systems, provide sustained consistent therapeutic release over time, while utilizing inexpensive mass producible constituents. In addition, these systems and devices are carefully designed with stable and safe components to ensure extended shelf life and stability. Such devices prove commercially viable in treating a wide variety of bacterial, fungal, parasitic, and viral infections, and in healing infected wounds.

[0067] Copper

[0068] Copper compounds have antimicrobial properties, and many different microorganisms are rapidly killed by copper ions. Recently, copper alloys have been approved for use by the U.S. Environmental Protection Agency (i.e. Reg 82012-1), due to their effective antimicrobial properties, on important bacteria such as methicillin-resistant S. aureus (MRSA), Salmonella enterica, and E. coli 0157, as well as on bacteriophages and Norovirus. Copper is used not only for medical applications, but is also used for surfaces, since it can prevent the spread of pathogens more effectively than stainless steel alone or silver. The antimicrobial mechanisms of copper ions include membrane damage, oxidative stress, and protein/DNA denaturation of bacteria and other microbes.

[0069] The bactericidal activity of copper is mainly attributed to the release of copper ions, which affect the integrity of the bacterial wall and/or membrane of bacteria, generate intracellular oxidative stress and are genotoxic, resulting in the death of microorganisms such as bacteria. Copper is an essential nutrient for humans as well as bacteria, but in high doses, copper ions that are released can cause a series of negative events in bacterial cells, including disrupting osmotic pressure (osmotic balance), weakening the cell wall and allowing contents to leak out resulting in death of microorganisms. In the implementations described herein, copper ions are released only in a sufficient amount to act as a bactericide, or to kill or neutralize bacteria or other pathogens or micro-organisms, while being harmless to human cells or cells of other living beings.

[0070] FIG. 3 illustrates the effects of copper ions released from the solution that inflates a balloon of a urinary catheter, and how copper can kill microbes that might form in the urinary tract of a patient during use of a urinary catheter.

[0071] The antimicrobials described above are each deliverable in inorganic form, and as such do not require a carrier such as triclosan or other potentially toxic substance.

[0072] Organic Antimicrobial Agents

[0073] Organic antimicrobial agents that can be used in the presently disclosed implementations include, but not limited to, quaternary ammonium biocides, including pyridinium biocides, benzalkonium chloride, cetrimide, benzethonium chloride, cetylpyridinium chloride, dequalinium acetate, dequalinium chloride. Other organic antimicrobial agents include phenol biocides such as chloroxylenol, parachlorometaxylenol, or 2,4,4′-trichloro-2′-hydroxydiphenol. Antiseptics that can be employed as the biocides used in the present invention include guanidines, such as alexidine, chlorhexidine, chlorhexidine gluconate, chlorhexidine acetate, chlorhexidine hydrochloride, Octenidine dihydrochloride (octenidine) and/or taurolidine.

[0074] Solution Example

[0075] In preferred exemplary implementations, an iodophor composition produces a stability iodine solution or composition. In some implementations, when the described solution or composition is dissolved in water or an aqueous solution (i.e. urine), or other solvent, other components of the composition, including, but not limited to, PVP-I powder, copper sulfate salt and sodium nitrite salt, completely dissolve. The cupric ion (Cu.sup.2+) can oxidize the iodide ion (I.sup.−) from PVP-I to produce iodine (I.sub.2), and this 12 molecule can act as antimicrobial agent to kill any bacteria on contact, as illustrated in Equation (1):

2Cu.sup.2++4I.sup.−.fwdarw.2CuI+I.sub.2  (1)

[0076] In some implementations, as shown in Equation (1), the mole ratio is 2 mole of copper sulfate that reacts with 4 mole iodide to produce 2 mole of cuprous iodine (CuI) and 1 mole of free iodine (I.sub.2).

[0077] This iodide ion (I.sup.−) present in the PVP-I solution is converted to iodine (I.sub.2) and this free iodine molecule acts as an antimicrobial agent to kill any bacteria it contacts. Further, this iodine molecule will impregnate into any material that it is exposed to or to which it contacts, to make these materials become antimicrobial themselves. Accordingly, these materials will have one or more antimicrobial features, such as killing any bacteria that come into contact with the surface of the material. Additionally, this antimicrobial material will prevent any bacteria from building on the surface, such as or on a biofilm on the surface.

[0078] The cuprous iodide (CuI) which is produced in the equation (1) can be oxidized by sodium nitrite in the antimicrobial systems. Nitrite ion NO.sup.2− oxidizes cupric iodide (CuI) to produce nitric oxide gas (NO), as according to equation (2):

Cu.sup.++NO.sup.2−2H.sup.+.fwdarw.Cu.sup.2++H.sub.2O+NO gas  (2)

[0079] Therefore, 1 mole of cupric iodine can react with 1 mole of sodium nitrite to produce 1 mole of nitric oxide gas. The concentration of the cupric salt is in the range of 0.001% to 0.5% by weight.

[0080] The reactions in equations (1) and (2) can occur simultaneously, or sequentially, and the preferred or optimal ratio is formulated to let all the sodium nitrile run out of the system first until no more nitric oxide gas is produced. At that time, only the cupric ion (Cu.sup.2+) oxidizes the iodide ion (I—) from PVP-I to iodine (I2) until all the PVP-I is run out. The brown color of the iodine solution disappears, and it will be a blue color from the remaining copper sulfate. At this time, the cupric ion (Cu.sup.2+) will continue to provide the antimicrobial properties. The solution is designed and formulated to change color in a pre-determined number of hours or days after administered, to act as an indicator that it is time to replace the solution and to indicate the working of the antimicrobial effects. Accordingly, the solution can be formulated and configured to change color within 1 to 10 days, or even an hour or more up to and including several weeks.

[0081] Consistent with implementations described herein, the iodophor solutions can be prepared by mixing together a source of elemental iodine (such as iodine crystal or PVP-I) with sodium citrate, sodium nitrite, copper sulfate penta hydrate, water and a pH buffer such as sodium citrate or sodium phosphate, or any combination thereof and in any quantity by weight. Finally, the pH of the solution can be adjusted to a desired value ranging from 3 to 6, but preferably a pH of 4-5. Suitable oxidizing agents are iodate, chlorate, nitrite and nitrate, which can be provided in amounts ranging from 0.001% to 0.5% by weight.

[0082] In other implementations, an iodophor composition provides a stable iodine solution by adding oxidizing agents such as sodium iodate and/or potassium iodate to the iodine solution, to convert iodide ions into free iodine as elemental iodine. This utilization of iodate can improve the stability of the elemental iodine over period of time. Since iodate contains three oxygen atoms, it is a strong oxidizing agent, generating 3 moles of Iodine per mole of iodate. Iodate react with iodide according to the following reaction in equation (3):

IO.sub.3.sup.−+5I.sup.−+6H.sup.+.fwdarw.3I.sub.2+3H.sub.2O  (3)

[0083] With this iodophor, an aqueous iodophor composition can be prepared such that the amount of elemental iodine (I.sub.2) is maintained at a level of between 0.05% to 1.25% by weight and 0.001% to 0.5% by weight of a source of iodate. The source of iodate may be selected from one or more inorganic compounds that include, but not limited to, sodium iodate, potassium iodate, or the like.

[0084] In yet another implementation, an iodophor composition can provide a stable iodine solution with added oxidizing agents, such as potassium iodate, to the iodine solution containing copper sulfate, to convert iodide ions into free iodine, or elemental iodine.

2CuSO4+4KIO.sub.3=2CuI+2K.sub.2SO4+I.sub.2  (4)

[0085] In the normal chemical aging process of the iodophor solution, the iodine in the iodophor convert to iodide ions cause the loss of the antimicrobial efficacy of the iodophor solution, by adding the iodate to the iodophor solution which reconvert iodide ions to iodine that make the iodophor regains the antimicrobial efficacy and make the iodophor solution has a longer shelf-life.

[0086] Any water-soluble oxidizing agents could be used in the composition in solutions described herein to oxidize iodide ions to elemental Iodine (I.sub.2). Suitable oxidizing agents are nitrate, chlorate, peroxide, Iodate, nitrite.

[0087] According to some implementations of an iodophor described herein, an aqueous iodophor composition is prepared such that the amount of element iodine (I.sub.2) is maintained a level between 0.05% to 1.25% by weight. 0.001% to 0.5% by weight of a source of iodate and the concentration of the cupric salt is in the range of 0.001% to 0.5% by weight. The source of iodate may be select from inorganic compounds that include, but are not limit to sodium iodate and potassium iodate. The iodine solutions in this invention are used on mucous membrane, inside human organs (such as bladder), rinsing open wounds so therefore no surfactants are used. Surfactants and/or other non-essential components may be an irritant, cause an allergic reaction, and/or may be toxic.

[0088] Iodophor solution in this invention are preferably prepared by mixing together the source of elemental Iodine (such as iodine crystal or PVP-I), iodate, water and pH buffer such as sodium citrate or sodium phosphate. Finally, the pH of the solution is adjusted to the desired value in the range 3-4. Since normal urine pH is slightly acidic, with usual values of 6.0 to 7.5, but the normal range is 4.5 to 8.0. A urine pH of 8.5 or 9.0 is often indicative of a urea-splitting organism, such as Proteus, Klebsiella, or Urea plasma urealyticum. An alkaline urine pH can signify struvite kidney stones, which are also known as “infection stones.” Urinary tract infections (UTIs) are one of the most common indications for antibiotics in both the inpatient and outpatient setting. A recent review article stated imaging should be considered for patients with a urinary pH of 7 or higher. Alkaline urine was defined as a urinary pH greater than or equal to 7, while acidic urine was defined as a urinary pH less than 7. Patients with alkaline urine are more likely to have recurrence of UTI.

[0089] The iodine solution preferably has a pH in the range of 3-6, such that the iodophor will have strong antimicrobial efficacy when it is used as a bladder irrigation to kill all the bacteria in an infected bladder, or used for filling the balloon of a Foley catheter to prevent catheter colonization and prevent the biofilm formation on the catheter tip.

[0090] Controlling the pH of the iodophor solution prolongs the shelf-life of the iodophor solution and also achieves other antimicrobial efficacy benefits for medical applications. Control of the pH may be augmented by adding a buffer to maintain the pH of the solution in the range of 3-6 and preferably a pH of 4-5. Suitable buffers include, without limitation, sodium acetate, ammonium acetate, sodium citrate, sodium phosphate dibasic heptahydrate, citric acid (such as sodium citrate buffer and citric acid), and sodium phosphate dibasic.

[0091] A portion or all of the above-described solutions or compositions can be provided as a solid, such as a powder, or as a semi-solid such as a gel or cream, or as a liquid. Each of these states can be used, inter alia, as a topical rub or application, or as a fill solution for a medical device, i.e. for filling a balloon of a Foley catheter, for example.

[0092] The table below illustrate exemplary implementations of a solution and formulation thereof, for a medical device fill, lock, flush or topical solution to provide antimicrobial properties and effects via components of the solution.

TABLE-US-00001 TABLE 1 Formula Zero Control Ingredients PVP-I Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 PVP-I 2.00 5.00 5.00 5.00 5.00 2.00 2.00 2.00 Sodium 0.00 1.00 1.00 1.00 0.50 1.30 1.09 0.62 Citrate Copper 0.00 0.50 1.68 0.50 1.00 1.50 1.52 1.00 Sulfate penta hydrate Sodium 0.00 1.25 3.00 0.66 1.00 1.00 1.00 1.00 Nitrite Potassium Iodate Potassium Iodide (KI) Water 98.00 92.20 89.30 92.80 92.50 94.20 94.40 95.40 HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Ingredients Formula 8 Formula 9 Formula 10 Formula 11 Formula 12 Formula 13 Formula 14 Formula 15 PVP-I 2.00 1.00 1.00 1.00 1.00 3.1 3.0 2.00 Sodium 0.50 1.00 1.04 0.55 0.56 0.5 1.0 1.00 Citrate Copper 1.00 1.55 1.00 1.00 0.63 0.2 1.0 0.05 Sulfate penta hydrate Sodium 1.16 1.13 1.00 1.00 0.59 1.0 1.5 Nitrite Potassium 0.10 Iodate Potassium Iodide (KI) Water 95.30 95.30 96.00 96.40 97.20 95.2 93.5 96.85 HCl q.s. q.s. q.s. q.s. q.s. q.s. q.s Total 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100 Ingredients Formula 16 Formula 17 Formula 18 Formula 19 Formula 20 Formula 21 Formula 22 Formula 23 PVP-I 1.06 3.50 1.00 3.00 0.50 0.50 0.50 Sodium 1.00 1.04 1.00 0.10 1.00 4.00 2.00 4.00 Citrate Copper 1.00 1.00 0.40 0.05 0.05 0.01 0.01 0.01 Sulfate penta hydrate Sodium 0.15 0.10 1.00 0.10 0.10 0.01 Nitrite Potassium 0.01 0.01 Iodate Potassium 0.13 Iodide (KI) Water 96.79 97.86 93.97 98.75 95.85 95.48 97.48 95.48 HCl q.s q.s q.s q.s q.s q.s q.s q.s Total 100 100 100 100 100 100 100 100 Ingredients Formula 24 Formula 25 Formula 26 PVP-I 0.50 2.00 0.50 Sodium Citrate 4.00 1.00 1.00 Copper Sulfate 0.00 0.10 0.10 penta hydrate Hydrogen 3.00 1.00 Peroxide Sodium Nitrite 0.00 0.10 0.00 Potassium 0.01 0.00 0.01 Iodate Potassium Iodide (KI) Water 95.49 95.80 97.39 HCl q.s q.s q.s Total 100 100 100

[0093] Applications

[0094] An antimicrobial solution as described above has many applications for infection control of HAIs. In the case of a urinary catheter (e.g., Foley catheter, as shown in FIG. 4), a system and apparatus is provided for preventing encrustation of the urine catheter in use (FIG. 5) to prevent colonization of the catheter by bacteria. In some implementations, diffusion and/or osmosis of antimicrobial agents from a solution are employed within a retention balloon of the catheter, as shown in FIG. 7. In some implementations, the urinary catheter simultaneously supplies three antimicrobial agents (free iodine, nitric oxide gas, and copper ion). In some cases, this is achieved by controlled release of antimicrobial agents in the antimicrobial solution directly into the urine from the balloon catheter and the communicating lumen itself, i.e. via diffusion and/or osmosis. This can also supply antimicrobial agents to the catheter material to impregnate the catheter material, such that the catheter material (i.e. tubing) becomes antimicrobial material to prevent the formation of a biofilm or other surface that could host bacterial growth.

[0095] Catheter materials suitable for use with the solutions described herein include polyurethane, natural rubber latex, synthetic polyisoprene latex, neoprene, styrene butadiene rubber, silicone or siliconized rubber latex material. Indwelling catheters are predominantly manufactured from natural rubber latex and silicone material. Some are made of synthetic isoprene latex or polyurethane. These polymers are suitable for manufacture of medical and surgical instruments such as endotracheal tubes, inhalation bags, intravenous catheters, centralize catheters, and urology catheters such as a Foley catheter. The two most commonly used blood-compatible materials for hemodialysis catheters are silicone and polyurethane. Medical grade silicone rubber has traditionally been considered the standard for long-term access in animals and humans. Silicone is resistant to most chemicals and is also very soft and flexible.

[0096] In yet other implementations, as illustrated in FIG. 6, a topical product of an antimicrobial solution, as described herein, can be applied by one of a number of applicator devices, from a swap to a foam applicator. The applicator can include a container for the antimicrobial solution.

[0097] While in some implementations, the antimicrobial components of a solution are delivered by diffusion and/or osmosis via a catheter balloon or other thin, permeable membrane or a medical device, the solution can be provided and stored in a container that inhibits such diffusion and/or osmosis. For instance, the solution can be packaged in a container with a wall thickness that inhibits any diffusion and/or osmosis, for at least a period of time, such as 2 years or more. Such a container can be made of polypropylene, polyethylene, polycarbonate or other plastic material, or any other thermoplastic polymer material of suitable thickness. Accordingly, a shelf life of the solution can be 2-3 years or more.

EXPERIMENTS AND EXAMPLES

[0098] A number of experiments were conducted using an “Iodine-Starch” test. This test is a chemical reaction that is used to test for the presence of starch or for iodine. The combination of starch and iodine is intensely blue-black in color. The interaction between starch and the triiodide anion (I-3) is the basis for iodometry.

[0099] Starch as an indicator: starch is often used in chemistry as an indicator for redox titrations where triiodide (I3−) is present. Starch forms a very dark blue-black complex solution with triiodide. However, the complex is not formed if only iodine or only iodide (I—) is present. The color of the starch complex is so deep, that it can be detected visually when the concentration of the iodine is as low as 20 μM at 20° C.

[0100] Experiment 1:

[0101] In an experiment to show that free iodine diffuses through a balloon membrane, such as may be used with a Foley catheter or other medical device, a balloon catheter was filled with an iodine solution. This iodine solution can be a tincture iodine or povidone iodine solution called iodophor. The balloon containing the iodine solution was then immersed into a water solution containing starch.

[0102] Using an iodine-starch test, a chemical reaction is allowed to slowly occur in the iodine solution. These chemical reactions release free iodine. The iodine I2 molecule diffuses through the membrane of the balloon material and reacts with the starch to make a deep blue color, the intensity of which depends on the concentration of the free iodine that diffused through the membrane.

[0103] 1) At time zero, it was demonstrated that the color of the water solution outside of the balloon was clear, indicating no presence of iodine in the water solution. After each successive day of the filled balloon being submersed in the water, the color of the water turned a deeper and deeper blue color (i.e. the blue color at day 3 was darker than the blue color at day 2, which in turn was darker than the blue color at day 1). This conclusively showed the gradual escape, via diffusion and/or osmosis, of free iodine from the balloon and into the water solution over a period of time.

[0104] 2) A Foley catheter has two tubes or lumens, one for filling the balloon and one for the release and conveyance of urine from a patient's bladder to a urine bag. In the experiment, both tubing was submerged in the starch/water solution. The experiment showed that the starch/water solution turned blue, showing that iodine from the balloon tubing escaped through the tubing wall and reacted with starch in the water from the other tubing.

[0105] 3) In an alternative aspect of this experiment, results showed that the iodine presence in the water solution outside the balloon, at time zero, as iodine is filled in the balloon, the water color is clear indicating no escape of iodine from the balloon. After day 1 and day 2, the water solution became increasingly deeper blue; demonstrating that the free iodine molecule came from the iodine solution (PVP-I Control solution—2% PVP-I in water only) inside the balloon, diffused through the balloon membrane to react with starch in the water solution. At day 3 the water solution is darker still, showing that free iodine will continue to escape the balloon and react with starch to make the water solution an ever darker blue color.

[0106] Experiment 2:

[0107] Another experiment was conducted to show that all iodine solutions will produce free iodine that diffuses through a balloon membrane, using a urine-based solution in which a balloon is immersed.

[0108] 1) This experiment showed that all the iodine solutions inside the balloon will have a chemical reaction to produce free iodine molecules of 12. The experiment showed that this free iodine will diffuse through the balloon membrane due to a difference in concentration per Le Chatelier's principle. Le Chatelier's principle states that if a stress is applied to a reaction mixture at equilibrium, the net reaction goes in the direction that relieves the stress. Change in the concentration of a reactant or product is one way to place a stress on a reaction at equilibrium. Therefore, the free iodine will slowly diffuse through the balloon membrane until all the chemical is reach to the equilibrium. In this case, when the Foley catheter balloon containing iodine solution is immersed in a urine solution, the free iodine molecule will slowly diffuse through the balloon membrane. The diffusion rate of the iodine depends on several factors, such as urine temperature, the thickness of the balloon membrane, the balloon surface area, the volume of the balloon, the volume of the iodine solution in the balloon. If we assume to keep every factor the same, the diffusion rate of iodine will depend on the formulation. For example, a tincture iodine will not be as stable as povidone iodine, so the tincture iodine will allow the chemical reaction quicker and allow the free iodine to escape faster than the PVP-I solution. Further, the Iodophor solution composed of only PVP-I in water was shown to not be stable and therefore will release the free iodine molecules faster than the Iodophor solution composed of PVP-I with a suitable pH buffer such as sodium bicarbonate, ammonium acetate, dibasic sodium phosphate, or sodium citrate.

[0109] 2) As the iodine molecules diffused through the balloon membrane per Le Chatelier's principle, the urine solution slowly became darker with more and more free iodine dissolved and the iodine solution inside the balloon was slowly lighter with less iodine in it. By day 3, the iodine solution inside the balloon disappeared due to all the iodine escaping out the balloon. However, where the balloon was filled with the formula 20 or another formula containing copper there, there was still color inside the balloon.

[0110] Table 2 shows the results with respect to Staphylococcus Aureus.

TABLE-US-00002 TABLE 2 Time Start CFU's per Point Date/Time ml T = 0 May 27, 2021/ 6.5 × 10.sup.7 5:10 pm T = 10 May 27, 2021/ 0 minutes 5:20 pm T = 24 May 28, 2021/ 0 hours 5:20 pm

[0111] Table 3 shows the results of other microbials.

TABLE-US-00003 TABLE 3 Report Lab F21-1355-00 T = 3 T = 24 hrs T = 72 hrs Sample Names T = 0 hrs (1 day) (3 days) Pseudomonas aeruginosa (Gram Negative) Positive Control 1.1 × 3.9 × 1.6 × 2.1 × 10.sup.3 10.sup.2 10.sup.4 10.sup.6 Negative Control 0 0 0 0 Neat Sample as 1.3 × 0 0 0 for Bladder Irrigation 10.sup.3 (No (No (No bacteria) bacteria) bacteria) Candida Albicans (Yeast) Positive Control 1.7 × 1.4 × 5.0 × 2.6 × 10.sup.3 10.sup.3 10.sup.3 10.sup.7 Negative Control 0 0 0 0 Neat Sample as 3.6 × 0 0 0 for Bladder Irrigation 10.sup.3 (No (No (No bacteria) bacteria) bacteria) Staphylococcus Aureus (gram Positive) Positive Control 3.2 × 8.1 × 1.8 × 3.3 × 10.sup.3 10.sup.3 10.sup.8 10.sup.8 Negative Control 0 0 0 0 Neat Sample as 3.0 × 0 0 0 for Bladder Irrigation 10.sup.3 (No (No (No bacteria) bacteria) bacteria) Enterococcus faecalis (Gram Positive) Positive Control 3.8 × 8.5 × 1.5 × 1.1 × 10.sup.3 10.sup.3 10.sup.8 10.sup.9 Negative Control 0 0 0 0 Neat Sample as 3.5 × 0 0 0 for Bladder Irrigation 10.sup.3 (No (No (No bacteria) bacteria) bacteria)

[0112] Although a few embodiments have been described in detail above, other modifications are possible. Other embodiments may be within the scope of the following claims.