Pharmaceutical storage devices and related compositions

Abstract

Drug storage devices and systems, and related methods of use, for administering a drug or therapeutic composition or agent to a patient are disclosed and described. In one embodiment, the storage device can include a storage reservoir configured to contain a drug or therapeutic agent. The storage device can be configured to be secured to a treatment area of ​​the patient, and the storage reservoir can be loaded with the drug or therapeutic agent for administration to the patient at a localized, targeted treatment area.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 860,632, filed June 12, 2019, which is incorporated herein by reference. [Background technology]

[0002] Nitric oxide (NO) is a small, unstable diatomic molecule. Its bond length is approximately 115 picometers and it dissolves in both hydrophilic and hydrophobic environments. It possesses a natural free radical-like activity, a short half-life, and is easily oxidized to nitrogen dioxide. In the body, nitric oxide can be produced endogenously by nitric oxide synthase (NOS) and is known to be involved in many physiological and pathological processes. For example, low levels of NO in the blood promote vasodilation to prevent ischemic injury, aid in wound healing, and are an effective antipathogen (e.g., antibacterial and antiviral). Conversely, high levels of NO in the blood cause tissue toxicity and contribute to inflammatory conditions such as septic shock, diabetes, and arthritis. The prior art documents relevant to the invention of this application are as follows (including documents cited in the international phase after the international filing date and documents cited when the application entered the national phase in other countries). (Prior art document) (Patent document) (Patent Document 1) International Publication No. 2008 / 116497 (Patent Document 2) US Patent Application Publication No. 2004 / 0161452 (Patent Document 3) U.S. Patent Application Publication No. 2006 / 0105028 (Patent Document 4) International Publication No. 2015 / 006528 (Patent Document 5) International Publication No. 2012 / 052561 (Patent Document 6) International Publication No. 2017 / 037684 (Patent Document 7) U.S. Patent Application Publication No. 2005 / 0089554 [Brief explanation of the drawings]

[0003] For a more complete understanding of the nature and advantages of the present invention, reference should be made to the following detailed description and accompanying drawings. [Figure 1A] FIG. 1A illustrates a medication storage device according to one embodiment of the present disclosure. [Figure 1B]FIG. 1B shows a cross-sectional view of a portion of a medication storage device according to one embodiment of the present disclosure. [Figure 2A] FIG. 2A shows various examples of medication storage devices of different shapes or configurations according to embodiments of the present disclosure. [Figure 2B] FIG. 2B shows various views of an exemplary medication storage device, according to one embodiment of the present disclosure. [Figure 3A] FIG. 3A shows various examples of storage reservoir portions of different drug storage devices according to one embodiment of the present disclosure. [Figure 3B] 3A-3B show various views of an exemplary storage reservoir portion of a drug storage device, according to one embodiment of the present disclosure. [Figure 4] FIG. 4 illustrates a method of manufacturing a medication storage device according to one embodiment of the present disclosure. [Figure 5A] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5B] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5C-5D] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5E] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5F] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5G] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 5H] 5A-5H illustrate various steps in applying a drug storage device to a patient's toe according to an embodiment of the present disclosure. [Figure 6]FIG. 6 illustrates how a medication storage device can be applied to the right and left toes according to one embodiment of the present disclosure. [Figure 7A] FIG. 7A illustrates a dual-barrel syringe and cork-stopper type dispensing nozzle according to one embodiment of the present disclosure. [Figure 7B] FIG. 7B shows a close-up view of a double-barrel syringe according to one embodiment of the present disclosure. [Figure 8A] Figure 8A is a graph showing that nitric oxide releasing solution (NORS) has a time- and dose-dependent antifungal effect on mycelial growth of T. rubrum, where X represents the NORS dose required for complete bactericidal effect. [Figure 8B] FIG. 8B is a graph showing that dose X of NORS rapidly kills Trichophyton mentagroftes mycelia within 10 minutes. [Figure 9A] Figure 9A is a graph showing positive results for the placebo (n=4) and treatment (n=8) groups. Samples were taken before the study (baseline) and 3, 17, and 31 days after the first treatment. Significance was tested using Fisher's test (**=p<0.01; *=p<0.05). [Figure 9B] Figure 9B is a graph of placebo (n=7) and treatment (n=13). CSSS was collected on day 1 pre-intervention and on day 31 of the study. Means with standard errors are shown. Significance was tested using a two-way ANOVA (***=p<0.001). [Figure 10] Figure 10 shows images of the results of the ex-vivo study of subject #2, showing (A) nail fungus cultured from a toe nail sample and (B) successful fungicidal effects after 8 hours of exposure daily for 7 days to nitric oxide-releasing gel (NORG) NORG-80. Note that the spot in container B is a nail clipping with no fungal growth after NORG exposure. [Figure 11]Figure 11 is a graph of C. acnes exposure to 60 mM NORG. ~105 cfu / mL of C. acnes was exposed to 60 mM NORS. No bacteria were detected after 3 minutes. n=3 (**=p<0.01, ***=p<0.001). [Figure 12] Figure 12 is a graph of measured nitric oxide release. 1 mL of 60 mM NORS and NORG at pH 3.5 was injected into a flow-over device connected to a chemiluminescence detector at a nitrogen gas flow rate of 1 L / min. n=3 [Figure 13] Figure 13 is a graph of the concentration of Staphylococcus aureus after exposure to 60 mM NORS and 60 mM NORG at pH 3.5. N=3. DETAILED DESCRIPTION OF THE INVENTION

[0004] Although the following detailed description contains many details for the purpose of illustration, those skilled in the art will understand that many variations and modifications can be made to the following details and are considered to be included herein. Accordingly, the following embodiments are described without loss of generality to, and without limitation of, the claims set forth. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. 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 disclosure belongs.

[0005] As used in this specification, the singular forms "a," "an," and "the" expressly support plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "particle" includes a plurality of particles.

[0006] In this application, terms such as "have," "have," "include," and "comprise," can have the meanings ascribed to them in U.S. patent law and can mean "includes," "including," and the like, and are generally construed as open-ended terms. The terms "consisting of" or "consisting of" are closed terms and include only those components, structures, steps, etc. that are specifically listed in association with such terms and that comply with U.S. patent law. The terms "consisting essentially of" or "consisting essentially of" have the meanings generally ascribed to them by U.S. patent law. In particular, such terms are generally closed terms, except to permit the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item with which they are used. For example, trace elements that are present in a composition but do not affect the nature or properties of the composition are permitted when present in "essentially consisting of" language, even if they are not explicitly set forth in the list of items following such terms. It is understood that when open-ended terms such as "having" or "comprising" are used in this written description, direct support must also be provided for the "essentially consisting of" and "consisting of" language, whether explicitly or implicitly stated.

[0007] Terms such as "first," "second," "third," and "fourth" in the detailed description and claims are used to distinguish between similar elements and not necessarily to describe a particular sequential or chronological order. Any terms so used are interchangeable under appropriate circumstances, and as a result, it should be understood that the embodiments described herein may, for example, operate in orders other than those illustrated or otherwise described herein. Similarly, if a method is described herein as including a series of steps, the order of the steps as presented herein is not necessarily the only order in which such steps may be performed; some of the described steps could conceivably be omitted and / or certain other steps not described herein could conceivably be added to the method.

[0008] Appearances of the phrases "in one embodiment" or "in one aspect" in this specification do not necessarily all refer to the same embodiment or aspect.

[0009] As used herein, "patient (subject)" refers to a mammal that may benefit from nitric oxide therapy, such as nitric oxide administered via the presentation or application of a nitric oxide-releasing solution (NORS) or a nitric oxide-releasing gel (NORG). In one aspect, the mammal may be a human.

[0010] As used herein, the terms "treat," "treatment," or "treating," when used in conjunction with administration of NORS or NORG, including compositions and dosage forms thereof, refer to administration to a patient who is either asymptomatic or symptomatic. In other words, "treat," "treating," or "treating" can be to reduce, ameliorate, or eliminate symptoms associated with a condition present in the patient, or can be prophylactic (i.e., to prevent or reduce the occurrence of symptoms). Such prophylactic treatment is also referred to as prevention of the condition.

[0011] As used herein, the terms "formulation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some respects, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents with a carrier or other excipient. A composition can be in almost any physical state, including a solid, liquid (i.e., solution), or gas. Furthermore, the term "dosage form" can include one or more formulations or compositions provided in a format for administration to a patient. In one example, the composition can be a nitric oxide-releasing solution.

[0012] As used herein, "NORS" refers to a nitric oxide (NO)-releasing solution, composition, or substance. In one embodiment, the NORS can be a nitric oxide-releasing gel (NORG). In one aspect, the NO released from the NORS / NORG can be a gas.

[0013] As used herein, terms such as "therapeutic agent" and "active agent" can be used interchangeably and refer to an agent that can provide a beneficial or positive effect to a patient when administered to a patient in an appropriate or effective amount. In one embodiment, NO can be a therapeutic agent. Terms such as "additional active agent," "co-active agent," and "secondary active agent" can be used interchangeably and refer to compounds, molecules, or materials other than nitric oxide that have physiological activity when administered to a patient in an effective amount. Exemplary additional active agents include, but are not limited to, antimicrobial agents (e.g., antifungal, antiviral, antibacterial agents), antioxidants, vitamins, and the like. As used herein, an "effective amount" of an agent is an amount sufficient to accomplish a specific task or function desired for the agent. A "therapeutically effective amount" of a composition, drug, or agent refers to a non-toxic but sufficient amount of the composition, drug, or agent to achieve a therapeutic result of treating or preventing a condition for which the composition, drug, or agent is known to be effective. It is understood that various biological factors can affect the ability of a substance to perform its intended task. Thus, an "effective amount" or a "therapeutically effective amount" may depend, in some cases, on such biological factors. Furthermore, while the achievement of a therapeutic effect can be assessed by a physician, veterinarian, or other qualified medical personnel using assessments known in the art, it is recognized that individual differences and response to treatment may make the achievement of a therapeutic effect a somewhat subjective determination. The determination of an effective amount or a therapeutically effective amount is within the ordinary skill of one of ordinary skill in the art of pharmaceutical science and medicine. See, for example, Meiner and Tonascia et al., "Clinical Trials: Design, Conduct, and Analysis," Monographs in Epidemiology and Biostatistics, Vol. 8 (1986).

[0014] As used herein, a "dosing regimen" or "regimen," such as a "therapeutic dosing regimen" or "prophylactic dosing regimen," refers to how, when, how much, and for how long a dose of a composition can or should be administered to a patient to achieve an intended treatment or effect.

[0015] As used herein, the terms "release" and "release rate" are used interchangeably to refer to the release or liberation, or rate, of a substance, including but not limited to a therapeutic agent such as NO, from a dosage form or composition. In one example, the therapeutic agent may be released in vitro. In another embodiment, the therapeutic agent may be released in vivo.

[0016] As used herein, "immediate release" or "immediate release" are used interchangeably and refer to the immediate or near-immediate (i.e., uninhibited or unrestricted) release of a drug or substance, including a therapeutic agent such as NO, from a composition or formulation.

[0017] As used herein, the term "controlled release" refers to the non-immediate release of a drug or substance, including a therapeutic agent such as NO, from a composition or formulation. Examples of specific controlled release types include, but are not limited to, extended or sustained release and delayed release. Any number of control mechanisms or components can be used to create the controlled release effect, including formulation components or composition, formulation characteristics or conditions such as pH, the environment in which the formulation is placed, or a combination of formulation components and the environment in which the formulation is placed. In one example, extended release can include release of a therapeutic agent at a level sufficient to provide a specific or intended non-immediate therapeutic effect or treatment for a specific or intended period of time. Specific controlled release profiles include extended or sustained release, pulsatile release, delayed release, etc.

[0018] As used herein, comparative terms such as "increase," "decrease," "better," "worse," "higher," "lower," "enhanced," "maximized," "minimized," and the like refer to a property of a device, component, composition, or activity that is measurably different from other devices, components, configurations, or activities, which are in surrounding or adjacent areas, similarly positioned, a single device or composition, or multiple comparable devices or compositions, groups or classes, groups or classes, or devices or configurations compared to the known state of the art. For example, an area of tissue treated with nitric oxide therapy, such as the nail and / or surrounding nail tissue, may have an "improved" appearance or condition (e.g., due to a reduction in fungal pathogens) after treatment compared to its pre-treatment state.

[0019] The term "coupled," as used herein, is defined as directly or indirectly connected in a chemical, mechanical, electrical, or non-electrical manner. Objects or structures that are "directly coupled" are those that are in physical contact or attached. Objects described herein as "adjacent" to one another may be in physical contact with one another, in close proximity to one another, or in the same general area or region of one another, depending on the context in which the phrase is used. Appearances of the phrases "in one embodiment" or "in one aspect" herein do not necessarily all refer to the same embodiment or aspect.

[0020] In the detailed description and claims, when terms such as "left," "right," "front," "rear," "top," "bottom," "upper," "lower," and the like are used, they are for purposes of explanation and not necessarily to describe permanent relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances, such that the embodiments described herein can, for example, operate in orientations other than those shown or otherwise described herein.

[0021] As used herein, the term "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, "substantially" surrounding a substance means that the substance is completely surrounded or nearly completely surrounded. The precise acceptable deviation from absolute completeness can depend on the specific context. Generally speaking, however, the proximity of completion is such that the overall result is the same as if absolute and complete completion had been achieved. The use of "substantially" also applies when used in the negative sense to refer to the complete or nearly complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free" of particles has the same effect as if the particles were completely absent, due to the complete absence or nearly complete absence of particles. In other words, a composition that is "substantially free" of a component or element may still actually contain such an element, so long as there is no measurable effect of such an element.

[0022] When used herein, the term "about" is used to provide flexibility for numerical range endpoints by providing that a given value may be "slightly above" or "slightly below" the endpoint. Unless otherwise specified, the use of the term "about" in reference to a particular number or numerical range should also be understood to provide support for such numerical condition or range without the term "about." For example, for convenience and brevity, a numerical range of "about 50 ml to about 80 ml" should also be understood to support the range "50 ml to 80 ml." Furthermore, it should be understood that support for the actual numerical value is provided even when the term "about" is used herein. For example, a description of "about" 30 should be interpreted as supporting values slightly above and below 30, as well as supporting the actual numerical value 30.

[0023] Where used herein, a plurality of items, structural elements, components, and / or materials may, for convenience, be presented in common lists. However, these lists should be construed as though each member of the list were individually identified as a separate and unique member. Accordingly, individual members of such lists should not be construed as de facto equivalents to other members of the same list solely based on presentation in a common grouping, unless otherwise stated.

[0024] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It should be understood that such range format is used merely for convenience and brevity and, therefore, should be flexibly interpreted as including within that range, not only the numerical values explicitly recited as range limits, but also all individual numerical values or subranges encompassed therein, as if they were explicitly written out. For example, a numerical range of "about 1 to about 5" should be interpreted as including not only the explicitly recited values of about 1 to about 5, but also each individual value and subrange within the stated range. Thus, this numerical range includes individual values such as 2, 3, and 4, subranges such as 1-3, 2-4, and 3-5, and includes 1, 2, 3, 4, and 5 individually, as well as decimal values such as 1.8, 2.3, 3.7, and 4.2.

[0025] This same principle applies to ranges when only one numerical value is stated as the minimum or maximum value, and such interpretation should be applied regardless of the width or nature of the range being stated.

[0026] References throughout this specification to an "example" mean that the particular feature, structure, or characteristic described in connection with the example is included in at least one embodiment. Thus, the appearances of the phrase "in one example" in various places throughout this specification do not necessarily all refer to the same embodiment.

[0027] Reference is made herein to devices, structures, systems, or methods that provide "improved" performance. Unless otherwise specified, it should be understood that such "improvement" is an assessment of the benefit obtained based on a comparison with a prior art device, structure, system, or method. Furthermore, it should be understood that the degree of improved performance may vary among the disclosed embodiments, and that equivalence or consistency in the amount, degree, or achievement of improved performance should not be assumed to be universally applicable. Illustrative Embodiments A first summary of embodiments of the present invention is provided below, followed by a more detailed description of specific embodiments. This first summary is intended to help the reader more quickly grasp the technical concepts, but is not intended to identify key or essential features thereof, nor is it intended to limit the scope of the claims as claimed.

[0028] As mentioned above, NO can provide many beneficial effects and is endogenously produced by the enzyme nitric oxide synthase (NOS). For example, low levels of NO in the blood promote vasodilation to prevent ischemic injury, aid in wound healing, and is an effective antibacterial agent. However, high levels of NO in the blood can cause tissue toxicity and may contribute to inflammatory conditions such as septic shock, diabetes, and arthritis. Therefore, although NO can provide a variety of therapeutic effects, it may be desirable to employ various protective measures to minimize excessive exposure to NO.

[0029] NO can be generated outside the body in a variety of ways. For example, NO can be generated by catalytic oxidation of ammonia, the extremely endothermic reaction of nitrogen and oxygen as a free gas, and from acidified nitrite. NO production from acidified nitrite can be measured in at least three ways. For example, NO production can be measured indirectly using chemiluminescence, gas chromatography-mass spectrometry (GC-MS), and / or using Griess reagent and a spectrophotometer set to a wavelength of 543 nm. An example of a specific NO quantification device and method is described in the applicant's co-pending U.S. patent application Ser. No. 16 / 541,084, filed August 14, 2019, which is incorporated herein by reference. Chemiluminescence is a well-known analytical technique that generally involves luminescence as a result of a chemical reaction. More specifically, the decay of an excited state molecule to a lower energy state produces luminescence that can be detected by a chemiluminescence analyzer / detector. As an example, nitric oxide (NO) reacts with ozone (O3) to produce excited NO, which then decays to a lower energy state and emits electromagnetic radiation that can be detected photoelectrically.

[0030] The acidified nitrite solution can be based on the following reaction:

number

[0031] This is also the basis for what are called nitric oxide-releasing solutions or substances (NORS). For example, nitrite agents, such as sodium nitrite or potassium nitrite, can react with a proton donor. The proton donor can be any type of acidifying agent to drive the reaction, but depending on the acidifying agent used, it may add undesirable intermediates or by-products. Acidified nitrite solutions have antibacterial properties and can be used to combat various types of infections, such as fungal infections caused by tinea pedis (athlete's foot), bacterial infections caused by Propionibacterium acnes, and various viral infections. The effectiveness of the antibacterial activity may depend on various factors, such as the pH of the composition, the concentration of nitrite available for reaction, the concentration of the acidifying agent to drive the reaction, and other stabilizing factors. The potential of NORS allows NO to be used for treatment without the use of NO gas from a pressurized canister.

[0032] While NORS and / or NORG can be highly effective antimicrobial compositions, maintaining effective concentrations of NO in a treatment area while minimizing toxic side effects to the patient can be challenging. Accordingly, the present disclosure relates to drug storage / delivery devices and related compositions that can help maintain effective concentrations of NO in a treatment area or location while minimizing toxic side effects by substantially containing NO within a storage reservoir (e.g., preventing or substantially preventing release from the storage reservoir in any direction other than toward the patient's administration site).

[0033] It should also be noted that when discussing the drug storage devices, NORS / NORG compositions, treatment systems, healing systems, and methods described herein, these relative discussions may be deemed applicable to other examples, whether or not explicitly discussed in the context. Thus, for example, when a nitrite agent is discussed in relation to a treatment system, such disclosure also relates to and is directly supported in that context by the treatment systems, drug storage devices, NORS / NORG compositions, and methods described herein, and vice versa.

[0034] Additionally, the NORS can include a nitrite agent, an acidifying agent, and an aqueous medium. The NORS can be formulated to release from about 1 ppb of NO to about 10,000 pmp of NO over a period of about 30 seconds to about 48 hours, or about 10 minutes to about 24 hours. More specifically, the nitrite agent and acidifying agent can be combined together in an aqueous carrier to form a nitric oxide-releasing solution or substance (NORS) as an antimicrobial agent, such as an antibacterial, antifungal, or antiviral agent, or a combination thereof.

[0035] NORS can include a variety of nitrite agents. Generally, any nitrite that can acidify to produce nitric oxide can be used. Non-limiting examples include sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotate nitrite, amyl nitrite, magnesium nitrite, etc., or combinations thereof.

[0036] The amount of nitrite agent can depend on the type of composition used. In some examples, the NORS can be in the form of a solution, cream, gel, ointment, etc. Depending on the specific formulation type, the nitrite agent can generally be present in the NORS in an amount of about 0.01% to about 10% by weight, based on the total weight of the composition. In other examples, the nitrite agent can be present in the NORS in an amount of about 0.01% to about 0.1% by weight, about 0.1% to about 1% by weight, about 1% to about 5% by weight, or about 5% to about 10% by weight, based on the total weight of the NORS. In some additional examples, the nitrite agent can be present in the NORS in an amount of about 0.1 millimolar (mM) to about 500 mM. In other examples, the nitrite agent can be present in the NORS at about 0.1 mM to about 10 mM, about 1 mM to about 10 mM, about 5 mM to about 50 mM, about 20 mM to about 200 mM, or about 50 mM to about 500 mM. In some particular examples, the nitrite agent can be present in the NORS in an amount of about 50 mM to about 150 mM.

[0037] Various acidifying agents can also be included in the NORS. Generally, any acidifying agent suitable for reacting with the nitrite agent without producing undesirable by-products can be used. In some specific examples, the acidifying agent can include organic acids such as ascorbic acid, ascorbyl palmitate, salicylic acid, malic acid, lactic acid, citric acid, formic acid, benzoic acid, tartaric acid, etc., or combinations thereof. In some additional examples, the acidifying agent can include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or combinations thereof. In some further examples, the acidifying agent can include combinations of organic and inorganic acids.

[0038] The acidifying agent can also be present in the NORS in varying amounts depending on the form of the NORS. In some examples, the NORS can be in the form of a solution, gel, cream, ointment, etc. Depending on the formulation type, the acidifying agent can generally be included in the NORS in an amount to achieve a pH of about 2.5 to about 5, or about 3 to about 4. In some specific examples, the acidifying agent can be present in the NORS in an amount of about 0.01 wt% to about 20 wt% based on the total weight of the NORS. In some specific examples, the acidifying agent can be included in the NORS in an amount of about 0.01 wt% to about 0.1 wt%, about 0.1 wt% to about 1 wt%, about 1 wt% to about 5 wt%, about 5 wt% to about 10 wt%, or about 10 wt% to about 20 wt% based on the total weight of the NORS. In some additional examples, the acidifying agent can be present in the NORS in an amount of about 0.1 millimolar (mM) to about 500 mM. In other examples, the acidifying agent can be present in the NORS in an amount of about 0.1 mM to about 10 mM, about 1 mM to about 10 mM, about 5 mM to about 50 mM, about 20 mM to about 200 mM, or about 50 mM to about 500 mM. In some particular examples, the acidifying agent can be present in the NORS in an amount of about 50 mM to about 150 mM.

[0039] Thus, the nitrite agent and acidifying agent can be present in a NORS in varying amounts depending on the particular type of formulation. In some examples, the nitrite agent and acidifying agent can be present in a NORS in a weight ratio of about 1:10 to about 10:1. In other examples, the nitrite agent and acidifying agent can be present in a NORS in a weight ratio of about 1:5 to about 5:1. In still other examples, the nitrite agent and acidifying agent can be present in a NORS in a weight ratio of about 1:3 to about 3:1, or about 1:2 to about 2:1.

[0040] In some embodiments, the acidifying agent can be present in an excess amount beyond that required to deplete the supply of available nitrite in forming NO. In such cases, the excess amount of acidifying agent can have a complementary or additional therapeutic effect on the patient as a supplemental or additional active agent in addition to the therapeutic effect provided by NO. For example, if the acidifying agent is salicylic acid, an excess amount beyond that required to react with nitrite to produce NO may provide unique therapeutic benefits for conditions such as athlete's foot and onychomycosis. Salicylic acid is known as an active ingredient in various pharmaceuticals formulated to treat skin conditions due to its desquamating properties. For example, salicylic acid can be used to treat warts, acne, athlete's foot, onychomycosis, and more. The desquamation of dead skin cells clears the area, thereby increasing the concentration of NO reaching living, infected tissue and further enhancing the effect of NO on infected, living tissue. Acids other than salicylic acid may also have a desquamating effect and / or otherwise aid in enhancing NO penetration. For example, salicylic acid or other acids may hydrate the keratin in the finger or toenail, thus making the nail more permeable to NO as well as providing greater access to the nail bed and other areas of infected tissue that are normally difficult to penetrate and / or invade.

[0041] The NORS can include a variety of aqueous carriers. Non-limiting examples include water, phosphate-buffered saline (PBS), Dulbecco's PBS, Tris-buffered saline (TBS), balanced salt solutions (BSS) such as Hank's BSS, Earle's BSS, Gray's BSS, and Pack's BSS, Simm's BSS, Tyrode's BSS, BSS Plus, lactated Ringer's solution, normal saline (i.e., 0.9% saline), half normal saline, and the like, or combinations thereof. Because the carrier can provide an environment in which the nitrite agent and acidifying agent can react to generate nitric oxide, it may be beneficial to house or contain the NORS in a pressurized container to inhibit or minimize nitric oxide production prior to application. After dispensing the NORS from the pressurized container, nitric oxide production can proceed rapidly.

[0042] In other examples, one or more of the nitrite agent and the acidifying agent can be encapsulated. In some examples, the nitrite agent can be encapsulated. In some examples, the acidifying agent can be encapsulated. When encapsulation is used, the encapsulating material can typically be present with the nitrite agent, the acidifying agent, or a combination thereof in a weight ratio of about 0.05:1 to 10:1. When one or more of the nitrite agent and the acidifying agent are encapsulated, the NORS can be stored in a pressurized container as described above, and the encapsulating material can be made fragile upon dispensing, etc., to minimize NO generation prior to application. An example of an encapsulated NORS is described in Applicant's co-pending U.S. patent application Ser. No. 16 / 352,741, filed March 13, 2019, which is incorporated herein by reference.

[0043] In some examples, the NORS can include a gelling agent, such as NORG. Non-limiting examples of suitable gelling agents can include xanthan gum starch, guar gum, locust bean gum, karaya gum, tragacanth gum, gum arabic, cellulose derivatives, alginates, pectin, carrageenan, gelatin, gellan, agar, and the like, and combinations thereof. The gelling agent can generally be present in the NORS in an amount that provides the NORS with a viscosity of about 3,000 centipoise to about 150,000 centipoise. In some specific examples, the gelling agent can be added to the NORS in an amount of about 0.5 wt. % to about 2 wt. %, about 1 wt. % to about 3 wt. %, about 2 wt. % to about 4 wt. %, or about 3 wt. % to about 5 wt. %, based on the total weight of the NORS.

[0044] As noted above, in some examples, the NORS may be contained or housed in a container, which may be a pressurized container or other suitable container. In some further examples, the NORS may be housed with instructions regarding application of the NORS to the treatment area.

[0045] The present disclosure also describes a treatment system that can include a nitrite composition having a viscosity of about 5,000 centipoise to about 100,000 centipoise and an acidifying component having a viscosity of about 5,000 centipoise to about 100,000 centipoise.

[0046] The nitrite composition can include a nitrite agent as described above. The nitrite agent can be present in the nitrite composition in various amounts. For example, the nitrite agent can generally be present in the nitrite composition in an amount of about 0.02% to about 20% by weight, based on the total weight of the composition. In other examples, the nitrite agent can be present in the nitrite composition in an amount of about 0.02% to about 0.2% by weight, about 0.2% to about 2% by weight, about 2% to about 10% by weight, or about 10% to about 20% by weight, based on the total weight of the nitrite composition. In some additional examples, the nitrite agent can be present in the nitrite composition in an amount of about 0.3 millimolar (mM) to about 1000 mM. In other examples, the nitrite agent can be present in the nitrite composition in an amount of about 0.2 mM to about 20 mM, about 2 mM to about 20 mM, about 10 mM to about 100 mM, about 40 mM to about 400 mM, or about 100 mM to about 1000 mM. In some examples, the nitrite composition can have a pH of about 5 to about 8 prior to mixing with the acidifying composition.

[0047] The acidifying composition can include an acidifying agent as described above. The acidifying agent can be included in the acidifying composition in various amounts. For example, the acidifying agent can generally be included in the acidifying composition in an amount that achieves a pH of about 2.5 to about 5, or about 3 to about 4, when mixed with the nitrite composition to prepare the NORS. Prior to mixing, the acidifying composition generally has a pH of about 2 to about 5. In some specific examples, the acidifying agent can be present in the acidifying composition in an amount of about 0.02 wt % to about 40 wt %, based on the total weight of the acidifying composition. In some specific examples, the acidifying agent can be included in the acidifying composition in an amount of about 0.02 wt % to about 0.2 wt %, about 0.2 wt % to about 2 wt %, about 2 wt % to about 10 wt %, about 10 wt % to about 20 wt %, or about 20 wt % to about 40 wt %, based on the total weight of the acidifying composition. In some additional examples, the acidifying agent can be present in the acidifying composition in an amount of about 0.2 millimolar (mM) to about 1000 mM. In other examples, the acidifying agent can be present in the acidifying composition in an amount of about 0.2 mM to about 20 mM, about 2 mM to about 20 mM, about 10 mM to about 100 mM, about 40 mM to about 400 mM, or about 100 mM to about 1000 mM.

[0048] The nitrite composition and the acidifying composition can independently comprise an aqueous carrier, which can be independently selected from water, phosphate buffered saline (PBS), Dulbecco's PBS, Alsever's solution, Tris-buffered saline (TBS), balanced salt solutions (BSS) such as Hank's BSS, Earle's BSS, Gray's BSS, Pak's BSS, Shim's BSS, Tyrode's BSS, BSS Plus, lactated Ringer's solution, normal saline (i.e., 0.9% saline), half normal saline, etc., or combinations thereof.

[0049] In some examples, one or more of the nitrite composition and the acidifying composition may contain a gelling agent. Non-limiting examples of gelling agents may include xanthan gum starch, guar gum, locust bean gum, karaya gum, tragacanth gum, gum arabic, cellulose derivatives, alginates, pectin, carrageenan, gelatin, gellan, agar, etc., or combinations thereof. The gelling agent may be added in various amounts depending on the formulation. In some examples, the gelling agent may be added to the nitrite composition and / or the acidifying composition in an amount of about 0.5% to about 5% by weight, based on the total weight of the individual compositions. In other examples, the gelling agent may be added to the nitrite composition and / or the acidifying composition in an amount of about 1% to about 3% by weight, based on the total weight of the individual compositions. In still other examples, the gelling agent can be added to the nitrite composition and / or the acidifying composition in an amount of about 0.5% to about 2% by weight, about 1% to about 3% by weight, about 2% to about 4% by weight, or about 3% to about 5% by weight, based on the total weight of the respective compositions.

[0050] It should also be noted that one or more of the nitrite agent and the acidifying agent may be encapsulated in the therapeutic system. In some instances, the nitrite agent may be encapsulated. In some instances, the acidifying agent may be encapsulated.

[0051] As described above, the nitrite composition and the acidifying composition can be combined to form NORS. However, in example treatment systems, the nitrite composition and the acidifying composition can be kept separate to prevent premature NO production prior to application. Thus, in some examples, the treatment system can include a container. In some examples, the container can be a dispensing container. In some cases, the nitrite composition and the acidifying composition can be separated from each other in separate containers or separate compartments of the same container. In some specific examples, the nitrite composition can be contained in a first compartment of the container, and the acidifying composition can be contained in a second compartment of the container. In other examples, the nitrite composition can be contained in a first container, and the acidifying composition can be contained in a second container. In some specific examples, the nitrite composition and the acidifying composition can be contained in separate compartments of a common container, but the individual compositions are mixed during or at the time of dispensing the compositions. For example, in some cases, the nitrite composition and the acidifying composition can be contained in separate compartments of the same container, and can be dispensed through a corkscrew or similar dispenser to facilitate mixing during dispensing. In other examples, the nitrite composition and the acidifying composition can be dispensed separately from a common container or separate containers to the treatment area and mixed manually at the treatment area.

[0052] In some examples, the nitrite composition and the acidifying composition can be packaged together in a common package, whether they are contained in a common container, separate containers, or a combination thereof. In some further examples, the package can further include instructions for applying the nitrite composition and the acidifying composition to the treatment area. The instructions will vary depending on the specific type of treatment system being used. In some embodiments, the nitrite and the acidifying composition can be premixed to allow the solution / gel to be activated, but maintained in a container that excludes or minimizes the presence of oxygen. Thus, reaction between the nitrite and the acidifying agent can be limited or prevented. For example, a bag-on valve device / system or the like can be used.

[0053] In some embodiments, the NORS composition may include, or may be otherwise combined with, or co-administered with, supplemental active agents. Supplemental or additional active agents may include any active or therapeutic agent suitable for administration for a given indication related to or complementary to the indication for which NO is administered. Exemplary supplemental or additional active agents may include, but are not limited to, antifungals, antiparasitics, antivirals, antibacterial agents, disinfectants, prebiotics, probiotics, vitamins, analgesics, anti-inflammatory agents, antioxidants, and exfoliants, among others. Additionally, other agents or components that supplement or otherwise enhance the effectiveness of NO and / or any supplemental active agents, such as penetration enhancers, emollients, thickeners, lubricants, softeners, and adjuvants, may be included in or co-administered with the NORS.

[0054] The present disclosure also describes a drug storage device that can be used in connection with a NORS, a therapy system, or other suitable drug. The drug storage device can include a housing having an interior wall that forms or defines a storage reservoir configured to contain nitric oxide therein when the device is attached to a patient. The device can also include a connection feature or member configured to attach the device to a patient.

[0055] Referring to the figures, FIG. 1A illustrates one non-limiting example of a drug storage device. The particular device illustrated in FIG. 1 is designed for placement around a phalange or toe. As shown in FIG. 1A, the drug storage device has a housing including a hollow channel or chamber for placement over the toe nail. When the device is placed in a patient, the inner wall of the hollow channel or chamber can define the inner diameter or wall of the storage reservoir, and the toe nail and surrounding tissue can form the base matrix of the storage reservoir. The housing of the device illustrated in FIG. 1A also includes lateral straps for wrapping laterally around the toe and distal straps (bunny ear straps) for wrapping around the tip of the toe. In some examples, a portion of the long side of the lateral straps can be wrapped around the toe and further form a cap or closure for sealing or closing the top of the storage reservoir on the opposite side of the toe nail. Thus, the drug storage device can provide a closed device or system by forming an enclosed storage reservoir to maintain an effective concentration of NO therein, concentrating NO delivery and therapy to a localized anatomical region while minimizing broader or systemic exposure to potentially toxic levels of NO. Localizing the drug in this manner not only protects surrounding and distal physiology from exposure to NO, but also concentrates NO exposure to the affected area of the patient's physiology (e.g., the toenail and surrounding tissues).

[0056] As shown in Figure IB, the drug storage device can include various layers. Layer 1 can represent the storage container. Layer 2 can represent an adhesive layer for bonding the various components of the housing together. Layer 3 can represent the strap portion of the housing to which storage container portion 1 is bonded via upper adhesive layer 2. Layer 4 can represent a release liner that can be removed to expose lower adhesive layer 2 for easier attachment of the device to a patient.

[0057] FIG. 2A illustrates various examples of strap components for a medication storage device. It should be noted that strap components are not required for all medication storage devices, but may be useful in some instances. It should also be noted that bunny ear straps or flaps are not required in all designs. However, in some instances, bunny ear straps or flaps can provide better fixation and / or conformance around the phalanges (e.g., fingers, toes) during placement of the device and help patients hold the device in place during physical activities such as walking, running, handling, and bathing. In some instances, as shown in the top embodiment of the strap components for the device in FIG. 2A , notches can be formed in the ends of the side straps to provide better fixation and / or conformance of the device around a body part. In some additional instances, as shown in the middle embodiment of the strap components for the device in FIG. 2A , the strap components can have slightly curved protrusions to provide a more conformal shape for the strap components to certain body parts. In some further examples, as shown in the embodiment of the lower part of the strap component of the device in FIG. 2A, the strap component may include one or more relief cuts along one or more side edges of the strap component to provide for further conformance of the strap component to certain body parts.

[0058] 2B shows an example of a strap component of a medication storage device. Dimensions of the various components are provided in millimeters (mm). However, it should be noted that the dimensions of the strap components are not particularly limited and may depend on the particular body part to which the device is coupled, the size of the treatment area, etc.

[0059] If a strap component is included, it can include or be made from a variety of materials. Non-limiting examples may include polyethylene, polyurethane, silicone, neoprene, ethylene propylene diene monomer rubber (EPDM), styrene butadiene rubber (SBR), etc., or combinations thereof. In some examples, the strap can be coated with a protective material that is chemically compatible with NO or inert so as not to react with NO. In some further examples, the strap component can be made from a foam material.

[0060] In some additional examples, the straps may include an adhesive for applying the strap components to the patient's body part. Non-limiting examples of suitable adhesives may include acrylic adhesives, cyanoacrylic adhesives, silicone adhesives, polyurethane adhesives, epoxies, and the like, or combinations thereof.

[0061] Figure 3A shows a non-limiting example of a storage reservoir for a drug storage device. As shown in the example of Figure 3A, the storage reservoir can have a variety of shapes and configurations. For example, as shown in the bottom example of Figure 3A, the storage reservoir is shaped to conform to or otherwise target the treatment area. This can be achieved with relief cuts, tailored shapes to the reservoir, etc., or a combination thereof.

[0062] FIG. 3B shows an example of a storage reservoir of a drug storage device. Dimensions of various components and features are provided in millimeters (mm). However, it should be noted that the dimensions of the drug storage device are not particularly limited and may depend on the particular body part to which the device is coupled, the size of the treatment area, etc. In some examples, the storage reservoir has a volume of about 1 ml to about 20 ml (e.g., when placed in a patient's body part). In one embodiment, the devices / systems described herein may have a volume of up to about 914 cm. 2In another embodiment, the devices / systems described herein can have a reservoir with a skin or tissue contact surface area of up to about 1 cm. In other embodiments, the depth can be up to about 0.16 cm. In yet other embodiments, the devices / systems described herein can have a reservoir with a volume of up to about 300 ml. In another embodiment, the volume can be up to about 146 ml.

[0063] As shown in FIG. 3B, the storage reservoir can be formed from individual components that are directly attachable to the patient or to the strap component or other base component. While not specifically shown, in some examples, the storage reservoir can form part of the strap component (e.g., integrally formed therewith rather than provided as a separate attachable component), such that the interior walls of the strap component or the like define or form the walls of the storage reservoir without the need to attach additional components to form the storage reservoir. In some further examples, the storage reservoir can include an adhesive. Non-limiting examples of adhesives can include acrylic adhesives, cyanoacrylic adhesives, silicone adhesives, polyurethane adhesives, epoxies, etc., or combinations thereof.

[0064] In some examples, the storage reservoir can include a hollow channel or cavity suitable for receiving the NORS, or the nitrite and acidifying compositions, or other suitable agents therein after the device is attached to a patient's body part. In other examples, the storage reservoir can be pre-loaded with the NORS, the nitrite and acidifying compositions, or other suitable agents prior to application of the device to a patient.

[0065] In one specific example, the base or substrate of the storage reservoir can initially be formed from a water-soluble membrane (e.g., a polyvinyl alcohol membrane). An inactivated NORS containing a nitrite agent and a dry acidifying agent can be filled in the lower compartment between the water-soluble membrane and the frangible membrane. An aqueous carrier can occupy the upper compartment between the frangible membrane and the storage reservoir cap, located opposite the water-soluble membrane. The water-soluble membrane is configured to be placed against the treatment area. Thus, once the device is placed on the treatment area, pressure can be applied to the cap to rupture the frangible membrane. The aqueous carrier can then flood the lower compartment containing the nitrite agent and acidifying agent, forming activated NORS and initiating NO production. Furthermore, the aqueous carrier can dissolve the water-soluble membrane, directly exposing the treatment area to the NORS. Other suitable methods of preloading the storage reservoir with the NORS, nitrite agent, and acidifying agent, or other suitable agents, can also be used.

[0066] The storage reservoir can further include a cap or closure. In some examples, when the drug storage device contains a preloaded drug, such as NORS, or other suitable drug, the cap or closure can be pre-attached to the drug storage device. In other examples, when the storage reservoir is a hollow channel or cavity, a portion of the drug storage device, such as a strap or base portion, can be folded over the storage reservoir to form the cap or closure. In yet other examples, a separate cap portion can be provided and applied to the storage reservoir after the drug is loaded therein.

[0067] The medication storage device can be adapted for attachment to various body parts of a patient, non-limiting examples of which may include a phalange (e.g., a finger or toe), arm, hand, leg, foot, torso, head, penis, nipple, neck, etc., or combinations thereof.

[0068] FIG. 4 illustrates one non-limiting example of a method for manufacturing a medication storage device. As shown in FIG. 4, the base or strap portion 1 can include a release line 4 removably adhered thereto. The base or strap portion 1 can include a cut area corresponding to the storage reservoir. An alignment block 5 can be inserted into the cut area to guide the storage reservoir 2 into proper alignment on the base or strap portion 1. The storage reservoir 2 can include adhesive 6 to facilitate attachment of the storage reservoir 2 to the strap portion. After the storage reservoir 2 is attached to the strap portion 1, the alignment block 5 can be removed. Additionally, the strap portion 1 can include adhesive 3 to facilitate attachment of the assembled device to a patient.

[0069] The present disclosure also discloses a method for treating a localized condition, such as an infection (e.g., a fungal, bacterial, or viral infection), inflammation, a wound, a scrape, a puncture, a laceration, a burn (including sunburn), psoriasis, acne, dermatitis, cyclokeratopathy, or a wart, in a patient that responds to nitric oxide (NO) treatment. The method for treating a localized condition can include applying a drug storage device to the patient. The device can form a storage reservoir around the treatment area. The method can further include introducing NO (e.g., using a NORS) into the storage reservoir. The drug storage device can be configured to substantially contain the NORS / NO within the storage reservoir.

[0070] The methods can be used to treat a variety of topical infections. In some instances, the topical infection can be a skin infection. Non-limiting examples of skin infections can include warts, molluscum contagiosum, tinea, carbuncles, furuncles, impetigo, pirondyl cysts, sporotrichosis, shingles, and the like, or combinations thereof. In some instances, the topical infection can be a nail infection. Non-limiting examples of nail infections can include onychomycosis, green nail syndrome, and the like, or combinations thereof. In some specific instances, these methods can be used to treat onychomycosis.

[0071] The drug storage device can be applied to the patient in a variety of ways. In some instances, the drug storage device can be applied via an adhesive. In other instances, the drug storage device can be applied by wrapping the device around a portion of the patient's body part, such as the hand, foot, arm, leg, torso, phalanges, penis, head, neck, or a combination thereof. In other instances, the drug storage device can be applied to the patient by a combination of methods, such as via a bandage (wrap), adhesive, hook-and-loop fastener, magnetic attachment, buckle, clip, cinch, etc.

[0072] Figures 5A-5I illustrate various possible steps in a method of applying a drug storage device to a patient. For example, Figure 5A illustrates removing a release liner from a drug storage device prior to application to a patient, exposing the adhesive on the application side of the device. Figure 5B illustrates initial application of the drug storage device to a portion of a patient's body (e.g., a toe). In this example, the toe nail and surrounding tissue form the target treatment area. Pressure is applied to adhere the device to the toe so that the storage reservoir surrounds the treatment area, forming an adhesive seal to contain the NO within the storage reservoir.

[0073] Figure 5C shows how any bunny ears can be folded over the tip of the phalanges to better fit the device to the toes. Next, the short ends of the strap portions of the device can be folded over the bunny ears. These portions can also include adhesive for adhering to the phalanges. Figure 5E shows how the device will look on the toes after the short sides of the bunny ear and strap components have been applied. Figure 5F shows how the long sides of the strap components can be folded under the toes, covering the short sides of the bunny ear and strap components. Figure 5G shows how this will look when applied to the toes. Furthermore, Figure 5G also shows that the NORS are applied within the storage reservoir in direct contact with the treatment area, with the nail and surrounding tissue forming the base of the storage reservoir. Next, Figure 5H shows how the long portions of the straps can be folded over the top of the storage reservoir to cover it and form yet another adhesive seal to contain the NO within the storage reservoir. Additionally, Figure 5H illustrates an external reservoir indicator, which can be a symbol, emblem, or other marking that substantially aligns with the periphery of the storage reservoir that is not covered under the long edge of the wrap in the closed state. The external reservoir indicator can allow the patient to interact with the device in a manner that does not interfere with and / or protect the contents of the storage reservoir. For example, the external reservoir indicator can have an outer portion that indicates where the patient should apply pressure to seal the periphery of the storage reservoir against the overlapping long edge of the wrap. Furthermore, the external reservoir indicator can allow identification of the chamber of the storage reservoir and prevent the patient from applying pressure to the device in a manner that could dislodge or adversely affect the NORS dispensed into the storage reservoir. The external reservoir indicator can be of any shape, size, or include any marking, sign, word, or orientation necessary to correspond to the particular size or shape of the storage reservoir and / or to alert the subject to the proper use of the device.

[0074] Figure 6 shows a comparative example of what the devices presented in Figures 5A-5H look like when worn on the left and right feet. In each case, the long side of the strap can be folded over the reservoir, covering it and forming an adhesive seal that contains the NO within the reservoir.

[0075] NO can be introduced into the storage reservoir in a variety of ways. In some examples, the nitrite composition and the acidifying composition can be mixed before being introduced into the storage reservoir. In some specific examples, the nitrite composition and the acidifying composition can be mixed when they are dispensed into the storage reservoir. In other examples, the nitrite composition and the acidifying composition can be mixed and then subsequently dispensed into the storage reservoir, or they can be mixed within the treatment reservoir. In some specific examples, the NORS can be pre-loaded into a container that can be pressurized to minimize NO production before dispensing and then dispensed into the storage reservoir. In other examples, the storage reservoir can contain an inactive NORS pre-loaded therein, which can be activated to generate NO after being placed in the treatment area.

[0076] A therapeutically effective amount of NO can be introduced into the storage unit. In one example, the therapeutically effective amount of NO can be about 1 ppm to about 10,000 ppm NO. In another example, the therapeutically effective amount can be about 40 ppm to about 1000 ppm NO. In another example, the therapeutically effective amount of NO can be about 4 ppm to about 400 ppm NO. In another example, the therapeutically effective amount of NO can be about 100 ppm to about 220 ppm NO. In another example, the therapeutically effective amount is about 50 ppm to about 200 ppm NO. In one particular example, the therapeutically effective amount can be about 160 ppm NO. In another example, the therapeutically effective amount can be 160 ppm or less NO.

[0077] When NO is delivered via a NORS, the NORS can generally be applied to the treatment area in an amount of about 0.5 milliliters (ml) to about 40 ml. In other examples, the NORS can be applied to the treatment area in an amount of about 1 ml to about 30 ml, about 5 ml to about 20 ml, or about 10 ml to about 20 ml. In other examples, the NORS can be applied to the treatment area in an amount of about 0.5 ml to about 5 ml, about 1 ml to about 10 ml, about 5 ml to about 15 ml, about 10 ml to about 20 ml, about 15 ml to about 25 ml, about 20 ml to about 30 ml, about 25 ml to about 35 ml, or about 30 ml to about 40 ml. In other examples, the NORS can be applied to the treatment area in an amount of about 0.5 grams (g) to about 40 g. In other examples, the NORS can be applied to the treatment area in an amount of about 1 g to about 10 g, about 5 g to about 15 g, about 10 g to about 20 g, about 15 g to about 25 g, about 20 g to about 30 g, about 25 g to about 35 g, or about 30 g to about 40 g.

[0078] The present disclosure also describes a treatment system. The treatment system can include a drug storage device and a dispensing device as described herein. The dispensing device can be a pump dispenser, a single-barrel syringe, a dual-barrel syringe, or the like. When a dual-barrel syringe is used, the dual-barrel syringe can include a tip configured to mix the individual components, such as the nitrite component and the acidifying component, as they are dispensed.

[0079] One non-limiting example of a dispensing device is provided in FIG. 7A. Specifically, the dispensing device includes a dual-barrel syringe 1 and a corkscrew mixing tip 2 configured to mix individual components, such as a nitrite composition and an acidifying composition, when dispensed. FIG. 7B provides additional details regarding the dual-barrel syringe. Specifically, the dual-barrel syringe may include a housing, a plunger that slidably engages the housing from point A to point B of the housing and vice versa, and a plunger seal that is chemically compatible with the individual components contained in the separate chambers of the syringe. A syringe cap may also be included to seal or otherwise enclose the dispensing end of the syringe.

[0080] In some instances, the treatment system can also include a therapy system as described herein. In yet other instances, the treatment system can also include a NORS as described herein. Example [Example]

[0081] Treatment of onychomycosis with nitric oxide-releasing gel Onychomycosis (OMC) is a common fungal infection of the toenails caused by dermatophytes, which cause white or yellow nail discoloration, nail thickening, and separation of the nail from the nail bed. OMC is a common nail disease, affecting more than 35 million people in the United States. It accounts for approximately half of all nail diseases. The global prevalence of onychomycosis is 10% of all adults. This rate increases to 20% in adults over 60 years of age. Systemic antifungal medications are the most effective treatment, with meta-analyses showing fungal cure rates of approximately 70% for terbinafine, 60% for itraconazole, and 50% for fluconazole. Oral administration causes systemic side effects, including nausea, dizziness, vomiting, and liver damage. Many patients are not candidates for these medications due to potential liver damage. Trichophyton resistance to terbinafine treatment is an emerging issue. Better topical medications to treat this disease are desperately needed.

[0082] In vitro studies were conducted with 10-30 minutes of exposure to nitric oxide-releasing solutions / gels. As shown in Figures 8A and 8B, NO can completely eradicate fungi associated with athlete's foot, completely killing mycelia and conidia. Furthermore, in human clinical trials, NORS demonstrated significant bactericidal activity and anti-inflammatory effects in subjects with athlete's foot (see Figures 9A and 9B).

[0083] Additionally, a blinded ex vivo study was conducted on 15 volunteers with suspected distal subungual mycosis of the toenail (OMCGN). NORG was evaluated as a fungicide compared to an existing comparator (10% efinaconazole). Toenail clippings were obtained during clinical visits to a podiatrist clinic. Half of the clippings were sent to an independent commercial laboratory for determination of a positive OMC diagnosis, determined by the presence of viable mycelia (KOH), and fungi (culture). The remaining half of the sample was sent to a university laboratory for testing. The samples were split; one half was cultured for fungal growth. The remaining sample was exposed to either 10% efinaconazole (continuously) or NORG-80 (8 hours per day) for 7 consecutive days. After exposure, the samples were shredded to expose the interior of the nail clippings and flattened to measure fungal growth. Evaluable samples required positive cultures and fungal cultures from KOH's independent laboratory and a positive fungal culture from a baseline sample before intervention. Fungal cure was defined as the absence of fungal growth 21 days after intervention.

[0084] Fifteen subjects were enrolled, and two samples met the protocol criteria for analysis, both belonging to the NORG-80 cohort. NORG-80 is bactericidal. The nail clippings turned orange-red, likely due to a known oxidation process that results in a color change (see Figure 10). This color change helps indicate that nitric oxide had penetrated the entire thickness of the nail tissue.

[0085] Based on these findings, it appears that NORG-80 can penetrate the toenail bed (e.g., the big toe nail) and eliminate fungi associated with OMC. [Example]

[0086] Exposure to NORS in C. acnes about 10 5 cfu / ml of C. acnes was exposed to 60 mM NORG. No bacteria were detected after 3 minutes. n=3 (**=p<0.01, ***=p<0.001). (See Figure 11). [Example]

[0087] Example 3 - Comparison of NORS and NORG A 60 mM nitric oxide-releasing solution (NORS) and a 60 mM nitric oxide-releasing gel (NORG) were prepared and compared for nitric oxide release. Approximately 1 ml of each pH 3.5 composition was introduced into a blow-over apparatus connected to a chemiluminescence detector to measure NO production. Nitrogen was used as the carrier gas at a flow rate of 1 L / min (see Figure 12 and Table 1). [Table 1]

[0088] Table 1 - Comparison results between NORS and NORG Additionally, Figure 13 shows the concentration of Staphylococcus aureus after exposure to 60 mM NORS and 60 mM NORG at pH 3.5. More specifically, approximately 10 cfu / mL of bacteria was added to the sample and vortexed for 5 seconds. After the exposure time was over, the reaction was neutralized with NaOH. The sample was then vortexed for 5 seconds, diluted, and plated. No significant differences were observed between the solution and gel at each time point. Illustrative Embodiments The following examples relate to particular technology embodiments and to particular features, elements, or steps that can be used or otherwise combined to achieve such embodiments.

[0089] In one example, a method is provided for treating a localized condition responsive to nitric oxide (NO) therapy in a patient, comprising applying to the patient a drug storage device that forms a storage reservoir around the treatment area and introduces a nitric oxide releasing substance (NORS) into the storage reservoir, the drug storage device configured to substantially contain the NO produced by the NORS in the storage reservoir.

[0090] In one example of a method of treating a local condition that responds to NO therapy, the local condition is a skin infection.

[0091] In one example of a method of treating a topical condition responsive to NO therapy, the skin infection comprises a wart, molluscum contagiosum, ringworm, carbuncle, furuncle, impetigo, pirondyl cyst, sporotrichosis, shingles, eczema, or a combination thereof.

[0092] In one example of a method of treating a local condition that responds to NO therapy, the local infection is a nail infection.

[0093] In one example of a method of treating a topical condition responsive to NO therapy, the nail infection comprises onychomycosis, green nail syndrome, or a combination thereof.

[0094] In one example of a method for treating a localized condition responsive to NO therapy, the drug storage device is applied via an adhesive.

[0095] In one example of a method for treating a localized condition responsive to NO therapy, the drug storage device is applied by wrapping the device around a portion of a patient's body part.

[0096] In one example of a method of treating a localized condition responsive to NO therapy, the body part is a hand, a foot, an arm, a leg, a torso, a phalanges, a penis, a nipple, a head, a neck, or a combination thereof.

[0097] In one example of a method for treating a local condition responsive to NO therapy, the storage reservoir has a volume of about 0.1 ml to about 20 ml.

[0098] In one example of a method for treating a local condition responsive to NO therapy, the NORS is introduced in an inactive state.

[0099] In one example of a method for treating a local condition responsive to NO therapy, a NORS is prepared and activated when it is introduced into a storage reservoir.

[0100] In one example of a method for treating a local condition that responds to NO therapy, the NORS is delivered as a gel.

[0101] In one example of a method for treating a local condition responsive to NO therapy, a NORS is activated within a storage reservoir.

[0102] In one example method of treating a local condition responsive to NO therapy, a NORS is formulated to release from about 10 ppm NO to about 5000 ppm NO.

[0103] In one example method of treating a local condition responsive to NO therapy, the NORS is formulated to release NO over a period of about 30 minutes to about 12 hours.

[0104] In one example, a nitric oxide releasing substance (NORS) including a nitrite agent, an acidifying agent, and an aqueous medium is included, wherein the NORS is formulated to release from about 1 ppm to about 10,000 ppm of NO over a period of from about 1 second to about 48 hours.

[0105] In one example of a NORS, the nitrite agent includes sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotate nitrite, amyl nitrite, magnesium nitrite, or a combination thereof.

[0106] In one example of a NORS, the nitrite agent is present in the NORS in an amount of about 0.01% to about 10% by weight.

[0107] In one example of a NORS, the acidifying agent includes 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.

[0108] In one example of a NORS, the acidifying agent is present in the NORS in an amount to achieve a pH of about 2.5 to about 5.

[0109] In one example of a NORS, the nitrite agent and the acidifying agent are present in the NORS in a weight ratio of about 1:10 to about 10:1.

[0110] In one example of a NORS, at least one of a nitrite agent and an acidifying agent is encapsulated by an encapsulating agent.

[0111] In one example of a NORS, the encapsulant material is present with a nitrite agent, an acidifying agent, or a combination thereof in a weight ratio of about 0.05:1 to about 10:1.

[0112] In one example of a NORS, the nitrite agent is encapsulated.

[0113] In one example of a NORS, the acidifying agent is encapsulated.

[0114] In one example of a NORS, the viscosity of the NORS is from about 3000 centipoise (cps) to about 150,000 cps.

[0115] In one example of a NORS, a drug storage and / or delivery device is provided having a housing with an interior wall forming a storage reservoir configured to contain a nitric oxide releasing substance (NORS) therein when the device is attached to a patient, and an attachment member configured to attach the device to a patient.

[0116] In one example, a drug storage and / or delivery device is provided, wherein the storage reservoir has a volume of about 1 ml to about 20 ml.

[0117] In one example, a drug storage and / or delivery device is provided, wherein the storage reservoir is a hollow channel extending through the housing.

[0118] In one example, a drug storage and / or delivery device is provided, wherein a storage reservoir contains an inactivated nitric oxide releasing solution (NORS).

[0119] In one example, a medication storage and / or delivery device is provided, wherein the attachment member includes a strap configured to wrap around a portion of a patient's body part.

[0120] In one example, a drug storage and / or delivery device is provided, wherein the body part is a phalange.

[0121] In one example, a medication storage and / or delivery device is provided, wherein the strap includes a laterally extending portion configured to wrap around the phalanges and a tip portion configured to wrap around the tip of the phalanges.

[0122] In one example, a medication storage and / or delivery device is provided, where a portion of the strap is configured to encase and cover a storage reservoir.

[0123] In one example, a medication storage and / or delivery device is provided, where the attachment member includes an adhesive layer configured to bond the storage device to a target treatment site on a patient.

[0124] In one example, a drug storage and / or administration device is provided, the device further comprising a cap configured to be placed over the storage reservoir to direct release of NO from the NORS towards the patient when the device is attached to the patient.

[0125] In one example, a treatment system is provided that includes a nitrite composition having a viscosity of about 5000 cps to about 100,000 cps and an acidifying composition having a viscosity of about 5000 cps to about 100,000 cps.

[0126] In one example of a therapeutic system, the nitrite composition includes a nitrite agent.

[0127] In one example of a treatment system, the nitrite agent comprises sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite, orotate nitrite, amyl nitrite, magnesium nitrite, or a combination thereof.

[0128] In one example of a treatment system, the acidifying composition includes an acidifying agent.

[0129] In one example of a treatment 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.

[0130] In one example of a treatment system, the nitrite composition, the acidifying composition, or both, include a gelling agent.

[0131] In one example of a therapeutic system, the gelling agent comprises xanthan gum starch, guar gum, locust bean gum, karaya gum, tragacanth gum, gum arabic, cellulose derivatives, alginates, pectin, carrageenan, gelatin, gellan, agar, or combinations thereof.

[0132] In one example of a treatment system, the nitrite composition has a pH of about 5 to about 8.

[0133] In one example of a treatment system, the acidifying composition has a pH of about 2 to about 5.

[0134] In one example, a treatment system including a drug storage device according to the devices described herein and a dispensing device is provided.

[0135] In one example of a treatment system, the dispensing device is a syringe.

[0136] In one example of a treatment system, the syringe is a dual-barrel syringe configured to mix the individual components during dispensing.

[0137] In one example of a treatment system, the system further includes a treatment system described herein.

[0138] In one example of a treatment system, the nitrite composition and the acidifying composition of the treatment system are pre-loaded into separate compartments of a dispensing device.

[0139] In one example of a treatment system, the nitrite composition and the acidifying composition of the treatment system are pre-loaded into separate dispensing devices.

[0140] In one example of a treatment system, the system further comprises a NORS as described herein.

[0141] In one example of a treatment system, the NORS is pre-loaded into a dispensing device.

[0142] In one example of a treatment system, the dispensing device is pressurized prior to dispensing to minimize the generation of NORS.

[0143] While the above examples illustrate the principles of the technology in one or more specific applications, it will be apparent to those skilled in the art that numerous variations in the embodiments, uses, and details are possible without departing from the inventive faculty and principles and concepts of the technology.

Claims

1. A drug storage device, comprising: a housing having an interior wall forming a storage reservoir, the storage reservoir having a hollow channel or chamber with a bottom opening configured to store a nitric oxide releasing substance (NORS) therein when the device is attached to a patient, the bottom opening configured adjacent to a treatment area to allow unimpeded release of nitric oxide to the treatment area; an attachment member configured to attach the device to the patient so that nitric oxide is administered to the patient; An apparatus having:

2. 10. The device of claim 1, wherein the storage reservoir has a volume of about 1 ml to about 20 ml.

3. 10. The device of claim 1, wherein the hollow channel extends through the housing.

4. 10. The device of claim 1, wherein the storage reservoir contains an inactivated nitric oxide releasing solution (NORS).

5. The device of claim 1 , wherein the attachment member comprises a strap configured to wrap around a portion of the patient's body part.

6. 6. The device of claim 5, wherein the body part is a phalange.

7. 6. The device of claim 5, wherein the strap includes a laterally extending portion configured to wrap around a phalange and a distal portion configured to wrap around a tip of the phalange.

8. 6. The device of claim 5, wherein a portion of the strap is configured to wrap around the storage reservoir so as to cover the storage reservoir.

9. The device of claim 1 , wherein the attachment member includes an adhesive layer configured to bond the retraction device to a target treatment site on a patient.

10. 10. The device of claim 1, further comprising a cap configured to be placed over the storage reservoir to direct release of NO from the NORS toward the patient when the device is attached to the patient.

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