WO2025156055A1 - System for dispensing spray gels for treatment of wounds and infections and methods of use thereof - Google Patents

Abstract

Systems and methods for dispensing spray gel for treatment of wounds and infections, such as in the form of a thermoreversible gel spray. A system may comprise a dispensing container comprising a container body, a container bag, and a spray actuator such as a de Laval nozzle. A gel with a viscosity of about 1,790 to about 36,430 cP with poloxamer(s) as the gellant. In some examples, a system may comprise a dispensing container comprising a container body that is pressurized to between about 2 bars and about 9 bars of pressure.

Description

SYSTEM FOR DISPENSING SPRAY GELS FOR TREATMENT OF WOUNDS AND INFECTIONS AND METHODS OF USE THEREOF

CROSS-REFERENCE

[0001] This application claims priority from US provisional patent application no. 63/624,986 filed January 25, 2024, the contents of which are incorporated herein by reference.

TECHNICAL FIELD

[0002] Example embodiments relate generally to systems and methods of dispensing gel sprays, and specifically to systems and methods of dispensing thermoreversible spray gel that adhere to the skin upon contact for the treatment of wounds and infections.

BACKGROUND

[0003] From a microbiological perspective, the primary function of normal, intact human and animal skin is to control microbial populations that live on the skin surface and to prevent underlying tissue from becoming colonized and invaded by potential pathogens. Exposure of subcutaneous tissue (i.e. , a wound) provides a moist, warm and nutritious environment that is conducive to microbial colonization and proliferation.

[0004] Any wound is at some risk of becoming infected. In the event of an infection and if a wound fails to heal, the patient suffers increased trauma as well as increased treatment costs. General wound management practices become more resource demanding. Over 2% of the US population suffers from such chronic, non-healing wounds and this costs the US health care system $20 billion a year. Wounds are an enormous problem worldwide in humans as well as in animals.

[0005] Currently, some of the most common topical preparations for the prevention and treatment of wounds have generally included the use of ointments, creams, lotions, pastes and gels.

[0006] Topical gel sprays have emerged as being advantageous for being economical, clean, safe and easy to apply, and less prone to cross-contamination. In comparison, for example, creams and lotions may be relatively difficult and time-consuming to apply, and the activity of any active compounds within an antimicrobial cream or lotion preparation may be adversely affected by the cream or lotion matrix.

[0007] It is therefore advantageous to provide improved systems and methods for the dispensing of improved gel sprays for the treatment of wounds and infections.

SUMMARY

[0008] Example embodiments relate to a system for dispensing spray gel for the treatment of wounds and infections and methods of use thereof.

[0009] In an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition in the container bag, the composition comprising (a) a poloxamer and (b) glycerol at a concentration of 1 %-10% (w/w), which gives a dynamic viscosity of 209.3 (200 rpm) to 1 ,484,333 cP (1 rpm) at 25 °C, and wherein the spray actuator has a de Laval nozzle. Preferably, the viscosity is between about 1 ,790 to about 36,430 cP at 25 °C using method provided. More preferably, the viscosity is between 12,480 to 23,760 cP at 25 °C using method provided.

[00010] The viscosity of each gel sample was measured at 25 ° C with a Brookfield DV2T viscometer at 100 rpm rotation speed using suitable spindle that gives 10 to 100% torque while measuring. Viscosity was measured 1 minute after the start of rotation.

[00011] In some example embodiments, the container body is pressurized to between about 2 bars and 9 bars of pressure.

[00012] In an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition comprising: (a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1 % of the composition, (b) sodium citrate (or potassium citrate) at a concentration of between about 0.1% to about 1 % of the composition, and (c) glycerol at a concentration of between about 1 % to about 10% of the composition, and (d) a poloxamer 407 at a concentration of between about 13% to about 24% of the composition.

[00013] In an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition comprising: (a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1% of the composition, (b) sodium citrate (or potassium citrate) at a concentration of between about 0.1% to about 1 % of the composition, and (c) glycerol at a concentration of between about 1% to about 10% of the composition, and (d) a poloxamer 188 at a concentration of about 37%_of the composition.

[00014] In an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition comprising: (a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1% of the composition, (b) sodium citrate (or potassium citrate) at a concentration of between about 0.1% to about 1 % of the composition, and (c) glycerol at a concentration of between about 1% to about 10% of the composition, and (d) a poloxamer 338 at a concentration of about 30% of the composition.

[00015] In some example embodiments, the poloxamer is a poloxamer 407 at a concentration of between about 16% to about 26% of the composition. In some example embodiments, the poloxamer is a poloxamer 188 at a concentration of about 37% of the composition. In some example embodiments, the poloxamer is a poloxamer 338 at a concentration of about 30% of the composition. In some example embodiments, the container body is pressurized to between about 2 bars and about 9 bars of pressure.

[00016] In an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator, wherein the container body is pressurizable to between about 2 bars and about 9 bars of pressure; and a composition comprising: (a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1 % of the composition, (b) sodium citrate (or potassium citrate) at a concentration of between about 0.1% to about 1% of the composition, (c) ) glycerol at a concentration of between about 1% to about 10% of the composition, and a poloxamer.

[00017] In some example embodiments, the container bag has a capacity volume of between about 30 mL to about 300 mL, more preferably 140 mL to 300 mL. In some example embodiments, the poloxamer is Poloxamer 407. In some example embodiments, the EDTA salt is either disodium EDTA or tetrasodium EDTA. In some example embodiments, the sodium citrate is trisodium citrate. In some example embodiments, the potassium citrate is tripotassium citrate. In some example embodiments, the composition further comprises a biguanide at a concentration of between about 0.01% to about 0.5% of the composition. In some example embodiments, the biguanide is polyhexamethylene biguanide (PHMB).

[00018] In some example embodiments, the composition further comprises one or more ingredients selected from: purified water, a buffer, a stabilizing agent, a gelling agent, a surfactant, a herbal, a vitamin, a mineral, an extra cellular matrix, an antimicrobial, an antibiotic, and a pH adjuster.

[00019] In some example embodiments, the composition further comprises an anti-infective compound selected from: DispersinB, alginate lyase, nisin, lactoferricin, serotransferrin, ovotransferrin, ovalbumin, ovomucoid, protamine sulfate, chlorohexidine, cetylpyridinium chloride, triclosan, silver sulfadiazine, benzalkonium chloride, hydrogen peroxide, citric acid, potassium citrate, 5-fluorouracil, cis-2-decenoic acid, DNase I, proteinase K, silver, gallium, bacteriocins, antimicrobial peptides and an enzyme that cleaves poly-B-1 ,6-N- acetylglucosamine.

[00020] In some example embodiments, the citric acid is at a concentration of between about 0.001% to about 0.1% of the composition, and the citric acid is anhydrous. In some example embodiments, the composition further comprises glycerol at a concentration of between about 1 % to about 10% of the composition.

[00021] In some example embodiments, the composition is prepared as either a spray or a thermoreversible gel spray.

[00022] Preferably the spray actuator has a de Laval nozzle. Preferably the nozzle internal orifice width is 0.3 mm. The nozzle orifice may be square.

[00023] In a preferred embodiment, the valve is a bag-on-valve with dip tube.

[00024] In an example embodiment, there is provided a method of preparing a composition as described herein for the treatment of wounds and infections, comprising the steps of: a) mixing together two or more of: purified water, anhydrous citric acid, sodium citrate, and an EDTA salt until a resulting mixture is substantially homogenous; b) cooling the resulting mixture until the resulting mixture is at a temperature of between about 2 degrees Celsius to about 20 degrees Celsius; c) mixing one or both of the poloxamer and glycerol into the resulting mixture until the resulting mixture is homogenous; and d) adding a biguanide to the resulting mixture.

[00025] In some example embodiments, the method further comprises storing the resulting mixture at room temperature.

[00026] In an example embodiment, there is provided a method of preparing a system as described herein for dispensing spray gel for the treatment of wounds and infections, comprising the steps of: a) pressurizing the container body to between about 2 bars to about 9 bars of pressure; b) inserting the container bag into the container body under pressure; and c) filling the container bag under pressure inside the container body with between about 140 mL to about 300 mL of a composition, thereby further pressurizing the dispensing container.

[00027] In an example embodiment, there is provided a method of dispensing using a system as described herein for dispensing spray gel for the treatment of wounds and infections, comprising the steps of: a) engaging the spray actuator; and b) releasing a built-up pressure from within the dispensing container, thereby releasing the composition through the spray actuator.

[00028] In some example embodiments, a propellant is held within a remaining space between the container body and the container bag and squeezes the composition through the spray actuator after the spray actuator is engaged, thereby releasing the composition through the spray actuator.

[00029] In some example embodiments, the method of dispensing is used to prevent or treat a wound infection.

[00030] In some example embodiments, the method of dispensing is used to treat one or more of humans, domestic animals, farm animals, zoo animals, pet animals, dogs, horses, cats, cattle, pigs, goats, and sheep.

BRIEF DESCRIPTION OF THE DRAWINGS

[00031] Reference will now be made, by way of example, to the accompanying drawings which show example embodiments, and in which:

[00032] Fig. 1 A is a front view of a schematic diagram of an example embodiment of a system for dispensing spray gel for treatment of wounds and infections.

[00033] Fig. 1 B is a cross-sectional view of the schematic diagram of Fig. 1A, prior to filling a container bag with a composition for the treatment of wounds and infections.

[00034] Fig. 1C is a cross-sectional view of the schematic diagram of Fig. 1A, after filling the container bag with the composition for the treatment of wounds and infections.

[00035] Fig. 2 is a process flow diagram for a method of preparing a composition for the treatment of wounds and infections.

[00036] Fig. 3 is a process flow diagram for a method of preparing the system of Fig. 1C for dispensing spray gel for the treatment of wounds and infections.

[00037] Fig. 4 is a diagram showing a cross-section of a de Laval nozzle orifice.

[00038] Fig. 5 is a graph showing the relationship between gel viscosity and rotation speed.

[00039] Fig. 6 is a diagram showing a cross section of a bag on valve in cannister system, full (left) and partially emptied (right).

[00040] Fig. 7 is a diagram showing a cross section of a bag on valve with dip tube in a cannister system.

[00041] Fig. 8 is a diagram showing the relationship between viscosity and poloxamer 407 concentration at different temperatures.

DETAILED DESCRIPTION

[00042] The present inventors have found that it is possible for gel preparations to exhibit thermoreversible properties, acting as a liquid antimicrobial carrier under certain temperatures and possibly certain pressure ranges, and coagulating into a gel under others. This thermoreversible property of gel preparations may be advantageous in applications where, for example, it is desirable to release a liquid antimicrobial formulation as a spray from a trigger spray device, and to have said liquid formulation then solidify into a gel formulation upon contact with a warmer surface such as human skin. In an additional advantageous thermorevisable property, the gel on skin can be readily reduced to a washable liquid by application of cold water. This is advantageous when a medical professional needs to examine or further treat the wound free of the gel.

[00043] The challenge with the manufacture of thermoreversible gel spray systems, however, is ensuring that a spray formulation is delivered in a sufficiently wide, yet targeted and homogenously-distributed spray pattern, and that the formulation adheres to the skin upon application in order to effectively work on the wound. For example, some concentrations of an active compound may result in a liquid formulation that is released as an uncontrolled mist, or may be runny when applied to the skin, thereby decreasing the exposure of the formulation at the desired location of treatment. Other concentrations may result in formulations that, may be too thick to be released as a spray, may “ooze” out of a nozzle as a highly viscous substance, or may be released as a narrow and thick stream of gel that does not allow for sufficiently broad coverage.

[00044] The present inventors have now provided improved systems and methods for the dispensing of thermoreversible gel sprays for the treatment of wounds and infections under optimized temperature and pressure ranges that result in a spray pattern that is sufficiently wide, yet targeted and homogenously-distributed, and that also adheres to the skin, and, in some embodiments, can wash off with cold water when needed.

[00045] The present inventors have now found methods and materials, including a nozzle type, which allows a poloxamer composition to be thick enough to form a gel, while still being able to spray from a container as a fluid.

[00046] Throughout the following, specific details are set forth in order to provide a more thorough understanding to persons skilled in the art. However, well-known elements may not have been shown or described in detail. Accordingly, the description and drawings are to be regarded in an illustrative, rather than a restrictive, sense.

[00047] The term "antimicrobial" refers to a compound or a composition that kills or inhibits or stops the growth of microorganisms, including, but not limited to bacteria, yeasts and mold. The term “topical antimicrobial” refers to antimicrobials that have been manufactured into a product that can be applied directly to the skin. [00048] The term "biofilm" refers to a structured community of microorganisms enclosed in a self produced extracellular polymeric matrix, and attached to a biotic or abiotic surface. Bacteria in a biofilm can be 1000 times more resistant to antibiotics/antimicrobials compared to their planktonic (free living) counterparts.

[00049] The term "antibiofilm” refers to inhibition of microbial biofilm formation and disruption or dispersal of preformed biofilms.

[00050] The term "infection" refers to the invasion and multiplication of microorganisms such as bacteria, yeast, mold, viruses, and parasites that are not normally present within the body. An infection may cause no symptoms and be subclinical, or it may cause symptoms and be clinically apparent. An infection may remain localized, or it may spread through the blood or lymphatic vessels to become systemic (body wide). Microorganisms that live naturally in the body are not considered infections.

[00051] The term "wound" refers to a type of injury in which skin is torn, cut, or punctured (an open wound), or where blunt force trauma causes a contusion (a closed wound). In pathology, it specifically refers to a sharp injury, or damages to the dermis of the skin.

[00052] The term "acute wound" refers to those that are new and in the first phase of healing. Acute wounds are characterized by skin layers that have been punctured or broken through by an external force or object. Any acute wound can progress to a chronic wound if it does not heal within the expected time frame or as a result of poor blood supply, oxygen, nutrients or hygiene. Acute wounds should be properly treated to avoid infection, inflammation or constant pressure. Acute wounds are categorized based on causes such as lacerations, abrasions, punctures, incisions, gunshots, burns, and type according to the size and depth (superficial or deep).

[00053] The term "chronic wound" refers to a wound that just will not repair itself over time. Chronic wounds are often thought to be "stuck" in one of the phases of wound healing, and are most often seen in the older adult population. Typically, if a wound is not healing as expected within 2-3 months, it is considered chronic. Chronic wounds include pressure ulcers (e.g. bed sores), arterial and venous leg ulcers, and diabetic ulcers.

[00054] The term "prevention" refers to at least preventing a condition associated with bacteria occurring in a mammal, particularly when the mammal is found to be predisposed to having the condition but has not yet been diagnosed as having it.

[00055] The term "mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports or pet animals, such as dogs, horses, cats, cattle, pigs, sheep, etc.

[00056] The term "treatment" refers to an intervention performed with the intention of preventing the further development or altering the pathology of an existing disorder. Accordingly, "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the infection as well as those in which the infection is to be prevented. In regards to wound infections, "treating” or “treatment" is intended to mean at least the mitigation of wound healing conditions associated with bacterial infections in a subject, such as a mammal, including but not limited to, a human, that is affected at least in part by the condition, and includes, but is not limited to, modulating, inhibiting the condition, and/or alleviating the condition.

[00057] The term "subject" refers to a living vertebrate such as mammal (preferably human and pet animals) in need of treatment.

[00058] The term "metal ion salt" refers to salt of a metal ion such as zinc chloride, zinc lactate, zinc citrate, zinc gluconate, zinc sulfate or zinc acetate, silver ion or silver sulfadiazine, silver sulfate, silver nitrate, and silver carbonate.

[00059] The term “high viscosity” as used herein refers to the fluid having a high amount of resistance to the flow, amongst its internal layers. Fluids with high viscosity are known as high-viscous fluids. These fluids when subjected to flow have very slow motion as they are highly resistant to flow and also oppose deformations.

[00060] The present invention relates to an application system for the transepidermal surface administration of pharmaceutical or cosmetic active agents, said system comprising a container accommodating a sprayable, active agent-containing composition, a propellant gas source for pressurized gas, and a spraying device, wherein container, propellant gas source, and spraying device are flow-connected with each other in such a manner that the propellant gas forces gel out of the spraying device when the spraying device is actuated, and wherein the composition is forced out of the spraying device in the form of a conical spray jet at an exit velocity of ^100 m/s, [00061] The present invention may teach systems and methods for easily and effectively dispensing anti-infective compositions offering antimicrobials and antibiofilm activity in the form of a gel spray. Such compositions may contain combinations of chelating agents with other antimicrobial agents, such as, for example, antimicrobials/antifilm compounds, metal ion salts with gelling agents, surfactants or stabilizing agents. Examples of chelating agents may include ethylenediaminetetraacetic acid (EDTA) salts and sodium citrate. An example for surfactant is a poloxamer.

[00062] According to an example embodiment, there is provided a system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition comprising: (a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001 % to about 0.1% of the composition, (b) sodium citrate at a concentration of between about 0.1 % to about 1% of the composition, (c) glycerol at a concentration of between about 1% to about 10% of the composition, and (d) a poloxamer at a concentration of between about 16% to about 26% of the composition.

[00063] As used herein, the term “poloxamer” refers to a non-ionic triblock class of copolymers comprising polyethylene oxide and polyprophylene oxide blocks. Poloxamer- based polymers often exhibit amphiphilic and surface active properties.

[00064] Poloxamer 407 is an example thermoreversible compound that becomes increasingly viscous at higher temperature ranges and less viscous at lower temperature ranges. As an example, poloxamer-based gels may exist in a liquid phase at room temperature, and may solidify into a gel-like substance at warmer temperatures, such as at body temperature when in contact with skin. Other Poloxamers with similar properties include Poloxamer 188 and Poloxamer 338.

[00065] According to an example embodiment, there is provided a method of preparing a composition for the treatment of wounds and infections. The method may be best illustrated in the process flow diagram of Fig. 2. The method may comprise the steps of: mixing together two or more of: purified water, anhydrous citric acid, sodium citrate, and EDTA salt until a resulting mixture is substantially homogenous (step 202); cooling the resulting mixture until the resulting mixture is at a temperature of between about 2 degrees Celsius to about 20 degrees Celsius (step 204); mixing one or both of poloxamer and glycerol into the resulting mixture until the resulting mixture is homogenous (step 206); and adding a biguanide to the resulting mixture (step 208). In some examples, the method may further comprise storing the resulting mixture at room temperature.

[00066] Referring to step 202, with stirring, chelating agents such as EDTA salts and sodium citrate may be dissolved in purified water, along with anti- infective compounds such as anhydrous citric acid. An example EDTA salt may be disodium EDTA or tetrasodium EDTA. In some examples, sodium citrate may be trisodium citrate.

[00067] Additionally, referring to steps 206 and 208, other antimicrobial peptides, antibiotics, antibiofilm compounds, quaternary ammonium compounds and surfactants may also be advantageously combined in the antimicrobial composition, such as poloxamers and/or biguanides. An example biguanide is polyhexamethylene biguanide (PHMB), and in some examples, the resulting composition may further comprise a biguanide such as PHMB at a concentration of between about 0.01% to about 0.5% of the composition. In some examples, glycerol may be added to the composition at a concentration of between about 1% to about 10% of the composition.

[00068] In some examples, antimicrobial compounds that may be advantageously used or combined in the composition, such as DispersinB, alginate lyase, nisin, lactoferricin, serotransferrin, ovotransferrin, ovalbumin, ovomucoid, protamine sulfate, chlorohexidine, cetylpyridinium chloride, triclosan, silver sulfadiazine, benzalkonium chloride, hydrogen peroxide, citric acid, potassium citrate, 5-fluorouracil, cis-2-decenoic acid, DNase I, proteinase K, silver, gallium, bacteriocins, antimicrobial peptides and an enzyme that cleaves poly-B-1 ,6- N-acetylglucosamine. In some examples, citric acid may be anhydrous, and/or may be added to the composition at a concentration of between about 0.001 % to about 0.1% of the composition.

[00069] In some examples, the composition may further comprise such additional ingredients as a buffer, a stabilizing agent, a gelling agent, a surfactant, a herbal, a vitamin, a mineral, an extra cellular matrix, an antimicrobial, an antibiotic, and/or a pH adjuster.

[00070] Generally, a composition of the invention comprises: (a) a small amount of at least one or two chelating agents; (b) a small amount of a metal ion salt or iron-sequestering glycoprotein or antimicrobial peptide or antibiotic or an antibiofilm compound; and (c) a sparing amount of at least one compounds from the group consisting of a stabilizing agent and/or a gelling agent and/or a surfactant, wherein, the amount of each component (a), (b), and (c) is sufficient to form, in combination, an effective anti- infective composition for prevention and treatment of acute and chronic wound infections (infections of cuts, bruises, surgical sites, lacerations, abrasions, punctures, incisions, gunshots, burns, pyoderma, atopic dermatitis, eczema, pressure ulcers, venous and artery leg ulcers, diabetic foot ulcers, etc.).

[00071] Reference will be made below in detail to exemplary embodiments which are illustrated in the accompanying drawings. Wherever possible, the same reference numerals used throughout the drawings refer to the same or like parts.

[00072] Figs. 1A to 1C illustrate an example embodiment of a system 100 for dispensing spray gel 12 for the treatment of wounds and infections. Referring to Fig. 1A, there is provided a front view of a schematic diagram of an example embodiment of the system 100. The system 100 may comprise of a dispensing container 2 comprising a container body 8 and a spray actuator 4 that may be housed within an actuator cap. The spray actuator 4 may comprise an actuator valve (not shown) and an actuator exit 6 from which a composition 12 for treating wounds and infections may be released.

[00073] Referring to Fig. 1 B, there is provided a cross-sectional view of the system 100 of Fig. 1A, wherein the system 100 comprises a dispensing container 2 comprising a container body 8, a container bag 10, and a spray actuator 4 that may be housed within an actuator cap. In preparing the system 100 of Fig. 1A, the container bag 10 may be empty and deflated prior to filling it with the composition 12 for treating wounds and infections, as best shown in Fig. 1 B.

[00074] Referring to Fig. 1C, there is provided a cross-sectional view of the system 100 of Fig. 1A, wherein the system 100 comprises a dispensing container 2 comprising a container body 8, a container bag 10, and a spray actuator 4 that may be housed within an actuator cap. As best shown in Fig. 1C, the container bag may be filled to receive and hold the composition 12 for treating wounds and infections. In some examples, the container bag may have a capacity volume of between about 140 mL to about 300 mL. In some examples, the dispensing container 2 may be considered a “bag-on-valve” type spray dispenser, wherein gel compounds such as the composition 12 may be held within a bag such as the container bag 10, such that the gel compounds are not in physical contact with the walls of the container body 8 or any propellant held within the walls of the container body 8.

[00075] The present invention may teach systems and methods for dispensing spray gel for the treatment of wounds and infections, wherein the aerosol gel is made up of a composition 12 comprising an EDTA salt at a certain concentration, sodium citrate at a certain concentration, and a poloxamer at a certain concentration. An example poloxamer may be Poloxamer 407, which is often used for its gelling properties at certain temperature ranges. Thus, in some examples, the composition 12 may be prepared as either a spray or a thermoreversible gel spray. Depending on the concentration of poloxamer within the composition, there may be a direct relationship between poloxamer concentration and viscosity of the resulting composition 12, and consequently a direct relationship between the viscosity of the composition 12 and the spray pattern of the resulting gel spray. Additionally, depending on the amount of pressure that exists within the container body 8 and that is exerted upon the container bag 10 when holding the composition 12, there may also be a direct relationship between the level of pressure within the system 100 and the spray pattern of the resulting gel spray.

[00076] In some examples, the composition 12 may be a thermoreversible gel that exists in a liquid state at room temperature, and which therefore may be released from the dispensing container 2 in liquid phase to facilitate aerosolization of the composition from the dispensing container 2 through the actuator exit 6. Testing has demonstrated, upon release of the composition 12 from the dispensing container 2, that in order to obtain an optimal spray pattern, defined herein as being in the form of a blade of sprayed gel measuring approximately 25 mm wide and 1 mm thick, the concentration of a surfactant such as Poloxamer 407 within the composition may be optimized to fall within a certain percentage range, such that an optimal viscosity range of the resulting gel composition 12 may consequently be obtained.

[00077] Simultaneously, it is also advantageous that the resulting gel composition 12, upon being expelled from the dispensing container and onto body temperature skin, sufficiently solidifies into a gel-like state so as not to run off the skin and thereby render the active compounds of the composition ineffective in working at the location of treatment. It has therefore also been demonstrated through testing that the concentration of a surfactant such as Poloxamer 407 within the composition 12 may be optimized to fall within a certain percentage range to ensure that the resulting gel composition solidifies into a sufficiently gellike state at body temperature such that it does not run easily off the skin and/or off a target location or wound upon being applied.

[00078] The inventors thus developed protocols to provide a testing procedure for assessing various defining parameters of bag on valve design for creating an antimicrobial gel. The protocols covered manufacturing of gel with different concentrations of Poloxamer, viscosity measurements, bag-on-valve actuator and bag selection, sprayability testing, and sprayability distribution analysis. Examples provided concern a composition comprising an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001 % to about 0.1% of the composition and citrate at a concentration of between about 0.1% to about 1 % of the composition.

[00079] The gel was screened for its viscosity and sprayability to eliminate gel that will not stay on skin and will not spray. Then spray patterns of different combinations of Poloxamer concentration, pressure in canister, actuator type and gel temperature were examined.

EXAMPLE 1 - POLOXAMER CONCENTRATION

[00080] Viscosity of the gel is measured using a Brookfield rotational viscometer. The instrument rotates a probe (called spindle) in the gel sample. Viscosity is determined by measuring the torque needed to turn the probe. The gel has been found to be a nonNewtonian fluid, which viscosity changes when rotation speed of the spindle changes (it also becomes runnier when shaken). For consistency, the rotation speed was fixed at 100 rpm while measuring viscosity, and a consistent spindle model, temperature and rotation speed of spindle was maintained.

[00081] Table 1 shows data relating to the relationships between concentration of a poloxamer such as Poloxamer 407 within the composition (%), viscosity of the resulting composition (cP) measured at 100 revolutions per minute (RPM) at room temperature (20°C) and 4 bars of pressure, the resulting spray pattern, and application on the skin (at body temperature). Testing demonstrates that at a concentration of approximately 16% of Poloxamer 407 within the composition, the resulting gel composition has a viscosity of approximately 70 cP at room temperature (20°C), and the resulting spray pattern takes the ideal form of a blade of sprayed gel that is about 25 mm wide and 1 mm thick, but the resulting gel composition upon application may still run easily off the skin. At a concentration of between approximately 13% to 15% of Poloxamer 407 within the composition, the resulting gel composition has a viscosity of between approximately 22 cP to 54 cP at room temperature (20°C), but the resulting spray pattern takes the form of uncontrolled mist, and the resulting gel composition upon application easily runs off the skin. It may be extrapolated that at increasingly lower concentrations of Poloxamer 407 below 13%, the viscosity of the resulting gel composition will progressively decrease and appear increasingly runnier upon application to the skin.

[00082] Conversely, at a concentration of approximately 27% of Poloxamer 407 within the composition, the resulting gel composition has a viscosity of approximately 34,121 cP at room temperature (20°C) and will stay on the skin upon application, but the resulting spray pattern takes the form of a narrow and thick layer of gel that is released from the dispensing container 2 with much difficulty, thereby not allowing for sufficiently broad coverage without further manipulations. It may be extrapolated that at increasingly higher concentrations of Poloxamer 407 above 27%, the viscosity of the resulting gel composition will progressively increase and be increasingly more difficult to expel from the dispensing container 2.

[00083] Optimally, at a concentration of between approximately 17% to 26% of Poloxamer 407 within the composition, the resulting gel composition has a viscosity of between approximately 150 cP to 31 ,231 cP at room temperature (20°C), the resulting spray pattern takes the ideal form of a blade of sprayed gel that is about 25 mm wide and 1 mm thick, and the resulting gel composition stays on the skin upon application.

Table 1 : Relationship between pluronic concentration (Poloxamer 407), viscosity (at room temp, and 4 bars of pressure), resulting spray pattern, and application on skin (at body temp.)

EXAMPLE 2 - PRESSURE OPTIMIZATION

[00084] Table 2 shows data relating to the relationship between the amount of pressure (in bars) within the container body 8 and that is exerted upon the composition 12 when held in the container bag 10, and the spray pattern of the resulting gel spray, at a Poloxamer 407 concentration of 20% within the composition (i.e., within the optimal thermoreversible range) and at room temperature (20°C). Testing demonstrates that when the total amount of pressure that is exerted on the composition 12 when being held in the container bag 10 is below approximately 2 bars, the resulting gel composition 12 is not released from the dispensing container 2 as a spray, but rather oozes out of the dispensing container 2 as a highly viscous gel substance. Conversely, when the total amount of pressure exerted on the composition 12 when held in the container bag 10 is above approximately 6 bars, the resulting gel composition 12 is released from the dispensing container 2 as fine, uncontrolled mist, which does not allow for effective, targeted, and homogenously-distributed application of the gel composition 12 onto a location of treatment. Optimally, when the total amount of pressure exerted on the composition 12 when held in the container bag 10 is between approximately 2 bars and 6 bars, the resulting spray pattern takes the form of a blade of sprayed gel that is about 25 mm wide and 1 mm thick, allowing for a sufficiently wide yet targeted and homogenously- distributed application of the gel composition 12 onto the skin.

Table 2: Relationship between pressure exerted on the composition when held in the container bag and spray pattern (at 20% poloxamer concentration and room temp.)

[00085] Therefore, according to an example embodiment, there is provided systems and methods of dispensing a thermoreversible spray gel for the treatment of wounds and infections comprising a dispensing container 2, which in turn comprises a container body 8, a container bag 10, and a spray actuator 4, wherein the container body 8 may be pressurizable to between about 2 bars and about 6 bars of pressure, which falls within an optimized pressure range for obtaining a resulting spray pattern in the form of an ideal blade of sprayed gel that is approximately 25 mm wide and 1 mm thick when expelled from the dispensing container 2. In some examples, the systems and methods of dispensing the thermoreversible spray gel for the treatment of wounds and infections may also comprise a composition 12, which in turn comprises an EDTA salt at a certain concentration, sodium citrate at a certain concentration, and a poloxamer such as Poloxamer 407 at a concentration of between about 16% to about 26% of the composition, which substantially falls within an optimized percent concentration range for obtaining a resulting spray pattern in the form of an ideal blade of sprayed gel that is approximately 25 mm wide and 1 mm thick when expelled from the dispensing container 2, and a gel composition 12 that also stays on the skin and does not run off the skin upon application.

EXAMPLE 3 - VISCOSITY OPTIMIZATION

[00086] A series of modified thermoreversible spray gel, with various concentrations of a poloxamer (Poloxamer 407) and glycerol, were prepared and tested with combinations of several bag-on-valves and actuator, in order to evaluate spray performance of these combinations and select those with the best performance.

[00087] Viscosity of gel samples from 14 to 45 °C were measured. To function optimally on the wounds the gel has to (a) solidify at room temperature; (b) stays on wound and (3) rinsible by cold water. Thus, viscosity of a functional gel should at least meet the following criteria: be lower than 1 ,000 cP at 12 to 14 °C and larger than 4,000 cP at 25 °C. This thermoreversible property of gel preparations is advantageous in applications as it is desirable to release a liquid antimicrobial formulation as a spray from a trigger spray device, and to have the liquid formulation then solidify into a gel formulation upon contact with a warmer surface such as human skin. The additional advantageous thermorevisable property is that the gel on skin can be readily reduced to a washable liquid by application of cold water.

Table 3. Gel samples that have viscosity below 1,000 cP at 12 to 14 °C and above 4,000 at 25°C

Gel samples with 15 to 22% a poloxamer (Poloxamer 407) fall into this criteria. Poloxamer 407 at 24 and 26% were not readily rinsible. They also did not meet viscosity at 12-14C <1000 cP criteria, which is indication of rinsible formulation.

EXAMPLE 4 - ACTUATOR COMPARISON

[00088] A series of thermoreversible spray gel samples with various a pluronic surfactant (Poloxamer) concentrations, from 13% to 26%, were prepared and loaded into test canisters with pressure adjustment mechanism. Various actuators were tested, including:

A. Product a commercially available de Laval nozzle from Aptar;

B. Modified version of nozzle A with the hole enlarged to 0.9 mm and

C. Pro Cap from Montana Colors, an actuator for spray painting;

D. Astro Fat Cap from Montana Colors

E. Soft Cap from Montana Colors

F. Leo Cap from Montana Colors

G. Super Fat Cap from Montana Colors

H. Transversal Cap from Montana Colors [00089] A, the de Laval nozzle (or convergent-divergent nozzle, CD nozzle or con-di nozzle) is a tube which is pinched in the middle, with a rapid convergence and gradual divergence. It is used to accelerate a compressible fluid to high speeds in the axial (thrust) direction, by converting the thermal energy of the flow into kinetic energy. The nozzle has a 0.3 mm orifice which preferably is square.

[00090] Gel samples were loaded into canisters and the spray widths were measured by spraying the gel onto an aluminum plate at room temperature at a height of 75mm. Only product A from Aptar, gave a satisfying spray pattern at mid to high Poloxamer 407 concentration (or viscosity).

[00091] Nozzle B produced a strong jet stream and no fan shape is observed at all a poloxamer (Poloxamer 407) concentration, resulting in thick gel deposition on the plate. At low Poloxamer 407 concentration this stream spatters while hitting the aluminium plate.

[00092] Nozzles C performed relatively well at low a poloxamer (Poloxamer 407) concentration but produced did not spray at higher concentrations e.g. above 18%). Nozzles D to H did not produce any spray but gel oozed/dispensed out when tested.

[00093] Aptar’s A de Laval actuator works is preferred for the present formulations because:

1. It has a wider channel, which allows a larger fluid flow to increase the speed of jet stream

2. It is equipped with a De Laval nozzle, which accelerates the jet stream of gel by converting the thermal energy of the flow into kinetic energy and makes it easier to break into smaller droplets.

3. The pinching of the tube massively increases shear stress in the composition as it is moving through. This effect appears to uniquely make the gel formation using the poloxamer possible.

4. While converting energy, this nozzle also cools the jet stream down to lower its viscosity. It also makes the gel to break into smaller droplets easier.

[00094] The de Laval Nozzle works on the principle of the conservation of energy. As the fluid enters the converging section of the nozzle, its velocity increases due to the decreasing cross-sectional area (see Figure 4). The higher the shear stress the lower the viscosity for poloxamer gels (see Figure 5). Shear stress is F/A and as the De Laval Nozzle narrows the shear stress cross sectional area is reduced resulting in an increase in shear stress. An increase in shear stress and shear velocity as it exits the pinch point results in a large reduction in viscosity of the poloxamer gel, enabling it to be spray from the nozzle. Once hitting the skin the gel immediately solidifies as it pressure is normalized back to hydrostatic pressure.

[00095] For actuator A an optimum range of a poloxamer (Poloxamer 407) is 17% to 22%. At 16%, although the spray width meets our criteria, the gel is too thin that does not solidify on the plate at room temperature, so it is rejected and not used in the ongoing study. For actuator A an optimum pressure is from 4 to 9 bar.

Table 4 Spray width of gel samples with 13 to 26% Poloxamer 407 at 4 to 9 bar pressure, with actuator (a) to (c)*

Actuator A de Laval nozzle from Aptar

Actuator C, Pro Cap from Montana Colors

[00096] * indicates spray width outside our acceptable range. Acceptable spray width is within

15 mm to 100 mm. Concentrations were also rejected due to the viscosity requirement, i.e. the rejections were based on viscosity or spray width, then cross-referenced to see which formulations meet both requirements.

[00097] Without wishing to be bound to any particular theory, the inventors believe that the following mechanism of action explains the importance of the de Laval nozzle. The narrow portion of the de Laval nozzle creates a shearing force. Poloxamers form thick gels. Some thick gels are thickened by a shearing force (e.g. Corn starch suspensions). The present inventors have found that poloxamers, surprisingly, are shear thinning gels, thus the shearing forces of the de Laval nozzle produce a particular synergy with poloxamers. As you increase the shear stress, poloxamers decrease in viscosity significantly (see Figure 5). In particular, when passing through the de Laval nozzle the shear thinning effect temporarily thins the composition, allowing it to spray like a liquid (without clumping or oozing) then on contact immediately return to its gel form.

EXAMPLE 5 - PRESSURE RANGE

[00098] With the spray width data, spray patterns of gel samples with Poloxamer 407 concentration from 17% to 22% were evaluated. The method of evaluation is by measuring their spray width and pattern after spraying the product onto a moving aluminium plate at room temperature. The plate was moving at 37.5mm/s constant speed and spray height was set at 75mm.

[00099] Gel samples with 19 to 22% Poloxamer 407 have spray width fall into our criteria, 15 to 100 mm, and it gives a fan shape spray pattern. Gel sample with 17% Poloxamer 407 did not stay on the plate. At high pressure (8 and 9 bar), spray width of gel sample with 18% Poloxamer 407 was too wide. Therefore, these concentrations are rejected. At 21 and 22% Poloxamer 407 concentration, spray pattern turns into a jet stream at 5 bar so the pressure must be carefully controlled when using these concentrations to keep a nice fan shape spray pattern.

Table 5 Spray width of gel samples with 17 to 22% Poloxamer 407 measured after being sprayed onto a moving plate.

EXAMPLE 6 - GLYCEROL

[000100] Citrate/EDTA gel samples were prepared based on fixed 20% Poloxamer 407 and various concentration of glycerol: 0, 2, 8 and 10%. We compared their spray performance with the gel containing 5% glycerol by measuring their spray width and spray pattern after spraying the product onto an aluminium plate. The plate was moving at 37.5mm/s and spray height was set at 75mm. Table 6 Spray width of gel samples with 20% Poloxamer 407 and 2 to 10% glycerol measured after being sprayed onto a moving plate*.

[000101] * indicates spray width outside our acceptable range. Acceptable spray width is within 15 mm to 100 mm.

[000102] The performance of gel samples with 2 to 8% glycerol are comparable with gel sample with 5% glycerol. The sample with no glycerol was too thin and it could not stay on the plate. And sample with 10% glycerol is too thick and it does not spray well at 5 bar.

EXAMPLE 7 - BAG DESIGN

[000103] A bag-on-valve (BoV) design with a dip tube was found to make discharging easier. Discharging all product in the canister seems impossible in the initial tests with BoV without dip tube. This happens after the gel was stored in the canister for 3 or more days. The reason of this is because the gel product is too viscous at room temperature. While it is discharged from the canister, gel close to the outlet is discharged first, making the bag collapse thus increase resistance and block the outflow of the remaining gel. As a result gel gets stuck in the bottom of the BoV. The problem is shown in Figure 6.

[000104] A related problem was the creation of a pinch point near the top of the bag. Only one half to a third of the gel was able to be expelled, due in part to the high viscosity of the gel.

[000105] These problems were solved by (a) using a BoV with dip tube 401 so that gel at the bottom is discharged first, and (b) use a smaller bag to reduce resistance, as shown in Figure 7. Diptube 401 is positioned inside the bag so that gel can be discharged from both the inner top 402 and inner bottom 403 of the can.

[000106] Table 7 shows BoV without dip tube discharges only 38.8% of the total amount of product in the canister whereas in the same condition, BoV with dip tube could discharge 96.1% of gel.

Table 7 a comparison of discharging gel with BoV with and without dip tube

[000107] This is particularly a problem for the larger bag sizes, less so for the smaller bag sized. The bag can collapse at the top part of the bag as the gel is discharged preventing additional gel to be discharged. Adding a dip tube resolves the issues.

[000108] According to an example embodiment, there is provided a method of preparing a system for dispensing a spray gel for the treatment of wounds and infections. The method may be best illustrated in the process flow diagram of Fig. 3. The method may comprise the steps of: pressurizing the container body 8 to between about 2 bars to about 6 bars of pressure (step 302); inserting the container bag 10 into the container body 8 under pressure (step 304); and filling the container bag 10 under pressure inside the container body 8 with between about 140 mL to 300 mL of the composition 12, thereby further pressurizing the dispensing container 2 (step 306). In some examples, the container bag 10 has a capacity volume of between about 140 mL to about 300 mL.

[000109] Referring to step 302, prior to filling the container bag 10 with the gel composition 12, the container body 8 by itself may be pressurized to a certain pressure level using traditional means of pressurizing containers, such as with the addition of a compressed gas or a liquefied gas as a propellant. Once the container body 8 has been pressurized, the container bag 10 when not filled with the composition 12 may be inserted into the container body 8 under pressure, as shown in step 304. This is best shown in Fig. 1 B. Finally, referring to step 306, the container bag 10, now under a certain amount of pressure within the container body 8, may be filled with the composition 12, such that the composition 12 is held within the container bag 10 prior to being released. This is best shown in Fig. 1C. The addition of the composition 12 to the container bag 10 while already under a certain amount of pressure within the container body 8 further increases the pressure levels within the dispensing container 2, thereby preparing the system 100 to dispense the composition 12 within the container bag 10 through the spray actuator 4 when the built-up pressure is released.

[000110] Thus by use of the bag on valve system, including a dip tube, the composition can be sprayed with the can in any orientation: upside down, sideways, etc.

[000111] Furthermore, by the use of the bag on valve system, propellant remains in the can but outside of the bag. Thus the propellant is not mixed with the gel. The propellant thus does not need any particular safety approval, does not need to be pharmaceutical grade, does not need to be tested for its effect on the wound and on the antimicrobial composition

[000112] According to an example embodiment, there is provided a method of dispensing using the systems as described herein, comprising the steps of: engaging the spray actuator; and releasing a built-up pressure from within the dispensing container, thereby releasing the composition through the spray actuator. In some examples, the method may further comprise dispensing multiple applications of the composition onto a skin surface or a wound, such as to prevent or treat a wound infection. In some examples, the method may be used to treat humans, domestic animals, farm animals, zoo animals, pet animals, dogs, horses, cats, cattle, pigs, goats, and sheep.

Claims

WHAT IS CLAIMED IS:

1. A system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; a composition in the container bag, the composition comprising a Poloxamer based gel, the composition having a viscosity of about 1,790 cP to about 36,430 cP as measured at 25 C and 100 rpm on a Brookfield rotational viscometer, and wherein the spray actuator has a de Laval nozzle.

2. A system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator; and a composition in the container bag, the composition comprising a poloxamer at a concentration of 13%-24% (w/w), and wherein the spray actuator has a de Laval nozzle.

3. A system comprising: a dispensing container comprising a container body, a container bag, and a spray actuator, wherein the container body is pressurized to between about 2 bars and about 9 bars of pressure; and a composition in the container bag, the composition comprising: a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1% of the composition; b) citrate at a concentration of between about 0.1% to about 1% of the composition; and c) a poloxamer.

4. The system of claim 3 wherein the spray actuator is a de Laval nozzle.

5. The system of claims 1 , 2 or 4 wherein the de Laval nozzle has an orifice and the internal orifice width is about 0.3 mm.

6. The system of claim 5 wherein the orifice is square.

7. The system of any of the preceding claims wherein the container body is pressurized to between about 2 bars and about 9 bars of pressure.

8. The system of claim 7 wherein the container body is pressurized to between about 5 bars and about 9 bars of pressure.

9. The system of the preceding claims, wherein the poloxamer is at a concentration of between about 13% to about 24% of the composition.

10. The system of claim 9, wherein the poloxamer is at a concentration of between about 18% to about 22% of the composition.

11. The system of claim 10, wherein the poloxamer is at a concentration of between about 16% to about 20% of the composition.

12. The system of the preceding claims, wherein the poloxamer is selected from the group consisting of Poloxamer 407, Poloxamer 188, and Poloxamer 338;

13. The system of the preceding claims, wherein the poloxamer is a combination of Poloxamer 407, Poloxamer 188, and/or Poloxamer 338.

14. The system of claim 13, wherein the poloxamer is Poloxamer 407.

15. The system of preceding claims, wherein the composition further comprises a topical antimicrobial that is not a Poloxamer.

16. The system of claim 15, wherein the antimicrobial comprises: a) an ethylenediaminetetraacetic acid (EDTA) salt at a concentration of between about 0.001% to about 0.1% of the composition; and b) a citrate at a concentration of between about 0.1% to about 1% of the composition.

17. The system of claim 16, wherein the EDTA is the acid form or salt form that is disodium EDTA or tetrasodium EDTA.

18. The system of claim 16 or 17, wherein the citrate is sodium citrate or trisodium citrate.

19. The system of the preceding claims, wherein the composition further comprises a biguanide at a concentration of between about 0.01% to about 0.5% of the composition.

20. The system of the preceding claims, wherein the biguanide is polyhexamethylene biguanide (PHMB).

21. The system of the preceding claims, wherein the composition further comprises one or more ingredients selected from: purified water, a buffer, a stabilizing agent, a gelling agent, a surfactant, a herbal, a vitamin, a mineral, an extra cellular matrix, an antimicrobial, an antibiotic, and a pH adjuster.

22. The system of the preceding claims, wherein the composition further comprises an anti- infective compound selected from: DispersinB, alginate lyase, nisin, lactoferricin, serotransferrin, ovotransferrin, ovalbumin, ovomucoid, protamine sulfate, chlorohexidine, cetylpyridinium chloride, triclosan, silver sulfadiazine, benzalkonium chloride, hydrogen peroxide, citric acid, potassium citrate, 5-fluorouracil, cis-2-decenoic acid, DNase I, proteinase K, silver, gallium, bacteriocins, antimicrobial peptides and an enzyme that cleaves poly-B-1 ,6-N-acetylglucosamine.

23. The system of the preceding claims, wherein the composition further comprises glycerol at a concentration of between about 1% to about 10% of the composition.

24. The system of the preceding claims, wherein the spray actuator has a valve and wherein the valve is a bag-on-valve.

25. The system of the preceding claims, wherein the spray actuator has a dip tube.

26. The system of the preceding claims, wherein the gel with a viscosity of about 1 ,790 cP tp about 36,430 cP as measured at 25 C and 100 rpm on a Brookfield rotational viscometer with Poloxamers as the gellant.

27. The system of the preceding claims wherein the container bag has a capacity volume of between about 30 mL to about 300 mL.

28. A method of preparing the composition of the preceding claims, comprising the steps of: a. mixing together two or more of: purified water, anhydrous citric acid, the citrate, and the EDTA salt until a resulting mixture is substantially homogenous; b. cooling the resulting mixture until the resulting mixture is at a temperature of between about 2 degrees Celsius to about 20 degrees Celsius; c. mixing one or both of the poloxamer and a glycerol into the resulting mixture until the resulting mixture is homogenous.

29. The method of claim 28 further comprising adding a biguanide to the resulting mixture.

30. The method of claims 28 or 29, further comprising storing the resulting mixture at room temperature.

31. A method of preparing the system of claims 1 to 27, comprising the steps of: a. pressurizing the container body; b. inserting the container bag into the container body under pressure; and c. filling the container bag under pressure inside the container body thereby further pressurizing the dispensing container.

32. The method of claim 31, wherein a propellant is held within a remaining space between the container body and the container bag and squeezes the composition through the spray actuator after the spray actuator is engaged, thereby releasing the composition through the spray actuator.

33. The method or system of the preceding claims, wherein the composition is used to prevent or treat a wound infection.

34. The method of claims 34 to 35, wherein the method is used to treat one or more of humans, domestic animals, farm animals, zoo animals, pet animals, dogs, horses, cats, cattle, pigs, goats and sheep.

35. The system or method of the preceding claims wherein the composition is thermoreversible.

36. The system or method of claim 35 wherein the composition solidifies into a gel formulation upon contact with a surface having a temperature of human skin.

37. The system or method of claim 36 wherein the gel becomes a washable liquid by application of cold water to the gel.