Semi-solid formulations of deferoxamine for the treatment of radiation therapy burns

Abstract

Described herein are semi-solid formulations comprising a gelling agent, solubilizer, and deferoxamine or a pharmaceutically acceptable sale thereof that can be used to prevent or mitigate skin injuries incurred during radiation therapy. In certain examples the formulations may be applied before radiation exposure to one or more of skin at, adjacent to, or between entry and exit sites of a beam of radiation configured to be directed at or through a patient's body.

Description

SEMI-SOLID FORMULATIONS OF DEFEROXAMINE FOR THE TREATMENT OF RADIATION THERAPY BURNSCLAIM OF PRIORITY

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 601,081 entitled SEMI-SOLID FORMULATIONS OF DEFEROXAMINE FOR THE TREATMENT OF RADIATION THERAPY BURNS filed on November 20, 2023, the contents of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.BACKGROUND

[0003] Deferoxamine or a pharmaceutically acceptable salt thereof is an active pharmaceutical ingredient. DFO has been shown to have preclinical success in the treatment and prophylaxis of diabetic and sickle cell ulcers, in addition to utility with radiation-injured bone and skin fibrosis. DFO has previously been used in formulations, such as patches, that could be utilized for transdermal treatment, but needs remain for a topical DFO treatment that can be used for effective treatment of skin injuries such as radiation bums.SUMMARY OF THE DISCLOSURE

[0004] In one aspect, there is described a system for a composition for the prevention of radiation therapy related injury, including: a gelling agent; a solubilizer; and deferoxamine (DFO) or a pharmaceutically acceptable salt thereof, in which the composition is a semi-solid formulation.

[0005] In certain examples, the gelling agent may include hydroxyethylcellulose, carbomer, hydroxylpropylcellulose or other gelling agents and polymers with thickening and gelling properties (e.g. xanthan gum, guar gum, methylcellulose, hydroxypropyl methylcellulose, acrylates / C10-30 alkyl acrylate crosspolymer, etc).

[0006] In certain examples, the gelling agent may include hydroxyethylcellulose.

[0007] In certain examples, the pharmaceutical vehicle may include Transcutol or other agents with similar properties, e.g. solubilizing, enhancing drug permeation, low volatility, hygroscopicity, compatibility with hydrophilic and hydrophobic excipients.

[0008] In certain examples, the composition may include a gel, lotion or cream.

[0009] In certain examples, the composition may include a gel.

[0010] In certain examples, the composition may be clear, opaque or colored.

[0011] In certain examples, the composition may have a viscosity of about 1,000 cP -100,000 cP.

[0012] In certain examples, the composition may have a concentration of about 0.1-5% gelling agent as weight percent of the composition.

[0013] In certain examples, the composition may have a concentration of about 1-5% gelling agent as weight percent of the composition.

[0014] In certain examples, the composition may have a concentration of about 25-55% solubilizer as weight percent of the composition.

[0015] In certain examples, the composition may have a concentration of about 30-50% solubilizer as weight percent of the composition.

[0016] In certain examples, the composition may have a concentration of about 5-15% DFO or a pharmaceutically acceptable salt thereof.

[0017] In certain examples, the composition may include preservatives (e.g., benzyl alcohol, phenoxyethanol, sodium benzoate, benzoic acid, citric acid, etc.), pH adjusters (e.g. sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, etc.), co-solvents (e.g. propylene glycol, butylene glycol, polyethylene glycol), colorants, fragrance and other additives.

[0018] In certain examples, the composition may be configured to release at least about 70% of DFO or a pharmaceutically acceptable salt thereof over 24 hours.

[0019] In yet other aspects, there is a method of manufacturing a composition for the prevention of radiation therapy related injury, including: providing a gelling agent; providing a pharmaceutical vehicle; providing DFO or a pharmaceutically acceptable salt thereof; and mixing the gelling agent, solubilizer and the DFO or a pharmaceutically acceptable salt thereof to form a semi-solid formulation.

[0020] In certain examples of this method, providing a gelling agent may include providing a gelling agent at a concentration of about 0.1-5% gelling agent as weight percent of the composition.

[0021] In certain examples of this method, providing a gelling agent may include providing a gelling agent at a concentration of about 1-5% gelling agent as weight percent of the composition.

[0022] In certain examples of this method, providing a solubilizer may include providing a solubilizer at a concentration of about 25-55% solubilizer as weight percent of the composition.

[0023] In certain examples of this method, providing a solubilizer may include providing a solubilizer at a concentration of about 30-50% solubilizer as weight percent of the composition.

[0024] In certain examples of this method, providing DFO or a pharmaceutically acceptable salt thereof may include providing DFO or a pharmaceutically acceptable salt thereof at a concentration of about 5-15%.

[0025] In certain examples of this method, providing a solubilizer comprises providing Transcutol.

[0026] In certain examples of this method, providing a gelling agent may include providing hydroxy ethylcellulose.

[0027] In certain examples of this method, mixing the gelling agent, solubilizer and the DFO or a pharmaceutically acceptable salt thereof may include mixing using one or more of cold mixing, high shear mixing, vacuum mixing, mechanical mixing, extrusion and blending.

[0028] In still other aspects, there is a method of mitigating or preventing a skin injury on a patient caused by radiation therapy, including: contacting the skin with a composition having a gelling agent, a solubilizer, and DFO or a pharmaceutically acceptable salt thereof prior to the patient receiving radiation therapy, in which the skin injury is mitigated or prevented.

[0029] In certain examples of this method, contacting the skin with the composition having a gelling agent, a solubilizer, or other excipients and DFO or a pharmaceutically acceptable salt thereof occurs 1-120 hours prior to 1-120 hours after the patient receives radiation therapy or radiation injury.

[0030] In still other aspects, there is a method of treating a skin injury on a patient caused by radiation therapy which includes: contacting the skin with a composition comprising a gelling agent, a solubilizer, and DFO or a pharmaceutically acceptable salt thereof prior to the patient receiving radiation therapy, thereby improving a condition of the skin.

[0031] In certain examples of this method, contacting the skin with the composition having a gelling agent, a solubilizer, or other excipients and DFO or a pharmaceuticallyacceptable salt thereof occurs 1-120 hours prior to 1-120 hours after the patient receives radiation therapy or radiation injury.

[0032] In certain examples of this method, contacting the skin with the composition includes applying the composition to irradiated skin daily, twice a day, three times a day, four times a day, every other day, every three days, etc.

[0033] In certain examples of this method, contacting the skin with the composition occurs immediately after radiation therapy.

[0034] In certain examples of this method, contacting the skin with the composition occurs 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 1-2 weeks, 2 weeks, 2-4 weeks, etc. after the patient received radiation therapy.

[0035] In certain examples of this method, contacting the skin with the composition results in one or more of improved skin elasticity, improved perfusion, improved dermal thickness, improved collagen density, improved 8-isoprostane assays, improved retention of desired collagen ultrastructure.

[0036] In certain examples of this method, an improvement may occur within 1 day, 2, days, 3 days, 4 days, 5 days, 6 days, 1 week, 1-2 weeks, 2 weeks, 2-3 weeks 3 weeks 3-4 weeks, etc.

[0037] In still other aspects, there is a method of mitigating or preventing a skin injury on a patient caused by radiation therapy, including: pre-treating one or more of: skin at or adjacent to an entry site, exit site, and in between the entry site and exit site on a body of a patient undergoing radiation exposure with a composition having a gelling agent, a solubilizer and deferoxamine (DFO); applying a beam of radiation directed to travel along a path from the entry site to the exit site on the body of the patient; and preventing or mitigating radiation exposure-related injury of the skin on the body of the patient via the composition.

[0038] In certain examples of this method, the radiation exposure includes external beam radiation configured for diagnostic, imaging, or treatment purposes.

[0039] In certain examples of this method, the radiation exposure includes brachytherapy and proton beam therapy, further in which the composition is only applied to one or more of: the skin at or adjacent to the entry site and skin at or adjacent to a region between the entry site and a target of the brachytherapy or proton beam therapy.

[0040] In certain examples of this method, the exit site on the body of the patient includes sweat glands and a urethral opening.BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The novel features of the invention are set forth with particularity in the claims that follow. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0042] FIG. 1 illustrates an exemplary hydrophobic-based ointment formulation to create a water-in-oil emulsion and associated components.

[0043] FIG. 2 shows in vitro DFO release, by dissolution, from DFO-patches.

[0044] FIGS. 3A and 3B shows in vitro DFOm release from formulation 9.

[0045] FIGS. 4 A and 4B illustrate the gradual release of DFOm over a period of 5 days during testing.

[0046] FIGS. 5 A and 5B demonstrate that DFOm release from the patch formulation reaches saturation at approximately 24 hours.

[0047] FIG. 6 shows in-vitro DFOm release from formulation 19.

[0048] FIGS. 7 A and 7B summarize an experimental Fe(III)-chelating Colorimetric Qualitative Test assay.

[0049] FIG. 8 illustrates results of in vitro drug release testing conducted on the lOOmg / g gel formulation of DFOm.

[0050] FIG. 9 illustrates the composition in use on a patient receiving radiation treatment.

[0051] FIG. 10 is a flow chart illustrating a method of using the composition to prevent or mitigate radiation exposure-related injury of the skin.DETAILED DESCRIPTION

[0052] Disclosed herein are semi solid formulations of deferoxamine (DFO) or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm)). These formulations can be used for the treatment or prevention of bums, such as radiation-induced fibrosis (RIF) incurred as a result of radiation therapy (e.g., external beam radiation, proton therapy, etc.) or other radiation injuries (e.g. sunburn).

[0053] DFO therapy has been used in clinical settings (e.g., for hemochromatosis treatment). More recently, a patch formulation of DFO has been developed, allowing DFO to be delivered in a more focused, localized manner. In the case of radiation-induced fibrosis, a patch formulation of DFO may not be a suitable vehicle for delivery of DFO as irradiated skin may experience significant desquamation following radiation exposure, which can make the application of adhesive ineffective and / or painful for a patient. Additionally, radiationtreatment may be applied in an anatomical area with significant contours, such as the head, neck, breast, and underarm, making application of an adhesive patch difficult. Finally, a patch may be harder to apply specifically to surgical incision and wounds on irradiated skin.

[0054] Described herein are semi solid formulations of DFO that can obviate the need for adhesive patches while allowing for a comfortable and focused DFO treatment of, for example, irradiated skin.

[0055] Topical and transdermal delivery is ideal in the setting of dermatologic disorders or injuries, avoiding the need for repeated intravenous access and targeting delivery more than an oral administration route. Transdermal delivery of DFO is complicated by a high atomic mass and hydrophilicity, which prevents penetration of the lipophilic stratum corneum and thus, different strategies have been implemented to augment topical therapy.

[0056] Advantageously, compositions described herein have been found to facilitate effective penetration of DFO or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm) into the skin. Composition described herein are also found to not affect the efficacy of the radiation therapy. Finally, the compositions described herein are found to form a visibly and texturally suitable material in which the active ingredient remains stable.

[0057] The compositions described herein comprise DFO or a pharmaceutically acceptable salt thereof (e.g., DFOm). In some embodiments, the concentration of the DFO or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm) in the compositions described herein is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v or v / v.

[0058] In some embodiments, the concentration of the DFO or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm) is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%,0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0059] In some embodiments, the concentration of the DFO or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm) is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v. v / v.

[0060] In some embodiments, the concentration of the DFO or a pharmaceutically acceptable salt thereof (e.g., deferoxamine mesylate (DFOm) is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0061] The DFO compositions described herein are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per application, and from 5 to 40 mg per application are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the DFO is administered, the subject to be treated, the skin area to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0062] A composition described herein typically contains an active ingredient comprising DFO or a pharmaceutically acceptable salt and / or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including but not limited inert soliddiluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0063] In some embodiments, the composition comprises DFO or a pharmaceutically acceptable salt thereof, a gelling agent (e.g., hydroxyethyl cellulose), and a solubilizer (e.g., Transcutol).

[0064] The compositions disclosed herein can take the form of topically spreadable compositions. Kits that include the compositions described herein are also contemplated. In certain embodiments, the composition is comprised in a container. The container can be a bottle, dispenser, or package. The container can dispense a pre-determined amount of the composition. In certain aspects, the compositions are dispensed in a spray, dollop, or liquid. The container can include indicia on its surface. The indicia can be a word, an abbreviation, a picture, or a symbol.

[0065] As noted above, in some embodiments, the composition can be formulated as a topical skin composition. The composition can have a dermatologically acceptable vehicle or carrier for the DFO active ingredient. The composition can further include a moisturizing agent or a humectant, emollient, a surfactant, a silicone containing compounds, a UV agent, an oil, and / or other ingredients known in the art. As the composition may be applied to the face, neck, scalp, arms or other skin areas, moisturizing components may be particularly useful. The composition can be a lotion, cream, gel, serum, emulsion (e.g., oil-in-water, water-in-oil, silicone-in-water, water-in-silicone, water-in-oil-in-water, oil-in-water, oil-in- water-in-oil, oil-in-water-in-silicone, etc.), ointments, milk, paste, etc. The composition can be formulated for topical skin application at least 1, 2, 3, 4, 5, 6, 7, or more times a day during use. In some embodiments, the compositions described herein can be storage stable or color stable, or both. It is also contemplated that the viscosity of the composition can be selected to achieve a desired result, e.g., depending on the type of composition desired, the viscosity of such composition can be from about 1,000 cP to 100,000 cP or any range or integer derivable therein.

[0066] In some embodiments, the composition can have a pH of about 4.5 to about 5.5. In other aspects, the pH can be in the range of 4.5 to 7.5.

[0067] The compositions described herein can also include any one of, any combination of, or all of the following additional ingredients: water, a moisturizing agent, a preservative, a thickening agent, a pH adjuster, a co-solvent a silicone containing compound, an essential oil, a structuring agent, a colorant, a fragrance, a vitamin, additional pharmaceutical ingredient, or an antioxidant, or any combination of such ingredients or mixtures of such ingredients. In certain embodiments, the composition can include at least two, three, four, five, six, seven,eight, nine, ten, or all of these additional ingredients identified in the previous sentence. The amounts of such ingredients can range from 0.0001% to 99.9% by weight or volume of the composition, or any integer or range in between.

[0068] Compositions described herein can be formulated into preparations in semi-solid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, slurries, ointments, pastes, emulsions.

[0069] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0070] Extended Release Properties. In some variations, the extended release formulation may release the DFO compound over a period of about 4 hr, about 8 hr, about 12 hr, about 24 hr, about 48 hr or more. In some variations, the extended release formulation may be a controlled release formulation where the DFO or a pharmaceutically acceptable salt thereof is released in a predetermined pattern over a period of time, which may be about 2 hr, about 4 hr, about 8 hr, about 12 hr, about 24 hr, about 48 hr or more. In some embodiments, about 80% of the DFO compound is released at the 24 hour mark (or about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, etc.).

[0071] Stabilizer. Owing to its hydrophilicity and tendency to crystallize, DFO compounds can be especially well suited for delivery when complexed with Polyvinylpyrrolidone (PVP). PVP is known to stabilize drugs in an amorphous form and to promote permeation of hydrophilic molecules. PVP may also be included in the extended release formulation to stabilize the DFO molecule within the reverse micelles. For example, PVP may be present at a concentration of from about 0.1 w / w% to about 25 w / w%, about 7 w / w% to about 20 w / w%, about 8 w / w% to about 18 w / wt%, about 10 w / w% to about 16 w / w%, about 10 w / w%, about 12 w / w%, about 14 w / w%, about 16 w / w%.

[0072] Other molecules for prevention of crystallization. The formulations may alternatively or additionally comprise other molecules to prevent crystallization of the DFO within the formulation, which may prevent crystallization within a vehicle or within thereverse micelles within a vehicle such as a lotion, gel, film or patch. They may include surfactants, emollients, fatty alcohols, fatty esters and the like. Such additives include, without limitation, one or more additives selected from octyl dodecanol at a concentration of from about 1.5 to about 4% w / w of polymer; dextrin derivatives at a concentration of from about 2% to about 5% w / w of polymer; polyethylene glycol (PEG) at a concentration of from about 2% to about 5% w / w of polymer; polypropylene glycol (PPG) at a concentration of from about 2% to about 5% w / w of polymer; mannitol at a concentration of from about 2% to about 4% w / w of polymer; Pol oxamer 407, 188, 401 and 402 at a concentration of from about 5% to about 10% w / w of polymer; and Pol oxamines 904 and 908 at a concentration of from about 2% to about 6% w / w of polymer. These compounds may also aid in penetration of the DFO or a pharmaceutically acceptable salt thereof into the skin.

[0073] The composition may comprise one or more gelling agents, including but not limited to, carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate / alkylacrylate copolymers, polyacrylamides, polysaccharides, such as hydroxypropylcellulose, natural gums and clays, and, as lipophilic gelling agents, representative are the modified clays such as bentones, fatty acid metal salts such as aluminum stearates and hydrophobic silica, or ethylcellulose (i.e., hydroxyethylcellulose or sodium carboxymethylcellulose 7H 4F) and polyethylene.

[0074] The matrix, e.g., a biodegradable polymer, may be present in the lotion, gel, or another semi-solid formulation in a concentration from about 25 %w / w to about 75 %w / w, about 35 %w / w to about 65% w / w, about 40%w / w to about 60%w / w, about 45%w / w to about 55%w / w, about 45%w / w, about 48%w / w, about 50 % w / w, about 51 % w / w, about 52%w / w, about 53%w / w, about 54%w / w, or about 55%w / w. In some embodiments, a lotion or cream may not include a matrix, but may include any other suitable vehicle or components as described herein.

[0075] Permeability enhancer. In some embodiments, the formulation may include a permeation enhancer, e.g. transcutol (diethylene glycol monoethyl ether), propylene glycol, dimethylsulfoxide (DMSO), menthol, 1 -dodecyl azepan -2-one (Azone), 2-nonyl-l,3- dioxolane (SEPA 009), sorbitan monolaurate (Span20), and dodecyl-2- dimethylaminopropanoate (DDAIP), which may be provided at a weight / weight concentration of from about 0.1% to about 80%, from about 20% to about 60%, about 30% to about 50%, about 35%-45%, about 40%, etc.

[0076] Cream, gel or lotion formulations. As described, in some variations, the DFO composition may be formulated in a gel or lotion composition (e.g., formulation). The formulation may include reverse micelles and the extended release components of theformulation as described herein, and may include any of the additional components as described herein such as stabilizers, permeation enhancers, crystallization inhibitors, and the like. The lotion or cream formulation may include a pharmaceutically acceptable vehicle to act as a diluent, dispersant or carrier, so as to facilitate its distribution and uptake when the formulation is applied to the skin. Vehicles other than or in addition to water can include liquid or solid emollients, solvents, humectants, thickeners and powders.

[0077] For topical delivery, deferoxamine embedded within a poloxamer gel (Pluronic® F127) provides an efficient and targeted means of delivery. Hydrogels responsive to external stimuli such as pH or temperature may be included. Hydrogels are based on different polysaccharides, such as alginate, cellulose, chitosan, and dextran, which in turn respond to different environmental stimuli. Specifically, a chitosan based hydrogel can be manipulated to respond to temperature and pH in various applications. Likewise, pol oxamers such as Pl 88 can be employed as a drug delivery gel and has demonstrated cytoprotective effects in animal models.

[0078] The pharmaceutically acceptable vehicle may be present in 5% to 99.9%, preferably from 25% to 80% by weight of the composition, and can, in the absence of other adjuncts, form the balance of the composition.

[0079] The compositions may be in the form of aqueous, aqueous / alcoholic or oily solutions; dispersions of the lotion or serum type; anhydrous or lipophilic gels; emulsions of liquid or semi-liquid consistency, which are obtained by dispersion of a fatty phase in an aqueous phase (O / W) or conversely (W / O); or suspensions or emulsions of smooth, semisolid or solid consistency of the cream or gel type. These compositions are formulated according to the usual techniques as are well known to this art.

[0080] When the DFO molecules are formulated in an emulsion, the proportion of the fatty phase may be from about 5% to about 80% by weight, and preferably from about 5% to about 50% by weight, relative to the total weight of the composition. Oils, emulsifiers and co-emulsifiers incorporated in the composition in emulsion form are selected from among those used conventionally in the cosmetic or dermatological field. The emulsifier and emulsifier may be present in the composition at a proportion from about 0.3% to about 30% by weight, or about 0.5% to about 20% by weight, relative to the total weight of the composition.

[0081] When the DFO molecules are formulated as an oily solution or gel, the fatty phase may constitute more than about 90% of the total weight of the composition. Exemplary oils which may be used according to this invention include mineral oils (liquid petrolatum), plant oils (liquid fraction of karite butter, sunflower oil), animal oils (perhydrosqualen(e), syntheticoils (purcellin oil), silicone oils (cyclomethicone) and fluoro oils (perfluoropoly ethers). Fatty alcohols, fatty acids (stearic acid) and waxes (paraffin wax, carnauba wax and beeswax) may also be used as fats.

[0082] Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from about 12 to about 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, squalene and isoparaffins.

[0083] The DFO molecule may be present within a cream, gel or lotion at a concentration of about O. lmM, about ImM, about lOnM, about lOOmM, about 500 mM, about lOOOmM, or any value therebetween.

[0084] In some embodiments, the formulation comprises a water-in-oil emulsion. A water-in-oil emulsion is an emulsion system in which the water phase is dispersed in the oil continuous phase. Emulsifiers, including natural polymers (polysaccharides, proteins, and so on) and chemical surfactants can be used to stabilize emulsions by reducing the interfacial tension between two phases.

[0085] FIG. 1 illustrates an exemplary hydrophobic-based ointment formulation to create a water-in-oil emulsion and associated components 100. Shown here is water-oil emulsion 102 including a water phase 106 surrounded by an oil phase 104. In certain examples, there is a hydrophilic interaction 108 between oil phase 104 and water phase 106, which may be at an interface 110 with hydrophobic active pharmaceutical ingredients (APIs 112) in the water phase 106 and lipophilic surfactant 114. In some embodiments, the oil hydrophobic base comprises paraffin and / or isopropyl myristate, which have been used in topical delivery formulations, such as reverse micelles or emulsions. Oil based ointments can be used to treat radiation bums as they can create an occlusive protective layer over the skin and prevent heat and water loss.

[0086] Plurol Oleique has been used in DFO containing patches, for example, as described in PCT Application No. PCT / US2019 / 052192 entitled IRON CHELATED COMPOUNDS FOR TREATING AESTHETIC SKIN CONDITIONS, filed September 20, 2019, the entire contents of which are incorporated by reference herein.

[0087] FIG. 2 shows in vitro DFO release, by dissolution, from DFO-patches 200. DFO- patches may be per standard manufacturing processes including TM10419 210, TM10422 212, and under varying conditions including: no sonication 206 and without Plurol Oleique (P.O.) 208. As shown here, the removal of Plurol® Oleique leads to faster release 204 of DFO (expressed as % DFOm 202) over time 203 from the patches compared to other conditions.

[0088] Example 1

[0089] Formulations 1-4 prepare using water in oil emulsions

[0090] Reagents:

[0091] PEG-8 caprylic / capric glycerides (Labrasol) - surfactant

[0092] Polyglyceryl-6 dioleate (Plurol® Oleique, P.O.) - surfactant

[0093] Liquid paraffin (L.P.) - oil phase

[0094] Isopropyl myristate (IPM) - oil phase

[0095] Water for Injection (WFI)

[0096] Deferoxamine mesylate (DFOm)

[0097] Preparation Method: The DFOm solution was prepared in WFI at concentration of 50mg / mL or 250 mg / mL. The hydrophobic base and DFO solution were mixed in a ratio of1 : 1, surfactant was added drop by drop to the oil / water mixture while vortexing. The samples were allowed to equilibrate for a minimum of 72h, then examined visually for phase separation behavior with or without ultracentrifugation.Table 1: Formulations 1-4 composition

[0098] As shown in Table 1, formulations demonstrating more stability and less phase separation may be desired.

[0099] Example 2[000100] Formulations 6 and 9 were prepared using a cold processing formulation approach[000101] Reagents:[000102] Polyglyceryl-3 diisostearate (Plurol Diisostearique, P.D.)- emulsifier[000103] Polyglyceryl-6 dioleate (Plurol Oleique, P.O.) - surfactant[000104] Mineral oil- oil phase [000105] Water for Injection (WFI)[000106] Deferoxamine mesylate (DFOm)[000107] Sodium Chloride (NaCl)[000108] Preparation Method: The aqueous phase (DFOm, NaCl, H20) and oil phase (P.D.,P.O. and mineral oil) were prepared separately and then mixed together using an overhead mixer for 40 minutes, followed by ultrasonication for 15 min.Table 2: Formulation 6 (DFOm-170mg / g) composition.Table 3: Formulation AZ9 (DFOm - 100 mg / g) composition [000109] Formulations 6 and 9 exhibited good consistency with some phase separation.The texture was thick.[000110] Formulation 9 was tested for drug release using a Franz cell system. The cream was evenly spread over a 0.45pm PES membrane and placed on a Franz cell. The releasestudy into receptor medium PBS was carried for 48h at 32 °C. After that, samples were analyzed by an HPLC method, specific to the API.[000111] FIGS. 3 A and 3B show in vitro DFOm release from formulation 9 300-301.[000112] As shown here, DFOm 304 reaches saturation at approximately 6 hours’ time 303. Within the first 24 hours, approximately 42% or approximately 23 mg / cm2 of DFOm is released percentage of cumulative drug release 312 and normalized cumulative drug release (mg / cmA2) 302, respectively, as shown by average plot line 306.[000113] Example 3[000114] Formulations 11-18 were prepared using the recipe from Formulation 9 with modifications to the mixing process, settings of mixer speed. It was found the mixing with a radial flow impeller providing high shear mixing at 3000 rpm for 30 minutes produced a homogenous, consistent and stable cream with thick texture (e.g., formulation 18).[000115] Formulation 18 preparation method: Aqueous phase (DFOm, NaCl, MgSO4, H20) and oil phase (P.D., P.D. and mineral oil) were prepared separately, mixed at 3000 rpm using the overhead mixer for 20 minutes (emulsification step) followed by mixing at lower speed ~ 500-1000 rpm for 10 minutes (homogenization step). Formulation 18 had a DFOm concentration of 30 mg / g.Table 4: Formulation AZ18 composition:Table 5: In vitro drug release settings:[000116] FIGS. 4 A and 4B illustrate the gradual release of DFOm over a period of 5 days during testing 400-401.[000117] FIG. 4A shows normalize average DROm release, mg / cmA2 404 over time 403 as shown by average plot line 406. Within the first 24 hours of time 403, approximately 10% or approximately 2 mg / cm2 of DFOm was released as normalized cumulative drug release 402. FIG. 4B shows average percentage cumulative DFOm release 414 over time 403 as shown by average plot line 406. By the end of 120 hours, the release reached approximately 74% cumulative drug release percentage 412 or approximately 12 mg / cm2.[000118] To further characterize the release profile parameters, the release of DFOm in W / O emulsion was compared to DFOm-patches (Lot TM10457, DFOm - 1 mg / cm2).[000119] FIGS. 5 A and 5B demonstrate that DFOm release from the patch formulation reaches saturation at approximately 24 hours 500-501.[000120] Within the initial 24-hour period of time 503, approximately 20% cumulative drug release 512 or approximately 0.2 mg / cm2 normalized cumulative drug release 502 of DFOm was released on average 514 / 504, respectively as shown by average plot line 506. Notably, there was significant variability among the samples, whereas the distribution of DFOm in the emulsion appeared more uniform. Consequently, using the release profile of the DFOm-patch formulation as a reference proved challenging due to the observed variability.[000121] Further embodiments were prepared configured to optimize the formulation to comprise a release rate between 12-24 hours.[000122] Example 4[000123] Propylene glycol (PG) was tested at a concentration of 1%, as indicated in an information update document. Formulations 19 and 20 were prepared using the aforementioned method, with the addition of PG to the water phase at a final concentration of 1%. However, no DFOm was released for these formulations in Franz cell condition with PBS (pH 7.4) receptor solvent and PES membrane at 32°C. Therefore, formulation 19 was retested for drug release with 30% ethanol in water as receptor solvent. At approximately 6, 24, and 51 hours, 1.1%, 13.4%, and 34.0% of DFOm was released, respectively.[000124] FIG. 6 shows in-vitro DFOm release from formulation 19 600.[000125] As shown here, in just over 50 hours of time 603, an average percentage 604 of cumulative drug release 602 for DFOm was just under 35%, as indicated by average plot line 606.[000126] FIGS. 7A and 7B summarize an experimental Fe(III)-chelating Colorimetric Qualitative Test assay 700 / 701.[000127] A modified Excella method based on chelation of Fe(III) ions by DFOm was used (adapted from an “Excella” colorimetric method). This colorimetric method involves a chemical reaction of a complex formation between Fe(III) ions and DFOm, which results in a color change to brown-dark brown, indicating the presence of active DFOm. As shown here, 5 ml of FeC13 solution in HC1 was added to 1g (or 1 ml) of a formulation including control-DFO 706 / 706’, FeC13 708 / 708’, blank 710 / 710’, AZ18 712 / 712’, AZ19 714 / 714’ and AZ21 716 / 716’ under non-mixed conditions 702 as shown in FIG. 7A and under mixed conditions 704 as shown in FIG. 7B, respectively. After adding FeC13 solution under nonmixed conditions 702, the color change is observed only in the control sample DFOm 706, which may be 30 mg / g concentration. However, under mixing conditions 704, the color change is observed in all formulations containing DFOm including DFO 706’, AZ18 712’, AZ19 714’ and AZ21 716’, thus indicating that DFO 706 / 706’ is active in all formulations 71277147716’ under mixed conditions 704.[000128] Extensive experimentation with different types of membranes (PES, silicone, PTFE, nylon, and Strat-M) and different receptor media (water, citrate buffer pH5.5, PBS pH7.4, 30 / 70 EtOH / H2O, and 30 / 70 EtOH / Citrate buffer pH 5.5) was conducted. It was found that conditions of 30 / 70 EtOH / H2O as the receptor medium and PES membrane provide a favorable and suitable environment for DFO release using the in vitro release method. PES is a hydrophilic membrane, and ethanol helps DFO release into the medium. [000129] Transcutol P was found to be an effective delivery vehicle for DFOm. Transcutol P can increase drug solubility in the vehicle, decrease drug charge through a solvent effect, enhance drug solubility and partitioning in the stratum comeum, and maintain hydrated dynamics in the stratum corneum without disrupting the lipid bilayer structures. Utilizing Transcutol P as a delivery vehicle, allowed improvement of the penetration and permeation of DFOm, leading to enhanced efficacy and therapeutic outcomes.[000130] Initially, the compatibility of DFOm with Transcutol P (TP) was assessed. A DFOm solution in water, with a final concentration of 100 mg / mL, was mixed with TP at final concentrations of 25%, 30%, and 40%. All three mixtures appeared clear, indicating that TP did not adversely affect the solubility of DFOm.[000131] Example s[000132] Subsequently, various polysaccharides were evaluated as potential gelling agents, including hydroxyethylcellulose, carbomer, and hydroxypropylcellulose. The DFOm and polysaccharide solutions were prepared separately, using the concentrations provided in table 6, and mixed together using vortexing. The formulations were visually assessed for texture and viscosity. Among the tested polysaccharides, hydroxy ethylcellulose yielded a clear gel with favorable texture and high viscosity, making it a suitable choice for the intended indication.Table 6: Formulation composition for selecting the gelling agent. [000133] Example 6[000134] For preclinical testing, formulations with DFOm concentration at 50mg / g and 100 mg / g of gel were prepared per the details provided below.Table 7: Formulation composition for varying the DFOm concentration.[000135] Preparation method[000136] Each formula contains:[000137] Transcutol P (40%)[000138] Hydroxyethyl cellulose (2%)[000139] Production of Hydroxy ethyl cellulose (4%)[000140] 1. Place Falcon tube on balance and tare balance[000141] 2 Deliver 1.2 g Hydroxy ethyl cellulose into tube[000142] 3. Deliver 38.4 g HPLC water into tube[000143] 4. Set to rotate over night[000144] Production of placebo cream[000145] 1. Place Falcon tube on balance and tare balance[000146] 2. Deliver 3.0 g of HPLC water into tube[000147] 3. Deliver 12.0 g of Transcutol P[000148] 4. Allow to cool[000149] 5. Deliver 15.0 g of Hydroxy ethyl cellulose directly into Tube[000150] 6. Set to rotate over night[000151] Production of 50 mg / g cream[000152] 1. Place Falcon tube on balance and tare balance[000153] 2. Deliver 1.5 g of HPLC water into tube[000154] 3. Deliver 12.0 g of Transcutol P[000155] 4. Wait 1 min to allow to cool[000156] 5. Deliver 1.5 g of DFOm[000157] 6. Swirl to mix the solution[000158] 7. Deliver 15.0 g of Hydroxy ethyl cellulose directly into Tube[000159] 8. Set to rotate over night[000160] Production of 100 mg / g cream[000161] 1. Place Falcon tube on balance and tare balance[000162] 2. Deliver 12.0 g of Transcutol P[000163] 3. Deliver 3.0 g of DFOm[000164] 4. Swirl to mix the solution[000165] 5. Deliver 15.0 g of Hydroxy ethyl cellulose directly into Tube[000166] 6. Set to rotate over night[000167] FIG. 8 illustrates results of in vitro drug release testing conducted on the lOOmg / g gel formulation of DFOm 800.[000168] As shown here, 46% of DFOm (%) 802 was released 804 into the water receptor media after 6 hours’ time 803. By the 24.5-hour mark, 83% of DFOm had been released, as shown by plot line 806. This release profile is considered favorable as it aligns with the patient's requirement to administer treatment once a day.[000169] The stability of DFO gel formulations was assessed according to specification, as indicated in tables 8 and 9 for 50 mg / g and 100 mg / g DFO gels, respectively. The formulations demonstrated stability during 12 months of storage under controlled conditions at 2°-8°C.Table 8: Summary of Results for Stability of 50mg / g DFO gelTable 9: Summary of Results for Stability of lOOmg / g DFO gel[000170] It was found that DFO gel at a concentration of lOOmg / g exhibited comparable efficacy to the DFO-patch in treating radiation burns.[000171] Methods of use [000172] An exemplary method of use of the composition described herein comprises spreading the composition on a user’s skin in a vicinity of a radiation therapy treatment area prior to receiving radiation therapy, wherein the DFO or a pharmaceutically acceptable salt thereof is released from the composition and penetrates into the skin.[000173] An exemplary method of use of the composition described herein comprises spreading the composition on a user’s skin in a vicinity of a radiation therapy treatment area prior to receiving radiation therapy, wherein the DFO or a pharmaceutically acceptable salt thereof is released from the composition and penetrates into the skin to help prevent bums during the radiation therapy.[000174] FIG. 9 illustrates the composition in use on a patient receiving radiation treatment 900.[000175] As shown here, the composition that releases DFO or a pharmaceutically acceptable salt thereof and penetrates the skin may be applied at and / or adjacent to an entry site 903 / 909 and an exit site 906 / 911 corresponding to a beam of radiation 902 / 908 going into or through the patient’s body to target a mass or area of interest 904 / 910 for imaging / diagnosis or treatment. Furthermore, the composition may be applied along or adjacent to a region between 907 / 912 the entry sites 903 / 909 and the exit sites 906 / 911 corresponding to the beam of radiation 902 / 908 going into or through the patient’s body, respectively.[000176] In various examples, the composition may be applied before radiation exposure in various methods of radiation use including external beam radiation as shown here, as well as brachytherapy or internal radiational therapy which may be delivered through catheters, as well as proton beam therapy in which protons are beamed only to the tumor and the beam does not exit the patient’s body. In examples of brachytherapy and proton beam therapy, the composition may not be applied at or adjacent to exit sites 906 / 911 on the patient’s body as the radiation beam may not be configured to exit the patient’s body. In such instances, the radiation exposure may be configured to leave the patient’s body over time via bodily fluids such as sweat and urine.[000177] FIG. 10 is a flow chart illustrating a method of using the composition to prevent or mitigate radiation exposure-related injury of the skin 1000.[000178] Method 1000 begins at block 1002 with pre-treating one or more of: skin at or adjacent to an entry site, exit site, and in between the entry site and exit site on a body of a patient undergoing radiation exposure with a composition having a gelling agent, a solubilizer and deferoxamine (DFO).[000179] Method 1000 continues at block 1004 with applying a beam of radiation directed to travel along a path from the entry site to the exit site on the body of the patient.[000180] Method 1000 concludes at block 1006 with preventing or mitigating radiation exposure-related injury of the skin on the body of the patient via the composition.[000181] An exemplary method of use of the composition described herein comprises spreading the composition on a user’s skin in a vicinity of a radiation therapy treatment area after receiving radiation therapy, wherein the DFO or a pharmaceutically acceptable salt thereof is released from the composition and penetrates into the skin to help heal skin damaged during the radiation therapy.[000182] The efficacy of DFO creams has been tested including determining whether the DFO creams described herein would be effective in treating irradiated, unwounded skin. It was found that mice that had undergone radiation treatment to the dorsum followed by four weeks of recovery were treated with various formulations of DFO, including DFO 50 mg / g cream DFO 100 mg / g cream, soluble DFO injections, DFO patch, control crem, or no treatment, daily for two weeks.[000183] This demonstrates that the 50 mg / g and 100 mg / g formulations of DFO described herein are both effective in administering DFO to experience the beneficial effects. Both the 50 mg / g and 100 mg / g formulations outperformed a control, demonstrating improved gross skin elasticity and cutaneous perfusion. The semi solid formulations were tested against a DFO patch and a soluble, injectable formulation. The 50 mg / g formulation was comparable to the injectable formulation across a number of metrics (including in vivo elasticity, dermal thickness, collagen density, and 8-isoprostane assays) and outperformed the injectable formulation, in some areas, including improved perfusion. The 100 mg / g formulations resulted in comparable treatment of irradiated skin as that of a previously tested DFO patch, when it came to collagen density, dermal thickness, 8-isprostane staining, and retention of basket-weave collagen ultrastructure and demonstrated superior results with regards to perfusion and CD31 expression. These superior results could indicate an improved angiogenic response with improved retention of the cream within the dermal and subcutaneous tissue compared the DP.[000184] It was also found that the semi-solid formulations of DFO, in particular the 100 mg / g formulation, led to a downregulation of CCL7 levels, potentially indicating a mechanism by which DFO treats radiation induced fibrosis.[000185] The efficacy of semi-solid DFO formulation in irradiated, wounded skin has also been assessed. Excisional wounds were created on the irradiated dorsum of mice and treated with either DFO 100 mg / g cream, a DFO patch, control cream, and untreated. The 100 mg / g formulation of DFO was found to be comparable to the DFO patch across measures including cutaneous perfusion, scar stiffness and speed of wound healing. The 100 mg / g formulation of DFO was found to outperform the DFO patch according to several metrics, including speed of wound healing, doppler perfusion at wound closure, and CD31 immunofluorescence.[000186] Further, it was also found that DFO treatment of chronically irradiated wounds results in a thicker dermis with more collagen deposition.[000187] Thus, the semi solid formulation of DFO may be effective in treating irradiated and excisionally wounded, irradiated skin. In chronically irradiated skin the 100 mg / g DFO semi solid formulation was found to improve vascularity more than any other DFO formulation studied to date.[000188] It should be appreciated that all combinations of the foregoing concepts and additional concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein and may be used to achieve the benefits described herein.[000189] The process parameters and sequence of steps described and / or illustrated herein are given by way of example only and can be varied as desired. For example, while the steps illustrated and / or described herein may be shown or discussed in a particular order, these steps do not necessarily need to be performed in the order illustrated or discussed. The various example methods described and / or illustrated herein may also omit one or more of the steps described or illustrated herein or include additional steps in addition to those disclosed.[000190] When a feature or element is herein referred to as being "on" another feature or element, it can be directly on the other feature or element or intervening features and / or elements may also be present. In contrast, when a feature or element is referred to as being "directly on" another feature or element, there are no intervening features or elements present. It will also be understood that, when a feature or element is referred to as being "connected", "attached" or "coupled" to another feature or element, it can be directly connected, attached or coupled to the other feature or element or intervening features or elements may be present. In contrast, when a feature or element is referred to as being "directly connected", "directly attached" or "directly coupled" to another feature or element, there are no intervening features or elements present. Although described or shown with respect to one embodiment, the features and elements so described or shown can apply to other embodiments. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed "adjacent" another feature may have portions that overlap or underlie the adjacent feature. [000191] Terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. For example, as used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features,steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".[000192] Spatially relative terms, such as "under", "below", "lower", "over", "upper" and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "under" or "beneath" other elements or features would then be oriented "over" the other elements or features. Thus, the exemplary term "under" can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms "upwardly", "downwardly", "vertical", "horizontal" and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.[000193] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature / element from another feature / element. Thus, a first feature / element discussed below could be termed a second feature / element, and similarly, a second feature / element discussed below could be termed a first feature / element without departing from the teachings of the present invention.[000194] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising” means various components can be co-jointly employed in the methods and articles (e.g., compositions and apparatuses including device and methods). For example, the term “comprising” will be understood to imply the inclusion of any stated elements or steps but not the exclusion of any other elements or steps.[000195] In general, any of the apparatuses and methods described herein should be understood to be inclusive, but all or a sub-set of the components and / or steps may alternatively be exclusive, and may be expressed as “consisting of’ or alternatively “consisting essentially of’ the various components, steps, sub-components or sub-steps. [000196] As used herein in the specification and claims, including as used in the examples and unless otherwise expressly specified, all numbers may be read as if prefaced by the word"about" or “approximately,” even if the term does not expressly appear. The phrase “about” or “approximately” may be used when describing magnitude and / or position to indicate that the value and / or position described is within a reasonable expected range of values and / or positions. For example, a numeric value may have a value that is + / - 0.1% of the stated value (or range of values), + / - 1% of the stated value (or range of values), + / - 2% of the stated value (or range of values), + / - 5% of the stated value (or range of values), + / - 10% of the stated value (or range of values), etc. Any numerical values given herein should also be understood to include about or approximately that value, unless the context indicates otherwise. For example, if the value " 10" is disclosed, then "about 10" is also disclosed. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. It is also understood that when a value is disclosed that "less than or equal to" the value, "greater than or equal to the value" and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value "X" is disclosed the "less than or equal to X" as well as "greater than or equal to X" (e.g., where X is a numerical value) is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.[000197] Although various illustrative embodiments are described above, any of a number of changes may be made to various embodiments without departing from the scope of the invention as described by the claims. For example, the order in which various described method steps are performed may often be changed in alternative embodiments, and in other alternative embodiments one or more method steps may be skipped altogether. Optional features of various device and system embodiments may be included in some embodiments and not in others. Therefore, the foregoing description is provided primarily for exemplary purposes and should not be interpreted to limit the scope of the invention as it is set forth in the claims.[000198] The examples and illustrations included herein show, by way of illustration and not of limitation, specific embodiments in which the subject matter may be practiced. As mentioned, other embodiments may be utilized and derived there from, such that structural and logical substitutions and changes may be made without departing from the scope of thisdisclosure. Such embodiments of the inventive subject matter may be referred to herein individually or collectively by the term “invention” merely for convenience and without intending to voluntarily limit the scope of this application to any single invention or inventive concept, if more than one is, in fact, disclosed. Thus, although specific embodiments have been illustrated and described herein, any arrangement calculated to achieve the same purpose may be substituted for the specific embodiments shown. This disclosure is intended to cover any and all adaptations or variations of various embodiments. Combinations of the above embodiments, and other embodiments not specifically described herein, will be apparent to those of skill in the art upon reviewing the above description.

Claims

CLAIMSWhat is claimed is:

1. A composition for the prevention of radiation therapy related injury, comprising a gelling agent; a solubilizer; and deferoxamine (DFO) or a pharmaceutically acceptable salt thereof wherein the composition is a semi-solid formulation.

2. The composition of claim 1, wherein the gelling agent comprises hydroxyethylcellulose, carbomer, hydroxylpropylcellulose or other gelling agents and polymers with thickening and gelling properties (e.g. xanthan gum, guar gum, methylcellulose, hydroxypropyl methylcellulose, acrylates / C10-30 alkyl acrylate crosspolymer, etc).

3. The composition of claim 1, wherein the gelling agent comprises hydroxy ethylcellulose.

4. The composition of claim 1, wherein the pharmaceutical vehicle comprises Transcutol or other agents with similar properties, e.g. solubilizing, enhancing drug permeation, low volatility, hygroscopicity, compatibility with hydrophilic and hydrophobic excipients.

5. The composition of claim 1, wherein the composition comprises a gel, lotion or cream.

6. The composition of claim 1, wherein the composition comprises a gel.

7. The composition of claim 1, wherein the composition is clear, opaque or colored.

8. The composition of claim 1, wherein the composition comprises a viscosity of about 1,000 cP - 100,000 cP.

9. The composition of claim 1, wherein the composition comprises a concentration of about 0.1-5% gelling agent as weight percent of the composition.

10. The composition of claim 1, wherein the composition comprises a concentration of about 1-5% gelling agent as weight percent of the composition.

11. The composition of claim 1, wherein the composition comprises a concentration of about 25-55% solubilizer as weight percent of the composition.

12. The composition of claim 1, wherein the composition comprises a concentration of about 30-50% solubilizer as weight percent of the composition.

13. The composition of claim 1, wherein the composition comprises a concentration of about 5-15% DFO or a pharmaceutically acceptable salt thereof.

14. The composition of claim 1, wherein the composition comprises preservatives (e.g. benzyl alcohol, phenoxyethanol, sodium benzoate, benzoic acid, citric acid, etc.), pH adjusters (e.g. sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, etc.), co-solvents (e.g. propylene glycol, butylene glycol, polyethylene glycol), colorants, fragrance and other additives.

15. The composition of claim 1, wherein the composition is configured to release at least about 70% of DFO or a pharmaceutically acceptable salt thereof over 24 hours.

16. A method of manufacturing a composition for the prevention of radiation therapy related injury, comprising providing a gelling agent; providing a pharmaceutical vehicle; providing DFO or a pharmaceutically acceptable salt thereof; mixing the gelling agent, solubilizer and the DFO or a pharmaceutically acceptable salt thereof to form a semi-solid formulation.

17. The method of claim 15, wherein providing a gelling agent comprises providing a gelling agent at a concentration of about 0.1-5% gelling agent as weight percent of the composition.

18. The method of claim 15, wherein providing a gelling agent comprises providing a gelling agent at a concentration of about 1-5% gelling agent as weight percent of the composition.

19. The method of claim 15, wherein providing a solubilizer comprises providing a solubilizer at a concentration of about 25-55% solubilizer as weight percent of the composition.

20. The method of claim 15, wherein providing a solubilizer comprises providing a solubilizer at a concentration of about 30-50% solubilizer as weight percent of the composition.

21. The method of claim 15, wherein providing DFO or a pharmaceutically acceptable salt thereof comprises providing DFO or a pharmaceutically acceptable salt thereof at a concentration of about 5-15%.

22. The method of claim 15, wherein providing a solubilizer comprises providing Transcutol.

23. The method of claim 15, wherein providing a gelling agent comprises providing hydroxy ethylcellulose.

24. The method of claim 15, wherein mixing the gelling agent, solubilizer and the DFO or a pharmaceutically acceptable salt thereof comprises mixing using one or more of cold mixing, high shear mixing, vacuum mixing, mechanical mixing, extrusion and blending.

25. A method of mitigating or preventing a skin injury on a patient caused by radiation therapy, comprising: contacting the skin with a composition comprising a gelling agent, a solubilizer, and DFO or a pharmaceutically acceptable salt thereof prior to the patient receiving radiation therapy, wherein the skin injury is mitigated or prevented.

26. The method of claim 24, wherein the contacting the skin with the composition comprising a gelling agent, a solubilizer, or other excipients and DFO or a pharmaceutically acceptable salt thereof occurs 1-120 hours prior to 1-120 hours after to the patient receiving radiation therapy or radiation injury.

27. A method of treating a skin injury on a patient caused by radiation therapy, comprising: contacting the skin with a composition comprising a gelling agent, a solubilizer, and DFO or a pharmaceutically acceptable salt thereof prior to the patient receiving radiation therapy, thereby improving a condition of the skin.

28. The method of claim 24, wherein the contacting the skin with the composition comprising a gelling agent, a solubilizer, or other excipients and DFO or a pharmaceutically acceptable salt thereof occurs 1-120 hours prior to 1-120 hours after to the patient receiving radiation therapy or radiation injury.

29. The method of claim 27, wherein contacting the skin with the composition comprises applying the composition to irradiated skin daily, twice a day, three times a day, four times a day, every other day, every three days, etc.

30. The method of claim 27, wherein contacting the skin with the composition occurs immediately after radiation therapy.

31. The method of claim 27, wherein contacting the skin with the composition occurs 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 1-2 weeks, 2 weeks, 2-4 weeks, etc. after the patient received radiation therapy.

32. The method of claim 27, wherein contacting the skin with the composition results in one or more of improved skin elasticity, improved perfusion, improved dermal thickness, improved collagen density, improved 8-isoprostane assays, improved retention of desired collagen ultrastructure.

33. The method of claim 32, wherein an improvement occurs within 1 day, 2, days, 3 days, 4 days, 5 days, 6 days, 1 week, 1-2 weeks, 2 weeks, 2-3 weeks 3 weeks 3-4 weeks, etc.

34. A method of mitigating or preventing a skin injury on a patient caused by radiation therapy, comprising: pre-treating one or more of: skin at or adjacent to an entry site, exit site, and in between the entry site and exit site on a body of a patient undergoing radiation exposure with a composition having a gelling agent, a solubilizer and deferoxamine (DFO); applying a beam of radiation directed to travel along a path from the entry site to the exit site on the body of the patient; and preventing or mitigating radiation exposure-related injury of the skin on the body of the patient via the composition.

35. The method of claim 34, wherein the radiation exposure includes external beam radiation configured for diagnostic, imaging, or treatment purposes.

36. The method of claim 34, wherein the radiation exposure includes brachytherapy and proton beam therapy, further wherein the composition is only applied to one or more of: the skin at or adjacent to the entry site and skin at or adjacent to a region between the entry site and a target of the brachytherapy or proton beam therapy.

37. The method of claim 36, wherein the exit site on the body of the patient including sweat glands and a urethral opening.

Images