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WO2025221973A1 - Formulations topiques de benzimidazole et procédés d'utilisation dans le traitement de dermatoses inflammatoires - Google Patents

Formulations topiques de benzimidazole et procédés d'utilisation dans le traitement de dermatoses inflammatoires

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Publication number
WO2025221973A1
WO2025221973A1 PCT/US2025/025121 US2025025121W WO2025221973A1 WO 2025221973 A1 WO2025221973 A1 WO 2025221973A1 US 2025025121 W US2025025121 W US 2025025121W WO 2025221973 A1 WO2025221973 A1 WO 2025221973A1
Authority
WO
WIPO (PCT)
Prior art keywords
mbz
mebendazole
composition
treatment
topical
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/025121
Other languages
English (en)
Inventor
Joaquin J. Jimenez
Naiem T. ISSA
John P. Mccook
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jjr&d LLC
Original Assignee
Jjr&d LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US19/180,752 external-priority patent/US20250241898A1/en
Application filed by Jjr&d LLC filed Critical Jjr&d LLC
Publication of WO2025221973A1 publication Critical patent/WO2025221973A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • the present invention relates to topical formulations of benzimidazoles, and specifically of mebendazole, and their use in treating and preventing inflammatory and other skin diseases and conditions, such as rosacea.
  • Mebendazole is an approved anthelminthic drug with favorable toxicity profile. It is generally given orally for intestinal helminthiasis. Dosing regimens have ranged from short-term low-dose treatments to long-term high-dose treatments over several months.
  • U.S. Patent Nos. 9,877,950 and 5,169,846 disclose the use of mebendazole as an anthelminthic for treatment of parasites and worms in animals.
  • mebendazole has also been shown to have significant antiproliferative activity across various cancer models. These include glioblastoma, breast, lung, ovarian, colon, osteosarcoma, melanoma cell lines among others. Clinical trials are currently assessing the utility of mebendazole for high-grade glioma, medulloblastoma and metastatic gastrointestinal cancer.
  • W02002058697 discloses the use of mebendazole for the treatment of cancers, including through topical application.
  • US20210369679 discloses the use of mebendazole with a non-steroidal anti-inflammatory (NSAID) for treating cancer, including skin cancer.
  • NSAID non-steroidal anti-inflammatory
  • mebendazole The anti-helminthic effect of mebendazole is attributed to its inhibition of tubulin, which disrupts the organism’s cytoskeletal network leading to parasite death. Mebendazole also inhibits mammalian tubulin but with lesser binding affinity. It is believed that inhibition of tubulin is also one mechanism by which mebendazole exerts a cytotoxic effect on tumor cells. In addition to its ability to bind and inhibit tubulin polymerization, mebendazole also binds and inhibits numerous cytoplasmic kinases that are critical to cancer initiation, progression and metastasis. Examples of these kinases include ABL1 , BRAF, DYRK1 B, JAK3, and PDGFR.
  • mebendazole has been found to cause an M2 to M1 phenotypic switch in monocyte/macrophage models. This could potentially explain the benefit of mebendazole in solid malignancies beyond its direct antiproliferative effect on tumor cells as the M1 macrophages induce direct and indirect anti-tumor effects.
  • mebendazole has been shown to uniquely upregulate ERK signaling in THP-1 monocytoid cells and human CD4+ T-cells isolated from patients with systemic lupus erythematosus with known defective ERK signaling, an effect that is unique to mebendazole and not the other benzimidazoles. It is therefore postulated that mebendazole may be of use in autoimmune diseases characterized by defective ERK signaling. Mebendazole treatment of scleroderma is disclosed, for example, in WO2019112031. It has not, however, been known to use benzimidazoles for the topical treatment of other inflammatory or autoimmune diseases and conditions of the skin, such as rosacea.
  • Rosacea is one of the most common inflammatory skin disorders in humans. Rosacea is a chronic inflammatory skin disorder characterized by facial flushing, telangiectasias, irritation, pain, papules, pustules and phymatous/granulomatous changes. There are four major subtypes: erythematotelangiectactic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea (PR), and ocular rosacea (OR). While initially thought to be vascular-driven disorder, rosacea is now appreciated to have a major immunologic component driving the disease process.
  • ETR erythematotelangiectactic rosacea
  • PPR papulopustular rosacea
  • PR phymatous rosacea
  • OR ocular rosacea
  • This immunologic component is driven by numerous processes: pro-inflammatory neuropeptide release by cutaneous nerve endings, changes in the inflammatory milieu by the local microbiome, components of resident innate immunity altering the cytokine milieu, among others. With respect to adaptive immunity, presence and proliferation of CD4+ and CD8+ T-cells have been shown to be increased in ETR and PPR compared to healthy skin.
  • mebendazole treatment composition that may be used for treating such skin conditions that has improved solubility and skin penetration ability.
  • Mebendazole is poorly soluble in water with an aqueous solubility of approximately 0.035mg/mL for mebendazole Polymorph C at 25 °C.
  • mebendazole has negligible solublility in most solvents other than DMSO (approximately 2% by weight).
  • Mebendazole is also freely soluble in formic acid.
  • DMSO and formic acid are not suitable as pharmaceutical vehicle ingredients for a skin treatment product, particularly a facial skin treatment composition (as rosacea primarily impacts the face), due to safety considerations.
  • a process and composition ingredients to increase the solubility of mebendazole in a pharmaceutical vehicle that would be appropriate for use on human and animal skin, particularly human facial skin.
  • a treatment composition comprises one or more benzimidazoles in a pharmaceutically acceptable vehicle for topical application and may be used for the treatment of an inflammatory or autoimmune disease and/or condition of the skin.
  • the disease or condition treated with a composition according to various embodiments herein is one affecting only animals (non-humans), only humans, or both animals and humans. Most preferably, compositions according to embodiments herein are used for the treatment of rosacea in humans.
  • a treatment composition is in a form of a full solution, wherein all of the one or more benzimidazoles are fully dissolved.
  • a treatment composition is in a form of a full suspension, wherein all of the one or more benzimidazoles remains in an undissolved, suspended form.
  • a treatment composition is partially a solution and a partially a suspension, wherein at least some of the one or more benzimidazoles are dissolved and at least some of the one or more benzimidazoles are undissolved and suspended in the composition.
  • a treatment composition comprises mebendazole or a salt of mebendazole or methyl 5-benzoylbenzimidazole-2 -carbamate (each referred to herein generally as MBZ).
  • the treatment composition comprises one or more of albenzadole, thiabenzadole, fenbenzadole, MBZ, or salts of the foregoing.
  • any other benzimidazoles may be substituted for or used in addition to mebendazole or MBZ referenced herein in connection with the description of various embodiments.
  • Mebenzadole exists in several polymorph crystalline states that include Polymorph A, B, and C.
  • Polymorph C is the preferred form for some embodiments of compositions of herein, but the others may also be used or may be excluded.
  • Salts of mebenzadole may include mebendazolium lactate, mebendazolium glycolate, and mebendazolium mesylate.
  • an MBZ treatment composition comprises around 0.01-1.0% mebendazole by weight, more preferably around 0.05- 0.25% by weight, and most preferably around 0.01 -0.075% by weight, in an MBZ gel composition, an MBZ cream base vehicle, or in another pharmaceutically acceptable vehicle for topical use with human and/or animal skin, with or without other active ingredients.
  • an MBZ treatment composition is in a form of a full solution, wherein all of the MBZ is fully dissolved.
  • an MBZ treatment composition is in a form of a full suspension, wherein all of the MBZ remains in an undissolved, suspended form.
  • an MBZ treatment composition is partially a solution and partially a suspension, wherein at least some of the MBZ is dissolved and at least some of the MBZ is undissolved and suspended in the composition.
  • the vehicle for the MBZ treatment composition is an aqueous or anhydrous solution, suspension or gel solution or suspension.
  • the composition comprises (1 ) around 0.01 -0.50% mebendazole by weight, more preferably around 0.05-0.25%, and most preferably around 0.01 -0.075%; (2) around 10-60% by weight total of one or more solvents, penetrants, and/or emulsifying ingredients, more preferably around 25-60%, most preferably around 40-55%; and (3) water.
  • the solvents and/or other ingredients preferably increase the solubility of MBZ to at least 5 times, more preferably at least 10 times or more of the solubility of MBZ in water, allowing less MBZ to be used to achieve increased skin penetration performance.
  • an MBZ treatment composition comprises a vehicle that does not increase the solubility of MBZ as much as other embodiments, thus requiring more MBZ to achieve to increase the skin penetration performance of such MBZ treatment compositions.
  • a vehicle is Vanicream® as described herein.
  • an MBZ treatment composition comprises 1.0-20.0% mebendazole by weight, more preferably around 1.0-10.0%, and most preferably around 1 .0-5.0%.
  • Such amounts of MBZ are particularly preferred when the vehicle for the MBZ treatment composition is an aqueous lotion, cream, emulsion or anhydrous suspension of mebendazole wherein the mebendozole is mostly in a non- soluble, crystalline form.
  • the solvents and/or other ingredients preferably increase the solubility of MBZ to no more than 10 times, more preferably no more than 5 times or less of the solubility of MBZ in water.
  • the mebendazole (or other benzimidazole) is physically nanosized in the composition.
  • the mebendazole (or other benzimidazole) is also preferably suspended and/or non-solubilized mebendazole and is encapsulated in the composition.
  • the mebendazole (or other benzimidazole) is solubilized as much as possible without DMSO, decylmethylsulfoxide, dimethylacetamide, and pyrrolidone solvents, and/or surfactants.
  • the mebendazole (or other benzimidazole) and at least one solvent are processed through a microfluidizer to form an MBZ (or other benzimidazole) concentrate composition and/or an MBZ (or other benzimidazole) treatment composition.
  • the mebendazole (or other benzimidazole) and at least one solvent are not processed through a microfluidizer to form an MBZ (or other benzimidazole) concentrate composition and/or an MBZ (or other benzimidazole) treatment composition.
  • These variations on the mebendazole (or other benzimidazole) may be used with any compositions comprising mebendazole (or other benzimidazole) according to embodiments of the compositions herein.
  • the vehicle in the composition comprises an aqueous lotion, cream, gel, solution, suspension, or ointment wherein the MBZ is present (1 ) fully dissolved form or (2) in both soluble (partially dissolved) and insoluble (partially undissolved) form, with the insoluble portion preferably suspended in the composition or (3) a fully suspended form.
  • Embodiments for a vehicle may comprise one or more of the following, and in some preferred embodiments all of the following: (1 ) water (preferably purified or deionized), (2) petrolatum, (3) sorbitol, (4) cetearyl alcohol, (5) propylene glycol, (6) ceteareth-20 (a polyethylene glycol ether of cetearyl alcohol), (7) simethicone, (8) glyceryl stearate, (9) PEG-30 Stearate (a polyethylene glycol ester of stearic acid), (10) sorbic acid, and (11 ) BHT (butylated hydroxytoluene).
  • a vehicle comprise one or more of the following, preferably all of the following: (1 ) water (preferably purified or deionized), (2) glycerin, (3) polyacrylic acid (preferably carbomer), (4) disodium ethylenediaminetetraacetic acid (EDTA), (5) cetyl alcohol, (6) stearyl alcohol, (7) glyceryl stearate and/or PEG 100 stearate, (8) polysorbate 80, (9) triethanolamine, and (10) phenoxyethanol. Any ingredient listed as potentially included in an embodiment or in one preferred embodiment, may also be excluded in another embodiment or another preferred embodiment.
  • an MBZ concentrate composition comprises: (1 ) mebendazole (or other benzimidazole) and (2) one or more compounds or ingredients that act as solvents, skin penetrants, and/or emulsifying agents.
  • at least one ingredient in category (2) acts as a solvent and an emulsifying agent.
  • an MBZ concentrate composition comprises: (1 ) mebendazole (or other benzimidazole); (2) a sorbitol based solvent, (3) an ethylene and/or propylene glycol based solvent, and (4) a solubilizer and/or emulsifying agent.
  • MBZ concentrate compositions comprise around 1.0-10.0% by weight mebendazole, more preferably around 3.0-6.0%, most preferably around 3.0-4.0%. According to still other embodiments, the amount of mebendazole in an MBZ concentrate composition is reduced to around 0.05-1.0% by weight, more preferably 0.05-0.2%, and most preferably 0.01 -0.075%.
  • a preferred ethylene glycol based solvent is diethylene glycol monoethyl ether (Transcutol P®), but others may also be used.
  • a preferred propylene glycol based solvent is propylene glycol monolaurate (Lauryl Glycol®), but others may also be used.
  • an MBZ concentrate composition comprises around 15.00-25.00% by weight total of the ethylene and/or propylene glycol based solvent, more preferably around 18.00-21.00%.
  • both an ethylene glycol based solvent and a propylene glycol based solvent are used together in an MBZ concentrate composition in weight ratios of around 80:20 to 70:30, more preferably around 75:25 to 65:35, and most preferably around 60:40.
  • a preferred sorbitol based solvent is dimethyl isosorbide (DM I).
  • DM I dimethyl isosorbide
  • an MBZ concentrate composition comprises around 32.00- 45.00% by weight of the sorbitol based solvent, more preferably around 36.00-40.00%.
  • a preferred solubilizer and/or emulsifying agent is polyoxyl 40 hydrogenated castor oil (Cremophor RH 40).
  • an MBZ concentrate composition comprises around 32.00-45.00% by weight of the solubilizer and/or emulsifying agent, more preferably around 36.00-40.00%.
  • the solvents used in compositions according to some embodiments are (1 ) preferably capable of dissolving MBZ at 10x or more the solubility of MBZ in water (which is approximately 35 ug/mL) and (2) suitable for use, in amounts necessary to dissolve MBZ for topical application to human or animal skin.
  • solvents/skin penetrants that may be used in addition to or as alternates to dimethyl isosorbide, diethylene glycol monoethyl ether, and Cremophor RH 40 include: caprylocaproyl macrogol-8 glycerides, propylene glycol monocaprylate, polyglyceryl-3 dioleate, diisopropyl adipate, diethyhexyl adipate, poly(glyceryl) adipate, salicylate esters, Cyrene (dihydrolevoglucosenone), Poloxamer 188, Poloxamer 407, Deep Eutectic Solvents or Natural Deep Eutectic Solvents which may contain one or more quarternary ammonium salt, quarternary phosphonium salt, urea, amide, carboxylic acid, alcohol, polyatom icalcohol, amine, glycerol, lactic acid, n-decanoic acid, choline chloride, t
  • a solvent used in compositions herein does not include an aprotic solvent, a polar aprotic solvent, a dipolar aprotic solvent, or a non-polar aprotic solvent.
  • a polyol is not used as a solvent in compositions herein.
  • a dipolar aprotic solvent is not used in combination with a polyol in compositions herein.
  • an aprotic solvent may be used in compositions according to some embodiments and the aprotic solvent may be polar, dipolar, or non-polar.
  • a polyol may be used as a solvent in compositions according to some embodiment herein and may or may not be used in combination with a dipolar aprotic solvent.
  • cyrene dihydrolevoglucosenone
  • cyrene may be used in compositions in place of aprotic or non-aprotic solvents.
  • cyrene may be excluded from compositions herein.
  • an MBZ concentrate composition is made by: (1 ) mixing the one or more solvents and mebendazole to form a first mixture; (2) heating the first mixture to a temperature within a first temperature range for a first period of time; and (3) mixing or stirring during the heating step, such as by using a magnetic stirrer.
  • the first period of time is around 5 to 20 minutes, more preferably around 5 to 15 minutes. Most preferably, the heating temperature and first period of time will not result in degradation of the MBZ of more than 10%, more preferably not more than 8% and most preferably not more than 5%.
  • the first temperature range is most preferably between at least 60 °C but less than a temperature at which MBZ will experience degradation of 5% or more. More preferably, the first temperature range is 60-100 °C, and most preferably 70-100 °C. Preferably, steps 1 -3 are carried out before mixing the MBZ or the first mixture with any water or aqueous based application vehicle.
  • an MBZ gel composition comprises (1 ) mebendazole (or other benzimidazole); (2) water, and (3) a gelling or thickening agent (or viscosity modifying agent).
  • an MBZ gel composition comprises (1 ) an MBZ concentrate composition, (2) water, and (3) a gelling or thickening agent (or viscosity modifying agent).
  • a preferred gelling/thickening/viscosity modifying agent is hydroxyethylcellulose, such as Natrosol® 250HX (pharma grade), but other agents may also be used.
  • an MBZ gel composition further comprises (4) a cyclodextrin compound to aid in solubility and to reduce precipitation of the MBZ.
  • a preferred cyclodextrin compound is hydroxypropyl beta cyclodextrin (Cavasol® W7 HP).
  • Other cyclodextrin compounds comprising alpha- and gamma-cyclodextrins and alternate chemical modifications of the alpha, beta and gamma cyclodextrins in addition to hydroxyalkylation including, methylation, ethylation, phosphated and sulfonated, may also be used.
  • an MBZ gel composition further comprises (5) an ethylene glycol based solvent, such as diethylene glycol monoethyl ether (Transcutol P®).
  • an MBZ gel composition comprises (1 ) mebendazole (or other benzimidazole); (2) water, (3) a gelling or thickening agent (or viscosity modifying agent), and (4) an ethylene glycol-based solvent.
  • an MBZ gel composition comprises (1 ) an MBZ concentrate composition, (2) water, (3) a gelling or thickening agent (or viscosity modifying agent), and (4) an ethylene glycol-based solvent.
  • a preferred gelling/thickening/viscosity modifying agent is hydroxyethylcellulose, such as Natrosol® 250HX (pharma grade), but other agents may also be used.
  • a preferred ethylene glycol-based solvent is diethylene glycol monoethyl ether (Transcutol P®), but others may also be used.
  • an MBZ gel composition comprises around 0.01-0.075% MBZ and around 15-45% ethylene glycol-based solvent. In some embodiments, an MBZ gel composition comprises around 0.04-0.07% MBZ and around 15-25% ethylene glycol-based solvent. In still other embodiments, an MBZ gel composition comprises around 0.04-0.06% MBZ and around 18-22% ethylene glycol based solvent. In some embodiments, an MBZ gel composition comprises around 0.5 to 1.5% of hydroxyehtylcellulose (a viscosity modifying agent). In some embodiments, an MBZ gel composition comprises around 15 to 25 % of an ethylene glycol-based solvent.
  • an MBZ gel composition comprises a ratio of ethylene glycol-based solvent, preferably Transcutol® P, to water of around 1 :2 to 1 :5, more preferably around 1 :4. In some embodiments, an MBZ gel composition comprises a ratio of ethylene glycol based solvent, preferably Transcutol® P, to water of greater than 1 :1 .5. These percentages and ratios are by weight.
  • an MBZ treatment composition comprises an MBZ gel composition that may be mixed with a vehicle or applied to skin for treatment without mixing with additional vehicle ingredients.
  • an MBZ treatment composition comprises an MBZ concentrate composition that is mixed with a vehicle prior to application to skin for treatment.
  • a method of treating an inflammatory or autoimmune disease and condition of the skin comprises topically applying a composition comprising one or more benzimidazoles in a pharmaceutically acceptable vehicle to an affected area of the skin at least once daily for a treatment period of at least two weeks, more preferably at least twelve weeks and continue to apply the composition to the affected facial area daily or every other day to prevent reoccurrence of a new rosacea outbreak.
  • the composition used in methods according to embodiments herein is one according to a preferred embodiment.
  • a composition comprising mebendazole plus a vehicle is applied to the affected area of the skin at a dosage rate of around 100 to 1000 milligrams, more preferably 50 to 500 milligrams to each side of the face to the affected areas.
  • Treatment compositions and methods according to embodiments herein have been shown to be effective in reducing viability of T-cells and in treating a patient with rosacea.
  • Treatment compositions according to embodiments herein have been shown to have greater skin permeation rates, including greater permeation in shorter period of time.
  • the inventors also have found that use of mebendazole according to some embodiments reduced the viability of T-cells in an in vitro model.
  • Use of preferred methods and composition ingredients for making an MBZ concentrate composition, an MBZ gel composition, and/or an MBZ treatment composition have also been shown to result in increased skin penetration and/or increased solubility of MBZ in a pharmaceutical vehicle appropriate for use on human and animal skin, particularly human facial skin.
  • the methods and compositions of the embodiments herein, particularly preferred embodiments provide advantages as a therapeutic agent for immunomodulation, particularly through a suppressive effect on CD8+ T-cells, for treatment of inflammatory and autoimmune diseases and conditions of the skin, particularly rosacea, with improved penetration and solubility of the MBZ.
  • FIG. 1 is a graph depicting the reduction in density of T-lymphocytes when exposed to various concentrations of a composition comprising mebendazole;
  • FIG. 2 is a graph depicting a reduction in the number of papules and pustules on the left (treated) cheek of a patient with rosacea when treated with a cream composition comprising 10% mebendazole by weight;
  • FIG. 3 contains photographs showing the left (treated) and right (untreated/control) cheeks of the patient with rosacea referenced in FIG. 2;
  • FIG. 4 is a graph depicting flux values at 0-6 hours compared to 6-24 hours for MBZ treatment compositions in Example 8;
  • FIG. 5 is a graph depicting flux values at 0-1 hours compared to 0-6 hours and compared to 6-24 hours for MBZ treatment compositions in different receptor fluids in Example 9;
  • FIGS. 6A-6B are tables showing data from Examples 6, 8, and 9;
  • FIG. 7 is a more complete t-table for treatment compositions for Example 9.
  • the mebendazole topical treatment compositions according to some embodiments of the disclosure are effective in the reduction of T-lymphocytes (see FIGS. 1 -3), and can be used as effective immune modulators alone, as well as in combination with an additional therapeutic agent, such as oxymetazoline. Accordingly, disclosed herein are methods of treating or preventing a disease or disorder in a subject (preferably a human), comprising administering to the subject a therapeutically effective amount of a composition comprising one or more benzimidazoles in a vehicle or carrier for topical application. Most preferably, the benzimidazole comprises mebendazole, which is in a topical cream vehicle or a topical gel as described herein.
  • the vehicle or carrier is a pharmaceutically acceptable carrier composition suitable to use on human and/or animal (non-human) skin.
  • the disease or disorder is an autoimmune disease or an inflammatory skin disorder.
  • the disease or disorder is rosacea.
  • treat refers to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
  • the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • proliferative treatment refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
  • the term “treat” and synonyms contemplate administering a therapeutically effective amount of a composition of the disclosure to an individual in need of such treatment.
  • treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
  • the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be affected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
  • prevention is art- recognized, and when used in relation to a condition, such as rosacea, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • prevention of rosacea includes, for example, reducing inflammation, restoring or reducing the levels of T-cell lymphocytes near hair follicles in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • compositions and methods disclosed herein comprise those for treating or preventing rosacea. In some cases, the compositions and methods disclosed herein comprise those for treating rosacea. In some cases, the compositions and methods disclosed herein comprise those for preventing rosacea.
  • Preferred MBZ treatment compositions comprise around 0.01-1.0% mebendazole by weight, more preferably around 0.05-0.5%, and most preferably around 0.01 -0.075%.
  • the amount of mebendazole may be increased to up to around 20.0% by weight, more preferably up to around 10.0%, and most preferably up to around 5.0% to allow for sufficient solubility and skin penetration of the mebendazole.
  • the balance of preferred MBZ treatment composition comprise pharmaceutically acceptable carrier or vehicle ingredients for topical administration and optionally one or more other pharmaceutically active ingredients.
  • a pharmaceutically active vehicle or carrier may comprise a lotion, cream, suspension, or ointment that is aqueous, or a clear or cloudy aqueous gel solution or gel suspension.
  • One preferred vehicle is a moisturizing cream or lotion comprising an emulsion for facial treatment or prevention of erythematotelangiectactic rosacea, papulopustular rosacea, and phymatous rosacea, and a sterile ophthalmic solution, suspension, emulsion, or ointment for treatment or prevention of ocular rosacea, wherein the MBZ is in solution, in suspension or in both suspension and solution.
  • the methods disclosed herein comprise administering to the subject one or more additional pharmaceutically active agents and/or such one or more additional pharmaceutically active agents may be included in a treatment composition according to embodiments herein.
  • the additional pharmaceutically active agent is an immunosuppressant, an anti-infective, calcineurin inhibitor, Janus kinase (JAK) inhibitor, retinoid or vasoconstricting agent.
  • the immunosuppressant is a corticosteroid.
  • the corticosteroid is hydrocortisone, triamcinolone, clobetasol, fluocinonide, etc.
  • the anti- infective agent is tetracycline, doxycycline, minocycline, erythromycin, metronidazole, ivermectin, etc.
  • the calcineurin inhibitor is cyclosporine, pimecrolimus or tacrolimus.
  • the JAK inhibitor is ruxolitinib, tofacitinib, baricitinib or oclacitinib.
  • the retinoid agent is azelaic acid, tretinoin, retinol.
  • the vasoconstricting agent is brimonidine, midodrine or oxymetazoline. In other embodiments, any of these ingredients may also be excluded from the composition or excluded from use in the methods of the disclosure. Chronic use of corticosteroids are excluded from the composition according to some embodiments as contraindicated.
  • compositions and methods of some embodiments herein involve topical application to the skin or ocular membranes
  • other non-active excipients which may aid in or induce penetration of the active benzimidazole agent(s) into the facial skin or ocular tissue may be used.
  • Substances termed “permeation enhancers,” are typically used in compositions designed to deliver drugs transdermally to increase the amount of the active that is delivered into the systemic circulation.
  • Permeation enhancers constitute various classes of compounds including certain compounds such as dimethylsulfoxide (DMSO) or other organic sulfoxides, methylsulfonylmethane, pyrrolidones, ethanol, propylene glycol, dimethylacetamide (DMA), and others that are capable of disrupting the barrier function of the stratum corneum.
  • DMSO dimethylsulfoxide
  • DMA dimethylacetamide
  • one or more of DMSO, other sulfoxides, DMA, pyrrolidones and other non-polar or polar aprotic solvents are used in compositions and methods herein, including topical formulations of benzimadazoles, including MBZ, to enhance skin penetration.
  • these ingredients are excluded from compositions and methods herein.
  • lipophilic compounds such as laurocapram (Azone); alpha-hydroxy and beta-hydroxy acids, fatty acids or alcohols such as oleic acid, oleyl alcohol, linoleic acid and the like; certain fatty acid esters such as isopropyl myristate, methyl nonanoate, methyl caprate and others.
  • Certain surfactants may also increase penetration of active agents through solubilization and reduction in interfacial surface tension or encapsulation of the active agent and may include PEG-40 hydrogenated castor oil, Cremophor® or other surfactants combining glyceryl polyethylene glycol oxystearate, fatty acid glyceryl polyglyceryl esters, polyethylene glycol, and glyceryl ethoxylates.
  • Encapsulation media for the benzimidazole drug substance or compositions may also include soy or egg based lecithin or chemically modified lecithin, phosphatidylcholine or modified phosphatidylcholine, beta-cyclodextrins, PLGA [poly(lactic-co-glycolic acid], dextran, chitosan, d-alpha-tocopheryl polyethylene glycol succinate polymers and poloxamer (polyoxyethylene-polyoxypropylene) block polymers.
  • Compositions according to some embodiments may comprise one or more of these ingredients or other permeation enhancers. In other embodiments, any of these ingredients may also be excluded from the composition or excluded from use in the methods of the disclosure.
  • compositions herein may include one surfactant but do not include a second surfactant or cosurfactant.
  • compositions according to certain embodiments do not include NSAIDs, 2,6-di-tert- butyl-4-methylphenol, phenyl-pentanedione/or pyridine/or phenylbenzene/or benzoxazine compounds (such as 3-(4-methozyphenyl)-1 ,5-bis(2-methoxyphenyl)-1 ,5- pentanedione).
  • NSAIDs 2,6-di-tert- butyl-4-methylphenol
  • phenyl-pentanedione/or pyridine/or phenylbenzene/or benzoxazine compounds such as 3-(4-methozyphenyl)-1 ,5-bis(2-methoxyphenyl)-1 ,5- pentanedione.
  • Hyaluronic acid/salt may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more methyl sulfoxides including without limitation DMSO and decylmethylsulfoxide, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more pyrrolidones including without limitation 2-pyrrolidone and N-mehtylpyrrolidone, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more dipolar aprotic solvents including without limitation DMSO and DMA, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more disubstituted amides including without limitation N,N-dimethylformamide, N,N-diethyltoluamide, or N,N-dimethylcaprylamide may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more linear alcohols including without limitation ethanol, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more branched alcohols including without limitation isopropanol or 2-octyldodecanol type, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more ketones including without limitation acetone or methyl ethyl ketone, may be included in some embodiments and may be excluded in other embodiments herein.
  • One or more alkyl ethers and/or alkyl esters including without limitation ethyl lactate, may be included in some embodiments and may be excluded in other embodiments herein.
  • the mebendazole content will typically be adjusted such that when the topical formulation is applied to a treatment area of a subject in need thereof, the amount of compound for reducing inflammation, (i.e. , for treating rosacea) is present in an amount effective to achieve at least one of: (i) reduction of T-cell viability, (ii) reduction of T-cell proliferation, (iii) reduction of T-cell activation, (iv) reduction of T-cell activity.
  • EXAMPLES Described in the below Examples 1 and 2 are methods for evaluating mebendazole for efficacy in modulating T-lymphocytes in an in vitro platform translatable to human skin disease and its clinical application with a MBZ treatment composition according to a preferred embodiment of the disclosure.
  • the results of these examples demonstrate that mebendazole is a promising immunomodulatory agent for treatment of rosacea and possibly other forms of inflammatory and neoplastic skin diseases driven by T-lymphocytes to ultimately improve the patient’s quality of life.
  • Examples 3-9 are compositions and methods for making treatment compositions comprising MBZ according to some embodiments of the disclosure, along with solubility analysis of MBZ in select solvents and Skin PAMPA testing of select treatment compositions for evaluation of skin penetration.
  • the following examples are provided for illustration and are not intended to limit the scope of the disclosure.
  • CTLL-2 (ATCC® TIB-214TM) are cytotoxic T lymphocytes that were purchased and cultured according to ATCC protocol. Once confluent, cells were seeded in a 12-well plate at a concentration of 55,000 cells/mL and treated, in triplicates, with a solution of mebendazole dissolved in dimethyl sulfoxide (DMSO) at varying mebendazole concentrations of 1 nM, 5 nM, 500 nM and 1 pM for comparison to a control that had only DMSO applied (without any mebendazole).
  • DMSO dimethyl sulfoxide
  • the maximum volume added to the 1 mL of each of the 12 wells was 10pL for the highest test concentration of mebenzadole and the control.
  • concentrations of mebendazole are within preferred embodiments of treatment compositions herein, preferred treatment compositions for use do not include DMSO.
  • MBZ has good solubility in DMSO (approximately 2% by weight), which is why it was selected as a solvent for this example; however, it is preferred to not use DMSO as a solvent in MBZ treatment compositions herein due to safety considerations with skin applications.
  • mebendazole is shown to dose dependently kill T-lymphocytes. The results indicate that mebenzadole significantly reduces the T-lymphocytes, in cell culture, starting at a test concentration of 1 nM (0.295 micrograms).
  • the inflammatory process induced by activated T-cells leads to the following changes that give rise to all sub-types of rosacea previously noted: angiogenesis, formation of papules and pustules, and granulomatous inflammation that leads to phymatous changes of the skin.
  • the recovery process is complex.
  • the activated T-cells must be deactivated (e.g., with mebendazole) and then the skin achieves homeostatic normalcy that resolves the cutaneous erythema, telangiectasias, papules, pustules and phymatous changes.
  • a clinical study was conducted to determine the effect of 10% mebendazole cream according to one preferred MBZ treatment composition applied daily according to one preferred treatment method on the remission of rosacea after 12 weeks.
  • a split-face study was performed where the Patient applied the MBZ treatment composition (comprising 10% mebendazole by weight) to the left side of her face and the vehicle cream (as a control, without any mebendazole) to the right side of her face nightly for 12 weeks.
  • the Patient is a 52-year-old female with clinically diagnosed papulopustular rosacea (PPR) of the face over decades. She received numerous treatments including topical ivermectin, topical metronidazole, topical steroids, topical antibiotics and systemic antibiotics. After discontinuation of the aforementioned treatments, her rosacea would flare with erythema, telangiectasias, papules and pustules. The Patient underwent a 4-week washout period without use of topical or systemic active medications prior to initiating the active (10% mebendazole) and control (vehicle) creams. The amount of mebendazole in the cream used in Example 2 is equivalent to a molar concentration of 0.339M and approximately 0.25 to 0.5 mL of the cream was applied to the left cheek of the Patient once per day.
  • PPR papulopustular rosacea
  • results are summarized in FIG. 2.
  • Reported categories are as follows: treated (10% mebendazole, left cheek) and control (vehicle, right cheek).
  • active (10% mebendazole) showed a decrease in the total number of papules and pustules of the left face (70.37%) whereas the vehicle did not result in a decrease, indicating an improvement of the rosacea when treated according to a preferred embodiment of the disclosure.
  • the results are also represented by photos in FIG. 3 depicting improvement of the rosacea of the left cheek with a 12-week nightly treatment with active (10% mebendazole) cream but no improvement of rosacea of the right cheek with 12-week nightly treatment with control (vehicle). Improvement is noted by reduction in papules and pustules as well as reduction in erythema and telangiectasias.
  • the MBZ treatment composition used in the treatment of the Patient was formulated by adding Mebenzadole Tablets, USP, 500mg, crushed to a fine powder, mixed until uniform and in a sufficient amount to make a 10% by weight mebenzadole suspension in a commercially available Vanicream® Moisturizing Skin Cream vehicle. No attempt to increase the solubility of the MBZ in the commercial Vanicream® vehicle was made.
  • the label ingredient listing (INCI; International Nomenclature Cosmetic Ingredient) for the Vanicream® Moisturizing Skin Cream, which is an oil-in-water emulsion cream base, is as follows: Purified water, petrolatum, sorbitol, cetearyl alcohol, propylene glycol, ceteareth-20(a polyethylene glycol ether of cetearyl alcohol), simethicone, glyceryl stearate, PEG-30 Stearate (a polyethylene glycol ester of stearic acid), sorbic acid, BHT (butylated hydroxytoluene).
  • MBZ is poorly soluble in water and it should be noted that the aqueous solubility of MBZ is approximately 0.035mg/mL (Polymorph C at 25 degrees C). In addition to negligible solubility in water, MBZ has negligible solublility in most solvents other than DMSO (approximately 2% by weight). MBZ is also freely soluble in formic acid. Neither DMSO nor formic acid is an appropriate pharmaceutical vehicle ingredient for a facial treatment product due to safety considerations. Thus, there is a need for a process to increase the solubility of MBZ in a pharmaceutical vehicle that would be appropriate for use on human and animal skin, particularly human facial skin.
  • solvent compositions 2-4 and 6 had better solubility than solvent compositions 1 and 5 (with dimethyl isosorbide or DMI) because undissolved, but small, solid particles remained in solvent compositions 1 and 5; however, each of the solvent compositions were assayed by UV-VIS spectrophotometric (300-325nm) or by HPLC (Mebendazole; LISP-NF Monograph) methods to determine the amount of MBZ in the compositions after the filtration step.
  • the solubility of MBZ was found to be highest in either solvent composition 1 (DMI) or2 (Transcutol P). However, this solubility is reduced to 10-20% of the theoretical maximum amount when the solvent compositions 1 and 2 are diluted 50% with deionized water. Although concentrations of up to 0.5% by weight MBZ can be achieved in undiluted solvent compositions containing (1 ) only MBZ and Transcutol P or (2) only MBZ and DMI, the resulting liquid solvent composition has undesirable cosmetic or aesthetic qualities, including a lingering oiliness on skin application.
  • Such issues can be avoided by diluting such solvent compositions with water (preferably deionized or purified water); however, the diluted solvent composition can be runny, making it difficult to apply to skin, particularly facial skin.
  • water preferably deionized or purified water
  • viscosity modifiers or gelling agents to create an MBZ treatment composition comprising a topical gel or thickened liquid.
  • Such viscosity modifiers or gelling agents may be part of a topical application vehicle to which MBZ (or an MBZ concentrate composition) is added or may be part of an MBZ gel composition further described herein.
  • solubility of MBZ increases in the final diluted composition or when mixed with an aqueous base vehicle, such as a preferred embodiment of an MBZ cream base composition herein.
  • an aqueous base vehicle such as a preferred embodiment of an MBZ cream base composition herein.
  • 0.10% w/w MBZ requires 80°C and 0.15% w/w MBZ requires 90°C for initial solubility.
  • one or more benzimidazoles, or specifically MBZ may be initially completely dissolved in compositions herein, with further processing as described herein and/or with storage, some of the benzimidazoles or MBZ may precipitate out of solution, thereby making some compositions herein partially a solution and partially a suspension.
  • an MBZ concentrate composition is made by: (1 ) mixing an ethylene or propylene glycol based solvent (preferably diethylene glycol monoethyl ether (Transcutol P®)) with a sorbitol based solvent (preferably dimethyl isosorbide) and 0.05-0.2% w/w MBZ (more preferably 0.01-0.075% w/w MBZ); (2) heating to a temperature within a first temperature range; and (3) mixing or stirring during the heating step, such as by using a magnetic stirrer.
  • the first period of time is around 5 to 20 minutes, more preferably around 5 to 15 minutes.
  • the heating temperature and first period of time will not result in degradation of the MBZ of more than 10%, more preferably not more than 8% and most preferably not more than 5%.
  • the first temperature range is most preferably between at least 60 °C but less than a temperature at which MBZ will experience degradation of 5% or more. More preferably, the first temperature range is 60-90 °C, and most preferably 70-90 °C.
  • steps 1 -3 are carried out before mixing the MBZ with any water or aqueous based application vehicle.
  • MBZ concentrate compositions according to preferred embodiments were prepared and added to a topical MBZ cream base (or vehicle) formulation according to a preferred embodiment for testing (as further described in Example 6).
  • Preferred embodiments of MBZ concentrate compositions for use in Example 6 are shown in Table 2.
  • an MBZ solvent/skin penetrant concentrate composition (formula 45-147) was prepared as follows: (1 ) MBZ was micronized to a an average particle size of around 3.5 to 4.0 microns; (2) the micronized MBZ powder is added to a liquid mixture of (a) a sorbitol based solvent (preferably dimethyl isosorbide), (b) an ethylene and/or propylene glycol based solvent (preferably diethylene glycol monoethyl ether (Transcutol P®), propylene glycol monolaurate (Lauryl Glycol®) 60:40), and (c) a solubilizer and/or emulsifying agent (preferably Cremophor RH 40/polyoxyl 40 hydrogenated castor oil); and (3) the MBZ powder is mixed with the liquid ingredients preferably at 25-50 °C, more preferably at 35-50 °C, and for 15-30 minutes or until a uniform white suspension of MBZ powder in the liquid is created.
  • a laboratory batch of 1 Kg of MBZ concentrate composition (formula 45- 147) was made according to the Trial Example 6 percentages in Table 2 and divided into substantially equal parts, some of which were microfluidized and some of which were not microfluidized, for use in preparing MBZ treatment compositions for use in Example 6.
  • part of the MBZ concentrate batch is processed at 35-45 °C through a Microfluidics EH-110 microfluidizer (Microfluidics, Inc.) at 14,000 psi for 3 discreet complete passes.
  • the MBZ concentrate batch is not processed further.
  • Average particle size for Dv(10), Dv(50), and Dv(90), which indicate the size median for which 10%, 50%, or 90%, respectively, of the particles within the distribution are smaller, are shown for each of the three samples. Four measurements were made for each of the three samples and an average of the four measurements is also shown in Table 3.
  • the average Dv(50) of the zero pass Sample 1 is 3.84 microns, which as expected is essentially the same as the Dv(50) of the micronized mebendazole compound powder used in the 45-147 formula.
  • 50% of all particles are smaller than 1.11 microns (the average Dv (50)).
  • 50% of all particles are smaller than 0.956 microns (the average Dv(50)).
  • the average Dv(90) of 45-147 particles after 6 passes through the microfluidizer for Sample 3 shows 90% of all particles are less than 3.3 microns.
  • the particle size analysis indicates that 3 or 6 discreet passes of 45-147 through the EH-110 microfluidizer substantially reduces the particle size distribution of undissolved MBZ as compared to the non-microfluidized sample. Additionally, 6 discreet passes achieves a larger reduction than 3 discreet passes. Reduction of the particle size may improve suspension uniformity over time in compositions according to embodiments herein in a suspension (or partial suspension) form and may improve MBZ skin penetration.
  • an MBZ concentrate composition may be microfluidized or a treatment composition (benzimidazoles/MBZ and a carrier) may be microfluidized.
  • a method of microfluidization comprises processing the composition to be microfluidized through a microfluidzer under one or more of the following conditions (1 ) a temperature in a range of 30-65°C, and more preferably 35-45 °C and/or (2) a pressure of 5,000-30,000 psi, more preferably 10,000-20,000 psi.
  • a preferred microfluidzer is a Microfluidics EH-110 microfluidizer (commercially available from Microfluidics, Inc.), but other microfluidizers may also be used.
  • the composition to be microfluidized may be passed through the microfluidizer for any number of discreet passes from 1 to 10 or more, but at least 3 passes is preferred.
  • the composition may be continuously passed through a microfluidizer until a stable particle size distribution is achieved. Either way, the composition may be microfluidized until the desired particle size for undissolved, suspended benzimidazole/MBZ is achieved.
  • microfluidization according to embodiments herein may achieve further reductions in undissolved benzimidazole/MBZ particle size in the composition, which may improve suspension uniformity over time in compositions according to embodiments herein in a suspension (or partial suspension) form and may improve MBZ skin penetration.
  • Example 6 For use in Example 6, the 45-147 MBZ concentrate batches of zero pass microfluidization (i.e. , not microfluidized) and 3-pass microfluidization as described above were then each mixed with an MBZ cream base (formula 45-149, according to the Trial Example 6 percentages in Table 4) in proportions that would create final MBZ treatment compositions containing 0.05%, 0.1 %, 0.25%, 0.5% and 1 % MBZ in the cream base vehicle (with ingredient amounts as shown in Table 5). This created a set of trial compositions that were microfluidized and a corresponding set (with the same ingredients/amounts) that were not microfluidized for testing in Example 6.
  • the topical MBZ cream base composition (also referred to as formulation 45-149) is an oil-in-water (O/W) type cream emulsion base vehicle, preferred embodiments of which are shown in Table 4.
  • O/W oil-in-water
  • the MBZ cream base preferably comprises an aqueous phase composition and an oil phase composition.
  • the aqueous phase composition is preferably made as follows: (1 ) mix the glycerin and phenoxyethanol together until a clear uniform solution is created; (2) add the deionized water to the solution with mixing; (3) heat the aqueous mixture to 60-70 °C, while continuing to mix/stir; (4) add the disodium EDTA with mixing until dissolved in the water phase; (5) slowly add the Carbomer 940 to the heated water phase by sprinkling on the water surface and mix for 45 minutes (maintaining temperature at 60-70 °C) until a uniform hydrated dispersion of the carbomer is created.
  • the oil phase composition is preferably separately made as follows: (1 ) mix the (a) cetyl alcohol, (b) stearyl alcohol, (c) glyceryl stearate (and) PEG 100 stearate (which is an emulsifier composition), and (d) polysorbate 80 together; (2) heat the mixture to 60-70 °C with mixing until a uniform liquid oil phase is created.
  • the MBZ cream base is preferably made by (1 ) adding the aqueous phase composition and the oil phase composition together; (2) heat to 60-70 °C with homogenization (Silverson L4RT-A homogenizer) at 5000-7000 rpm for 15-30 minutes; (3) cool to around 35-50°C, more preferably around 35 °C, and add the triethanolamine while mixing until a smooth and uniform mixture is formed; and (4) further cool to around 25 °C (around room temperature). As further described below, it is most preferred that the MBZ concentrate composition be added and mixed with the MBZ cream base composition prior to cooling in step (4).
  • the final MBZ treatment compositions according to these embodiments were made by mixing the required amount of MBZ concentrate composition, previously heated to 35-50 °C, with the required amount of MBZ cream base composition, also previously heated to 35-50 °C, in the desired proportions, followed by cooling to room temperature.
  • MBZ concentrate (45-147) not processed (“zero” passes) through an EH- 110 microfluidizer and MBZ concentrate microfluidized (3 passes) as described previously were both used to create test formulations shown in Table 5.
  • Table 5 shows the amounts of ingredients for the MBZ cream base 45-149 as added to varying amounts of MBZ concentrate composition 45-147 to create a range of MBZ topical treatment compositions referred to herein as 45-151 A through 45-151 E having 0.05% up to 1 % by weight MBZ.
  • Example 6 Skin PAMPA Testing for Permeation of MBZ With or Without Microfluidization
  • Example 6 For use in Example 6, the MBZ treatment compositions 45-151 A through 45-151 E from Example 5 (Table 5) were created twice where one set of the treatment compositions used the first half of the lab batch of MBZ concentrate 45-147 that had been processed through the microfluidizer (3 passes) as previously described and a second set of the treatment compositions used the second half of the lab batch of MBZ concentrate 45-147 that had not been processed (zero passes) through the microfluidizer.
  • the microfluidized set is referred to with an added “M” (/.e., 45-151 A- M through 45-151 E-M) and the not microfluidized set is referred to without the added “M” (J.e., 45-151A through 45-151 E).
  • the treatment compositions in Example 6 correspond to those of the same letter in Example 5 (Table 5).
  • 45-151A-M is the same as 45-151 A but the MBZ concentrate was processed through a microfluidizer in 45-151A-M.
  • MBZ treatment compositions 45-151A-M through 45-151 E-M (with microfiluidization of the MBZ concentrate) and 45-151A through 45-151 E (without microfluidization) were evaluated for skin penetration using the Skin PAMPA- Parallel Artificial Membrane Permeability Assay- in vitro artificial skin model (Pion, Inc.).
  • Another treatment composition comprising Vanicream® plus 10% by weight MBZ as used in Example 2 was also tested as a control for comparison to the MBZ treatment compositions using MBZ concentrate compositions and MBZ cream base compositions according to some preferred embodiments herein.
  • the Vanicream® plus 10% by weight MBZ (referred to treatment composition 45-151 G) is also considered an MBZ treatment composition according to an embodiment of the disclosure, but for purposes of these tests was treated as the control.
  • Table 6 lists the compositions tested in the Skin PAMPA skin model, where 150 microliters of each composition was applied to the Skin PAMPA artificial skin membrane and a PAMPA receptor (or acceptor media) fluid of 20% aqueous Hydroxypropyl-beta-cyclodextrin solution in a Prisma HT TM buffer.
  • Prisma HT TM is a proprietary universal buffer concentrate formed by several compounds with pKa values evenly spaced to produce a constant buffer capacity in the range pH 3-10.
  • the ionic strength of the PRISMA HTTM is about 10 mM. For all trials, measurements were taken at 1 , 6, and 24 hour intervals and the temperature was 32 °C. For some of the trials, measurements were also taken at 0.25 and 0.5 hour intervals.
  • negative controls of the MBZ cream base (without MBZ) and Vanicream (without MBZ added) were also evaluated in the SKIN PAMPA tests to measure any interference in the UV assay of MBZ in the PAMPA acceptor plate solution.
  • the UV absorbance of the negative control vehicles (Vanicream or MBZ cream base) was subtracted from the UV assay of their corresponding test compositions with MBZ. Table 6 lists the average permeated mass of MBZ through the artificial skin membrane, as well as the standard deviation, for each of the MBZ treatment compositions tested.
  • Table 7B lists total permeated mass of MBZ through the artificial skin membrane for each of the MBZ treatment compositions tested in Example 6.
  • Mebendazole flux and permeated amount is observed to increase with an increase of treatment composition loading, although permeated amount does not appear to increase proportionally with concentration of MBZ in the treatment compositions. Additionally, although the amounts using Vanicream® as the base vehicle for MBZ are slightly higher than when using the MBZ cream base as the base vehicle, no significant increase can be observed between the MBZ cream base vehicles containing 0.5 % or 1 % MBZ and the Vanicream plus 10% MBZ control.
  • the 45-151 G Vanicream plus 10% MBZ control uses 10-20X the amount of MBZ compared to the 1 % and 0.5% amounts in the treatment compositions using the MBZ concentrate (with its solvents designed to increase the solubility of the mebendazole and its penetration) in the MBZ cream base as the vehicle, there is a substantial improvement achieved through the use of the MBZ cream base according to preferred embodiments herein as they require substantially less active MBZ to achieve similar simulated dermal penetrations in the PAMPA model.
  • microfluidization processing used for the MBZ concentrate 45-147 and used in the 45-151 D-M and 45-151 E-M treatment compositions appears to have had no significant effect on MBZ penetration over the longer term 24 hour test. However, typically, the first 6 hours application is the more important interval for skin penetration and improvements were seen in that time frame for the microfluidized samples.
  • a thickened or gel composition containing MBZ is preferably one that can be directly applied to the skin with or without being pre-mixed with a separate vehicle or other vehicle ingredients, such as MBZ cream base compositions or Vanicream®.
  • MBZ cream base compositions or Vanicream® MBZ cream base compositions or Vanicream®.
  • gel is not intended to be limiting and includes thickened compositions, such as creams, ointments, suspensions, and emulsions, preferably having a viscosity of around 5,000 to 400,000 centipoise, more preferably of around 20,000 to 200,000 centipoise, that are suitable for application to human and/or animal skin.
  • MBZ gel compositions include MBZ in combination with one or more of the other ingredients as shown in Table 8.
  • Table 8 Mebendazole Gel Compositions
  • Table 9 lists preferred embodiments of MBZ gel compositions 45- 173A through 45-173F. According to one embodiment, these compositions were prepared and the at least partial dissolution of the MBZ in these compositions was achieved by: (1 ) moderate magnetic stirrer mixing of the Transcutol P and DMI and MBZ; (2) heating at the stated temperature (60, 70, 80, or 90 °C) for a first period of time of 5-15 minutes; (3) continuing to mix/stir during the heating step, such as by using the magnetic stirrer; and followed by (4) slow addition of water (preferably deionized), and any other ingredients (such as Natrosol gellant) at 35-50 °C , while continuing to mix/stir to force cooling to room temperature within 15 minutes.
  • water preferably deionized
  • any other ingredients such as Natrosol gellant
  • steps (1 )-(3) are carried out prior to the addition of water in step (4).
  • one or more other ingredients such as the viscosity modifying agents or gelling agents may be pre-mixed or pre-hydrated in the water prior to step (4).
  • a cyclodextrin compound preferably hydroxypropyl beta-cyclodextrin (Cavasol® W7 HP)
  • the cyclodextrin compound is preferably first dissolved in the deionized water prior to the addition of the viscosity modifying agent (preferably hydroxyethylcellulose (Natrosol)).
  • viscosity modifying agents such as carboxymethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate, Carbomer, or other pharmaceutically acceptable viscosity modifying agents may be used in place of or in addition to hydroxyethylcellulose (Natrosol).
  • Other ingredients that may improve or maintain stability of the compositions according to the disclosure such as antioxidants, including ascorbic acid or ascorbate salts or ascorbyl esters, ferulic acid, ubidecarenone, dl-alpha tocopherol, BHT, BHA, or other pharmaceutically acceptable antioxidants may be added to the compositions according to some embodiments herein, as will be understood by those of ordinary skill in the art. Such antioxidant ingredients may be beneficial in improving or maintaining MBZ product stability.
  • Example 8 Following the PAMPA study in Example 6, additional Skin PAMPA tests were conducted for Example 8.
  • the purpose of Example 8 was to evaluate compositions that contained soluble mebendazole and minor amounts of insoluble suspended mebendazole at varying concentrations of total mebendazole in a topical gel treatment composition to try to achieve maximum penetration of mebendazole.
  • Transcutol P is both a good solvent and penetrant for mebendazole and has been used in topical delivery systems at concentrations up to 45% by weight based on previous listing in the FDA Inactive Ingredient Database.
  • combinations of Transcutol P and dimethylisosorbide (DMI) were evaluated; however, the solubility of mebendazole did not appear to be significantly enhanced with the DMI, so Transcutol P was used without DMI in Example 8.
  • DMI dimethylisosorbide
  • Table 10 shows the amounts of ingredients for the MBZ topical treatment compositions 145-185A, 145-185C, and 145-185E, having 0.05% or 0.1 % by weight MBZ along with Transcutol P, Natrasol® 250HX, and water.
  • composition 145-185G comprised Vanicream® plus 10% by weight MBZ as a control for comparison to the MBZ treatment compositions using MBZ with varying amounts of Transcutol P according to some embodiments of the disclosure.
  • compositions with Transcutol P, Natrasol® 250HX, and water but no MBZ were also tested as controls, as was composition 145-185H which was Vanicream® without any MBZ.
  • the primary purpose of these tests was to evaluate varying amounts of MBZ with varying amounts of Transcutol P, which was previously identified as both a good solvent for MBZ and a good skin penetrant.
  • Dimethylisosorbide was not used in the treatment compositions in Example 8.
  • the Vanicream® plus 10% by weight MBZ using in 145-185G is also considered an MBZ treatment composition according to an embodiment of the disclosure, but for purposes of these tests was treated as the control.
  • MBZ treatment compositions 145-185A, 145-185C, 145-185E and the control compositions were evaluated for skin penetration using the Skin PAMPA- Parallel Artificial Membrane Permeability Assay- in vitro artificial skin model (Pion, Inc.).
  • a sample of 150 microliters of each composition was applied to the Skin PAMPA artificial skin membrane (donor plate) with a PAMPA receptor (or acceptor media) fluid of 20% aqueous Hydroxypropyl-beta-cyclodextrin solution in a Prisma buffer. This is the same acceptor media used in Example 6.
  • Six replicates for each composition were tested. For all trials, measurements were taken at 0.25, 0.5, 1 , 6, and 24 hour intervals and the temperature was 32 °C.
  • a reference plate of known standards of MBZ with a 20% aqueous Hydroxypropyl-beta-cyclodextrin solution, with concentration ranges of 3.125-62.5 pg/mL were also evaluated in the SKIN PAMPA tests and the sum of absorbance within a wavelength range of 310-370 nm was used for sample quantitation for any interference in the UV assay of MBZ in the PAMPA acceptor plate solution. The UV absorbance of these known samples was subtracted from the UV assay of their corresponding test compositions with MBZ.
  • Tables 11A-11 B list the average permeated mass of MBZ through the artificial skin membrane, as well as the standard deviation, for each of the MBZ treatment compositions tested. [0102] Table 11A - Average Permeated Mass of Mebendazole at each time point/SKIN PAMPA for Example 8
  • Table 11 C lists total permeated mass of MBZ through the artificial skin membrane for each of the MBZ treatment compositions tested in Example 8.
  • FIG. 4 is a graph depicting flux values at 0-6 hours compared to 6-24 hours for MBZ treatment compositions in Example 8.
  • Example 8 The controls without MBZ had zero permeated MBZ, as expected.
  • treatment composition 145-185C had the highest permeability across all time points, reaching a maximum normalized permeated amount of MBZ of 16.4 pg/cm2, despite being the lowest concentration of MBZ (0.05%) and lowest concentration of Transcutol P (20%) of the treatment compositions tested.
  • the second highest permeating formulation tested in this study was 145-185G, which is the Vanicream plus 10% MBZ treatment composition, reaching a maximum normalized permeated amount of MBZ of 16.1 pg/cm2.
  • treatment composition 145-185G Given the much higher concentration of MBZ in treatment composition 145-185G, a higher permeated amount is expected; however, the fact that treatment composition 145-185C had such a permeated amount (and even higher than 145-185G) with so much less MBZ in the treatment composition was unexpected.
  • Example 6 the permeability of mebendazole through the PAMPA membrane is slow; however, unlike in Example 6, mebendazole in Example 8 can be observed in the acceptor plate at the 30 minute time point for treatment compositions 145-185A, 145-185C, 145-185E and 145-185G.
  • the treatment compositions in Example 8 also have a higher flux in the 0-6 hour time than the 6-24 hour time points. This is true for all four treatment compositions containing mebendazole (145-185A, 145-185C, 145-185E and 145- 185G). This shows an improved absorbance in the relevant time point for a topical drug for these treatment compositions according to embodiments herein.
  • treatment composition 145-185G had a lower permeability than previously observed for the 45-151 G Vanicream plus 10% MBZ treatment composition used in Example 6.
  • Treatment composition 145-185G is materially the same as 45-151 G except for a storage period between the time the tests for Examples 6 and 8 were conducted.
  • the results in Example 8 show approximately four times lower cumulative permeated mass and flux than previously identified in Example 6.
  • treatment composition 45-151 G had 75.98 pg/cm 2 total permeated mass at 24 hours, with a flux of 0.024 pg/cm 2 /min at 0-6 hours and 0.013 pg/cm 2 /min.
  • treatment composition 145-185g had 16.09 pg/cm 2 total permeated mass at 24 hours, with a flux of 0.148 pg/cm 2 /min at 0-6 hours and 0.01 pg/cm 2 /min at 6-24 hours.
  • these differences appear to due to changes in the UV active compounds in the Vanicream or in other structural changes in the Vanicream components or emulsion occurring between the time the tests for Example 6 were conducted and the tests for Example 8 and 9 were conducted, which could cause shifting in the base line spectra or permeation restrictions due to emulsion structural changes biasing results.
  • treatment composition 145-185C comprising 20% Transcutol P and 0.05% MBZ had higher flux/penetration and total normalized 24hr penetration (pg/cm 2 ) than treatment composition 145-185E comprising 0.1 % MBZ with 40% Transcutol P and treatment composition 145-185A comprising 0.05% MBZ and 40% Transcutol P.
  • the ratio of Transcutol P to water for treatment composition 145-185C was approximately 1 :4.
  • Example 9 Additional Skin PAMPA Testino With Different Receptor Fluid
  • additional Skin PAMPA tests were conducted on the same treatment compositions 145-185A, 145-185C, 145-185E, and 145-185G as used in Example 8 (see Table 10) using different receptor fluids (or acceptor media).
  • Example 9 repeated the testing of Example 8 for these treatment compositions with two new receptor fluids (or acceptor media) for comparison to the 20% hydroxypropyl beta-cyclodextrin (Cavasol®) used in Example 8. These two new receptor fluids were: (1 ) 20% dimethylsulfoxide (DMSO), and (2) 20% Polysorbate 80 (Tween 80) surfactant. Each receptor fluid also included Prisma buffer. Samples were taken at 1 hour, 6 hours, and 24 hours. The results of Example 9 were somewhat mixed. Table 12 lists total permeated mass of MBZ through the artificial skin membrane for each of MBZ treatment compositions tested with different receptor fluids.
  • FIGS. 6A-6B are tables showing the data from Examples 6, 8, and 9 for comparison.
  • each of treatment compositions 145-185C, 145-185-E, and 145-185G showed higher cumulative (total) permeated mass for the compositions in the initial PAMPA testing with 20% Cavasol compared to the 20% DMSO acceptor solutions at the 24-hour time point.
  • 145-185E reached 2.74 pg in Cavasol and 0.06 pg in DMSO, which is surprising given the solubility of MBZ in DMSO.
  • treatment composition 145-185E showed a higher cumulative mass at the 6- hour time point in the DMSO (1.305 pg) compared to the Cavasol (0.29 pg), which performed the lowest at this time point. This is reflected in the flux data in FIG. 5 with the DMSO acceptor having a much greater flux at 0-1 hour and 0-6-hours time intervals compared to the Cavasol acceptor for treatment composition 145-185-E. Additionally, for treatment compositions 145-185C and 145-185G, total permeated mass at the 24-hour time point was higher in DMSO than in Tween, but was the opposite for treatment composition 145-185E.
  • Treatment compositions 45-151 B-M (a cream with 0.1 % MBZ with microfluidization) and 45-151 B (a cream with 0.1 % MBZ without microfluidization) from Example 6 can also be compared to the treatment compositions in Example 9.
  • the full list of ingredients for these treatment compositions is included in Table 5 (for 45-151 B), but each included 84.05% water, 1 .06% dimethyl isosorbide, and 0.55% Transcutol P.
  • the highest cumulative permeated mass at 24 hours was the microfluidized treatment composition 45-151 B-M with 25 pg/cm 2 whereas treatment composition 45-151 B without microfluidization was 16.8 pg/cm 2 ..
  • Both treatment compositions 45-151 B and 45-151 B-M have a greater average permeated mass than treatment composition 145-185-E in Cavasol at the earlier 6-hour time point, at 2.19 pg, 2.31 pg, 0.29 pg, respectively. It should be noted that this is similar to the 0.05% formulations 145-185C, 45-151A-M and 45-151A in Cavasol for which the 6-hour time points are 0.426 pg, 1.94 pg, and 1.84 pg, respectively. [0119] In the Tween acceptor solution, treatment composition 145-185C reached the lowest total permeated mass (7.5 pg), with the 20% Cavasol performing the best (16.4 pg), after 24 hours.
  • the 45-151 series of MBZ cream formulations and the 10% MBZ in Vanicream contain a large excess of undissolved MBZ compared to the mostly solubilized MBZ with minor amounts of suspended MBZ in the 145-185 MBZ gel formulation series.
  • the high amounts of undissolved and suspended MBZ in the 45-151 formula series results in relatively higher flux and MBZ permeation in the 6-24 hour time frame and relatively low flux and penetration in the 0-6 hour time frame.
  • the 145-185 formulations, and particularly the 145-185 A and 145-185C (0.05% MBZ) formulations showed higher flux and average permeated mass during the important 0-6 hr time frames for daily use topical facial product application..
  • treatment composition 145-185C (0.05% MBZ) with a 20% Cavasol acceptor solution has a greater flux within the first hour (0.11 pg), compared to both treatment compositions 45-151 A and 45-151 B-M where flux results of 0.03 pg and 0.02 pg were found, respectively, also in the presence of a 20% Cavasol acceptor solution.
  • a similar trend of greater flux for treatment composition 145-185C can be seen with the 20% DMSO acceptor solution.
  • the increased 0-1 hour flux of treatment composition 145-185-C compared to the previous 0.05% MBZ treatment compositions may be significant for pharmacological activity due to the length of time it is practical for cream-based treatment compositions to be absorbed through a patient’s skin.
  • the average permeated mass of MBZ in the first 30 minutes is nearly 10 times higher for 145-185C (Cavasol receptor) vs any of the 45-151 or 45-151 -M series formulations at this early time point.
  • Treatment composition 145-185-E (0.1 % MBZ) and using 20% Tween or 20% Cavasol shows a lower 0-1 hour, 0-6 hours and 6-24 hours flux compared to the 0.1 % formulations in Example 6 (45-151 B-M and 45-151 B).
  • the DMSO solution does appear to improve the 0-1 hour and 0-6 hours flux of treatment composition 145-185-E compared to the Cavasol acceptor.
  • the improvement with 20% DMSO is not as great for the 0.1 % mebendazole treatment composition 145-185E as compared to the 0.05% mebendazole treatment composition 145-185C. Without being bound by theory, this could occur due to the permeability of DMSO passing through the membrane and solubilizing the MBZ, whilst with the cyclodextrin only draws the already solubilized MBZ into the acceptor solution.
  • Table 14 lists the average permeated mass of MBZ through the artificial skin membrane, as well as the standard deviation, for each of the MBZ treatment compositions tested in Example 9. This data can be compared to Tables 11A-11 B for these treatment composition in the Cavasol receptor fluid.
  • Example 9 From the results in Example 8, the 24-hour total mebendazole permeated amount was higher for the Ex. 145-185C treatment composition compared to both Exs. 145-185A and 145-185E treatment compositions with the cyclodextrin receptor. As can be seen in Example 9, the Ex. 145-185C treatment composition also had higher total 24- hour penetration amounts as compared to Ex. 145-185E with 20% DMSO as the acceptor. The 20% Tween receptor gave lower flux rates and lower total penetration than the cyclodextrin or the DMSO for all the test formulations but the lower flux rates for the Exs. 145-185C and 145-185E were comparable.
  • the 145-185-C treatment composition In addition to the surprising results that showed the 145-185-C treatment composition to deliver higher amount of mebendazole at lower concentrations of both the API (MBZ) and the Transcutol P solvent/penetrant, the 145-185-C treatment composition also delivers more mebendazole in a shorter period of time; i.e., a faster rate of mebendazole penetration.
  • Tables 11A-11 B show the flux rates or average permeated mass of mebendazole/time period for the 145-185C treatment composition in the Cavasol receptor fluid to be clearly higher than the 145-185A and 145-185E treatment compositions in the Cavasol receptor fluid during the 0-6 hour period.
  • treatment composition 145-185C Similar faster and higher flux rates are also shown for the 145-185C treatment composition compared to the 1 5-185E treatment composition in Table 14 for 0-1 hour and 0-6 hour periods in the DMSO and Tween receptor fluids. These results indicate that treatment composition 145- 185C according to an embodiment herein has a faster rate of penetration in each of the three different receptor fluid solvents tested - hydroxypropyl beta-cyclodextrin, DMSO, and Tween 80.
  • the penetration amount for 145-185-C was statistically greater than 145-185-A (0.05% MBZ/40% Transcutol) at the 95% confidence limit and 145-185-C (0.05% MBZ/20% Transcutol) penetration amount was greater than 145-185-E (0.1 % MBZ/40% Transcutol) at the 90% confidence limit.
  • additional MBZ gel compositions include MBZ in combination with one or more of the other ingredients as shown in Tables 17-18.
  • topical compositions, MBZ concentrate compositions, and MBZ treatment compositions comprise ingredients and amounts according to one or more of the following Embodiments: [0137] Embodiment 1 .
  • An aqueous topical composition for treating or preventing an inflammatory or autoimmune disease or condition of human skin comprising 0.01 to 1 % of one or more benzimidazole compounds and 15 to 45% of an ethylene glycol based solvent, the percentages by weight of the topical composition, wherein the one or more benzimidazole compounds are (1 ) fully dissolved in the aqueous topical composition, or (2) remain undissolved and suspended in the aqueous topical composition, or (3) partially dissolved in the aqueous topical composition and partially undissolved and suspended in the aqueous topical composition.
  • Embodiment 2 The topical composition of Embodiment 1 wherein the ethylene glycol based solvent comprises diethylene glycol monoethyl ether; and wherein the one or more benzimidazole compounds comprises mebendazole.
  • Embodiment 3 The topical composition of Embodiment 2 wherein topical composition is in a gel form and further comprises water and a viscosity modifying agent.
  • Embodiment 4 The topical composition of Embodiment 3 wherein the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 5 The topical composition of Embodiment 4 comprising around 0.5 to 1.5% of the hydroxyehtylcellulose.
  • Embodiment 6 The topical composition of any one of Embodiments 1 -5 wherein the one or more benzimidazole compounds comprises mebendazole and wherein the disease or condition comprises any form of rosacea.
  • Embodiment 7 The topical composition of any one of Embodiments 2-6 wherein the topical composition comprises: around 0.03 to 0.07% of the mebendazole; around 18 to 22% of the diethylene glycol monoethyl ether.
  • Embodiment 8 The topical composition of any one of Embodiments 1 -7 further comprising a cyclodextrin compound.
  • Embodiment 9 The topical composition of Embodiment 8 wherein the cyclodextrin compound comprises hydroxypropyl beta-cyclodextrin.
  • Embodiment 10 The topical composition of Embodiment 9 comprising around 5 to 9% of the hydroxypropyl beta-cyclodextrin.
  • Embodiment 11 The topical composition of any one of Embodiments 1 - 10 wherein topical composition is in a gel form and further comprises water and a viscosity modifying agent.
  • Embodiment 12 The topical composition of Embodiment 11 wherein the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 13 The topical composition of Embodiment 12 comprising around 0.5 to 1.5% of the hydroxyehtylcellulose.
  • Embodiment 14 A topical composition for treating or preventing an inflammatory or autoimmune disease or condition of human skin comprising 0.25 to 20% of one or more benzimidazole compounds, the percentage by weight of the topical composition.
  • Embodiment 15 The topical composition of Embodiment 14 further comprising a carrier suitable for application to human skin.
  • Embodiment 16 The topical composition of Embodiment 15 wherein the carrier comprises a cream, gel, lotion, liquid, emulsion, aerosol spray, non-aerosol spray, suspension, or ointment.
  • Embodiment 17 The topical composition of any one of Embodiments 15-
  • Embodiment 18 The topical composition of any one of Embodiments 14-
  • Embodiment 19 The topical composition of any one of Embodiments 14-
  • the disease or condition comprises any form of rosacea.
  • Embodiment 20 The topical composition of any one of Embodiments 14-
  • the one or more benzimidazole compounds comprises one or more of fenbenzadole, albenzadole, and thiabenzadole.
  • Embodiment 21 The topical composition of any one of Embodiments 14-
  • topical composition comprises around 1 -30% of a mebendazole concentrate composition and around 70-99% of vehicle composition suitable for application to human skin, the percentages by weight of the topical composition.
  • Embodiment 22 The topical composition of Embodiment 21 wherein the mebendazole concentrate composition comprises: around 1-10% mebendazole; around 32-45% of a sorbitol based solvent; around 15-25% of a glycol based solvent comprising an ethylene glycol based solvent, or a propylene glycol based solvent, or both; and around 32-45% total of a solubilizer or emulsifying agent or both; and wherein the percentages are by weight of the mebendazole concentrate composition.
  • Embodiment 23 The topical composition of Embodiment 22 wherein: the sorbitol based solvent comprises dimethyl isosorbide; the ethylene glycol based solvent comprises diethylene glycol monoethyl ether and the propylene glycol based solvent comprises propylene glycol monolaurate; and the solubilizer comprises polyoxyl 40 hydrogenated castor oil.
  • Embodiment 24 The topical composition of any one of Embodiments 14-
  • topical composition comprises around 0.01 to 1 % mebendazole by weight of the topical composition.
  • Embodiment 25 The topical composition of any one of Embodiments 14-
  • topical composition has a viscosity of around 5000 to 400,000 centipoise.
  • Embodiment 26 The topical composition of any one of Embodiments 14-
  • the one or more benzimidazole compounds (or mebendazole) as an ingredient prior to any dissolution in the topical composition (or the mebendazole concentrate composition) comprise solid particles and wherein at least 50% of the solid particles have a particle size of around 3.5 to 4.0 microns or less.
  • Embodiment 27 An aqueous mebendazole treatment composition for topically treating or preventing an inflammatory or autoimmune disease or condition of human skin, the aqueous mebendazole treatment composition comprising: around 0.01 -1 % of one or more benzimidazole compounds; around 5-25% of a sorbitol based solvent; and/or around 15-50% of a glycol based solvent comprising an ethylene glycol based solvent, or a propylene glycol based solvent, or both; and wherein the percentages are by weight of the aqueous mebendazole treatment composition.
  • Embodiment 28 The aqueous mebendazole treatment composition of Embodiment 27 wherein: the one or more benzimidazole compounds comprises mebendazole; and/or the sorbitol based solvent comprises dimethyl isosorbide; and/or the ethylene glycol based solvent comprises diethylene glycol monoethyl ether; and/or the propylene glycol based solvent comprises propylene glycol monolaurate; and/or wherein the aqueous mebendazole composition has a viscosity of around 5,000 to 400,000 centipoise and/or wherein the 50% the mebendazole has a particle size of around 3.5 to 4.0 microns or less as an ingredient prior to any dissolution in the aqueous mebendazole composition.
  • Embodiment 29 The aqueous mebendazole treatment composition of any one of Embodiments 27-28 further comprising: around 1 -10% total of a solubilizer or emulsifying agent or both; around 1 -15% of a cyclodextrin compound; and/or around 0.5-3% of a viscosity modifying agent.
  • Embodiment 30 The aqueous mebendazole treatment composition of Embodiment 29 wherein: the solubilizer comprises polyoxyl 40 hydrogenated castor oil; the cyclodextrin compound comprises hydroxypropyl beta-cyclodextrin; and/or the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 31 The aqueous mebendazole treatment composition of any one of Embodiments 27-30 wherein the composition is a gel.
  • Embodiment 32 The aqueous mebendazole treatment composition of any one of Embodiments 27-31 wherein the glycol based solvent is both the diethylene glycol monoethyl ether and the propylene glycol monolaurate in a weight ratio of around 55:45 to 65:35.
  • the glycol based solvent is both the diethylene glycol monoethyl ether and the propylene glycol monolaurate in a weight ratio of around 55:45 to 65:35.
  • Embodiment 33 An aqueous topical suspension for treating or preventing an inflammatory or autoimmune disease or condition of human skin comprising: (1 ) 0.01 to 1 % of one or more benzimidazole compounds, wherein at least some of the one or more benzimidazole compounds remain in undissolved form in the aqueous topical suspension; and (2) 15 to 45% of an ethylene glycol based solvent; wherein the percentages are by weight of the aqueous topical suspension; and wherein the aqueous topical suspension does not include any aprotic solvents.
  • Embodiment 34 The aqueous topical suspension of Embodiment 33 wherein the ethylene glycol based solvent comprises diethylene glycol monoethyl ether; and wherein the one or more benzimidazole compounds comprises mebendazole.
  • Embodiment 35 The aqueous topical suspension of any one of Embodiments 33-34 wherein aqueous topical suspension is in a gel form and further comprises water and a viscosity modifying agent.
  • Embodiment 36 The aqueous topical suspension of Embodiment 35 wherein the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 37 The aqueous topical suspension of Embodiment 36 comprising around 0.5 to 1.5% of the hydroxyehtylcellulose.
  • Embodiment 38 The aqueous topical suspension of any one of Embodiments 33-37 wherein the one or more benzimidazole compounds comprises mebendazole.
  • Embodiment 39 The aqueous topical suspension of any one of Embodiments 34-38 wherein the aqueous topical suspension comprises:(1 ) around 0.03 to 0.07% of the mebendazole; and (2) around 18 to 22% of the diethylene glycol monoethyl ether.
  • Embodiment 40 The aqueous topical suspension of any one of Embodiments 33-39 further comprising a cyclodextrin compound.
  • Embodiment 41 The aqueous topical suspension of Embodiment 40 wherein the cyclodextrin compound comprises hydroxypropyl beta-cyclodextrin.
  • Embodiment 42 The aqueous topical suspension of Embodiment 41 comprising around 5 to 9% of the hydroxypropyl beta-cyclodextrin.
  • Embodiment 43 The aqueous topical suspension of any one of Embodiments 33-42 wherein aqueous topical suspension is in a gel form and further comprises water and a viscosity modifying agent.
  • Embodiment 44 The aqueous topical suspension of Embodiment 43 wherein the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 45 The aqueous topical suspension of Embodiment 44 comprising around 0.5 to 1.5% of the hydroxyehtylcellulose.
  • Embodiment 46 The aqueous topical suspension of any one of Embodiments 34-45 wherein the topical composition comprises: around 0.03 to 0.07% of the mebendazole; around 18 to 22% of the diethylene glycol monoethyl ether.
  • Embodiment 47 The aqueous topical suspension of any one of Embodiments 34-46 wherein the one or more benzimidazole compounds comprises one or more of fenbenzadole, albenzadole, and thiabenzadole.
  • Embodiment 48 The aqueous topical suspension of any one of Embodiments 34-47 wherein the topical composition comprises around 1 -30% of a mebendazole concentrate composition and around 70-99% of vehicle composition suitable for application to human skin, the percentages by weight of the aqueous topical suspension.
  • Embodiment 49 The aqueous topical suspension of Embodiment 48 wherein the mebendazole concentrate composition comprises: around 1 -10% mebendazole; around 32-45% of a sorbitol based solvent; around 15-25% of a glycol based solvent comprising an ethylene glycol based solvent, ora propylene glycol based solvent, or both; and around 32-45% total of a solubilizer or emulsifying agent or both; and wherein the percentages are by weight of the mebendazole concentrate composition.
  • Embodiment 50 The aqueous topical suspension of Embodiment 49 wherein: the sorbitol based solvent comprises dimethyl isosorbide; the ethylene glycol based solvent comprises diethylene glycol monoethyl ether and the propylene glycol based solvent comprises propylene glycol monolaurate; and the solubilizer comprises polyoxyl 40 hydrogenated castor oil.
  • Embodiment 51 The aqueous topical suspension of any one of Embodiments 33-50 wherein the aqueous topical suspension has a viscosity of around 5000 to 400,000 centipoise.
  • Embodiment 52 The aqueous topical suspension of any one of Embodiments 33-51 wherein the one or more benzimidazole compounds as an ingredient prior to any dissolution in the aqueous topical suspension (or the mebendazole concentrate composition) comprise solid particles and wherein at least 50% of the solid particles have a particle size of around 3.5 to 4.0 microns or less.
  • a method of treating or preventing an inflammatory or autoimmune disease or condition of human or animal skin comprises steps, ingredients, and amounts according to one or more of the following Embodiments:
  • Embodiment 53 A method for treating or preventing an inflammatory or autoimmune disease or condition of human skin, the method comprising applying a topical composition comprising a carrier and 0.01 to 20% by weight of one or more benzimidazole compounds to an area of a subject's skin affected by the disease or condition.
  • Embodiment 54 The method of Embodiment 53 wherein the carrier is aqueous.
  • Embodiment 55 The method of any one of Embodiments 53-54 wherein the carrier comprises a cream, gel, lotion, liquid, emulsion, aerosol spray, non-aerosol spray, suspension, or ointment for topical application to skin.
  • the carrier comprises a cream, gel, lotion, liquid, emulsion, aerosol spray, non-aerosol spray, suspension, or ointment for topical application to skin.
  • Embodiment 56 The method of any one of Embodiments 53-55 wherein the one or more benzimidazole compounds comprises mebendazole
  • Embodiment 57 The method of any one of Embodiments 53-56 wherein the disease or condition comprises any form of rosacea.
  • Embodiment 58 The method of any one of Embodiments 52-57 wherein the applying step is repeated at least once per day for a treatment period comprising at least two weeks.
  • Embodiment 59 The method of any one of Embodiments 53-58 wherein the applying step comprises applying around 0.025 to 0.5 g to each side of the facial skin affected by rosacea of the topical composition.
  • Embodiment 60 The method of any one of Embodiments 53-59 wherein the method achieves a reduction in the number of cutaneous cytotoxic CD+8 T-cells of 50% or greater in the area of skin at the end of the treatment period compared to a number of cutaneous cytotoxic CD+8 T-cells in the area prior to the treatment period.
  • Embodiment 61 The method of any one of Embodiments 53-60 wherein the method achieves a reduction of a number of papules or pustules or diffuse redness intensity of 25% or greater on the area of skin at the end of the treatment period compared a number of papules or pustules on the area prior to the treatment period.
  • Embodiment 62 The method of any one of Embodiments 53-60 wherein the method achieves a reduction of a number of papules or pustules or diffuse redness intensity of 25% or greater on the area of skin at the end of the treatment period compared a number of papules or pustules on the area prior to the treatment period.
  • any one of Embodiments 53-61 further comprising repeating the applying step at least once per day for a treatment period comprising at least twelve weeks; wherein the one or more benzimidazole compounds comprises mebendazole; wherein the carrier comprises a cream, gel, lotion, liquid, emulsion, aerosol spray, non-aerosol spray, suspension, or ointment for topical application to skin; wherein the disease or condition comprises any form of rosacea; and wherein the method achieves a reduction in the number of cutaneous cytotoxic CD+8 T-cells of 50% or greater in the area of skin at the end of the treatment period compared to a number of cutaneous cytotoxic CD+8 T-cells in the area prior to the treatment period.
  • Embodiment 63 The method of any one of Embodiments 53-62 wherein the topical composition is according to any one of Embodiments 1 -13.
  • Embodiment 64 The method of any one of Embodiments 532-62 wherein the topical composition is according to any one of Embodiments 14-26.
  • Embodiment 65 The method of any one of Embodiments 53-62 wherein the topical composition is the aqueous mebendazole treatment composition according to any one of Embodiments 27-32.
  • Embodiment 66 The method of any one of Embodiments 53-62 wherein the topical composition is the aqueous topical suspension according to any one of Embodiments 33-52.
  • Embodiment 67 A method for treating or preventing an inflammatory or autoimmune disease or condition of human skin, the method comprising applying a topical composition comprising to an area of human skin affected by the disease or condition; wherein the topical composition comprises an aqueous carrier and 0.01 to 1 % by weight of one or more benzimidazole compounds; and wherein the aqueous topical suspension does not include any aprotic solvents.
  • Embodiment 68 The method of Embodiment 67 wherein the topical composition is in a suspension form wherein at least some of the one or more benzimidazole compounds are in undissolved form suspended in the topical composition.
  • Embodiment 69 The method of any one of Embodiments 67-68 wherein the one or more benzimidazole compounds comprises mebendazole and wherein the disease or condition comprises any form of rosacea.
  • Embodiment 70 The method of any one of Embodiments 67-69 wherein applying the topical composition is repeated at least once per day for a treatment period comprising at least two weeks; and wherein applying the topical composition comprises applying around 0.025 to 0.5 g to the area of human skin; and wherein the area of human skin comprises facial skin.
  • Embodiment 71 The method of any one of Embodiments 67-70 wherein the method achieves a reduction in the number of cutaneous cytotoxic CD+8 T-cells of 50% or greater in the area of human skin at an end of the treatment period compared to a number of cutaneous cytotoxic CD+8 T-cells in the area of human skin prior to the treatment period.
  • Embodiment 72 The method of any one of Embodiments 67-71 wherein the topical composition is according to any one of Embodiments 1 -13.
  • Embodiment 73 The method of any one of Embodiments 67-71 wherein the topical composition is according to any one of Embodiments 14-26.
  • Embodiment 74 The method of any one of Embodiments 67-71 wherein the topical composition is the aqueous mebendazole treatment composition according to any one of Embodiments 27-32.
  • Embodiment 75 The method of any one of Embodiments 67-71 wherein the topical composition is the aqueous topical suspension according to any one of Embodiments 33-52.
  • a method of making a benzimidazole treatment composition, or a mebendazole treatment composition, for topically treating or preventing an inflammatory or autoimmune disease or condition of human skin comprises steps, ingredients, and amounts according to one or more of the following paragraphs:
  • Embodiment 76 A method of making a benzimidazole treatment composition for topically treating or preventing an inflammatory or autoimmune disease or condition of human skin, the method comprising: (1 ) adding an amount of one or more solvents and an amount of one or more benzimidazole compounds to form a first mixture; and (2) heating the first mixture to a first temperature within a first temperature range for a first period of time while mixing or stirring to form a heated mixture; and wherein the amount of the one or more benzimidazole compounds is around 0.01 -1 .0, preferably around 0.01 -0.2%, more preferably 0.01 -0.075%, by weight of the benzimidazole treatment composition.
  • Embodiment 77 The method of Embodiment 76 wherein the first period of time is around 5 to 20 minutes, more preferably around 5 to 15 minutes; and/or wherein the first temperature range is at least 60 °C but less than a temperature at which the one or more benzimidazole compounds will experience degradation of 5% or more.
  • Embodiment 78 The method of any one of Embodiments 76-77 wherein the amount of mebendazole is 0.05-0.075%.
  • Embodiment 79 The method of any one of Embodiments 76-78 wherein the first temperature range is 60-90 °C.
  • Embodiment 80 The method of any one of Embodiments 76-78 wherein the first temperature range is 70-100 °C, more preferably 70-90 °C .
  • Embodiment 81 The method of any one of Embodiments 76-80 wherein the first period of time is 5 to 15 minutes.
  • Embodiment 82 The method of any one of Embodiments 76-81 wherein the one or more solvents comprise a sorbitol based solvent, or a glycol based solvent or both.
  • Embodiment 83 The method of Embodiment 82 wherein: (1 ) the sorbitol based solvent comprises dimethyl isosorbide; and/or (2) the glycol based solvent comprises diethylene glycol monoethyl ether, propylene glycol monolaurate, or both.
  • Embodiment 84 The method of any one of Embodiments 76-83 further comprising: cooling the heated composition to a second temperature within a second range of temperatures by adding water and mixing or stirring to form a cooled composition; and wherein the second range of temperatures is around 35-50 °C.
  • Embodiment 85 The method of Embodiment 84 wherein the cooling the heated mixture is completed in 15 minutes or less.
  • Embodiment 86 The method of any one of Embodiments 84-85 further comprising dissolving an amount of a viscosity modifying agent or an amount of an antiprecipitation agent or both in the water prior to the cooling step.
  • Embodiment 87 The method of Embodiment 86 wherein the viscosity modifying agent comprises hydroxyethylcellulose.
  • Embodiment 88 The method of any one of Embodiments 86-87 wherein the anti-precipitation agent comprises a cyclodextrin compound and the amount of the anti-precipitation agent is around 2-10% by weight of the mebendazole treatment composition.
  • Embodiment 89 The method of Embodiment 88 wherein cyclodextrin compound comprises hydroxypropyl beta-cyclodextrin.
  • Embodiment 90 The method of any one of Embodiments 86-89 wherein the heated composition or the cooled composition or the mebendazole treatment composition is microfluidized in a microfluidizer at 5,000-30,000 psi for at least one pass.
  • Embodiment 91 The method of Embodiment 90 wherein the heated composition or the cooled composition or the mebendazole treatment composition is microfluidized in a microfluidizer at 5,000-20,000 psi for at least three passes.
  • Embodiment 92 The method of any one of Embodiments 86-89 wherein the method does not comprise a microfluidization step.
  • Embodiment 93 The method of any one of Embodiments 76-88 wherein the heated composition or the benzimidazole treatment composition is microfluidized in a microfluidizer at 5,000-30,000 psi for at least one pass.
  • Embodiment 94 The method of Embodiment 93 wherein the heated composition or the benzimidazole treatment composition is microfluidized in a microfluidizer at 5,000-20,000 psi for at least three passes.
  • Embodiment 95 The method of any one of Embodiments 76-94 wherein the benzimidazole treatment composition has a viscosity of around 5,000 to 400,000 centipoise.
  • Embodiment 96 The method of any one of Embodiments 76-95 wherein the one or more benzimidazole compounds as an ingredient prior to adding and mixing with the one or more solvents comprises solid particle, the method further comprising micronizing the one or more benzimidazole compounds so that at least 50% of the solid particles have a particle size of around 3.5 to 4.0 microns prior to the adding step.
  • Embodiment 97 The method of any one of Embodiments 76, 78, or 82- 96 wherein the first temperature range is 25-50 °C and the first time period is 15-30 minutes.
  • Embodiment 98 The method of any one of Embodiments 76-97 wherein at least some of the one or more benzimidazole compounds remains in undissolved form and suspended in the mebendazole treatment composition.
  • Embodiment 99 The method of any one of Embodiments 76-98 wherein the benzimidazole treatment composition does not include any aprotic solvents.
  • Embodiment 100 The method of any one of Embodiments 76-99 wherein the one or more benzimidazole compounds comprises one or more of fenbenzadole, albenzadole, and thiabenzadole.
  • Embodiment 101 The method of any one of Embodiments 76-99 wherein the one or more benzimidazole compounds comprises mebendazole.
  • Embodiment 102 The method of any one of Embodiments 76-99 wherein the benzimidazole treat composition is according to any one of Embodiments 1 -13.
  • Embodiment 103 The method of any one of Embodiments 76-99 wherein the benzimidazole treat composition is according to any one of Embodiments 14-26.
  • Embodiment 104 The method of any one of Embodiments 76-99 wherein the benzimidazole treat composition is the aqueous mebendazole treatment composition according to any one of Embodiments 27-32.
  • Embodiment 105 The method of any one of Embodiments 76-99 wherein the benzimidazole treatment composition is the aqueous topical suspension according to any one of Embodiments 33-52.
  • Embodiments of compositions and methods of the disclosure are capable of achieving one or more of the following benefits: (1 ) reducing T-lymphocyte cell density by at least around 50 %, more preferably by at least around 90 % compared to before treatment with a mebendazole composition; (2) reducing the number of papules and/or pustules or diffuse redness on the skin of a rosacea patient by at least around 25%, more preferably by at least around 75% compared to before treatment with a mebendazole composition; (3) reducing the appearance of swelling on the skin compared to before treatment with a mebendazole composition; (4) reducing a level of itchiness, or hot or burning sensation on the skin compared to before treatment with a mebendazole composition; and/or (5) for the treatment of erythematotelangiectactic rosacea, a significant reduction in the redness “a” or “a*” value of the facial skin is demonstrated with the topical mebenzadole
  • the “a” or “a*” value is an objective measurement of redness as measured by the Hunter L,a,b (Hunter Labs) and CIE L*a*b* (CIELAB) colorimeters, the Minolta CR type colorimeters or other suitable colorimeter or chromameter. Visible changes in redness can be detected in colorimeter a* units as low as 0.2 units and a decrease in one (1 .0) or more a or a* colorimeter units after topical treatment of erythematotelangiectactic rosacea is generally considered to show clinical efficacy.
  • Embodiments of MBZ treatment compositions and methods according to the disclosure are also capable of achieving cumulative skin penetrations after 24 hours of at least 5 ug of MBZ , more preferably at least 10 pg, most preferably at least 15pg. These amounts are as measured in acceptor solution using the Skin PAMPA tests described herein and based on application of 150 pL MBZ Treatment Composition to 0.3 cm 2 artificial skin membrane.
  • any ingredient other than the benzimidazole described as included in an embodiment herein may also be excluded from such embodiment. Unless specifically excluded, any ingredients, preferred features, and/or optional ingredients any treatment composition embodiment and/or method steps described herein may be used with any other embodiment, even if not specifically described herein with that particular embodiment.
  • Any treatment composition embodiment herein may comprise, consist essentially of, or consist of any combination of ingredients described herein.
  • References herein to water include potable water, distilled water, deionized water, or other forms of purified, filtered, or cleaned water suitable for use in topical skin treatment compositions. These forms of water may be substituted for references herein to deionized water, other than in the claims.

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Abstract

L'invention concerne des compositions et des procédés destinés à traiter et prévenir des affections cutanées inflammatoires et auto-immunes, en particulier la rosacée, à l'aide d'un ou de plusieurs composés de benzimidazole appliqués de manière topique dans un excipient pharmaceutiquement acceptable destiné à être utilisé sur la peau. Un composé de benzimidazole préféré comprend du mébendazole. Une composition de traitement comprend de préférence de 0,05 à 0,075 pour cent en poids de mébendazole, et peut comprendre jusqu'à 20,0 % de mébendazole, dans un excipient ou un véhicule aqueux comprenant une crème, un gel, une lotion, un liquide, une émulsion, une pulvérisation d'aérosol, une pulvérisation non aérosol, une suspension ou une pommade et est appliquée au moins une fois par jour sur une période de traitement d'au moins deux semaines pour conduire à une réduction de lymphocytes T CD+8 cytotoxiques cutanés, de papules, de pustules, de gonflement, d'apparition de rougeur ou d'inflammation, et/ou de démangeaisons, et de sensation de chaleur ou de brûlure dans la zone affectée par rapport à des niveaux de prétraitement.
PCT/US2025/025121 2024-04-18 2025-04-17 Formulations topiques de benzimidazole et procédés d'utilisation dans le traitement de dermatoses inflammatoires Pending WO2025221973A1 (fr)

Applications Claiming Priority (6)

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US202463635923P 2024-04-18 2024-04-18
US63/635,923 2024-04-18
US202463650567P 2024-05-22 2024-05-22
US63/650,567 2024-05-22
US19/180,752 US20250241898A1 (en) 2022-06-21 2025-04-16 Topical Benzimidazole Formulations and Methods for Use in Treating Inflammatory Dermatoses
US19/180,752 2025-04-16

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050137244A1 (en) * 2003-12-17 2005-06-23 Albert Boeckh Topical formulations comprising 1-N-arylpyrazole derivatives and amitraz
WO2007067470A2 (fr) * 2005-12-06 2007-06-14 Wyeth Compositions non aqueuses de benzimidazole
US9259390B2 (en) * 2003-08-13 2016-02-16 The University Of Houston System Parenteral and oral formulations of benzimidazoles
WO2023249992A2 (fr) * 2022-06-21 2023-12-28 Jjr&D, Llc Formulations topiques de benzimidazole et procédés d'utilisation dans le traitement de dermatoses inflammatoires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9259390B2 (en) * 2003-08-13 2016-02-16 The University Of Houston System Parenteral and oral formulations of benzimidazoles
US20050137244A1 (en) * 2003-12-17 2005-06-23 Albert Boeckh Topical formulations comprising 1-N-arylpyrazole derivatives and amitraz
WO2007067470A2 (fr) * 2005-12-06 2007-06-14 Wyeth Compositions non aqueuses de benzimidazole
WO2023249992A2 (fr) * 2022-06-21 2023-12-28 Jjr&D, Llc Formulations topiques de benzimidazole et procédés d'utilisation dans le traitement de dermatoses inflammatoires

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