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WO2025010400A2 - Compositions et procédés aux fins d'un traitement amélioré de plaies cutanées - Google Patents

Compositions et procédés aux fins d'un traitement amélioré de plaies cutanées Download PDF

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Publication number
WO2025010400A2
WO2025010400A2 PCT/US2024/036875 US2024036875W WO2025010400A2 WO 2025010400 A2 WO2025010400 A2 WO 2025010400A2 US 2024036875 W US2024036875 W US 2024036875W WO 2025010400 A2 WO2025010400 A2 WO 2025010400A2
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WO
WIPO (PCT)
Prior art keywords
formulation
mpa
pharmaceutical composition
mpas
insulin
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/US2024/036875
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English (en)
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WO2025010400A3 (fr
Inventor
David M. SAILORS
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Eleos Pharmaceuticals Inc
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Eleos Pharmaceuticals Inc
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Publication date
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Publication of WO2025010400A2 publication Critical patent/WO2025010400A2/fr
Publication of WO2025010400A3 publication Critical patent/WO2025010400A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0061—Use of materials characterised by their function or physical properties
    • A61L26/0066—Medicaments; Biocides

Definitions

  • compositions e.g., formulations
  • topical compositions comprising insulin
  • methods for making the same and methods for treating wounds, which in preferred embodiments are diabetic foot ulcers, using the same.
  • Skin wounds are known to develop frequently in subjects suffering from a wide genre of diseases, disorders, conditions, and injuries including infections (e.g., cellulitis), autoimmune (e.g., diabetes mellitus type 1) and other metabolic diseases (e.g., diabetes mellitus type 2), cancers, allergic reactions (e.g., contact dermatitis), and exposure to certain parasitic species (e.g., Sarcopetes Scabiei).
  • infections e.g., cellulitis
  • autoimmune e.g., diabetes mellitus type 1
  • other metabolic diseases e.g., diabetes mellitus type 2
  • cancers e.g., allergic reactions (e.g., contact dermatitis)
  • allergic reactions e.g., contact dermatitis
  • parasitic species e.g., Sarcopetes Scabiei
  • DFUs diabetic foot ulcers
  • U.S. systemic blood sugar
  • Patent No. 11 ,369,664 This is so even where the blood sugar of the patient is not severely elevated (e.g., between 110-170 mg/dl).
  • administration of insulin directly to the DFU can result in wound closure and healing. While the compositions used in those studies were very efficacious, there is a need for improved compositions and methods for healing of skin wounds such as DFUs using local, topical administration of insulin thereto. Administration of insulin to such skin wounds by injection would be considered by those of ordinary skill in the art to be untenable in an outpatient care setting due to difficulties associated with the mechanics of administration by injection and also patient discomfort and, therefore, patient compliance.
  • the present disclosure features formulations and pharmaceutical compositions including insulin as the active pharmaceutical ingredient with an unexpected dependence of treatment efficacy on the viscosity of the topical formulations or pharmaceutical composition.
  • the disclosure further features methods for using topical formulations and pharmaceutical compositions including insulin, methods of treating skin wounds, and kits containing said topical formulations.
  • the topical formulations of the present disclosure contain a mixture of several excipients including but not limited to a bioadhesive agent, a tissue hydrator, a wound-healing promoting agent, a surfactant, a plasticizer, a thickening agent, and a pharmaceutically acceptable solvent.
  • the present disclosure features a topical formulation including insulin, wherein the formulation exhibits a complex viscosity of from about 1 mPas to about 50000 mPas (e.g., from about 100 mPas to about 49000 mPas, from about 200 mPas to about 48000 mPas, from about 300 mPas to about 47000 mPas, from about 400 mPas to about 46000 mPa s, from about 500 mPas to about 45000 mPas, from about 600 mPas to about 44000 mPas, from about 700 mPas to about 43000 mPas, from about 800 mPas to about 42000 mPas, from about 900 mPas to about 41000 mPa s, from about 1000 mPas to about 40000 mPa s, from about 1150 mPas to about 39000 mP
  • the formulation exhibits a complex viscosity of about 1 mPa s, about 100 mPa s, about 200 mPa s, about 300 mPas, about 400 mPas, about 500 mPas, about 600 mPas, about 700 mPa s, about 800 mPas, about 900 mPa s, about 1000 mPas, about 1100 mPas, about 1200 mPas, about 1300 mPas, about 1400 mPas, about 1500 mPas, about 1600 mPas, about 1700 mPas, about 1800 mPas about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPa s, about 2300 mPa s, about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700
  • the storage modulus of the formulation is from about 100 mPa to about 150000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa, about 60000
  • the loss modulus of the formulation is from about 100 mPa to about 150000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa, about 60000
  • the storage modulus of the formulation is greater than the loss modulus of the formulation at 1 unit of applied strain.
  • the formulation further includes a) a surfactant; b) a tissue hydrator; c) a wound-healing promoting agent; d) a bioadhesive agent; and e) a pharmaceutically acceptable solvent.
  • the insulin includes a) a fast-acting insulin; b) an intermediate-acting insulin; or c) a long-acting insulin.
  • the fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine.
  • the intermediate-acting insulin is an isophane insulin or a Neutral Protamine Hagedorn insulin.
  • the long-acting insulin selected from insulin glargine, insulin detemir, or insulin degludec.
  • the formulation includes from about 0.1 units of insulin per 10 g of the formulation to about 200 units of insulin per 10 g of the formulation or composition (e.g., from about 0.5 units per 10 g of the formulation to about 190 units per 10 g of the formulation or composition, from about 1 unit per 10 g of the formulation or composition to about 180 units per 10 g of the formulation or composition, from about 1 .5 units per 10 g of the formulation or composition to about 170 units per 10 g of the formulation or composition, from about 2 units per 10 g of the formulation or composition to about 160 units per 10 g of the formulation or composition, from about 2.5 units per 10 g of the formulation or composition to about 150 units per 10 g of the formulation or composition, from about 3 units per 10 g of the formulation or composition to about 140 units per 10 g of the formulation or composition, from about
  • the formulation includes from about 1 wt% to about 50 wt% surfactant (e.g., from about 1 .1 wt% to about 49 wt%, from about 1 .2 wt% to about 48 wt%, from about 1 .3 wt% to about 47 wt%, from about 1 .4 wt% to about 46 wt%, from about 1 .5 wt% to about 45 wt%, from about 1 .6 wt% to about 44 wt%, from about 1 .7 wt% to about 43 wt%, from about 1 .8 wt% to about 42 wt%, from about 1.9 wt% to about 41 wt%, from about 2 wt% to about 40 wt%, from about 2.2 wt% to about 39 wt%, from about 2.4 wt% to about 38 wt%, from about 2.6 wt% to about 37 wt%, from
  • the surfactant is a poloxamer. In some embodiments, the poloxamer is poloxamer 407.
  • the formulation includes from about 0.01 wt% to about 5 wt% tissue hydrator (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1.75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt% to about 1 .55 wt %
  • the tissue hydrator includes glycerin or a pharmaceutically acceptable salt thereof.
  • the formulation includes from about 0.001 wt% to about 1 wt% woundhealing promoting agent (e.g., from about 0.005 wt% to 0.9 wt%, from about 0.01 wt% to 0.8 wt%, from about 0.015 wt% to 0.7 wt%, from about 0.02 wt% to about 0.6 wt%, from about 0.025 wt% to about 0.5 wt%, from about 0.03 wt% to about 0.4 wt%, from about 0.035 wt% to about 0.3 wt%, from about 0.04 wt% to about 0.2 wt%, from about 0.045 wt% to about 0.1 wt%, from about 0.046 wt% to about 0.09 wt%, from about 0.047 wt% to about 0.08 wt%, from about 0.048 wt% to about 0.07 wt%, or from about 0.049 wt
  • the wound-healing promoting agent includes hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • the formulation includes from about 0.1 wt% to about 5 wt% bioadhesive agent (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1.75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt% to about 1 .55 w
  • the bioadhesive agent is a carbomer.
  • the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof.
  • the polycarbophil is Noveon® AA-1 Polycarbophil USP.
  • the pharmaceutically acceptable solvent is water.
  • the formulation is a topical formulation.
  • the formulation is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid.
  • the formulation is used for the treatment of a skin wound.
  • the skin wound is one or more of a blister, a lesion, a cut, a bruise, a cancer, a puncture, a breech, an ulcer, a papule, a plaque, a nodule, a vesicle, a bulla, a pustule, a cyst, an erosion, inflammation, swelling, an infection, a fissure, a wheal, a telangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.
  • the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer. In some embodiments, the skin wound is a diabetic foot ulcer.
  • the skin wound is an infection, and the infection is a bacterial infection (e.g., cellulitis, impetigo, staphylococcal infections, etc.), a viral infection (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.).
  • the skin wound is inflammation, further wherein the inflammation is eczema.
  • the formulation is characterized by a release of at least 90% of the insulin in one minute with mixing at room temperature in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the disclosure features a pharmaceutical composition, including: insulin, a surfactant; c) a tissue hydrator; d) a wound-healing promoting agent; e) a bioadhesive agent; and f) a pharmaceutically acceptable solvent.
  • the insulin includes one or more of: a) a fast-acting insulin; b) an intermediate-acting insulin; c) a long-acting insulin.
  • the insulin includes a fast acting insulin, wherein the fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine.
  • the insulin includes an intermediate-acting insulin, wherein the intermediate-acting insulin is an isophane insulin or a Neutral Protamine Hagedorn insulin.
  • the insulin includes a long-acting insulin selected from insulin glargine, insulin detemir, or insulin degludec.
  • the pharmaceutical composition includes from about 0.1 units of insulin per 10 g of the pharmaceutical composition to about 200 units of insulin per 10 g of the pharmaceutical composition (e.g., from about 0.5 units per 10 g of the formulation or composition to about 190 units per 10 g of the formulation or composition, from about 1 unit per 10 g of the formulation or composition to about 180 units per 10 g of the formulation or composition, from about 1 .5 units per 10 g of the formulation or composition to about 170 units per 10 g of the formulation or composition, from about 2 units per 10 g of the formulation or composition to about 160 units per 10 g of the formulation or composition, from about 2.5 units per 10 g of the formulation or composition to about 150 units per 10 g of the formulation or composition, from about 3 units per 10 g of the formulation or composition to about 140 units per 10 g of the formulation or composition, from about 3.5 units per 10 g of the formulation or composition to about 130 units per 10 g of the formulation or composition, from about 4 units per 10 g of the formulation or composition to about
  • the pharmaceutical composition includes from about 1 wt% to about 50 wt% surfactant (e.g., from about 1 .1 wt% to about 49 wt%, from about 1 .2 wt% to about 48 wt%, from about 1.3 wt% to about 47 wt%, from about 1 .4 wt% to about 46 wt%, from about 1 .5 wt% to about 45 wt%, from about 1 .6 wt% to about 44 wt%, from about 1 .7 wt% to about 43 wt%, from about 1 .8 wt% to about 42 wt%, from about 1 .9 wt% to about 41 wt%, from about 2 wt% to about 40 wt%, from about 2.2 wt% to about 39 wt%, from about 2.4 wt% to about 38 wt%, from about 2.6 wt% to about 37 wt%,
  • the surfactant is a poloxamer. In some embodiments, the poloxamer is poloxamer 407.
  • the pharmaceutical composition includes from about 0.1 wt% to about 5 wt% tissue hydrator (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1 .75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt% to about 1 .55 w
  • the tissue hydrator includes glycerin or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition includes from about 0.001 wt% to about 1 wt% wound-healing promoting agent (e.g., from about 0.005 wt% to 0.9 wt%, from about 0.01 wt% to 0.8 wt%, from about 0.015 wt% to 0.7 wt%, from about 0.02 wt% to about 0.6 wt%, from about 0.025 wt% to about 0.5 wt%, from about 0.03 wt% to about 0.4 wt%, from about 0.035 wt% to about 0.3 wt%, from about 0.04 wt% to about 0.2 wt%, from about 0.045 wt% to about 0.1 wt%, from about 0.046 wt% to about 0.09 wt%, from about 0.047 wt% to about 0.08 wt%, from about 0.048 wt% to about 0.07 wt%, or from about 0.049 wt% to
  • the wound-healing promoting agent includes hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is from about 0.1 wt% to about 5 wt% bioadhesive agent (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1 .75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt% to about 1 .
  • the bioadhesive agent is a carbomer.
  • the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof.
  • the polycarbophil is Noveon® AA-1 Polycarbophil USP.
  • the pharmaceutically acceptable solvent is water.
  • the pharmaceutical composition exhibits a complex viscosity of from about 1 mPa s to about 50000 mPa s (e.g., from about 100 mPa s to about 49000 mPa s, from about 200 mPa s to about 48000 mPa s, from about 300 mPa s to about 47000 mPa s, from about 400 mPa s to about 46000 mPa s, from about 500 mPa s to about 45000 mPa s, from about 600 mPa s to about 44000 mPa s, from about 700 mPa s to about 43000 mPa s, from about 800 mPa s to about 42000 mPa s, from about 900 mPa s to about 41000 mPa s, from about 1000 mPa s to about 40000 mPa s, from about 1150 mPa s to
  • the formulation exhibits a complex viscosity of about 1 mPas, about 100 mPas, about 200 mPas, about 300 mPas, about 400 mPas, about 500 mPas, about 600 mPa s, about 700 mPas about 800 mPas, about 900 mPa s, about 1000 mPa s, about 1100 mPas, about 1200 mPas, about 1300 mPas, about 1400 mPa s, about 1500 mPas, about 1600 mPas, about 1700 mPas, about 1800 mPa s, about 1900 mPa s, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s, about 2400 mPa s, about 2500 mPas, about 2600 mPa s 3 about 2
  • the storage modulus of the pharmaceutical composition is from about 50000 mPa to about 200000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa, about
  • storage modulus of the pharmaceutical composition is from about 50000 mPa to about 200000 mPa.
  • the loss modulus of the pharmaceutical composition is from about 100 mPa to about 150000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000
  • the storage modulus of the pharmaceutical composition is greater than the loss modulus of the pharmaceutical composition at 1 unit of applied strain.
  • the pharmaceutical composition is a topical pharmaceutical composition.
  • the pharmaceutical composition is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid.
  • the pharmaceutical composition further includes a wound dressing.
  • the wound dressing includes one or more of a bandage, a pad, a particle, a paste, a sheet, a solution, netting, gauze, collagen, foam, hydrocolloid, or hydrogel.
  • the wound dressing includes a hydrogel, wherein the hydrogel comprises a hydrogel sheet, an amorphous hydrogel, and/or an impregnated hydrogel. In some embodiments, the wound dressing includes a bandage.
  • one or more of the insulin, surfactant, tissue hydrator, wound-healing promoting agent, bioadhesive agent, or pharmaceutically acceptable solvent are absorbed by the wound dressing.
  • the pharmaceutical composition is used for the treatment of a skin wound.
  • the skin wound is one or more of a blister, a lesion, a cut, a bruise, a cancer, a puncture, a breech, an ulcer, a papule, a plaque, a nodule, a vesicle, a bulla, a pustule, a cyst, an erosion, inflammation, swelling, an infection, a fissure, a wheal, a telangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.
  • the skin wound is an ulcers, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer. In some embodiments, the skin wound is a diabetic foot ulcer.
  • the skin wound is an infection, and the infection is a bacterial infection (e.g., cellulitis, impetigo, staphylococcal infections, etc.), a viral infection (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.).
  • the skin wound is inflammation, further wherein the inflammation is eczema.
  • the pharmaceutical composition is characterized by a release of at least 90% of the insulin within one minute with mixing at room temperature in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the disclosure features a pharmaceutical composition including insulin, at least one bioadhesive agent, at least one tissue hydrator, at least one wound-healing promoting agent, at least one surfactant, and at least one pharmaceutically acceptable excipient, the composition exhibiting a complex viscosity of about 7000 mPa s to 20000 mPa s, and at least 90% release of insulin by one minute with mixing at room temperature in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • the complex viscosity of the pharmaceutical composition is about 14000 mPa s.
  • application of the composition to a skin wound of a mammal, the skin wound exhibiting a glucose concentration therein greater than the systemic blood glucose of the mammal results in a wound closure ratio of at least about 0.5 by day 9 after the application.
  • the wound closure ratio at day 9 after the application is about the same as that of insulin alone.
  • the pharmaceutical composition includes from about 0.15 units of insulin to about 10 units of insulin, about 100 mg of a bioadhesive agent, about 100 mg of a tissue hydrator, about 5 mg of a wound-healing promoting agent, from about 1 wt% to about 15 wt% surfactant, and water.
  • the insulin is Novolin 70/30 Insulin
  • the bioadhesive agent is Noveon® AA- 1 Polycarbophil USP
  • the tissue hydrator is glycerin
  • the wound-healing promoting agent is hyaluronic acid
  • the surfactant is poloxamer 407.
  • the disclosure features a pharmaceutical composition
  • a pharmaceutical composition comprising: insulin, poloxamer 407, glycerin or a pharmaceutically acceptable salt thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof, Noveon® AA-1 Polycarbophil USP, and water.
  • the pharmaceutical composition is from about 0.05 to about 200 units of insulin per 10 g of the composition, from about 1 wt% to about 50 wt% poloxamer 407, from about 0.1 wt% to about 5 wt% glycerin or a pharmaceutically acceptable salt thereof, from about 0.001 wt% to about 5 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof, from about 0.1 wt% to about 5 wt% hyaluronic acid Noveon® AA-1 Polycarbophil USP, and the rest of the composition is water.
  • the pharmaceutical composition is: 50 units of Novalin 70/30 insulin per 10 grams of the pharmaceutical composition, 10 wt% poloxamer 407, 1 wt % glycerin or a pharmaceutically acceptable salt thereof, 0.05 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof, 1 wt% Noveon® AA-1 Polycarbophil USP, and the rest of the composition is water.
  • the pharmaceutical composition is further characterized by a viscosity from about 7000 mPa s to about 20000 mPa s.
  • the pharmaceutical composition is an ointment, cream, lotion, gel, oil, liniment, or liquid.
  • the pharmaceutical composition is used to treat a diabetic foot ulcer.
  • the disclosure provides a method of treating a skin wound in a human subject in need of treatment includes: a) determining the subject has a skin wound; and b) administering a topical formulation of the first aspect, or a pharmaceutical composition of the second aspect.
  • the disclosure provides a method of treating a skin wound in a human subject that has been diagnosed to have a skin wound, the method including administering a topical formulation of the first aspect, or a pharmaceutical composition of the second aspect.
  • the disclosure provides a method of treating a skin wound in a human subject in need of treatment including: a) determining the subject has a skin wound; and b) administering a pharmaceutical composition to the subject including: insulin, polycarbophil, glycerin, hyaluronic acid, poloxamer 407, and water.
  • the disclosure provides a method of treating a skin wound in a human subject that has been diagnosed to have a skin wound, the method including administering a pharmaceutical composition to the subject including: insulin, polycarbophil, glycerin, hyaluronic acid, poloxamer 407, and water.
  • the skin wound further includes a glucose level at the site of a skin ailment or in surrounding tissue within about one inch of the outer edge of the skin ailment that is greater than the subject’s systematic blood glucose level.
  • the skin wound is one or more of a blister, a lesion, a cut, a bruise, a cancer, a puncture, a breech, an ulcer, a papule, a plaque, a nodule, a vesicle, a bulla, a pustule, a cyst, an erosion, inflammation, swelling, an infection, a fissure, a wheal, a telangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.
  • the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer. In some embodiments, the skin wound is a diabetic foot ulcer.
  • the skin wound is an infection, and the infection is a bacterial infection (e.g., cellulitis, impetigo, staphylococcal infections, etc.), a viral infection (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.).
  • the skin wound is inflammation, further wherein the inflammation is eczema.
  • the method further includes applying the composition to the skin wound over the course of a treatment period. In some embodiments, the composition is applied to the skin wound in multiple doses over the course of a treatment period. In some embodiments, the method further includes applying the composition to the skin wound one or more times per day over the course of a treatment period. In some embodiments, the method further includes applying the composition to the skin wound one or more times per week over the course of a treatment period. In some embodiments, the method further includes applying the composition to the skin wound one or more times per month over the course of a treatment period. In some embodiments, the treatment period has a duration of about one day to about one year. In some embodiments, the treatment period has a duration of about one month to about 11 months.
  • the treatment period has a duration of about three months to about nine months. In some embodiments, the treatment period has a duration of about six months. In some embodiments, the subject is diagnosed as having either type I diabetes mellitus, type II diabetes mellitus, or a diabetes associated condition or disorder.
  • the subject upon administration of the composition to the subject, the subject exhibits partial or complete healing of the skin wound. In some embodiments, partial to complete healing occurs within 90 days. In some embodiments, partial to complete healing occurs within 60 days. In some embodiments, partial to complete healing occurs within 30 days.
  • the disclosure features a kit including a formulation of the first aspect or a pharmaceutical composition the second aspect and a package insert.
  • the package insert instructs a user of said kit to administer the pharmaceutical composition to a subject suffering from a skin wound.
  • the skin wound is one or more of a blister, a lesion, a cut, a bruise, a cancer, a puncture, a breech, an ulcer, a papule, a plaque, a nodule, a vesicle, a bulla, a pustule, a cyst, an erosion, inflammation, swelling, an infection, a fissure, a wheal, a telangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.
  • the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer. In some embodiments, the skin wound is a diabetic foot ulcer.
  • the skin wound is an infection, and the infection is a bacterial infection (e.g., cellulitis, impetigo, staphylococcal infections, etc.), a viral infection (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.).
  • the skin wound is inflammation, further wherein the inflammation is eczema.
  • the package insert instructs a user of said kit to administer the pharmaceutical composition topically to the skin wound. In some embodiments, the package insert instructs the user to administer the pharmaceutical composition to the skin wound one or more times per day. In some embodiments, the package insert instructs the user to administer the pharmaceutical composition one or more times per week. In some embodiments, the package insert instructs the user to administer the pharmaceutical composition one or more times per month.
  • administering refers to providing a formulation or composition (e.g., a formulation or a composition described herein) to a subject.
  • Administration to a subject may be by any appropriate route; for example, the administration may be topical administration, in the form of a patch, liquid, gel, lotion, paste, cream, foam, powder, sheet, serum, ointment, or stick.
  • the term “topical” refers to administration of a formulation or pharmaceutical composition to any skin or exposed mucosal surface.
  • Skin includes any exposed epidermal region of the subject’s body, including, without limitation, the skin of the subject’s face, hands, legs, neck, abdominal area, eyes, nose, and chest.
  • the skin or exposed mucosal surface may have a wound such as a skin wound, including an ulcer (e.g., a diabetic foot ulcer), an infection (e.g., a bacterial infection), or suffer from inflammation (e.g., eczema).
  • skin wound refers to damage to skin tissue. Skin wounds may be caused by, e.g., a disease, an ailment, an infection, or trauma.
  • the skin wound is one or more of a blister, a lesion, a cut, a bruise, a cancer, a puncture, a breech, an ulcer, a papule, a plaque, a nodule, a vesicle, a bulla, a pustule, a cyst, an erosion, inflammation, swelling, an infection, a fissure, a wheal, a telangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.
  • the skin wound is an ulcers, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer. In some embodiments, the skin wound is a diabetic foot ulcer.
  • the skin wound is an infection, and the infection is a bacterial infection (e.g., cellulitis, impetigo, staphylococcal infections, etc.), a viral infection (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.).
  • the skin wound is inflammation, further wherein the inflammation is eczema.
  • beneficial or desired results can include, but are not limited to, alleviation of one or more symptoms or conditions; diminishment of extent of disease, disorder, condition, or injury; stabilizing (i.e., not worsening) state of disease, disorder, condition, or injury; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, condition, or injury; and remission (whether partial or total), whether detectable or undetectable.
  • “Palliating” a disease, disorder, condition, or injury means that the extent and/or undesirable clinical manifestations of the disease, disorder, condition, or injury are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • treatment may be measured as, e.g., a reduction in the size of the skin wound, a decrease in pain experienced by a subject suffering from the skin wound, reduction in the number of wound sites (e.g., sores, ulcers, etc.), reduce itching at the wound site, etc.
  • the success of a treatment may be measured by the “wound closure ratio” of the skin wound.
  • wound closure ratio refers to the relative size of the skin wound before the start of treatment, to the size of the skin wound at the measured timepoint (e.g., 1 day post treatment, 2 days post treatment, etc.). For example, at a measured timepoint, the wound is 50% the size of the wound prior to treatment.
  • a physician or subject administering a formulation or composition of this disclosure may expect a wound closure ratio of at least 10% (e.g., at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 99%, etc.) after a duration (e.g., after 1 week of treatment, after 2 weeks of treatment, after 3 weeks of treatment, after 4 weeks of treatment, after 1 month of treatment, after 2 months of treatment, after 3 months of treatment, after 4 months of treatment, after 5 months of treatment, after 6 months of treatment, etc.).
  • a duration e.g., after 1 week of treatment, after 2 weeks of treatment, after 3 weeks of treatment, after 4 weeks of treatment, after 1 month of treatment, after 2 months of treatment, after 3 months of treatment, after 4 months of treatment, after 5 months of treatment, after 6 months of treatment, etc.
  • the “active pharmaceutical ingredient” or API (used interchangeably herein) of a pharmaceutical composition refers to the material or materials which are the primary molecular or biological ingredients responsibly for the desired effect at the microscopic level.
  • a molecule or molecules of a drug which directly promote wound healing would be considered the active pharmaceutical ingredients of the composition.
  • the API is insulin.
  • insulin refers to the wild type peptide hormone produced by pancreatic beta cell islets encoded by the INS gene. Insulin serves the primary function of controlling the level of sugar in the blood of an animal.
  • insulin refers to wild type human insulin and the related wild type peptides produced for similar function in other vertebrate animals (e.g., pigs, cattle, etc.), and synthetic variants thereof.
  • Human wild type insulin is a 51 amino acid peptide chain.
  • Insulins of the present disclosure include single chain monomers, chain dimers (e.g., two chains joined via a disulfide bond), and multimers (e.g., hexamers) of chains associated with one or more hydrated metal ions.
  • Insulin is commonly measured in the art in “international units” or “units” of insulin. 1 unit of insulin is defined as 0.0347 mg of pure, crystalline insulin. The concentration of insulin in a formulation or composition may be measured in units of insulin per grams of the pharmaceutical composition (U/g) or in units of insulin per milliliter of the pharmaceutical composition (U/mL).
  • Insulin for medical applications is typically divided into three subcategories: fast acting insulin (e.g., insulin glulisine (e.g., Apidra, Apidra SoloStar), insulin lispro (e.g., Humalog, Liprolog, Ademlog, URLi, LY900014, Ly-275585), insulin aspart ((e.g., Novolog, NovoRapid, Fiasp, Kirsty, Trurapi, Truvelog), etc.), short-acting or intermediate-acting insulin (e.g., Humulin R, Novolin R, an isophane insulin (e.g., Novolin N, Humulin N, Insulatard, Neutral Protamine Hagedorn insulin), etc.), or long-acting insulin (e.g., insulin degludec (e.g., Tresiba), insulin detemir (e.g., Levemir), insulin glargine (e.g., Lantus, Toujeo, Bas
  • a “bioadhesive agent” is a material which adheres to biological tissue (e.g., skin) or the mucous membrane of living organisms.
  • the bioadhesive agent can be polycarbophil, shellac, soy hydrolysate, Notaden frog glue, chitosan, gelatin, lectin, hyperbranched polyglycerol, alginate, cellulose, levodopa, combinations thereof, and/or the like.
  • the bioadhesive agent is a carbomer.
  • the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof.
  • the polycarbophil can be Noveon® AA-1 Polycarbophil USP.
  • tissue hydrator refers to a material which can increase the water content of nearby biological tissue e.g., through maintaining a large water concentration in the vicinity of the tissue or preventing the loss of water from the tissue.
  • the tissue hydrator can be glycerin or a pharmaceutically acceptable salt thereof.
  • a “wound-healing promoting agent” is a material which aids in the healing of a skin wound through a process secondary to that of the pharmaceutically active ingredient.
  • the wound-healing promoting agent may bind to a receptor protein on the surface of a skin cell to improve the cellular intake of a pharmaceutically active ingredient.
  • a wound-healing promoting agent is distinct from an active pharmaceutical ingredient.
  • the wound-healing promoting agent can be glycerin, hyaluronic acid, lanolin, liquid paraffin, urea, propylene glycol, lactic acid, human nutrient vitamins, collagens, mixtures thereof, and/or the like.
  • the wound-healing promoting agent is glycerin.
  • surfactant refers to a material which increases the solubility material in a solvent.
  • the solubility of a non-polar molecule in water may be improved by including a surfactant.
  • surfactants may also be used as thickening agents of a formulation or composition.
  • the surfactant can be an anionic surfactant such as sodium stearate, a cationic surfactant such as benzalkonium chloride, a zwitterionic or an amphoteric surfactants as phosphatidylcholine, or a nonionic surfactants such as poloxamer 407.
  • the surfactant is a poloxamer.
  • the poloxamer is poloxamer 407
  • thickening agent refers to a substance which increases the viscosity of a composition as the relative amount of the thickening agent is increased. In a composition including more than one component, more than one of the components may have the properties of a thickening agent. As used in this disclosure, thickening agent refers to a component of the composition which is varied to change the viscosity of the composition. A thickening agent may serve additional roles in the pharmaceutical composition (i.e. , the surfactant, the tissue hydrator, etc.). As used herein, “viscosity” refers to the internal friction of a fluid due to motion of the atoms or molecules which make up the fluid against adjacent atoms or molecules of the fluid.
  • viscosity refers to a complex viscosity, (i.e., the dynamic viscosity of a fluid, when the external force is an oscillating force).
  • viscosity refers to a kinematic viscosity (i.e., the resistive flow of a fluid under the weight of gravity).
  • viscosity refers to a dynamic viscosity (i.e., the resistive flow of a fluid resulting from an external force).
  • viscosity refers to the volume viscosity, bulk viscosity, or dilatation viscosity, used interchangeably herein, (i.e., the resistance of a fluid to compression or expansion).
  • viscosity complex viscosity
  • MCR 92 Anton Paar Modular Compact Rheometer
  • the viscosity of a composition can be modified by one of skill in the art through increasing the relative amounts of the thickening agent or thickening agents in the composition.
  • the viscosity of the composition is from about 1 mPa s to about 50000 Pa s (e.g., from about 100 mPa s to about 20000 mPa s, from about 250 mPa s to about 14000 mPa s, from about 1000 mPa s to about 13000 mPa s, from about 4000 mPa s to about 12000 mPa s, or from about 10000 mPa s to about 12000 mPa s).
  • An optimal viscosity is determined by one of skill in the art to be the viscosity which results in either the most complete healing of the skin wound, or most rapid healing of the skin wound.
  • the complex viscosity of the preferred compositions of this disclosure are from about 4000 mPa s to about 20000 mPa s, from about 7000 mPa to about 20000 mPa s, and most preferably about 14000 mPa s.
  • Suitable complex viscosities can preferably be determined by those of ordinary skill in the art using the techniques disclosed herein, and/or other techniques available to those of ordinary skill in the art.
  • weight percent refers to the percentage of the total weight of the composition which is comprised of the specified ingredient. For example, the weight percent of 1 mg of a material in a composition of total weight 1000 mg which is comprised in part of the aforementioned material, would be 0.1 weight percent.
  • weight percent and “percent by weight” are used interchangeably in this disclosure.
  • the weight percent of a material in a composition uses the unit notation of “wt%” (i.e., 0.1 wt% is used to represent 0.1 weight percent). Formulations of the present disclosure may be identified by the wt% of their components.
  • wound dressing refers to a material or combination of materials which are applied to a wound site to protect the wound from further harm.
  • Wound dressings are commonly employed in conjunction with a pharmaceutical composition to, e.g., protect the wound from the environment, ensure continuous contact of the pharmaceutical composition and the wound, or reduce bleeding at the wound site.
  • Wound dressings may include an absorbent pad and an adherent which ensures adherence to biological tissue. The wound dressing may absorb the pharmaceutical composition of this disclosure.
  • Exemplary wound dressings include bandages (e.g., roller bandages, tubular bandages, triangular bandages, wraps, compression bandages, steri strips, sutures, etc.), pads, particles, pastes, sheets (e.g., silicone sheets), solutions, nettings, gauzes (e.g., gauze sponges, gauze rolls, etc.), collagens (e.g., equine collagens and bovine collagens, both hydrolyzed and non-hydrolyzed), foams (e.g., polyurethane foams), hydrocolloids (e.g., methyl cellulose, gelatin, pectin, etc.), or hydrogels (e.g., Tegaderm®, Avogel®, Aquasite®, etc.).
  • bandages e.g., roller bandages, tubular bandages, triangular bandages, wraps, compression bandages, steri strips, sutures, etc.
  • pads e.g., silicone sheets
  • solutions netting
  • “Mucolox,” “MucoLox,” and “MucoLoxTM” refer to the commercially available bioadhesive gel MucoLoxTM, available from Professional Compounding Centers of America - PCCA, USA.
  • MucoLoxTM is a bioadhesive polymer gel consisting of , isomalt ( 20 wt%), sodium benzoate (0.35 wt%), potassium sorbate (0.2 wt%), tetra sodium ethylenediaminetetracetate dihydrate (0.1 wt%), simethicone (0.2 wt%), glycerin (3.0 wt%), sodium hyaluronate (0.1 wt%), tamarindus indica seed polysaccharide (Xilogel®) (0.5 wt%), poloxamer 407 (1 wt%) zea mays starch and carbomer (Proloc 15) (1 wt%), pullulan (5 wt%), and purified water (68.55 wt%). MucoLoxTM is known in the art as the base of topical formulations and pharmaceutical compositions.
  • Percent (%) sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • Figs. 1A-1B show the rheological properties and appearance of Formulation 1.
  • Fig. 1A shows the storage modulus (G') and loss modulus (G") of Formulation 1 from a strain of 0.1 to 10000.
  • Fig. 1B shows an image of Formulation 1.
  • Formulation 1 is an opaque mixture.
  • Figs. 2A-2B show the rheological properties and appearance of Formulation 2.
  • Fig. 2A shows the storage modulus (G') and loss modulus (G") of Formulation 2 from a strain of 0.1 to 10000.
  • Fig. 2B shows an image of Formulation 2.
  • Formulation 2 is noticeably more viscous than Formulation 1 , with Formulation 2 exhibiting gel-like properties.
  • Figs. 3A-3B show the rheological properties and appearance of Formulation 3.
  • Fig. 3A shows the storage modulus (G') and loss modulus (G") of Formulation 3 from a strain of 0.1 to 10000.
  • Fig. 3B shows an image of Formulation 3.
  • Formulation 3 is a viscous gel, similar to Formulation 2.
  • Fig. 4 shows the complex viscosities of a Formulation 1 , Formulation 2, and Formulation 3.
  • the complex viscosity increases with increasing poloxamer concentration (viscosity of Formulation 1 ⁇ viscosity of Formulation 2 ⁇ viscosity of Formulation 3).
  • Figs. 5A-5B show solutions mixed to form the gel of the present disclosure.
  • Fig. 5A shows the contents of the first container (hyaluronic acid, glycerin, a variable weight percent of poloxamer and insulin dissolved in water, and insulin).
  • Fig. 5B shows the contents of container 2 (polycarbophil dissolved in water). The reported weight percent of poloxamer given is the weight percent of the poloxamer in the final gel.
  • Figs. 6A-6B shows the release profile of insulin from topical formulations of varying viscosity.
  • Fig. 6A shows the release profile for Formulation 4, Formulation 5, Formulation 6, and Formulation 7.
  • Figs. 7A-7F show the blood glucose levels of mouse subjects in the dosing experiments, measured over time as “days post-surgery.” Data is shown for the first 15 days post-surgery.
  • Numerical identifiers in the legend refer to specific mice in the experiments. Said numerical identifiers are common between Fig. 7A and Fig. 9, Fig. 7B and Fig. 10, Fig. 7C and Fig. 11 , Fig. 7D and Fig. 12, Fig. 7E and Fig. 13, and Fig. 7F and Fig. 14.
  • Fig. 7A shows the blood glucose level over time of the saline group.
  • Fig. 7B shows the blood glucose level over time of the insulin group.
  • Fig. 7A shows the blood glucose level over time of the insulin group.
  • FIG. 7C shows the blood glucose over time of the single dose group.
  • Fig. 7D shows the blood glucose over time of the multi-dose group.
  • Fig. 7E shows the blood glucose overtime of the ’’MucoLox” group.
  • Fig. 7F shows the blood glucose over time of the “MucoLox/insulin” group.
  • Figs. 8A-8F show the wound closure ratio of mice in the four examined groups over time.
  • Fig. 8A shows the wound closure on day 2.
  • Fig. 8B shows the wound closure on day 6.
  • Fig. 8C shows the wound closure on day 9.
  • Fig. 8D shows the wound closure on day 12.
  • Fig. 8E shows the wound closure on day 15.
  • Fig. 8F shows the wound closure ratio over the course of the 15 day experiment.
  • Fig. 9 shows images of the wounds of two mice in the saline group over time.
  • Fig. 10 shows images of the wounds of four mice in the insulin group over time.
  • Fig. 11 shows images of the wounds of four mice in the single dose group over time.
  • Fig. 12 shows images of the wounds of five mice in the multi-dose group over time.
  • Fig. 13 shows images of the wounds of four mice in the MucoLox group over time.
  • Fig. 14 shows images of the wounds of four mice in the MucoLox/insulin group over time.
  • Figs. 15A-15H show the histopathological analysis of skin biopsies stained with H&E.
  • Fig. 15A shows an image of wound regeneration in the insulin group.
  • Fig. 15B shows an image of wound regeneration in the single dose group.
  • Fig. 15C shows an image of wound regeneration in the multi-dose group.
  • Fig. 15D shows an image of wound regeneration in the MucoLox group.
  • Fig. 15E shows an image of wound regeneration in the MucoLox/insulin group.
  • Fig. 15F shows an image of wound regeneration in the saline group.
  • the dotted line denotes the boundary of the epithelium in each image.
  • GT denotes regions of granulation tissue.
  • the scale bar in Figs. 15A-15F is 180 pm.
  • Fig. 15G shows the epidermal tissue thickness of all examined groups.
  • Fig. 15H shows the granulation tissue thickness of all examined groups.
  • SD refers to the single dose group
  • Fig. 16 shows images of the wounds of exemplary mice of the Saline Group, the Insulin Group, the Formulation 4 Group, the Formulation 5 Group, the Formulation 3 Group, the Formulation 7 Group, the Formulation 8 Group, and the Formulation 10 group over time.
  • Fig. 17 shows the wound closure ratio of mice in the eight examined groups over time.
  • the Formulation 7 Group, the Formulation 8 Group, and the Formulation 10 Group showed consistent and higher wound closure rates throughout the study, with the Formulation 7 Group outperforming the Formulation 8 Group, and the Formulation 8 Group outperforming the Formulation 10 Group.
  • Fig. 18 shows the histological analysis of skin tissue sections taken from exemplary mice in each of the eight groups. Areas highlighted in rectangles with solid lines show epidermal-dermal separation. Areas highlighted in rectangles with dashed lines are areas of scar tissue. Areas highlighted in triangles point to neovascularization. The * mark denotes areas including inflammatory cells. Areas highlighted in circles or ovals are areas including a skin appendage.
  • Fig. 19 shows the average granulation thickness in treated tissue of each examined group after treatment.
  • Fig. 20 shows the average growth of new blood vessels in treated tissue of each examined group after treatment.
  • Fig. 21 shows the average epidermal thickness in treated tissue of each examined group after treatment.
  • Fig. 22 shows the average dermal/epidermal separation in treated tissue of each examined group after treatment.
  • Fig. 23 shows the growth of skin appendages in treated tissue of each examined group after treatment.
  • Skin wounds often occur as a side effect or a major manifestation of many diseases, disorders, conditions, and injuries. Even after a disease is cured or successfully managed, the lingering effects of skin wounds can cause lifelong problems for a subject. Healing of skin wounds, therefore, is a critical component of treatment. Medical practitioners frequently attempt to treat skin wounds with a variety of topical formulations applied at the wound site to promote healing.
  • the prior art describes the use of insulin as the active pharmaceutical ingredient for wound-healing, both when the wound is caused by a disease related to insulin production (e.g., diabetes mellitus type I) or insulin signaling (e.g., diabetes mellitus type II), and for skin wounds not caused by insulin production or insulin signaling disorders (see, e.g., US Patent No. 5,591 ,709).
  • a disease related to insulin production e.g., diabetes mellitus type I
  • insulin signaling e.g., diabetes mellitus type II
  • compositions e.g., formulations
  • topical compositions including at least one active pharmaceutical ingredient (API), in some preferred embodiments being insulin, with unexpected treatment benefits that, in preferred embodiments, depend on the viscosity of the compositions.
  • compositions comprising the API (preferably insulin) disclosed herein comprise a mixture of several excipients including but not limited to at least one bioadhesive agent, at least one tissue hydrator, at least one wound-healing promoting agent, at least one surfactant, at least one plasticizer, at least one thickening agent, and at least one pharmaceutically acceptable excipient (e.g., a solvent).
  • excipients including but not limited to at least one bioadhesive agent, at least one tissue hydrator, at least one wound-healing promoting agent, at least one surfactant, at least one plasticizer, at least one thickening agent, and at least one pharmaceutically acceptable excipient (e.g., a solvent).
  • the composition (e.g., formulation) comprises, in addition to the API (e.g., in preferred embodiments being insulin), at least one bioadhesive agent, at least one tissue hydrator, at least one wound-healing promoting agent, at least one surfactant, at least one plasticizer, at least one thickening agent, and at least one pharmaceutically acceptable excipient (e.g., solvent).
  • the disclosure further provides methods for making and using such compositions, preferably topical compositions including an API (preferably insulin), to treat skin wounds, and kits containing said topical formulations and instructions for use. This disclosure also provides methods for making the compositions.
  • Viscosity refers to a measurement of the rate of deformation within a fluid material. As an outside displacement force acts on a layer of a fluid material, referred to as “shear force,” the fluid material responds by moving, referred to as “flow.” Due to internal friction between moving atoms, ions, or molecules within the material, fluids resist flow in response to the applied shear force. Viscosity is therefore a measure of the resistance to flow in a material.
  • the viscosity measured is the dynamic viscosity.
  • the viscosity measured is the kinematic viscosity.
  • the viscosity measured is the volume viscosity.
  • the viscosity measured is the complex viscosity.
  • complex viscosity refers to the viscosity measured by rotating source of shear force (see, e.g., P. J. Cullen et al, Rotation Rheometry Using Complex Geometries; Journal of Texture Studies, 34: 1-20 (2002)). In some embodiments, these measurements are performed using a rotational rheometer, using strain sweep analysis.
  • the rheological properties of a composition are commonly determined by comparing two quantities: the storage modulus of the composition (G') and the loss modulus (G"). As strain is applied to a composition, both G' and G" decrease reflecting the loss of the material’s elastic properties and the release of the stored mechanical energy as heat, respectively. For fluids with no solid-like properties (i.e., a liquid), the storage modulus never exceeds the loss modulus. For fluids which exhibit some solid-like properties (e.g., semisolids such as gels or cream), G' > G" below some critical strain.
  • formulations of the present disclosure have a G' from about 100 mPa to about 150000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa,
  • formulations of the present disclosure have a G" from about 100 mPa to about 150000 mPa (e.g., from about 1000 mPa to about 140000 mPa, from about 2500 mPa to about 130000 mPa, from about 5000 mPa to about 120000 mPa, from about 10000 mPa to about 110000 mPa, from about 25000 mPa to about 100000 mPa, from about 50000 mPa to about 90000 mPa, about 100 mPa, about 1000 mPa, about 2000 mPa, about 3000 mPa, about 4000 mPa, about 5000 mPa, about 6000 mPa, about 7000 mPa, about 8000 mPa, about 9000 mPa, about 10000 mPa, about 20000 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa,
  • Viscosity of formulations and compositions of the present disclosure may be controlled by changing the relative amount of a thickening agent.
  • exemplary thickening agents of the disclosure include: polysaccharides (e.g., glucomannan, mannan oligosaccharide, and galactomannan), gums (e.g., locust bean gum, xanthan gum, and guar), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose, alginic acid, salts of alginic acid (e.g., sodium, calcium, magnesium, potassium, and mixed salts thereof), pectin, poloxamers (e.g., poloxamer 407), castor oil and its derivatives, silicones, organosilicones, carrageenan, gelatin, agar, maltodextrin, amitriptyline, tamoxifen, verapamil, polyethylene glycol, petroleum jelly, carbomers, silica, benton
  • the viscosity of a composition can be further modified through the inclusion of, e.g., an ionic agent (e.g., NaCI) or a plasticizer (e.g., glycerin).
  • an ionic agent e.g., NaCI
  • a plasticizer e.g., glycerin
  • a component in a composition as a thickening agent does not exclude it from serving another role described by the disclosure (e.g., a surfactant, tissue hydrator, bioadhesive agent, wound-healing promoting agent, etc.).
  • the thickening agent may also function as a surfactant (e.g., a poloxamer such as poloxamer 407).
  • the formulation exhibits a viscosity of from about 1 mPa s to about 50000 mPa s (e.g., from about 100 mPa s to about 49000 mPa s, from about 200 mPa s to about 48000 mPa s, from about 300 mPa s to about 47000 mPa s, from about 400 mPa s to about 46000 mPa s, from about 500 mPa s to about 45000 mPa s, from about 600 mPa s to about 44000 mPa s, from about 700 mPa s to about 43000 mPa s, from about 800 mPa s to about 42000 mPa s, from about 900 mPa s to about 41000 mPa s, from about 1000 mPa s to about 40000 mPa s, from about 1150 mPa s to about 39
  • the formulation exhibits a viscosity of about 1 mPa s, about 100 mPa s, about 200 mPas, about 300 mPas, about 400 mPas, about 500 mPas, about 600 mPas, about 700 mPa s, about 800 mPa s, about 900 mPas, about 1000 mPa s, about 1100 mPas, about 1200 mPas, about 1300 mPas, about 1400 mPas, about 1500 mPas, about 1600 mPas, about 1700 mPas, about 1800 mPa s 3 about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s 3 about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700
  • the formulation exhibits a kinematic viscosity of from about 1 mPa sto about 50000 mPas (e.g., from about 100 mPas to about 49000 mPa s, from about 200 mPas to about 48000 mPas, from about 300 mPas to about 47000 mPa s, from about 400 mPas to about 46000 mPas, from about 500 mPas to about 45000 mPas, from about 600 mPas to about 44000 mPa s, from about 700 mPas to about 43000 mPas, from about 800 mPas to about 42000 mPas, from about 900 mPas to about 41000 mPas, from about 1000 mPas to about 40000 mPa s, from about 1150 mPas to about 39000 mPas, from about 1300 mP
  • the formulation exhibits a dynamic viscosity of about 1 mPa s, about 100 mPas, about 200 mPa s, about 300 mPas, about 400 mPas, about 500 mPa s, about 600 mPas, about 700 mPa s 3 about 800 mPas, about 900 mPa s, about 1000 mPas, about 1100 mPa s, about 1200 mPas, about 1300 mPa s, about 1400 mPas, about 1500 mPas, about 1600 mPa s, about 1700 mPas, about 1800 mPa s 3 about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s 3 about 2400 mPas, about 2500 mPas, about 2600 mPa s
  • the formulation exhibits a volume viscosity of from about 1 mPas to about 50000 mPas (e.g., from about 100 mPas to about 49000 mPas, from about 200 mPas to about 48000 mPas, from about 300 mPas to about 47000 mPas, from about 400 mPas to about 46000 mPas, from about 500 mPas to about 45000 mPas, from about 600 mPas to about 44000 mPas, from about 700 mPas to about 43000 mPas, from about 800 mPas to about 42000 mPas, from about 900 mPas to about 41000 mPas, from about 1000 mPas to about 40000 mPas, from about 1150 mPas to about 39000 mPas, from about 1300 mPas to about 38000 m
  • the formulation exhibits a complex viscosity of from about 1 mPas to about 50000 mPas (e.g., from about 100 mPas to about 49000 mPas, from about 200 mPas to about 48000 mPas, from about 300 mPas to about 47000 mPas, from about 400 mPas to about 46000 mPas, from about 500 mPas to about 45000 mPas, from about 600 mPas to about 44000 mPas, from about 700 mPas to about 43000 mPas, from about 800 mPas to about 42000 mPas, from about 900 mPas to about 41000 mPas, from about 1000 mPas to about 40000 mPas, from about 1150 mPas to about 39000 mPas, from about 1300 mPas to about 38000 m
  • the formulation exhibits a complex viscosity of about 1 mPa s, about 100 mPas, about 200 mPa s, about 300 mPas, about 400 mPas, about 500 mPa s, about 600 mPas, about 700 mPa s 3 about 800 mPas, about 900 mPa s, about 1000 mPas, about 1100 mPa s, about 1200 mPas, about 1300 mPa s, about 1400 mPas, about 1500 mPas, about 1600 mPa s, about 1700 mPas, about 1800 mPa s 3 about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s 3 about 2400 mPas, about 2500 mPas, about 2600 mPa s
  • the complex viscosity of the preferred compositions of this disclosure are from about 7000 mPa s to about 20000 mPa s, and most preferably about 14000 mPa s.
  • Suitable complex viscosities can preferably be determined by those of ordinary skill in the art using the techniques disclosed herein, and/or other techniques available to those of ordinary skill in the art.
  • the viscosity is modified by changing the weight percent of the thickening agent, e.g., the surfactant (such as poloxamer 407), from about 1 wt% to about 50 wt% (e.g., from about 1.1 wt% to about 49 wt%, from about 1 .2 wt% to about 48 wt%, from about 1 .3 wt% to about 47 wt%, from about 1 .4 wt% to about 46 wt%, from about 1 .5 wt% to about 45 wt%, from about 1 .6 wt% to about 44 wt%, from about 1 .7 wt% to about 43 wt%, from about 1 .8 wt% to about 42 wt%, from about 1 .9 wt% to about 41 wt%, from about 2 wt% to about 40 wt%, from about 2.2 wt% to about 39 wt%,
  • Formulations and compositions of the present disclosure preferably include insulin.
  • Wild-type human insulin is a peptide hormone produced by beta cells of the pancreas and is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats, and protein by, inter alia, promoting the absorption of glucose from the blood into fat, liver, and skeletal muscle cells.
  • insulin also refers to anabolic hormones with a largely similar amino acid sequence (e.g., at least about 80% sequence identity, about 85% sequence identity, about 90% sequence identity, about 95% sequence identity, about 99% sequence identity, etc.), tertiary and quaternary protein structure, and function.
  • insulin may refer to any one of these peptide hormones.
  • Insulin disturbance e.g., loss of sensitivity to insulin or the inability to produce insulin
  • insulinoma e.g., loss of sensitivity to insulin or the inability to produce insulin
  • diabetes e.g., type 1 diabetes mellitus and type 2 diabetes mellitus.
  • Wild-type human insulin is a 51 amino acid protein composed of two independent chains, connected by a disulfide bond.
  • the structure of insulin is strongly conserved across species of origin.
  • porcine and bovine insulin both commonly used in treatment of humans
  • Insulin is often stored by mammalian organisms as a hexamer incorporating one or more hydrated cations (e.g., Zn 2+ xH2 ⁇ D).
  • the hexamer is typically more stable to degradation and decomposition, and typically acts over a longer period of time (i.e., has a longer action profile).
  • Several different types of insulin for use in medication are available.
  • Insulin is commonly produced via recombinant DNA technology, wherein DNA encoding for the desired modified insulin protein is introduced into an organism, e.g., a plant (e.g., safflower) or a bacteria cell (e.g., Escherichia coli or Saccharomyces cerevisiae bacteria). The bacterium then produces the desired insulin medium which is then purified and included in a variety of pharmaceutical compositions.
  • a plant e.g., safflower
  • bacteria cell e.g., Escherichia coli or Saccharomyces cerevisiae bacteria
  • the DNA sequence used by the bacterium to produce insulin can be of a variety of origin species, e.g., porcine insulin, bovine insulin, or human insulin.
  • the insulin may be formulated for use in a non-human subject (e.g. Vetsulin®).
  • the different types of insulin are identified by their “action profile,” alternatively referred to as their pharmacokinetic profile, i.e. , how long it takes the insulin to begin to act in the mammal (e.g., within 15 minutes, within 30 minutes, within 1 hour, within 2 hours), when the insulin reaches its peak activation (e.g., after 1 hour, after 2 hours, after 12 hours), and how long the effects of the insulin last in the mammal (e.g., less than 2 hours, less than 3 hours, less than 4 hours, less than 24 hours).
  • action profile alternatively referred to as their pharmacokinetic profile, i.e. , how long it takes the insulin to begin to act in the mammal (e.g., within 15 minutes, within 30 minutes, within 1 hour, within 2 hours), when the insulin reaches its peak activation (e.g., after 1 hour, after 2 hours, after 12 hours), and how long the effects of the insulin last in the mammal (e.g., less than 2 hours, less than 3 hours
  • Insulin and insulin mutants are therefore categories as belonging to one of three categories: fast-acting insulin and which onsets in approximately 30 minutes with a peak after 1 -3 hours (e.g., insulin glulisine, insulin lispro, insulin aspart, Humulin R, Novolin R, etc.), intermediate-acting insulin which onsets after 1-3 hours and reaches a peak after 4-8 hours (e.g., Humalin N, Novolin N, isophane insulins (including Hypurin isophane insulins), Neutral Protamine Hagedorn (NPH) insulin, etc.), and long-acting insulin which onsets in approximately 1 hour and lasts for about 16 to about 24 hours (e.g., insulin detemir, insulin glargine, insulin degludec, etc.) Insulin may be administered as a mixture of the different types (e.g., the different types of insulin may be pre-mixed or the different types of insulin may be administered simultaneously).
  • fast-acting insulin e.g
  • the different types of insulin can be administered in separate doses (i.e., sequentially administering one type of insulin followed by a separate administration of a second type of insulin, optionally wherein one or both insulins are administered topically)
  • the doses may be separated by a span of time, e.g., less than 1 minute, less than 10 minutes, less than 1 hour, less than 6 hours, or less than 1 day.
  • the insulin is Novolin 70/30, a 70:30 mixture of NPH insulin to fast acting insulin (e.g., wild type human insulin).
  • the insulin can be a) a fast-acting insulin; b) an intermediate-acting insulin; c) a long-acting insulin; or d) a combination thereof.
  • the fast-acting insulin selected from insulin aspart (e.g., Novolog, NovoRapid, Fiasp, Kirsty, Trurapi, Truvelog), insulin lyspro (e.g., Humalog, Liprolog, Ademlog, URLi, LY900014, Ly-275585), or insulin gluisine (e.g., Apidra, Apidra SoloStar).
  • insulin aspart e.g., Novolog, NovoRapid, Fiasp, Kirsty, Trurapi, Truvelog
  • insulin lyspro e.g., Humalog, Liprolog, Ademlog, URLi, LY900014, Ly-275585
  • insulin gluisine e.g., Apidra, Apidra SoloStar
  • the intermediate-acting insulin is an isophane insulin (e.g., Novolin N, Humulin N, Insulatard, Neutral Protamine Hagedorn insulin).
  • the long-acting insulin selected from insulin glargine (e.g., Lantus, Toujeo, Basaglar), insulin detemir (e.g., Levemir), or insulin degludec (e.g., Tresiba), or as is otherwise disclosed herein or may be determined to be suitable by those of ordinary skill in the art using the techniques disclosed herein.
  • insulin glargine e.g., Lantus, Toujeo, Basaglar
  • insulin detemir e.g., Levemir
  • insulin degludec e.g., Tresiba
  • Insulin dosage is commonly measured in the art in “international units” or “units” of insulin.
  • One unit of insulin is defined as 0.0347 mg of pure, crystalline insulin.
  • Insulin is commonly sold at a concentration of 100 units/mL (3.47 mg of pure, crystalline insulin per one mL of pharmaceutical composition), also referred to as “U-100” insulin.
  • the topical formulation or composition of the present disclosure includes about 0.1 unit of insulin per 10 g of the total weight of the topical formulation or composition to about 200 units of insulin per 10 g of the total weight of the topical formulation or composition (e.g., from about 0.5 units per 10 g of the formulation to about 190 units per 10 g of the formulation or composition, from about 1 unit per 10 g of the formulation to about 180 units per 10 g of the formulation or composition, from about 1 .5 units per 10 g of the formulation to about 170 units per 10 g of the formulation or composition, from about 2 units per 10 g of the formulation to about 160 units per 10 g of the formulation or composition, from about 2.5 units per 10 g of the formulation to about 150 units per 10 g of the formulation or composition, from about 3 units per 10 g of the formulation to about 140 units per 10 g of the formulation or composition, from about 3.5 units per 10 g of the formulation to about 130 units per 10 g of the formulation or composition, from about 4 units per 10 g of
  • the topical formulation or composition of the present disclosure includes about 0.1 units of insulin per 10 g of the formulation or composition, about 0.15 units of insulin per 10 g of the formulation or composition, about 0.2 units of insulin per 10 g of the formulation or composition, about 0.25 units per 10 g of the formulation or composition, about 0.3 units of insulin per 10 g of the formulation or composition, about 0.35 units of insulin per 10 g of the formulation or composition, about 0.4 units of insulin per 10 g of the formulation or composition, about 0.45 units of insulin per 10 g of the formulation or composition, about 0.5 units per 10 g of the formulation or composition, about 0.6 units of insulin per 10 g of the formulation or composition, about 0.7 units on insulin per 10 g of the formulation or composition, about 0.8 units of insulin per 10 g of the formulation or composition, about 0.9 units of insulin per 10 g of the formulation or composition, about 1 unit of insulin per 10 g of the formulation or composition, about 1 .2 units of insulin per 10 g of the formulation or composition, about 1
  • a bioadhesive is a material which adheres to biological tissue or the mucous membrane of living organisms.
  • a topical formulation not which does not include a bioadhesive agent would only weakly associate with biological material and therefore be less efficient at healing a skin wound.
  • Bioadhesive agents may additionally serve as thickening agents.
  • bioadhesive agents work through weak, non-covalent chemical or electrostatic interactions between the topical formulation and the biological material.
  • Example bioadhesive agents include shellac, soy hydrolysate, Notaden frog glue, chitosan, gelatin, lectin, hyperbranched polyglycerol, alginate, poly(acrylic acid) and poly(acrylic acid) derivatives, cellulose, levodopa (i.e., L-DOPA), etc.
  • the bioadhesive agent is Noveon® AA- 1 Polycarbophil USP.
  • the topical formulation or composition includes from about 0.01 wt% to about 5 wt% of a bioadhesive agent (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1 .75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt
  • the topical formulation or composition includes, e.g., about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1 .2 wt%, about 1 .25 wt%, about
  • a tissue hydrator is a material which aids in biological tissue’s ability to retain water. When biological tissue loses water (i.e., becomes dehydrated), the volume of blood cycled to the wound site decreases. This in turn reduces the oxygen and nutrients absorbed by cells at the wound site, slowing the healing process.
  • Tissue hydrators typically act through either retaining moisture themselves and increasing water in the vicinity of the skin wound (e.g., glycerin or hyaluronic acid) or through preventing the loss of water from tissue surrounding the wound site (e.g., silicone gel sheets).
  • the tissue hydrator can be glycerin or a pharmaceutically acceptable salt thereof.
  • the tissue hydrator is glycerin or a pharmaceutically acceptable salt thereof.
  • Glycerin is a three carbon molecule of Formula (II)
  • Glycerin is water soluble and hydroscopic. This allows glycerin to increase the water content of contacted biological tissue by absorbing water molecules from the atmosphere and contacting it with biological tissue (i.e., a tissue hydrator). Glycerin is also ideal for pharmaceutical compositions, as it is non-toxic and biodegradable.
  • the topical formulation or composition includes from about 0.01 wt% to about 2 wt% glycerin (e.g., from about 0.02 wt% to about 4 wt%, from about 0.03 wt% to about 3 wt%, from about 0.04 wt% to about 2 wt%, from about 0.05 wt% to about 1 .95 wt %, from about 0.1 wt% to about 1 .9 wt %, from about 0.15 wt% to about 1 .85 wt %, from about 0.2 wt% to about 1 .8 wt%, from about 0.25 wt% to about 1 .75 wt %, from about 0.3 wt% to about 1 .7 wt%, from about 0.35 wt% to about 1 .65 wt %, from about 0.4 wt% to about 1 .6 wt%, from about 0.45 wt% to about 1
  • the topical formulation or composition includes, e.g., about 0.05 wt%, about 0.1 wt%, about 0.15 wt%, about 0.2 wt%, about 0.25 wt%, about 0.3 wt%, about 0.35 wt%, about 0.4 wt%, about 0.45 wt%, about 0.5 wt%, about 0.55 wt%, about 0.6 wt%, about 0.65 wt%, about 0.7 wt%, about 0.75 wt%, about 0.8 wt%, about 0.85 wt%, about 0.9 wt%, about 0.95 wt%, about 1 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1.2 wt%, about 1.05 wt%, about 1.1 wt%, about 1.15 wt%, about 1 .2 wt%, about 1 .25 wt%, about
  • a wound-healing promoting agent serves to bind to proteins on the surface of skin cells to promote wound-healing and drug delivery.
  • Wound-healing promoting agents may act by repairing the extracellular matrix in and around the wound site.
  • Wound-healing promoting agents may also be referred to as “skin conditioners,” “moisturizers,” “lubricants,” or “emollients” herein.
  • Wound-healing promoting agents of this disclosure include hyaluronic acid, lanolin, liquid paraffin, urea, propylene glycol, lactic acid, ammonium lactate, petroleum, salicylic acid, and human nutrient vitamins (e.g., vitamin A, vitamin B, vitamin C, etc.), collagen I, collagen III, collagen V, collagen VI, collagen VII, collagen XVI, elastin, laminin, fibrillin, or heparan sulfate proteoglycan 2, carnosine and its derivatives (e.g., N-octanoyl carnosine).
  • the wound-healing promoting agents of this disclosure may be used in combination in a pharmaceutical composition of this disclosure.
  • Wound-healing promoting agents further include any pharmaceutically acceptable salts of the above named excipients.
  • the wound-healing promoting agent can be hyaluronic acid or a pharmaceutically acceptable salt thereof
  • the topical formulation or composition includes from about 0.001 wt% to 1 wt% of a wound-healing agent (e.g., from about 0.005 wt% to 0.9 wt%, from about 0.01 wt% to 0.8 wt%, from about 0.015 wt% to 0.7 wt%, from about 0.02 wt% to about 0.6 wt%, from about 0.025 wt% to about 0.5 wt%, from about 0.03 wt% to about 0.4 wt%, from about 0.035 wt% to about 0.3 wt%, from about 0.04 wt% to about 0.2 wt%, from about 0.045 wt% to about 0.1 wt%, from about 0.046 wt% to about 0.09 wt%, from about 0.047 wt% to about 0.08 wt%, from about 0.048 wt% to about 0.07 wt%, or from about 0.001 w
  • the topical formulation or composition includes, e.g., about 0.001 wt%, about 0.005 wt%, about 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.03 wt%, about 0.035 wt%, about 0.04 wt%, about 0.05 wt%, about 0.055 wt%, about 0.06 wt%, about 0.065 wt%, about 0.07 wt%, about 0.075 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.2 wt%, about 0.22
  • the wound-healing promoting agent is hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., the sodium salt).
  • Hyaluronic acid is a polymeric organic acid of Formula (III):
  • Hyaluronic acid and its sodium salt - sodium hyaluronate - are a critical component of the extracellular matrix of multicellular organisms.
  • hyaluronic acid is a major component of the extracellular matrix of skin cells.
  • the natural presence of hyaluronic acid facilitates healing at wound sites.
  • the lack of hyaluronic acid in skin e.g., as a side effect of a wound such as sunburn) slows healing and can lead to buildup of degradation products in the skin, further delaying or preventing wound healing.
  • Hyaluronic acid promotes more efficient action of the active ingredient (e.g., insulin) of the composition.
  • hyaluronic acid may act by repairing the extracellular matrix in and around the wound site, improving the action of the active pharmaceutical ingredients on treating other symptoms and causes of the skin wound.
  • Hyaluronic acid is typically purchased and administered in either its neutral acidic form or as the sodium salt of hyaluronic acid - sodium hyaluronate.
  • the topical formulation includes from about 0.001 wt% to 1 wt% of a hyaluronic acid or a pharmaceutically acceptable salt thereof (e.g., from about 0.005 wt% to 0.9 wt%, from about 0.01 wt% to 0.8 wt%, from about 0.015 wt% to 0.7 wt%, from about 0.02 wt% to about 0.6 wt%, from about 0.025 wt% to about 0.5 wt%, from about 0.03 wt% to about 0.4 wt%, from about 0.035 wt% to about 0.3 wt%, from about 0.04 wt% to about 0.2 wt%, from about 0.045 wt% to about 0.1 wt%, from about 0.046 wt% to about 0.09 wt%, from about 0.047 wt% to about 0.08 wt%, from about 0.048 wt% to about 0.07 w
  • the topical formulation includes, e.g., about 0.001 wt%, about 0.005 wt%, about 0.01 wt%, about 0.015 wt%, about 0.02 wt%, about 0.025 wt%, about 0.03 wt%, about 0.035 wt%, about 0.04 wt%, about 0.05 wt%, about 0.055 wt%, about 0.06 wt%, about 0.065 wt%, about 0.07 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.2 wt%, about 0.22 wt%
  • Surfactants are a class of molecules which change the surface tension at the interface between two materials.
  • Surfactant molecules are typically long, high molecular weight materials with distinct molecular blocks of different polarity, e.g., a polar water-soluble section (e.g., a hydrophilic “head”) and a non-polar fat-soluble section (e.g., a hydrophobic “tail”).
  • the sections of a surfactant are commonly referred to as the “head” of the molecule, meaning the terminal end of the molecule which has an electrostatic interaction with water (i.e. , the “polar” group), and the “tail” of the molecule, meaning the terminal end of the molecule which has weak to no interactions with water (i.e., the “nonpolar” group).
  • Surfactants may include a polar head at one terminus of the molecule or more than one terminus of the molecule of the molecule. Surfactants serve to decrease the surface tension at the interfaces between two different materials (e.g., biological tissue and an ointment or gel). In topical formulations and compositions, surfactants may additionally serve to solubilizes water-insoluble drugs in the body’s aqueous environment.
  • Surfactants of this disclosure are divided into four broad classes: anionic surfactants (e.g., sodium stearate, sodium lauryl sarcosinate, sodium lauryl sulfate, docusate sodium, sodium 7-ethyl-2- methyl-4-undecyl sulfate (i.e., Niaproof 4), sodium N-lauroyl-N-methyl-taurate, sodium tetradecane sulfonate, sodium dioxyethylene lauryl ether sulfate, sodium trioxyethylene alky ether acetate), cationic surfactants (e.g., benzalkonium chloride, benzyldimethyltetradecylammonium, cetyltrimethylammonium bromide, 3-hexdecyl-1-hydroxyethylimidazolium bromide, oxyethyl-3-hexadecylimidazolium bromide, hexadecylethy
  • Anionic surfactants are distinguished by their negatively charged head group.
  • Cationic surfactants are distinguished by their positively charged head group.
  • Zwitterionic surfactants have both positive and negative charges in the molecular structure of the head group.
  • Non-ionic surfactants have no positive or negative formal charges in the molecular structure but do contain a strongly polarized electric dipole at the head group.
  • the surfactant is poloxamer 407.
  • the formulation or composition includes from about 1 wt% to about 50 wt% of a surfactant (from about 1.1 wt% to about 49 wt%, from about 1 .2 wt% to about 48 wt%, from about 1.3 wt% to about 47 wt%, from about 1 .4 wt% to about 46 wt%, from about 1 .5 wt% to about 45 wt%, from about 1 .6 wt% to about 44 wt%, from about 1 .7 wt% to about 43 wt%, from about 1 .8 wt% to about 42 wt%, from about 1 .9 wt% to about 41 wt%, from about 2 wt% to about 40 wt%, from about 2.2 wt% to about 39 wt%, from about 2.4 wt% to about 38 wt%, from about 2.6 wt% to about 37 wt%, from about
  • the formulation or composition includes about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1 .3 wt%, about 1 .4 wt%, about 1 .5 wt%, about 1 .6 wt%, about 1 .7 wt%, about 1 .8 wt%, about 1 .9 wt%, about 2 wt%, about 2.2 wt%, about 2.4 wt%, about 2.6 wt%, about 2.8 wt%, about 3 wt%, about 3.2 wt%, about 3.4 wt%, about 3.6 wt%, about 3.8 wt%, about 4 wt%, about 4.25 wt%, about
  • wt% 7.5 wt%, about 8 wt%, about 8.5 wt%, about 9 wt%, about 10 wt%, about 10.5 wt%, about 11 .5 wt%, about 12 wt%, about 12.5 wt%, about 12 wt%, about 13.5 wt%, about 14 wt%, about 14.5 wt%, about 15 wt%, about 15.5 wt%, about 16 wt%, about 16.5 wt%, about 17 wt%, about 17.5 wt%, about 18 wt%, about 18.5 wt%, about 19 wt%, about 19.5 wt%, about 20 wt%, about 20.5 wt%, about 21 wt%, about
  • the surfactant is a poloxamer.
  • Poloxamers are a general class of block copolymer materials of Formula (IV).
  • Poloxamers are ABA triblock copolymers where the A polymer blocks are poly(ethylene oxide) (PEO) and the B polymer block is polypropylene oxide) (PPO). Each block includes several monomer units (e.g. a monomer units of PEO and b monomer units of PPO). There exist many different known poloxamer materials, each differing in the number of monomer units included in each block. Poloxamers are commonly identified by a three-or-more-digit number, e.g., poloxamer 407.
  • poloxamer 407 refers to a poloxamer material made of an about 4000 Da PPO block, and which is about 70% PPE by weight.
  • mice of the C57/B6 genome homozygous for the diabetes spontaneous mutation Lepr db (i.e., C57/B6 db/db male and female mice) were purchased from Jackson Laboratory. Animals were housed in a barrier facility with a controlled ambient temperature of 22°C and a 14/10-h light-dark cycle. Animals were fed a standard laboratory diet and sterilized water. All animals were weighed using a digital scale on the day of surgery.
  • mice were housed in the animal care facility for a minimum of 1 week prior to surgery. The animals were assigned to one of six groups for analysis. The groups and their associated treatment protocol are summarized in Table 3.
  • the mean percent wound closure ratio for the saline group, the insulin group, the single dose group, the multi-dose group, the MucoLox group, and the MucoLox/insulin group at day 15 were: 28 ⁇ 10, 56 ⁇ 18, 72 ⁇ 18, 69 ⁇ 20, 37 ⁇ 9.8, and 37 ⁇ 17 respectively (Fig. 8). Images of the wounds at days 0, 2, 6, 9, 12, and 15 are provided as Fig. 9 (saline group), Fig. 10 (insulin group), Fig. 11 (single dose group), Fig. 12 (multi-dose) Fig. 13 (MucoLox group), and Fig. 14 (MucoLox/insulin group).
  • This example demonstrates the effectiveness of the topical formulations of the present disclosure for healing skin wounds. Further, the example demonstrates improved effectiveness of insulin topical formulations of the present disclosure in treating skin wounds (e.g., diabetic foot ulcers).
  • mice selected from the groups in Table 3.
  • Fig. 15F Samples from the insulin group, single dose group, multi-dose group, MucoLox group, and MucoLox/insulin group were covered by a thin layer of epithelium (Figs. 15A-E). Importantly, the size of the epidermis layer was larger in both the single dose and multiple dose groups than in either the insulin group or the MucoLox group (Fig. 15G). Further, the granulation tissue was also thicker in the single dose group compared to all other examined groups. The insulin treated group also resulted in increased vascularization (Fig. 15H).
  • Example 4 The study of Example 4 was repeated on an increased scale. 64 C57/B6 db/db mice (32 female, 32 male) were investigated. Animals were housed in a barrier facility with a controlled ambient temperature of 22°C and a 14/10-h light-dark cycle. Animals were fed a standard laboratory diet and sterilized water. All animals were weighed using a digital scale on the day of surgery. Blood was collected in live, awake animals between 10:00 and 11 :00 a.m. Glucose was measured by glucometer. BG was measured prior to surgery (i.e., day 0) and repeated on day 1 , 2, 9, 12 and 15 after surgery.
  • mice were housed in the animal care facility for a minimum of 1 week prior to surgery. The animals were assigned to one of eight groups for analysis. The groups and their associated treatment protocol are summarized in Table 4.
  • mice On the day of surgery, mice were anesthetized and the dorsal area was shaved using an electric shaver. Full thickness dermal wounds were created using 4 mm biopsy punches and splinted with 10 mm silicone rings with a 5 mm inner diameter. The blood glucose level of each mouse was measured on days 0, 1 , 2, 9, 12, and 15. The wound was covered with Opsite® bandages. Wound edges were measured on days 0, 2, 6, 9, 12, and 15. The BG of mice in each group are summarized in Tables 5 to 12 (BG measured in mg/dL). Fig. 16 shows images of the injured tissue in exemplary mice over the 15 day period. The BG of each mouse in the Saline Group over time is summarized in Table 5:
  • BG levels in the Saline Group remained high throughout the study with fluctuations. In the untreated mice of the Saline Group, BG levels were largely uncontrolled, with frequent instances of HL.
  • BG levels in the Insulin Group showed a decreasing trend initially but fluctuated significantly. Although insulin treatment was successful at lowering blood sugars initially, the large variability in number of HL instances suggests the control was inconsistent.
  • the BG levels of the Formulation 4 Group fluctuated significantly, but generally decreased over time.
  • BG BG > 600 mg/dL *: BG not measured Similar to the Formulation 4 group, the BG levels of the Formulation 5 Group showed significant fluctuations. However, unlike the Formulation 4 group, the BG levels of the Formulation 5 Group generally trend towards stabilization, demonstrating that the higher Poloxamer 407 content improves BG control and reduces HL instances.
  • the BG levels of the Formulation 7 Group generally decreased over time. Fluctuations in the Formulation 7 group were generally less than the Formulation 4 or Formulation 5 groups. BG levels were generally closer to normal ranges with less variability and fewer HL instances.
  • the BG levels of the Formulation 8 Group showed frequent HL instances and variability over time.
  • the Formulation 8 Group shows an increase in HL instances and variability compared with the Formulation 7 group, suggesting an optimal range of poloxamer in a formulation for BG control and reduced variability.
  • the BG levels of the Formulation 10 group showed moderate improvement with fluctuations and frequent HL instances.
  • the wound closure ratio in each group was then determined (Fig. 17).
  • the Formulation 7 Group, the Formulation 8 Group, and the Formulation 10 Group showed consistent and higher wound closure rates throughout the study, with the Formulation 7 Group outperforming the Formulation 8 Group, and the Formulation 8 Group outperforming the Formulation 10 Group.
  • a histological analysis of skin tissue sections from exemplary mice in each group is shown in Fig. 18.
  • Treated tissue in each group was also analyzed for granulation (Fig. 19), angiogenesis (Fig. 20), epidermal thickness (Fig. 21), dermal/epidermal separation (Fig. 22), and the growth of skin appendages (e.g., hair follicles and glands; Fig. 23).
  • Topical compositions of the present disclosure (e.g., Formulation 1 , Formulation 2, Formulation 3, Formulation 4, Formulation 5, Formulation 7, and Formulation 8) outperformed prior art formulations (e.g., MucoLoxTM based formulations, e.g., Formulation 10).
  • topical compositions including a higher concentration of poloxamer (e.g., Formulation 7 and Formulation 8) showed particular effectiveness in wound healing.
  • Example 7 Treatment of Skin Wounds In Human Subjects via an Insulin-Based Topical Formulation of Optimal Viscosity for Insulin Delivery to a Skin Wound
  • a composition comprising about 100 mg insulin (e.g., 0.15 U of Novolin 70/30 Insulin), about 100 mg Noveon® AA-1 Polycarbophil USP (as a bioadhesive agent), about 100 mg glycerin (as a tissue hydrator), about 5 mg hyaluronic acid (as a wound-healing promoting agent), about any of 100 (1 wt%), 500 (5 wt%), 1000 (10 wt%) or, preferably, 1500 (15 wt%) mg poloxamer 407 (as a surfactant), and a pharmaceutically acceptable excipient (preferably water, adjusted depending on the amount of surfactant included in the composition) having a complex viscosity of greater than about 7000 mPa s, preferably about 14000 mPa s, and exhibiting at least 90% release of insulin by one minute at room temperature in PBS, is applied to skin wound of a human being.
  • a pharmaceutically acceptable excipient preferably water, adjusted depending on
  • composition is applied to the skin wound site once per day, or once per day for five days, and wound healing is monitored and measured using the wound closure ratio as was performed in Example 5 (see, e.g., Figs. 15A-15H) and Example 6 (See, e.g., Fig. 17).

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Abstract

La présente divulgation propose des formulations topiques à base d'insuline et des compositions pharmaceutiques à viscosité régulable, ainsi que leurs procédés d'utilisation aux fins du traitement de plaies cutanées. Dans certains modes de réalisation, la formulation présente une viscosité d'environ 1 mPa-s à environ 50 000 mPa-s, préférentiellement d'environ 7 000 à 20 000 mPa-s. Des formulations et des compositions données à titre d'exemple de la divulgation comprennent celles contenant de l'insuline (p. ex. en une quantité d'environ 0,1 à environ 200 unités), du poloxamère 407 (p. ex. d'environ 1 % en poids à environ 50 % en poids), de la glycérine (p. ex. d'environ 0,1 % en poids à environ 5 % en poids), de l'acide hyaluronique (p. ex. d'environ 0,001 % en poids à environ 1 % en poids) et du polycarbophile (p. ex. d'environ 0,1 % en poids à environ 5 % en poids).
PCT/US2024/036875 2023-07-05 2024-07-05 Compositions et procédés aux fins d'un traitement amélioré de plaies cutanées Pending WO2025010400A2 (fr)

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