Compositions and methods for improved treatment of skin wounds

Abstract

The present disclosure provides topical, insulin-based formulations and pharmaceutical compositions of controllable viscosity, as well as methods of using the same for the treatment of skin wounds. In some embodiments, the formulation has a viscosity of from about 1 mPa·s to about 50000 mPa·s, preferably about 7000 to 20000 mPa·s. Exemplary formulations and compositions of the disclosure include those containing insulin (e.g., in an amount of from about 0.1 to about 200 units), poloxamer 407 (e.g., from about 1 wt% to about 50 wt%), glycerin (e.g., from about 0.1 wt% to about 5 wt%), hyaluronic acid (e.g., from about 0.001 wt% to about 1 wt%), and polycarbophil (e.g., from about 0.1 wt% to about 5 wt%).

Description

[0001] COMPOSITIONS AND METHODS FOR IMPROVED TREATMENT OF SKIN WOUNDS

[0002] FIELD OF THE DISCLOSURE

[0003] This disclosure relates to compositions (e.g., formulations), preferably 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.

[0004] BACKGROUND OF THE DISCLOSURE

[0005] 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). If left untreated, independent of the status of the underlying ailment, skin wounds will often cause lasting pain, scarring of the tissue, and incapacitation. Additionally, subjects suffering from skin wounds are at higher risk for further bacterial / viral / fungal infection and potentially, eventual sepsis / organ failure.

[0006] In the United States alone there are 37 million diabetics and 96 million pre-diabetics. About 25% of diabetic patients at some point suffer from diabetic foot ulcers (DFUs) which known to be very difficult to heal. Even with closure, DFUs are known to re-open in about 50% of patients within 12 months, resulting in about 130000 amputations in 2021 . According to the US Centers for Disease Control, this results in about USD$13 billion in additional spending, and costs per patient of about USD$17000, not including the lack of productivity due to incapacitation. It was recently found that the blood sugar in the tissue surrounding a DFU wound bed is elevated (e.g., over 500 mg / dl) as compared to systemic blood sugar (see, e.g., U.S. 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). As shown in the ‘664 patent, 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.

[0007] Accordingly, there is a clear need to develop methods and medicines which can be used either independently or in tandem with treatment for the underlying ailment to aid in skin wound treatment. The formulations, compositions and methods disclosed herein address such needs.

[0008] SUMMARY OF THE DISCLOSURE

[0009] 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.

[0010] In a first aspect, 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 mPas, from about 1300 mPas to about 38000 mPas, from about 1450 mPas to about 37000 mPa s, from about 1600 mPas to about 36000 mPas, from about 1750 mPas to about 35000 mPa s, from about 1900 mPas to about 34000 mPas, from about 2050 mPas to about 33000 mPas, from about 2200 mPas to about 32000 mPas, from about 2350 mPas to about 31000 mPa s, from about 2500 mPas to about 30000 mPas, from about 2650 mPas to about 29000 mPas, from about 2800 mPas to about 28000 mPas, from about 2950 mPas to about 37000 mPas, from about 3100 mPas to about 26000 mPas, from about 3250 mPas to about 25000 mPa s, from about 3400 mPas to about 24000 mPas, from about 3550 mPas to about 23000 mPas, from about 3700 mPas to about 22000 mPa s, from about 3850 mPas to about 21000 mPas, from about 4000 mPas to about 20000 mPa s, from about 4100 mPas to about 19800 mPas, from about 4200 mPas to about 19600 mPas, from about 4300 mPas to about 19400 mPas, from about 4400 mPas to about 19200 mPa s, from about 4500 mPas to about 19000 mPas, from about 4600 mPas to about 18800 mPas, from about 4700 mPas to about 18600 mPas from about 4200 mPas to about 18400 mPas, from about 4100 mPas to about 18200 mPas, from about 5000 mPas to about 18000 mPa s, from about 5100 mPas to about 17800 mPas, from about 5200 mPas to about 17600 mPas, from about 5300 mPas to about 17400 mPa s, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPa s, from about 5600 mPas to about 16800 mPas, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPa s, from about 6100 mPas to about 15800 mPas, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPa s, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPas, from about 6600 mPas to about 14800 mPa s, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPa s, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPas, from about 7400 mPas to about 13600 mPa s, from about 7500 mPas to about 13500 mPas, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s3from about 8000 mPas to about 13000 mPas, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPas, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPas, from about 8900 mPas to about 12100 mPa s, from about 9000 mPas to about 12000 mPas, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPa s, from about from about 9300 mPas to about 11700 mPa s, from about 9400 mPas to about 11600 mPas, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPas, from about 7000 mPas to about 7500 mPas, from about 7500 mPas to about 8000 mPa s, from about 8000 mPas to about 8500 mPa s, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPas, from about 10500 mPa s, from about 10500 mPa sto about 11000 mPa s, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPa s, from about 12000 mPas to about 12500 mPas, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPas. In some embodiments, 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 mPa s, about 2800 mPa s, about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPa s, about 3800 mPas, about 3900 mPa s3about 4000 mPas, about 4100 mPas, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPas, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPas, about 5200 mPa s, about 5300 mPa s, about 5400 mPas, about 5500 mPa s, about 5600 mPa s, about 5700 mPa s, about 5800 mPa s, about 5900 mPas, about 6000 mPa s, about 6100 mPa s, about 6200 mPa s, about 6300 mPa s, about 6400 mPa s3about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s3about 7000 mPa s, about 7100 mPas about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPa s, about 7700 mPa s, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPas, about 8200 mPa s, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPa s, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPas, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPas, about 9700 mPa s, about 9800 mPa s, about 9900 mPas, about 10000 mPas, about 10100 mPa s, about 10200 mPa s, about 10300 mPas, about 10400 mPas, about 10500 mPa s, about 10600 mPas, about 10700 mPa s, about 10800 mPas, about 10900 mPas, about 11000 mPas, about 11100 mPa s, about 11200 mPa s, about 11300 mPas, about 11400 mPas, about 11500 mPas, about 11600 mPa s, about 11700 mPa s, about 11800 mPas, about 11900 mPas, about 12000 mPas, about 12100 mPa s, about 12200 mPa s, about 12300 mPas, about 12400 mPas, about 12500 mPas, about 12600 mPa s, about 12700 mPa s, about 12800 mPas, about 12900 mPa s3about 13000 mPa s, about 13100 mPas about 13200 mPas about 13300 mPas, about 13400 mPas, about 13500 mPas, about 13600 mPa s, about 13700 mPa s, about 13800 mPas, about 13900 mPas, about 14000 mPas, about 14100 mPa s, about 14200 mPa s, about 14300 mPas, about 14400 mPas, about 14500 mPas, about 14600 mPa s, about 14700 mPa s, about 14800 mPas, about 14900 mPas, about 15000 mPas, about 15200 mPa s, about 15400 mPa s, about 15600 mPas, about 15800 mPas, about 16000 mPas, about 16200 mPa s, about 16400 mPa s, about 16600 mPa s, about 16800 mPa s, about 17000 mPa s, about 17200 mPa s, about 17400 mPa s, about 17600 mPa s, about 17800 mPa s, about 18000 mPa s, about 18200 mPa s, about 18400 mPa s, about 18600 mPa s, about 18800 mPa s, about 19000 mPa s, about 19200 mPa s, about 19400 mPa s, about 19600 mPa s, about 19800 mPa s, about 20000 mPa s about 20500 mPa s, about 21000 mPa s, about 21500 mPa s, about 22000 mPa s, about 22500 mPa s, about 23000 mPa s, about 23500 mPa s, about 24000 mPa s. about 24500 mPa s, about 25000 mPa s, about 25500 mPa s, about 26000 mPa s, about 26500 mPa s, about 27000 mPa s, about 27500 mPa s, about 28000 mPa s, about 28500 mPa s, about 29000 mPa s, about 29500 mPa s, about 30000 mPa s, about 31000 mPa s, about 32000 mPa s, about 33000 mPa s, about 34000 mPa s, about 35000 mPa s, about 36000 mPa s, about 37000 mPa s, about 38000 mPa s, about 39000 mPa s, about 40000 mPa s, about 41000 mPa s, about 42000 mPa s, about 43000 mPa s, about 44000 mPa s, about 45000 mPa s, about 46000 mPa s, about 47000 mPa s, about 48000 mPa s, about 49000 mPa s, or about 50000 mPa s).

[0011] In some embodiments, 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 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain. In some embodiments, storage modulus of the formulation is from about 50000 mPa to about 200000 mPa.

[0012] In some embodiments, 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 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain. In some embodiments, the loss modulus of the formulation is from about 20000 mPa about 100000 mPa.

[0013] In some embodiments, the storage modulus of the formulation is greater than the loss modulus of the formulation at 1 unit of applied strain.

[0014] In some embodiments, 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.

[0015] In some embodiments, the insulin includes a) a fast-acting insulin; b) an intermediate-acting insulin; or c) a long-acting insulin. In some embodiments, the fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine. In some embodiments, the intermediate-acting insulin is an isophane insulin or a Neutral Protamine Hagedorn insulin. In some embodiments, the long-acting insulin selected from insulin glargine, insulin detemir, or insulin degludec. In some embodiments, 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

[0016] 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 120 units per 10 g of the formulation or composition, from about 4.5 units per 10 g of the formulation or composition to about 110 units per 10 g of the formulation or composition, from about 5 units per 10 g of the formulation or composition to about 100 units per 10 g of the formulation or composition, from about 5.5 units per 10 g of the formulation or composition to about 90 units per 10 g of the formulation or composition, from about 6 units per 10 g of the formulation or composition to about 80 units per 10 g of the formulation or composition, from about 6.5 units per 10 g of the formulation or composition to about 70 units per 10 g of the formulation or composition, from about 7 units per 10 g of the formulation or composition to about 60 units per 10 g of the formulation or composition, from about 7.5 units per 10 g of the formulation or composition to about 50 units per 10 g of the formulation or composition, from about 8 units per 10 g of the formulation or composition to about 40 units per 10 g of the formulation or composition, from about

[0017] 8.5 units per 10 g of the formulation or composition to about 30 units per 10 g of the formulation or composition, from about 9 units per 10 g of the formulation or composition to about 20 units per 10 g of the formulation or composition, 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 1.4 units of insulin per 10 g of the formulation or composition, about 1.6 units of insulin per 10 g of the formulation or composition, about 1 .8 units of insulin per 10 g of the formulation or composition, about 2 units of insulin per 10 g of the formulation or composition, about 2.2 units of insulin per 10 g of the formulation or composition, about 2.4 units of insulin per 10 g of the formulation or composition, about 2.6 units of insulin per 10 g of the formulation or composition, about 2.8 units of insulin per 10 g of the formulation or composition about 3 units of insulin per 10 g of the formulation or composition, about 3.25 units of insulin per 10 g of the formulation or composition, about 3.5 units of insulin per 10 g of the formulation or composition, about 3.75 units of insulin per 10 g of the formulation or composition, about 4 units of insulin per 10 g of the formulation or composition, about 4.25 units of insulin per 10 g of the formulation or composition, about 4.75 units of insulin per 10 g of the formulation or composition about 5 units of insulin per 10 g of the formulation or composition, about 5.5 units of insulin per 10 g of the formulation or composition, about 6 units of insulin per 10 g of the formulation or composition, about 6.5 units of insulin per 10 g of the formulation or composition, about 7 units of insulin per 10 g of the formulation or composition about 7.5 units of insulin per 10 g of the formulation or composition, about 8 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition units of insulin per 10 g of the formulation or composition, about 9 units of insulin per 10 g of the formulation or composition, about 9.5 units of insulin per 10 g of the formulation or composition, about 10 units of insulin per 10 g of the formulation or composition, about 11 units of insulin per 10 g of the formulation or composition, about 12 units of insulin per 10 g of the formulation or composition, about 13 units of insulin per 10 g of the formulation or composition, about 14 units of insulin per 10 g of the formulation or composition, about 15 units of insulin per 10 g of the formulation or composition, about 16 units of insulin per 10 g of the formulation or composition, about 17 units of insulin per 10 g of the formulation or composition, about 18 units of insulin per 10 g of the formulation or composition, about 19 units of insulin per 10 g of the formulation or composition, about 20 units of insulin per 10 g of the formulation or composition, about 21 units of insulin per 10 g of the formulation or composition, about 22 units of insulin per 10 g of the formulation or composition, about 23 units of insulin per 10 g of the formulation or composition, about 24 units of insulin per 10 g of the formulation or composition, about 25 units of insulin per 10 g of the formulation or composition, about 26 units of insulin per 10 g of the formulation or composition, about 27 units of insulin per 10 g of the formulation or composition, about 28 units of insulin per 10 g of the formulation or composition about 29 units of insulin per 10 g of the formulation or composition, about 30 units of insulin per 10 g of the formulation or composition, about 32 units of insulin per 10 g of the formulation or composition, about 34 units of insulin per 10 g of the formulation or composition, about 36 units of insulin per 10 g of the formulation or composition, about 38 units of insulin per 10 g of the formulation or composition, about 40 units of insulin per 10 g of the formulation or composition, about 42 units of insulin per 10 g of the formulation or composition, about 44 units of insulin per 10 g of the formulation or composition, about 46 units of insulin per 10 g of the formulation or composition, about 48 units of insulin per 10 g of the formulation or composition, about 50 units of insulin per 10 g of the formulation or composition, about 55 units of insulin per 10 g of the formulation or composition, about 60 units of insulin per 10 g of the formulation or composition, about 65 units of insulin per 10 g of the formulation or composition, about 70 units of insulin per 10 g of the formulation or composition, about 75 units of insulin per 10 g of the formulation or composition, about 80 units of insulin per 10 g of the formulation or composition, about 85 units of insulin per 10 g of the formulation or composition about 85 units of insulin per 10 g of the formulation or composition, about 90 units of insulin per 10 g of the formulation or composition, about 95 units of insulin per 10 g of the formulation or composition, about 100 units of insulin per 10 g of the formulation or composition, about 110 units of insulin per 10 g of the formulation or composition, about 120 units of insulin per 10 g of the formulation or composition, about 130 units of insulin per 10 g of the formulation or composition, about 140 units of insulin per 10 g of the formulation or composition, about 150 units of insulin per 10 g of the formulation or composition, about 160 units of insulin per 10 g of the formulation or composition, about 170 units of insulin per 10 g of the formulation or composition, about 180 units of insulin per 10 g of the formulation or composition, about 190 units of insulin per 10 g of the formulation or composition, or about 200 units of insulin per 10 g of the formulation or composition).

[0018] In some embodiments, 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 about 2.8 wt% to about 36 wt%, from about 3 wt% to about 35 wt%, from about 3.2 wt% to about 34 wt%, from about 3.4 wt% to about 33 wt%, from about 3.6 wt% to about 32 wt%, from about 3.8 wt% to about 31 wt%, from about 4 wt% to about 30 wt%, from about 4.2 wt% to about 30 wt%, from about 4.4 wt% to about 30 wt%, from about 4.6 wt% to about 30 wt%, from about 4.8 wt% to about 30 wt%, from about 5 wt% to about 30 wt%, from about 4.2 wt% to about 29 wt%, from about 4.4 wt% to about 28 wt%, from about 4.6 wt% to about 27 wt%, from about 4.8 wt% to about 26 wt%, from about 5 wt% to about 25 wt%, from about 5.5 wt% to about 24.5 wt%, from about 6 wt% to about 24 wt%, from about 6.5 wt% to about 23.5 wt%, from about 7 wt% to about 23 wt%, from about 7.5 wt% to about 22.5 wt%, from about 8 wt% to about 22 wt%, from about 8.5 wt% to about 23 wt%, from about 9 wt% to about 22 wt%, from about 9.5 wt% to about 21 wt%, from about 10 wt % to about 20 wt%, from about 10.5 wt% to about 19.5 wt%, from about 11 wt% to about 19 wt%, from about 11 .5 wt% to about 18.5 wt%, from about 12 wt% to about 18 wt%, from about

[0019] 12.5 wt% to about 17.5 wt%, from about 13 wt% to about 17 wt%, from about 13.5 wt% to about 16.5 wt%, from about 14 wt% to about 16 wt%, from about 14.5 wt% to about 15.5 wt%, 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 4.5 wt%, about 4.75 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 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

[0020] 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 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about

[0021] 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%).

[0022] In some embodiments, the surfactant is a poloxamer. In some embodiments, the poloxamer is poloxamer 407.

[0023] In some embodiments, 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 %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%, about 0.01 wt%, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1.65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1.85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%).

[0024] In some embodiments, the tissue hydrator includes glycerin or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, 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% to about 0.06 wt%, 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 O.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%, about 0.24 wt%, about 0.26 wt%, about 0.28 wt%, about 0.3 wt%, about 0.32 wt%, about 0.34 wt%, about 0.36 wt%, about 0.38 wt%, about 0.4 wt%, about 0.42 wt% about 0.44 wt%, about 0.46 wt%, about 0.48 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%, or about 1 wt%).

[0026] In some embodiments the wound-healing promoting agent includes hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, 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 wt %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1.9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%).

[0028] In some embodiments, the bioadhesive agent is a carbomer. In some embodiments, the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof. In some embodiments, the polycarbophil is Noveon® AA-1 Polycarbophil USP.

[0029] In some embodiments, the pharmaceutically acceptable solvent is water.

[0030] In some embodiments, the formulation is a topical formulation. In some embodiments, the formulation is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid. In some embodiments, the formulation is used for the treatment of a skin wound. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0031] In some embodiments, 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).

[0032] In a second aspect, 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.

[0033] In some embodiments, the insulin includes one or more of: a) a fast-acting insulin; b) an intermediate-acting insulin; c) a long-acting insulin. In some embodiments, the insulin includes a fast acting insulin, wherein the fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine. In some embodiments, the insulin includes an intermediate-acting insulin, wherein the intermediate-acting insulin is an isophane insulin or a Neutral Protamine Hagedorn insulin. In some embodiments, the insulin includes a long-acting insulin selected from insulin glargine, insulin detemir, or insulin degludec.

[0034] In some embodiments, 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 120 units per 10 g of the formulation or composition, from about 4.5 units per 10 g of the formulation or composition to about 110 units per 10 g of the formulation or composition, from about 5 units per 10 g of the formulation or composition to about 100 units per 10 g of the formulation or composition, from about 5.5 units per 10 g of the formulation or composition to about 90 units per 10 g of the formulation or composition, from about 6 units per 10 g of the formulation or composition to about 80 units per 10 g of the formulation or composition, from about 6.5 units per 10 g of the formulation or composition to about 70 units per 10 g of the formulation or composition, from about 7 units per 10 g of the formulation or composition to about 60 units per 10 g of the formulation or composition, from about 7.5 units per 10 g of the formulation or composition to about 50 units per 10 g of the formulation or composition, from about 8 units per 10 g of the formulation or composition to about 40 units per 10 g of the formulation or composition, from about 8.5 units per 10 g of the formulation or composition to about 30 units per 10 g of the formulation or composition, from about 9 units per 10 g of the formulation or composition to about 20 units per 10 g of the formulation or composition, 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 .4 units of insulin per 10 g of the formulation or composition, about 1.6 units of insulin per 10 g of the formulation or composition, about 1.8 units of insulin per 10 g of the formulation or composition, about 2 units of insulin per 10 g of the formulation or composition, about 2.2 units of insulin per 10 g of the formulation or composition, about 2.4 units of insulin per 10 g of the formulation or composition, about 2.6 units of insulin per 10 g of the formulation or composition, about 2.8 units of insulin per 10 g of the formulation or composition about 3 units of insulin per 10 g of the formulation or composition, about 3.25 units of insulin per 10 g of the formulation or composition, about 3.5 units of insulin per 10 g of the formulation or composition, about

[0035] 3.75 units of insulin per 10 g of the formulation or composition, about 4 units of insulin per 10 g of the formulation or composition, about 4.25 units of insulin per 10 g of the formulation or composition, about

[0036] 4.75 units of insulin per 10 g of the formulation or composition about 5 units of insulin per 10 g of the formulation or composition, about 5.5 units of insulin per 10 g of the formulation or composition, about 6 units of insulin per 10 g of the formulation or composition, about 6.5 units of insulin per 10 g of the formulation or composition, about 7 units of insulin per 10 g of the formulation or composition about 7.5 units of insulin per 10 g of the formulation or composition, about 8 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition units of insulin per 10 g of the formulation or composition, about 9 units of insulin per 10 g of the formulation or composition, about 9.5 units of insulin per 10 g of the formulation or composition, about 10 units of insulin per 10 g of the formulation or composition, about 11 units of insulin per 10 g of the formulation or composition, about 12 units of insulin per 10 g of the formulation or composition, about 13 units of insulin per 10 g of the formulation or composition, about 14 units of insulin per 10 g of the formulation or composition, about 15 units of insulin per 10 g of the formulation or composition, about 16 units of insulin per 10 g of the formulation or composition, about 17 units of insulin per 10 g of the formulation or composition, about 18 units of insulin per 10 g of the formulation or composition, about 19 units of insulin per 10 g of the formulation or composition, about 20 units of insulin per 10 g of the formulation or composition, about 21 units of insulin per 10 g of the formulation or composition, about 22 units of insulin per 10 g of the formulation or composition, about 23 units of insulin per 10 g of the formulation or composition, about 24 units of insulin per 10 g of the formulation or composition, about 25 units of insulin per 10 g of the formulation or composition, about 26 units of insulin per 10 g of the formulation or composition, about 27 units of insulin per 10 g of the formulation or composition, about 28 units of insulin per 10 g of the formulation or composition about 29 units of insulin per 10 g of the formulation or composition, about 30 units of insulin per 10 g of the formulation or composition, about 32 units of insulin per 10 g of the formulation or composition, about 34 units of insulin per 10 g of the formulation or composition, about 36 units of insulin per 10 g of the formulation or composition, about 38 units of insulin per 10 g of the formulation or composition, about 40 units of insulin per 10 g of the formulation or composition, about 42 units of insulin per 10 g of the formulation or composition, about 44 units of insulin per 10 g of the formulation or composition, about 46 units of insulin per 10 g of the formulation or composition, about 48 units of insulin per 10 g of the formulation or composition, about 50 units of insulin per 10 g of the formulation or composition, about 55 units of insulin per 10 g of the formulation or composition, about 60 units of insulin per 10 g of the formulation or composition, about 65 units of insulin per 10 g of the formulation or composition, about 70 units of insulin per 10 g of the formulation or composition, about 75 units of insulin per 10 g of the formulation or composition, about 80 units of insulin per 10 g of the formulation or composition, about 85 units of insulin per 10 g of the formulation or composition about 85 units of insulin per 10 g of the formulation or composition, about 90 units of insulin per 10 g of the formulation or composition, about 95 units of insulin per 10 g of the formulation or composition, about 100 units of insulin per 10 g of the formulation or composition, about 110 units of insulin per 10 g of the formulation or composition, about 120 units of insulin per 10 g of the formulation or composition, about 130 units of insulin per 10 g of the formulation or composition, about 140 units of insulin per 10 g of the formulation or composition, about 150 units of insulin per 10 g of the formulation or composition, about 160 units of insulin per 10 g of the formulation or composition, about 170 units of insulin per 10 g of the formulation or composition, about 180 units of insulin per 10 g of the formulation or composition, about 190 units of insulin per 10 g of the formulation or composition, or about 200 units of insulin per 10 g of the formulation or composition).

[0037] In some embodiments, 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%, from about 2.8 wt% to about 36 wt%, from about 3 wt% to about 35 wt%, from about 3.2 wt% to about 34 wt%, from about 3.4 wt% to about 33 wt%, from about 3.6 wt% to about 32 wt%, from about 3.8 wt% to about 31 wt%, from about 4 wt% to about 30 wt%, from about 4.2 wt% to about 30 wt%, from about 4.4 wt% to about 30 wt%, from about 4.6 wt% to about 30 wt%, from about 4.8 wt% to about 30 wt%, from about 5 wt% to about 30 wt%, from about 4.2 wt% to about 29 wt%, from about 4.4 wt% to about 28 wt%, from about 4.6 wt% to about 27 wt%, from about 4.8 wt% to about 26 wt%, from about 5 wt% to about 25 wt%, from about 5.5 wt% to about 24.5 wt%, from about 6 wt% to about 24 wt%, from about 6.5 wt% to about

[0038] 23.5 wt%, from about 7 wt% to about 23 wt%, from about 7.5 wt% to about 22.5 wt%, from about 8 wt% to about 22 wt%, from about 8.5 wt% to about 23 wt%, from about 9 wt% to about 22 wt%, from about 9.5 wt% to about 21 wt%, from about 10 wt % to about 20 wt%, from about 10.5 wt% to about 19.5 wt%, from about 11 wt% to about 19 wt%, from about 11 .5 wt% to about 18.5 wt%, from about 12 wt% to about 18 wt%, from about 12.5 wt% to about 17.5 wt%, from about 13 wt% to about 17 wt%, from about 13.5 wt% to about 16.5 wt%, from about 14 wt% to about 16 wt%, from about 14.5 wt% to about 15.5 wt%, 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 4.5 wt%, about 4.75 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 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

[0039] 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 21 .5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%.

[0040] In some embodiments, the surfactant is a poloxamer. In some embodiments, the poloxamer is poloxamer 407.

[0041] In some embodiments, 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 wt %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%, about 0.01 wt%, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about

[0042] 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about

[0043] 4.9 wt%, or about 5 wt%).

[0044] In some embodiments, the tissue hydrator includes glycerin or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments, 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 about 0.06 wt%, 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 O.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%, about 0.24 wt%, about 0.26 wt%, about 0.28 wt%, about 0.3 wt%, about 0.32 wt%, about 0.34 wt%, about 0.36 wt%, about 0.38 wt%, about 0.4 wt%, about 0.42 wt% about 0.44 wt%, about 0.46 wt%, about 0.48 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%, or about 1 wt%).

[0046] In some embodiments the wound-healing promoting agent includes hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, 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 .55 wt %, from about 0.5 wt% to about 1.5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about

[0048] 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about

[0049] 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt%).

[0050] In some embodiments, the bioadhesive agent is a carbomer. In some embodiments, the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof. In some embodiments, the polycarbophil is Noveon® AA-1 Polycarbophil USP.

[0051] In some embodiments, the pharmaceutically acceptable solvent is water.

[0052] In some embodiments, 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 about 39000 mPa s, from about 1300 mPa s to about 38000 mPa s, from about 1450 mPa s to about 37000 mPa s, from about 1600 mPa s to about 36000 mPa s, from about 1750 mPa s to about 35000 mPa s, from about 1900 mPa s to about 34000 mPa s, from about 2050 mPa s to about 33000 mPa s, from about 2200 mPa s to about 32000 mPa s, from about 2350 mPa s to about 31000 mPa s, from about 2500 mPa s to about 30000 mPa s, from about 2650 mPa s to about 29000 mPa s, from about 2800 mPa s to about 28000 mPa s, from about 2950 mPa s to about 37000 mPa s, from about 3100 mPa s to about 26000 mPa s, from about 3250 mPa s to about 25000 mPa s, from about 3400 mPa s to about 24000 mPa s, from about 3550 mPa s to about 23000 mPa s, from about 3700 mPa s to about 22000 mPa s, from about 3850 mPa s to about 21000 mPa s, from about 4000 mPa s to about 20000 mPa s, from about 4100 mPa s to about 19800 mPa s, from about 4200 mPa s to about 19600 mPa s, from about 4300 mPa s to about 19400 mPa s, from about 4400 mPa s to about 19200 mPa s, from about 4500 mPa s to about 19000 mPa s, from about 4600 mPa s to about 18800 mPa s, from about 4700 mPa s to about 18600 mPa s from about 4200 mPa s to about 18400 mPa s, from about 4100 mPa s to about 18200 mPa s, from about 5000 mPa s to about 18000 mPa s, from about 5100 mPa s to about 17800 mPas, from about 5200 mPas to about 17600 mPa s, from about 5300 mPas to about 17400 mPas, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPas, from about 5600 mPas to about 16800 mPa s, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPa s, from about 6100 mPas to about 15800 mPas, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPa s, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPa s, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPa s, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPas, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPas, from about 7900 mPas to about 13100 mPa s, from about 8000 mPas to about 13000 mPas, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPa s, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s3from about 8800 mPas to about 12200 mPa s, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPas, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPa s to about 11700 mPas, from about 9400 mPas to about 11600 mPas, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPas, from about 9800 mPas to about 11200 mPa s, from about 9900 mPas to about 11100 mPas, from about 7000 mPas to about 7500 mPas, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPas, from about 11000 mPas to about 11500 mPa s, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, 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 s3about 2700 mPas, about 2800 mPas about 2900 mPa s, about 3000 mPas, about 3100 mPa s3about 3200 mPas, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPas, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPas, about 4100 mPas, about 4200 mPas, about 4300 mPas, about 4400 mPa s, about 4500 mPas, about 4600 mPas, about 4700 mPa s, about 4800 mPa s, about 4900 mPa s, about 5000 mPas, about 5100 mPas, about 5200 mPas, about 5300 mPa s, about 5400 mPa s, about 5500 mPa s, about 5600 mPas, about 5700 mPas, about 5800 mPa s, about 5900 mPa s, about 6000 mPa s, about 6100 mPa s, about 6200 mPa s, about 6300 mPas, about 6400 mPas, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPas, about 7000 mPa s, about 7100 mPa s about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPa s about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPas, about 8200 mPas, about 8300 mPas, about 8400 mPa s, about 8500 mPa s, about 8600 mPas, about 8700 mPas, about 8800 mPas, about 8900 mPa s, about 9000 mPas, about 9100 mPas, about 9200 mPa s, about 9300 mPa s, about 9400 mPa s, about 9500 mPas, about 9600 mPas, about 9700 mPas, about 9800 mPa s, about 9900 mPa s, about 10000 mPas, about 10100 mPas, about 10200 mPas, about 10300 mPa s, about 10400 mPa s, about 10500 mPa s, about 10600 mPas, about 10700 mPas, about 10800 mPa s, about 10900 mPa s, about 11000 mPas, about 11100 mPas, about 11200 mPa s, about 11300 mPas, about 11400 mPa s, about 11500 mPas, about 11600 mPas, about 11700 mPas, about 11800 mPa s, about 11900 mPa s, about 12000 mPas, about 12100 mPas, about 12200 mPas, about 12300 mPa s, about 12400 mPa s, about 12500 mPas, about 12600 mPas, about 12700 mPas, about 12800 mPa s, about 12900 mPas, about 13000 mPas, about 13100 mPa s about 13200 mPas, about 13300 mPas, about 13400 mPas, about 13500 mPas, about 13600 mPas, about 13700 mPas, about 13800 mPa s, about 13900 mPa s, about 14000 mPas, about 14100 mPas, about 14200 mPas, about 14300 mPa s, about 14400 mPa s, about 14500 mPas, about 14600 mPas, about 14700 mPas, about 14800 mPa s, about 14900 mPa s, about 15000 mPas, about 15200 mPas, about 15400 mPas, about 15600 mPa s, about 15800 mPa s, about 16000 mPas, about 16200 mPas, about 16400 mPas, about 16600 mPas, about 16800 mPa s, about 17000 mPas, about 17200 mPas, about 17400 mPas, about 17600 mPa s, about 17800 mPa s, about 18000 mPas, about 18200 mPas, about 18400 mPas, about 18600 mPa s, about 18800 mPa s, about 19000 mPas, about 19200 mPas, about 19400 mPas, about 19600 mPas, about 19800 mPa s, about 20000 mPas about 20500 mPas, about 21000 mPas, about 21500 mPa s, about 22000 mPa s, about 22500 mPas, about 23000 mPas, about 23500 mPas, about 24000 mPas. about 24500 mPa s, about 25000 mPas, about 25500 mPas, about 26000 mPas, about 26500 mPas, about 27000 mPa s, about 27500 mPas, about 28000 mPas, about 28500 mPas, about 29000 mPa s, about 29500 mPa s, about 30000 mPas, about 31000 mPas, about 32000 mPas, about 33000 mPa s, about 34000 mPa s, about 35000 mPas, about 36000 mPas, about 37000 mPas, about 38000 mPa s, about 39000 mPa s, about 40000 mPas, about 41000 mPas, about 42000 mPas, about 43000 mPa s, about 44000 mPa s, about 45000 mPas, about 46000 mPas, about 47000 mPas, about 48000 mPa s, about 49000 mPa s, or about 50000 mPa s).

[0053] In some embodiments, 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 60000 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain. In some embodiments, storage modulus of the pharmaceutical composition is from about 50000 mPa to about 200000 mPa. In some embodiments, 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 mPa, about 30000 mPa, about 40000 mPa, about 50000 mPa, about 60000 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain. In some embodiments, the loss modulus of the pharmaceutical composition is from about 20000 mPa about 100000 mPa.

[0054] In some embodiments, the storage modulus of the pharmaceutical composition is greater than the loss modulus of the pharmaceutical composition at 1 unit of applied strain.

[0055] In some embodiments, the pharmaceutical composition is a topical pharmaceutical composition. In some embodiments, the pharmaceutical composition is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid. In some embodiments, the pharmaceutical composition further includes a wound dressing.

[0056] In some embodiments, 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.

[0057] In some embodiments, 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.

[0058] In some embodiments, 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.

[0059] In some embodiments, the pharmaceutical composition is used for the treatment of a skin wound. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0060] In some embodiments, 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).

[0061] In a third aspect, 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).

[0062] In some embodiments, the complex viscosity of the pharmaceutical composition is about 14000 mPa s. In some embodiments, 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. In some embodiments, the wound closure ratio at day 9 after the application is about the same as that of insulin alone.

[0063] In some embodiments, 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.

[0064] In some embodiments, 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, and the surfactant is poloxamer 407.

[0065] In a fourth aspect, the disclosure features 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. In some embodiments, 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. In some embodiments, 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.

[0066] In some embodiments, the pharmaceutical composition is further characterized by a viscosity from about 7000 mPa s to about 20000 mPa s. In some embodiments, the pharmaceutical composition is an ointment, cream, lotion, gel, oil, liniment, or liquid. In some embodiments, the pharmaceutical composition is used to treat a diabetic foot ulcer.

[0067] In a fifth aspect, 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.

[0068] In a sixth 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.

[0069] In a seventh 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. In an eighth 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 pharmaceutical composition to the subject including: insulin, polycarbophil, glycerin, hyaluronic acid, poloxamer 407, and water.

[0070] In some aspects of the fifth, sixth, seventh, or eighth aspect, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0071] In some embodiments, 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. In some embodiments, 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.

[0072] In some embodiments, 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.

[0073] In a seventh aspect, the disclosure features a kit including a formulation of the first aspect or a pharmaceutical composition the second aspect and a package insert. In some embodiments, the package insert instructs a user of said kit to administer the pharmaceutical composition to a subject suffering from a skin wound. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0074] In some embodiments, 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.

[0075] Other embodiments are also provided by this disclosure as will be apparent to those of ordinary skill in the art.

[0076] Definitions

[0077] As used herein, “about” refers to a range of values from 10% less than the recited value to 10% greater than the recited value.

[0078] As used herein, the terms “administering” and “administration” refer 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.

[0079] As used herein in the context of administration of a composition to a subject, 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. In some embodiments, 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).

[0080] As used herein, “skin wound” refers to damage to skin tissue. Skin wounds may be caused by, e.g., a disease, an ailment, an infection, or trauma. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0081] As used herein, and as well understood in the art, “to treat” a condition or “treatment” of various diseases, disorders, conditions, or injuries is an approach for obtaining beneficial or desired results, such as clinical results. 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. In the context of skin wounds, 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. In some embodiments, the success of a treatment may be measured by the “wound closure ratio” of the skin wound. As used herein, “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.).

[0082] As used herein, 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. For example, a molecule or molecules of a drug which directly promote wound healing would be considered the active pharmaceutical ingredients of the composition. In preferred embodiments of this disclosure, the API is insulin.

[0083] As used herein, “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. As used herein, 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, Basaglar), etc.). Additional examples of suitable insulins are known to those of ordinary skill in the art, the suitability of which can be determined using the methods disclosed herein.

[0084] As used herein, a “bioadhesive agent” is a material which adheres to biological tissue (e.g., skin) or the mucous membrane of living organisms. In some embodiments, 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. In some embodiments, the bioadhesive agent is a carbomer. In some embodiments, the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof. In some preferred embodiments, the polycarbophil can be Noveon® AA-1 Polycarbophil USP.

[0085] As used herein, “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. In some preferred embodiments, the tissue hydrator can be glycerin or a pharmaceutically acceptable salt thereof.

[0086] As used herein, 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. For example, 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. In some embodiments, 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. In some preferred embodiments, the wound-healing promoting agent is glycerin.

[0087] As used herein, “surfactant” refers to a material which increases the solubility material in a solvent. For example, the solubility of a non-polar molecule in water may be improved by including a surfactant. In some embodiments of the present disclosure, surfactants may also be used as thickening agents of a formulation or composition. In some embodiments, 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. In some embodiments, the surfactant is a poloxamer. In some preferred embodiments, the poloxamer is poloxamer 407

[0088] As used herein, “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. Materials of higher viscosity have a higher resistance to flow, and therefore provide more resistive force to motion of a material through the fluid composition. Viscosity is commonly given the unit centipoise (cP), pascal seconds (Pa s), or millipascal seconds (mPa s) (1 cP = 1 mPa s = 0.001 Pa s). In some embodiments, viscosity refers to a complex viscosity, (i.e., the dynamic viscosity of a fluid, when the external force is an oscillating force). By convention of the prior art, the radial component of the unit of complex viscosity (e.g., Pa s / degrees) is dropped, and the units of complex viscosity are equivalent to the units of viscosity (e.g., Pa s). In some embodiments, viscosity refers to a kinematic viscosity (i.e., the resistive flow of a fluid under the weight of gravity). In some embodiments, viscosity refers to a dynamic viscosity (i.e., the resistive flow of a fluid resulting from an external force). In some embodiments, 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). In the methods of this disclosure, viscosity (complex viscosity) is measured using strain-sweep analysis using Anton Paar Modular Compact Rheometer (MCR 92) using a parallel-plate geometry (40 mm diameter), using a stress sweep of 0.1 Pa to 10 Pa, and a frequency sweep range of 0.1 to 10 Hz. 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. In preferred embodiments, 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.

[0089] As used herein, “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. The terms “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.

[0090] As used herein, “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.).

[0091] As used herein, “Mucolox,” “MucoLox,” and “MucoLox™” (used interchangeably herein) refer to the commercially available bioadhesive gel MucoLox™, available from Professional Compounding Centers of America - PCCA, USA. MucoLox™ 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%). MucoLox™ is known in the art as the base of topical formulations and pharmaceutical compositions.

[0092] 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.

[0093] The definitions of other terms not included in this section will be apparent to those of ordinary skill in the art from this disclosure and / or what is known and / or commonly used in the art.

[0094] BRIEF DESCRIPTION OF THE DRAWINGS

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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).

[0099] 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.

[0100] 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. Fig. 6B shows the cumulative insulin release at t=0 and t=1 hour.

[0101] 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. 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.

[0102] 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.

[0103] Fig. 9 shows images of the wounds of two mice in the saline group over time.

[0104] Fig. 10 shows images of the wounds of four mice in the insulin group over time.

[0105] Fig. 11 shows images of the wounds of four mice in the single dose group over time.

[0106] Fig. 12 shows images of the wounds of five mice in the multi-dose group over time.

[0107] Fig. 13 shows images of the wounds of four mice in the MucoLox group over time.

[0108] Fig. 14 shows images of the wounds of four mice in the MucoLox / insulin group over time.

[0109] 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. In both Figs. 15G-15H, SD refers to the single dose group and MD refers to the multi-dose group.

[0110] 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.

[0111] 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.

[0112] Fig. 19 shows the average granulation thickness in treated tissue of each examined group after treatment.

[0113] Fig. 20 shows the average growth of new blood vessels in treated tissue of each examined group after treatment.

[0114] Fig. 21 shows the average epidermal thickness in treated tissue of each examined group after treatment.

[0115] Fig. 22 shows the average dermal / epidermal separation in treated tissue of each examined group after treatment.

[0116] Fig. 23 shows the growth of skin appendages in treated tissue of each examined group after treatment.

[0117] DETAILED DESCRIPTION OF THE INVENTION

[0118] 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).

[0119] The present disclosure demonstrates a surprising dependence of the efficacy of the treatment of skin wounds on the viscosity of topical formulations or compositions with insulin as the active pharmaceutical ingredient (API). The present disclosure provides compositions (e.g., formulations), preferably 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. The 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). In some embodiments, 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.

[0120] The sections that follow provide a description of exemplary topical formulations and compositions of the present disclosure, methods of treatment using such exemplary topical formulations and compositions, and kits containing the same.

[0121] Topical Compositions

[0122] Viscosity

[0123] 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.

[0124] There are several ways to define experimentally the viscosity of a composition of this disclosure, each of which are applicable here to determine whether a composition meets the parameters of such compositions. Experimental definitions of viscosity depend on the method used to measure the viscosity, e.g., the shear force being applied to the surface of the material or the bulk, or the shear force being varied with time or constant. In some embodiments, the viscosity measured is the dynamic viscosity. In some embodiments, the viscosity measured is the kinematic viscosity. In some embodiments, the viscosity measured is the volume viscosity. In some embodiments, the viscosity measured is the complex viscosity. The term “complex viscosity” as used herein, 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.

[0125] 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. In some embodiments, 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, about 60000 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain. In some embodiments, 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, about 60000 about 70000 mPa, about 80000 mPa, about 90000 mPa, about 100000 mPa, about 110000 mPa, about 120000 mPa, about 130000 mPa, about 140000 mPa, about 150000 mPa, etc.) at one unit of applied strain.

[0126] 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, bentonite, magnesium aluminum silicate, corn starch, and cetyl alcohol. 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). The use of 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.). For example, the thickening agent may also function as a surfactant (e.g., a poloxamer such as poloxamer 407).

[0127] In some embodiments, 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 39000 mPa s, from about 1300 mPa s to about 38000 mPa s, from about 1450 mPa s to about 37000 mPa s, from about 1600 mPa s to about 36000 mPa s, from about 1750 mPa s to about 35000 mPa s, from about 1900 mPa s to about 34000 mPa s, from about 2050 mPa s to about 33000 mPa s, from about 2200 mPa s to about 32000 mPa s, from about 2350 mPa s to about 31000 mPa s, from about 2500 mPa s to about 30000 mPa s, from about 2650 mPa s to about 29000 mPa s, from about 2800 mPa s to about 28000 mPa s, from about 2950 mPa s to about 37000 mPa s, from about 3100 mPa s to about 26000 mPa s, from about 3250 mPa s to about 25000 mPa s, from about 3400 mPa s to about 24000 mPa s, from about 3550 mPa s to about 23000 mPa s, from about 3700 mPa s to about 22000 mPa s, from about 3850 mPa s to about 21000 mPa s, from about 4000 mPa s to about 20000 mPa s, from about 4100 mPa s to about 19800 mPa s, from about 4200 mPa s to about 19600 mPa s, from about 4300 mPa s to about 19400 mPa s, from about 4400 mPa s to about 19200 mPa s, from about 4500 mPa s to about 19000 mPa s, from about 4600 mPa s to about 18800 mPa s, from about 4700 mPa s to about 18600 mPa s from about 4200 mPa s to about 18400 mPa s, from about 4100 mPa s to about 18200 mPa s, from about 5000 mPa s to about 18000 mPa s, from about 5100 mPa s to about 17800 mPa s, from about 5200 mPa s to about 17600 mPa s, from about 5300 mPa s to about 17400 mPa s, from about 5400 mPa s to about 17200 mPa s, from about 5500 mPa s to about 17000 mPa s, from about 5600 mPas to about 16800 mPa s, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPas, from about 6100 mPas to about 15800 mPas, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPa s, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPas, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPas, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPa s, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPas, from about 7600 mPas to about 13400 mPa s, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s3from about 8000 mPas to about 13000 mPas, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPa s, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPas, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPa s, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPas, from about 9100 mPas to about 11900 mPa s, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPas to about 11700 mPas, from about 9400 mPas to about 11600 mPas, from about 9500 mPas to about 11500 mPa s, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPas, from about 7000 mPas to about 7500 mPas, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPas, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, 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 s3about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s3about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700 mPa s, about 2800 mPa s3about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPa s, about 4100 mPa s, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPa s, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPa s, about 5200 mPas, about 5300 mPa s3about 5400 mPas, about 5500 mPas about 5600 mPa s, about 5700 mPas, about 5800 mPa s3about 5900 mPas, about 6000 mPas about 6100 mPa s, about 6200 mPa s, about 6300 mPa s3about 6400 mPa s, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s, about 7000 mPa s, about 7100 mPa s, about 7200 mPas, about 7300 mPa s, about 7400 mPas, about 7500 mPas, about 7600 mPas, about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPa s, about 8200 mPas, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPas, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPa s, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPa s, about 9700 mPas, about 9800 mPa s about 9900 mPas, about 10000 mPas, about 10100 mPas, about 10200 mPa s, about 10300 mPas, about 10400 mPas, about 10500 mPas, about 10600 mPa s, about 10700 mPas, about 10800 mPas, about 10900 mPas, about 11000 mPa s, about 11100 mPa s, about 11200 mPa s, about 11300 mPas, about 11400 mPas, about 11500 mPa s, about 11600 mPa s, about 11700 mPas, about 11800 mPas, about 11900 mPas, about 12000 mPa s, about 12100 mPa s, about 12200 mPas, about 12300 mPas, about 12400 mPas, about 12500 mPa s, about 12600 mPa s, about 12700 mPas, about 12800 mPas, about 12900 mPa s, about 13000 mPas, about 13100 mPas, about 13200 mPa s, about 13300 mPas, about 13400 mPas, about 13500 mPa s, about 13600 mPa s, about 13700 mPas, about 13800 mPas, about 13900 mPas, about 14000 mPa s, about 14100 mPa s, about 14200 mPas, about 14300 mPas, about 14400 mPas, about 14500 mPa s, about 14600 mPa s, about 14700 mPas, about 14800 mPas, about 14900 mPas, about 15000 mPa s, about 15200 mPa s, about 15400 mPas, about 15600 mPas, about 15800 mPas, about 16000 mPa s, about 16200 mPa s, about 16400 mPas, about 16600 mPa s about 16800 mPa s, about 17000 mPas, about 17200 mPa s, about 17400 mPas, about 17600 mPas, about 17800 mPas, about 18000 mPa s, about 18200 mPa s, about 18400 mPas, about 18600 mPas, about 18800 mPas, about 19000 mPa s, about 19200 mPa s, about 19400 mPas, about 19600 mPa s about 19800 mPa s, about 20000 mPas about 20500 mPas, about 21000 mPas, about 21500 mPas, about 22000 mPas, about 22500 mPa s, about 23000 mPa s, about 23500 mPas, about 24000 mPas, about 24500 mPas, about 25000 mPa s, about 25500 mPas, about 26000 mPas, about 26500 mPa s about 27000 mPa s, about 27500 mPas, about 28000 mPa s, about 28500 mPas, about 29000 mPas, about 29500 mPas, about 30000 mPas, about 31000 mPa s, about 32000 mPas, about 33000 mPas, about 34000 mPas, about 35000 mPa s, about 36000 mPa s, about 37000 mPas, about 38000 mPas, about 39000 mPas, about 40000 mPa s, about 41000 mPa s, about 42000 mPas, about 43000 mPas, about 44000 mPas, about 45000 mPa s, about 46000 mPa s, about 47000 mPas, about 48000 mPas, about 49000 mPas, or about 50000 mPa s).

[0128] In some embodiments, 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 mPas to about 38000 mPas, from about 1450 mPas to about 37000 mPas, from about 1600 mPas to about 36000 mPa s, from about 1750 mPas to about 35000 mPas, from about 1900 mPas to about 34000 mPas, from about 2050 mPas to about 33000 mPas, from about 2200 mPas to about 32000 mPas, from about 2350 mPas to about 31000 mPas, from about 2500 mPas to about 30000 mPa s, from about 2650 mPas to about 29000 mPas, from about 2800 mPas to about 28000 mPas, from about 2950 mPas to about 37000 mPa s, from about 3100 mPas to about 26000 mPas, from about 3250 mPas to about 25000 mPa s, from about 3400 mPas to about 24000 mPas, from about 3550 mPas to about 23000 mPas, from about 3700 mPas to about 22000 mPas, from about 3850 mPas to about 21000 mPa s, from about 4000 mPas to about 20000 mPas, from about 4100 mPas to about 19800 mPas, from about 4200 mPas to about 19600 mPas, from about 4300 mPas to about 19400 mPas, from about 4400 mPas to about 19200 mPas, from about 4500 mPas to about 19000 mPa s, from about 4600 mPas to about 18800 mPas, from about 4700 mPas to about 18600 mPas from about 4200 mPas to about 18400 mPas, from about 4100 mPas to about 18200 mPas, from about 5000 mPas to about 18000 mPa s, from about 5100 mPas to about 17800 mPas, from about 5200 mPas to about 17600 mPas, from about 5300 mPas to about 17400 mPas, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPas, from about 5600 mPas to about 16800 mPas, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPas, from about 6100 mPas to about 15800 mPa s, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPas, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPa s, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPas, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPa s, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s, from about 8000 mPas to about 13000 mPa s, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPas, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPas, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPa s, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPas to about 11700 mPas, from about 9400 mPas to about 11600 mPa s, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPa s, from about 7000 mPas to about 7500 mPa s, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPas, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, the formulation exhibits a kinematic 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 s3about 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 s3about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s3about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700 mPa s, about 2800 rnPa s about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPa s, about 4100 mPa s, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPa s, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPa s, about 5200 mPas, about 5300 mPa s about 5400 mPas, about 5500 mPa s about 5600 mPa s, about 5700 mPas, about 5800 mPa s about 5900 mPas, about 6000 mPa s about 6100 mPa s, about 6200 mPa s, about 6300 mPa s about 6400 mPa s, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s, about 7000 mPas, about 7100 mPas, about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPas, about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPa s, about 8200 mPas, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPas, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPa s, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPa s, about 9700 mPas, about 9800 mPa s about 9900 mPas, about 10000 mPas, about 10100 mPas, about 10200 mPa s, about 10300 mPas, about 10400 mPas, about 10500 mPas, about 10600 mPa s, about 10700 mPas, about 10800 mPas, about 10900 mPas, about 11000 mPa s, about 11100 mPa s, about 11200 mPa s, about 11300 mPas, about 11400 mPas, about 11500 mPa s, about 11600 mPa s, about 11700 mPas, about 11800 mPas, about 11900 mPas, about 12000 mPa s, about 12100 mPa s, about 12200 mPas, about 12300 mPas, about 12400 mPas, about 12500 mPa s, about 12600 mPa s, about 12700 mPas, about 12800 mPas, about 12900 mPa s, about 13000 mPas, about 13100 mPas, about 13200 mPa s, about 13300 mPas, about 13400 mPas, about 13500 mPa s, about 13600 mPa s, about 13700 mPas, about 13800 mPas, about 13900 mPas, about 14000 mPa s, about 14100 mPa s, about 14200 mPas, about 14300 mPas, about 14400 mPas, about 14500 mPa s, about 14600 mPa s, about 14700 mPas, about 14800 mPas, about 14900 mPas, about 15000 mPa s, about 15200 mPa s, about 15400 mPas, about 15600 mPas, about 15800 mPas, about 16000 mPa s, about 16200 mPa s, about 16400 mPas, about 16600 mPa s about 16800 mPa s, about 17000 mPas, about 17200 mPa s, about 17400 mPas, about 17600 mPas, about 17800 mPas, about 18000 mPa s, about 18200 mPa s, about 18400 mPas, about 18600 mPas, about 18800 mPas, about 19000 mPa s, about 19200 mPa s, about 19400 mPas, about 19600 mPa s about 19800 mPa s, about 20000 mPas about 20500 mPas, about 21000 mPas, about 21500 mPas, about 22000 mPas, about 22500 mPa s, about 23000 mPa s, about 23500 mPas, about 24000 mPas, about 24500 mPas, about 25000 mPa s, about 25500 mPas, about 26000 mPas, about 26500 mPa s about 27000 mPa s, about 27500 mPas, about 28000 mPa s, about 28500 mPas, about 29000 mPas, about 29500 mPas, about 30000 mPas, about 31000 mPa s, about 32000 mPas, about 33000 mPas, about 34000 mPas, about 35000 mPa s, about 36000 mPa s, about 37000 mPas, about 38000 mPas, about 39000 mPas, about 40000 mPa s, about 41000 mPa s, about 42000 mPas, about 43000 mPas, about 44000 mPas, about 45000 mPa s, about 46000 mPa s, about 47000 mPas, about 48000 mPas, about 49000 mPas, or about 50000 mPa s.

[0129] In some embodiments, the formulation exhibits a dynamic viscosity of from about 1 mPa sto 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 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 mPas, from about 1150 mPas to about 39000 mPas, from about 1300 mPas to about 38000 mPas, from about 1450 mPas to about 37000 mPas, from about 1600 mPas to about 36000 mPas, from about 1750 mPas to about 35000 mPas, from about 1900 mPas to about 34000 mPas, from about 2050 mPas to about 33000 mPas, from about 2200 mPas to about 32000 mPas, from about 2350 mPas to about 31000 mPas, from about 2500 mPas to about 30000 mPas, from about 2650 mPas to about 29000 mPas, from about 2800 mPas to about 28000 mPas, from about 2950 mPas to about 37000 mPa s, from about 3100 mPas to about 26000 mPas, from about 3250 mPas to about 25000 mPas, from about 3400 mPas to about 24000 mPas, from about 3550 mPas to about 23000 mPas, from about 3700 mPas to about 22000 mPas, from about 3850 mPas to about 21000 mPas, from about 4000 mPas to about 20000 mPas, from about 4100 mPas to about 19800 mPas, from about 4200 mPas to about 19600 mPas, from about 4300 mPas to about 19400 mPas, from about 4400 mPas to about 19200 mPas, from about 4500 mPas to about 19000 mPas, from about 4600 mPas to about 18800 mPas, from about 4700 mPas to about 18600 mPas from about 4200 mPas to about 18400 mPas, from about 4100 mPas to about 18200 mPas, from about 5000 mPas to about 18000 mPas, from about 5100 mPas to about 17800 mPas, from about 5200 mPas to about 17600 mPas, from about 5300 mPas to about 17400 mPas, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPas, from about 5600 mPas to about 16800 mPas, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPas, from about 6100 mPas to about 15800 mPas, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPas, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPas, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPas, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPa s, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s, from about 8000 mPas to about 13000 mPa s, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPas, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPas, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPa s, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPas to about 11700 mPas, from about 9400 mPas to about 11600 mPa s, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPa s, from about 7000 mPas to about 7500 mPa s, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPa s, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, 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 s3about 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 s3about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s3about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700 mPa s, about 2800 mPa s3about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPa s, about 4100 mPa s, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPa s, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPa s, about 5200 mPas, about 5300 mPa s3about 5400 mPas, about 5500 mPas about 5600 mPa s, about 5700 mPas, about 5800 mPa s3about 5900 mPas, about 6000 mPas about 6100 mPa s, about 6200 mPa s, about 6300 mPa s3about 6400 mPa s, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s, about 7000 mPa s, about 7100 mPa s, about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPa s, about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPa s, about 8200 mPas, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPas, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPa s, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPa s, about 9700 mPas, about 9800 mPa s3about 9900 mPas, about 10000 mPas, about 10100 mPas, about 10200 mPa s, about 10300 mPas, about 10400 mPas, about 10500 mPa s, about 10600 mPa s, about 10700 mPas, about 10800 mPas, about 10900 mPas, about 11000 mPa s, about 11100 mPa s, about 11200 mPa s, about 11300 mPas, about 11400 mPas, about 11500 mPa s, about 11600 mPa s, about 11700 mPas, about 11800 mPas, about 11900 mPas, about 12000 mPa s, about 12100 mPa s, about 12200 mPas, about 12300 mPas, about 12400 mPas, about 12500 mPa s, about 12600 mPa s, about 12700 mPas, about 12800 mPas, about 12900 mPa s, about 13000 mPas, about 13100 mPa s, about 13200 mPa s, about 13300 mPas, about 13400 mPas, about 13500 mPa s, about 13600 mPa s, about 13700 mPas, about 13800 mPas, about 13900 mPas, about 14000 mPa s, about 14100 mPa s, about 14200 mPas, about 14300 mPas, about 14400 mPas, about 14500 mPa s, about 14600 mPa s, about 14700 mPas, about 14800 mPas, about 14900 mPas, about 15000 mPa s, about 15200 mPa s, about 15400 mPas, about 15600 mPas, about 15800 mPas, about 16000 mPa s, about 16200 mPa s, about 16400 mPas, about 16600 mPa s3about 16800 mPa s, about 17000 mPas, about 17200 mPa s, about 17400 mPas, about 17600 mPas, about 17800 mPas, about 18000 mPa s, about 18200 mPa s, about 18400 mPas, about 18600 mPas, about 18800 mPas, about 19000 mPa s, about 19200 mPa s, about 19400 mPas, about 19600 mPa s3about 19800 mPa s, about 20000 mPas about 20500 mPas, about 21000 mPas, about 21500 mPas, about 22000 mPas, about 22500 mPa s, about 23000 mPa s, about 23500 mPas, about 24000 mPas, about 24500 mPas, about 25000 mPa s, about 25500 mPas, about 26000 mPas, about 26500 mPa s3about 27000 mPa s, about 27500 mPas, about 28000 mPa s, about 28500 mPas, about 29000 mPa s, about 29500 mPas, about 30000 mPas, about 31000 mPa s, about 32000 mPas, about 33000 mPas, about 34000 mPas, about 35000 mPa s, about 36000 mPa s, about 37000 mPas, about 38000 mPas, about 39000 mPas, about 40000 mPa s, about 41000 mPa s, about 42000 mPas, about 43000 mPas, about 44000 mPas, about 45000 mPa s, about 46000 mPa s, about 47000 mPas, about 48000 mPas, about 49000 mPas, or about 50000 mPa s.

[0130] In some embodiments, 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 mPas, from about 1450 mPas to about 37000 mPas, from about 1600 mPas to about 36000 mPas, from about 1750 mPas to about 35000 mPas, from about 1900 mPas to about 34000 mPas, from about 2050 mPas to about 33000 mPas, from about 2200 mPas to about 32000 mPas, from about 2350 mPas to about 31000 mPas, from about 2500 mPas to about 30000 mPas, from about 2650 mPas to about 29000 mPa s, from about 2800 mPas to about 28000 mPas, from about 2950 mPas to about 37000 mPas, from about 3100 mPas to about 26000 mPas, from about 3250 mPas to about 25000 mPas, from about 3400 mPas to about 24000 mPas, from about 3550 mPas to about 23000 mPas, from about 3700 mPas to about 22000 mPas, from about 3850 mPas to about 21000 mPas, from about 4000 mPas to about 20000 mPas, from about 4100 mPas to about 19800 mPas, from about 4200 mPas to about 19600 mPas, from about 4300 mPas to about 19400 mPas, from about 4400 mPas to about 19200 mPas, from about 4500 mPas to about 19000 mPas, from about 4600 mPas to about 18800 mPa s, from about 4700 mPas to about 18600 mPas from about 4200 mPas to about 18400 mPas, from about 4100 mPas to about 18200 mPas, from about 5000 mPas to about 18000 mPas, from about 5100 mPas to about 17800 mPas, from about 5200 mPas to about 17600 mPas, from about 5300 mPas to about 17400 mPas, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPas, from about 5600 mPas to about 16800 mPas, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPas, from about 6100 mPas to about 15800 mPa s, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPas, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPa s, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPas, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPa s, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s, from about 8000 mPas to about 13000 mPa s, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPas, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPas, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPa s, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPas to about 11700 mPas, from about 9400 mPas to about 11600 mPa s, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPa s, from about 7000 mPas to about 7500 mPa s, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPas, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, the formulation exhibits a volume viscosity of about 1 mPas, about 100 mPas, about 200 mPa s, about 300 mPas, about 400 mPas, about 500 mPa s, about 600 mPas, about 700 mPa s3about 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 s3about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s3about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700 mPa s, about 2800 mPa s3about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPa s, about 4100 mPa s, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPa s, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPa s, about 5200 mPas, about 5300 mPa s3about 5400 mPas, about 5500 mPas about 5600 mPa s, about 5700 mPas, about 5800 mPa s3about 5900 mPas, about 6000 mPas about 6100 mPa s, about 6200 mPa s, about 6300 mPa s3about 6400 mPa s, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s, about 7000 mPa s, about 7100 mPa s, about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPa s, about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPa s, about 8200 mPas, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPas, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPa s, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPa s, about 9700 mPas, about 9800 mPa s3about 9900 mPas, about 10000 mPas, about 10100 mPas, about 10200 mPa s, about 10300 mPas, about 10400 mPas, about 10500 mPa s, about 10600 mPa s, about 10700 mPas, about 10800 mPas, about 10900 mPas, about 11000 mPa s, about 11100 mPa s, about 11200 mPa s, about 11300 mPas, about 11400 mPas, about 11500 mPa s, about 11600 mPa s, about 11700 mPas, about 11800 mPas, about 11900 mPas, about 12000 mPa s, about 12100 mPa s, about 12200 mPas, about 12300 mPas, about 12400 mPas, about 12500 mPa s, about 12600 mPa s, about 12700 mPas, about 12800 mPas, about 12900 mPa s, about 13000 mPas, about 13100 mPa s, about 13200 mPa s, about 13300 mPas, about 13400 mPas, about 13500 mPa s, about 13600 mPa s, about 13700 mPas, about 13800 mPas, about 13900 mPas, about 14000 mPa s, about 14100 mPa s, about 14200 mPas, about 14300 mPas, about 14400 mPas, about 14500 mPa s, about 14600 mPa s, about 14700 mPas, about 14800 mPa s, about 14900 mPas, about 15000 mPa s, about 15200 mPa s, about 15400 mPas, about 15600 mPas, about 15800 mPas, about 16000 mPa s, about 16200 mPa s, about 16400 mPas, about 16600 mPa s about 16800 mPa s, about 17000 mPas, about 17200 mPa s, about 17400 mPas, about 17600 mPas, about 17800 mPas, about 18000 mPa s, about 18200 mPa s, about 18400 mPas, about 18600 mPas, about 18800 mPas, about 19000 mPa s, about 19200 mPa s, about 19400 mPas, about 19600 mPa s about 19800 mPa s, about 20000 mPas about 20500 mPas, about 21000 mPas, about 21500 mPas, about 22000 mPas, about 22500 mPa s, about 23000 mPa s, about 23500 mPas, about 24000 mPas, about 24500 mPas, about 25000 mPa s, about 25500 mPas, about 26000 mPas, about 26500 mPa s about 27000 mPa s, about 27500 mPas, about 28000 mPa s, about 28500 mPas, about 29000 mPas, about 29500 mPas, about 30000 mPas, about 31000 mPa s, about 32000 mPas, about 33000 mPas, about 34000 mPas, about 35000 mPa s, about 36000 mPa s, about 37000 mPas, about 38000 mPas, about 39000 mPas, about 40000 mPa s, about 41000 mPa s, about 42000 mPas, about 43000 mPas, about 44000 mPas, about 45000 mPa s, about 46000 mPa s, about 47000 mPas, about 48000 mPas, about 49000 mPas, or about 50000 mPa s.

[0131] In some embodiments, 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 mPas, from about 1450 mPas to about 37000 mPas, from about 1600 mPas to about 36000 mPas, from about 1750 mPas to about 35000 mPas, from about 1900 mPas to about 34000 mPas, from about 2050 mPas to about 33000 mPas, from about 2200 mPas to about 32000 mPas, from about 2350 mPas to about 31000 mPas, from about 2500 mPas to about 30000 mPas, from about 2650 mPas to about 29000 mPas, from about 2800 mPas to about 28000 mPas, from about 2950 mPas to about 37000 mPa s, from about 3100 mPas to about 26000 mPas, from about 3250 mPas to about 25000 mPas, from about 3400 mPas to about 24000 mPas, from about 3550 mPas to about 23000 mPas, from about 3700 mPas to about 22000 mPas, from about 3850 mPas to about 21000 mPas, from about 4000 mPas to about 20000 mPas, from about 4100 mPas to about 19800 mPas, from about 4200 mPas to about 19600 mPas, from about 4300 mPas to about 19400 mPas, from about 4400 mPas to about 19200 mPas, from about 4500 mPas to about 19000 mPas, from about 4600 mPas to about 18800 mPas, from about 4700 mPas to about 18600 mPas from about 4200 mPas to about 18400 mPas, from about 4100 mPas to about 18200 mPas, from about 5000 mPas to about 18000 mPas, from about 5100 mPas to about 17800 mPas, from about 5200 mPas to about 17600 mPas, from about 5300 mPas to about 17400 mPas, from about 5400 mPas to about 17200 mPas, from about 5500 mPas to about 17000 mPas, from about 5600 mPas to about 16800 mPas, from about 5700 mPas to about 16600 mPas, from about 5800 mPas to about 16400 mPas, from about 5900 mPas to about 16200, from about 6000 mPas to about 16000 mPas, from about 6100 mPas to about 15800 mPa s, from about 6200 mPas to about 15600 mPas, from about 6300 mPas to about 15400 mPas, from about 6400 mPas to about 15200 mPas, from about 6500 mPas to about 15000 mPa s, from about 6600 mPas to about 14800 mPas, from about 6700 mPas to about 14600 mPas, from about 6800 mPas to about 14400 mPas, from about, from about 6900 mPas to about 14200 mPas, from about from about 7000 mPas to about 14000 mPas, from about 7100 mPas to about 13900 mPa s, from about 7200 mPas to about 13800, from about 7300 mPas to about 13700 mPas, from about 7400 mPas to about 13600 mPas, from about 7500 mPas to about 13500 mPa s, from about 7600 mPas to about 13400 mPas, from about 7700 mPas to about 13300 mPas, from about 7800 mPas to about 13200 mPa s, from about 7900 mPas to about 13100 mPa s, from about 8000 mPas to about 13000 mPa s, from about 8100 mPas to about 12900 mPas, from about 8200 mPas to about 12800 mPas, from about 8300 mPas to about 12700 mPas, from about 8400 mPas to about 12600 mPa s, from about 8500 mPas to about 12500 mPas, from about 8600 mPas to about 12400 mPas, from about 8700 mPas to about 12300 mPa s, from about 8800 mPas to about 12200 mPas, from about 8900 mPas to about 12100 mPas, from about 9000 mPas to about 12000 mPa s, from about 9100 mPas to about 11900 mPas, from about 9200 mPas to about 11800 mPas, from about from about 9300 mPas to about 11700 mPas, from about 9400 mPas to about 11600 mPa s, from about 9500 mPas to about 11500 mPas, from about 9600 mPas to about 11400 mPas, from about 9700 mPas to about 11300 mPa s, from about 9800 mPas to about 11200 mPas, from about 9900 mPas to about 11100 mPa s, from about 7000 mPas to about 7500 mPa s, from about 7500 mPas to about 8000 mPas, from about 8000 mPas to about 8500 mPas, from about 8500 mPas to about 9000 mPas, from about 9000 mPas to about 9500 mPas, from about 9500 mPas to about 10000 mPa s, from about 10500 mPas, from about 10500 mPas to about 11000 mPas, from about 11000 mPas to about 11500 mPas, from about 11500 mPas to about 12000 mPas, from about 12000 mPas to about 12500 mPa s, from about 12500 mPas to about 13000 mPas, from about 13000 mPas to about 13500 mPas, or from about 13500 mPas to about 14000 mPa s). In some embodiments, 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 s3about 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 s3about 1900 mPas, about 2000 mPas, about 2100 mPas, about 2200 mPas, about 2300 mPa s3about 2400 mPas, about 2500 mPas, about 2600 mPa s, about 2700 mPa s, about 2800 mPa s3about 2900 mPas, about 3000 mPas, about 3100 mPa s, about 3200 mPa s, about 3300 mPas, about 3400 mPas, about 3500 mPa s, about 3600 mPa s, about 3700 mPas, about 3800 mPas, about 3900 mPa s, about 4000 mPa s, about 4100 mPa s, about 4200 mPas, about 4300 mPas, about 4400 mPas, about 4500 mPas, about 4600 mPa s, about 4700 mPa s, about 4800 mPas, about 4900 mPas, about 5000 mPas, about 5100 mPa s, about 5200 mPas, about 5300 mPa s3about 5400 mPas, about 5500 mPas about 5600 mPa s, about 5700 mPas, about 5800 mPa s3about 5900 mPas, about 6000 mPas about 6100 mPa s, about 6200 mPa s, about 6300 mPa s3about 6400 mPa s, about 6500 mPas, about 6600 mPas, about 6700 mPas, about 6800 mPas, about 6900 mPa s, about 7000 mPa s, about 7100 mPa s, about 7200 mPas, about 7300 mPas, about 7400 mPas, about 7500 mPas, about 7600 mPa s, about 7700 mPas, about 7800 mPas, about 7900 mPas, about 8000 mPas, about 8100 mPa s, about 8200 mPas, about 8300 mPas, about 8400 mPas, about 8500 mPa s, about 8600 mPa s, about 8700 mPas, about 8800 mPas, about 8900 mPas, about 9000 mPas, about 9100 mPa s, about 9200 mPa s, about 9300 mPas, about 9400 mPas, about 9500 mPas, about 9600 mPa s, about 9700 mPas, about 9800 mPa s3about 9900 mPas, about 10000 mPas, about 10100 mPas, about 10200 mPa s, about 10300 mPa s, about 10400 mPa s, about 10500 mPa s, about 10600 mPa s, about 10700 mPa s, about 10800 mPa s, about 10900 mPa s, about 1 1000 mPa s, about 11100 mPa s, about 11200 mPa s, about 11300 mPa s, about 11400 mPa s, about 1 1500 mPa s, about 11600 mPa s, about 11700 mPa s, about 11800 mPa s, about 11900 mPa s, about 12000 mPa s, about 12100 mPa s, about 12200 mPa s, about 12300 mPa s, about 12400 mPa s, about 12500 mPa s, about 12600 mPa s, about 12700 mPa s, about 12800 mPa s, about 12900 mPa s, about 13000 mPa s, about 13100 mPa s, about 13200 mPa s, about 13300 mPa s, about 13400 mPa s, about 13500 mPa s, about 13600 mPa s, about 13700 mPa s, about 13800 mPa s, about 13900 mPa s, about 14000 mPa s, about 14100 mPa s, about 14200 mPa s, about 14300 mPa s, about 14400 mPa s, about 14500 mPa s, about 14600 mPa s, about 14700 mPa s, about 14800 mPa s, about 14900 mPa s, about 15000 mPa s, about 15200 mPa s, about 15400 mPa s, about 15600 mPa s, about 15800 mPa s, about 16000 mPa s, about 16200 mPa s, about 16400 mPa s, about 16600 mPa s about 16800 mPa s, about 17000 mPa s, about 17200 mPa s, about 17400 mPa s, about 17600 mPa s, about 17800 mPa s, about 18000 mPa s, about 18200 mPa s, about 18400 mPa s, about 18600 mPa s, about 18800 mPa s, about 19000 mPa s, about 19200 mPa s, about 19400 mPa s, about 19600 mPa s about 19800 mPa s, about 20000 mPa s about 20500 mPa s, about 21000 mPa s, about 21500 mPa s, about 22000 mPa s, about 22500 mPa s, about 23000 mPa s, about 23500 mPa s, about 24000 mPa s, about 24500 mPa s, about 25000 mPa s, about 25500 mPa s, about 26000 mPa s, about 26500 mPa s about 27000 mPa s, about 27500 mPa s, about 28000 mPa s, about 28500 mPa s, about 29000 mPa s, about 29500 mPa s, about 30000 mPa s, about 31000 mPa s, about 32000 mPa s, about 33000 mPa s, about 34000 mPa s, about 35000 mPa s, about 36000 mPa s, about 37000 mPa s, about 38000 mPa s, about 39000 mPa s, about 40000 mPa s, about 41000 mPa s, about 42000 mPa s, about 43000 mPa s, about 44000 mPa s, about 45000 mPa s, about 46000 mPa s, about 47000 mPa s, about 48000 mPa s, about 49000 mPa s, or about 50000 mPa s. In preferred embodiments, 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.

[0132] In some embodiments, 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%, from about 2.4 wt% to about 38 wt%, from about 2.6 wt% to about 37 wt%, from about 2.8 wt% to about 36 wt%, from about 3 wt% to about 35 wt%, from about 3.2 wt% to about 34 wt%, from about 3.4 wt% to about 33 wt%, from about 3.6 wt% to about 32 wt%, from about 3.8 wt% to about 31 wt%, from about 4 wt% to about 30 wt%, from about 4.2 wt% to about 30 wt%, from about 4.4 wt% to about 30 wt%, from about 4.6 wt% to about 30 wt%, from about 4.8 wt% to about 30 wt%, from about 5 wt% to about 30 wt%, from about 4.2 wt% to about 29 wt%, from about 4.4 wt% to about 28 wt%, from about 4.6 wt% to about 27 wt%, from about 4.8 wt% to about 26 wt%, from about 5 wt% to about 25 wt%, from about 5.5 wt% to about 24.5 wt%, from about 6 wt% to 24 wt%, from about 6.5 wt% to 23.5 wt%, from about 7 wt% to 23 wt%, from about 7.5 wt% to 22.5 wt%, from about 8 wt% to 22 wt%, from about 8.5 wt% to 23 wt%, from about 9 wt% to 22 wt%, from about 9.5 wt% to 21 wt%, from about 10 wt % to 20 wt%, from about 10.5 wt% to

[0133] 19.5 wt%, from about 11 wt% to 19 wt%, from about 11 .5 wt% to 18.5 wt%, from about 12 wt% to 18 wt%, from about 12.5 wt% to 17.5 wt%, from about 13 wt% to 17 wt%, from about 13.5 wt% to 16.5 wt%, from about 14 wt% to 16 wt%, from about 14.5 wt% to 15 wt%, 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 4.5 wt%, about 4.75 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 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

[0134] 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 21 .5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about

[0135] 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt%).

[0136] Insulin

[0137] 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. As used herein, 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. As used in the present disclosure, unless otherwise specified, “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) is associated with a variety of disorders including insulinoma, metabolic syndrome, polycystic ovary syndrome, and diabetes (e.g., type 1 diabetes mellitus and type 2 diabetes mellitus).

[0138] 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. For example, porcine and bovine insulin (both commonly used in treatment of humans) are also 51 amino acid proteins, differing in only three and one amino acid residues, respectively. Insulin is often stored by mammalian organisms as a hexamer incorporating one or more hydrated cations (e.g., Zn2+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. Some of these different types of insulin typically differ from wild type insulin via changes to the amino acid chain and / or removing the hydrated cation. Others include further excipients that increase the speed of action of insulin in human bodies. 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. 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. In some embodiments, the insulin may be formulated for use in a non-human subject (e.g. Vetsulin®).

[0139] 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). 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). Alternatively, 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. In some embodiments, the insulin is Novolin 70 / 30, a 70:30 mixture of NPH insulin to fast acting insulin (e.g., wild type human insulin). In some embodiments, the insulin can be a) a fast-acting insulin; b) an intermediate-acting insulin; c) a long-acting insulin; or d) a combination thereof. In some embodiments, 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). In some embodiments, the intermediate-acting insulin is an isophane insulin (e.g., Novolin N, Humulin N, Insulatard, Neutral Protamine Hagedorn insulin). In some embodiments, 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.

[0140] 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.

[0141] In some embodiments, 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 formulation to about 120 units per 10 g of the formulation or composition, from about 4.5 units per 10 g of the formulation to about 110 units per 10 g of the formulation or composition, from about 5 units per 10 g of the formulation to about 100 units per 10 g of the formulation or composition, from about 5.5 units per 10 g of the formulation to about 90 units per 10 g of the formulation or composition, from about 6 units per 10 g of the formulation to about 80 units per 10 g of the formulation or composition, from about 6.5 units per 10 g of the formulation to about 70 units per 10 g of the formulation or composition, from about 7 units per 10 g of the formulation to about 60 units per 10 g of the formulation or composition, from about 7.5 units per 10 g of the formulation to about 50 units per 10 g of the formulation or composition, from about 8 units per 10 g of the formulation to about 40 units per 10 g of the formulation or composition, from about 8.5 units per 10 g of the formulation to about 30 units per 10 g of the formulation or composition, from about 9 units per 10 g of the formulation to about 20 units per 10 g of the formulation or composition,

[0142] In some embodiments, 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 .4 units of insulin per 10 g of the formulation or composition, about 1 .6 units of insulin per 10 g of the formulation or composition, about 1 .8 units of insulin per 10 g of the formulation or composition, about 2 units of insulin per 10 g of the formulation or composition, about 2.2 units of insulin per 10 g of the formulation or composition, about 2.4 units of insulin per 10 g of the formulation or composition, about 2.6 units of insulin per 10 g of the formulation or composition, about 2.8 units of insulin per 10 g of the formulation or composition about 3 units of insulin per 10 g of the formulation or composition, about 3.25 units of insulin per 10 g of the formulation or composition, about 3.5 units of insulin per 10 g of the formulation or composition, about

[0143] 3.75 units of insulin per 10 g of the formulation or composition, about 4 units of insulin per 10 g of the formulation or composition, about 4.25 units of insulin per 10 g of the formulation or composition, about

[0144] 4.75 units of insulin per 10 g of the formulation or composition about 5 units of insulin per 10 g of the formulation or composition, about 5.5 units of insulin per 10 g of the formulation or composition, about 6 units of insulin per 10 g of the formulation or composition, about 6.5 units of insulin per 10 g of the formulation or composition, about 7 units of insulin per 10 g of the formulation or composition about 7.5 units of insulin per 10 g of the formulation or composition, about 8 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition, about 8.5 units of insulin per 10 g of the formulation or composition units of insulin per 10 g of the formulation or composition, about 9 units of insulin per 10 g of the formulation or composition, about 9.5 units of insulin per 10 g of the formulation or composition, about 10 units of insulin per 10 g of the formulation or composition, about 11 units of insulin per 10 g of the formulation or composition, about 12 units of insulin per 10 g of the formulation or composition, about 13 units of insulin per 10 g of the formulation or composition, about 14 units of insulin per 10 g of the formulation or composition, about 15 units of insulin per 10 g of the formulation or composition, about 16 units of insulin per 10 g of the formulation or composition, about 17 units of insulin per 10 g of the formulation or composition, about 18 units of insulin per 10 g of the formulation or composition, about 19 units of insulin per 10 g of the formulation or composition, about 20 units of insulin per 10 g of the formulation or composition, about 21 units of insulin per 10 g of the formulation or composition, about 22 units of insulin per 10 g of the formulation or composition, about 23 units of insulin per 10 g of the formulation or composition, about 24 units of insulin per 10 g of the formulation or composition, about 25 units of insulin per 10 g of the formulation or composition, about 26 units of insulin per 10 g of the formulation or composition, about 27 units of insulin per 10 g of the formulation or composition, about 28 units of insulin per 10 g of the formulation or composition about 29 units of insulin per 10 g of the formulation or composition, about 30 units of insulin per 10 g of the formulation or composition, about 32 units of insulin per 10 g of the formulation or composition, about 34 units of insulin per 10 g of the formulation or composition, about 36 units of insulin per 10 g of the formulation or composition, about 38 units of insulin per 10 g of the formulation or composition, about 40 units of insulin per 10 g of the formulation or composition, about 42 units of insulin per 10 g of the formulation or composition, about 44 units of insulin per 10 g of the formulation or composition, about 46 units of insulin per 10 g of the formulation or composition, about 48 units of insulin per 10 g of the formulation or composition, about 50 units of insulin per 10 g of the formulation or composition, about 55 units of insulin per 10 g of the formulation or composition, about 60 units of insulin per 10 g of the formulation or composition, about 65 units of insulin per 10 g of the formulation or composition, about 70 units of insulin per 10 g of the formulation or composition, about 75 units of insulin per 10 g of the formulation or composition, about 80 units of insulin per 10 g of the formulation or composition, about 85 units of insulin per 10 g of the formulation or composition about 85 units of insulin per 10 g of the formulation or composition, about 90 units of insulin per 10 g of the formulation or composition, about 95 units of insulin per 10 g of the formulation or composition, about 100 units of insulin per 10 g of the formulation or composition, about 110 units of insulin per 10 g of the formulation or composition, about 120 units of insulin per 10 g of the formulation or composition, about 130 units of insulin per 10 g of the formulation or composition, about 140 units of insulin per 10 g of the formulation or composition, about 150 units of insulin per 10 g of the formulation or composition, about 160 units of insulin per 10 g of the formulation or composition, about 170 units of insulin per 10 g of the formulation or composition, about 180 units of insulin per 10 g of the formulation or composition, about 190 units of insulin per 10 g of the formulation or composition, or about 200 units of insulin per 10 g of the formulation or composition. Bioadhesive Agents

[0145] 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. Typically, 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. In preferred embodiments, the bioadhesive agent is Noveon® AA- 1 Polycarbophil USP.

[0146] In some embodiments, 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% to about 1 .55 wt %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%).

[0147] In some embodiments, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about

[0148] 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about

[0149] 4.9 wt%, or about 5 wt% of a bioadhesive agent.

[0150] In some embodiments, the bioadhesive agent is a polyacrylic acid derivative (e.g., a carbomer). In some embodiments, the polyacrylic acid derivative is a carbomer. In some embodiments, the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof (e.g., a calcium salt). In some embodiments the polycarbophil is Noveon® AA-1 Polycarbophil USP, a commercially available high molecular weight polyacrylate polymer crosslinked with divinyl glycol.

[0151] Polycarbophil is an ionic polyacrylic acid derivative of Formula (l-A):

[0152]

[0153] In some embodiments, polycarbophil is in a salt form (e.g., calcium polycarbophil) of Formula (l-B)

[0154] Formula (l-B)

[0155] Polycarbophils are known in the art to have excellent bioadhesive properties.

[0156] In some embodiments, the topical formulation or composition includes from about 0.01 wt% to about 5 wt% polycarbophil or a pharmaceutically acceptable salt thereof (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 %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1.05 wt%). In some embodiments, the topical formulation is, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about

[0157] 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% polycarbophil or a pharmaceutically acceptable salt thereof.

[0158] Tissue Hydrator

[0159] 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). In preferred embodiments, the tissue hydrator can be glycerin or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the topical formulation or composition includes from about 0.01 wt% to about 5 wt% of a 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 %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%).

[0161] In some embodiments, the 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

[0162] 1 .2 wt%, about 1 .25 wt%, about 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about 4.9 wt%, or about 5 wt% of a tissue hydrator.

[0163] In some embodiments, the tissue hydrator is glycerin or a pharmaceutically acceptable salt thereof. Glycerin is a three carbon molecule of Formula (II)

[0164] Formula (II)

[0165] 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.

[0166] In some embodiments, 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 .55 wt %, from about 0.5 wt% to about 1 .5 wt%, from about 0.55 wt% to about 1 .45 wt %, from about 0.6 wt% to about 1 .4 wt%, from about 0.65 wt% to about 1 .35 wt %, from about 0.7 wt% to about 1 .3 wt%, from about 0.75 wt% to about 1 .25 wt %, from about 0.8 wt% to about 1 .2 wt%, from about 0.85 wt% to about 1 .15 wt %, from about 0.9 wt% to about 1.1 wt% from about 0.95 wt% to about 1 .05 wt%).

[0167] In some embodiments, 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 1 .3 wt%, about 1 .35 wt%, about 1 .4 wt%, about 1 .45 wt%, about 1 .5 wt%, about 1 .55 wt%, about 1 .6 wt%, about 1 .65 wt%, about 1 .7 wt%, about 1 .75 wt%, about 1 .8 wt%, about 1 .85 wt%, about 1 .9 wt%, about 1 .95 wt%, about 2 wt%, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about

[0168] 2.9 wt%, about 3 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4 wt%, about 4.1 wt%, about 4.2 wt%, about 4.3 wt%, about 4.4 wt%, about 4.5 wt%, about 4.6 wt%, about 4.7 wt%, about 4.8 wt%, about

[0169] 4.9 wt%, or about 5 wt% glycerin or a pharmaceutically acceptable salt thereof.

[0170] Wound-Healing Promoting Agent

[0171] 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.

[0172] 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. In preferred embodiments, the wound-healing promoting agent can be hyaluronic acid or a pharmaceutically acceptable salt thereof

[0173] In some embodiments, 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 0.049 wt% to about 0.06 wt%).

[0174] In some embodiments, 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 wt%, about 0.24 wt%, about 0.26 wt%, about 0.28 wt%, about 0.3 wt%, about 0.32 wt%, about 0.34 wt%, about 0.36 wt%, about 0.38 wt%, about 0.4 wt%, about 0.42 wt% about 0.44 wt%, about 0.46 wt%, about 0.48 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%, or about 1 wt% of a wound-healing agent.

[0175] In some embodiments, 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):

[0176] Formula (III)

[0177] Hyaluronic acid and its sodium salt - sodium hyaluronate - are a critical component of the extracellular matrix of multicellular organisms. In particular, hyaluronic acid is a major component of the extracellular matrix of skin cells. In skin, 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. For example, 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.

[0178] In some embodiments, 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 wt%, or from about 0.049 wt% to about 0.06 wt%).

[0179] In some embodiments, 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%, about 0.24 wt%, about 0.26 wt%, about 0.28 wt%, about 0.3 wt%, about 0.32 wt%, about 0.34 wt%, about 0.36 wt%, about 0.38 wt%, about 0.4 wt%, about 0.42 wt% about 0.44 wt%, about 0.46 wt%, about 0.48 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%, or about 1 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0180] Surfactants

[0181] 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.

[0182] 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, hexadecylethylpyrrolidinium bromide, or L-arginine ethyl ester dihydrochloride), zwitterionic or amphoteric surfactants (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, amidosulfobetaine-16, cocamidopropylbetaine, hexadecyl phosphocholine, luaryldimethylamine N-oxide, 3-[(3-cholamidopropyl)dimethylammonio]-1 -propanesulfonate (i.e., the CHAPS surfactant), 3-[(3- cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (i.e., the CHAPSO surfactant) betatine, sulfo betatine), and nonionic surfactants (polysorbate, polyoxyethylene esters (e.g., macrogol (15)-hydroxystearate), poloxamer triblock copolymers (e.g., poloxamer 61 , poloxamer 85, poloxamer 123, poloxamer 188, poloxamer 407, etc.), poloxamine triblock copolymers (e.g., poloxamine 908, poloxamine 1107, poloxamine 1307, etc.) ethylene oxide / propylene oxide copolymers, castor oil and its derivatives, polyol esters). 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. In preferred embodiments, the surfactant is poloxamer 407.

[0183] In some embodiments, 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 2.8 wt% to about 36 wt%, from about 3 wt% to about 35 wt%, from about 3.2 wt% to about 34 wt%, from about 3.4 wt% to about 33 wt%, from about 3.6 wt% to about 32 wt%, from about 3.8 wt% to about 31 wt%, from about 4 wt% to about 30 wt%, from about 4.2 wt% to about 30 wt%, from about 4.4 wt% to about 30 wt%, from about 4.6 wt% to about 30 wt%, from about 4.8 wt% to about 30 wt%, from about 5 wt% to about 30 wt%, from about 4.2 wt% to about 29 wt%, from about 4.4 wt% to about 28 wt%, from about 4.6 wt% to about 27 wt%, from about 4.8 wt% to about 26 wt%, from about 5 wt% to about 25 wt%, from about 5.5 wt% to about 24.5 wt%, from about 6 wt% to about 24 wt%, from about 6.5 wt% to about

[0184] 23.5 wt%, from about 7 wt% to about 23 wt%, from about 7.5 wt% to about 22.5 wt%, from about 8 wt% to about 22 wt%, from about 8.5 wt% to about 23 wt%, from about 9 wt% to about 22 wt%, from about 9.5 wt% to about 21 wt%, from about 10 wt % to about 20 wt%, from about 10.5 wt% to about 19.5 wt%, from about 11 wt% to about 19 wt%, from about 11 .5 wt% to about 18.5 wt%, from about 12 wt% to about 18 wt%, from about 12.5 wt% to about 17.5 wt%, from about 13 wt% to about 17 wt%, from about 13.5 wt% to about 16.5 wt%, from about 14 wt% to about 16 wt%, from about 14.5 wt% to about 15.5 wt%, etc.).

[0185] In some embodiments, 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

[0186] 4.5 wt%, about 4.75 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about

[0187] 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

[0188] 21 .5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about

[0189] 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about

[0190] 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about

[0191] 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt% of a surfactant.

[0192] In some embodiments, the surfactant is a poloxamer. Poloxamers are a general class of block copolymer materials of Formula (IV).

[0193] Formula (IV)

[0194] 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. In this notation, all digits except the final digit, multiplied by 100, represents the approximate (e.g., + / - 10% of the recited value) molecular weight of the central PPO block, and the final digit, multiplied by 10, represents the approximate percent weight of PEO in the material. For example, poloxamer 407 refers to a poloxamer material made of an about 4000 Da PPO block, and which is about 70% PPE by weight.

[0195] Due to their hydrophobic cores and hydrophilic ends, poloxamers are ideal viscosity modulating agents for topical compositions (i.e., a thickening agent, e.g., ointment, cream, lotion, gel, oil, liniment, liquids, etc.). This disclosure highlights the use of poloxamer to create a pharmaceutical composition for the treatment of diabetic foot ulcers.

[0196] In a preferred embodiment, the poloxamer is poloxamer 407, also referred to in the art as “P407” and “poloxamer F127”, having the approximate chemical formula HO(C2H4O)x(C3HeOy)(C2H4O)zH wherein the sum of x and y is about 200.45, and z is about 65.17. The average molecular weight of poloxamer 407 is about 12600 g / mol. In some embodiments, the poloxamer is a variant of poloxamer 407, such as a variant of the formula HO(C2H4O)x(C3H6Oy)(C2H4O)zH, wherein the sum of x and y is from about 190 to about 210 and z is from about 60 to 70. In some embodiments, the average molecular weight of the poloxamer is from about 12000 g / mol to about 13000 g / mol. In will be understood by those of skill in the art that The viscosity of the topical formulation or composition may be controlled by changing the relative amount of poloxamer 407.

[0197] In some embodiments, the topical formulation or composition includes from about 1 wt% to about 50 wt% poloxamer 407 (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 about 2.8 wt% to about 36 wt%, from about 3 wt% to about 35 wt%, from about 3.2 wt% to about 34 wt%, from about 3.4 wt% to about 33 wt%, from about 3.6 wt% to about 32 wt%, from about 3.8 wt% to about 31 wt%, from about 4 wt% to about 30 wt%, from about 4.2 wt% to about 30 wt%, from about 4.4 wt% to about 30 wt%, from about 4.6 wt% to about 30 wt%, from about 4.8 wt% to about 30 wt%, from about 5 wt% to about 30 wt%, from about 4.2 wt% to about 29 wt%, from about 4.4 wt% to about 28 wt%, from about 4.6 wt% to about 27 wt%, from about 4.8 wt% to about 26 wt%, from about 5 wt% to about 25 wt%, from about 5.5 wt% to about 24.5 wt%, from about 6 wt% to 24 wt%, from about 6.5 wt% to 23.5 wt%, from about 7 wt% to 23 wt%, from about 7.5 wt% to 22.5 wt%, from about 8 wt% to 22 wt%, from about

[0198] 8.5 wt% to 23 wt%, from about 9 wt% to 22 wt%, from about 9.5 wt% to 21 wt%, from about 10 wt % to 20 wt%, from about 10.5 wt% to 19.5 wt%, from about 11 wt% to 19 wt%, from about 11 .5 wt% to 18.5 wt%, from about 12 wt% to 18 wt%, from about 12.5 wt% to 17.5 wt%, from about 13 wt% to 17 wt%, from about 13.5 wt% to 16.5 wt%, from about 14 wt% to 16 wt%, from about 14.5 wt% to 15 wt%, etc.).

[0199] In some embodiments, the topical formulation or composition includes, e.g., 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 4.5 wt%, about 4.75 wt%, about 5 wt%, about 5.5 wt%, about 6 wt%, about 6.5 wt%, about 7 wt%, about 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

[0200] 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 21.5 wt%, about 22 wt%, about 22.5 wt%, about 23 wt%, about 23.5 wt%, about 24 wt%, about 24.5 wt%, about 25 wt%, about 25.5 wt%, about 26 wt%, about 26.5 wt%, about 27 wt%, about

[0201] 27.5 wt%, about 28 wt%, about 28.5 wt%, about 29 wt%, about 29.5 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, or about 50 wt% of poloxamer 407.

[0202] Plasticizers

[0203] Formulation or compositions of the present disclosure may include a plasticizer. A plasticizer is a material added to a composition to decrease its viscosity. Plasticizers typically work through changing the intra-material interactions within a composition. In some embodiments, this occurs through introducing new interactions between the plasticizer and the bulk of the composition. For certain compositions, a plasticizer, even in small amounts, is necessary to give the composite a low enough viscosity to be incorporated into a topical treatment. Any component of a formulation or composition of the present disclosure may serve as a plasticizer (e.g., as a surfactant, wound-healing agents, bioadhesive agents, wound-healing promoting agent, among others). Thickening Agents

[0204] The viscosity of the 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, bentonite, magnesium aluminum silicate, corn starch, and cetyl alcohol. 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). Any component of a formulation or composition of the present disclosure may serve as a thickening agent (e.g., as a surfactant, wound-healing agents, bioadhesive agents, wound-healing promoting agent, among others).

[0205] Pharmaceutical Excipients

[0206] In some embodiments, the pharmaceutically acceptable excipient is a solvent. In some embodiments, the solvent is a class 3 solvent according to the Q3C guidelines provided by United States Department of Health and Human Services. In some embodiments, the solvent is water, an alcohol (e.g., ethanol, isopropyl alcohol, 1 -butanol, 2-butanol, etc.), acetone, or a combination thereof. In preferred embodiments, the solvent is water.

[0207] Wound Dressings

[0208] The formulations or compositions of the present disclosure may be administered in combination with a wound dressing. Wound dressings are commonly applied to skin wounds to promote treatment and / or to directly apply a pharmaceutical composition to a wound. A wound dressing may, for example, include gauze, netting, a sheet, a pad, or a bandage capable of delivering a therapeutically effective amount of a pharmaceutical composition to a wound site. Wound dressings may further include an adhesive (e.g., a bioadhesive acrylic polymer) to improve adherence of the wound dressing to the wound site. Exemplary wound dressings include bandages, pads, particles, pastes, sheets, solutions, nettings, gauzes, collagens, foams, hydrocolloids, or hydrogels. A wound dressing may be modified (e.g., kirigami bandages) in order to improve adherence of the wound dressing to the skin and prevent breakage of the wound dressing. Wound dressings may further include an adhesive configured to adhere the wound dressing to the skin of a subject. Further wound dressings and methods of using wound dressings to deliver topical formulations or compositions are known in the art (see, e.g., US Patent Application Nos.: 17 / 272,004 and 16 / 472,144 the wound dressings of which are incorporated herein by reference).

[0209] One or more component of a formulation or composition of the present disclosure may be adsorbed by the wound dressing. The wound dressing may include an absorbent component (e.g., netting, gauze, etc.) configured to absorb a formulation or composition and release the formulation or composition proximal to the applied site.

[0210] The formulations or compositions of the present disclosure may be administered to a skin wound in combination with a wound dressing multiple times over the course of the treatment period, e.g., one or more times per day, one or more times per week, one or more times per month over the course of a treatment period. The formulations or compositions of the present disclosure may be administered to a skin wound in combination with a wound dressing for the entirety of a treatment period, or only part of a treatment period.

[0211] Kits

[0212] The pharmaceutical compositions described herein can be provided in a kit for use in treating a skin wound (e.g., a diabetic foot ulcer). The kit can include a package insert that instructs a user of the kit, such as a physician of skill in the art, to perform any one of the methods described herein. The kit may optionally include a syringe or other device for administering the composition. In some embodiments, the kit may include one or more additional therapeutic agents. In some embodiments, the kit may include a wound dressing (e.g., bandages, pads, particles, pastes, sheets, solutions, nettings, gauzes, collagens, foams, hydrocolloids, or hydrogels). In some embodiments, the pharmaceutical composition may be absorbed by the wound dressing.

[0213] The kit can include a package insert that instructs a user of the kit, such as a physician of skill in the art, to perform any one of the methods described herein. The kit may optionally include a syringe or other device for administering the composition. In some embodiments, the kit may include one or more additional therapeutic agents.

[0214] Diseases, Disorders, Conditions, or Injuries

[0215] Formulation or compositions of the present disclosure may be used in the treatment of a variety diseases, disorders, conditions, or injuries. Exemplary diseases, disorders, conditions, or injuries formulations or compositions of the present disclosure may be used in the treatment of include any disease, disorder, condition, or injury which impacts the skin (e.g. the dermis or epidermis) of a subject. Formulations or compositions of the present disclosure may be applied topically either to or proximal to the site of a wound in the skin of a subject.

[0216] Skin Wounds

[0217] Formulations or compositions of the present disclosure may be used to treat a variety of skin wounds. Exemplary skin wounds that formulations or compositions of the present disclosure may treat include blisters, lesions, cuts, bruises, cancers (e.g., skin cancers), punctures, breeches, ulcers (e.g., venous leg ulcer, diabetic foot ulcer, decubital ulcer, etc.), papules, plaques, nodules, vesicles, bullae, pustules, cysts, erosions, inflammation, swelling, infections, fissures (e.g., anal fissures), wheals, telangiectasia, burrows, scale, crusts, lichenification of the skin, abrasions, indurations, burns, rashes, sores (e.g., bed sores, pressure sores, etc.), dermal fibrosis, scleroderma, vasculitis, or atrophy. Exemplary sources of skin wounds include trauma (e.g., bruising, cuts, and other forms of damage), burns, cancer, or underlying medical conditions (e.g., type I diabetes mellitus, type II diabetes mellitus). Further exemplary skin wounds are known in the art (see, e.g., US Patent No.: 8,247,384 and 11 ,446,331 the skin wounds of which are incorporated by reference herein).

[0218] Inflammation and Swelling

[0219] In some embodiments, the skin wound is inflammation and / or swelling of the skin. Formulation or compositions of the disclosure may be used to reduce inflammation, swelling, or redness in the skin of a subject (e.g., eczema). Exemplary sources of inflammation, swelling, or redness include contact dermatitis, seborrheic dermatitis, nummular dermatitis, stasis dermatitis, atopic dermatitis, and dermatitis herpetiformis, among others. In some embodiments, the inflammation is due to exposure to ultraviolet (UV) radiation.

[0220] Infection

[0221] In some embodiments, the skin wound is a skin infection. Formulations or compositions of the disclosure may be used to treat an infection in the skin of a subject. Skin infections occur when a foreign body (e.g., a bacteria, a virus, a fungus or a parasite) infect the skin of a subject. Exemplary skin infections include bacterial infections (e.g., cellulitis, impetigo, staphylococcal infections, etc.), viral infections (e.g., shingles, warts, herpes simplex, etc.), fungal infections (e.g., tinea pedis, dermatophytosis, etc.), and parasitic infections (e.g., lice, Sarcopetes Scabiei, etc.). Other exemplary infections are known in the art (see, e.g., US Patent No.: 8,226,965; 10,370,449; and 6,960,201 the skin wounds of which are incorporated herein by reference).

[0222] Methods of Treatment

[0223] Skin wounds are known to develop frequently in subjects suffering from a wide genre of diseases, including bacterial or viral infections (e.g., cellulitis), autoimmune diseases (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). If left untreated, independent of the underlying ailment, skin wounds will often cause lasting pain and scaring of the tissues. Additionally, subjects suffering from skin wounds are at higher risk for further bacterial / viral / fungal infection and eventual sepsis / organ failure. It is often necessary to treat skin wounds separate from their causal disease or condition, as the skin wound can often remain long after the underlying disease or diseases are treated or managed. Left untreated, cell death and / or scaring resulting from the skin wound can leave subjects in lifelong pain.

[0224] The present disclosure provides methods for the treatment of skin wounds by application of a topical formulation or composition including a multitude of ingredients serving as both active ingredients of the composition and excipients. In some embodiments, the topical formulation or composition is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid. Beyond the chemical composition of the topical formulation or composition, the resultant physical properties of the formulation or composition can have powerful effects on the treatment efficacy of the gel. This disclosure provides methods for improving the treatment of skin wounds by using a topical formulation or composition of optimal viscosity. In some embodiments, that optimal viscosity for a particular subject has been predetermined by one of skill in the art. In some embodiments, the formulation or composition is applied multiple times over the course of the treatment period, e.g., one or more times per day, one or more times per week, one or more times per month over the course of a treatment period .

[0225] In some embodiments, the formulation or composition is applied in conjunction with a wound dressing. Exemplary wound dressings include bandages, pads, particles, pastes, sheets, solutions, nettings, gauzes, collagens, foams, hydrocolloids, and hydrogels. In some embodiments, the wound dressing is a bandage. In some embodiments, the composition is absorbed by the wound dressing. In some embodiments, the wound dressing adheres to the skin of the subject. In some embodiments, a formulation or composition may be applied with a wound dressing multiple times over the course of the treatment period, e.g., one or more times per day, one or more times per week, one or more times per month over the course of a treatment period. The formulations or compositions of the present disclosure may be administered to a skin wound in combination with a wound dressing for the entirety of a treatment period, or only part of a treatment period.

[0226] In some embodiments, the skin wound or wounds that are treated by the methods of this disclosure may include one or more of: a blister, lesion, cut, wound, bruise, puncture, breech, infection, infection of a limb, ulcer, venous leg ulcer, diabetic foot ulcer, decubital ulcer, papule, plaque, nodule, vesicle, bulla, pustule, cyst, erosion, fissure, wheal, telangiectasia, burrow, scale, crust, lichenification, excoriation, abrasion, induration, burn, rash, bed sores, pressure sores, dermal fibrosis, scleroderma, anal fissures, vasculitis, or atrophy. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.), a fungal infection (e.g., tinea pedis, dermatophytosis, etc.), or a parasitic infection (e.g., lice, Sarcopetes Scabiei, etc.). In some embodiments, the skin wound is inflammation, further wherein the inflammation is eczema.

[0227] Using the compositions and methods of the disclosure, a subject or person of skill in the art may administer a topical formulation including insulin, a surfactant (e.g., an anionic surfactant such as sodium stearate, a cationic surfactant such as benzalkonium chloride, a zwitterionic or amphoteric surfactants such as phosphatidylcholine, a nonionic surfactants such as poloxamer 407, etc.), a tissue hydrator (e.g., glycerin, hyaluronic acid, silicone gel, etc.), a wound-healing promoting agent (e.g., hyaluronic acid, lanolin, liquid paraffin, urea, propylene glycol, lactic acid, human nutrient vitamins, collagens, etc.), a bioadhesive agent (e.g., polycarbophil, shellac, soy hydrolysate, Notaden frog glue, chitosan, gelatin, lectin, hyperbranched polyglycerol, alginate, cellulose, levodopa, etc.), and a pharmaceutically acceptable solvent (e.g., water) at or proximal to a skin wound. The insulin may be fast acting (e.g., insulin aspart, insulin lyspro, or insulin gluisine), intermediate acting (e.g., Neutral Protamine Hagedorn insulin or an isophane insulin), or slow acting insulin (e.g., insulin glargine, insulin detemir, or insulin degludec). The skin wounds to which the topical formulation can be applied include but are not limited to a lesion, cut, wound, bruise, puncture, breech, infection, infection of a limb, ulcer, venous leg ulcer, diabetic foot ulcer, decubital ulcer, papule, plaque, nodule, vesicle, bulla, pustule, cyst, erosion, fissure, wheal, telangiectasia, burrow, scale, crust, lichenification, excoriation, abrasion, induration, burn, rash, bed sores, pressure sores, dermal fibrosis, scleroderma, anal fissures, vasculitis, or atrophy, or as otherwise disclosed herein.

[0228] Using the compositions and methods described herein, a medical practitioner of skill in the art can apply a topical formulation or composition to a subject with a skin wound or instruct a subject to do likewise. In some embodiments, the topical formulation or composition is packaged in a kit. In some embodiments, the kit also includes a package insert instructing a subject or medical practitioner to administer the topical formulation or composition, either alone or with a wound dressing, to the wound site. In some embodiments, the package insert instructs the subject or medical practitioner to administer the topical formulation or composition to the wound site (optionally with a wound dressing) one or more times per day. In some embodiments, the package insert instructs the subject or medical practitioner to administer the topical formulation or composition to the wound site one or more times per week. In some embodiments, the package insert instructs the subject or medical practitioner to administer the topical formulation or composition to the wound site one or more times per month. In some the package insert instructs that treatment continues for a duration of treatment (e.g., one or more times per day, one or more times per week, one or more times per month over the course of a treatment period, etc.). In some embodiments, the package insert instructs the subject or a medical practitioner to continue treatment until an endpoint of treatment is reached. In some embodiments, the endpoint of treatment is partial or complete healing of the skin wound. In some embodiments, the endpoint of treatment occurs within 90 days. In some embodiments, the endpoint of treatment occurs within 60 days. In some embodiments, the endpoint of treatment occurs within or 30 days. In some embodiments, the endpoint of treatment occurs within about 15 days, where in preferred embodiments at least about 50% wound closure is observed (see, e.g., Figs. 8-14).

[0229] The compositions of this disclosure are preferably topical compositions that can be used to apply at least one active pharmaceutical ingredient (API) onto and into a skin wound such as, in a preferred example, a diabetic foot ulcer. The use of a topical composition to treat and heal such skin wounds provides clear advantages over conventionally administered insulin, which is typically injected. This includes the practicality of application (e.g., injection into a wound as compared to the application of a topical composition), leading to greater patient compliance and, therefore, wound healing in an outpatient setting. In preferred embodiments, preferred compositions of this disclosure comprise at least one type of insulin, at least one bioadhesive agent (e.g., a carbomer such as polycarbophil, Noveon® AA-1 Polycarbophil USP), at least one tissue hydrator (e.g., glycerin), at least one wound-healing promoting agent (e.g., hyaluronic acid), at least one surfactant (e.g., poloxamer 407), and optionally at least one plasticizer and at least one thickening agent; and, exhibit a suitable complex viscosity, storage modulus, and loss modulus as determined using the methods described herein (preferred) or other methods available to those of ordinary skill in the art. A composition exhibiting a complex viscosity of less than about 250 mPa s (e.g., Formulation 1 of the Examples) would not be suitable for use as a topical composition as it lacks the viscosity required of an effective topical composition (e.g., one that stays in place on the skin wound and releases the API (preferably insulin) onto and / or into the wound). In preferred embodiments, then, the compositions of this disclosure exhibit a complex viscosity of about 4000 mPa s to about 20000 mPa s, such as about 7000 to about 20000 mPa s, or preferably about 13000 to about 15000 mPa s (e.g., as in Formula 3 of the Examples). The preferred compositions of this disclosure also exhibit maximal rate of release of the API (preferably insulin) after about one (1) hour at room temperature and continue to release the API (preferably insulin) at a relatively constant rate for a total of at least about four hours (see, e.g., Figs. 6A-6B). In preferred embodiments, the composition is characterized by the release of at least about 90-99% of the API (preferably insulin), after one hour incubation in room temperature phosphate buffered saline (PBS). Preferred compositions of this disclosure also exhibit wound closure (as determined by measuring the wound closure ratio) in a mouse animal model that is at least about the same as insulin alone (e.g., Novolin 70 / 30 Insulin) and significantly improved (i.e., exhibiting a higher wound closure ratio) by six days after administration of a single topical administration as compared to a MucoLox-insulin composition (e.g., Formulation 10 of the examples) and / or a control saline composition, or by nine, 12 and / or 15 days after administration of a single or multiple doses (preferably daily for five days) topical administration as compared to a MucoLox-insulin composition and / or a control saline composition (see Figs. 8-15). Preferred compositions of this disclosure do not affect, or at least do not significantly affect, the systemic blood glucose of the mammals having the skin wounds upon which the preferred composition is administered.

[0230] Preferred compositions of this disclosure comprise at least one type of 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 4000 mPa s to 20000 mPa s (e.g., 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). In preferred embodiments, the complex viscosity of the composition is about 14000 mPa s. In preferred embodiments, 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. In preferred embodiments, the wound closure ratio at day 9 after the application is about the same as that of insulin alone. In preferred embodiments, the composition comprises about 100 mg or 0.15 U insulin about 100 mg of a bioadhesive agent, about 100 mg of a tissue hydrator, about 5 mg of a wound-healing promoting agent, and about 1-15% surfactant, and water In preferred embodiments,, the composition, 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, and the surfactant is poloxamer 407. Preferred compositions of this disclosure can comprise 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 (e.g., glycerin) (tissue hydrator), about 5 mg hyaluronic acid (a wound-healing promoting agent), and about any of 100 (1 wt%), 500 (5 wt%), 1000 (10 wt%) or, preferably, 1500 (15 wt%) mg poloxamer 407 (a surfactant), and a pharmaceutically acceptable excipient (preferably water, adjusted depending on the amount of surfactant included in the composition) and 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. Thus, the most preferred compositions of this disclosure comprising at least one type of insulin, at least one bioadhesive agent (e.g., a carbomer such as polycarbophil, Noveon® AA-1 Polycarbophil USP), at least one tissue hydrator (e.g., glycerin), at least one wound-healing promoting agent (e.g., hyaluronic acid), at least one surfactant (e.g., poloxamer 407), and optionally at least one plasticizer and at least one thickening agent, has a complex viscosity of greater than about 7000 mPa s, preferably about 14000 mPa s as measured using the strain-sweep technique presented in Example 2 herein (i.e., using an Anton-Paar Modular Compact Rheometer (MCR 92) using a parallel plate geometry (40 mm diameter) from 0.1 to 1000 Pa of the applied strain), and exhibiting at least 90%, preferably at least 95%, and even more preferably at least 99%, release of insulin by one minute at room temperature in PBS using the technique presented in Example 3 herein (i.e., by measuring the insulin content of a solution of phosphate buffered saline (PBS) gently shaken in the presence of the composition at room temperature). This disclosure also provides methods of manufacturing such compositions by combining the components at the proper ratio and packaging the mixed composition into a container such as a vial, tube or the like. This disclosure also provides a container comprising a preferred composition of this disclosure. This disclosure also provides methods for treating and / or healing skin wounds using a preferred composition of this disclosure. This disclosure also provides kits for treating and / or healing skin wounds using a preferred composition of this disclosure, the kit comprising a preferred composition of this disclosure, preferably in a container, and instructions for use. Other embodiments are also provided by this disclosure as will be apparent to those of ordinary skill in the art.

[0231] EXAMPLES

[0232] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used and evaluated and are intended to be purely exemplary of this disclosure.

[0233] Example 1 : Generation of Exemplary Topical Formulations

[0234] To identify a method for generating a variety of topical formulations, test Formulations 1-7 were prepared using the following procedure. A first container was prepared containing hyaluronic acid, glycerin, poloxamer 407, and optionally insulin (Novolin 70 / 30) dissolved in sterile water. A second container was prepared by dissolving polycarbophil in water. Both containers were slowly stirred until clear. Equal volumes from each container were then mixed until the resulting mixture was transparent with no visible precipitates. Separately, the polycarbophil was dissolved in an equal volume of sterile water and stirred until the solution was transparent with no visible precipitates. The two solutions were then mixed in a separate container with stirring until a uniform consistency was achieved. Formulation 9 is commercially available MucoLox™, as defined herein, comprising 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%). Formulation 9 is commercially available MucoLox™ further including 0.15 units of insulin.

[0235] Exemplary formulations formed using the above methods are summarized in Table 1 .

[0236] Table 1. Composition of Formulations Formed at a 10 g scale

[0237] These studies demonstrate that topical formulations exemplary of the present disclosure, including variable amounts of poloxamer 407, hyaluronic acid, Noveon® AA-1 Polycarbophil USP, glycerin, insulin, and water (Formulations 1-8), can be formed.

[0238] Example 2: Effect of Poloxamer 407 Concentration on Complex Viscosity

[0239] To evaluate the use of the surfactant of the composition (i.e. , poloxamer 407) as a thickening agent, and the resulting effect of concentration of the surfactant on the viscosity of the resulting composition, the following study was carried out. The complex viscosities of Formulations 1-3 were examined by strain-sweep experiments using an Anton-Paar Modular Compact Rheometer (MCR 92) using a parallel plate geometry (40 mm diameter) from 0.1 to 1000 Pa of applied strain.

[0240] Formulation 1 , Formulation 2, and Formulation 3 were examined to determine their complex viscosity. The results of the strain-sweep analysis on are shown in Table 2 (see Figs. 1A-1B for the strain sweep experiments on the Formulation 1 composition, Figs. 2A-2B for the strain sweep experiments on Formulation 2, and Figs. 3A-3B, for the strain-sweep experiments on Formulation 3). Fig. 4 shows the comparison of the complex viscosities determined from these experiments. Table 2. Complex Viscosity Measurements of Exemplary Poloxamer Formulations

[0241] Formulation 1 did not form a gel, remaining a free-flowing liquid. Such a formulation was found to not be sufficiently viscous for topical administration, and was not administrable via a syringe or tube (Fig. 1B). Conversely, both Formulation 2 and Formulation 3 were gel-like compositions administrable through a syringe (see, e.g., Fig. 2B and Fig. 3B). Formulation 2 was a low viscosity, sticky soft gel. Formulation 3 was a high viscosity, sticky gel.

[0242] From these studies, it was concluded that Formulation 1 did not form a gel. Formulation 2 and Formulation 3 formed a low viscosity and a high viscosity gel, respectively. From these data, it was inferred that an optimal gel could be formed using, e.g., a formulation of from about 5% poloxamer to about 30 wt% (from about 4000 mPa s to about 20000 mPa s), such as a formulation of from about 10% poloxamer to about 30 wt% (from about 7500 mPa s to about 20000 mPa s), for use in topical administration of insulin.

[0243] Example 3: Measurement of Insulin Release Profile

[0244] Formulations 4-7 of were measured for their insulin release profile. For the compositions of this example, insulin release was determined by measuring the insulin content of a solution of phosphate buffered saline (PBS) gently shaken in the presence of the formulation at room temperature. Solutions prepared prior to mixing to create each formulation are shown in Fig. 5.

[0245] 1 g of each formulation was added to a 25 mL falcon tube. 25 mL of PBS solution was then slowly added to the falcon tube. The PBS solution was added through the tube’s wall in order to prevent gel disruption. The mixture was slowly shaken at 50 rpm and 25 °C. At predetermined timepoints (0, 1 , 2, 4, 8, and 24 hours) a 0.5 mL aliquot of supernatant was taken from a fixed depth in the tube and replaced with 0.5 mL of fresh PBS solution. Insulin levels were measured using a commercially available Insulin ELISA kit - an enzyme immunoassay with near 100% reactivity to insulin and most insulin analogues, and a low reactivity to proinsulin.

[0246] As shown in Fig. 6A, the insulin release for all formulations reached the highest level after 1 h incubation at room temperature, after which the release remained constant. The graph shows the release up to 4 hrs. incubation. Fig. 6B shows the cumulative release for all formulations at t=0 and 1 hr. The burst release immediately after adding PBS to insulin-incorporated gels (Oh) varied slightly for different formulations. At t=Oh, the cumulative release of insulin (in units of released insulin / mL of supernatant) was 53.3±2.6 for Formulation 4, 61 .7±23.0 for Formulation 5, 43.1 ±8.4 for Formulation 6, and 47.45±0.9 for Formulation 7. The differences between Formulations 4-7 were not statistically significant. The cumulative release of insulin after 1 h incubation at room temperature (in units of % of released insulin) was 99.6±17 for Formulation 4, 99.5±10 for Formulation 5, 96.1 ±17 for Formulation 6, and 98.1 ±10 for Formulation 7. From these studies, we concluded that topical formulations including insulin and one or more excipients (e.g., glycerol, hyaluronic acid, poloxamer 407, and polycarbophil) were found to release insulin, with the majority of insulin being released from the formulation within 1 hour.

[0247] Example 4: Pilot In-Vivo Study

[0248] An in-vivo mouse study using diabetic mice was carried out to demonstrate the effects of different dosing profiles on wound closure.

[0249] Mice of the C57 / B6 genome homozygous for the diabetes spontaneous mutation Leprdb(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.

[0250] Blood was collected in live, awake animals between 10:00 and 11 :00 a.m. Glucose was measured by glucometer. Blood glucose (BG) was measured prior to surgery (i.e., day 0) and repeated on day 1 , 2, 9, 12 and 15 after surgery (Fig. 7).

[0251] 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.

[0252] Table 3. Treatment Protocols for in-vivo Mouse Studies

[0253] 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 (i.e., a prior art post-surgical dressing, see e.g., British Patent No.: 1 ,280,631). Wound edges were measured on days 0, 2, 6, 9, 12, and 15 (Fig. 8). Wound closure was calculated as a ratio of final wound area to initial wound area. The total number of animals that underwent surgery was 27 db / db mice (14 female and 13 male). One mouse died before surgery and a total of 27 animals survived the full study period. As shown in Fig. 7, 60% of total mice showed increased BG the day after surgery. On day 1 (one day post-surgery), mice in the insulin group displayed the highest average blood sugar. This remained true on day 15 (Fig. 7B).

[0254] Up to day 6, the wound closure measurement shows that the multi-dose group exhibited a delay compared to other groups. On day 12 post-surgery, all groups show improved wound closures relative to the saline group. The wound closures percent on day 12 post-surgery were: 23±1 .2, 46±0.9, 52±6.5, 58±21 , 24±13, 22±15 for the saline group, the insulin group, the single dose group, the multi-dose group, the MucoLox group, and the MucoLox / insulin group, respectively. On day 15 post-surgery, mice in the single and multi-dose groups showed significantly higher levels of wound closure compared to saline. 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).

[0255] There was no observed correlation between wound closure rate and severity of diabetes (as measured by mouse blood glucose level).

[0256] 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).

[0257] Example 5: Histopathological Study

[0258] Further experiments were carried out to study the skin condition and wound-healing of mice selected from the groups in Table 3.

[0259] The treated animals were sacrificed to collect the wounds and surrounding tissues (e.g., skin tissue and subcutaneous tissue). The collected wounds were fixed using Formalin solution for 48 hours and then embedded in a paraffin block. The samples were cut into 7 um sections and put on glass slides. The slides were stained with Hematoxylin and eosin (H&E) stain according to the standard instructions and morphological changes of skin tissue were studied.

[0260] Samples from the saline group exhibited a newly formed epithelium, a thin layer of the clot and granulation tissue which cover the wound. In the dermis, the granulated tissue with inflammatory cells was also observed (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).

[0261] From these studies, we concluded that mice treated with compositions of the present invention demonstrated increased wound-healing, as measured by epidermis growth, when compared to mice treated with insulin or MucoLox alone. Example 6: Comparison of Topical Compositions

[0262] 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.

[0263] 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.

[0264] Table 4. Treatment Protocols for Large Scale Mouse Studies

[0265] 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:

[0266] Table 5. Saline Group HL: BG > 600 mg / dL

[0267] *: BG not measured

[0268] 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.

[0269] The BG of each mouse in the Insulin Group over time is summarized in Table 6:

[0270] Table 6. Insulin Group

[0271] HL: BG > 600 mg / dL *: BG not measured

[0272] 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.

[0273] The BG of each mouse in the Formulation 3 Group over time is summarized in Table 7:

[0274] Table 7. Formulation 3 Group

[0275] HL: BG > 600 mg / dL *: BG not measured

[0276] The BG levels of the Formulation 3 Group were routinely high and variable, demonstrating that a composition without insulin does not lower a subject’s BG.

[0277] The BG of each mouse in the Formulation 4 Group over time is summarized in Table 8:

[0278] Table 8. Formulation 4 Group

[0279] HL: BG > 600 mg / dL *: BG not measured

[0280] The BG levels of the Formulation 4 Group fluctuated significantly, but generally decreased over time. The frequent HL and fluctuations indicated it was not very effective in maintaining stable control of BG.

[0281] The BG of each mouse in the Formulation 5 Group over time is summarized in Table 9:

[0282] Table 9. Formulation 5 Group

[0283] HL: 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.

[0284] The BG of each mouse in the Formulation 7 Group over time is summarized in Table 10:

[0285] Table 10. Formulation 7 Group

[0286] HL: BG > 600 mg / dL *: BG not measured

[0287] 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.

[0288] The blood glucose of each mouse in the Formulation 8 Group over time is summarized in

[0289] Table 11 :

[0290] Table 11. Formulation 8 Group

[0291] HL: BG > 600 mg / dL *: BG not measured

[0292] The BG levels of the Formulation 8 Group showed frequent HL instances and variability over time.

[0293] Notably, 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.

[0294] The blood glucose of each mouse in the Formulation 10 Group over time is summarized in Table 12:

[0295] Table 12. Formulation 10 Group

[0296] HL: BG > 600 mg / dL *: BG not measured

[0297] The BG levels of the Formulation 10 group showed moderate improvement with fluctuations and frequent HL instances.

[0298] 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).

[0299] 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., MucoLox™ based formulations, e.g., Formulation 10). Moreover, topical compositions including a higher concentration of poloxamer (e.g., Formulation 7 and Formulation 8) showed particular effectiveness in wound healing.

[0300] 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

[0301] 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. The 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).

[0302] OTHER EMBODIMENTS

[0303] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each independent publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the invention that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are in the claims.

Claims

CLAIMS1 . A topical formulation comprising insulin, wherein the formulation exhibits a complex viscosity of from about 1 mPa s to about 50000 mPa s.

2. The formulation of claim 1 , wherein the formulation exhibits a complex viscosity of from about 1000 mPa s to about 40000 mPa s.

3. The formulation of claim 1 or claim 2, wherein the formulation exhibits a complex viscosity of from about 2500 mPa s to about 30000 mPa s.

4. The formulation of any one of claims 1 to 3, wherein the formulation exhibits a complex viscosity of from about 4000 mPa s to about 20000 mPa s.

5. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of about 4500 mPa s to about 19000 mPa s.

6. The formulation of any one of claims 1 to 5, wherein the formulation exhibits a complex viscosity of from about 5000 mPa s to about 18000 mPa s.

7. The formulation of any one of claims 1 to 6, wherein the formulation exhibits a complex viscosity of 5500 mPa s to about 17000 mPa s.

8. The formulation of any one of claims 1 to 7, wherein the formulation exhibits a complex viscosity of from about 6000 mPa s to about 16000 mPa s.

9. The formulation of any one of claims 1 to 8, wherein the formulation exhibits a complex viscosity of from about 6500 mPa s to about 15000 mPa s.

10. The formulation of any one of claims 1 to 9, wherein the formulation exhibits a complex viscosity of from about 7000 mPa s to about 14000 mPa s.11 . The formulation of any one of claims 1 to 10, wherein the formulation exhibits a complex viscosity of from about 7500 mPa s to about 13500 mPa s.

12. The formulation of any one of claims 1 to 1 1 , wherein the formulation exhibits a complex viscosity of from about 8000 mPa s to about 13000 mPa s.

13. The formulation of any one of claims 1 to 12, wherein the formulation exhibits a complex viscosity of from about 8500 mPa s to about 12500 mPa s.

14. The formulation of any one of claims 1 to 13, wherein the formulation exhibits a complex viscosity of from about 9000 mPa s to about 12000 mPa s.

15. The formulation of any one of claims 1 to 14, wherein the formulation exhibits a complex viscosity of from about 9500 mPa s to about 11500 mPa s.

16. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 4000 mPa s to about 5000 mPa s.

17. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 5000 mPa s to about 6000 mPa s.

18. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 6000 mPa s to about 7000 mPa s.

19. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 7000 mPa s to about 8000 mPa s.

20. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 8000 mPa s to about 9000 mPa s.21 . The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 9000 mPa s to about 10000 mPa s.

22. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 10000 mPa s to about 11000 mPa s.

23. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 11000 mPa s to about 12000 mPa s.

24. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 12000 mPa s to about 13000 mPa s.

25. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 13000 mPa s to about 14000 mPa s.

26. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 14000 mPa s to about 15000 mPa s.

27. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 15000 mPa s to about 16000 mPa s.

28. The formulation of any one of claims 1 to 4, wherein the formulation exhibits a complex viscosity of from about 16000 mPa s to about 17000 mPa s.

29. The formulation of any one of claims 1 to 4 , wherein the formulation exhibits a complex viscosity of from about 17000 mPa s to about 18000 mPa- s.

30. The formulation of any one of claims 1 to 4 , wherein the formulation exhibits a complex viscosity of from about 18000 mPa s to about 19000 mPa- s.31 . The formulation of any one of claims 1 to 4 , wherein the formulation exhibits a complex viscosity of from about 19000 mPa s to about 20000 mPa- s.

32. The formulation of any one of claims 1 to 4 , wherein the formulation exhibits a complex viscosity of from about 7000 mPa s to about 20000 mPa s33. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 7500 mPa s.

34. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 8000 mPa s.

35. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 8500 mPa s.

36. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 9000 mPa s.

37. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 9500 mPa s.

38. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 10000 mPa s.

39. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 10500 mPa s.

40. The formulation of any one of claims 1 to 1 0, wherein the formulation exhibits a complex viscosity of about 11000 mPa s.

41. The formulation of any one of claims 1 to 10, wherein the formulation exhibits complex viscosity of about 11500 mPa s.

42. The formulation of any one of claims 1 to 10, wherein the formulation exhibits a complex viscosity of about 12000 mPa s.

43. The formulation of any one of claims 1 to 10, wherein the formulation exhibits a complex viscosity of about 12500 mPa s.

44. The formulation of any one of claims 1 to 10, wherein the formulation exhibits a complex viscosity of about 13000 mPa s.

45. The formulation of any one of claims 1 to 10, wherein the formulation exhibits a complex viscosity of about 13500 mPa s.

46. The formulation of any one of claims 1 to 45, wherein the storage modulus of the formulation is from about 50000 mPa to about 200000 mPa.

47. The formulation of any one of claims 1 to 46, wherein the loss modulus of the formulation is from about 20000 mPa about 100000 mPa.

48. The formulation of any one of claims 1 to 47, wherein the storage modulus of the formulation is greater than the loss modulus of the formulation at 1 unit of applied strain.

49. The formulation of any one of claims 1 to 48, further comprising: a) a surfactant; b) a tissue hydrator; c) a wound-healing promoting agent; d) a bioadhesive agent; and e) a pharmaceutically acceptable solvent.

50. The formulation of any one of claims 1 to 49, wherein the insulin comprises one or more of: a) a fast-acting insulin; b) an intermediate-acting insulin; or c) a long-acting insulin.51 . The formulation of claim 50, wherein the insulin comprises a fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine.

52. The formulation of claim 50, wherein the insulin comprises an intermediate-acting insulin selected from isophane insulin or Neutral Protamine Hagedorn insulin.

53. The formulation of claim 50, wherein the insulin comprises a long-acting insulin selected from insulin glargine, insulin detemir, or insulin degludec.

54. The formulation of any one of claims 1 to 53, wherein the formulation comprises from about 0.1 units of insulin per 10 g of the formulation to about 200 units of insulin per 10 g ofthe formulation.

55. The formulation of any one of claims 1 to 54, wherein the formulation comprises from about 1 unit of insulin per 10 g of the formulation to about 180 units per 10 g of the formulation.

56. The formulation of any one of claims 1 to 55, wherein the formulation comprises from about 2 units of insulin per 10 g of the formulation to about 160 units per 10 g of the formulation.

57. The formulation of any one of claims 1 to 56, wherein the formulation comprises from about 3 units of insulin per 10 g of the formulation to about 140 units per 10 g of the formulation.

58. The formulation of any one of claims 1 to 57, wherein the formulation comprises from about 4 units of insulin per 10 g of the formulation to about 120 units per 10 g of the formulation.

59. The formulation of any one of claims 1 to 58, wherein the formulation comprises from about 5 units of insulin per 10 g of the formulation to about 100 units per 10 g of the formulation.

60. The formulation of any one of claims 1 to 59, wherein the formulation comprises from about 6 units of insulin per 10 g of the formulation to about 80 units per 10 g of the formulation.61 . The formulation of any one of claims 1 to 60, wherein the formulation comprises from about 7 units of insulin per 10 g of the formulation to about 60 units per 10 g of the formulation.

62. The formulation of any one of claims 1 to 61 , wherein the formulation comprises from about 8 units of insulin per 10 g of the formulation to about 40 units per 10 g of the formulation.

63. The formulation of any one of claims 1 to 62, wherein the formulation comprises from about 9 units of insulin per 10 g of the formulation to about 20 units per 10 g of the formulation.

64. The formulation of any one of claims 1 to 59, wherein the formulation comprises about 10 units of insulin per 10 g of the formulation.

65. The formulation of any one of claims 1 to 59, wherein the formulation comprises about 20 units of insulin per 10 g of the formulation.

66. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 30 units of insulin per 10 g of the formulation.

67. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 40 units of insulin per 10 g of the formulation.

68. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 50 units of insulin per 10 g of the formulation.

69. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 60 units of insulin per 10 g of the formulation.

70. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 70 units of insulin per 10 g of the formulation.71 . The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 80 units of insulin per 10 g of the formulation.

72. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 90 units of insulin per 10 g of the formulation.

73. The formulation of any one of claims 1 to 59 , wherein the formulation comprises about 100 units of insulin per 10 g of the formulation.

74. The formulation of any one of claims 1 to 73 , wherein the formulation comprises from about 1 wt% to about 50 wt% surfactant.

75. The formulation of any one of claims 1 to 74 , wherein the formulation comprises from about 5 wt% to about 30 wt% surfactant.

76. The formulation of any one of claims 1 to 75 , wherein the formulation comprises from about 6 wt% to 28 wt% surfactant.

77. The formulation of any one of claims 1 to 76 , wherein the formulation comprises from about 7 wt% to 26 wt% surfactant.

78. The formulation of any one of claims 1 to 77 , wherein the formulation comprises from about 8 wt% to 24 wt% surfactant.

79. The formulation of any one of claims 1 to 78 , wherein the formulation comprises from about 9 wt% to 22 wt% surfactant.

80. The formulation of any one of claims 1 to 79 , wherein the formulation comprises from about 10 wt% to 20 wt% surfactant.81 . The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 10.5 wt% surfactant.

82. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 11 wt% surfactant.

83. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 11 .5 wt% surfactant.

84. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 12 wt% surfactant.

85. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 12.5 wt% surfactant.

86. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 13 wt% surfactant.

87. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 13.5 wt% surfactant.

88. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 14 wt% surfactant.

89. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 14.5 wt% surfactant.

90. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 15 wt% surfactant.91 . The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 15.5 wt% surfactant.

92. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 16 wt% surfactant.

93. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 16.5 wt% surfactant.

94. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 17 wt% surfactant.

95. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 17.5 wt% surfactant.

96. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 18 wt% surfactant.

97. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 18.5 wt% surfactant.

98. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 19 wt% surfactant.

99. The formulation of any one of claims 1 to 80 , wherein the formulation comprises about 19.5 wt% surfactant.

100. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 20 wt% of surfactant101 . The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 20.5 wt% surfactant.

102. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 21 wt% surfactant.

103. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 21 .5 wt% surfactant.

104. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 22 wt% surfactant.

105. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 22.5 wt% surfactant.

106. The formulation of any one of claims 1 to 75 , wherein the formulation comprises about 23 wt% surfactant.

107. The formulation of any one of claims 1 wherein the formulation comprises about 23.5 wt% surfactant.

108. The formulation of any one of claims 1wherein the formulation comprises about 24 wt% surfactant.

109. The formulation of any one of claims 1wherein the formulation comprises about 24.5 wt% surfactant.

110. The formulation of any one of claims 1wherein the formulation comprises about 25 wt% surfactant.

111. The formulation of any one of claims 1wherein the formulation comprises about 25.5 wt% surfactant.

112. The formulation of any one of claims 1wherein the formulation comprises about 26 wt% surfactant.

113. The formulation of any one of claims 1wherein the formulation comprises about 26.5 wt% surfactant.

114. The formulation of any one of claims 1wherein the formulation comprises about 27 wt% surfactant.

115. The formulation of any one of claims 1wherein the formulation comprises about 27.5 wt% surfactant.

116. The formulation of any one of claims 1wherein the formulation comprises about 28 wt% surfactant.

117. The formulation of any one of claims 1wherein the formulation comprises about 28.5 wt% surfactant.

118. The formulation of any one of claims 1wherein the formulation comprises about 29 wt% surfactant.

119. The formulation of any one of claims 1 wherein the formulation comprises about 29.5 wt% surfactant.

120. The formulation of any one of claims 1 to 75, wherein the formulation comprises about 30 wt% surfactant.

121. The formulation of any one of claims 1 to 120, wherein the formulation comprises a surfactant, wherein the surfactant comprises poloxamer 407.

122. The formulation of any one of claims 1 to 121 , wherein the formulation comprises from about 0.01 wt% to about 5 wt% tissue hydrator.

123. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 0.5 wt% tissue hydrator.

124. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 1 wt% tissue hydrator.

125. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 1 .5 wt% tissue hydrator.

126. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 2 wt% tissue hydrator.

127. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 2.5 wt% tissue hydrator.

128. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 3 wt% tissue hydrator.

129. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 3.5 wt% tissue hydrator.

130. The formulation of any one of claims 1 to 122, wherein the formulation comprises about 4 wt% tissue hydrator.131 . The formulation of any one of claims 1 to 122, wherein the formulation comprises about 4.5 wt% tissue hydrator.

132. The formulation of any one of claims 1 to 131 , wherein the formulation comprises a tissue hydrator, wherein the tissue hydrator comprises glycerin or a pharmaceutically acceptable salt thereof.

133. The formulation of any one of claims 1 to 132, wherein the formulation comprises from about 0.001 wt% to about 1 wt% wound-healing promoting agent.

134. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.01 wt% wound-healing promoting agent.

135. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.025 wt% wound-healing promoting agent.

136. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.05 wt% wound-healing promoting agent.

137. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.075 wt% wound-healing promoting agent.

138. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.1 wt% wound-healing promoting agent.

139. The formulation of any one of claims 1 to 133, wherein the formulation comprises about 0.5 wt% wound-healing promoting agent.

140. The formulation of any one of claims 1 to 133, wherein the formulation comprises a woundhealing promoting agent, and the wound-healing promoting agent comprises hyaluronic acid or a pharmaceutically acceptable salt thereof.

141. The formulation of any one of claims 1 to 140, wherein the formulation comprises from about 0.1 wt% to about 5 wt% bioadhesive agent.

142. The formulation of any one of claims 1 to 141 , wherein the formulation comprises from about 0.1 wt% to about 2 wt% bioadhesive agent.

143. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 0.5 wt% bioadhesive agent.

144. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 1 wt% bioadhesive agent.

145. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 1 .5 wt% bioadhesive agent.

146. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 2 wt% bioadhesive agent.

147. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 2.5 wt% bioadhesive agent.

148. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 3 wt% bioadhesive agent.

149. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 3.5 wt% bioadhesive agent.

150. The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 4 wt% bioadhesive agent.151 . The formulation of any one of claims 1 to 141 , wherein the formulation comprises about 4.5 wt% bioadhesive agent.

152. The formulation of any one of claims 1 to 151 , wherein the formulation comprises a bioadhesive agent, and wherein the bioadhesive agent comprises a carbomer.

153. The formulation of claim 152, wherein the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof.

154. The formulation of claim 153, wherein the polycarbophil is Noveon® AA-1 Polycarbophil USP.

155. The formulation of any one of claims 1 to 154, wherein the pharmaceutically acceptable solvent is water.

156. The formulation of any one of claims 1 to 155, wherein the formulation is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid.

157. The formulation of any one of claims 1 to 156, wherein the formulation is a gel.

158. The formulation of any one of claims 1 to 157, wherein the formulation is used for the treatment of a skin wound.

159. The formulation of claim 158, wherein 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.

160. The formulation of claim 159, wherein the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer.161 . The formulation of claim 160, wherein the skin wound is a diabetic foot ulcer.

162. The formulation of claim 160, wherein the skin wound is an infection, and the infection is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.

163. The formulation of claim 159, wherein the skin wound is inflammation, further wherein the inflammation is eczema.

164. The formulation of any one of claims 1 to 163, wherein the formulation is characterized by the release of at least 90% of the insulin of the formulation within one minute with mixing at room temperature in phosphate buffered saline (PBS).

165. A pharmaceutical composition, comprising: a) insulin b) a surfactant; c) a tissue hydrator; d) a wound-healing promoting agent; e) a bioadhesive agent; and f) a pharmaceutically acceptable solvent.

166. The pharmaceutical composition of claim 165, wherein the insulin comprises one or more of: a) a fast-acting insulin; b) an intermediate-acting insulin; or c) a long-acting insulin.

167. The pharmaceutical composition of claim 165 or claim 166, wherein the insulin comprises a fast acting insulin, wherein the fast acting insulin selected from insulin aspart, insulin lyspro, or insulin gluisine.

168. The pharmaceutical composition of claim 165 or claim 166, wherein the insulin comprises an intermediate-acting insulin, wherein the intermediate-acting insulin is an isophane insulin or a Neutral Protamine Hagedorn insulin.

169. The pharmaceutical composition of claim 165 or claim 166, wherein the insulin comprises a long- acting insulin selected from insulin glargine, insulin detemir, or insulin degludec.

170. The pharmaceutical composition of any one of claims 165 to 169, wherein the pharmaceutical composition comprises 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.

171. The pharmaceutical composition of any one of claims 165 to 170, wherein the pharmaceutical composition comprises from about 1 unit of insulin per 10 g of the pharmaceutical composition to about 180 units per 10 g of the pharmaceutical composition.

172. The pharmaceutical composition of any one of claims 165 to 171 , wherein the pharmaceutical composition comprises from about 2 units of insulin per 10 g of the pharmaceutical composition to about 160 units per 10 g of the pharmaceutical composition.

173. The pharmaceutical composition of any one of claims 165 to 172, wherein the pharmaceutical composition comprises from about 3 units of insulin per 10 g of the pharmaceutical composition to about 140 units per 10 g of the pharmaceutical composition.

174. The pharmaceutical composition of any one of claims 165 to 173, wherein the pharmaceutical composition comprises from about 4 units of insulin per 10 g of the pharmaceutical composition to about 120 units per 10 g of the pharmaceutical composition.

175. The pharmaceutical composition of any one of claims 165 to 174, wherein the pharmaceutical composition comprises from about 5 units of insulin per 10 g of the pharmaceutical composition to about 100 units per 10 g of the pharmaceutical composition.

176. The pharmaceutical composition of any one of claims 165 to 175, wherein the pharmaceutical composition comprises from about 6 units of insulin per 10 g of the pharmaceutical composition to about 80 units per 10 g of the pharmaceutical composition.

177. The pharmaceutical composition of any one of claims 165 to 176, wherein the pharmaceutical composition comprises from about 7 units of insulin per 10 g of the pharmaceutical composition to about 60 units per 10 g of the pharmaceutical composition.

178. The pharmaceutical composition of any one of claims 165 to 177, wherein the pharmaceutical composition comprises from about 8 units of insulin per 10 g of the pharmaceutical composition to about 40 units per 10 g of the pharmaceutical composition.

179. The pharmaceutical composition of any one of claims 165 to 178, wherein the pharmaceutical composition comprises from about 9 units of insulin per 10 g of the pharmaceutical composition to about 20 units per 10 g of the pharmaceutical composition.

180. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 10 units of insulin per 10 g of the pharmaceutical composition.

181. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 20 units of insulin per 10 g of the pharmaceutical composition.

182. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 30 units of insulin per 10 g of the pharmaceutical composition.

183. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 40 units of insulin per 10 g of the pharmaceutical composition.

184. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 50 units of insulin per 10 g of the pharmaceutical composition.

185. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 60 units of insulin per 10 g of the pharmaceutical composition.

186. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 70 units of insulin per 10 g of the pharmaceutical composition.

187. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 80 units of insulin per 10 g of the pharmaceutical composition.

188. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 90 units of insulin per 10 g of the pharmaceutical composition.

189. The pharmaceutical composition of any one of claims 165 to 179, wherein the pharmaceutical composition comprises about 100 units of insulin per 10 g of the pharmaceutical composition.

190. The pharmaceutical composition of any one of claims 165 to 189, wherein the pharmaceutical composition comprises from about 1 wt% to about 50 wt% surfactant.

191. The pharmaceutical composition of any one of claims 165 to 190, wherein the pharmaceutical composition comprises from about 5 wt% to about 30 wt% surfactant.

192. The pharmaceutical composition of any one of claims 165 to 191 , wherein the pharmaceutical composition comprises from about 6 wt% to 28 wt% surfactant.

193. The pharmaceutical composition of any one of claims 165 to 192, wherein the pharmaceutical composition comprises from about 7 wt% to 26 wt% surfactant.

194. The pharmaceutical composition of any one of claims 165 to 193, wherein the pharmaceutical composition comprises from about 8 wt% to 24 wt% surfactant.

195. The pharmaceutical composition of any one of claims 165 to 194, wherein the pharmaceutical composition comprises from about 9 wt% to 22 wt% surfactant.

196. The pharmaceutical composition of any one of claims 165 to 195, wherein the pharmaceutical composition comprises from about 10 wt % to 20 wt% surfactant.

197. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 10.5 wt% surfactant.

198. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 11 wt% surfactant.

199. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 11 .5 wt% surfactant.

200. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 12 wt% surfactant.201 . The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 12.5 wt% surfactant.

202. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 13 wt% surfactant.

203. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 13.5 wt% surfactant.

204. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 14 wt% surfactant.

205. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 14.5 wt% surfactant.

206. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 15 wt% surfactant.

207. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 15.5 wt% surfactant.

208. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 16 wt% surfactant.

209. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 16.5 wt% surfactant.

210. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 17 wt% surfactant.

211. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 17.5 wt% surfactant.

212. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 18 wt% surfactant.

213. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 18.5 wt% surfactant.

214. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 19 wt% surfactant.

215. The pharmaceutical composition of any one of claims 165 to 196, wherein the pharmaceutical composition comprises about 19.5 wt% surfactant.

216. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 20 wt% of surfactant.

217. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 20.5 wt% surfactant.

218. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 21 wt% surfactant.

219. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 21 .5 wt% surfactant.

220. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 22 wt% surfactant.221 . The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 22.5 wt% surfactant.

222. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 23 wt% surfactant.

223. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 23.5 wt% surfactant.

224. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 24 wt% surfactant.

225. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 24.5 wt% surfactant.

226. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 25 wt% surfactant.

227. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 25.5 wt% surfactant.

228. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 26 wt% surfactant.

229. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 26.5 wt% surfactant.

230. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 27 wt% surfactant.231 . The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 27.5 wt% surfactant.

232. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 28 wt% surfactant.

233. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 28.5 wt% surfactant.

234. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 29 wt% surfactant.

235. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 29.5 wt% surfactant.

236. The formulation of any one of claims 165 to 191 , wherein the formulation comprises about 30 wt% surfactant.

237. The pharmaceutical composition of any one of claims 165 to 236, wherein the surfactant comprises poloxamer 407.

238. The pharmaceutical composition of any one of claims 165to 237, wherein the pharmaceutical composition comprises from about 0.1 wt% to about 5 wt% tissue hydrator.

239. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 0.5 wt% tissue hydrator.

240. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 1 wt% tissue hydrator.241 . The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 1 .5 wt% tissue hydrator.

242. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 2 wt% tissue hydrator.

243. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 2.5 wt% tissue hydrator.

244. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 3 wt% tissue hydrator.

245. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 3.5 wt% tissue hydrator.

246. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 4 wt% tissue hydrator.

247. The pharmaceutical composition of any one of claims 165 to 238, wherein the pharmaceutical composition comprises about 4.5 wt% tissue hydrator.

248. The pharmaceutical composition of any one of claims 165 to 247, wherein the tissue hydrator comprises glycerin or a pharmaceutically acceptable salt thereof.

249. The pharmaceutical composition of any one of claims 165 to 248, wherein the pharmaceutical composition comprises from about 0.001 wt% to about 1 wt% wound-healing promoting agent.

250. The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.01 wt% wound-healing promoting agent.251 . The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.025 wt% wound-healing promoting agent.

252. The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.05 wt% wound-healing promoting agent.

253. The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.075 wt% wound-healing promoting agent.

254. The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.1 wt% wound-healing promoting agent.

255. The pharmaceutical composition of any one of claims 165 to 249, wherein the pharmaceutical composition comprises about 0.5 wt% wound-healing promoting agent.

256. The pharmaceutical composition of any one of claims 165 to 255, wherein the wound-healing promoting agent comprises hyaluronic acid or a pharmaceutically acceptable salt thereof.

257. The pharmaceutical composition of any one of claims 165 to 256, wherein the pharmaceutical composition is from about 0.1 wt% to about 5 wt% bioadhesive agent.

258. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition is from about 0.1 wt% to about 2 wt% bioadhesive agent.

259. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 0.5 wt% bioadhesive agent.

260. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 1 wt% bioadhesive agent.261 . The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 1 .5 wt% bioadhesive agent.

262. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 2 wt% bioadhesive agent.

263. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 2.5 wt% bioadhesive agent.

264. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 3 wt% bioadhesive agent.

265. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 3.5 wt% bioadhesive agent.

266. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 4 wt% bioadhesive agent.

267. The pharmaceutical composition of any one of claims 165 to 257, wherein the pharmaceutical composition comprises about 4.5 wt% bioadhesive agent.

268. The pharmaceutical composition of any one of claims 165 to 267, wherein the bioadhesive agent is a carbomer.

269. The pharmaceutical composition of claim 268, wherein the carbomer is polycarbophil or a pharmaceutically acceptable salt thereof.

270. The pharmaceutical composition of claim 269, wherein the polycarbophil is Noveon® AA-1 Polycarbophil USP.271 . The pharmaceutical composition of any one of claims 165 to 270, wherein the pharmaceutically acceptable solvent is water.

272. The pharmaceutical composition of any one of claims 165 to 271 , wherein the pharmaceutical composition exhibits a complex viscosity of from about 1 mPa s to about 50000 mPa s.

273. The pharmaceutical composition of any one of claims 165 to 272, wherein the pharmaceutical composition exhibits a complex viscosity of from about 1000 mPa s to about 40000 mPa s.

274. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 2500 mPa s to about 30000 mPa s.

275. The pharmaceutical composition of any one of claims 165 to 274, wherein the pharmaceutical composition exhibits a complex viscosity of from about 4000 mPa s to about 20000 mPa s.

276. The pharmaceutical composition of any one of claims 165 to 275, wherein the pharmaceutical composition exhibits a complex viscosity of about 4500 mPa s to about 19000 mPa s.

277. The pharmaceutical composition of any one of claims 165 to 276, wherein the pharmaceutical composition exhibits a complex viscosity of from about 5000 mPa s to about 18000 mPa s.

278. The pharmaceutical composition of any one of claims 165 to 277, wherein the pharmaceutical composition exhibits a complex viscosity of 5500 mPa s to about 17000 mPa s.

279. The pharmaceutical composition of any one of claims 165 to 278, wherein the pharmaceutical composition exhibits a complex viscosity of from about 6000 mPa s to about 16000 mPa s.

280. The pharmaceutical composition of any one of claims 165 to 279, wherein the pharmaceutical composition exhibits a complex viscosity of from about 6500 mPa s to about 15000 mPa s.281 . The pharmaceutical composition of any one of claims 165 to 280, wherein the pharmaceutical composition exhibits a complex viscosity of from about 7000 mPa s to about 14000 mPa s.

282. The pharmaceutical composition of any one of claims 165 to 281 , wherein the pharmaceutical composition exhibits a complex viscosity of from about 7500 mPa s to about 13500 mPa s.

283. The pharmaceutical composition of any one of claims 165 to 282, wherein the pharmaceutical composition exhibits a complex viscosity of from about 8000 mPa s to about 13000 mPa s.

284. The pharmaceutical composition of any one of claims 165 to 283, wherein the pharmaceutical composition exhibits a complex viscosity of from about 8500 mPa s to about 12500 mPa s.

285. The pharmaceutical composition of any one of claims 165 to 284, wherein the pharmaceutical composition exhibits a complex viscosity of from about 9000 mPa s to about 12000 mPa s.

286. The pharmaceutical composition of any one of claims 165 to 285, wherein the pharmaceutical composition exhibits a complex viscosity of from about 9500 mPa s to about 11500 mPa s.

287. The pharmaceutical composition of any one of claims 165 to 273 wherein the pharmaceutical composition exhibits a complex viscosity of from about 4000 mPa s to about 5000 mPa s.

288. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 5000 mPa s to about 6000 mPa s.

289. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 6000 mPa s to about 7000 mPa s.

290. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 7000 mPa s to about 8000 mPa s.291 . The pharmaceutical composition of any one of claims 165 to 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 8000 mPa s to about 9000 mPa s.

292. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 9000 mPa s to about 10000 mPa s.

293. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 10000 mPa s to about 11000 mPa s.

294. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 11000 mPa s to about 12000 mPa s.

295. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 12000 mPa s to about 13000 mPa s.

296. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 13000 mPa s to about 14000 mPa s.

297. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 14000 mPa s to about 15000 mPa s.

298. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 15000 mPa s to about 16000 mPa s.

299. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 16000 mPa s to about 17000 mPa s.

300. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 17000 mPa s to about 18000 mPa s.301 . The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 18000 mPa s to about 19000 mPa s.

302. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 19000 mPa s to about 20000 mPa s.

303. The pharmaceutical composition of any one of claims 165 to 273, wherein the pharmaceutical composition exhibits a complex viscosity of from about 7000 mPa s to about 20000 mPa s.

304. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 7500 mPa s.

305. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 8000 mPa s.

306. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 8500 mPa s.

307. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 9000 mPa s.

308. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 9500 mPa s.

309. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 10000 mPa s.

310. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 10500 mPa s.

311. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 11000 mPa s.

312. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 11500 mPa s.

313. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 12000 mPa s.

314. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 12500 mPa s.

315. The pharmaceutical composition of any one of claims 165 to 261 , wherein the pharmaceutical composition exhibits a complex viscosity of about 13500 mPa s.

316. The pharmaceutical composition of any one of claims 165 to 315, wherein the storage modulus of the pharmaceutical composition is from about 50000 mPa to about 200000 mPa.

317. The pharmaceutical composition of any one of claims 165 to 316, wherein the loss modulus of the pharmaceutical composition is from about 20000 mPa about 100000 mPa.

318. The pharmaceutical composition of any one of claims 165 to 317, wherein the storage modulus of the pharmaceutical composition is greater than the loss modulus of the pharmaceutical composition at 1 unit of applied strain.

319. The pharmaceutical composition of any one of claims 165 to 318, wherein the pharmaceutical composition is a topical pharmaceutical composition.

320. The pharmaceutical composition of any one of claims 165 to 319, wherein the pharmaceutical composition is in the form of an ointment, cream, lotion, gel, oil, liniment, semisolid, or liquid.321 . The pharmaceutical composition of any one of claims 165 to 320, further comprising a wound dressing.

322. The pharmaceutical composition of claim 321 , wherein the wound dressing comprises one or more of a bandage, a pad, a particle, a paste, a sheet, a solution, netting, gauze, collagen, foam, hydrocolloid, or hydrogel.

323. The pharmaceutical composition of claim 322, wherein the wound dressing comprises a hydrogel, wherein the hydrogel comprises a hydrogel sheet, an amorphous hydrogel, and / or an impregnated hydrogel.

324. The pharmaceutical composition of any one of claims 321 to 323, wherein the wound dressing comprises a bandage.

325. The pharmaceutical composition of any one of claims 321 to 324, wherein 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.

326. The pharmaceutical composition of any one of claims 165 to 324, wherein the pharmaceutical composition is used for the treatment of a skin wound.

327. The pharmaceutical composition of claim 326, wherein 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, atelangiectasia, a burrow, scale, crust, lichenification of the skin, an abrasion, an induration, a burn, a rash, a sore, dermal fibrosis, scleroderma, vasculitis, or atrophy.

328. The pharmaceutical composition of claim 326, wherein the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer.

329. The pharmaceutical composition of claim 328, wherein the skin wound is a diabetic foot ulcer.

330. The pharmaceutical composition of claim 327, wherein the skin wound is an infection, and the infection is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.331 . The pharmaceutical composition of claim 327 wherein the skin wound is inflammation, further wherein the inflammation is eczema.

332. The pharmaceutical composition of any one of claims 165 to 331 , wherein the composition is characterized by the release of at least 90% of the insulin of the formulation within one minute with mixing at room temperature in phosphate buffered saline (PBS).

333. A pharmaceutical composition comprising 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).

334. The pharmaceutical composition of claim 333 wherein the complex viscosity is about 14000 mPa s.

335. The pharmaceutical composition of claim 333 or claim 334, wherein 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.

336. The pharmaceutical composition of claim 335 wherein the wound closure ratio at day 9 after the application is about the same as that of insulin alone.

337. The pharmaceutical composition of any one of claims 333 to 336, wherein the composition comprises 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.

338. The pharmaceutical composition of any one of claims 333 to 337, wherein 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, and the surfactant is poloxamer 407.

339. A pharmaceutical composition comprising: a) insulin; b) poloxamer 407; c) glycerin or a pharmaceutically acceptable salt thereof; d) hyaluronic acid or a pharmaceutically acceptable salt thereof; e) Noveon® AA-1 Polycarbophil USP; and f) water.

340. The pharmaceutical composition of claim 339, wherein the composition is: a) from about 0.05 to about 200 units of insulin per 10 g of the composition; b) from about 1 wt% to about 50 wt% poloxamer 407; c) from about 0.1 wt% to about 5 wt% glycerin or a pharmaceutically acceptable salt thereof; d) from about 0.001 wt% to about 5 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof; e) from about 0.1 wt% to about 5 wt% hyaluronic acid Noveon® AA-1 Polycarbophil USP; and f) the rest of the composition is water.341 . The pharmaceutical composition of claim 339 or claim 340, wherein the composition is: a) 50 units of Novalin 70 / 30 insulin per 10 grams of the composition; b) 10 wt% poloxamer 407; c) 1 wt % glycerin or a pharmaceutically acceptable salt thereof; d) 0.05 wt% hyaluronic acid or a pharmaceutically acceptable salt thereof; e) 1 wt% Noveon® AA-1 Polycarbophil USP; and f) the rest of the composition is water.

342. The pharmaceutical composition of any one of claims 339 to 341 , wherein the composition is further characterized by a viscosity from about 7000 mPa s to about 20000 mPa s.

343. The pharmaceutical composition of any one of claims 339 to 342, wherein the composition is an ointment, cream, lotion, gel, oil, liniment, or liquid.

344. The pharmaceutical composition of any one of claims 339 to 343, wherein the composition is used to treat a diabetic foot ulcer.

345. A method of treating a skin wound in a human subject in need of treatment comprising: a) determining the subject has a skin wound; andb) administering the topical formulation of any one of claims 1 to 164, or the pharmaceutical composition of claims 165 to 344.

346. A method of treating a skin wound in a human subject that has been diagnosed to have a skin wound, the method comprising administering the topical formulation of any one of claims 1 to 164, or the pharmaceutical composition of claims 165 to 344.

347. A method of treating a skin wound in a human subject in need of treatment comprising: a) determining the subject has a skin wound; and b) administering a pharmaceutical composition to the subject comprising: insulin, polycarbophil, glycerin, hyaluronic acid, poloxamer 407, and water.

348. A method of treating a skin wound in a human subject that has been diagnosed to have a skin wound, the method comprising administering a pharmaceutical composition to the subject comprising: insulin, polycarbophil, glycerin, hyaluronic acid, poloxamer 407, and water.

349. The method of any one of claims 345 to 348, wherein the skin wound further comprises 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.

350. The method of any one of claims 345 to 349, wherein 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.351 . The method of claim 350, wherein the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer.

352. The method of claim 351 , wherein the skin wound is a diabetic foot ulcer.

353. The method of claim 350, wherein the skin wound is an infection, and the infection is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.

354. The method of claim 350 wherein the skin wound is inflammation, further wherein the inflammation is eczema.

355. The method of any one of claims 345 to 354, further comprising applying the composition to the skin wound over the course of a treatment period.

356. The method of claim 355, wherein the composition is applied to the skin wound in multiple doses over the course of a treatment period.

357. The method of any one of claims 345 to 356, further comprising applying the composition to the skin wound one or more times per day over the course of a treatment period.

358. The method of any one of claims 345 to 356, further comprising applying the composition to the skin wound one or more times per week over the course of a treatment period.

359. The method of any one of claims 345 to 356, further comprising applying the composition to the skin wound one or more times per month over the course of a treatment period.

360. The method of any one of claims 357 to 359, wherein the treatment period has a duration of about one day to about one year.361 . The method of any one of claims 357 to 360, wherein the treatment period has a duration of about one month to about 11 months.

362. The method of any one of claims 357 to 361 , wherein the treatment period has a duration of about three months to about nine months.

363. The method of any one of claims 357 to 362, wherein the treatment period has a duration of about six months.

364. The method of any one of claims 345 to 363, wherein the subject is diagnosed as having either type I diabetes mellitus, type II diabetes mellitus, or a diabetes associated condition or disorder.

365. The method of any one of claims 345 to 364, wherein upon administration of the composition to the subject, the subject exhibits partial or complete healing of the skin wound.

366. The method of claim 365, wherein partial to complete healing occurs within 90 days.

367. The method of claim 365 or claim 366, wherein partial to complete healing occurs within 60 days.

368. The method of any one of claims 365 to 367, wherein partial to complete healing occurs within 30 days.

369. A kit comprising the formulation of any one of claims 1 to 164 or the pharmaceutical composition of any one of claims 165-344 and a package insert.

370. The kit of claim 369, wherein the package insert instructs a user of said kit to administer the pharmaceutical composition to a subject suffering from a skin wound.371 . The kit of claim 370, wherein 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.

372. The kit of claim 371 , wherein the skin wound is an ulcer, wherein the ulcer is selected from a venous leg ulcer, a diabetic foot ulcer, or a decubital ulcer.

373. The kit of claim 372, wherein the skin wound is a diabetic foot ulcer.

374. The kit of claim 371 , wherein the skin wound is an infection, and the infection is a bacterial infection, a viral infection, a fungal infection, or a parasitic infection.

375. The kit of claim 371 wherein the skin wound is inflammation, further wherein the inflammation is eczema.

376. The kit of any one of claims 369 to 375, wherein the package insert instructs a user of said kit to administer the pharmaceutical composition topically to the skin wound.

377. The kit of any one of claims 369 to 375, wherein the package insert instructs the user to administer the pharmaceutical composition to the skin wound one or more times per day.

378. The kit of any one of claims 369 to 375, wherein the package insert instructs the user to administer the pharmaceutical composition one or more times per week.

379. The kit of any one of claims 369 to 375, wherein the package insert instructs the user to administer the pharmaceutical composition one or more times per month.