WO2016123317A1

WO2016123317A1 - Topical formulations of growth factors

Info

Publication number: WO2016123317A1
Application number: PCT/US2016/015326
Authority: WO
Inventors: Stephen I. HSU; Hua YAO; Carl Grant MANGLEBURG
Original assignee: Prometheon Pharma, Llc
Priority date: 2015-01-28
Filing date: 2016-01-28
Publication date: 2016-08-04
Also published as: TW201636045A

Abstract

Provided herein are compositions, methods of treatment using such compositions, and methods of making such compositions wherein the compositions comprise a large molecule. The compositions, and devices and kits comprising such compositions provide new and useful improvements as alternatives for addressing diseases, disorders and symptoms thereof in a subject.

Description

Topical Formulations of Growth Factors

The transdermal patch segment of the pharmaceutical industry currently commands a relatively small share of the rapidly growing global drug delivery market ($21.5 billion in 2010, projected growth to $31.5 billion by 2015). Approved patches are currently available for drugs with properties that lend themselves to passive permeation across the skin when applied topically such as estrogen, nicotine, nitroglycerin, scopolamine, fentanyl and clonidine.

To date, patch-based penetration enhancement formulations have been limited to delivering small chemical drugs below a molecular weight size of 500 daltons (the so-called "rule of 500") due to the physical constraints of effectively transporting large water-soluble compounds across the thick, keratin-rich, armor-like outer layer of skin (stratum corneum). The underlying cellular layers that comprise the viable epidermis, also present a rate-limiting barrier to transdermal drug delivery after successful penetration of the stratum corneum. The barrier to drug diffusion across the epidermis is probably the presence of tight junctions. Removal of the full epidermis increased skin permeability by 1-2 orders of magnitude depending on the molecule delivered.

Currently, there is a need for improved delivery of large molecular weight molecules across skin and both locally and systemically in order to address diseases, disorders, and symptoms thereof in patients in need.

SUMMARY

Provided herein are compositions, methods of treatment using such compositions, and methods of making such compositions wherein the compositions comprise one or more large molecules (e.g. peptides or proteins). The compositions, and devices and kits comprising such compositions provide new and useful improvements as alternatives for addressing diseases, disorders and symptoms thereof in a subject.

One aspect is a composition comprising propylene glycol (PG), poloxamer 188 (P188), laurocapram (LP) and insulin-like growth hormone 1 (IGF-1). Another aspect is a composition comprising propylene glycol (PG), poloxamer 188 (P188), and insulin-like growth hormone 1 (IGF-1). The composition is any herein wherein:

the ratio of propylene glycol (PG) poloxamer 188 (P188), and laurocapram (LP) is 49:39: 12 (by weight);

the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 53:42:5 (by weight);

the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 55:43:2 (by weight);

the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 56:44:0 (by weight);

the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is

40-60:40-60:0-12 (by weight);

the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 20-80:20-80:0-20 (by weight);

the IGF-1 is lyophilized IGF-1;

the IGF-1 is present in a range of 0.001-10 mg/50 μί;

further comprising human growth hormone (hGH);

the hGH is present in a range of 0.001-10 mg/50 μί;

the composition herein that is devoid of laurocapram; the permeation of therapeutic agent (e.g., IGF-1) through EpiDermFT is at least 0.1 μg /cm²/hr 168, 144, 120, 96, 72, 48, or 24 hours after initial administration;

wherein the administration of IGF-1 is provided at a rate that provides the permeation of IGF-1 through EpiDermFT™ at least 0.1 μg /cm²/hr 168, 144, 120, 96, 72, 48, or 24 hours after initial administration;

the IGF-1 is administered such that serum IGF-1 accumulation of at least 5-200 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);

the IGF-1 is administered such that serum IGF-1 accumulation of at least 10-150 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);

the IGF-1 is administered such that serum IGF-1 accumulation of at least 5-100 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);

the IGF-1 is administered such that serum IGF-1 accumulation of at least 10-125 ng/mL is achieved over 24-168 consecutive hours (e.g., 168, 144, 120, 96, 72, 48, or 24 hours);

the IGF-1 is administered at a dosage of 0.01-100 mg/day;

the IGF-1 is administered at a dosage of 0.1-50 mg/day;

the IGF-1 is administered at a dosage of 0.01-15 mg/day.

the composition herein that is devoid of laurocapram.

Another aspect is a kit comprising a composition herein and a device for topical administration of the composition herein. In other aspects, the kit is that wherein:

the device is a patch; the composition herein is in solid form;

the composition herein is in gel form;

the patch further comprises an adhesive material;

the patch further comprises a cover material to protect the composition herein during shipping and storage;

the patch is 1 x 1 (cm x cm) to 8 x 8 (cm x cm);

the patch is 1 x 1, 2 x 2, 3 x 3, 4 x 4, 5 x 5, 6 x 6, 7 x 7, or 8 x 8 (cm x cm).

Another aspect is a device comprising a composition herein and a patch. In other aspects, the device is that wherein:

the patch comprises a backing;

the patch comprises an adhesive;

the patch comprises a laminate coated with a composition;

the patch comprises a release liner;

the patch comprises the composition herein in solid form;

the patch comprises the composition herein in gel form;

the patch is 1 x 1 (cm x cm) to 8 x 8 (cm x cm);

Accumulation of active agent via sustained release patch can be calculated based on the steady-state flux rate across a surface area of 0.6 cm into a total receptor volume of 2.5 ml. For example, at the minimum dose of 0.005 mg/0.6 cm associated with a steady-state

2 2

flux rate of 0.1 μg/cm /hr, accumulation across a 0.6 cm area in the first 24 hrs is: (0.1 μg/cm²/hr) x 0.6 cm² x 24 hr/2.5 ml = 0.576 μg/ml. After 168 hrs, the cumulative accumulation is: (0.1 μg /cm²/hr) x 0.6 cm² x 168 hr/2.5 ml = 4.032 μg/ml. In an aspect, the device (e.g., topical patch or gel) provides a steady-state flux

(permeation) of active agent at a constant rate. At a minimum steady-state flux of 0.1 μg/cm 2 /hr over a surface area of 0.6 cm 2 , 1.44 μg is delivered in 24 hours. The rate remains the same during each consecutive 24 hours (1 day) for up to 7 days because the receptor fluid from the previous 24 hours is completely removed and replaced with the same volume of fresh receptor fluid. So, whether 24 or 168 hours after administration, the steady-state flux remains the same. This model not only assesses transdermal transport as a measure of accumulation of permeant as a function of time to demonstrate constant and consistent delivery (curve should be linear; slope defines dose-response). It is also a model that reflects 100% metabolism and elimination each 24 hours because receptor fluid is completely replenished at each sampling time (24 hours), as required under "sink" conditions for the calculation of steady state flux using Fick's first law of diffusion.

Another aspect is a composition disclosed herein for continuous or intermittent topical administration and transdermal delivery of large molecule perishable drugs (e.g. peptides or proteins) useful for enhancing or promoting local hair thickness or fullness. It may also be useful for enhancing or promoting local hair growth in all forms of alopecia (e.g.

andro genetic alopecia, chemotherapy-induced alopecia, etc.) through local effects on hair follicles. In one aspect the composition described herein is in solid form. In another aspect, the composition described herein is in gel form.

Another aspect is a method for the delivery of compositions disclosed herein for continuous or intermittent topical administration and transdermal delivery of large molecule perishable drugs (e.g. peptides or proteins) useful for promoting or enhancing local hair fullness or thickness, or hair growth in all forms of alopecia through local effects on hair follicles (e.g. androgenetic alopecia, chemotherapy-induced alopecia, etc.) comprising administration of any composition herein to the subject. The method can include continuous or intermittent administration of the composition over any appropriate time interval.

Another aspect is a method for the delivery of compositions disclosed herein for treating hormone deficiency in a subject comprising administration of a composition herein to the subject. In aspects, the method is that wherein:

the administration is topically;

the administration of IGF- 1 is provided at a rate that provides the permeation of IGF- 1 through EpiDermFT™ at at least 75 ng/cm 24 hours after initial administration;

the administration of IGF- 1 is provided at a rate that provides the permeation of IGF- 1 through EpiDermFT™ at at least 75 ng/cm 48 hours after initial administration;

the administration of IGF- 1 is provided at a rate that provides the permeation of IGF- 1 through EpiDermFT™ at at least 200 ng/cm 72 hours after initial administration;

the composition is in solid form;

the composition is in gel form.

In other aspects, the method is that wherein: the administration is topically via a thin layer of gel applied over the affected skin surface area of the body including but not limited to the scalp, eyebrows, axilla, and pubic area for enhancing or promoting local hair thickness or fullness. It may also be useful for enhancing or promoting local hair growth in all forms of alopecia (e.g. androgenetic alopecia, chemotherapy-induced alopecia, etc.) through local effects on hair follicles present in areas of the body including but not limited to the scalp, eyebrows, axilla, and pubic area; the IGF-1 is administered at a range of 0.0001-100 ppm; the administration of IGF-1 is via a gel applied to the affected area for 6-12 hours/day; the administration of IGF-1 is via a gel applied to the affected area once every 1-7 days; the administration of IGF- 1 is via a gel applied to the affected area once every other day;

the administration of IGF- 1 is via a gel applied to the affected area once every two- three days;

the administration of IGF- 1 is via a gel applied to the affected area once daily every other day or three times weekly;

the administration of IGF-1 is via a gel applied to the affected area as continuous once daily therapy;

the administration of IGF- 1 is via a gel applied to the affected area for a treatment cycle (e.g., days or weeks), separated by a no-treatment period (e.g., days or weeks);

the administration of IGF- 1 is via a gel applied to the affected area for a treatment cycle of 1-12 consecutive weeks, separated by a no-treatment period of 1-12 consecutive weeks;

the device is a pre-measured volume dispensed as a single-use gel packet;

the composition herein is in solid form;

the composition herein is in gel form;

the gel packet further comprises a cover material to protect the composition herein during shipping and storage;

the gel packet is 1 cm 2 to 100 cm 2 ;

Another aspect is a device comprising a gel composition herein and a packet. The packet is a package or container (e.g., bag, pouch, etc.) made of a material suitable for containing the gel composition for transport or storage. In other aspects, the device is that wherein: the gel packet comprises a pre-measured volume for single-use;

the gel packet comprises the composition herein in solid form;

the gel packet comprises the composition herein in gel form;

the gel packet is 1 cm 2 to 100 cm 2 ;

the gel packet is between about 1 and about 100 square centimeters in size, including range of integers (e.g., 1-10, 5-50, 50-100, etc.), or any integer between about 1 and about 100 the gel packet can be between about 1 and about 25 cubic centimeters in size.

The therapeutic-agent-containing formulation can include a thermo- sensitive polymer. In some embodiments, the thermo- sensitive polymer can include a poloxamer or a

poloxamine. The poloxamer can be poloxamer 188.

The device (e.g., a patch or topical gel) can comprise a dermoadhesive agent. The dermoadhesive agent in the therapeutic-agent-containing formulation can be selected from the group including propylene glycol, dipropylene glycol, polyethylene glycol, glycerine, butylene glycol, glycol derivatives with glycerol esters, and non-ionizable glycol ether derivatives.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 showing dose-response of optimized IGF-1 Topicon™ formulations across a full thickness metabolically active human skin equivalent achieved as a determinant of dose (mg/0.6 cm²).

FIG. 2 showing that cell viability of tissues treated with optimized IGF-1 Topicon by MTT assay is not dose-dependent. FIG. 3 showing that cell viability of tissues treated with optimized IGF-1 Topicon by MTT assay is not time-dependent.

FIG. 4 shows the results of local topical application of an optimized IGF-1 Topicon gel compared to minoxidil in stimulating and maintaining hair growth in hairless CD rats.

DEFINITIONS

This disclosure can be better understood with reference to the following definitions: As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

As used herein, the terms "comprises," "comprising," "containing," "having," and the like can have the meaning ascribed to them under U.S. patent law and can mean "includes," "including," and the like.

Unless specifically stated or obvious from context, the term "or," as used herein, is understood to be inclusive.

The term "perforation" shall be understood to refer to a series of holes made into a material that allows easy separation of two sections of the material. The holes may be circular or may be elongated. The process of creating perforations involves puncturing the material with a tool. Perforations can be formed by a hole punch or a cutting edge that includes "nicks," (i.e., indentations) where the two sections of the material are not separated. Alternately, perforations can be made by a cutting wheel or a grinding wheel that includes nicks in the wheel's circumference.

Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (as well as fractions thereof unless the context clearly dictates otherwise).

DETAILED DESCRIPTION OF THIS DISCLOSURE

At least one embodiment of this disclosure provides co-polymer/enhancer formulations for passive topical and transdermal delivery of large molecule drugs for local or systemic therapy. Advantageously, in the preferred embodiments, the co -polymer/enhancer formulations disclosed herein are comprised of individual components generally regarded as safe (GRAS) and are thermo-sensitive, or dermoadhesive, and enhance the penetration of therapeutics across skin or other surfaces. The individual components may possess two or more of these three properties (primary, secondary and/or tertiary properties). The co- polymer/enhancer formulations can be embodied as a passive transdermal delivery patch that delivers one or more therapeutics continuously for up to 7 days or more. Also provided are therapeutic uses of the co-polymer/enhancer co-polymer/enhancer formulations for non- invasive, needle-free delivery of large peptide drugs including but not limited to IGF-1, hGH, etc.

In a preferred embodiment, the delivery system comprises co-polymers of poloxamer 188 (P188) and propylene glycol (PG), the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration- enhancing peptides), and one or more therapeutic agents. In a preferred embodiment, the delivery formulation disclosed herein can be used for transdermal delivery of large molecule perishable drugs (e.g. peptides or proteins) into the systemic circulation useful for enhancing or promoting growth or other clinical conditions associated with IGF-1 deficiency in a subject.

In a preferred embodiment, the delivery system comprises co-polymers of poloxamer

188 (P188) and propylene glycol (PG), and optionally, other classes of penetration-enhancing compounds (including short penetration-enhancing peptides), and one or more therapeutic agents. In a preferred embodiment, the delivery formulation disclosed herein can be used as a gel for continuous or intermittent topical application and transdermal delivery (repeatedly over same site) of large molecule perishable drugs (e.g. peptides or proteins) useful for enhancing or promoting local hair growth in all forms of alopecia through local effects on hair follicles (e.g. androgenetic alopecia, chemotherapy-induced alopecia, etc.).

In a preferred embodiment for systemic delivery, the delivery system comprises copolymers of poloxamer 188 (P188) and propylene glycol, the penetration-enhancer laurocapram (Azone) and, optionally, other classes of penetration-enhancing compounds (including short penetration-enhancing peptides), and one or more therapeutic agents.

In a preferred embodiment for local topical delivery (e.g. IGF-1 gel for therapy of alopecia), the delivery system comprises co-polymers of poloxamer 188 (P188) and propylene glycol and, optionally, other classes of penetration-enhancing compounds (including short penetration-enhancing peptides), and one or more therapeutic agents. In one embodiment, the delivery system comprises (or consisting essentially of) co-polymers of poloxamer 188 (P188) and propylene glycol and one or more therapeutic agents (e.g., IGF-1, hGH). In one embodiment, no azone is used in the formulation because repeated application of azone to the same skin site, e.g., for treatment of alopecia, could be irritating to the site of administration and the subject. The doses of composition used for local topical administration, as well as the number of administrations, can be varied according to various parameters, and especially as a function of the method of administration used, severity of the hair loss (e.g., alopecia), age of patients, or alternatively of the desired duration of treatment. The methods for administration herein include wherein the topical application is administered in periodically (e.g., chronically, over years, months, weeks, days, hours) regularly or irregularly (i.e., with intermittent alternating treatment/non-treatment ("rest") periods).

The co-polymer/enhancer formulations disclosed herein are thermo-sensitive; that is, solid at room temperature for ease of application, for example, to the skin (30-32° C) or insertion into the vaginal canal to coat the cervical transformation zone (core body temperature of 37° C), and transition (melt) to a gel or liquid phase at these physiological temperatures. The co-polymer ratio between poloxamer 188 and propylene glycol may be altered to define the transition temperature. For example, a co-polymer/enhancer formulation comprised of 44% poloxamer 188 and 56% propylene glycol may determine a solid-to-gel transition at skin temperature 30-32° C, while a co-polymer/enhancer formulation comprised of 70% poloxamer 188 and 30% propylene glycol) may determine a solid-to-gel transition at core body temperature of 37° C. Furthermore, the co -polymer/enhancer formulations in gel or liquid phase adhere to and enhance large and small molecule penetration across the skin or mucosa.

Advantageously, the co-polymer/enhancer formulations disclosed herein allow for non-invasive, targeted delivery of therapeutics across the skin and mucosal surfaces. Additionally, the present co-polymer/enhancer formulations use safe, inexpensive ingredients, are easy to administer and are suitable for use in a wide range of clinical settings. The co-polymer/enhancer formulations can easily be administered by healthcare workers or by self-administration by the patient, and under conditions of extreme temperature, high humidity, poor lighting, lack of space or lack of adequate supply of electricity or water.

Co-Polymer/Enhancer Formulation for Topical Delivery of Therapeutic Compounds

One aspect of this disclosure provides co-polymer/enhancer formulations for topical delivery of therapeutics. Advantageously, the co-polymer/enhancer formulations of this disclosure are thermo- sensitive, mucoadhesive or dermoadhesive, and enhance the penetration of therapeutics across the full thickness of the skin or mucosal surfaces.

In one embodiment, the novel topical delivery formulation comprises a thermo- sensitive polymer, a mucoadhesive or dermoadhesive agent, a penetration enhancer and, optionally, one or more therapeutic agents (e.g., large molecule therapeutic agent, growth factor).

In one embodiment, the co-polymer/enhancer formulation comprises co-polymer of one or more thermo-sensitive polymers, one or more mucoadhesive or dermoadhesive agents and one or more penetration-enhancing agents. In a preferred embodiment, the co- polymer/enhancer formulation comprises co-polymer of poloxamer 188 and propylene glycol, the penetration-enhancer laurocapram and, optionally, one or more therapeutic agents.

In one embodiment, the co-polymer/enhancer formulation comprises one or more polymeric materials including, but not limited to, poloxamer and poloxamine. Poloxamers useful according to this disclosure include, but are not limited to, poloxamer 188, 407, 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, and 403. Poloxamines useful according to this disclosure include, but are not limited to, poloxamine 304, 504, 701, 702, 704, 707, 901, 904, 908, 1101, 1102, 1104, 1301, 1302, 1304, 1307, 1501, 1502, 1504, and 1508. In certain embodiments, the co-polymer/enhancer formulation can comprise one or more polymeric materials including, but not limited to, polylactic acid and copolymers, polyvinyl acetate, celluloses and derivatives (such as carboxymethyl cellulose, cellulose acetate, cellulose acetate propionate, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyalkyl methyl celluloses and alkyl celluloses), crosslinked dextrans, polyethylene glycol, diethylaminoethyl dextran, poly(cyanoacrylates), copolymers of PEG and PLA, poly(lactic-co-glycolic acid), poly(ortho esters) and hydrogels. Preferably, the polymeric material is pharmaceutically-acceptable, biodegradable, mucoadhesive or dermoadhesive and/or enhances the penetration of therapeutics across the skin and/or mucosal surface.

In one embodiment, the co-polymer/enhancer formulation further comprises one or more mucoadhesive or dermoadhesive agents. In one embodiment the mucoadhesive or dermoadhesive agent promotes adhesion of the co-polymer/enhancer formulation to the skin or mucosa membranes. Preferably, the mucoadhesive or dermoadhesive agent also enhances the penetration of therapeutics across the skin and/or mucosal surface.

Mucoadhesive or dermoadhesive agents useful according to this disclosure include, but are not limited to, polyols such as, propylene glycol, dipropylene glycol, polyethylene glycol, glycerine and butylene glycol; glycol derivatives with glycerol esters, such as, oleic acid esters of propylene glycol; and non-ionizable glycol ether derivatives, such as, ethoxydiglycol.

Mucoadhesive or dermoadhesive agents useful according to this disclosure, can also include polymers such as, polyethylene glycol caprylic/capric glycerides; vinyl polymers (e.g., polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate, polyvinyl alcohol and polyvinyl pyrrolidone); cellulosic derivatives, such as, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and carboxymethyl cellulose; polysaccharides, such as, alginic acid and sodium alginate. In one embodiment, the topical delivery formulation further comprises one or more penetration enhancers. Penetration enhancers useful according to this disclosure include, but are not limited to, laurocapram, diethylene glycol, monoethyl ether, n-decyl methyl sulfoxide, dimethyl sulfoxide, dimethylacetamidedimethylformamide, sucrose monooleate, amides and other nitrogenous compounds (e.g., urea, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine), organic acids (e.g., citric acid and succinic acid), N-methyl-2-pyrrolidine, borage oil, tetrahydropiperine (THP), alcohols (e.g., methanol, ethanol, propanol, octanol, benzyl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol), fatty acids (e.g., oleic acid), fatty acid esters (e.g., isopropyl myristate, isopropyl palmitate), polyols (e.g., propylene glycol, polyethylene glycol, glycerol), polyethylene glycol monolaurate and lecithin.

Preferably, the co-polymer/enhancer formulation is solid or semi-solid at room temperature, begins to melt at temperatures slightly below, and completely melts at physiological temperatures. Generally, room temperature is below 30 °C, below 28 °C, below 25 °C, below 23 °C, below 20 °C, or below 18 °C.

In certain embodiments, the co-polymer/enhancer formulation melts, or begins to melt, at a temperature ranging from about 30 °C to 42 °C, 32 °C to 40 °C, 33 °C to 40 °C, 35 °C to 38 °C, or 34 °C to 37 °C. In certain embodiments, the co-polymer/enhancer formulation melts, or begins to melt, at a temperature above 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, or 37 °C. In certain embodiments, the biopolymer formulation melts, or begins to melt, at a temperature below 45 °C, 44 °C, 43 °C, 42 °C, 41 °C, 40 °C, 39 °C, 38 °C, 37 °C, 36 °C, 35 °C, or 34 °C.

The desired thermal property of the co-polymer/enhancer formulation can be achieved by adjusting the relative ratio (e.g., in terms of weight percentages or molar amounts) of various ingredients including, the thermo- sensitive polymeric material, the mucoadhesive agent, the penetration enhancer and/or the therapeutic agent.

In certain embodiments, the co-polymer/enhancer formulation comprises a thermo- sensitive polymeric material at a weight percentage of about 20% to about 95%, about 25% to about 90%, about 30% to about 85%, about 35% to about 80%, about 40% to about 70%, about 50% to about 90%, about 50% to about 85%, about 60% to about 80%, about 30% to about 40%, about 30% to about 50%, about 70% to about 90%, about 70% to about 85% or about 70% to about 80%.

In certain embodiments, the co-polymer/enhancer formulation comprises a mucoadhesive or dermoadhesive agent at a weight percentage of about 5% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 20%, about 5% to about 30%, about 5% to about 20%, about 5% to about 15% or about 15% to about 30%.

In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration ranging from about 1 to about 10 %, about 2 to about 9%, about 3 to about 8%, about 4 to about 7%, or about 2 to about 5% by weight

In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration above 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% or 30% by weight.

In certain embodiments, the co-polymer/enhancer or co-polymer/retardant formulation comprises a penetration enhancer or penetration retardant, respectively, at a concentration below 70%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6% or 5% by weight.

In certain specific embodiments, the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 100:0, 90: 10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 0:100. In preferred embodiments, the co- polymer/enhancer formulation comprises poloxamer 188 and propylene glycol at a ratio (w/w) of about 70:30 (37 °C or core body temperature) or 44:56 (30-32 °C or skin temperature). In certain embodiments, the co-polymer/enhancer formulation comprises no laurocapram.

In certain embodiments, the co-polymer/enhancer formulation comprises laurocapram at a concentration of about 1 to about 12 %, about 2 to about 11%, about 3 to about 10%, about 4 to about 9%, or about 2 to about 6% by weight. In one embodiment, the co- polymer/enhancer formulation comprises about 2% laurocapram.

In certain specific embodiments, the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol (combined) at a ratio (w/w) of about 100-0, and the enhancer at a ratio (w/w) of about 0: 100, wherein the total equals 100. In certain specific embodiments, the co-polymer/enhancer formulation comprises poloxamer 188 and propylene glycol (combined) at a ratio (w/w) of about 100-0: 100-0, wherein the total equals 100. For example, an embodiment where propylene glycol (PG) and poloxamer 188 (P188) is recited as 100-0:0-100 (by weight), includes specific embodiments such as, for example, 60 (PG): 40 (P188); 45 (PG): 55 (P188); 55 (PG): 45 (P188); 40 (PG): 60 (P188); or 56 (PG): 44(P188). For example, an embodiment where propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is recited as 20-80:20-80:0-20 (by weight), includes specific embodiments such as, for example, 49 (PG): 39 (P188): 12 (LP); or 50 (PG): 40 (P188): 10 (LP); or 56 (PG): 44 (P188): 0 (LP). In a preferred embodiment for transdermal patch delivery of IGF- 1 into the systemic circulation for hormone replacement therapy or transdermal gel delivery of IGF-1 for local topical application useful for enhancing or promoting local hair growth in all forms of alopecia through local effects on hair follicles (e.g. androgenetic alopecia, chemotherapy- induced alopecia, etc.), the co-polymer/enhancer formulation comprises 0% laurocapram. In a preferred embodiment for transdermal patch co-delivery of IGF-1 and hGH into the systemic circulation for hormone replacement therapy, the co -polymer/enhancer formulation comprises 12% laurocapram.

The co-polymer/enhancer formulation can be used for topical delivery of a variety of small or large therapeutic agents not previously achieved using penetration enhancers including, but not limited to, large peptides and proteins, nucleic acids, compounds with unique physicochemical structures and/or properties not considered amenable to passive transdermal or transmucosal delivery. The peptides and proteins suitable for use in the compositions and methods herein can be those having under 5000 amino acids (aa), under 1000 amino acids (aa), under 500 amino acids (aa), under 100 amino acids (aa), under 50 amino acids (aa), over 5000 amino acids (aa), over 1000 amino acids (aa), over 500 amino acids (aa), over 100 amino acids (aa), or over 50 amino acids (aa).

In one embodiment, hormones can include any human hormone, e.g., including but not limited to human insulin-like growth factor 1 (IGF-1), or human growth hormone (hGH). In one embodiment, hormones can include any non-human or animal hormone, e.g., including but not limited to hormones or growth factors suitable for veterinary use, e.g., bovine growth hormone.

In certain embodiments, the co-polymer/enhancer formulation comprises laurocapram at a concentration of about 0.1 M to about 1 M, about 0.2 M to about 0.9 M, about 0.3 M to about 0.8 M, about 0.4 M to about 0.7 M or about 0.2 M to about 0.5 M. In a preferred embodiment, the co-polymer/enhancer formulation comprises about 0.4 M laurocapram.

In certain embodiments, the co-polymer/enhancer formulation comprises a therapeutic agent at a concentration ranging from about 0.1 mM to about 3 mM, about 0.1 mM to about 2 mM, about 1 mM to about 1.5 mM, about 0.5 mM to about 2 mM, or about 0.5 mM to about 1.5 mM. Amounts of therapeutic agents incorporated into co-polymer/enhancer formulations disclosed herein can also be determined by those skilled in the art (e.g., based upon age, bioavailability of a therapeutic agent, etc.) such that the therapeutic agent is delivered to a subject in amounts that effect a local or systemic therapeutic benefit to the subject.

In one embodiment the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation of this disclosure using any standard topical patch design or variations thereof, having in common the direct application (bio-interface) with the skin or mucosal surface. In a specific embodiment the method comprises administering, to skin or mucosal surface of a subject, a co-polymer/enhancer formulation comprising poloxamer 188 and propylene glycol, laurocapram and, optionally, one or more therapeutic agents.

The term "subject," as used herein, describes an organism, including mammals such as primates, to which treatment with the formulations according to the subject disclosure can be provided. Mammalian species that can benefit from the disclosed methods of treatment include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and domesticated animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters.

In certain embodiments the co-polymer/enhancer formulation of this disclosure is administered to skin or mucosal surfaces including, but not limited to, cervix, vagina, anus, rectum, eye, ear, nose, thorax, vulva, larynx, and head and neck. Embodiments of this disclosure allow for topical delivery of therapeutics across the full-thickness skin barrier including the keratinized apical layer of skin (stratum corneum), the epidermal cell layer, and the dermis, and/or mucosa. At least one embodiment allows for topical delivery of therapeutics across non-keratinized surface of skin and/or mucosa. At least one embodiment allows for topical delivery of therapeutics into, or across, multiple layers of cervical squamous epithelial cells. At least one embodiment allows for topical delivery of therapeutics to the basal keratinocytes of skin and/or mucosa.

At least one embodiment can be used as a non-invasive topical transdermal or transmucosal delivery system (or device) applied to normal skin or mucosal surfaces to obviate the need for subcutaneous injection of therapeutic compounds. A patch for topical transdermal delivery of a composition herein can include any suitable material (e.g., transdermal system, backings, liners, membranes and tapes, and the like) well known in the transdermal delivery art. Such materials are commercially available from various sources and known in the art. See for example, those available from Tapemark, St. Paul, MN.

Other aspects useful in application of this technology and embodiments herein are described in International Patent Application No. PCT/US2014/030259 incorporated by reference.

Formulations and Formulations for Topical Administration

The subject disclosure also provides for therapeutic or pharmaceutical formulations comprising the co-polymer/enhancer formulation in a form that can be combined with a pharmaceutically acceptable carrier. In a preferred embodiment the therapeutic or pharmaceutical formulation is solid at room temperature and transitions to a gel or liquid at desired physiological temperatures.

The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum oil such as mineral oil, vegetable oil such as peanut oil, soybean oil and sesame oil, animal oil or oil of synthetic origin.

Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The therapeutic formulation, if desired, can also contain minor amounts of wetting, emulsifying or pH buffering agents. These formulations can take the form of creams, foam, patches, lotions, drops, sprays, gel, oils, aerosol, powders, ointment, solutions, suspensions, emulsion and the like. The formulation can be formulated with traditional binders and carriers such as triglycerides. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such formulations contain a therapeutically effective amount of the therapeutic formulation, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

The subject disclosure also provides for the modification of the ingredient such that it is more stable once administered to a subject, i.e., once administered it has a longer time period of effectiveness as compared to the unmodified form. Such modifications are well known to those of skill in the art, e.g., microencapsulation, etc.

The amount of the therapeutic or pharmaceutical formulation of this disclosure which is effective in the treatment of a particular disease, condition or disorder will depend on the route of administration and the seriousness of the disease, condition or disorder and should be decided according to the judgment of the practitioner and each patient's circumstances.

Further, at least one embodiment provides kits containing therapeutic compositions herein. Preferably, the formulations of this disclosure are stable in a wide range of temperatures below the desired melting temperature. In one embodiment the active therapeutic agents can be reconstituted by mixing pre-measured quantities of each component immediately prior to use. The kits can include a covering package material (e.g., plastic, foil, polymer material, etc.) suitable to protect the kit and its contents (e.g., active agent, patch, gel, device) from degradation and contamination.

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

EXAMPLES

Following are examples that illustrate procedures for practicing this disclosure. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

MATERIALS

Poloxamer 188 (P188, catalog # PI 169) was purchased from Spectrum Laboratory Products Inc. (Gardena, CA, USA). Azone (laurocapram) was purchased from NetQem (Durham, NC, USA). Propylene glycol (1,2-propanediol, catalog* P4347 and all other chemicals and reagents were purchased from Sigma- Aldrich (Saint Louis, MO, USA). IGF-1 Quantikine® ELISA kits were purchased from R&D Systems Inc. (Minneapolis, MN, USA). Tegaderm films were purchased from 3M Health Care (St. Paul, MN, USA). The dermatoscope model DE300 was purchased from Firefly Global (Belmont, MA, USA). MTT was purchased from Sigma-Aldrich (Saint Louis, MO, USA). FORMULATION PREPARATION

Topicon™ formulation was prepared by mixing propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) at the ratio of 49:39: 12 or 53:42:5 or 56:44:0 (by weight) at room temperature and melted in a 37 °C water bath. The mixture was then homogenized with a vortex and an ultrasonic water bath at a frequency of 40 kHz. To incorporate the active ingredient, lyophilized IGF-1 was added to Topicon™ at 37 °C to make the master stock formula. The working stocks of IGF- 1 were prepared by serial dilutions of the master stock (1 ng^L) in Topicon™ at 37 °C. In this application, the doses (as per 50 of IGF-1

2 2 2 2 tested were 0.005 mg/0.6 cm , 0.05 mg/0.6 cm , 0.1 mg/0.6 cm , and 0.5 mg/0.6 cm for in vitro permeation studies.

In another application, the doses of an optimized IGF-1 Topicon gel tested were 0.005 ng/50

(10 ppm), applied topically for in vivo studies in the CD hairless rat. For comparison of efficacy, commercial 5% minoxidil (Rogaine^®) was applied topically at a dose of 20 μΐ_^ of 5% (50,000 ppm).

EXAMPLE 1 - IGF-1 steady-state flux across a full thickness metabolically active human skin equivalent achieved by treatment with optimized IGF-1 Topicon™ formulation The skin permeation studies were performed in triplicate on EpiDermFT™ human skin equivalents (EFT-300, surface area 0.6 cm ), which have a significantly thicker dermis than other models (e.g. StrataTest), which may make it a more physiologic model. The MatTek EpidermFT (EFT-300) tissues are also documented to have more of the structural features of the basement membrane. The cultured skin tissues and the maintenance medium were purchased from MatTek Corporation (Ashland, MA, USA). These skin tissues were used according to the manufacturer's instructions. Before the tissues were used for experiments, they were transferred from the original shipping cell culture plates to Costar® 6-well plates (Corning Incorporated Life Sciences, Tewksbury, MA) containing 1.0 mL of maintenance medium. The tissues were then equilibrated at 37 °C, 5% C0₂ in a humidified incubator overnight. On the second day the old medium was replaced by 2.5 mL of fresh pre- warmed maintenance medium that functioned as the receptor medium, and the tissues were equilibrated at 32 °C (average skin temperature), 5% C0₂ in a humidified incubator until the time of formula application. We studied optimized IGF-1 Topicon formulations to determine steady-state flux in a full-thickness human skin model MatTek EpidermFT (EFT- 300). Fifty μL· of formula was dispensed onto the apical surface of the tissue with a

Microman^® micropipette. After dosing, the tissues were returned to the 32 °C incubator. The receptor medium was replaced by fresh medium in the 6-well plate at the basolateral side of the cell culture inserts at preset intervals for up to 7 days to create the sink conditions required for calculation of steady-state flux. IGF-1 concentration was determined using an ELISA kit (IGF-1 Quantikine^®) performed in triplicate (three independent sample

measurements) on triplicate tissues at each time point.

The cumulative amount of IGF-1 that permeated through a unit area of skin was plotted as a function of time. The steady-state flux ( _ss, the permeation rate) is calculated from the slope of the linear portion of the accumulation graph using Fick's law under infinite sink conditions. This model not only assesses transdermal transport as a measure of accumulation of permeant as a function of time to demonstrate constant and consistent delivery (curve should be linear; slope defines dose-response). It is also a model that reflects 100% metabolism and elimination each 24 hours because receptor fluid is completely replenished at each sampling time, as required under "sink" conditions for the calculation of steady state flux using Fick's first law of diffusion. In this representative study, we observed a dose-response for IGF-1 in the range of

0.005-0.5 mg/0.6 cm 2 over the course of the 7-day protocol (FIG. 1). Saturation was not observed with the highest dose included in this study (0.5 mg/0.6 cm ). Table 1 shows the calculated steady- state permeation rate (J_ss) achieved by treatment with optimized IGF-1 Topicon™ formulations as a determinant of dose (mg/0.6 cm ) in FIG. 1. Table 2 shows the feasibility of a IGF-1 Topicon™ patch (size and dose) to achieve and maintain a clinically meaningful therapeutic plasma level by simulated PK modeling that combines highly robust in vitro permeation data (FIG. 1) with the reported PK profile for IGF-1 injection in children with IGF-1 deficiency (IGFD) and growth failure. Table 3 shows a summary of values used in or derived from simulated PK modeling as in Table 2 for an 8 cm x 8 cm patch with the highest dose/0.6 cm tested in FIG. 1.

Table I shows that the highest steady-state flux (J, observed was 0.75

micrograms/cmVh. The EpidermFT model is a robust in vitro model with a stratum corneum 3-times the thickness of normal human skin. It is a PK model that reflects 100% metabolism and elimination each 24 hours under "sink" conditions for the calculation of steady state flux using Fick's first law of diffusion.

Table 1. Steady-State Permeation Rate (Flux, J_ss) of hIGF-1 in Topicon™ Formulation.

Dose (mg/0.6 cm²) 0.005 0.05 0.1 0.5

J_ss ^g/cm²/h) 0.10 0.35 0.56 0.75

The feasibility of a IGF-1 Topicon™ patch (size and dose) to achieve and maintain a clinically meaningful therapeutic plasma level can by assessed by simulated PK modeling that combines highly robust in vitro permeation data (FIG. 1) with the reported PK profile for IGF-1 injection in children with IGF-1 deficiency (IGFD) and growth failure. The target physiologic normal steady- state plasma IGF- 1 concentration is defined as 150 ng/mL (Ct) by 24 hours after patch application for the purposes of simulated pharmacokinetic (PK) modeling. This target value was chosen because the aim of both pediatric and adult GH replacement therapy is to achieve IGF- 1 levels ideally within the middle to upper third of the normal clinical reference range.

The PK simulation model used to extrapolate in vivo data (Table 2-3) from in vitro permeation data (Table 1) is based on a non-compartmental analysis (NCA) and performed using PKSolver (an add-in PK software for Excel). The simulation model assumes that the PK of IGF-1 delivered by an Topicon™ patch IGF- 1 follows first order elimination kinetics such that elimination of the drug is directly proportional to its serum concentration, which is dependent on its terminal half-life (Ti_/2). First order kinetics implies that elimination of a fraction of drug administered (e.g., 50%) in the first T ₂ is independent of the concentration of drug administered as in the case of most of drugs when they are used at their therapeutic doses.

PK Simulation Model Equations

1) The first order elimination rate constant Kel (min- 1) is calculated by Equation 1 : 0.693/T_1/2

2) The required input rate of IGF- 1 ko ^g/min) to reach the target serum IGF-1 level Ct (150 ng/mL) can be calculated by Equation 2: k₀ = C_t*V_d*K_ei/(l-e^AK_ei*t)

[Vd (mL) is the volume of distribution, t (min) is time, K_ei is derived in Equation 1, and T ₂ is the terminal half-life]

3) The IGF- 1 input amount per unit area Q ^g/cm ) per unit time (t) from a IGF-1 Topicon™ patch containing a total dose D_p (mg) is calculated by Equation 3: J_ss*D_p*t 4) The patch size S (cm ) needed to achieve target serum IGF-1 level can be calculated by Equation 4: ko/ J_ss

5) The duration of action Dt (days) of an IGF-1 Topicon™ patch can be calculated by Equation 5: D_t/ J_SS*S

Based on PK simulation modeling, Table 2 shows the relationship between patch size, dose/area, total dose per patch, and duration of action. The in vivo studies and published PK data shown in Tables 2-3 support the feasibility of developing an effective Topicon™ extended-wear IGF-1 that can achieve and maintain a target serum IGF-1 level of 150 ng/mL continuously for >7 days.

Pafeti Si e, Dose, and Duration of Action to Achieve

!argel Plasma Concentration (150 ng rnl}

Dose/area

0.005 0.06 0.1 0.5

R t si e 21 X 21 11 x 11 9 X 8 x 8

(cm x cm)

Dose

4 11 14 51 g/patct

Duration

0.1 11 22 10.9

(days)

Table 3

EXAMPLE 2 - Cell viability of tissues treated with optimized IGF-1 Topicon formulations by MTT assay are not dose-dependent or time-dependent

We assessed cell viability as a function of treatment dose (FIG. 2) of optimized IGF-1 Topicon formulation on MatTek EpidermFT (EFT-300) full thickness human skin tissues using a standard MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay at the end of a representative 7-day study as described in FIG. 1. The results represent average + standard deviation of triplicate tissues. Percent viability is the ratio of the MTT assay colorimetric readout for treated tissues compared to untreated tissues arbitrarily assumed to have 100% viability. Over the dose range of 0.005-0.5 mg/0.6 cm , cell viability was approximately 80% for all tissues. No statistically significant difference was observed across 2-orders of magnitude up to the saturating dose of 0.5 mg//0.6 cm .

We assessed cell viability as a function of treatment course of 1, 3, 5, 7 days (FIG. 3) with the saturating dose of 0.5 mg/0.6 cm² of optimized IGF-1 Topicon™ formulation on MatTek EpidermFT (EFT-300) full thickness human skin tissues using a standard MTT [3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The results represent average + standard deviation of triplicate tissues. Percent viability is the ratio of the MTT assay colorimetric readout for treated tissues compared to untreated tissues arbitrarily assumed to have 100% viability. Over the time course of 1-7 days, cell viability was approximately 80% for all tissues. No statistically significant difference was observed in the cell viability of tissues treated with the saturating dose of 0.5 mg/0.6 cm . These MTT assays showed that epidermal cell viability was preserved, independent of dose or time.

EXAMPLE 3 - Intermittent topical application of an optimized IGF-1 Topicon™ gel promotes sustained hair growth in a rat model of androgenetic alopecia.

CD hairless rats are a genetic strain characterized by absent or sparse hair growth. Hair follicle stem cells are present, but are inactive. Hair growth tends to be curled due to the tortuous conformation of the sparse follicles that produce a hair shaft. Although not a testosterone-induced model of androgenetic alopecia, the CD hairless rat has been suggested to be a reasonable model for therapeutic studies since the histopathologic features are essentially identical. Namely, the essential similarities of hair follicles between androgenetic alopecia and CD hairless rates (fuzzy rats) are small size, a mosaic pattern of cyclic growth, and vellus hair production of the hair follicles. Using this model, if the drug induces an enlargement of these vellus follicles, the same drug may likely induce a similar effect on the vellus follicles in androgenetic alopecia.

Normal 10-week old CD hairless rats (FIG. 4, left column) were treated topically with either 0.005 ng/50 (1 ppm) or 0.05 ng/50 (10 ppm) of IGF-1 Topicon™ gel, or 20 of commercial 5% minoxidil (ROGAINE^®) (50,000 ppm). The treatment regimen was Monday, Wednesday, and Friday for 6 hours daily to replicate a dosing regimen intended for nighttime application during sleep in human subjects. The treatment application site was the same in each animal (intrascapular region). Treatment was continuous for 26 calendar days and then stopped (middle column). Documentation of the status of hair growth was continued for an additional 30 calendar days after cessation of treatment (right column). The total observation period was 8-weeks.

Pre-treatment hair growth was minimal and similar as expected in CD hairless rats of this age (FIG. 4, left column). Treatment with two extremely low concentrations of IGF-1 or with 5% minoxidil resulted in total body hair growth to a similar degree by the end of the treatment course (FIG. 4, middle column). Response to topical therapy was characterized by longer and denser hair growth in all treatment groups. However, after 30-days without therapy, the IGF-1 treated animals manifested sustained hair growth in a dose-dependent manner (FIG. 4, right column, 1st and 2nd rows), whereas minoxidil treated animals displayed dramatic hair loss (FIG. 4, right column, 3rd row), consistent with the predicted time-dependent "shedding" phase as observed in human subjects treated continuously with topical minoxidil. Onset of shedding in the minoxidil group was first observed 24-days post- treatment and was nearly complete by 30-days post-treatment. The continued post-treatment maintenance of hair growth in the IGF-1 treated animals is consistent with the positive feedback loop that results in the prolongation of anagen that may last for many full hair follicle life cycles, even after IGF-1 treatment is discontinued.

The generalized hair growth observed in CD hairless rats suggests that even intermittent treatment with IGF-1 TopiconENOO™ gel applied topically at a dose of 50 μΐ_^ of a 1 ppm formulation results in systemic absorption of exogenous IGF-1 and its binding to IGF-1 receptors expressed on hair follicle stem cells over the entire CD hairless rat.

Intended Mechanism of Action of Topicon™ ThermoMatrix™ -Mediated Passive Transdermal Delivery Remarkably, the complex structure of skin morphology has not been fully elucidated. It was first proposed that the fat layer of the stratum corneum extracellular space is composed of saturated long-chain ceramides, free fatty acids and cholesterol in a 1: 1: 1 molar ratio. The fat layer was thought to exist as a single and coherent gel phase. It was not until 2012 that the use of very high magnification cryoelectron microscopy (EM) of vitreous skin section defocus series, molecular modeling, and EM simulation was used to determine the atomic structure of the stratum corneum lipid matrix in situ, in its near-native state. The structure is composed of stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety; the free fatty acid is associated with the long- chain fatty acid moiety of the ceramide.

Topicon ThermoMatrix -mediated passive transdermal delivery of large molecule drugs (e.g., insulin, IGF-1, hGH) is hypothesized to occur by the synergistic effects of its components (thermosensitive polymer, dermoadhesive agent, and a chemical penetration enhancer)— all of which contribute chemical penetration enhancing properties. The Topicon ThermoMatrix formulation developed in 2010 anticipated the atomic structure of the stratum corneum extracellular lipid matrix reported by Norlen's group (2012). This led to the inclusion of a specific non-ionic amphipathic tri-block copolymer (poloxamer 188) intended to form "pores" that disrupt the lipid matrix of the stratum. The lipophilic polyoxypropylene core was envisioned to interact with the surrounding structure of the extracellular lipid matrix (free fatty acid, cholesterol, ceramide) of the stratum corneum and to form the outer wall of the pore, while the non-ionic (no net charge) hydrophilic flanking polyoxyethylene arms would form the inner wall that facilitates drug delivery through a pathway created in the center of the pore.

The sizes of such putative pores might differ over a range in a stochastic distribution. The size distribution of such putative pores might follow a bell- shaped curve, such that small molecule drugs "pass through" all of the pores, intermediate-sized drugs (e.g. insulin) pass through the majority of pores constituting the pores with dimensions distributed across the central portion of the bell-shaped curve, and large drugs (e.g. hGH or larger) only pass through a smaller number of large pores at the upper size distribution of the bell-shaped curve. If this is the case, one strategy for increasing the flux of large molecules is to shift the bell-shaped curve towards the upper size distribution (i.e. "shift curve to the right"). The ability to achieve this requires a more detailed understanding of the 3-D structure of the entire membrane domains of the stratum corneum.

EQUIVALENTS

The functions of several elements may, in alternative embodiments, be carried out by fewer elements, or a single element. Similarly, in some embodiments, any functional element may perform fewer, or different, operations than those described with respect to the illustrated embodiment.

While certain embodiments according to this disclosure have been described, this disclosure is not limited to just the described embodiments. Various changes and/or modifications can be made to any of the described embodiments without departing from the spirit or scope of this disclosure. Also, various combinations of elements, steps, features, and/or aspects of the described embodiments are possible and contemplated even if such

combinations are not expressly identified herein.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications, and other references cited herein are hereby expressly incorporated herein in their entireties by reference.

Claims

CLAIMS What is claimed is:

1. A composition comprising propylene glycol (PG), poloxamer 188 (P188), laurocapram (LP) and IGF-1.

2. The composition of claim 1, wherein the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 56:44:0 (by weight).

3. The composition of claim 1, wherein the ratio of propylene glycol (PG), poloxamer 188 (P188), and laurocapram (LP) is 50:50:0 (by weight).

4. The composition of claim 1, wherein the IGF-1 is lyophilized IGF-1.

5. The composition of claim 1 is in solid form.

6. The composition of claim 1 is in gel form.

7. The composition of claim 1 that is devoid of laurocapram.

8. The composition of claim 1, wherein the IGF-1 is present in a dose range of 0.001-10

9. The composition of claim 1, further comprising hGH present in a dose range of 0.001-10 mg/50 μΙ_

10. A method of promoting or enhancing local hair fullness and thickness, or hair growth in a subject comprising administration of the composition of claim 1 in gel form.

11. The method of claim 10, wherein the administration is topically via a gel applied repeatedly to the same or different affected area of hair or skin, including but not limited to the scalp, eye brows, axilla, and pubic area.

12. The method of claim 10, wherein IGF-1 is administered via a gel at a dose range of 0.0001-100 ppm.

13. The method of claim 10, wherein IGF-1 is administered via a gel for 1-2 times/day and on a treatment regimen of every other day or three times weekly.

14. The method of claim 13, wherein the IGF-1 is administered via a gel as continuous once daily therapy.

15. The method of claim 14, wherein the treatment is maintained for a cycle of 1-12 consecutive weeks, separated by a no-treatment period of 1-12 consecutive weeks.

16. The method of claim 10, wherein the administration of IGF-1 is provided at a rate that provides the permeation of IGF-1 through EpiDermFT at at least 0.1 μg/cm /hr 24 hours after initial administration.

17. The composition of claim 1, wherein the composition provides the permeation of IGF-1 at a rate that provides the permeation of IGF-1 through EpiDermFT at at least 0.1 μg/cm /hr 24 hours after initial administration.

18. The method of claim 17, wherein the composition provides the permeation of IGF-1 at a rate that provides the permeation of IGF-1 through EpiDermFT is at least 0.1 μg /cm /hr 48 hours after initial administration.

19. The method of claim 18, wherein the composition provides the permeation of IGF-1 at a rate that provides the permeation of IGF-1 through EpiDermFT is at least 0.1 μg /cm /hr 168 hours after initial administration.

20. A kit comprising a composition of claim 1 and a device for topical administration of the composition of claim 1.

21. The kit of claim 20, wherein the device is a patch.

22. The kit of claim 20, wherein the composition of claim 1 is in solid form.

23. The kit of claim 21, wherein the patch further comprises an adhesive material.

24. The kit of claim 21, further comprising a cover material to protect the composition of claim 1 during shipping and storage.

25. The kit of claim 20, wherein the device is an applicator for contact with the subject.

26. The kit of claim 20, wherein the device is an applicator with a sponge.

27. The kit of claim 20, wherein the device is an applicator with a brush.

28. The kit of claim 20, wherein the composition of claim 1 is in gel, foam, or cream form.

29. The kit of claim 20, wherein the composition of claim 1 is in gel form.

30. A device comprising a composition of claim 1 and a patch.

31. The device of claim 30, wherein the patch comprises a backing.

32. The device of claim 30, wherein the patch comprises an adhesive.

33. The device of claim 30, wherein the patch comprises a laminate coated with the composition of claim 1.

34. The device of claim 30, wherein the patch comprises the composition of claim 1 in solid form.

35. A method of treating hormone deficiency in a subject comprising administration of the composition of claim 1 to the subject.

36. The method of claim 35, wherein the administration is topically.

37. The method of claim 36 wherein the administration of IGF-1 is provided at a rate that provides the permeation of IGF-1 through EpiDermFT at at least 75 ng/cm 24 hours after initial administration.

38. The method of claim 36, wherein the administration of IGF-1 is provided at a rate that provides the permeation of IGF-1 through EpiDermFT at at least 75 ng/cm 48 hours after initial administration.

39. The method of claim 36, wherein the administration of IGF-1 is provided at a rate that provides the permeation of IGF-1 through EpiDermFT at at least 200 ng/cm 72 hours after initial administration.

40. The method of claim 36, wherein the composition of claim 1 is in solid form.

41. The method of claim 36, wherein the composition of claim 1 is in gel form.