US 2016O184245A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0184245 A1 Eberting (43) Pub. Date: Jun. 30, 2016 (54) FORMULATIONS FOR EPIDERMAL REPAIR A647/8 (2006.01) A61K 8/44 (2006.01) (71) Applicant: Cheryl Lee EBERTING, Alpine, UT A647/24 (2006.01) (US) A618/55 (2006.01) A613 L/455 (2006.01) (72) Inventor: Cheryl Lee Eberting, Alpine, UT (US) A618/49 (2006.01) A613 L/19 (2006.01) A619/00 2006.O1 (22) PCT Filed: Jul. 25, 2014 A61O 19/00 :08: A618/42 (2006.01) (86). PCT No.: PCT/US1.4/48226 (52) U.S. Cl. S371 (c)(1), CPC ................. A61 K31/164 (2013.01); A61K 8/42 (2) Date: Jan. 25, 2016 (2013.01); A61 K3I/575 (2013.01); A61K 8/63 (2013.01); A61 K3I/20 (2013.01); A61K 8/361 Related U.S. Application Data (2013.01); A61 K3I/23 (2013.01); A61K 8/37 (60) Provisional application No. 61/858,513, filed on Jul. (2013.01); A61 K3I/133 (2013.01); A61K 8/41 25, 2013, provisional application No. 61/896,215, (2013.01); A61 K47/12 (2013.01); A61K 8/365 filed on Oct. 28, 2013, provisional application No. (2013.01); A61 K47/183 (2013.01); A61K 8/44 61/968,078, filed on Mar. 20, 2014, provisional appli- (2013.01); A61 K47/24 (2013.01); A61K 8/55 cation No. 62/005,702, filed on May 30, 2014. (2013.01); A61 K3I/455 (2013.01); A61 K 8/4926 (2013.01); A61K 31/19 (2013.01); Publication Classification A6 IK3I/573 (2013.01); A61 K9/0014 (2013.01); A61O 19/007 (2013.01); A61 K (51) Int. Cl. 2800/5922 (2013.01); A61 K 2800/48 (2013.01) A6 IK3I/64 (2006.01) A 6LX3/575 (2006.01) (57) ABSTRACT A6 IK 8/63 (2006.01) A6 IK3I/20 (2006.01) The present disclosure is directed to dermatological formu A6 IK 8/36 (2006.01) lations and their use for treating a variety of dermatological A6 IK3I/23 (2006.01) diseases and disorders, and for repairing and restoring a dis A6 IK S/37 (2006.01) rupted epidermal barrier, inhibiting inflammation, restoring a A6 IK3I/33 (2006.01) proper environment for maintaining a balanced symbiotic A6 IK 8/4I (2006.01) microbiome, and inhibiting the growth of pathogenic micro A6 IK 47/12 (2006.01) organisms in the epidermis—the outer layer of mammalian A6 IK 8/365 (2006.01) skin. Patent Application Publication Jun. 30, 2016 Sheet 1 of 2 US 2016/0184245 A1 Patent Application Publication Jun. 30, 2016 Sheet 2 of 2 US 2016/O184245 A1 &r / & s S US 2016/0184245 A1 Jun. 30, 2016 FORMULATIONS FOR EPIDERMAL REPAIR 0005. The stratum corneum of the epidermis is primarily responsible for the water permeability barrier function of the TECHNICAL FIELD skin, which is critical for preventing excessive dryness of the skin, as well as dehydration of the underlying tissues. Three 0001. The present disclosure is directed to dermatological main factors contribute to the establishment of this water formulations and their use for repairing and restoring a dis permeability barrier within the stratum corneum: First, the rupted epidermal barrier. The disclosed formulations are intercellular, hydrophobic lipids form the only continuous designed to Supplement and replenish the natural lipid com pathways through the stratum corneum, and thereby block the ponents of the epidermis, inhibit inflammation, restore the transport of water molecules. Second, the corneocytes, which conditions required for maintaining a balanced symbiotic are surrounded by hydrophobic envelopes, are tightly linked epidermal microbiome, and inhibit the growth of pathogenic to each other by specialized connective organelles known as microorganisms in the epidermis—the outer layer of mam corneodesmosomes. Third, the intracellular and extracellular malian skin. The disclosed formulations are useful for the hygroscopic materials known as natural moisturizing factors treatment of Subjects suffering from skin or mucous mem brane disturbances characterized by epidermal disruption, specifically retain water in the outer layer of the stratum inflammation, and, in some embodiments, Superinfection COCl. with pathogenic microorganisms. 0006 Moreover, the intercellular lipids in the stratum cor neum of human skin form two lamellar phases (extended lamellar sheets of ordered lipid molecules) in two planes that BACKGROUND lie parallel to the skin surface, with repeat distances of 0002 Human skin is composed of several morphologi approximately 6 and 13 nm. These lamellar phases are cally distinct layers. The outer-most layer of the skin, the respectively referred to as the short periodicity phase and the epidermis, is composed of 4 to 5 sub-layers depending on long periodicity phase. Within these lamellar phases the lipids where on the body the skin is located. These sub-layers, from are highly organized in a tightly-packed, mostly lateral, the outer-most layer to the inner-most layer, include the Stra orthorhombic state. The orthorhombic packing, in addition to tum corneum, the stratum lucidum (which is present only in the presence of the long periodicity phase, is thought to be thick skin, Such as the Soles of feet and palms of hands), the critical for normal barrier function. stratum granulosum, the stratum spinosum and the stratum 0007. It is believed that the long alkyl chains of the fatty basale. acids and lipids within the lipid matrix of the stratum corneum 0003. The underlying layers of the epidermis are referred are needed to induce the formation of the orthorhombic lattice to as the "viable epidermis, and form a dynamic, constantly observed in mixtures of ceramides and cholesterols. Further self-renewing tissue that ultimately generates the stratum cor more, it has been shown, using tape stripping and electron neum—the layer exposed to the external environment. Skin microscopy that this highly organized lipid lamellar phase is cells, known as keratinocytes, grow and divide within the missing from between the corneocytes in the outer most lay basal layer, and undergo a number of changes in both struc ers of dry skin. ture and composition as they migrate outwards through the 0008. From the above, it is clear that the human epidermis stratum spinosum and stratum granulosum to the stratum comprises a complex and heterogeneous mix of lipids, pre corneum, ultimately differentiating into corneocytes, which dominantly consisting of Saturated lipids, cholesterol, and make up the stratum corneum. cholesterolesters, and long-chained fatty acids, with the satu 0004 Corneocytes of the stratum corneum are flat, dead rated lipids being primarily a complex mixture of different cells comprised mostly of keratin filaments and water, and types of ceramides. This heterogeneous mix of lipids is Surrounded by a densely cross-linked protein layer (the largely responsible for the “epidermal barrier' formed by “cornified envelope') that is, in turn, chemically linked to a healthy human skin. lipid envelope. The lipid envelope acts as an interface 0009. A healthy, intact epidermal barrier plays a vital role between the Stacked layers of corneocytes, forming a lipo in protecting mammals, and particularly humans, from the philic and non-polar layer between the hydrophilic corneo outside world. It serves as a physical barrier to simulta cytes. The intercellular lipid layers between layers of corneo neously prevent the entry of harmful pathogens, irritants, cytes are a complex matrix consisting of a wide variety of allergens and other noxious chemical species, and the exit of ceramides, cholesterol, cholesterol esters, and free fatty excessive amounts of water, thereby providing protection acids. Although estimates vary, one study using advanced and from infection, irritation and dehydration. Moreover, healthy carefully controlled methods revealed these lipid layers com human skin, with its intact epidermal barrier, plays an impor prise, on average, about 47% ceramides; 24% cholesterol: tant role in thermoregulation, and provides a relatively strong 18% cholesterol esters; and 11% fatty acids, by weight. exterior layer that is resistant to physical damage by abrasion (Norlen, et al., Inter- and intra-individual differences in or puncture. human stratum corneum lipid content related to physical 0010. In contrast, a disrupted and dysfunctional epidermal parameters of skin barrier function in vivo. J. Invest. Derma barrier is a hallmark of atopic dermatitis, Xerosis, ichthyosis, tol. 1999 January; 112(1): 72-7.) The vast majority of these irritant dermatitis, allergic contact dermatitis, dyshidrosis, lipids arise from the secretory organelles, known as lamellar Seborrheic dermatitis, psoriasis, all forms of cutaneous lupus bodies, or lamellar granules, within keratinocytes. These erythematosus (CLE) including acute, Subacute, and chronic lamellar granules fuse with the cell membrane and release cutaneous lupus, rosacea, acne, and many other papulosqua their contents into the extracellular space once the kerati mous skin disorders. Similarly, it appears that a disrupted and nocytes reach the stratum granulosum?stratum corneum dysfunctional epidermal barrier is a hallmark of many, if not interface. Following their release, these lipids self-organize all, forms of photodermatoses, including idiopathic, genetic, into the lamellar sheets that are a distinctive molecular char metabolic and exogenous photodermatoses. It is widely acteristic of the stratum corneum. believed that such a dysfunctional barrier can result from a US 2016/0184245 A1 Jun. 30, 2016 perturbation—deficiency, Surplus or alteration—of the lipid esters of fatty acids disclosed herein, in the presence or species that are normally present in an intact, healthy epider absence of 183-glycyrrhetinic acid and/or a glucocorticoid mis. Additionally, abnormalities in the descquamation of the and/or niacinamide, to establish and maintain an acidic pH epidermis, an overly exuberant inflammatory process, or the within the epidermis that is important for treating epidermal loss or imbalance of the naturally occurring antibacterial barrier defects and/or repairing, replenishing or maintaining lipids within the epidermis, have been implicated in a subset an effective epidermal barrier.