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

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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. It has further been discovered of these diseases. Consequently, there is a need for therapeu that the effectiveness of the formulations disclosed hereincan tic compositions that can be administered to repaira disrupted be enhanced by reestablishing a gradient of calcium ions epidermal barrier and restore an intact healthy epidermal (Ca") within diseased epidermis that is reminiscent of the barrier. Moreover, there is a need for methods of treatment calcium ion gradient observed in healthy epidermal tissues. that utilize such therapeutic compositions. The components of the formulations disclosed herein have 0011. The formulations disclosed herein address multiple been chosen to work synergistically, by addressing character defects in the epidermal barrier that are known from studies of istic defects observed in defective or diseased epidermal tis dermatological diseases and disorders, and do so in a targeted Sue as identified in human patients suffering from specific and Synergistic fashion. The disclosed formulations provide a dermatological diseases or disorders. As described in more combination of essential skin lipid species that are often detail in the disclosure and examples provided below, other found to be deficient in disrupted skin, to restore an intact, ingredients are envisioned as components of these formula healthy epidermal barrier. These formulations specifically tions, and different combinations of the disclosed ingredients exclude those skin lipid species that are found to be in excess may show greater efficacy in treating specific dermatological in diseased skin. In addition to providing essential lipid spe diseases and disorders by addressing the defects that are cies, the disclosed formulations also provide specific anti characteristically found in these diseases and disorders. inflammatory and antimicrobial components, and compo 0015 While not wishing to be bound by any one theory, nents to establish an appropriately acidic pH of the skin, so the components of the compositions and formulations dis that the skin Supports the presence of synergistic beneficial closed herein work synergistically to repair and restore the microbiota and resists invasion and Superinfection by harmful epidermal barrier by Supplementing the natural lipid compo or pathogenic microorganisms. The formulations also pro nents of the skin, while also correcting other imbalances, such vide components designed to establish and maintain an as alterations in pH, calcium gradient, and associated alter appropriate calcium gradient within the skin so as to induce ations in microbial flora, commonly observed in diseased the viable epidermis to synthesize and secrete the lipids, and skin, and while reducing inflammation resulting from a vari particularly ceramides, that comprise the lamellar phases cru ety of causes. cial in establishing an intact, effective epidermal barrier. DEFINITIONS BRIEF DESCRIPTION OF THE FIGURES 0016. As used herein, the term “epidermal barrier' or 0012 FIG. 1 depicts the chest and neck area of a patient “barrier refers to those characteristics or properties of having cutaneous lupus erythematosus, prior to treatment healthy skin that isolate and protect underlying living tissue with the disclosed formulations. from the external environment. Such characteristics or prop 0013 FIG. 2 depicts the chest and neck area of the same erties of the epidermal barrier serve to protect the body from patient following twice-daily administration of the disclosed infection by pathogens, inflammation in response to irritants formulations for approximately three weeks, as described in or allergens, and excessive transepidermal water loss, etc. the Examples section below. 0017. The term “therapeutically effective amount as used herein, refers to any amount of a specific component or combination of components (i.e., formulation), that will DETAILED DESCRIPTION cause a reduction of symptoms, or relief from Symptoms, 0014. It has been discovered that topical application of when applied, either once, or repeatedly over time. Therapeu formulations comprising combinations of sphingolipids (e.g., tically effective amounts can be readily determined by skilled phytosphingolipids, such as ceramide 3), cholesterol esters, artisans using routine experimentation using tests and mea very long chained fatty acids, and, optionally, fatty alcohol Sures commonly employed in the art, or can be based upon the esters of fatty acids such as isostearyl isosterate, can be used Subjective response of patients undergoing treatment. In to treat epidermal barrier defects and/or repair, replenish or those formulations where the components work synergisti maintain an effective epidermal barrier. It has also been dis cally to restore the epidermal barrier, the therapeutically covered that glycyrrhetinic acid, and particularly 183-glycyr effective amounts of each component, when used in combi rhetinic acid, which has anti-inflammatory, antiviral, antifun nation, may be found to be less than the therapeutically effec gal, antiprotozoal, and antibacterial activities, when applied tive amounts when the components are used separately. topically along with a glucocorticoid and/or niacinamide, 0018. As used herein, “microbiome' refers to the totality either in a simple combination, or in combination with the of microbiota (i.e., microorganisms), their genetic elements formulations of sphingolipids, cholesterol esters, very long (genomes, etc.), and environmental interactions in a particu chained fatty acids, and, optionally, fatty alcohol esters of lar environment. Importantly, the skin can be considered as an fatty acids disclosed herein, can potentiate the anti-inflam ecosystem Supporting a range of symbiotic microbial com matory activity of the glucocorticoid and can therefore be munities that live in distinct niches. Studies characterizing the used to treat epidermal barrier defects and/or repair, replenish microbiota that inhabit these different niches, and their sym or maintain an effective epidermal barrier. It has further been biotic interactions with the innate immune defense system of discovered that gluconolactone can be used in combination the skin, are beginning to provide insights into the effects this with the formulations of sphingolipids, cholesterol esters, microbiota has on the balance between skin health and dis very long chained fatty acids, and optionally fatty alcohol ease (Gallo and Nakatsuji, Microbial symbiosis with the US 2016/0184245 A1 Jun. 30, 2016

innate immune defense system of the skin. J. Invest. Derma wherein, tol. 2011 October; 131(10): 1974-80). The effectiveness of X is either H-, a monosaccharide, or an oligosaccharide; antimicrobial agents in the management of Some common R" is either —(C=O)—or —CH2—, skin disorders Supports a role for microbes in pathophysiol R’ is either —(CH=CH)– or -(CHOH)—CH-; ogy. Elucidation of the baseline skin microbiomes is the first R is any one of the following: step toward testing the therapeutic potential of manipulating 0022 (a) Co-C, alkyl; the microbiome in skin disorders. Grice, et al., Topographical 0023 (b) C-hydroxy-C-C alkyl: and temporal diversity of the human skin microbiome. Sci 0024 (c) ()-hydroxy-Co-Co alkyl; ence 2009 May 29: 324(5931): 1190-2. Indeed, an initial 0025 (d) C,c)-hydroxy-C-C alkyl; or study of psoriasis (Gao, et al., Substantial alterations of the 0026 (e) alkanoyl as define by Formula II: cutaneous bacterial biota in psoriatic lesions. PLoS ONE. 2008; 3(7): e2719) and an animal model of ichthyosis (Schar Schmidt, et al., Filaggrin deficiency confers a paracellular Formula II barrier abnormality that reduces inflammatory thresholds to irritants and haptains. J Invest Dermatol. 2009 September; R-O-C-R6, 124(3): 496-506) revealed selective microbial shifts associ ated with skin diseases. Hence, targeted therapies to maintain healthy skin might require not only inhibiting the growth of wherein pathogenic bacteria, but also promoting the growth of sym 0027 R is either divalent Co-C, alkyl or divalent biotic bacteria. Grice, et al., Topographical and temporal C-hydroxy-Co-Co alkyl, and diversity of the human skin microbiome. Science 2009 May I0028) R' is either monovalent Co-Calkyl (preferably monovalent Cs-Co alkyl), or monovalent C.-hydroxy 29: 324(5931): 1190-2. Co-C alkyl (preferably monovalent C-hydroxy-Cls 0019 While not wishing to be bound by any one theory, it Coalkyl); and is believed that measures taken to restore a balanced symbi R" is Co-Co alkyl. otic skin microbiome can treat specific forms of dermatitis 0029 Relative to the generic definition provided above, and other dermatological conditions. Hence, one of the objec “ceramides.” are those compounds of Formula I, wherein tives behind the formulations of the present disclosure is to 0030 X is H. : correct abnormal aspects of diseased epidermis to promote 0031) R' is (C=O) ; the establishment and maintenance of a balanced symbiotic 0032 R is either (CH=CH) or -(CHOH) skin microbiome. It is believed that this can be accomplished CH : by using the disclosed formulations to address imbalances in I0033 R is alkyl or C-hydroxyalkyl; and Such factors as the lipid composition, and particularly the I0034) R' is Co-Co alkyl. composition of lipids known to suppress growth of patho 0035 Relative to the generic definition provided above, genic microorganism, epidermal pH, and epidermal calcium “co-esterified ceramides' or “acylceramides.” are those com gradient. Additionally, the use of components with known pounds of Formula I, wherein antibiotic activities to specifically impact the skin micro 003.6 X is H. : biome is contemplated. 0037) R' is (C=O) ; 0038 R is either —(CH=CH)– or -(CHOH)– Components of the Disclosed Formulations: CH2—, 0020 Epidermal sphingolipids are a class of lipids com I0039 R is alkanoyl with alkyl or C-hydroxyalkyl as both prising, for example, ceramides, acylceramides, glycoceram RandR; and ides or glucosylceramides, and sphingomyelin. All of these 10040) R' is Co-Co alkyl. compounds contain a sphingosine, or closely-related "sphin 0041 Relative to the generic definition provided above, goid base' (i.e., dihydrosphingosine, phytosphingosine, or “cerebrosides are those compounds of Formula I, wherein 6-hydroxy Sphingosine) bound to either an acyl (non-hy 0042 X is a monosaccharide: droxy) fatty acid, an O-hydroxy fatty acid, or an esterified 0043 R' is —(C=O)–: ()-hydroxy fatty acid, through an amide linkage at the amino 0044 R is either —(CH=CH)– or -(CHOH)— group of the sphingosine. In some cases, these sphingolipids CH : contain a saccharide moiety (i.e., monosaccharide or an oli I0045 R is alkyl or C-hydroxyalkyl; and gosaccharide) linked by a glycosidic bond to the terminal 10046) R' is Co-Co alkyl. hydroxyl group of the sphingosine moiety. Such compounds 0047 Relative to the generic definition provided above, are known as “glucosylceramides.” “co-esterified cerebrosides’ or “acylglycosyl sphingolipids' are those compounds of Formula I, wherein 0021 Generically, sphingolipids can be described as com 0048 X is an oligosaccharide, particularly a disaccharide; pounds of Formula I: 0049) R' is (C=O) ; 0050 R is either (CH=CH) or -(CHOH) CH2—, Formula I 10051) R' is alkanoyl with alkyl or C-hydroxyalkyl as both in-R-R RandR; and X-O-CH-CH-CH-R-R, 0052 R is Co-Co alkyl. OH 0053 Relative to the generic definition provided above, “co-esterified cerebrosides' or “complex glycosphingolipids' are also those compounds of Formula I, wherein US 2016/0184245 A1 Jun. 30, 2016

0054 X is a oligosaccharide, particularly a disaccharide; 0061 Generally preferred classes of sphingolipids used in 0055) R' is (C=O) ; the disclosed formulations are those in which R" is 0056 R is either (CH=CH) or -(CHOH) (C=O)—and R is —(CH=CH)– CH-. 0062 Ceramides in the human stratum corneum play key 0057 R is alkyl or C-hydroxyalkyl; and physicochemical roles in establishing the barrier functions of 0.058 R is Co-Co alkyl. the skin. The structures of those diverse ceramide species in 0059. As used herein, the term “alkyl refers to straight- the stratum corneum, had not been comprehensively chained or branched-chain groups that can be saturated (i.e., described, until characterization by normal-phase liquid containing all single bonds) or unsaturated (i.e., containing chromatography connected to electrospray ionization-mass one or more double bonds), and either monovalent or divalent spectrometry was conducted. These studies led to the discov as determined by their position within the structure provided ery of a new ceramide class consisting of C-hydroxy fatty acid as Formula I. In most instances, straight-chained alkyl groups and dihydrosphingosine moieties, in addition to the 10 classes are preferred in the disclosed formulations. Alkyl groups previously known. These studies revealed that the ceramides identified as “O-hydroxyalkyl are derived from C-hydroxy of the human stratum corneum comprise long-chain (more fatty acids, with the C-position referring to the carbon adja than Cs)-containing sphingoids and a great number of iso cent to the carboxyl group involved in an ester or amide baric species (Masukawa, et al., Characterization of overall linkage. ceramide species in human stratum corneum. J. Lipid Res. 0060. The term “fatty acid residue” refers to the that por 2008 July; 49: 1466–76). The ceramide species identified in tion of a fatty acid that remains after removal of the COOH human stratum corneum by these studies include the follow group. ing species:

Fatty acid Non-hydroxy fatty acid N n--~. Sphingoid OH

Dihydrosphingosine CERNDS) DS)

HN

~ OHOH

Sphingosine CERNS IS)

HN

~"N OH

Phytosphingosine CERNP P

HN 2 OH

OH OH

6-hydroxy sphingosine CERNH) H

HN 2 OH n1 NOH OH US 2016/0184245 A1 Jun. 30, 2016

-continued Fatty acid C-hydroxy fatty acid A n--~~~~OH Sphingoid OH Dihydrosphingosine CERADS DS)

HN

~OHOH Sphingosine CERLAS) Sl

HN

~OHn1 NOH Phytosphingosine CERAP |P) H2N OH

OH OH

6-hydroxy sphingosine CERAH H

HN 2 OH n1 NOH OH

Fatty acid Esterified co-hydroxy fatty acid EO)

Sphingoid o-ha-n-N-a-N-N-n-n OH

Dihydrosphingosine CEREODS) DS)

HN

~OHOH Sphingosine CEREOS) Sl

HN

~OHN OH US 2016/0184245 A1 Jun. 30, 2016

-continued

Phytosphingosine CEREOP) |P) HN 2 OH

OH OH 6-hydroxy sphingosine CEREOH) H HN 2 OH N-1 noH OH

0063 Source: Masukawa, et al., Characterization of over terol and/or lanosterol) esters used in the disclosed formu all ceramide species in human stratum corneum.J. Lipid Res. lations are those comprising fatty acids having between 10 2008 July:49:1466-76. and 30 carbons (i.e., Co-Co). In certain embodiments, com 0064. The ceramides to be used in the disclosed formula mercial preparations of cholesterol/lanosterol esters are used tions are chosen from at least one of the following: Cer 1 as components of the disclosed formulations. Generally, Such (EOS), Cer2NS), Cer3 NP, Cer 4EOH), Cer 5 IAS), Cer commercial preparations comprise a mixture of cholesterol/ 6 AP, Cer 7 AH., Cer 8 NH, and Cer9 EOP, as identi lanosterol esters comprising fatty acids of differing lengths. fied in Holleran, et al., Epidermal sphingolipids: Metabolism, For example the commercial preparation known as 'super function and roles in skin disorders. FEBS Lett. 2006; 580: sterol comprises a mixture of Co-Co cholesterol and/or 5456-66. The letter designations in the brackets (e.g., EOS). lanosterol esters. Suitable cholesterol and/or lanosterol esters NS, and NP) of the ceramides listed immediately above, correspond to the same designations in brackets in the table include, for example, cholesterol oleate, cholesterol laurate, above, such that, for example, “Cer 1 EOS is the ceramide cholesterol myristate, cholesterol palmitate, cholesterol formed by an amide bond formed between the amino group of Stearate, cholesterol arachidate, cholesterol behenate, choles the Sphingoid base, Sphingosine, and the hydroxyl of the terol lignocerate, cholesterol cerotate, cholesterol montanate, carboxylate group of the fatty acid, esterified co-hydroxy fatty cholesterol melissate, lanosterol oleate, lanosterol laurate, acid. lanosterol myristate, lanosterol palmitate, lanosterol Stearate, lanosterol arachidate, lanosterol behenate, lanosterol lignoc 0065 While not wishing to be bound by any one theory, it erate, lanosterol cerotate, lanosterol montanate, and lanos is believed that disruptions in the epithelial barrier caused by terol melissate. imbalances in the ceramide composition of the skin contrib ute to a variety of skin diseases and disorders. Consequently, 0068. Importantly, when a range of carbon atoms is pre the formulations of the present disclosure are designed to sented, that range optionally includes all of the individual replenish particular ceramides that might be found in reduced integers found between the limits of that range. For example, concentrations in diseased skin, relative to healthy skin, in "Co-C20 optionally includes Co, C1, C12, C1s, C14. Cls. order to reestablish an appropriate balance of ceramides and C. C7, Cs, Co and Co. However, that range can also be other lipids within the skin. Additionally, in some embodi limited to only the even integers between the limits of that ments, the formulations of the present disclosure are designed range. For example, "Co-Co can optionally include only to activate the ceramide production pathways in the underly Co. C12, C14: C16 Cls: C20 C22, C24 C26. C2s. and Cao. ing layers of the skin, and thereby increase the overall content 0069. While not wishing to be bound by any one theory, it and alter the composition of ceramides in newly-formed skin. is believed that disruptions in the epithelial barrier caused by 0.066. In some embodiments the formulations of the imbalance in the cholesterol and/or lanosterol ester compo present disclosure provide omega-hydroxy ceramides, sition of the skin, and particularly in relation to the non because omega-hydroxy ceramides have been found to be esterified cholesterol and/or lanosterol composition of the deficient in diseased skin from patients suffering from atopic skin, contribute to a variety of diseases and disorders. Con dermatitis. (Macheleidt, et al., Deficiency of epidermal pro sequently, the formulations of the present disclosure are tein-bound ()-hydroxyceramides in atopic dermatitis. J. designed to replenish particular cholesterol and/or lanosterol Invest. Dermatol. 2002 July; 119(1):166-73.) esters that are found in reduced concentrations in diseased 0067 “Cholesterol esters.” are cholesterol molecules hav skin, relative to healthy skin, in order to reestablish an appro ing a fatty acid moiety attached through an ester bond. The priate balance of cholesterol and/or lanosterol esters with ester bond is formed between the carboxylate group of the other lipids, and particularly non-esterified cholesterol and/or fatty acid and the hydroxyl group of cholesterol. As used lanosterol within the epidermis. Moreover, the formulations herein, “lanosterol ester” refers to a fatty acid ester of lanos of the present disclosure specifically exclude free cholesterol terol, wherein the ester bond is formed between the carboxy and/or lanosterol; since it has been shown that diseased skin late group of a fatty acid and the free hydroxyl group of from human patients Suffering from atopic dermatitis and lanosterol. Exemplary cholesterol and lanosterol (“choles eczema have an overabundance of free cholesterol. (Di US 2016/0184245 A1 Jun. 30, 2016

Nardo, et al., Ceramide and cholesterol composition of the Invest. Dermatol. 2002 July; 119(1):166-73.) Thus, it is skin of patients with atopic dermatitis. Acta Derm. Venereol. believed that supplementation with VLCFAs is desired to (Stockh) 1998; 78:27-30.) reestablish or reinforce the epithelial barrier and thereby pro 0070 Fatty acids are defined as “carboxylic acids with mote healthy skin. Consequently, the formulations of the long aliphatic tails and the aliphatic tails of naturally-occur present disclosure are designed to provide VLCFAS, Such as ring fatty acids may be saturated or unsaturated. The term lignoceric acid (C), cerotic acid (C), montanic acid (Cs) “very long chain fatty acids.” “VLC fatty acids” or and melissic acid (Co) to the epidermis. “VLCFAs' refer to fatty acids having an aliphatic chain of 0073. “Isostearyl isostearate” refers to the isooctadecyl more than 22 carbons. Exemplary VLCFAs include lignoc ester of isooctadecanoic acid (also known as Stearic acid), eric acid (C24), cerotic acid (C2), montanic acid (C2s) and having the molecular formula of CH7O and the following melissic acid (Cm). Such VLCFAs can be isolated from Structure: botanical sources, such as candelilla wax, obtained from the cuticle of the Euphorbia cerifera plant, or from other natu O rally-occurring sources, or can be chemically synthesized from smaller building block reactants. VLCFAs can also be isolated from beeswax, and Such preparations can be used in the formulations or the present disclosure. However, such 0074 Isostearyl isostearate is a representative of a class of preparations of VLCFAs from beeswax can contain trace compounds formed by linking a fatty alcohol to a fatty acid amounts of allergens, and are thus not preferred. through an ester bond, which can generally be referred to as “fatty esters of fatty acids,” or “FEFAs.” Although the (0071. The suitability of free fatty acids to contribute to embodiments the formulations disclosed herein specifically barrier function appears to depend on their chain length and comprise isostearyl isoStearate, it should be recognized that their state of saturation, since both of these characteristics other FEFAs can be used in place of, or in addition to, isos influence their ability to form highly ordered intercellular tearyl isostearate. When alternative FEFAs are used in the membrane structures (Small, D. M. Lateral chain packing in disclosed formulations, they should contain approximately lipids and membranes. J. Lipid Res. 1984; 25:1490-1500). the same number of carbons as isoStearyl isostearate, such as VLCFAs are highly hydrophobic and have a greater ability to for example Cs2, Css. Csa, Css. Cso, Caz, Css, Cao and Cao prevent water loss than short chain fatty acids when incorpo with approximately half of the carbons residing in the ali rated into the lamellar phases of the stratum corneum. Satu phatic chain of the fatty alcohol and approximately half in the rated fatty acids are more resistant to oxidation than unsatur aliphatic chain of the fatty acid. ated fatty acids and are also able to align and form more 0075 While not wishing to be bound by any one theory, it highly ordered crystalline arrays at skin temperature (Höltje is believed that isostearyl isostearate, and related FEFAs, et al., Molecular dynamics simulations of stratum corneum when topically applied, can effectively promote a healthy lipid models: fatty acids and cholesterol. Biochem. Biophys. epidermal barrier and reduce trans-epidermal water loss Acta 2001; 1511:156-67). Modeling studies on VLCFAs and (TEWL) by promoting tighter packing of the lipids within the long chain ceramides suggest that these lipids more readily skin, thereby promoting internal occlusion of water. See: form crystalline arrays that are impermeable to water Pennick, et al., Superior effect of isostearyl isostearate on (Forslind, B. A domain mosaic model of the skin barrier. Acta improvement in stratum corneum water permeability barrier Derm. Venereol. (Stockh) 1994; 74:1-6). Such crystalline function as examined by the plastic occlusion stress test. Int. arrays appear to be essential for effective barrier function, J. Cosm. Sci. 2010 August; 32(4): 304-12 and Dederen, et al., since this laterally-arrayed lipid organization is known to be Emollients are more than sensory ingredients: the case of Isostearyl Isostearate. Int. J. Cosm. Sci. 2012:34: 502-10. altered in several skin diseases (Pilgram, et al., Aberrant lipid 0076 “Phytosphingosine, which is also known as “4-D- organization in stratum corneum of patients with atopic der hydroxysphinganine' refers to a species of sphingoid base matitis and lamellar ichthyosis. J. Invest. Dermatol. 2001; having the molecular formula of CHNO, and the struc 117:710-7). ture: 0072 While not wishing to be bound by any one theory, it is believed that disruptions in the epithelial barrier caused by imbalance in the fatty acid composition of the skin, contribute H2N HO to a variety of diseases and disorders of the skin. Specifically, to---~". in certain diseases of the skin, Such as atopic dermatitis or OH eczema, the epidermis appears to be deficient in VLCFAs, Such as lignoceric acid (C24), cerotic acid (C2), montanic 0077 N-Stearoyl-phytosphingosine is a sphingolipid acid (Cs) and melissic acid (Co), while having unchanged comprising the Cs fatty acid, octadecanoic acid (also known amounts, or in some cases, an excess of shorter-chained fatty as Stearic acid) and phytosphingosine, wherein in the car acids, such as palmitic acid (C), oleic acid (Cs) and Stearic boxyl group of octadecanoic acid forms an amide bond with acid (Cs). (Macheleidt, et al., Deficiency of epidermal pro the amine of phytosphingosine. N-Stearoyl-phytosphin tein-bound ()-hydroxyceramides in atopic dermatitis. J. gosine has the molecular formula CH7NO, and the struc ture: US 2016/0184245 A1 Jun. 30, 2016

0078. It has been demonstrated that when applied to the immune dominance, and a decrease in B-cell antibody pro skin of mice, N-Stearoyl-phytosphingosine and phytosphin duction. Hence, when administered to a mammal, cortisol gosine effectively inhibited histamine-induced scratching prevents the release of substances in the body that cause behavior. These studies further revealed that these com inflammation. Consequently, cortisol is used to treat condi pounds inhibited the expression of the allergic cytokines, tions resulting from overactivity of the B-cell mediated anti IL-4 and TNF-alpha, and inhibited the activation of the tran body response, as seen in inflammatory diseases, rheumatoid Scription factors, NF-kappaB and c-jun, in histamine-stimu diseases, and allergies. 0082 In some embodiments of the disclosed formulations lated skin. Further, both compounds were shown to exhibit hydrocortisone, or an analog thereof, including, for example, potent anti-histamine effects in the Magnus test using guinea the synthetic glucocorticoids kenelog/triamcinolone, clobe pig ileum, an art-accepted model for testing anti-histamine tasol, betamethasone, fluticaSone, fluocinonide, etc., or com activity. Ryu, et al., Anti-scratching behavior effects of binations thereof, are incorporated as an anti-inflammatory N-Stearoyl-phytosphingosine and 4-hydroxysphinganine in agent. Such embodiments of the disclosed formulations are mice. Lipids. 2010 July; 45(7):613-8. intended for use on diseased skin exhibiting an inappropriate 0079 While not wishing to be bound by any one theory, it or excessive inflammatory response. Such embodiments of is believed that incorporation of N-stearoyl-phytosphin the disclosed formulations are also intended for use on the gosine and phytosphingosine into the disclosed formulations skin of Subjects exhibiting allergic dermatitis, or other dis will inhibit the expression of IL-4 and TNF-alpha, and will eases or disorders that involve an inappropriate or excessive also exhibit anti-histamine and anti-inflammatory activity, response to an exogenous or endogenous allergen. when topically applied to human skin. I0083) "Glycyrrhetinic acid is a pentacyclic triterpenoid 0080 Additionally, phytosphingosine, and other sphin derivative of the beta-amyrin type obtained from the hydroly goid bases and fatty acids are known to poses antibacterial sis of glycyrrhizic acid (glycyrrhizin). and antimycotic activity (Fischer, et al., Antibacterial activity I0084. Glycyrrhizic acid has the structure: of sphingoid bases and fatty acids against Gram-positive and Gram-negative bacteria. Antimicrob. Agents Chemother: 2012 March; 56(3):1157-61 and Veerman, et al., Phytosph ingosine kills Candida albicans by disrupting its cell mem brane. Biol. Chem. 2010 January; 391 (1):65-71). Hence, while not wishing to be bound by any one theory, phytosph HOOC ingosine is included in Some embodiments of the disclosed HO formulations to inhibit the growth of undesired, or patho HO genic, Gram-positive and Gram-negative bacteria, Such as HOOC Staphylococcus aureus, as well as Candida albicans, and HO other pathogenic fungi. In other embodiments of the dis HO closed formulations, D-sphingosine, dihydrosphingosine, or OH the fatty acid, lauric acid, or combinations thereof, including combinations with phytosphingosine, can be used to limit the growth of undesired, or pathogenic, Gram-positive and I0085 While glycyrrhetinic acid, and particularly 18f3-gly Gram-negative bacteria, such as Staphylococcus aureus, as cyrrhetinic acid, has the structure: well as Candida albicans, and other pathogenic fungi. 0081 “Hydrocortisone” which is also known as “corti Sol' is a steroid hormone, and more specifically a glucocor ticoid, normally produced by the Zona fasciculata of the adre nal cortex of mammals. It is released in response to stress and low levels of blood glucocorticoids, and it primarily functions to increase blood Sugar through gluconeogenesis; Suppress the immune system; and aid in fat, protein and carbohydrate metabolism. Synthetic forms of cortisol, and closely-related analogs, have been used to treat a variety of diseases. Hydro cortisone and its analogs act by down-regulating the interleu kin-2 receptor (IL-2R) on “helper' (CD4") T-cells, resulting in the inability of interleukin-2 to up-regulate the Th2 (hu moral) immune response, which results in a Th1 (cellular) US 2016/0184245 A1 Jun. 30, 2016

I0086) 18B-Glycyrrhetinic acid is the major metabolite of acid, glycyrrhizic acid, carbenoXolone, chenodeoxycholic glycyrrhizic acid, and is an important constituent of licorice acid, or PF-877423, or combinations thereof, can potentiate and licorice root. Glycyrrhetinic acid can be chemically Syn the activity of simultaneously or Subsequently administered thesized or can be obtained by extraction from licorice root. corticosteroids. Consequently, in one aspect, the disclosed Although it is used as a flavoring, and it masks the bitter taste formulations comprise a combination of 183-glycyrrhetinic of drugs like aloe and quinine, 183-glycyrrhetinic acid is also acid, glycyrrhizic acid, carbenoXolone, chenodeoxycholic known to have a variety of other activities. (Krähenbühl, et al., acid, or PF-877423, or combinations thereof, and a corticos Kinetics and dynamics of orally administered 18f3-glycyrrhe teroid, such as cortisol (i.e., hydrocortisone) or an analog tinic acid inhumans. J. Clin. Endocrinol. Metab. 1994 March; thereof, including, for example, the synthetic glucocorticoids 78(3):581-5). kenelog/triamcinolone, clobetasol, betamethasone, flutica 0087 Moreover, both glycyrrhizic acid and 18f3-Glycyr Sone, fluocinonide, etc., or combinations thereof, in a phar rhetinic acid have been shown to exhibit corticosteroid-like maceutically acceptable carrier. In another aspect the dis anti-inflammatory and anti-allergic activity. These com closed formulations comprise a combination of 18B pounds apparently act indirectly by potentiating the activity glycyrrhetinic acid, glycyrrhizic acid, carbenoXolone, of corticosteroids. In vitro, glycyrrhetinic acid is known to chenodeoxycholic acid, or PF-877423, or combinations inhibit A4B-reductase, an enzyme that competitively inacti thereof, and a corticosteroid in the presence of a therapeutic Vates steroid hormones, and 11B-hydroxysteroid dehydroge composition comprising specific sphingolipids, cholesterol nase, the enzyme that deactivates cortisol (Hikino H. Recent esters, very long chained fatty acids, and, optionally, fatty research on Oriental medicinal plants. In: Wagner H. Hikino alcohol esters of fatty acids, as disclosed herein. H. Farnsworth N R, eds. Economic and medicinal plant 0091 "Niacinamide,” which is also known as “nicotina research. Vol. 1. London, Academic Press, 1985:53-85.). mide' and “nicotinic acid amide' refers to the amide of nico Glycyrrhizin given intraperitoneally has been shown to Sup tinic acid (or vitamin B or niacin). Niacinamide has been press contact dermatitis in mice, and was found to be more shown to decrease transepidermal water loss in atopic derma effective than prednisolone, but is ineffective when adminis titis and has been shown to be a more effective moisturizer tered orally (Bradley P R, ed. British herbal compendium, than white petrolatum on atopic dry skin (Soma, et al., Mois Vol. 1. Bournemouth, British Herbal Medicine Association, turizing effects oftopical nicotinamide on atopic dry skin. Int. 1992: 145-148.). J. Dermatol. 2005 March; 44(3):197-202). Mechanistically, 0088. In vitro, glycyrrhizic acid has been shown to inhibit niacinamide has been shown to improve the epidermal per the growth of Staphylococcus aureus, Mycobacterium Smeg meability barrier by stimulating the de novo synthesis of matis, and Candida albicans (Mitscher LA et al., Antimicro ceramides (e.g., glucosylceramide and sphingomyelin) bial agents from higher plants. Antimicrobial isoflavanoids through up-regulated expression of serine palmitoyltrans and related Substances from Glycyrrhiza glabra L. var. ferase—the rate-limiting enzyme in sphingolipid synthesis typica. J. Natural Products, 1980; 43:259-269). (Tanno, et al., Nicotinamide increases biosynthesis of cera 0089 Carbenoxolone is a synthetic derivative of glycyr mides as well as other stratum corneum lipids to improve the rhetinic acid, also inhibits 11B-hydroxysteroid dehydroge epidermal permeability barrier. Br. J. Dermatol. 2000 Sep nase, as does chenodeoxycholic acid (Diederich, et al. In the tember; 143(3): 523-31). Niacinamide also has demonstrated search for specific inhibitors of human 113-hydroxysteroid anti-inflammatory activity that may be of benefit to patients dehydrogenase (113-HSDs): chenodeoxycholic acid selec with inflammatory skin conditions (Niren. Pharmacologic tively inhibits 11 B-HSD-I. Euro. J. Endocrinol. 2000 Febru doses of nicotinamide in the treatment of inflammatory skin ary: 142(2): 200-7) (Cheng, et al., The development and SAR conditions: a review. Cutis 2006 January; 77(1 Suppl): 11-6), of pyrrolidine carboxamide 11 beta-HSD1 inhibitors, Bioorg. including Such conditions as acne Vulgaris and atopic derma Med. Chem. Lett. 2010 May 1, 20(9) 2897-902) and titis. Moreover, niacinamide can Suppress antigen-induced, PF-877423 (Johansson, et al., 2-Amino-1,3-thiazol-4(5H)- lymphocytic transformation and inhibit 3'-5' cyclic AMP ones as potent and selective 11 beta-hydroxysteroid dehydro phosphodiesterase, and also has demonstrated ability to block genase type 1 inhibitors: enzyme-ligand co-crystal structure the inflammatory actions of iodides known to precipitate or and demonstration of pharmacodynamic effects in C57BL/6 exacerbate inflammatory acne (Shalita, et al., Topical nicoti mice.J. Med. Chem. 2008 May 22:51 (10):2933-43). Conse namide compared with clindamycin gel in the treatment of quently, carbenoXolone, chenodeoxycholic acid, and inflammatory acne Vulgaris. Int. J. Dermatol. 1995 June; PF-877423, and combinations thereof, can be used in place 34(6):434-7). of, or in combination with 18f3-glycyrrhetinic acid and/or 0092. While not wishing to be bound by any one theory it glycyrrhizic acid in the disclosed formulations. is believed that the inclusion of niacinamide in the disclosed 0090 While not wishing to be bound by any one theory, it formulations can provide synergistic therapeutic benefits that is believed that formulations comprising 183-glycyrrhetinic ultimately result from these demonstrated activities of niaci acid, glycyrrhizic acid, carbenoXolone, chenodeoxycholic namide. In particular, it is believed that niacinamide, in com acid, or PF-877423, or combinations thereof, can be thera bination with 183-glycyrrhetinic acid, glycyrrhizic acid, car peutically beneficial in repairing and restoring a healthy epi benoxolone, chenodeoxycholic acid, or PF-877423, or dermal barrier due to the activities identified above. In par combinations thereof, and optionally in the presence of a ticular, the demonstrated antibacterial activities of 18f3 corticosteroid, such as cortisol (i.e., hydrocortisone) or an glycyrrhetinic acid and/or glycyrrhizic acid against analog thereof, including, for example, the synthetic gluco Staphylococcus aureus, Mycobacterium smegmatis, and corticoids kenelog/triamcinolone, clobetasol, betametha Candida albicans Suggest that therapeutic amounts of these Sone, fluticaSone, fluocinonide, etc., or combinations thereof, compounds can be used to reduce the amount of such patho can provide synergistic therapeutic benefits when such ingre gens on or in epidermal tissues. Moreover, it is believed that dients are provided topically in a simple combination, or in topical or parenteral administration of 183-glycyrrhetinic combination with the formulations of sphingolipids, choles US 2016/0184245 A1 Jun. 30, 2016

terol esters, very long chained fatty acids, and, optionally, skin surface and its impact on the barrier function. Skin Phar fatty alcohol esters offatty acids disclosed herein. It is further macol. Physiol. 2006; 19(6): 296-302). believed that such combinations of niacinamide and 18f3 0096 Changes in skin pH can play a role in the pathogen glycyrrhetinic acid, glycyrrhizic acid, carbenoXolone, cheno esis, prevention and treatment of irritant contact dermatitis, deoxycholic acid, or PF-877423, or combinations thereof, atopic dermatitis, ichthyosis, rosacea, acne Vulgaris, Candida and optionally a corticosteroid, such as cortisol (i.e., hydro albicans infections and wound healing. The acidity of the cortisone) or an analog thereof, including, for example, the skin Surface is thought to be bacteriostatic for Some pathogens synthetic glucocorticoids kenelog/triamcinolone, clobetasol, since many prefer to grow at a neutral pH. A correlation betamethasone, fluticasone, fluocinonide, etc., or combina tions thereof, when provided topically in a simple combina between pH and bacterial growth has been described for tion, or in combination with the formulations of sphingolip propionibacteria after the use of alkaline soap on the forehead ids, cholesterol esters, very long chained fatty acids, and, (Korting, et al., Influence of repeated washings with soap and optionally, fatty alcohol esters of fatty acids disclosed herein, synthetic detergents on pH and resident flora of the skin of can be used to treat epidermal barrier defects, to repair, forehead and forearm. Results of a cross-over trial in health replenish or maintain an effective epidermal barrier, and/or to probationers. Acta Derm Venereol 1987; 67(1): 41-7) and for treat a variety of dermatological disease and disorders asso the development of mycoses in skin folds in patients with ciated with such epidermal barrier defects. diabetes and patients on dialysis (Yosipovitch, et al., Skin 0093. The normal pH on the surface of healthy adult skin surface pH in intertriginous areas in NIDDM patients. Pos is acidic, due to the components of the stratum corneum, sible correlation to candidal intertrigo. Diabetes Care 1993; sebum and Sweat Secretion. Indeed, careful studies have 16(4): 560-3). found that the natural skin Surface pH is on average 4.7, i.e., (0097. In view of the importance of pH on the health of the below 5 (Lambers, et al., Natural skin surface pH is on aver skin and the intactness of the epidermal barrier, the disclosed age below 5, which is beneficial for its resident flora. Int. J. Cosmet. Sci. 2006 October 28(5):359-70). The acidic pH of formulations are designed to maintain a pH as close to the the horny layer of the stratum corneum is referred to the acid range of 4.6 to 5.6 as possible. These pH values are in the mantle, and is important for cutaneous antimicrobial range of optimal activity of beta-glucocerebrosidase and acid defense, through maintenance of naturally-occurring, resi sphygomyelinase and in the range of a healthy epidermal dent skin flora. In diseased skin this acid mantle is often barrier. A disrupted epidermal barrier has an abnormally alka compromised, and the pH of the skin can be neutral to slightly line pH which leads to the serine protease mediated inactiva alkaline. Shifts in the pH of the skin are known to affect the tion and metabolism of the beta-glucocerebrosidase and acid microbiome of the skin, and alkaline pHs can allow for or even promote the growth of undesired or pathogenic micro sphingomyelinase enzymes, which are responsible for the organisms. Restoring the normal acid mantle of the skin is production of ceramides. The disrupted, alkaline skin barrier promotes healthy skin by Supporting the growth of protective is also unable to support a healthy microbiome, since it pro microbiota found on healthy skin, while inhibiting the growth motes the growth of harmful bacteria like Staphylococcus of microorganisms characteristically found on diseased skin aureus and Propionibacterium acnes, while inhibiting the (Id.). growth of “friendly' bacteria such as Staphylococcus epider 0094 Moreover, the pH of the skin follows a gradient midis. This shift in the microbiome of the skin leads to the across the horny layer (from less than 5.0 at the surface to cycle of increased alkalinity, Superinfection of pathogenic neutral in the basal layers), thereby influencing the activities bacteria, and a disrupted epidermal barrier. of the pH-dependent enzymes that regulate skin cornification, 0098. Although the acid dissociation constants of citric descuamation and homeostasis of barrier function. These enzymes—beta-glucocerebrosidase and acidic sphingomy and lactic acids are such that citrate and lactate buffers can be elinase-are essential for ceramide production, lipid process used to maintain appropriately-acidic pHs, these organic ing and lamellar formation and secretion, and are known to acids are not ideal for use in the disclosed formulations have pH optima of around 5.0 (Vaccaro, et al., Characteriza because they can readily crystallize, forming crystals that tion of human glucosylsphingosine glucosyl hydrolase and irritate the skin, and can readily form addition salts that can comparison with glucosylceramidase. Eur: J. Biochem. 1985 also readily crystallize, forming crystals that can irritate the Jan. 15: 146(2):315–21; Takagi, et al., Beta-glucocerebrosi dase activity in mammalian stratum corneum. J. Lipid Res. skin. Consequently, in most embodiments, citric acid and 1999 May; 40(5):861-9). Additionally, in a neutral or alkaline lactic acid are not used as acidifying agents in the disclosed environment, beta-glucocerebrosidases and acid sphingomy formulations. Instead, glucono delta-lactone, lactobionic elinases are inactivated and metabolized by epidermal serine acid, or C-hydroxyacids, 3-hydroxyacids, or other polyhy proteases, which have pH optima in the neutral-to-alkaline droxy acids, or combinations thereof, are used as preferred range. Consequently, formation of the lamellar extracellular acidifying agents to lower the pH of the formulations to the arrangement of barrier lipids requires an acidic milieu. desired range of 4.6 to 5.6. 0095 Endogenous and exogenous factors affect the acid 0099 “Glucono delta-lactone, which is also known as ity of the skin, with the most important factors being age, “gluconolactone.” “D-Glucono-1,5-lactone.” “1.5-D-glu anatomic site, the use of detergents (soaps or synthetic deter conolactone.” “1.5-delta-gluconolactone.” “D-Gluconic acid gents) and cosmetic products, occlusion by body folds or Ö-lactone.” or “GDL refers to a lactone (cyclic ester) or dressings, skin irritants and the use of topical pharmacologi oxidized derivative of D-Gluconic acid, with the following cal substances (Schmid-Wendtner and Korting. The pH of the Structure: US 2016/0184245 A1 Jun. 30, 2016 11

Lactobionic acid has a pKa of 3.8. Like glucono delta-lac tone, because lactobionic acid possesses multiple hydroxyl functional groups, it can act as a metalion chelator, or seques trant. Like glucono delta-lactone, when chelating iron in par ticular, lactobionic acid inhibits the production of hydroxyl radicals, thereby functioning as an antioxidant. Additionally, pure lactobionic acid is hygroscopic and forms a gel contain ing about 14% water from atmospheric moisture. (Draelos. Procedures in Cosmetic Dermatology Series: Cosmeceuti Gluconolactone is a polyhydroxy acid (PHA) that is capable cals. Elsevier Health Sciences, Oct. 31, 2008: 256 pp.) Con of chelating metals and may also scavenge free radicals. sequently, lactobionic acid is used as an acidifying agent in When dissolved in water, it is partially hydrolyzed to gluconic some embodiments of the disclosed formulations, either acid, with the balance between the lactone form and the acid alone or in combination with glucono delta-lactone. form established as a chemical equilibrium. Gluconic acid is a noncorrosive, nonvolatile, nontoxic, mild organic acid with 0102 Although glucono delta-lactone and lactobionic a pKa of 3.7 (Ramachandranet al., Gluconic Acid: A Review. acid are specifically named as acidifying agents for use in the Food Technol. Biotechnol. 2006: 44(2): 185-95.). On account presently disclosed formulations, other acidifying agents can of these properties, glucono delta-lactone is used as both a be utilized in these formulations, either in place of, or in “sequestrant' and an “acidifier in foods. “Sequestrants, a combination with glucono delta-lactone and/or lactobionic term generally used in the context of food additives, improve acid. In some embodiments, eitheran C-hydroxyacid, a B-hy the quality and stability of the food products by forming droxyacid, or another polyhydroxy acid, or any combination chelate complexes with metal ions, especially copper, iron thereof, can be used in the disclosed formulations, either in and nickel ions, which otherwise serve as catalysts in the place of, or in combination with glucono delta-lactone and/or oxidation of the fats in the food. In particular, by chelating lactobionic acid. The advantages of particular hydroxyacids free iron ions, glucono delta-lactone blocks the formation of for clinical and cosmeceutical use are well documented, and hydroxyl radicals, thereby serving as an antioxidant. the use of Such hydroxyacids in particular embodiments of 0100. In addition, glucono delta-lactone is also known to the disclosed formulations is contemplated. (See Green et al., have photoprotective activity (Bernstein, et al., The polyhy Clinical and cosmeceutical uses of hydroxyacids. Clin. Der droxy acid gluconolactone protects against ultraviolet radia matol. 2009 September-October; 27(5):495-501. tion in an in vitro model of cutaneous photoaging. Dermatol. Surg. 2004 February: 30(2 Pt 1): 189-95), and, as an alpha 0103 Ethylenediaminetetraacetic acid (EDTA) is also a hydroxyacid, glucono delta-lactone, is known to enhance sequestrant, and is often used to improve the stability of stratum corneum descquamation, improve skin appearance, personal care products (shampoos and cosmetics). Its effec and prevent skin irritation (Berardesca et al., Alpha hydroxy tiveness lies in its ability to function as a hexadentate (“six acids modulate stratum corneum barrier function. Br. J. Der toothed') ligand and chelating agent, "sequestering metal matol. 1997 December; 137(6):934-8). Consequently, glu ions such as Ca" and Fe". In some embodiments of the cono delta-lactone is utilized as an acidifying agent in some disclosed formulations, a calcium chelator, such as EDTA or embodiments of the disclosed formulations for its ability to phytic acid is used as a sequestrant or preservative, or to acidify the skin, protect the skin from damage by ultraviolet specifically alter the calcium gradient known to exist in radiation, lessen or preventirritation, enhance desired stratum healthy skin. corneum descuamation, and improve skin appearance. In 0104. The amount of EDTA used in the presently dis Some embodiments, glucono delta-lactone is used in combi closed formulations is carefully chosen to provide sufficient nation with lactobionic acid. chelationability to remove calcium from the outermost layers 0101 Lactobionic acid, which is also known as “4-O-B- of the stratum corneum, and to encourage the formation of a galactopyranosyl-D-gluconic acid, or "galactosylgluconic calcium gradient reminiscent of that of healthy skin, in which acid, is a "sugar acid.” and is technically a disaccharide calcium concentrations gradually increase through the Stra formed from gluconic acid and galactose with the following tum basale and the stratum spinosum, to reach a peak in the Structure: outer stratum granulosum, before diminishing through the stratum lucidum and stratum corneum. It is believed that this

characteristic calcium gradient in the epidermis is important for permeability barrier homeostasis, epidermal cell differen tiation, and regulating descquamation of corneocytes at the surface of the skin (Elias, et al., Origin of the epidermal calcium gradient: Regulation by barrier status and role of active vs passive mechanisms. Invest. Dermatol. 2002: 119: 1269-1274). While not wishing to be bound by theory, it is believed that the use of EDTA in the disclosed formulations can help establish a calcium gradient reminiscent of that found in healthy skin, and thereby support permeability bar rier homeostasis, epidermal cell differentiation, and the proper desquamation of corneocytes at the Surface of the skin. 0105. Additionally, by chelating free iron ions, EDTA blocks the formation of hydroxyl radicals, thereby serving as an antioxidant. US 2016/0184245 A1 Jun. 30, 2016

Additional Ingredients: and 18f3-glycyrrhetinic acid. In other embodiments the for mulations can comprise a combination of gluconolactone, 0106 Provided herein are exemplary formulations com niacinamide, 183-glycyrrhetinic acid, and a sphingolipid, prising different subsets of ingredients selected from the such as ceramide 3. In still other embodiments the formula chemical moieties described above, and additional ingredi tions can comprise a combination of gluconolactone, niaci ents as described below. In some embodiments these formu namide, 183-glycyrrhetinic acid, a sphingolipid, such as cera lations are intended for topical administration to the skin mide 3, and a glucocorticoid. Such formulations can also and/or mucous membranes of mammalian Subjects, and par contain any combination of dermatologically acceptable dilu ticularly humans, in need of Such treatment. ents or vehicles, thickeners, humectants, emulsifiers, emol 0107. In addition to the ingredients described above, as lients, structure agents, conditioning agents, antioxidants, would be appreciated by the artisan skilled in the preparation preservatives and/or pH adjusters, Sufficient to impart the of formulations designed for topical application to the skin, desired physical characteristics on the final formulation. the disclosed formulations can also contain a wide variety of 0110. In some embodiments the combinations of compo dermatologically acceptable diluents or vehicles, thickeners, nents used in the formulation are specifically chosen for topi humectants, emulsifiers, emollients, structure agents, condi cal administration. In some embodiments the components are tioning agents, antioxidants, preservatives and pH adjusters. specifically chosen for treating a particular disease or disor The list below is not meant to be fully inclusive or limiting, der. When “combination approaches” are used for treatment but is provided as a general guide. Example diluents or of a particular disease or disorder, particular combinations of vehicles include water, dermatologically acceptable alcohols, components may be chosen for topical administration, while petrolatum, or combinations thereof. Dermatologically other combinations of components may be chosen for oral, acceptable alcohols can be selected from the simple short intralesional, or parenteral administration. When such "com chain alcohols and the toxicologically safe polyols. Examples bination approaches' are used for treatment of a particular include ethanol, isopropanol, propylene glycol, and glycerol. disease or disorder, the combination of components chosen Especially preferred is a member selected from the group for topical administration, and the combination of compo consisting of ethanol, isopropanol, and mixtures thereof. nents chosen for oral, intralesional, or parenteral administra Example thickeners include gums, such as Xantham gum. tion, are carefully selected such that the formulation for topi Example humectants include propanediol and glycerin. cal administration is therapeutically complementary to the Example emulsifiers include glyceryl Stearate, cetyl alcohol, formulation for oral or parenteral administration. polyglyceryl-10 pentastearate, behenyl alcohol and sodium Stearoyl lactylate, and combinations thereof. Example emol Dosage Forms and Packaging: lients include petrolatum, caprylic/capric triglyceride, and isostearyl isostearate. Example structural agents include 0111. The disclosed formulations can take various forms. waxes, such as Euphorbia cerifera (Candelilla) wax, bees For example, the disclosed formulations for topical adminis wax, Chinese Wax and paraffin wax. In some embodiments, tration can be in the form of ointments, lotions, creams, waxes, such as Euphorbia cerifera (Candelilla) wax, bees foams, gels, Solutions or sprays. The disclosed formulations wax, Chinese wax and paraffin wax, and VLCFAs can serve can also be incorporated into dedicated applicators, such as as both structure agents and skin conditioning agents. saturated pads, to facilitate administration to the skin. When Example conditioning agents include Co-Co cholesterol “combination approaches' are used for treatment of a par esters. Example antioxidants include BHT (butylated ticular disease or disorder, the formulations for topical hydroxytoluene) and BHA (butylated hydroxyanisole), toco administration will generally be different from the formula pherols, such as Vitamin E derivatives, and propyl gallate. tions for oral, intralesional, or parenteral administration. Example preservatives include gluconolactone, gluconic 0112 The disclosed formulations may be packaged to pro vide a single dose or multiple doses, and to provide a conve acid, EDTA, 1.2-hexanediol, and caprylyl glycol. nient means of transport, handling, and administration. The 0108. The disclosed formulations can also include, for disclosed formulations may also be packaged in Such away as example, any other ingredients know to be effective for appli to protect the formulation from oxidation, bacterial contami cation to the epidermis, and particularly ingredients that are nation, or other forms of deterioration or degradation. For known to not be irritants or cause any allergic reactions when example, the disclosed formulations for topical administra applied to the skin. tion can be packaged into crimped tubes, airless containers, or sealed foil-lined packets, which may optimally contain Alternative Combinations of Components of the Disclosed enough of the formulation for a single application, or a lim Formulations: ited number of applications. Whereas, the formulations for 0109. In particular embodiments, the disclosed formula oral or parenteral administration can be packaged in any tions contain combinations of specific Subsets of the compo suitable container. The disclosed formulations for topical nents disclosed above. For example, the disclosed formula administration can be packaged in larger containers designed tion may contain, at minimum, combinations of two, three, for multiple applications. When packaged in Such larger con four, five, or more of the following components: gluconolac tainers, those containers may be equipped with pumps or tone and/or lactobionic acid; niacinamide; 183-glycyrrhe other mechanisms designed to facilitate the delivery of an tinic acid and/or glycyrrhizic acid; one or more sphingolipids, appropriate Volume of the formulation, while reducing the including, for example, ceramide 3 (i.e., "CERNP’); one or likelihood of contamination or oxidation. more cholesterol esters; one or more VLCFAs; isostearyl isosterate; phytosphingosine; one or more glucocorticoid, Ointment Formulations: including hydrocortisone and/or an analog thereof, and 0113. In some embodiments the disclosed formulations EDTA. For example, in some embodiments the formulations for topical administration are ointments. Ointments are gen can comprise a combination of gluconolactone, niacinamide, erally defined as formulations lacking any aqueous materials. US 2016/0184245 A1 Jun. 30, 2016

0114. The ointment formulations of the present disclosure waxes used in the formulation is also chosen carefully to comprise combinations of different types of waxes in addition create an ointment formulation with the desired physical to the components described more fully above. In some properties, as outlined above for the wax components of the embodiments, the ointment formulations of the present dis formulations. The ratio of ceramides and phytosphingosine to closure comprise a combination of microcrystalline wax, a waxy components is also chosen to insure that the ceramides VLCFA, and paraffin. and phytosphingosine stay solubilized in the final ointment 0115 Microcrystalline waxes are a type of wax produced preparation. The method of manufacture outlined in the during the petroleum refining process by de-oiling petrola Examples below was chosen to fully solubilize the ceramides tum. In contrast to the more familiar paraffin wax which and phytosphingosine, and maintain them in a solubilized contains mostly unbranched alkanes, microcrystalline wax state, without damaging these components through thermal contains a higher percentage of isoparaffinic (branched) stress. There are, however, many other ways of solubilizing hydrocarbons and naphthenic hydrocarbons, and consists of ceramides and phytosphingosine that the artisan skilled in the high molecular weight saturated aliphatic hydrocarbons. As art of preparing dermatological formulations might employ. its name implies, microcrystalline wax is characterized by the Such methods of solubilizing ceramides are contemplated for fineness of its crystals relative to the larger crystals of paraffin use in preparing the formulation disclosed herein. Aspects of wax. Microcrystalline wax is generally darker, more viscous, the Disclosed Formulations: denser, tackier and more elastic than paraffin waxes, and has 0119. In a first aspect, the disclosed formulations for topi both a higher molecular weight and melting point. The elastic cal administration are compositions comprising therapeuti and adhesive characteristics of microcrystalline waxes are cally effective amounts of at least one of each of the follow related to the non-straight chain components which they con ing: tain. Typical microcrystalline wax crystal structure is Small 0120 a ceramide: and thin, making them more pliable than paraffin wax. 0121 a cholesterol and/or lanosterol ester; and 0116 Paraffin wax is a white or colorless soft solid derived O122. VLCFA. from petroleum that consists of a mixture of hydrocarbon I0123. In some embodiments of this aspect, the disclosed molecules containing between twenty and forty carbon formulations for topical administration further comprise isos atoms. It is solid at room temperature and begins to melt tearyl isostearate. above approximately 37°C. (99 F); with a boiling point of 0.124. In other embodiments of this aspect, the disclosed >370° C. (698°F). formulations for topical administration further comprise a 0117 The ratio of microcrystalline wax, to VLCFA, to therapeutically effective amount of phytosphingosine. paraffin used in the ointment formulations disclosed herein is 0.125. In other embodiments of this aspect, the disclosed chosen to control the physical properties of the final ointment formulations for topical administration further comprise an formulation. The physical properties influenced by the ratio acidifying agent to maintain a pH in the range of 4.6 to 5.6, of microcrystalline wax, to VLCFA, to paraffin include the wherein the acidifying agent is gluconolactone, lactobionic Viscosity and melting temperature of the final ointment for acid, or an O-hydroxyacids, a B-hydroxyacids, or another mulation. The viscosity must be sufficiently thick at room polyhydroxy acid, or combinations thereof. temperature to promote ease of handling. Ointments having I0126. In other embodiments of this aspect, the disclosed too great viscosity (i.e., overly “thick” ointments) can be formulations for topical administration further comprise a difficult to expel or extrude from the containers in which they calcium chelator, wherein the calcium chelator is ethylenedi are routinely stored, such as a crimped tube. Generally oint aminetetraacetic acid (EDTA) or phytic acid. ments having too great viscosity at room temperature present I0127. In other embodiments of this aspect, the disclosed even greater problems at colder temperatures (i.e., at tem formulations for topical, intralesional, oral or parenteral perature below room temperature). Ointments having too administration further comprise a therapeutically effective little viscosity (i.e., overly “thin ointments) can be difficult amount of nicotinamide. to handle or apply due to their more liquid consistency. Gen I0128. In other embodiments of this aspect, the disclosed erally ointments having too little viscosity present even formulations for topical, intralesional or parenteral adminis greater problems at warmer temperatures (i.e., Such as tem tration further comprise atherapeutically effective amount of perature above room temperature). The melting temperature 18B-glycyrrhetinic acid, glycyrrhizic acid, carbenoXolone, of the final ointment formulation greatly influences the ease chenodeoxycholic acid, or PF-877423, or combinations in handling and the ease in applying these formulations. The thereof. melting temperature of the final ointment formulation also I0129. In other embodiments of this aspect, the disclosed influences the feel of the ointment formulation on the skin, formulations for topical, intralesional, oral, or parenteral after it has been applied. An overly viscous formulation can administration further comprise a therapeutically effective feel greasy or sticky. Ideally the ointment formulations of the amount of hydrocortisone oran analog thereof, including, for present disclosure liquefy once applied to the skin, as a result example, the synthetic glucocorticoids kenelog/triamcino of the warmth of the skin to which the ointment formulation lone, clobetasol, betamethasone, fluticasone, fluocinonide, is applied. etc., or combinations thereof. 0118 All of the formulations for topical administration 0.130. In some embodiments of this aspect, the ceramide according to the present disclosure can also comprise ceram included in the disclosed formulations is chosen from at least ides. Both the type and the amount of ceramide included in one of Cer 1 EOS. Cer2NS, Cer 3 NP, Cer 4EOH, Cer the formulation may be altered or adjusted to adapt the for 5AS. Cer 6 AP, Cer 7AH, Cer 8 NH, and Cer9EOP. mulation for specific therapeutic objectives. In the ointment I0131. In some embodiments of this aspect, the cholesterol formulations of the present disclosure, ceramide 3 is used as and/or lanosterol ester included in the disclosed formulations a skin conditioning agent, along with phytosphingosine. The is chosen from at least one of cholesterol oleate, cholesterol ratio of the ceramide 3 and phytosphingosine to the various laurate, cholesterol myristate, cholesterol palmitate, choles US 2016/0184245 A1 Jun. 30, 2016

terol stearate, cholesterol arachidate, cholesterol behenate, 0.155. In some embodiments of this aspect, the disclosed cholesterol lignocerate, cholesterol cerotate, cholesterol formulations for topical administration further comprise isos montanate, cholesterol melissate, lanosterol oleate, lanos tearyl isostearate. terol laurate, lanosterol myristate, lanosterol palmitate, lanos 0156. In some embodiments of this aspect, the disclosed terol Stearate, lanosterol arachidate, lanosterol behenate, formulations for topical administration are compositions lanosterol lignocerate, lanosterol cerotate, lanosterol mon wherein the concentrations of the different ingredients in tanate, and lanosterol melissate. percent weight per weight (w/w), if present, range as follows: 0.132. In some embodiments of this aspect, the VLCFA included in the disclosed formulations is chosen from at least (O157 ceramide, 0.0001-10% (w/w): one of lignoceric acid, cerotic acid, montanic acid, and mel 0158 cholesterol ester, 0.0001-10% (w/w): issic acid, and preferably chosen from at least one of cerotic 0159 VLCFA, 0.001-10% (w/w); and acid, montanic acid, and melissic acid. 0160 isostearyl isostearate, 0.01-10% (w/w). 0133. In this first aspect, the disclosed formulations for 0.161. In a third aspect the disclosed formulations for topi topical administration are compositions wherein the concen cal administration are formulations comprising any of the trations of the different ingredients in percent weight per preceding components, and further comprising at least one weight (W/w), if present, range as follows: dermatologically acceptable diluent or vehicle, thickener, I0134 ceramide, 0.0001-10% (w/w); humectant, emulsifier, emollient, structure agent, condition 0.135 cholesterol and/or lanosterol ester, 0.0001-10% ing agent, antioxidant, preservative or pH adjuster. (w/w); 0162. In this aspect, the dermatologically acceptable dilu 0.136 VLCFA, 0.01-10% (w/w); ents or vehicles comprise water, a dermatologically accept I0137 phytosphingosine, 0.0001-10% (w/w): able alcohol, or petrolatum, or combinations thereof. I0138 isostearyl isostearate, 0.01-10% (w/w): 0.139 acidifying agent to maintain a pH of 5.0–5.6, X-Y Patient Population: % (w/w); (O140 EDTA or phytic acid, 0.01-2.0% (w/w); (0163 The disclosed formulations are intended for use on 0141 nicotinamide, when present, 0.1-10.0% (w/w), mammalian skin, including, for example, the skin of humans, 0.142 183-glycyrrhetinic acid, glycyrrhizic acid, car domestic pets, livestock and other farm animals. When used benoxolone, chenodeoxycholic acid, or PF-877423, or on human Subjects, or human patients in need of Such treat combinations thereof, when present, 0.0001-10% ment, the human patients may be of any age or gender, (w/w), although specific formulations may be developed for treating 0.143 hydrocortisone, or an analog thereof, including, human patients within specific age ranges, or of a particular for example, the synthetic glucocorticoids kenelog/tri gender. amcinolone, clobetasol, betamethasone, fluticaSone, fluocinonide, etc., or combinations thereof, when Diseases, Disorders and Conditions to Treat: present, 0.05-10.0% (w/w), and (0164. The disclosed formulations are intended to treat dis 0144 gluconolactone, when present, 0.1-8.0% (w/w). eases or disorders or conditions of the skin and mucous mem 0145. In a second aspect, the disclosed formulations for branes which result in, or are characterized by, disruptions or topical administration are a composition comprising thera dysfunctions of the epidermal barrier, and dermal or epider peutically effective amounts of at least one of each of the mal inflammation, or which are characterized by inflamma following: tion, irritation, abnormal descquamation and/or alterations in 0146 183-glycyrrhetinic acid, glycyrrhizic acid, car the epidermal microbiome. The disclosed formulations may benoxolone, chenodeoxycholic acid, or PF-877423, or com also be used prophylactically, in order to prevent, or lessen the binations thereof, and symptoms of a disease, disorder, or condition before it fully 0147 hydrocortisone, or an analog thereof, including, for develops. example, the synthetic glucocorticoids kenelog/triamcino 0.165. As such, the disclosed formulations may be used for lone, clobetasol, betamethasone, fluticasone, fluocinonide, treating, lessening the symptoms of, or preventing the Symp etc., or combinations thereof. toms of any of the following diseases, disorders, or condi 0148. In this second aspect, the disclosed formulations for tions: topical administration area composition wherein the concen 0166 a) Atopic and seborrheic dermatitis and other trations of the different ingredients in percent weight per genetically predisposed dermatitides; weight (W/w) range as follows: 0.167 b) Eczematous dermatitis induced by environ 0149 183-glycyrrhetinic acid, glycyrrhizic acid, car mental or occupational insults, specifically allergic and benoxolone, chenodeoxycholic acid, or PF-877423, or com irritant contact, eczema craquelee, radiation and stasis binations thereof, 0.0001-10% (w/w), and 0150 hydrocortisone, or an analog thereof, including, for dermatitis; example, the synthetic glucocorticoids kenelog/triamcino 0168 c) Ulcers and erosions due to cutaneous trauma lone, clobetasol, betamethasone, fluticasone, fluocinonide, including chemical or thermal burns or vascular com etc., or combinations thereof, 0.001-10.0% (w/w). promise or ischemia including venous, arterial, embolic 0151. In some embodiments of this aspect, the disclosed or diabetic ulcers; formulations for topical administration further comprise (0169 d) Ichthyoses: therapeutically effective amounts of at least one of each of the (0170 e) Epidermolysis bullosa; following: 0171 f) Psoriasis and other papulosquamous disorders: 0152 a ceramide: 0172 g) Cutaneous changes of intrinsic aging Such as 0153 a cholesterol and/or lanosterol ester; and Xerosis or Grover's Disease and/or dermatoheliosus; 0154 a VLCFA. 0173 h) Mechanical friction blistering: US 2016/0184245 A1 Jun. 30, 2016 15

(0174 i) Corticosteroid atrophy, for reversal and preven according to the response of the patient, and the efficacy of the tion; treatment, as will be judged by the patient themselves, or by 0.175 j) Cutaneous lupus erythematosus including a health care provider who is directing the treatment. Specific acute and chronic cutaneous lupus; details regarding the methods of treatment can be defined by 0176 k) Steroid responsive dermatoses: a health care provider overseeing the treatment, or by the (0177 l) Rosacea; patient, as results are obtained. Effective results will, in most 0.178 m) Photodermatoses including idiopathic photo cases, be achieved by topical application of a disclosed for dermatoses such as polymorphic or polymorphous light mulation in a thin layer directly over the affected area or eruption (PMLE), chronic actinic dermatitis, solar urti caria, actinic prurigo, and hydroa vacciniforme; genetic areas, or in the area where one seeks to obtain a desired result. photodermatoses including cutaneous porphyrias, 0188 In some embodiments, treatment may consist of Bloom's syndrome, Xeroderma pigmentosum, reticular topical application of thin layers of particular disclosed for erythematous mucinosis, and Subacute cutaneous lupus mulations in a particular order. In other embodiments, treat erythematosus; metabolic photodermatoses, including ment may consist of topical application of thin layers of porphyrias and pellagra, and exogenous photoderma particular disclosed formulations in a particular order, inter toses including drug-induced photosensitivity (both spersed with over-the-counter formulations, such as 1% phototoxic and photoallergenic), pseudoporphyria, and hydrocortisone cream. For example, in some embodiments, phytophotodermatitis; as well as other underlying skin treatment may consist of topical application of a thin layer of disorders that are exacerbated by exposure of the skin to a cream formulation, Such as Exemplary Formulation C or Sunlight, including Darier's disease, Herpes simplex, Exemplary Formulation D, followed by topical application of vitiligo, lupus, cutaneous lupus, and dermatomyositis; a thin layer of an ointment formulation, Such as Exemplary 0179 n) Symptoms of mycosis fungoides, a cutaneous Formulation A. In other embodiments, treatment may consist T-cell lymphoma also known as Alibert-Bazin syndrome of topical application of a thin layer of a cream formulation, or granuloma fungoides; such as Exemplary Formulation C, followed by topical appli 0180 o) Acne: cation of a thin layer of an over-the-counter formulation of 0181 p) Flushing of the skin; and 1% hydrocortisone cream, followed by topical application of 0182 q) Keratosis Pilaris. a thin layer of an ointment formulation, Such as Exemplary 0183 The disclosed formulations for topical administra Formulation A. Alternatively, in other embodiments, treat tion may also be used to fortify the epidermal barrier of a ment may consist of topical application of a thin layer of a patient in order to prevent or reduce symptoms of an occupa cream formulation, such as Exemplary Formulation D, which tionally or environmentally induced or genetically predis contains 1% hydrocortisone, followed directly by topical posed cutaneous disorder, by administering a therapeutically application of a thin layer of an ointment formulation, Such as effective amount of a disclosed formulation to the skin of such Exemplary Formulation A. In still other embodiments, treat a patient. ment may consist of topical application of a thin layer of a 0184 The disclosed formulations for topical administra lotion formulation, such as Exemplary Formulation B, fol tion may also be used to fortify the epidermal barrier of a lowed by topical application of a thin layer of an ointment premature infant under 33 weeks gestational age, by admin formulation, Such as Exemplary Formulation A. In Such istering a therapeutically effective amount of a disclosed for multi-layer applications, the ointment formulation would mulation to the skin of Such a premature infant. usually be the last to be applied, so that it can form a more 0185. The disclosed formulations for topical administra impervious external barrier and facilitate trans-epidermal dif tion may also be used to prevent or reduce cutaneous irritation fusion of the contents of the underlying layers. or disruption of the epidermal barrier in patients being admin 0189 Depending upon the disease, disorder, or condition istered a therapeutic agent which produces cutaneous irrita to be treated, and its severity, and whether the treatment is tion and/or disrupts the epidermal barrier, by administering a being done for therapeutic or prophylactic reasons, effective therapeutically effective amount of a disclosed formulation to results may be obtained with application rates of from one the skin of Such a patient, prior to, concurrent with, or after application every week, to once every day, to multiple appli administration of the therapeutic agent which produces cuta cations per day. In some embodiments the Exemplary Formu neous irritation and/or disrupts the epidermal barrier. lations are applied twice a day, with a first application at the 0186 The disclosed formulations for topical administra start of a patient’s day, following a bath or shower, and the tion may also be used to protect skin that is to be exposed to second application at the end of the day, immediately prior to ionizing radiation, by administering a therapeutically effec the patient retiring for sleep. Traditionally, such applications tive amount of a disclosed formulation to the skin that is to be would occur in the morning and evening, but the time of exposed to ionizing radiation, prior to that skin being exposed application can be adjusted to the patient’s daily schedule or the ionizing radiation. routine. In all embodiments, the duration of the treatment regimen can be adjusted according to the patient’s needs and Methods of Treatment: according to the patient's disease or disorder's response to the 0187. The methods of treatment to be employed with the treatment. Treatment can either be discontinued, or its fre disclosed formulations will vary depending upon the disease, quency lessened, once symptoms diminish or disappear. disorder, or condition to be treated, and its severity. The Alternatively, it may be advantageous for treatments to con methods will also vary depending upon the nature of the tinue for a fixed period beyond the diminution or disappear Subject to be treated; their species, gender, and age, etc. Opti ance of symptoms, and in other cases, it may be advantageous mal methods of treatment, including the choice of specific for treatment to continue indefinitely as a prophylactic treat formulation, the form of that formulation, the frequency of ment in patients who suffer from chronic disruption of the administration, and the duration of treatment will be adjusted epidermal barrier. US 2016/0184245 A1 Jun. 30, 2016

0190. In other embodiments, the administration of par Manufacturing Procedure: ticular Subset of components described above can be via an oral, parenteral, or intralesional route, while another Subset of 0194 1. Combine all Phase A ingredients and heat mix components can be via a topical route. In other words, the ture to 85°C.; mixing with moderate agitation. methods of treatment may combine the oral, parenteral, or 0.195 2. Mix until all waxes have melted and the mix intralesional administration of a Subset of components with ture becomes homogenous. the topical administration of another Subset of components. 0196) 3. Cool to 75° C. These so-called “combined approaches to administration of 0.197 4. With mixture held at 75° C. add each Phase B the components described above will necessarily take into component, one at a time, and mix until all have been account the pharmacological characteristics of each indi melted and a homogenous mixture has been formed. vidual component, including the human body's ability to (0198 5. Slowly cool to 35° C. and package. absorb, distribute, metabolize and excrete (ADME) the individual components when administered either orally, Exemplary Formulation A parenterally, or intralesionally. These “combined approaches to administration of the components will also SkinTreatment Ointment necessarily take into account the toxicity of each individual component when administered orally, parenterally, or intrale 0199. sionally. In some instances, the route of administration of a particular ingredient, such as, for example, ceramides and gluconolactone, will be limited to topical administration. For Component other ingredients, such as, for example, niacinamide, the Phase (INCI Nomenclature) % by Weight Function route of administration may be topical, intralesional, A Microcrystalline Wax 8.750 Viscosity Increasing parenteral, or oral, or some combination thereof. For still Agent other ingredients, such as, for example, 183-glycyrrhetinic A Euphorbia cerifera 0.01-10.0 Skin Conditioning Agent (Candelilla) Wax acid or glycyrrhizic acid, the route of administration may be A Ceramide 3 0.0001-5.0 Skin Conditioning Agent topical, intralesional, parenteral, or oral, or a combination A Phytosphingosine 0.0001-5.0 Skin Conditioning Agent thereof. When ingredients are to be administered parenterally, B Petrolatum 3.0-99.0 Skin Conditioning Agent B Coco-Caprylate 1S.OO Emollient they can be administered via any suitable parenteral route, B Caprylic Capric 16.97 Skin Conditioning Agent including, for example, Subcutaneously, intramuscularly, Triglyceride intravenously, or intraperitoneally, or some combination B Paraffin 4.OO Skin Conditioning Agent thereof. When ingredients are to be administered intralesion B Isostearyl Isostearate 0.01-8.0 Emollient ally, they can be administered via percutaneous injection B Glycyrrhetinic Acid 0.0001-5.0 Skin Conditioning Agent B Co-3o 0.0001-5.0 Skin Conditioning Agent within a skin lesion. The preferred parenteral route used in Cholesterol, Lanosterol such “combined approaches' will be chosen based upon a Esters variety of characteristics, including improved efficacy and/or reduced toxicity and/or adverse effects that might arise through topical administration alone. Exemplary Formulation B Concentrations/Dosages: 0191 The concentrations of the various ingredients of the 0200 Provided herewith is a second exemplary formula disclosed formulations may vary widely, and will vary tion that is a lotion according to the disclosed formulations according to the route of administration. A typical range of provided herein. concentration for each ingredient in topical formulations is from about 0.001% to about 10%. For all components having Manufacturing Procedure: an effect on the epidermal barrier, regardless of the route of 0201 1. Disperse the xanthan gum in water and start administration, the amount of an ingredient to be incorpo heating to 70-75° C. rated is to be a therapeutically-effective amount. The specific 0202 2. Add remaining Phase A ingredients while heat concentrations of ingredients will depend upon the disease, ing, mix until the niacinamide dissolves. disorder or condition being treated, its severity, and the treat 0203 3. Mix Phase B ingredients together and heat to ment regimen, including the route of administration, being 75-800 C. used. When taken into consideration, these factors will guide the skilled artisan in determining what final concentrations to 0204 4. Mix until uniform. use for the various ingredients. 0205 5. Slowly add Phase B to Phase A and mix until 0.192 The following examples are being provided for the uniform. purpose of illustration only. They are not intended to be 0206 6. Homogenize at 3,500 RPM for 5 minutes with limiting in any manner, and are not provided to specifically a Silverson Mixer Homogenizer (Silverson Machines, define or limit the scope of the disclosed formulations. Inc., East Long Meadow, Mass.). Examples 0207 7. Cool with mixing to 40-45° C. 0208 8. Add Phase C (1.2-henanediol caprylyl glycol) Exemplary Formulations and mix until uniform. Exemplary Formulation A 0209) 9. Cool with mixing to room temperature. 0193 Provided herewith is a first exemplary formulation 0210 10. While mixing, adjust pH to 4.6 to 5.6 with that is an ointment according to the disclosed formulations Phase D (a 20% solution of gluconolactone). provided herein. 0211 11. Aliquot into packaging. US 2016/0184245 A1 Jun. 30, 2016 17

Exemplary Formulation B Exemplary Formulation C SkinTreatment Lotion Skin Treatment Cream 0212 0226

COMPONENT 96 BY COMPONENT 96 BY PHASE (INCINOMENCLATURE) WEIGHT FUNCTION PHASE (INCINOMENCLATURE) WEIGHT FUNCTION A WATER (AQUA) 71.33 DILUENT A WATER (AQUA) SO.O1 DILUENT A XANTHAN GUM O.6O THICKENER A XANTHAN GUM O4O THICKENER A DISODIUM EDTA O.OS CHELATING A DISODIUM EDTA O.OS CHELATING AGENT AGENT A PROPANEDIOL 2.OO HUMECTANT A PROPANEDIOL 2.OO HUMECTANT A GLYCERIN 1.OO HUMECTANT A GLYCERIN 2.OO HUMECTANT A NLACINAMIDE O.40 ACTIVE A NIACINAMIDE O4O ACTIVE B POLYGLYCERYL-10 3.00 EMULSIFIER B POLYGLYCERYL-10 S.OO EMULSIFIER PENTASTEARATE, PENTASTEARATE, BEHENYLALCOHOL, BEHENYL ALCOHOL, SODIUMSTEAROYL SODIUMSTEAROYL LACTYLATE LACTYLATE B CAPRYLICACAPRIC 7.50 EMOLLIENT B PETROLATUM 12.00 EMOLLIENT TRIGLYCERIDE B CAPRYLICCAPRIC 1O.SO EMOLLIENT B GLYCERYL STEARATE 1.50 EMULSIFIER TRIGLYCERIDE B NEOPENTYL GLYCOL 7.50 EMOLLIENT B ISOSTEARYLISOSTEARATE 2.00 EMOLLIENT DIHEPTANOATE B GLYCERYL STEARATE 1.50 EMULSIFIER B EUPHORBA CERIFERA 1.OO STRUCTURE B NEOPENTYL GLYCOL 9.00 EMOLLIENT (CANDELILLA). WAX AGENT DIHEPTANOATE B CETYLALCOHOL 1.50 EMULSIFIER B EUPHORBA CERIFERA 1.OO STRUCTURE B C10-30 1.OO CONDITIONING (CANDELILLA). WAX AGENT CHOLESTEROL AGENT B CETYLALCOHOL 1.50 EMULSIFIER LANOSTEROL B Co-3o 1.OO CONDITIONING ESTERS CHOLESTEROL AGENT B CERAMIDE 3 O.OS ACTIVE LANOSTEROL B GLYCYRREHETINIC ACID O.SO ACTIVE ESTERS B PHYTOSPINGOSINE O.10 ACTIVE B CERAMIDE 3 O.OS ACTIVE C 1.2-HEXANEDIOL, 0.75 PRESERVATIVE B PHYTOSPINGOSINE O.10 ACTIVE CAPRYLYL GLYCOL B GLYCYRREHETINIC ACID OSO ACTIVE D WATER, 0.22 pH ADJUSTOR C 12-HEXANEDIOL, 0.75 PRESERVATIVE GLUCONOLACTONE CAPRYLYL GLYCOL 20% D WATER, 0.24 pH ADJUSTER GLUCONOLACTONE 20% Exemplary Formulation C 0213 Provided herewith is a third exemplary formulation Exemplary Formulation D that is an creme according to the disclosed formulations pro vided herein. 0227 Provided herewith is a fourth exemplary formula tion that is an creme comprising 1% hydrocortisone as an Manufacturing Procedure: anti-inflammatory according to the disclosed formulations provided herein. 0214) 1. Disperse the xanthan gum in water and start heating to 70-75° C. Manufacturing Procedure: 0215 2. Add remaining Phase A ingredients while heat ing, mix until the niacinamide dissolves. 0228 1. Disperse the xanthan gum in water and start 0216 3. Mix Phase B ingredients together and heat to heating to 70-75° C. 75-800 C. 0229 2. Add remaining Phase A ingredients while heat 0217. 4. Mix until uniform. ing, mix until the niacinamide dissolves. 0218 5. Slowly add Phase B to Phase A and mix until 0230 3. Mix Phase B ingredients together and heat to uniform. 75-800 C. 0219. 6. Homogenize at 3,500 RPM for 5 minutes with 0231. 4. Mix until uniform, making certain that the a Silverson Mixer hydrocortisone acetate is dissolved. 0220 Homogenizer (Silverson Machines, Inc.; East Long 0232 5. Slowly add Phase B to Phase A and mix until Meadow, Mass.). uniform. 0221) 7. Cool with mixing to 40-45° C. 0233 6. Homogenize at 3,500 RPM for 5 minutes with 0222 8. Add Phase C (1.2-henanediol, caprylylglycol) a Silverson Mixer Homogenizer (Silverson Machines, and mix until uniform. Inc., East Long Meadow, Mass.). 0223) 9. Cool with mixing to room temperature. 0234 7. Cool with mixing to 40-45° C. 0224 10. While mixing, adjust pH to 4.6 to 5.6 with 0235 8. Add Phase C (1.2-henanediol caprylyl glycol) Phase D (a 20% solution of gluconolactone). and mix until uniform. 0225 11. Aliquot into packaging. 0236 9. Cool with mixing to room temperature. US 2016/0184245 A1 Jun. 30, 2016 18

0237 10. While mixing, adjust pH to 4.6 to 5.6 with scribed, and had taken, courses of orally-administered Phase D (a 20% solution of gluconolactone). plaquenyl, courses of orally-administered aspirin, and 0238 11. Aliquot into packaging. courses of orally-administered chloroquin, with little or no effect. All attempts to reduce the patient’s suffering from Exemplary Formulation D cutaneous lupus erythematosus had brought little to no relief. 0242. The patient was instructed to topically apply to the SkinTreatment Cream with 1% Hydrocortisone affected areas, the cream of Exemplary Formulation C, fol Acetate lowed by an over-the-counter 1% hydrocortisone cream, fol lowed the ointment of Exemplary Formulation A, in sequen 0239) tial thin coatings at night. She was also instructed to topically apply to the affected areas, the cream of Exemplary Formu COMPONENT 96 BY lation C, followed by an over-the-counter 1% hydrocortisone PHASE (INCINOMENCLATURE) WEIGHT FUNCTION cream, in sequential thin coatings in the morning. 0243 FIG. 1 depicts the chest and neck area of this patient A WATER (AQUA) 49.01 DILUENT A XANTHAN GUM O.4O THICKENER prior to treatment with the formulations of the present disclo A DISODIUM EDTA O.OS CHELATING sure. FIG. 2 depicts the chest and neck area of the same AGENT patient after approximately 3 weeks of the treatment regimen A PROPANEDIOL 2.OO HUMECTANT described above. A GLYCERIN 2.OO HUMECTANT A NLACINAMIDE O.40 ACTIVE 1. A composition comprising therapeutically effective B POLYGLYCERYL-10 S.OO EMULSIFIER amounts of at least one of each of the following: PENTASTEARATE, BEHENYLALCOHOL, a ceramide; SODIUM STEAROYL a cholesterol/lanosterol ester, and LACTYLATE a very long chain fatty acid (VLCFA). B PETROLATUM 12.00 EMOLLIENT B CAPRYLICACAPRIC 10.50 EMOLLIENT 2. The composition of claim 1, further comprising isos TRIGLYCERIDE tearyl isostearate. B ISOSTEARYLISOSTEARATE 2.00 EMOLLIENT 3. The composition of claim 1, further comprising a thera B GLYCERYL STEARATE 1.50 EMULSIFIER peutically effective amount of phytosphingosine. B NEOPENTYL GLYCOL 9.00 EMOLLIENT DIHEPTANOATE 4. The composition of claim 1, further comprising an acidi B. HYDROCORTISONE 1.OO ANTI-IN fying agent to maintain a pH of 4.6-5.6, wherein the acidify ACETATE FLAMMATORY ing agent comprises a polyhydroxy acid. B EUPHORBA CERIFERA 1.OO STRUCTURE (CANDELILLA). WAX AGENT 5. The composition of claim 1, further comprising a cal B CETYLALCOHOL 1.50 EMULSIFIER cium chelator, wherein the calcium chelator is ethylenedi B Co-3o 1.OO CONDITIONING aminetetraacetic acid (EDTA) or phytic acid. CHOLESTEROL AGENT LANOSTEROL 6. The composition of claim 1, further comprising a thera ESTERS peutically effective amount of nicotinamide. B CERAMIDE 3 O.OS ACTIVE 7. The composition of claim 1, further comprising a thera B PHYTOSPINGOSINE O.10 ACTIVE peutically effective amount of 183-glycyrrhetinic acid, gly B GLYCYRREHETINIC ACID O.SO ACTIVE C 1.2-HEXANEDIOL, 0.75 PRESERVATIVE cyrrhizic acid, carbenoXolone, chenodeoxycholic acid, or CAPRYLYL GLYCOL PF-877423, or combinations thereof. D WATER, 0.24 pH ADJUSTER 8. The composition of claim 1, further comprising a thera GLUCONOLACTONE peutically effective amount of hydrocortisone, triamcino 20% lone, clobetasol, betamethasone, fluticasone, or fluocinonide, or combinations thereof. 9. The composition of claim 1, wherein the ceramide is Exemplary Methods of Treatment chosen from at least one of Cer 1 EOS. Cer 2 NS. Cer 3 NP, Cer 4 (EOH), Cer 5 IAS, Cer 6 AP, Cer 7 AH., Cer Cutaneous Lupus Erythematosus: 8 NH), and Cer9 |EOP. 0240 A patient presented with a three year history of 10. The composition of claim 1, wherein the cholesterol cutaneous lupus erythematosus. She had been Suffering from and/or lanosterol ester is chosen from at least one of choles systemic lupus erythematosus for Some time before the rash terol oleate, cholesterol laurate, cholesterol myristate, cho that is characteristic of cutaneous lupus erythematosus lesterol palmitate, cholesterol Stearate, cholesterol arachi appeared on her chest, arms, neck and face. date, cholesterol behenate, cholesterol lignocerate, 0241 Prior to treatment with a treatment regime utilizing cholesterol cerotate, cholesterol montanate, cholesterol mel the formulations of the present disclosure, this patient had issate, lanosterol oleate, lanosterol laurate, lanosterol been treated with several different treatment regimens repre myristate, lanosterol palmitate, lanosterol Stearate, lanosterol senting the standard of care for cutaneous lupus erythemato arachidate, lanosterol behenate, lanosterol lignocerate, lanos SuS patients. In particular, she had been using over-the terol cerotate, lanosterol montanate, and lanosterol melissate. counter and prescription topical creams and ointments, 11. The composition of claim 1, wherein the VLCFA is including maximal strength hydrocortisone cream applied chosen from at least one of lignoceric acid, cerotic acid, multiple times per day, with little or no effect. She had been montanic acid, and melissic acid. prescribed, and had taken, prednisone orally for several 12. The composition of claim 1, wherein the concentra months, with little or no effect. She had been administered tions of ingredients, in percent weight per weight (w/w), if cortisone shots, with little or no effect. She had been pre present, range as follows: US 2016/0184245 A1 Jun. 30, 2016 19

ceramide, 0.0001-10% (w/w): wherein the composition comprises a ceramide, a choles cholesterol and/or lanosterol ester, 0.0001-10% (w/w); terol/lanosterol ester, and a very long chain fatty acid VLCFA, 0.01-10% (w/w); (VLCFA); and phytosphingosine, 0.0001-10% (w/w); wherein the disease, disorder, or condition is selected from: isostearyl isostearate, 0.01-10% (w/w); a) Atopic and seborrheic dermatitis; acidifying agent to maintain a pH of 4.6-5.6, X-Y% (w/w); b) Eczematous dermatitis; EDTA or phytic acid, 0.01-2.0% (w/w); c) Ulcers and erosions due to cutaneous trauma; nicotinamide, when present, 0.01-10.0% (w/w), d) Ichthyoses: 18B-glycyrrhetinic acid, glycyrrhizic acid, carbenoXolone, e) Epidermolysis bullosa; chenodeoxycholic acid, or PF-877423, or combinations f) Psoriasis and other papulosquamous disorders; thereof, when present, 0.0001-5% (w/w), g) Cutaneous changes of intrinsic aging: hydrocortisone or an analog thereof, including, for h) Mechanical friction blistering: example, the synthetic glucocorticoids kenelog/triamci i) Corticosteroid atrophy; nolone, clobetasol, betamethasone, fluticaSone, fluoci j) Cutaneous lupus erythematosus; nonide, etc., or combinations thereof, when present, k) Steroid-responsive dermatoses; 0.001-10.0% (w/w), and I) Rosacea; gluconolactone, when present, 0.01-8.0% (w/w). m) Photodermatoses; 13. A composition comprising therapeutically effective n) Symptoms of mycosis fungoides; amounts of: o) Acne; 18B-glycyrrhetinic acid, glycyrrhizic acid, carbenoXolone, p) Flushing of the skin; and chenodeoxycholic acid, or PF-877423, or combinations q) Keratosis Pilaris. thereof, and 21. The method of claim 20, wherein said patient is a hydrocortisone, triamcinolone, clobetasol, betamethasone, human patient. fluticasone, fluocinonide, or combinations thereof. 22. The method of claim 20, wherein the composition is 14. The composition of claim 13, further comprising a applied to the affected skin of a patient one or more times a therapeutically effective amount of day over a multiday period. a ceramide; 23-27. (canceled) a cholesterol ester; 28. The method of claim 20, wherein the composition is a VLCFA; and administered to a premature infant under 33 weeks gesta isostearyl isostearate. tional age. 15.-19. (canceled) 29. The composition of claim 1, wherein the composition is 20. A method of treating, lessening the symptoms of, or effective to treat a disease, disorder, or condition of the skin. preventing the symptoms of a disease, disorder, or condition, 30. The composition of claim 13, wherein the composition the method comprising administering a therapeutically effec is effective to treat a disease, disorder, or condition of the skin. tive amount of a composition to the affected skin of a patient, k k k k k