Treatment of skin disorders with short-chain fatty acids

Abstract

The present disclosure describes methods of treating a condition comprising administering a pharmaceutical composition comprising at least one short-chain fatty acid (SCFA). The disclosed methods can be used to treat skin disorders or autoimmune disorders.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 479,404, filed January 11, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Short-chain fatty acids (SCFAs) are saturated fatty acids consisting of one polar carboxylic acid moiety and a hydrophobic hydrocarbon chain, of which acetate (C2), propionate (C3), and butyrate (C4) are the most common and well-studied molecules.

[0003] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0004] Disclosed herein are methods for treating or reducing the likelihood of developing a disease or disorder, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthetic precursor, compound containing an SFCA moiety, derivatives thereof, and combinations thereof.

[0005] Disclosed herein are methods of treating a condition, the method comprising: a) administering to a subject in need thereof a first pharmaceutical composition, the first pharmaceutical composition comprising a therapeutically effective amount of a compound that is a short-chain fatty acid or a pharmaceutically acceptable salt thereof; and b) administering to the subject a second pharmaceutical composition, the second pharmaceutical composition comprising a therapeutically effective amount of a phosphodiesterase 4 (PDE4) inhibitor.

[0006] Disclosed herein is a method of treating a condition, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a first pharmaceutical composition comprising at least one SCFA and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective to treat the condition in combination with the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA, and the reduced amount of the second therapy is less than the amount of the second therapy that is therapeutically effective for the condition in the absence of the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA. [Brief explanation of the drawings]

[0007] [Figure 1] IL-22 levels after treatment with NativeSkin®, InflammaSkin® control, and betamethasone are shown.

[0008] [Figure 2] Hematoxylin & Eosin (H&E) staining of NativeSkin® samples on days 0 and 7 is shown.

[0009] [Figure 3] H&E staining of the InflammaSkin® group after no treatment or treatment with betamethasone, Otezla® (apremilast), or SCFA is shown.

[0010] [Figure 4] K16 expression in NativeSkin® samples on days 0 and 7 is shown.

[0011] [Figure 5] 1 shows K16 expression in the InflammaSkin® group after no treatment or treatment with betamethasone, Otezla® (apremilast), or SCFA.

[0012] [Figure 6]IL-17A expression in NativeSkin® samples and InflammaSkin® groups after no treatment or treatment with betamethasone, Otezla® (apremilast), or SCFAs containing butyrate and propionate is shown.

[0013] [Figure 7] Shown is the fold change in IL-17A expression in the InflammaSkin® group after no treatment or treatment with betamethasone, Otezla® (apremilast), or SCFA.

[0014] [Figure 8] 1 shows TNF-α expression in NativeSkin® samples and InflammaSkin® groups without treatment or after treatment with betamethasone, Otezla® (apremilast), or SCFA.

[0015] [Figure 9] Shown is the fold change in TNF-α expression in the InflammaSkin® group after no treatment or treatment with betamethasone, Otezla® (apremilast), or SCFA.

[0016] [Figure 10] Figure 1 shows cytokine release of IFN-γ, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, MIP-3α, and TNF-α from NativeSkin® samples and InflammaSkin® groups without treatment or after treatment with betamethasone, Otezla® (apremilast), or SCFA.

[0017] [Figure 11] Figure 1 shows cytokine release of IFN-γ from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0018] [Figure 12] Figure 1 shows cytokine release of IL-17A from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0019] [Figure 13] Figure 1 shows cytokine release of IL-21 from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0020] [Figure 14] Figure 1 shows cytokine release of IL-22 from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0021] [Figure 15] Figure 1 shows cytokine release of IL-23 from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0022] [Figure 16] Figure 1 shows cytokine release of IL-27 from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0023] [Figure 17] Figure 1 shows cytokine release of IL-31 from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0024] [Figure 18]Figure 1 shows cytokine release of MIP-3α from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0025] [Figure 19] Figure 1 shows cytokine release of TNF-α from the InflammaSkin® group after no treatment or treatment with Otezla® (apremilast) or SCFA.

[0026] [Figure 20] ELISA analysis of TNF-α from NativeSkin® samples and InflammaSkin® groups without treatment or after treatment with betamethasone, Otezla® (apremilast), or SCFA is shown.

[0027] [Figure 21] Figure 1 shows disease severity scores over time in IMQ psoriatic mice imiquimod (IMQ) without treatment or after treatment with Otezla® (apremilast) at 25 mg / kg twice daily or a fixed dose of SCFA twice daily.

[0028] [Figure 22] 1 shows disease severity scores in an imiquimod (IMQ)-induced psoriasis model mouse after no treatment or treatment with Otezla® (apremilast) at 25 mg / kg twice daily, 6 days after disease induction on day 0.

[0029] [Figure 23] Figure 1 shows disease severity scores in imiquimod (IMQ)-induced psoriasis model mice after no treatment or treatment with a fixed dose of SCFA twice daily, 6 days after disease induction on day 0.

[0030] [Figure 24]1 shows dorsal skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after no treatment or treatment with 25 mg / kg Otezla® (apremilast) twice daily or a fixed dose of SCFA twice daily.

[0031] [Figure 25] 1 shows the dorsal skin thickness of imiquimod (IMQ)-induced psoriasis model mice after no treatment or treatment with Otezla® (apremilast) at 25 mg / kg twice daily, 6 days after disease induction on day 0.

[0032] [Figure 26] FIG. 1 shows the dorsal skin thickness of imiquimod (IMQ)-induced psoriasis model mice after no treatment or treatment with a fixed dose of SCFA twice daily, 6 days after disease induction on day 0.

[0033] [Figure 27] FIG. 1 shows ear skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after no treatment or treatment with 10 mg / kg etanercept, 25 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0034] [Figure 28] 1 shows ear skin thickness in imiquimod (IMQ)-induced psoriasis model mice after no treatment or treatment with Otezla® (apremilast) at 25 mg / kg twice daily, 6 days after disease induction on day 0.

[0035] [Figure 29] FIG. 1 shows ear skin thickness in imiquimod (IMQ)-induced psoriasis model mice after no treatment or treatment with a fixed dose of SCFA twice daily, 6 days after disease induction on day 0.

[0036] [Figure 30]FIG. 1 shows ear skin thickness in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, either without treatment or treatment with 10 mg / kg etanercept, 25 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0037] [Figure 31] Figure 1 shows transepidermal water loss (TEWL) over time in an imiquimod (IMQ)-induced psoriasis model mouse after no treatment, or treatment with 25 mg / kg Otezla® (apremilast) twice daily or a fixed dose of SCFA twice daily.

[0038] [Figure 32] Figure 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis after no treatment or treatment with Otezla® (apremilast) at 25 mg / kg twice daily or a fixed dose of SCFAs twice daily.

[0039] [Figure 33] 1 shows disease severity scores over time in an imiquimod (IMQ)-induced psoriasis model mouse after no treatment or treatment with Otezla® (apremilast) at 7 mg / kg twice daily or low dose SCFAs twice daily.

[0040] [Figure 34] Figure 1 shows disease severity scores in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, following no treatment or treatment with 2.5 mg / kg, 5 mg / kg, or 7 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0041] [Figure 35]Figure 1 shows TNF-α levels in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, either without treatment or after treatment with 2.5 mg / kg, 5 mg / kg, or 7 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0042] [Figure 36] Figure 1 shows IL-23 levels in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, following no treatment or treatment with 2.5 mg / kg, 5 mg / kg, or 7 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0043] [Figure 37] Figure 1 shows IL-17A levels in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, following no treatment or treatment with 2.5 mg / kg, 5 mg / kg, or 7 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFA twice daily.

[0044] [Figure 38] FIG. 1 shows ear skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, Otezla® (apremilast) alone at 2.5 mg / kg, 5 mg / kg, or 7 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 2.5 mg / kg, 5 mg / kg, or 7 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0045] [Figure 39]FIG. 1 shows ear skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, Otezla® (apremilast) alone at 2.5 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 2.5 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0046] [Figure 40] FIG. 1 shows ear skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, Otezla® (apremilast) alone at 5 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 5 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0047] [Figure 41] FIG. 1 shows ear skin thickness over time in a mouse model of imiquimod (IMQ)-induced psoriasis after treatment with no treatment, Otezla® (apremilast) alone at 7 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 7 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0048] [Figure 42] Figure 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis after treatment with no treatment, Otezla® (apremilast) alone at 2.5 mg / kg, 5 mg / kg, or 7 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or Otezla® (apremilast) at 2.5 mg / kg, 5 mg / kg, or 7 mg / kg twice daily in combination with a fixed dose of SCFAs twice daily.

[0049] [Figure 43]FIG. 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis following treatment with no treatment, Otezla® (apremilast) alone at 2.5 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or Otezla® (apremilast) at 2.5 mg / kg twice daily in combination with a fixed dose of SCFAs twice daily.

[0050] [Figure 44] FIG. 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis following treatment with no treatment, Otezla® (apremilast) alone at 5 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or Otezla® (apremilast) in combination with a fixed dose of SCFAs twice daily.

[0051] [Figure 45] FIG. 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis following treatment with no treatment, Otezla® (apremilast) alone at 7 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or Otezla® (apremilast) at 7 mg / kg twice daily in combination with a fixed dose of SCFAs twice daily.

[0052] [Figure 46] FIG. 1 shows dorsal skin scaling over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, Otezla® (apremilast) alone at 25 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 25 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0053] [Figure 47]FIG. 1 shows dorsal skin scaling in an imiquimod (IMQ)-induced psoriasis model mouse 6 days after disease induction on day 0, following treatment with no treatment, Otezla® (apremilast) alone at 25 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 25 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0054] [Figure 48] FIG. 1 shows cumulative dorsal skin scaling in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, Otezla® (apremilast) alone at 25 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or a combination of Otezla® (apremilast) at 25 mg / kg twice daily and a fixed dose of SCFAs twice daily.

[0055] [Figure 49] FIG. 1 shows the percentage weight loss over time in a mouse model of imiquimod (IMQ)-induced psoriasis following treatment with no treatment, Otezla® (apremilast) alone at 25 mg / kg twice daily, a fixed dose of SCFAs alone twice daily, or Otezla® (apremilast) at 25 mg / kg twice daily in combination with a fixed dose of SCFAs twice daily.

[0056] [Figure 50] Plasma TNF-α at 6 and 26 hours in an LPS animal model treated with vehicle or a fixed dose of SCFA twice daily is shown.

[0057] [Figure 51] An example of a schematic diagram of the evaluation of an imiquimod (IMQ)-induced psoriasis model mouse is shown.

[0058] [Figure 52]FIG. 1 shows disease severity scores over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) twice daily.

[0059] [Figure 53] Figure 1 shows disease severity scores in an imiquimod (IMQ)-induced psoriasis model mouse 6 days after disease induction on day 0, following treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast).

[0060] [Figure 54] Figure 1 shows cumulative disease severity scores in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) twice daily, from day 0 to day 6 after disease induction.

[0061] [Figure 55]Figure 1 shows disease severity scores in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) 5 days after disease induction on day 0.

[0062] [Figure 56] Figure 1 shows disease severity scores in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) four days after disease induction on day 0.

[0063] [Figure 57] FIG. 1 shows dorsal skin scaling over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) twice daily.

[0064] [Figure 58]FIG. 1 shows dorsal skin scaling in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, following treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast).

[0065] [Figure 59] FIG. 1 shows dorsal skin scaling in imiquimod (IMQ)-induced psoriasis model mice 5 days after disease induction on day 0, following treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast).

[0066] [Figure 60] FIG. 1 shows ear skin thickness over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) twice daily.

[0067] [Figure 61]FIG. 1 shows ear skin thickness in imiquimod (IMQ)-induced psoriasis model mice 6 days after disease induction on day 0, following treatment with no treatment or 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast), or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast).

[0068] [Figure 62] Figure 1 shows the percentage weight loss over time in an imiquimod (IMQ)-induced psoriasis model mouse after treatment with no treatment, 10 mg / kg etanercept, 12 mg / kg Otezla® (apremilast), 25 mg / kg Otezla® (apremilast), a fixed dose of SCFAs twice daily, a fixed dose of SCFAs in combination with 12 mg / kg Otezla® (apremilast) twice daily, or a fixed dose of SCFAs in combination with 25 mg / kg Otezla® (apremilast) twice daily.

[0069] [Figure 63] An example image of a healthy control mouse is shown.

[0070] [Figure 64] Examples of images of imiquimod (IMQ)-induced psoriasis model and control mice are shown.

[0071] [Figure 65] 1 shows example images of imiquimod (IMQ)-induced psoriasis model mice after treatment with 10 mg / kg etanercept.

[0072] [Figure 66] 1 shows example images of an imiquimod (IMQ)-induced psoriasis model mouse after treatment with 12 mg / kg of Otezla® (apremilast).

[0073] [Figure 67] 1 shows example images of an imiquimod (IMQ)-induced psoriasis model mouse after treatment with 25 mg / kg of Otezla® (apremilast).

[0074] [Figure 68] Example images of imiquimod (IMQ)-induced psoriasis model mice after treatment with a fixed dose of SCFA twice daily are shown.

[0075] [Figure 69] 1 shows example images of an imiquimod (IMQ)-induced psoriasis model mouse after treatment with a fixed dose of SCFAs in combination with 12 mg / kg of Otezla® (apremilast) twice daily.

[0076] [Figure 70] 1 shows example images of an imiquimod (IMQ)-induced psoriasis model mouse after treatment with a fixed dose of SCFAs in combination with 25 mg / kg of Otezla® (apremilast) twice daily. DETAILED DESCRIPTION OF THE INVENTION

[0077] Short-chain fatty acids (SCFAs) "Short-chain fatty acids" (SCFAs) are fatty acids with an aliphatic tail that is shorter than that of long-chain fatty acids. Short-chain fatty acids can be derivatized to provide salts or esters thereof, for example, pharmaceutically acceptable salts and esters of fatty acids (e.g., sodium butyrate, arginine butyrate).

[0078] In some embodiments, the compositions disclosed herein comprise at least one SCFA. In some embodiments, the compositions disclosed herein comprise at least one short chain fatty acid (SCFA), SCFA precursor, SCFA biosynthetic precursor, derivative thereof, SCFA moiety, or combination thereof.

[0079] In some embodiments, the compositions disclosed herein comprise at least one SCFA or a compound comprising an SCFA moiety. In some embodiments, the compositions disclosed herein comprise at least two SCFAs. In some embodiments, the compositions disclosed herein comprise at least three SCFAs.

[0080] Non-limiting examples of SCFAs or SCFA moieties include acetic acid, butyric acid (BA), C3-C12 fatty acids, C3-C10 fatty acids, C3-C8 fatty acids, methoxyacetic acid, valproic acid (VPA), propionic acid, 3-methoxypropionic acid, ethoxyacetic acid, formic acid, isobutyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate, e.g., phenylbutyrate, isobutyrate, pivaloyloxymethylbutyrate, monoacetone glucose 3-butyrate), isovaleric acid, isocaprylic acid, benzoic ... Examples of suitable hydroxycarboxylic acids include sucralose, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, dodecanoic acid, (4R)-4-hydroxypentanoic acid, 2-ethylhydroxyacrylic acid, 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid, 2-methylbut-2-enoic acid, 2-oxobutanoic acid, 3-hydroxypentanoic acid, 3-methylbut-2-enoic acid, butenoic acid, methylbutyric acid, dimethylbutyric acid, pentadienoic acid, pentenoic acid, pivalic acid, propynoic acid, and combinations thereof.

[0081] Non-limiting examples of SCFAs or SCFA moieties include compounds or structures having at least 12 carbon atoms, at least 11 carbon atoms, at least 10 carbon atoms, at least 9 carbon atoms, at least 8 carbon atoms, at least 7 carbon atoms, at least 6 carbon atoms, at least 5 carbon atoms, at least 4 carbon atoms, at least 3 carbon atoms, and at least 2 carbon atoms. In some embodiments, SCFAs or SCFA moieties include compounds or structures having 13 or fewer carbon atoms, 12 or fewer carbon atoms, 11 or fewer carbon atoms, 10 or fewer carbon atoms, 9 or fewer carbon atoms, 8 or fewer carbon atoms, or 7 or fewer carbon atoms.

[0082] In some embodiments, the SCFA or SCFA moiety is not a branched fatty acid. In some embodiments, the SCFA or SCFA moiety is a branched fatty acid.

[0083] In some embodiments, short chain fatty acids (SCFAs) regulate cytokines. In some embodiments, the cytokines are pro-inflammatory cytokines. Non-limiting examples of cytokines include TNFα, IFNγ, IL-17A, IL-21, IL-22, IL-23, IL-27, IL-31, IL-10, and MIP-3α.

[0084] In some embodiments, the cytokine is TNFα. In some embodiments, the cytokine is IL-17. In some embodiments, the cytokine is IL-17A. In some embodiments, the cytokine is IL-22. In some embodiments, the cytokine is IL-23. In some embodiments, the cytokine is IL-10.

[0085] In some embodiments, short-chain fatty acids (SCFAs) regulate multiple cell signaling proteins, including, but not limited to, IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, IL-10, Notch, Hedgehog, Wnt (beta-catenin), matrix metalloproteinases 9 and 10, tissue inhibitor of metalloproteinases, Nodal, and NF-κB signaling. In some embodiments, signaling proteins regulated by SCFAs regulate biological pathways or processes, including, but not limited to, inflammation, immunity, proliferation, differentiation, apoptosis, oncogenesis, DNA transcription, cytokine production, cell survival, angiogenesis, fibrosis, and cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, and ultraviolet radiation.

[0086] In some embodiments, the methods disclosed herein include treating or reducing the likelihood of developing a medical disease or disorder characterized by elevated levels or aberrant expression of at least one of IL-18, TLR3, IFN-γ, TNFα, TGF-β, MyD88, PI3K / Akt, JAK / STAT, Smad 2 / 3, Smad 4, or IL-10 signaling. In some embodiments, the methods disclosed herein include treating or reducing the likelihood of developing a medical disease or disorder characterized by decreased levels or aberrant expression of NF-κB signaling.

[0087] In some embodiments, the compositions disclosed herein comprise at least one compound comprising a precursor of an SCFA or a portion thereof, non-limiting examples of precursors include plant cell wall polysaccharides, dietary non-starch polysaccharides (NSPs), lactate, succinate, formate, 1,2-propenedol, trypamine, indole, indole-3-acetate, and combinations thereof.

[0088] In some embodiments, the compositions disclosed herein comprise at least one compound comprising a biosynthetic precursor of an SCFA or a portion thereof. Non-limiting examples of biosynthetic precursors include acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, vitamin D, and combinations thereof.

[0089] In some embodiments, the compositions disclosed herein comprise a salt of SCFA or a derivative thereof. Non-limiting examples of salts of butyric acid include sodium butyrate, magnesium butyrate, and calcium butyrate. In some embodiments, the compositions comprise one or more of magnesium butyrate and calcium butyrate.

[0090] In some embodiments, the compositions disclosed herein comprise butyric acid or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions disclosed herein comprise propionic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions disclosed herein comprise butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compositions disclosed herein comprise acetic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions disclosed herein comprise butyric acid or a pharmaceutically acceptable salt thereof, propionic acid or a pharmaceutically acceptable salt thereof, and acetic acid or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compositions disclosed herein comprise derivatives of SCFAs. In some embodiments, the derivatives comprise at least one SCFA moiety linked to at least one additional moiety. In some embodiments, the derivatives comprise at least one SCFA moiety linked to at least one polyethylene glycol (PEG) moiety. In some embodiments, the SCFA moiety linked to the PEG moiety hydrolyzes under low pH conditions to produce a SCFA molecule and a PEG molecule.

[0093] In some embodiments, the compositions disclosed herein include a combination of SCFAs and / or derivatives thereof, hi some embodiments, the compositions are prepared in an amount of at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, or more of each or all of the compounds in the composition.

[0094] For example, derivatives of SCFAs having substituents on the carbon chain, such as OH, SH, NH, methyl, ethyl, halogen, and other groups that do not interfere with the therapeutic activity of the compound, can also be used. In some embodiments, the compounds disclosed herein comprise at least one SCFA linked to at least one additional moiety, such as OH, SH, NH, methyl, ethyl, halogen, and other groups that do not interfere with the therapeutic activity of the compound. In some embodiments, the SCFA is PEGylated.

[0095] In some embodiments, the compositions disclosed herein include a precursor of an SCFA, alone or in combination with one or more SCFAs, non-limiting examples of precursors of SCFAs include formate, lactate, succinate, 1,2-propendol, trypamine, indole, and indole-3-acetate.

[0096] In some embodiments, the compositions disclosed herein comprise precursors of SCFA biosynthesis, alone or in combination with one or more SCFAs. Non-limiting examples of precursors of SCFA biosynthesis include formate, lactate, succinate, acetyl-CoA carboxylase inhibitors, adenosine monophosphate kinase (AMPK) activators, and vitamin D.

[0097] In some embodiments, a compound comprising at least one SCFA or a compound comprising an SCFA moiety disclosed herein is combined with one or more compounds, such as one or more additional therapeutic agents for a particular disease or disorder. In some embodiments, the SCFA is present in the same composition as the one or more additional therapeutic agents. In some embodiments, the composition includes at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, or more than 10 additional therapeutic agents.

[0098] psoriasis Psoriasis is a chronic autoimmune disorder that affects the skin.The clinical appearance of psoriasis results from the dysregulated interaction between immune cells (e.g., dendritic cells [DC] and T cells) and keratinocytes, which leads to the inflammatory process that drives the disease.Skin inflammation causes rapid proliferation of keratinocytes, which ultimately leads to scaling of the skin surface, which commonly presents as dry, raised, red skin lesions (plaques) covered with silvery-white scales.

[0099] Non-limiting examples of psoriasis include plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, and psoriatic arthritis.

[0100] In some embodiments, recruitment of innate and adaptive immune cells that secrete pro-inflammatory cytokines contributes to the pathogenesis of psoriasis. Cytokines play an important role in the development and progression of the disease. Non-limiting examples of cytokines that contribute to the pathogenesis of psoriasis include IL-23 and IL-17.

[0101] Furthermore, Tregs have impaired suppressive function, resulting in an altered T helper 17 / Treg balance. In some embodiments, cytokine antagonists (e.g., anti-TNF, such as etanercept) are used in the treatment of plaque psoriasis (Ps) and psoriatic arthritis (PsA).

[0102] The IL-23 / IL-17 immune axis can drive skin inflammation in psoriasis, resulting from interactions between keratinocytes and immune cells, such as Th17 cells. In some embodiments, pharmacological blockade of the IL-23 / IL-17 immune axis results in clinical efficacy in psoriasis. In some embodiments, pharmacological modulation of the IL-23 / IL-17 immune axis is evaluated with different drug modalities and administrations (e.g., topical and systemic).

[0103] Human Th17 differentiation requires IL-1β, IL-6, TGF-β, and IL-23 to maintain IL-17 and IL-22 production from Th17 cells. IL-17 induces the expression of other pro-inflammatory mediators, such as IL-17C, IL-19, and IL-36, in keratinocytes. These mediators, along with IL-17 and IL-22, contribute to keratinocyte activation and epidermal hyperplasia, accompanied by the expression of keratinin 16 and S100A7. Furthermore, increased levels of IFN-γ in psoriatic skin due to activation of skin-resident Th1 cells contribute to inflammatory activation of keratinocytes.

[0104] An autoimmune disease or disorder can involve an immune response to self-antigens that results in inflammation or destruction of healthy tissue in a subject, e.g., a mammal such as a human. Non-limiting examples of autoimmune diseases include arthritis (e.g., rheumatoid arthritis, e.g., acute arthritis, chronic rheumatoid arthritis, gouty arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, osteoarthritis, arthritis), infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, spondyloarthritis, and juvenile-onset rheumatoid arthritis, osteoarthritis, chronic progressive arthritis, osteoarthritis, primary chronic polyarthritis, reactive arthritis, and ankylosing spondylitis), inflammatory hyperproliferative skin diseases, psoriasis, such as plaque psoriasis, guttate psoriasis, pustular psoriasis, plaque psoriasis, inverse psoriasis, erythrodermic psoriasis, seborrheic psoriasis, and nail psoriasis, dermatitis (contact dermatitis, chronic contact dermatitis, allergic dermatitis, allergic contact dermatitis) urticaria, including chronic allergic urticaria and chronic idiopathic urticaria (including chronic autoimmune urticaria), polymyositis / dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (systemic sclerosis, including systemic sclerosis, multiple sclerosis (MS), such as spino-optical MS, primary progressive MS (PPMS), and relapsing-remitting MS (RRMS), progressive systemic sclerosis, and disseminated sclerosis. disseminata), and ataxic sclerosis, inflammatory bowel disease (IBD) (e.g. Crohn's disease, autoimmune-mediated gastrointestinal disease, colitis, e.g. ulcerative colitis, ulcerative colitis). ulcerosa), microscopic colitis, collagenous colitis, polypoid colitis, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, episcleritis, respiratory distress syndrome (including adult respiratory distress syndrome or acute respiratory distress syndrome (ARDS)), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, autoimmune blood disorders, rheumatoid spondylitis, sudden hearing loss, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis,and limbic encephalitis and / or brainstem encephalitis, uveitis, e.g. anterior uveitis, acute anterior uveitis, granulomatous uveitis, non-granulomatous uveitis, phacoallergic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome, e.g. chronic or acute glomerulonephritis, e.g. primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membranous or membranoproliferative GN (MPGN) (including types I and II), and rapidly progressive GN, allergic conditions, allergic reactions, eczema (including allergic or atopic eczema), asthma, e.g. asthma bronchiale, bronchial asthma, asthma, and autoimmune asthma, conditions involving T cell infiltration and chronic inflammatory responses, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE) or systemic lupus erythematosus, e.g., cutaneous SLE, subacute cutaneous lupus erythematosus, neonatal lupus syndrome (NLE), disseminated lupus erythematosus, lupus (including nephritis, encephalitis, childhood, non-renal, extrarenal, discoid, alopecia), juvenile-onset (Type I) diabetes (including childhood insulin-dependent diabetes mellitus (IDDM)), adult-onset diabetes (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, immune responses associated with cytokines and T lymphocyte-mediated acute and delayed hypersensitivity, tuberculosis, sarcoidosis, granulomatous diseases (lymphocytic granulomatous disease), granulomatosis, Wegener's granulomatosis, agranulocytosis), vasculitides, such as vasculitis [large vasculitis (including polymyalgia rheumatica and giant cell (Takayasu) arteritis), medium vasculitis (including Kawasaki disease and polyarteritis nodosa), microscopic polyarteritis, central nervous system vasculitis, necrotizing, cutaneous or hypersensitivity vasculitis, systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS)], temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond-Blackfan anemia, hemolytic anemia or immune hemolytic anemia (including autoimmune hemolytic anemia (AIHA)), pernicious anemia anemia) (pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or pure red cell aplasia (PRCA), factor VIII deficiency,Hemophilia A, autoimmune neutropenia, pancytopenia, leukopenia, diseases with leukocyte extravasation, central nervous system inflammatory disorders, sepsis, multiorgan dysfunction syndromes such as those secondary to trauma or hemorrhage, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, antiphospholipid syndrome, allergic neuritis, Behçet's disease, Castleman syndrome, Goodpasture's syndrome, Raynaud's syndrome, Sjögren's syndrome, Stevens-Johnson syndrome, pemphigoid, e.g., bullous pemphigoid and cutaneous pemphigoid, pemphigus (pemphigus vulgaris, pemphigus foliaceus, mucous membrane pemphigoid, and and pemphigus erythematosus), autoimmune polyendocrinopathy, Reiter's disease or syndrome, immune complex nephritis, antibody-mediated nephritis, neuromyelitis optica, polyneuropathy, chronic neuropathy such as IgM polyneuropathy or IgM-mediated neuropathy, thrombocytopenia (e.g. occurring in patients with myocardial infarction), e.g. thrombotic thrombocytopenic purpura (TTP) and autoimmune or immune-mediated thrombocytopenia, e.g. idiopathic thrombocytopenic purpura (ITP) (including chronic or acute ITP), autoimmune diseases of the testes and ovaries (including autoimmune orchitis and oophoritis), primary thyroid dysfunction hypothyroidism, hypoparathyroidism, autoimmune endocrine disorders, such as autoimmune thyroiditis, Hashimoto's disease, thyroiditis such as chronic thyroiditis (Hashimoto's thyroiditis) or subacute thyroiditis, autoimmune thyroid diseases, idiopathic hypothyroidism, Graves' disease, polyglandular syndromes such as autoimmune polyendocrine syndrome (or polyendocrinopathy syndrome), paraneoplastic syndromes (including paraneoplastic neurological syndromes, such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome), stiff-man or stiff-person syndrome, encephalomyelitis, such as allergic encephalomyelitis or allergic encephalomyelitis Myelitis and experimental allergic encephalomyelitis (EAE), myasthenia gravis including thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus-myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan syndrome, lymphocytic interstitial pneumonia, bronchiolitis obliterans (non-transplant) and nonspecific interstitial pneumonia (NSIP), Guillain-Barré syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, primary biliary cirrhosis, pulmonary cirrhosis, autoimmune bowel syndrome, celiac disease,Celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear diseases, e.g. autoimmune inner ear disease (AIED), autoimmune hearing loss, opsoclonus-myoclonus syndrome (OMS), polychondritis, e.g. refractory or relapsing polychondritis, pulmonary alveolar proteinosis, amyloidosis, scleritis, non-cancerous lymphoma lymphocytosis, primary lymphocytosis (including monoclonal B-cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS)), peripheral neuropathy, paraneoplastic syndromes, channelopathies such as epilepsy, migraine, cardiac arrhythmias, myopathy, hearing loss, blindness, periodic paralysis, and channelopathies of the central nervous system, autism, inflammatory myopathy, focal segmental glomerulosclerosis (FSG) S), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, fibromyalgia, multiple endocrine deficiency, Schmidt's syndrome, adrenal inflammation, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases, diabetic nephropathy, Dressler's syndrome, alopecia areata, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), male and female autoimmune infertility, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent glaucoma, Abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird fancier's lung, allergic granulomatous vasculitis, benign lymphocytic vasculitis, Alport's syndrome, alveolitis including allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reactions, leprosy, malaria, leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Samter's syndrome syndrome), Kaplan's syndrome, dengue fever, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial pulmonary fibrosis, idiopathic pulmonary fibrosis, fibrosis of any organ or tissue, cystic fibrosis, endophthalmitis, persistent erythema elevatum, erythroblastosis fetalis, eosinophilic fasciitis, Shulman's syndrome, Felty's syndrome, filariasis, cyclitis such as chronic cyclitis, heterochromic cyclitis iridocyclitis, or Fuchs' cyclitis, Henoch-Schönlein purpura, human immunodeficiency virus (HIV) infection, echovirus infection, cardiomyopathy, Alzheimer's disease, parvovirus infection,Rubella virus infection, post-vaccination syndrome, congenital rubella infection, Epstein-Barr virus infection, mumps, Evans syndrome, autoimmune dysgonadism, Sydenham chorea, poststreptococcal nephritis, thromboangiitis obliterans, thyrotoxicosis, tabes dorsalis, choroiditis, giant cell polymyalgia, endocrine ophthalmopathy, chronic hypersensitivity pneumonitis, keratoconjunctivitis sicca, epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, autoimmune retinopathy, arthritis, bronchitis, chronic obstructive airway disease, silicosis, aphthous stomatitis, arteriosclerotic disorders, spermatogenesis imperfecta, Autoimmune hemolysis, Beck's disease, cryoglobulinemia, Dupuytren's contracture, phacosensitivity endophthalmitis, allergic enterocolitis, erythema nodosum leprosum, idiopathic facial nerve palsy, chronic fatigue syndrome, rheumatic fever, Hammann-Rich disease, sensorineural hearing loss, paroxysmal hemoglobinuria, hypogonadism, focal ileitis, leukopenia, infectious mononucleosis, transverse myelitis, primary idiopathic myxedema, nephrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, acute polyradiculitis, pyoderma gangrenosum, Quervain's thyroiditis, acquired splenic atrophy, infertility due to antisperm antibodies, nonmalignant thymoma, vitiligo, SCID and Epstein-Barr virus. Stein-Barr virus-associated diseases, acquired immunodeficiency syndrome (AIDS), parasitic diseases such as leishmaniasis, toxic shock syndrome, food poisoning, conditions with T-cell infiltration, leukocyte adhesion deficiency, immune responses related to cytokines and T lymphocyte-mediated acute and delayed hypersensitivity, diseases with leukocyte extravasation, multiorgan dysfunction syndromes, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane diseases, allergic neuritis, autoimmune polyendocrinopathy, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine deficiency, peripheral neuropathy, autoimmune polyendocrine syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), alopecia totalis, dilated cardiomyopathy, epidermolysis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, or sphenoid sinusitis, eosinophil-related disorders such as eosinophilia, pulmonary infiltrate eosinophilia, eosinophilic myalgia syndrome, Löffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopulmonary aspergillosis,Aspergilloma or eosinophil-containing granuloma, anaphylaxis, seronegative spondyloarthritis, polyglandular autoimmune disease, sclerosing cholangitis, scleral, episcleral, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia-telangiectasia, autoimmune disorders associated with connective tissue diseases, rheumatism, neurological diseases, diseases involving ischemia-reperfusion injury, decreased blood pressure response, vascular insufficiency, vasodilation, tissue damage, cardiovascular ischemia, hyperalgesia, cerebral ischemia, and angiogenesis, allergic hypersensitivity disorders, glomerulonephritis, reperfusion injury, myocardial or other tissue reperfusion injury, skin diseases with an acute inflammatory component, acute purulent meningitis, or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndrome, cytokine-induced toxicity, acute severe inflammation, chronic refractory inflammation, pyelitis, pulmonary cirrhosis, diabetic retinopathy, diabetic aortopathy, intimal hyperplasia, peptic ulcer, valvulitis, and endometriosis.

[0105] In some embodiments, the methods disclosed herein include treating a condition. In some embodiments, the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, treating includes causing clearance of psoriatic lesions in a subject in need of treatment.

[0106] In some embodiments, the methods disclosed herein comprising the SCFAs disclosed herein reduce epidermal / dermal separation. In some embodiments, the methods disclosed herein comprising the SCFAs disclosed herein reduce the likelihood of post-inflammatory skin deterioration.

[0107] Psoriasis Model Preclinical skin models mimic the inflammatory characteristics of psoriasis.

[0108] InflammaSkin® Psoriasis Model

[0109] The InflammaSkin® human psoriasis model is an ex vivo psoriasis skin model with T cell-driven inflammation characterized by a Th1 / Th17 phenotype. This model allows for the evaluation of the response of real human skin. Non-limiting examples of evaluations using the ex vivo psoriasis skin model include evaluating the response to preventative biologics, therapeutic biologics, and small molecule drugs after topical or subcutaneous administration.

[0110] The mouse imiquimod (IMQ)-induced psoriasis model exhibits most of the characteristics of human psoriasis, including the phenotypic and histological features of skin lesions and the involvement of the IL-23 / IL-17 axis.

[0111] The murine imiquimod (IMQ) psoriasis model is induced, for example, by topical administration of Aldara Cream (containing 5% IMQ, a TLR7 / 8 ligand; Meda Pharma GmbH) to the shaved dorsal skin and ears of female Balb / c (approximately 20 g) mice and is used to evaluate the pathogenic mechanisms involved in the development of psoriasis and to analyze novel therapeutic candidates for psoriasis.

[0112] Mouse imiquimod (IMQ) model

[0113] Repeated daily application of IMQ for six consecutive days rapidly induced skin inflammation in mice with pathological and histological characteristics of human psoriasis, including the development of skin erythema and scaling, acanthosis, altered keratinocyte differentiation, angiogenesis, and skin infiltration of immune cells. The involvement of a dysregulated IL-23 / IL-17 axis and the overproduction of other inflammatory cytokines, such as IL-1, IL-36, and IL-22, are pathways involved in human psoriasis, and these are recapitulated in IMQ-induced psoriasis.

[0114] situation The present disclosure describes methods and systems for treating a condition, the methods and systems comprising administering a pharmaceutical composition comprising at least one short-chain fatty acid (SCFA), SCFA precursor, SCFA biosynthetic precursor, compound comprising an SFCA moiety, derivatives thereof, and combinations thereof. In some embodiments, the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, the condition is an autoimmune disorder.

[0115] Disclosed herein are methods for treating or reducing the likelihood of developing at least one disease or disorder in a subject, comprising administering to the subject at least one composition comprising an SCFA or a compound comprising an SCFA moiety, optionally in combination with at least one additional agent or therapy.

[0116] In some embodiments, the compositions disclosed herein increase the number of disease-free days, decrease the severity of a disease or disorder, reduce the risk of developing a disease or disorder, reduce the risk of recurrence of a disease or disorder, or a combination thereof in a subject. In some embodiments, the compositions disclosed herein increase the number of disease-free days in a subject by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more compared to a subject not receiving treatment. In some embodiments, the compositions disclosed herein reduce the severity of a disease or disorder in a subject by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more compared to a subject not receiving treatment.In some embodiments, the compositions disclosed herein reduce the risk of developing a disease or disorder in a subject by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more compared to a subject not receiving treatment. In some embodiments, the compositions disclosed herein reduce the risk of recurrence of a disease or disorder in a subject by at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60% or more compared to a subject not receiving treatment.

[0117] Non-limiting examples of diseases and disorders that may be treated, reduced likelihood, or ameliorated include inflammatory diseases and various cancer diseases. Non-limiting examples of inflammatory diseases and disorders include asthma, arthritis, allergic rhinitis, psoriasis, atopic dermatitis, inflammatory bowel disease, Crohn's disease, allergic or autoimmune diseases or disorders associated with cesarean section delivery of newborns, uveitis, and vasculitis.

[0118] skin disorders

[0119] In some embodiments, the SCFAs disclosed herein are effective in treating skin disorders. In some embodiments, the combination of at least one SCFA with at least one other skin disorder treatment may be effective as a therapeutic approach for treating skin disorders.

[0120] Disclosed herein are methods for treating, inhibiting, preventing, or alleviating a skin disease or disorder by administering to a subject in need thereof a composition comprising the SCFAs disclosed herein, optionally in combination with at least one additional agent or therapy. Non-limiting examples of skin diseases and disorders include psoriasis, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, plaque psoriasis, seborrheic psoriasis, erythrodermic psoriasis, nail psoriasis, psoriatic arthritis, systemic lupus erythematosus (SLE) rash, scleroderma (systemic sclerosis), diabetic skin conditions, rheumatoid arthritis and associated skin rashes (rheumatoid vasculitis), melanoma, vitiligo, eczema (atopic dermatitis), dyshidrotic eczema, rosacea, hives, impetigo, cellulitis, contact dermatitis, stomatitis, acne, lichen planus, actinic keratosis, ichthyosis vulgaris, dermatomyositis, and pemphigoid.

[0121] Disclosed herein are methods for treating, inhibiting, preventing, or alleviating a skin disease or disorder, comprising administering to a subject in need thereof a composition comprising the SCFAs disclosed herein.

[0122] In some embodiments, the subject suffering from the skin disorder is a human. In some embodiments, the subject suffering from the skin disorder is a non-human animal.

[0123] In some embodiments, the compositions disclosed herein comprise at least one SCFA and at least one second compound for use as a therapeutic agent for treating skin disorders. In some embodiments, the SCFA comprises one or more of formic acid, acetic acid, propionic acid, isobutyric acid, butyric acid, tributyrin, N-acetylbutyrate (and other forms of butyrate), isovaleric acid, valeric acid, isocaproic acid, caproic acid, lactic acid, succinic acid, pyruvic acid, octanoic acid, and dodecanoic acid. In some embodiments, the second compound comprises one or more of a PDE4 inhibitor, an anti-inflammatory compound, a disease-modifying antirheumatic drug (DMARD), an immunosuppressant, a biological agent, and a Cox-2 inhibitor.

[0124] In some embodiments, a composition for use in a method of treating a skin disorder comprises 900 mg of butyrate, 100 mg of propionate, 10 mg of apremilast, 10 mg of magnesium, and 50 IU of vitamin D3.

[0125] In some embodiments, an exemplary daily oral dosage for use in the methods of treating skin disorders comprises about 3600 mg of butyric acid or a pharmaceutically acceptable salt thereof (e.g., sodium butyrate), about 400 mg of propionic acid or a pharmaceutically acceptable salt thereof (e.g., sodium propionate), about 40 mg of a magnesium source (e.g., magnesium chloride), and about 200 IU of vitamin D3. In some embodiments, an exemplary dosage for use in the methods of treating skin disorders comprises about 900 to about 1800 mg of butyric acid or a pharmaceutically acceptable salt thereof (e.g., sodium butyrate), about 100 to about 200 mg of propionic acid or a pharmaceutically acceptable salt thereof (e.g., sodium propionate), about 10 to about 20 mg of a magnesium source (e.g., magnesium chloride), and about 50 to about 100 IU of vitamin D3, administered one to four times daily. In some embodiments, the composition is administered 1 to 4 times daily for at least 1 week, at least 2 weeks, at least 3 weeks, or more than 3 weeks.

[0126] In some embodiments, an exemplary dosage for use in the methods of treating a skin disorder comprises about 1 to about 2 g of butyric acid or a pharmaceutically acceptable salt thereof (e.g., sodium butyrate), about 100 mg of propionic acid or a pharmaceutically acceptable salt thereof (e.g., sodium propionate), about 10 to about 15 mg of Otezla, about 10 to about 20 mg of a magnesium source (e.g., magnesium chloride), and about 80 to about 100 IU of vitamin D3.

[0127] In some embodiments, the compositions comprising at least one SCFA are enteric-coated, time-release, and sustained-release capsules.

[0128] In some embodiments, the method for treating a skin disorder comprises administering an oral formulation of SCFA in combination with a topical ointment. An example of a topical ointment for use in treating a skin disorder comprises about 40% clobetasol (0.05%) cream, about 20% calcipotriene (vitamin D, 0.005%) cream, about 20% vitamin E (0.5%) cream, and about 20% salicylic acid (10%) cream. Another example of a topical ointment for use in treating a skin disorder comprises about 40% clobetasol (0.05%) cream, about 20% calcipotriene (vitamin D, 0.005%) cream, about 20% vitamin E (0.5%) cream, and about 20% zinc cream. In some embodiments, zinc is used together with salicylic acid in the topical ointment.

[0129] Medication and Administration When carrying out the methods or uses provided herein, a therapeutically effective amount of the compound described herein is administered to a subject with a disease or condition to be treated.The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.The subject can be, for example, a human, an elderly person, an adult, an adolescent, a pre-adolescent, a child, a toddler, an infant, or a newborn.The subject can be a patient.

[0130] The particular dose of the compound required to treat a condition may vary depending on the severity of the condition, the route of administration, and related factors as may be determined by the attending physician.

[0131] A therapeutically effective amount of a compound of the present disclosure can be expressed as mg of compound per kg of subject body weight.

[0132] In some embodiments, the therapeutically effective amount is 1-1,000 mg / kg, 1-500 mg / kg, 1-250 mg / kg, 1-100 mg / kg, 1-50 mg / kg, 1-25 mg / kg, or 1-10 mg / kg. In some embodiments, the therapeutically effective amount is about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, about 1,000 mg / kg. 0 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, about 150 mg / kg, about 200 mg / kg, about 250 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1,000 mg / kg.

[0133] The compounds described herein may be present in a composition at an amount of about 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg, about 100 mg to about 110 mg, about 115 mg to about 120 mg, about 125 mg to about 130 mg, about 135 mg to about 140 mg, about 145 mg to about 150 mg, about 155 mg to about 160 mg, about 165 mg to about 170 mg, about 175 mg to about 180 mg, about 185 mg to about 190 mg, about 190 mg to about 205 mg, about 205 mg to about 210 mg, about 215 mg to about 220 mg, about 225 mg to about 230 mg, about 235 mg to about 240 mg, about 245 mg to about 250 mg, about 255 mg to about 260 mg, about 265 mg to about 270 mg, about 275 mg to about 280 mg, about 285 mg to 5mg to about 100mg, about 100mg to about 125mg, about 125mg to about 150mg, about 150mg to about 175mg, about 175mg to about 200mg, about 200mg to about 225mg, about 225mg to about 250mg, about 250mg to about 300mg, about 300mg to about 325mg, Approx. 325 mg ~ approx. 350 mg, approx. 350 mg ~ approx. 400 mg, approx. 400 mg ~ approx. 425 mg, approx. 425 mg ~ approx. 450 mg, approx. 450 mg ~ approx. 500 mg, approx. g, approx. 625 mg ~ approx. 650 mg, approx. 650 mg ~ approx. 700 mg, approx. 700 mg ~ approx. 725 mg, approx. 725 mg ~ approx. 750 mg, approx. 750 mg ~ approx. 800 mg, approx. 25mg, about 925mg to about 950mg, about 950mg to about 1000mg, about 1000mg to about 1025mg, about 1025mg to about 1050mg, about 1050mg to about 1100mg, about 1100mg to about 1125mg, about 1125mg to about 1150mg, about 1150mg to about 1200mg, about 1200mg to about 1225mg, about 1225mg to about 1250mg, about 1250mg to about 1300mg, about 1300mg to about 1325mg, about 1325mg to about 1350mg, about 1350mg to about 1400mg, about 1400mg to about 1425mg, about 142 5mg to about 1450mg, about 1450mg to about 1500mg, about 1500mg to about 1525mg, about 1525mg to about 1550mg, about 1550mg to about 1600mg, about 1600mg to about 1625mg, about 1625mg to about 1650mg, about 1650mg to about 1700mg,It can be present in the range of about 1700 mg to about 1725 mg, about 1725 mg to about 1750 mg, about 1750 mg to about 1800 mg, about 1800 mg to about 1825 mg, about 1825 mg to about 1850 mg, about 1850 mg to about 1900 mg, 1900 mg to about 1925 mg, about 1925 mg to about 1950 mg, or about 1950 mg to about 2000 mg.

[0134] The compounds described herein may be present in compositions at about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 260 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 50mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 475mg, about 500mg, about 525mg, about 550mg, about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 850mg, about 875mg, about 900mg, about 925mg, about 950mg, about 975mg, about 1000mg, about 1025mg, about 1050mg, about 1075mg, about 1100mg, about 1125mg, about 1150mg, about 1175mg, about 1200m g, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about It can be present in an amount of about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.

[0135] In some embodiments, the therapeutically effective amount of propionate is about 45 μg / mL. In some embodiments, the propionate is Ca-propionate. In some embodiments, the therapeutically effective amount of Ca-propionate is about 45 μg / mL. In some embodiments, the therapeutically effective amount of butyrate is about 1 mM. In some embodiments, the butyrate comprises Ca-butyrate and / or Mg-butyrate.

[0136] In some embodiments, the therapeutically effective amount of propionate is about 60 mg / kg / day. In some embodiments, the propionate is Ca-propionate. In some embodiments, the therapeutically effective amount of Ca-propionate is about 60 mg / kg / day.

[0137] In some embodiments, the therapeutically effective amount of butyrate is about 1800 mg / kg / day. In some embodiments, the butyrate comprises Ca-butyrate and / or Mg-butyrate.

[0138] In some embodiments, the therapeutically effective amount of butyrate is about 850 mg / kg / day. In some embodiments, the butyrate comprises Ca-butyrate and / or Mg-butyrate.

[0139] In some embodiments, a therapeutically effective amount can be administered 1 to 35 times per week, 1 to 14 times per week, or 1 to 7 times per week, hi some embodiments, a therapeutically effective amount can be administered 1 to 10 times per day, 1 to 5 times per day, or 1, 2, or 3 times per day.

[0140] In some embodiments, the therapeutically effective amount can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 times.

[0141] In some embodiments, the compounds disclosed herein can be administered in therapeutically effective amounts by a variety of forms and routes, including, for example, intravenous, intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, otic, nasal, intraocular, and topical administration. Non-limiting examples of parenteral or systemic administration include subcutaneous, intravenous, intraperitoneal, and intramuscular injection.

[0142] In some embodiments, the pharmaceutical compositions disclosed herein are generally formulated for oral or topical (i.e., dermal, ocular, and mucosal surface) administration, with the most suitable route in any given case depending on the nature and severity of the condition being treated and the nature of the particular active agent being used.

[0143] Topical preparations

[0144] In some embodiments, the pharmaceutical compositions, compositions, or compounds disclosed herein may be administered topically and therefore may be formulated in a form suitable for topical administration, i.e., as a pH-balanced cream formulation. The barrier to topical administration of pharmaceuticals is the stratum corneum of the epidermis. The stratum corneum is a highly resistant layer composed of proteins, cholesterol, sphingolipids, free fatty acids, and various other lipids, and contains keratinocytes and living cells. One of the factors limiting the penetration rate (flux) of a compound through the stratum corneum is the amount of active substance that can be loaded or applied onto the skin surface. The greater the amount of active substance applied per unit area of ​​skin, the greater the concentration gradient between the skin surface and the underlying layers, resulting in a greater diffusion force of the active substance through the skin. Therefore, a formulation containing a higher concentration of active substance is more likely to provide a more consistent rate of penetration of the active substance through the skin than a formulation with a lower concentration, all other conditions being equal.

[0145] Formulations suitable for topical administration include, but are not limited to, liquid or semi-liquid formulations, such as liniments, lotions, oil-in-water or water-in-oil emulsions, such as creams, ointments, or pastes, and solutions or suspensions. Furthermore, formulations suitable for topical administration can be in the form of creams and liquids, including, for example, syrups, suspensions or emulsions, inhalants, sprays, mousses, oils, gels, and solids. Topically administrable formulations can contain, for example, about 1% to about 10% (w / w) of the active ingredient. However, the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration can further include one or more of the additional ingredients described herein.

[0146] Permeation enhancers may also be used. These materials increase the rate at which drugs penetrate the skin. Non-limiting examples of enhancers include ethanol, glycerol monolaurate, PGML (polyethylene glycol monolaurate), and dimethyl sulfoxide. Other enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, and N-methyl-2-pyrrolidone.

[0147] In some embodiments, the topically active pharmaceutical composition is combined with other ingredients, such as adjuvants, antioxidants, chelating agents, surfactants, foaming agents, humectants, emulsifiers, thickeners, buffers, or preservatives. In some embodiments, a permeation or penetration enhancer is included in the composition and is effective in improving transdermal penetration of the active ingredient into and through the stratum corneum compared to a composition lacking the permeation enhancer. Non-limiting examples of permeation enhancers include oleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids, dimethyl sulfoxide, polar lipids, or N-methyl-2-pyrrolidone. In some embodiments, the composition further comprises a hydrotropic agent, which functions to increase the structural disorder of the stratum corneum, thereby allowing for increased transport through the stratum corneum. Non-limiting examples of hydrotropic agents include isopropyl alcohol, propylene glycol, and sodium xylene sulfonate.

[0148] Topically active pharmaceutical compositions should be applied in an amount effective to affect the desired change. In some embodiments, the active compound is present in an amount of about 0.0001% to about 15% by weight, about 0.0005% to about 5% by weight, or about 0.001% to about 1% by weight of the composition.

[0149] Oral formulation

[0150] In some embodiments, the pharmaceutical compositions, compositions, or compounds disclosed herein are orally administered and are therefore formulated in a form suitable for oral administration, i.e., as solid or liquid formulations.Suitable solid oral formulations include tablets, capsules, pills, granules, and pellets.Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, and oils.When formulated as a capsule, the composition of the present invention comprises a hard gelatin capsule in addition to the active compound and an inert carrier or diluent.In some embodiments, the formulation for oral administration is an enteric-coated, sustained-release capsule.

[0151] Formulations suitable for oral administration may be provided in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions. Such formulations may be prepared by any suitable method of pharmacy, including bringing into association the active compound with a suitable carrier (which may contain one or more accessory ingredients, as described above). Generally, the formulations of the present invention are prepared by uniformly and intimately mixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, tablets may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, and / or surfactant / dispersant. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid binder.

[0152] The delayed release dosage units may be coated with the delayed release polymeric coating using conventional techniques, for example, using conventional coating pans, airless spray techniques, fluidized bed coating equipment (with or without a Wurster insert).

[0153] An exemplary method for preparing sustained-release tablets is by compressing a drug-containing blend, such as a blend of granules, prepared using a direct blending, wet granulation, or dry granulation process. Sustained-release tablets can also be molded rather than compressed, starting with a wet material containing a suitable water-soluble lubricant. However, tablets are manufactured using compression rather than molding. A method for forming a sustained-release drug-containing blend is to directly mix drug particles with one or more excipients, such as a diluent (or filler), binder, disintegrant, lubricant, glidant, and colorant. Instead of direct blending, drug-containing blends can be prepared using a wet granulation process or a dry granulation process. Active agent-containing beads can also be prepared by any one of several techniques, starting from a fluid dispersion. For example, a method for preparing drug-containing beads involves dispersing or dissolving an active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, or a plasticizer. The mixture is used to coat bead cores, such as sugar spheres, having a size of approximately 60-20 mesh.

[0154] An alternative procedure for preparing drug beads is by blending the drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants, etc., extruding the blend, spheronizing the extrudate, drying, and optionally coating to form immediate release beads.

[0155] Delayed-release formulations are created by coating a solid dosage form with a film of a polymer that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine. Delayed-release dosage units can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into either a tablet or a capsule. Examples of coating materials include bioerodible, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and may also be enteric polymers. Enteric polymers solubilize in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon.Non-limiting examples of coating materials for providing delayed release include cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose, acrylic acid polymers and copolymers such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and polymers sold under the tradename Eudragit® (Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 or above), Eudragit® L-100 (soluble at pH 6.0 or above), Eudragit® S (soluble at pH 6.0 or above as a result of a higher degree of esterification), 7.0 and above), and Eudragits® NE, RL, RS (water-insoluble polymers with different degrees of permeability and swelling), other methacrylic resins, vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer, enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose, and guar gum, zein, and shellac. Combinations of different coating materials may also be used. Multiple coatings using different polymers may also be applied.

[0156] The coating composition may contain conventional additives such as plasticizers, pigments, colorants, stabilizers, and glidants. Plasticizers reduce the brittleness of the coating and may comprise approximately 10% to 50% by weight of the dry weight of the polymer. Non-limiting examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are used to stabilize particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants may reduce the sticking effect during film formation and drying and may comprise approximately 25% to 100% by weight of the polymer weight in the coating solution. One glidant is talc. Other glidants, such as magnesium stearate and glycerol monostearate, may also be used. Pigments such as titanium dioxide may also be used. Small amounts of anti-foaming agents, such as silicones (e.g., simethicone), may also be added to the coating composition.

[0157] In addition to the therapeutic or diagnostic agent (or optionally other desired molecule for delivery), the particles may include excipients, for example, sugars such as lactose, proteins such as albumin, and / or surfactants.

[0158] In some embodiments, the treatment regimen comprises daily oral administration of short-chain fatty acids. In some embodiments, about 600 mg of butyric acid or a pharmaceutically acceptable salt thereof, such as sodium butyrate, is administered three times a day (a total of about 1800 mg / day) for at least one week. In some embodiments, the treatment regimen comprises oral administration of two capsules containing about 600 mg of butyric acid or a pharmaceutically acceptable salt thereof, such as sodium butyrate, three times a day (a total of about 3600 mg / day) for at least one week. In some embodiments, the treatment regimen comprises oral administration of two capsules containing about 600 mg of butyric acid or a pharmaceutically acceptable salt thereof, such as sodium butyrate, three times a day (a total of about 3600 mg / day) for at least one week, followed by oral administration of a capsule containing about 600 mg of butyric acid or a pharmaceutically acceptable salt thereof, such as sodium butyrate, three times a day (a total of about 1800 mg / day) for at least one week.

[0159] The compounds of the present disclosure, whether administered alone or in combination with a modulator of oxidative stress, can be administered to a subject, e.g., a human or animal patient, in need of such administration.

[0160] Pharmaceutical Composition A pharmaceutical composition can be a combination of any compound described herein with other chemical components, such as pharmaceutically acceptable carriers, stabilizers, binders, diluents, dispersants, suspending agents, thickeners, solubilizers, or excipients. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The pharmaceutical composition facilitates administration of the compound to an organism.

[0161] Non-limiting examples of pharmaceutically acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0162] In some embodiments, the pharmaceutical compositions provided herein include a buffer as an excipient. Non-limiting examples of buffers include potassium phosphate, sodium phosphate, phosphate buffer, citrate buffer, sodium citrate buffered saline (SSC), acetate, saline, normal saline, phosphate buffered saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), citric acid monohydrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and any combination thereof.

[0163] In some embodiments, the pharmaceutical compositions provided herein comprise an alcohol as an excipient. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactylol, fucitol, lactitol, and any combination thereof.

[0164] Pharmaceutical preparations can be formulated with polyethylene glycol (PEG). PEGs with molecular weights ranging from about 300 g / mol to about 10,000,000 g / mol can be used. Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000.

[0165] Additional excipients that can be used in the compositions described herein include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerosal, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate phthalate, microcrystalline cellulose, chloroform, citric acid, edetic acid, and ethylcellulose.

[0166] In some embodiments, the pharmaceutical compositions provided herein comprise an aprotic solvent as an excipient. Non-limiting examples of aprotic solvents include perfluorohexane, α,α,α-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, Freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxyethane, 2-methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N-methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane, dimethyl sulfoxide, and propylene carbonate.

[0167] The amount of excipient in the pharmaceutical compositions described herein may be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, or about 3% by weight of the compound in the pharmaceutical formulation. %, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000%.

[0168] The amount of excipient in the pharmaceutical compositions described herein may be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1% or about 1% by weight or volume of the unit dosage form. The concentration can be 0.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100%.

[0169] In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by 5% or less, 10% or less, 15% or less, 20% or less, 25% or less, 30% or less, 35% or less, 40% or less, 45% or less, 50% or less, 55% or less, 60% or less, 65% or less, 70% or less, 75% or less, 80% or less, 85% or less, 90% or less, 95% or less, or 99% or less.

[0170] The compositions disclosed herein may be used as a complete food, as a food component, as a dietary supplement or part of a dietary supplement, or as a feed additive, and may be in liquid, semi-solid, or solid form. The compositions disclosed herein may also be in the form of a pharmaceutical composition. The compositions, dietary supplements, foods, baby food products, feed additives, and / or pharmaceutical compositions disclosed herein may be advantageously utilized in methods for promoting the health of individuals.

[0171] The compositions disclosed herein may be in liquid, semi-solid, or solid form. For example, they may be administered as tablets, gel packs, capsules, gelatin capsules, flavored drinks, powders that can be reconstituted into such drinks, cooking oils, salad oils or dressings, sauces, syrups, mayonnaise, or margarines. Additionally, food and dietary supplements may include, but are not limited to, dairy products, baby food, infant formula, beverages, bars, powders, food toppings, beverages, cereals, ice cream, candy, snack mixes, baked goods, and fried foods. Non-limiting examples of beverages include energy drinks, nutritional drinks, smoothies, sports drinks, orange juice, and other fruit drinks. Non-limiting examples of bars include meal replacements, nutritional bars, snack bars, and energy bars, as well as extruded bars. Non-limiting examples of dairy products include yogurt, yogurt drinks, cheese, and milk.

[0172] In some embodiments, the food or dietary supplement can further comprise herbs, herbal extracts, fungal extracts, enzymes, fiber sources, minerals, and vitamins. In some embodiments, microalgae oils and microalgae biomass can be used in the compositions of the present invention for both therapeutic and non-therapeutic uses. Thus, the compositions, food, and animal feed additives disclosed herein can be used for therapeutic or non-therapeutic purposes.

[0173] In some embodiments, the methods disclosed herein include treating a condition. In some embodiments, the condition is a skin disorder. In some embodiments, the condition is psoriasis. In some embodiments, treating includes causing clearance of psoriatic lesions in a subject in need of treatment.

[0174] In some embodiments, the methods disclosed herein comprising the SCFAs disclosed herein reduce epidermal / dermal separation. In some embodiments, the methods disclosed herein comprising the SCFAs disclosed herein prevent post-inflammatory skin deterioration.

[0175] In some embodiments, a therapeutically effective amount can be an amount effective to treat a condition, treat a skin disorder, treat psoriasis, or treat an autoimmune disorder.

[0176] In some embodiments, a therapeutically effective amount can be an amount effective to result in clearance of psoriatic lesions in a subject in need thereof, which clearance can be at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0177] In some embodiments, a therapeutically effective amount can be an amount effective to reduce epidermal / dermal separation in skin, where the size of the epidermal / dermal separation can be reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.

[0178] In some embodiments, a therapeutically effective amount can be an amount effective to prevent post-inflammatory skin deterioration.

[0179] Pharmaceutically acceptable salts. The present disclosure provides the use of pharmaceutically acceptable salts of any compound described herein. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt may be an organic acid or an inorganic acid. The base added to the compound to form the base addition salt may be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt.

[0180] Metal salts can result from the addition of an inorganic base to a compound described herein. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0181] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0182] Ammonium salts can result from the addition of ammonia or an organic amine to a compound described herein. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, piperazole, imidazole, or pyrazine.

[0183] In some embodiments, the ammonium salt is a triethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a piprazole salt, an imidazole salt, or a pyrazine salt.

[0184] Acid addition salts can result from the addition of an acid to a compound described herein. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharinic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0185] In some embodiments, the salt is hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0186] The methods disclosed herein can include administering to a patient or subject a compound of the present disclosure, alone or in combination with a second compound.

[0187] combination In some embodiments, the methods disclosed herein further comprise administering a therapeutically effective amount of a second therapy. In some embodiments, the second therapy exhibits synergistic effects with the compound comprising a short-chain fatty acid or a pharmaceutically acceptable salt thereof. In some embodiments, the second therapy exhibits an additive therapeutic effect with the compound comprising a short-chain fatty acid or a pharmaceutically acceptable salt thereof. In some embodiments, the compound comprising a short-chain fatty acid or a pharmaceutically acceptable salt thereof exhibits an additive therapeutic effect with the second therapy.

[0188] In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a therapeutically effective amount of a compound comprising a short chain fatty acid or a pharmaceutically acceptable salt thereof and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective to treat the condition in combination with the therapeutically effective amount of the compound comprising a short chain fatty acid or a pharmaceutically acceptable salt thereof, and the reduced amount of the second therapy is less than the amount of the second therapy that is therapeutically effective for the condition in the absence of the therapeutically effective amount of the compound comprising a short chain fatty acid or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the combination may be present in a single formulation, or may be present separately and administered sequentially (either first a composition comprising a molecule comprising at least one SCFA or SCFA moiety, followed by a composition comprising an additional agent, or first a composition comprising an additional agent, followed by a composition comprising at least one SCFA or molecule comprising an SCFA moiety). In some embodiments, the at least one SCFA or molecule comprising an SCFA moiety is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the composition comprising at least one additional agent is administered to the subject. , 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration to the subject.In other embodiments, the composition comprising at least one additional agent is administered within about 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, 0.25 hours, 0.5 hours, 0.75 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 minutes, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours The subject may be administered the agonist / agonist inhibitor 1 hour, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 hours, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks prior to administration of the agonist / agonist inhibitor 1 hour, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks,

[0190] PDE4 inhibitors

[0191] In some embodiments, the methods disclosed herein include administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof in combination with one or more phosphodiesterase 4 (PDE4) inhibitors. Non-limiting examples of PDE4 inhibitors include apremilast (Otezla®), roflumilast (Daxas®), crisaborole (5-(4-cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole, AN-2728, Eucrisa®), pefcalcitol (M5181), and HFP034 (butyl 2-[2-(2-fluorophenyl)acetamido]benzoate). In some embodiments, the methods disclosed herein include administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof and one or more PDE4 inhibitors. In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof in combination with a composition comprising one or more PDE4 inhibitors.

[0192] Biological Agents

[0193] In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof in combination with one or more biologic drugs, including, but not limited to, etanercept (Enbrel®), infliximab (Remicade®), apremilast (Otezla®), and adalimumab (Humira®).

[0194] Further non-limiting biologic drugs include ustekinumab, secukinumab, ixekizumab, guselkumab, and risankizumab.

[0195] In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof, and further one or more biological agents. In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA or a biologically active derivative or precursor thereof, in combination with a composition comprising one or more biological agents.

[0196] Magnesium, Vitamin D3, and Vitamin E

[0197] In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and further comprising one or more of magnesium, vitamin D3, and vitamin E (d-α-tocopherol acetate). Magnesium is a cofactor for over 300 enzymes that regulate a variety of biochemical reactions, including the regulation of blood glucose levels, detoxification, etc. Vitamin D3 deficiency frequently occurs in patients with immune disorders. Vitamin E has unique antioxidant activity.

[0198] In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, and further comprising a source of one or more of magnesium, vitamin D3, and vitamin E. In some embodiments, the methods disclosed herein comprise administering to a subject in need thereof a composition comprising at least one SCFA, or a biologically active derivative or precursor thereof, in combination with a composition comprising a source of one or more of magnesium, vitamin D3, and vitamin E.

[0199] In some embodiments, the compositions disclosed herein include a source of magnesium. In some embodiments, the compositions disclosed herein include an inorganic magnesium salt, such as magnesium chloride, magnesium carbonate, or magnesium phosphate. In some embodiments, the compositions disclosed herein include vitamin D3. In some embodiments, the compositions disclosed herein include vitamin E.

[0200] Any of the embodiments disclosed herein can be used in combination or individually. For example, any pharmaceutically acceptable excipient, method, technique, solvent, or compound disclosed herein can be used with any other pharmaceutically acceptable excipient, method, technique, solvent, or compound disclosed herein to achieve any therapeutic result. The compounds, excipients, and other formulation components can be present in any such formulation in any amount, ratio, or percentage disclosed herein, and any such combination can be used therapeutically for any purpose described herein. [Example]

[0201] Example 1: Treatment of skin disorders with short-chain fatty acids - Suppression of Th1 / Th17 inflammation Various assays were designed and tested in an ex vivo human skin psoriasis model (e.g., Genoskin's InflammaSkin® model), as shown and described in Figures 1-9. Assays included assessment of IL-22 cytokine secretion, hematoxylin and eosin (H&E) staining (e.g., incidence of pyknosis, vacuolization, and epidermal / dermal peeling), K16 expression in the epidermis, and cytokine expression / secretion of TNF-α and IL-17A.

[0202] PSO-InflammaSkin® Model Culture and Treatment

[0203] A total of 16 biopsies, each 15 mm in diameter, were prepared from a single donor. Two NativeSkin® models with 12 / 15 mm silicone rings were prepared from the biopsies according to standard procedures and cultured under cell culture conditions (37°C, 5% CO2, maximum humidity) for 7 days with 2 mL of standard NativeSkin® medium changed daily. Fourteen PSO-InflammaSkin® models with 12 / 15 mm silicone rings were prepared by inducing in situ activation and Th17 / Th1 polarization of skin-resident T cells with a proprietary cocktail and cultured under cell culture conditions (37°C, 5% CO2, maximum humidity) for 7 days with 2 mL of PSO-InflammaSkin® culture medium changed daily.

[0204] From days 1 to 6, the models were treated systemically with 1 μM Otezla or short-chain fatty acids (SCFAs), or topically with the positive control 0.05% betamethasone.

[0205] In these experiments, the SCFA administered was 45 μg / mL Ca-propionate and 1 mM salt mixture (Ca-butyrate and Mg-butyrate).

[0206] On day 7, the supernatants were collected and stored at -80°C, and the skin models from all conditions were carefully removed from the molds. The skin biopsies were re-punched to remove the area under the silicone ring, fixed in 10% buffered formalin, and processed for paraffin wax embedding.

[0207] IL-22 release / ELISA assay

[0208] Immunoassays, such as enzyme-linked immunosorbent assays (ELISAs), were used. IL-22 release in the supernatants was assessed using an ELISA human IL-22 kit (Abcam, product number ab216170). Samples and standards were analyzed in duplicate. Control conditions were analyzed only to confirm the response of donor samples to T cell activation and the positive control betamethasone. Plates were read on a VICTOR Nivo multimode microplate reader. Values ​​are expressed in pg / mL. For each condition, individual values, means, and SEM were plotted using GraphPad Prism. Statistical analysis was performed using one-way ANOVA.

[0209] On day 7, the donor sample had IL-22 levels >25 pg / mL (approximately 100 pg / mL), indicating that the donor sample responded to pro-inflammatory / T cell activation. Furthermore, the donor also responded with a reduction in inflammation. Figure 1 shows that IL-22 levels are reduced on day 7 with the positive treatment control, betamethasone, compared to the InflammaSkin® control. Therefore, the results from the donor sample can be used for further analysis.

[0210] Histological analysis - Hematoxylin & Eosin (H&E) staining

[0211] Skin structure, integrity, and viability were assessed using hematoxylin and eosin (H&E) staining after treatment with betamethasone, 10–15 mg of Otezla® (apremilast), or SCFAs containing butyric and propionic acids. Observed H&E features included pyknosis, vacuolization, and epidermal / dermal separation. H&E staining was performed on 5 μm-thick paraffin-embedded skin cross sections. Three representative photographs were acquired at 40x magnification using a Leica DMi1 microscope. Figure 2 shows representative images of NativeSkin® samples at day 0 and day 7 for analyzing skin structural integrity and viability. Day 0 and day 7 NativeSkin® samples did not show signs of pyknosis / vacuolization (indicative of cell death) or epidermal / dermal separation and appeared healthy. Therefore, donor samples were determined to have maintained viability over the culture period in the absence of inflammation / T cell activation.

[0212] Figure 3 shows representative images of H&E staining after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. All five replicates from the untreated InflammaSkin® group showed reduced epidermal cell viability, as indicated by pyknotic and vacuolated cells and epidermal / dermal separation.

[0213] Betamethasone treatment of the InflammaSkin® model appeared to reduce the incidence of vacuolation and epidermal / dermal separation. Evidence of massive pyknosis was observed, particularly in the upper layers of the epidermis. The greatest difference between betamethasone and the untreated InflammaSkin® model appeared to be a reduction in epidermal / dermal separation. Some variation in the degree of inflammation / damage was observed among the three replicates. For example, replicate 2 appeared to have a histology more similar to untreated InflammaSkin® than the other two replicates.

[0214] Systemic treatment of the InflammaSkin® model with Otezla also appeared to reduce the incidence of pyknosis, vacuolation, and epidermal / dermal separation. Variation in the degree of inflammation / damage was observed among the three replicates. Replicate 1 appeared to retain the most damage to the skin (with epidermal / dermal separation and numerous pyknosis / vacuolated epidermal cells) and appeared similar to the histological findings of untreated InflammaSkin®. Replicates 2 and 3 showed some vacuolation and pyknosis in the upper layers of the epidermis, but the basal layer of the epidermis appeared healthier. This observation indicates skin healing. A larger, healthier area of ​​the basal layer of the epidermis was observed in the betamethasone-treated InflammaSkin® sample than in the control.

[0215] Systemic SCFA treatment of the InflammaSkin® model also appeared to enhance skin health. Nuclear pyknosis / vacuolization in the epidermal layer was observed, which was very similar to the histological findings of the untreated InflammaSkin® model and very similar to those of the betamethasone-treated InflammaSkin® model. Epidermal / dermal separation with SCFA was significantly less observed in the treated model compared to the untreated InflammaSkin® model, suggesting that SCFAs have some effect in preventing skin deterioration after inflammation induction.

[0216] Histological analysis - anti-K16 immunostaining

[0217] The type 1 keratin K16 is upregulated in hyperproliferative conditions such as psoriasis. Anti-K16 immunostaining was performed on 5 μm-thick paraffin-embedded skin sections using a primary antibody anti-K16 (Sigma, SAB4501660, rabbit IgG at a dilution of 1 / 100 volume / volume) and a secondary antibody (LifeTech, A21428 Alexa Fluor 647 at a dilution of 1 / 500 volume / volume). Representative photographs were acquired at 40x magnification using a Zeiss AxioImager M2 microscope. Figure 4 shows representative images of anti-K16 immunostaining in the InflammaSkin® model at day 0 and day 7. The InflammaSkin® model at day 7 demonstrates that K16 is upregulated.

[0218] Figure 5 shows representative images of anti-K16 immunostaining after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. In Genoskin's InflammaSkin® model, K16 was upregulated in treated samples compared to uninflamed NativeSkin® controls (where K16 was either not expressed or was barely expressed). Some variability in K16 expression was observed across the five replicates. K16 expression (except for replicate 1) appeared fairly uniform from the basal to the epidermal layers.

[0219] Betamethasone, Otezla, and SCFAs all also reduced K16 expression in the epidermis. For Otezla and SCFAs, less K16 expression was observed in the basal / suprabasal epidermal layers than in the upper layers of the epidermis (compared to expression throughout the epidermis).

[0220] Cytokine analysis - multiplex assay

[0221] Human pro-inflammatory cytokines released into the supernatant were quantified using the V-PLEX Human IL-17A Kit (MesoScale Discovery, Catalog Number: K151RFD-1) and the V-PLEX Human TNFα Kit (MesoScale Discovery, Catalog Number: K151QWD-1). Values ​​are expressed in pg / mL. For each condition, individual values, means, and SEM were plotted using GraphPad Prism. Statistical analysis was performed using one-way ANOVA.

[0222] IL-17A is a cytokine upregulated in both the psoriasis and Genoskin InflammaSkin® models. Figure 6 shows IL-17A expression after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. Figure 7 shows the fold change in IL-17A from untreated samples after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. IL-17A was expressed as expected in the untreated InflammaSkin® model. All three treatments, betamethasone, Otezla, and SCFAs, significantly reduced IL-17A compared to untreated InflammaSkin® controls, although no statistical significance was observed among the three different treatments. IL-17A levels were reduced by approximately 70% with betamethasone, 95% with Otezla, and 80% with SCFAs. Although not statistically significant, both Otezla and SCFAs were more effective than betamethasone treatment in reducing this cytokine level in the InflammaSkin® model.

[0223] TNF-α is a cytokine that is upregulated in psoriasis and is also slightly upregulated in Genoskin's InflammaSkin® model (Jardet et al, 2020 Exp Derm).

[0224] Figure 8 shows TNF-α expression after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. Figure 9 shows the fold change in TNF-α from untreated samples after treatment with betamethasone, 10-15 mg of Otezla® (apremilast), or SCFAs containing butyrate and propionate. TNF-α was expressed as expected in the untreated InflammaSkin® model. Betamethasone significantly reduced TNF-α levels (approximately 40%) compared to the untreated InflammaSkin® model. SCFAs slightly reduced TNF-α levels (approximately 15%). In the InflammaSkin® model, Otezla appeared to significantly increase TNF-α release by nearly two-fold, rather than reducing TNF-α levels, as expected (Schafer, 2012, Biochemical Pharmacology).

[0225] Example 2: Treatment of skin disorders with short-chain fatty acids - Evaluation of Th17 cytokine response Various assays were designed and tested in an ex vivo human skin psoriasis model (e.g., Genoskin's InflammaSkin® model) as shown and described in Figures 10-20. The assays included evaluation of various cytokines (e.g., IL-17A Gen B, IL-21, IL-22, IL-23, IFN-γ, and TNF-α).

[0226] PSO-InflammaSkin® models were cultured and treated as described in Example 1. In these experiments, the SCFA administered was 45 μg / mL Ca-propionate and 1 mM salt mixture (Ca-butyrate and Mg-butyrate).

[0227] Cytokine analysis - multiplex assay

[0228] Human pro-inflammatory cytokines released into the supernatant were quantified using the V-PLEX Human IL-17A Kit (MesoScale Discovery, Catalog Number: K151RFD-1) and the V-PLEX Human custom Pro-inflammatory Kit. Plate 1 contained the Pro-inflammatory Panel 1 (Human) Kit Catalog Number K15049 (panels IFN-γ and TNF-α). Plate 2 contained the TH17 Panel 1 (Human) Kit Catalog Number K15049 (panels IL-17A Gen B, IL-21, IL-22, IL-23, IL-27, IL-31, and MIP-3α).

[0229] Samples were diluted 4-fold for plate 2 and 2-fold for plate 1. Samples and standards were evaluated in duplicate. Plates were read on a MesoScale Discovery Quickpleax SQ 120 plate reader and values ​​were expressed in pg / mL.

[0230] Statistical analysis was performed. Each condition was compared to the untreated InflammaSkin® condition. First, the normality of the distributions of the two comparison groups was assessed. If the two distributions were not normal, a nonparametric Mann-Whitney-Wilcoxon test was performed. If the two distributions were normal, equality of variance was assessed using Fisher's test for variances. If the variances were equal, a Student's t-test was performed. If the variances were unequal, a Welch's test was performed.

[0231] Cytokine / chemokine release into the culture medium was assessed using the TH17 Panel + IFN-γ and TNFa V-plex kit (IL-17A Gen.B, IL-21, IL-22, IL-23, IL-27, IL-31, MIP-3α, TNFα, and IFN-γ) from MSD. IL-23 was added exogenously to the culture medium to maintain inflammation in the InflammaSkin® model over the course of the experiment. As a result, many values ​​were above the limit of detection and were not plotted.

[0232] Figure 10 shows cytokine expression after treatment with betamethasone, Otezla® (apremilast), or SCFAs containing butyrate and propionate. Betamethasone significantly reduced most of the cytokines / chemokines evaluated: IFN-γ, IL-17A, IL-22, and TNFα. Only one of three replicate samples reduced IL-23 levels sufficiently that IL-23 was within the limits of detection. Betamethasone treatment of the InflammaSkin® model increased IL-27 cytokine secretion by approximately 30%.

[0233] Figures 10-19 show cytokine expression after treatment with Otezla® (apremilast) or SCFAs including butyrate and propionate.

[0234] Otezla reduced several key cytokines associated with TH17 inflammation. Otezla significantly reduced secretion of IFN-γ (Figures 10 and 11), IL-22 (Figures 10 and 14), and IL-17A (Figures 10 and 12) from the InflammaSkin® model. Otezla also reduced IL-31 (Figures 10 and 17), but this was not significantly different from the untreated InflammaSkin® model. Otezla reduced IL-17A levels more than betamethasone treatment (Figure 10). Otezla significantly increased secretion of TNF-α from the InflammaSkin® model (Figures 10 and 19). However, TNFα was approximately 1 pg / mL in the untreated InflammaSkin® model, and approximately 2 pg / mL (by MSD) or 13 pg / mL (by ELISA; Figure 20). Cytokines such as IFN-γ, IL-22, and IL-17A, which approached 100 pg / mL in the untreated InflammaSkin® model, were dramatically reduced by Otezla. In addition to TNFα, Otezla also increased the secretion of MIP-3α (Figures 10 and 18) and IL-21 (Figures 10 and 13) by approximately 50% compared to the untreated InflammaSkin® model.

[0235] SCFAs reduced IFN-γ (Figures 10 and 11), IL-17A (Figures 10 and 12), IL-22 (Figures 10 and 14), IL-31 (Figures 10 and 17), and TNFα (Figures 10 and 19). SCFA treatment of the InflammaSkin® model did not result in as much reduction in IFNγ, IL-17A, or IL-22 as Otezla®. Only one of three replicate samples reduced IL-23 levels sufficiently to fall within the limits of detection (Figures 10 and 15). TA1 also did not cause an increase in TNFα in the InflammaSkin® model as did Otezla® (Figures 10 and 19). MIP-3α increased approximately two-fold with SCFA treatment of the InflammaSkin® model (Figures 10 and 18).

[0236] Example 3: Combined treatment of skin disorders using short chain fatty acids Assays are performed to evaluate the effectiveness of combination therapy combining at least one SCFA with at least one second compound for treating skin diseases and disorders, including psoriasis.

[0237] The combination of at least one SCFA and at least one second compound provides effective treatment for one or more skin disorders. Additional compounds contemplated for use include PDE4 inhibitors, anti-inflammatory compounds, disease-modifying antirheumatic drugs (DMARDs), immunosuppressants, biological agents, Cox-2 inhibitors, apremilast, or combinations thereof, and / or other agents. Non-limiting examples of these and other compounds useful in combination are disclosed herein.

[0238] Combination of SCFAs with PDE4 inhibitors (e.g., apremilast)

[0239] Combination of SCFA treatment and apremilast: The daily oral dose is about 1 to about 2 g of butyric acid or a pharmaceutically acceptable salt thereof (e.g., sodium butyrate), about 100 mg of propionic acid or a pharmaceutically acceptable salt thereof (e.g., sodium propionate), about 10 to about 15 mg of apremilast, about 10 to about 20 mg of a magnesium source (e.g., magnesium chloride), about 80 to about 100 IU of vitamin D3, and about 50 to about 100 IU of vitamin E (d-α-tocopherol acetate).

[0240] For psoriasis, the combination with a topical ointment is important. A daily oral dose of SCFAs is used by applying an ointment consisting of 2 / 5 parts clobetasol (0.05%), 1 / 5 part calcipotriene (vitamin D, 0.005%), 1 / 5 part salicylic acid (10%), and 1 / 5 part vitamin E (0.5%). All of these components are used (separately) as topical treatments.

[0241] The efficacy of the combination therapy will be evaluated relative to the efficacy of monotherapy for each test compound. Assays to determine the synergistic effects of SCFAs in combination with PDE4 inhibitors will also be evaluated.

[0242] Example 4: Treatment of skin disorders with short-chain fatty acids Various assays were designed and tested in the mouse imiquimod (IMQ)-induced psoriasis model, as shown and described in Figures 21 to 31. The anti-inflammatory activities of the PDE4 inhibitor apremilast and SCFAs were evaluated in the mouse imiquimod (IMQ)-induced psoriasis model.

[0243] Imiquimod (IMQ)-induced psoriasis model

[0244] Topical application of IMQ, a TLR7 / 8 ligand and potent immune activator, induced and exacerbated psoriasis in mice. The murine IMQ-induced psoriasis (IMQ Ps) model was initiated by repeated topical application of Aldara cream (containing 5% IMQ) for 6 consecutive days. Female Balb / c mice (9 weeks old at time of receipt, ordered 20 g, Charles River, Sulzfeld, Germany; n = 10 per group, except for healthy controls, n = 4) received topical application of 62.5 mg of commercially available IMQ cream (5% Aldara) to the previously shaved (approximately 2 cm × 3 cm) and depilated (Pilka cream) dorsal skin (day -1) and 7 mg to the skin on the outside of the right ear daily for 6 consecutive days. This corresponds to a daily dose of approximately 3.5 mg of IMQ. Healthy control mice were also included in the study and were treated with vehicle cream (Vaseline; Bombastus-Werke AG) alone instead of IMQ. Additionally, an IMQ disease control group was included.

[0245] Before treatment began on the day of disease induction (day 0), mice were randomized into respective groups based on body weight. To evaluate the anti-inflammatory effects of the two test compounds in murine IMQ psoriasis, mice were treated with either 25 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) or a fixed dose of SCFA (in ddH2O) by oral gavage twice daily (BID) starting on day 0.

[0246] In these experiments, the SCFAs administered were 120 mg / kg / day of Ca-propionate and 2,146 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0247] IMQ psoriasis is characterized by the rapid induction of skin inflammation, including skin erythema, scaling, and acanthosis, accompanied by immune cell infiltration, and is pathologically and histologically similar to human psoriasis.

[0248] Psoriasis Severity Score

[0249] Disease severity scores were assessed daily from the induction of psoriasis by IMQ application (day 0) until the end of the study (day 6). Psoriasis severity on the dorsal skin of mice was assessed using a modified scoring system developed by van der Fits et al., which is based on the clinical PASI (Psoriasis Area and Severity Index) and takes into account skin erythema, scaling, and skin thickening. Scoring was performed by the same laboratory technician throughout the experiment. Each parameter was scored independently on a scale of 0 to 3. [Table 1]

[0250] The sum score (erythema + scaling + thickening) was named the disease severity score (scale 0–9) and served as a marker of the severity of dorsal skin inflammation. Additionally, ear thickness of the right ear was measured daily using an automated caliper (Bayer AG, Germany).

[0251] During the study, parameters including disease severity score (erythema, scaling, thickening) were assessed in the psoriatic dorsal skin, and the degree of ear thickening in the IMQ-treated right ear. All IMQ-control mice developed a psoriatic phenotype in the dorsal skin over the study period, and subsequently showed increased ear thickness (Figures 27-29), as well as elevated disease severity scores (Figures 21-23) and increased dorsal thickness (Figures 24-26).

[0252] Treatment with the PDE4 inhibitor apremilast at 50 mg / kg / day significantly reduced the severity of psoriasis in IMQ-treated mice throughout the experimental period, thereby demonstrating efficacy comparable to that of standard of care (SoC) etanercept (which served as a technical control) (Figures 21 and 22). A fixed dose of SCFA also significantly reduced disease severity scores on days 5 and 6 (Figures 21 and 23), accompanied by a suppressive effect on ear thickness throughout the study period (Figures 27, 29, and 30).

[0253] Both compounds reduced skin erythema, scaling and skin thickening as assessed by disease severity scores (Figures 21-23) and separate measurements of dorsal / ear skin thickness (Figures 24-26 and Figures 27-28).

[0254] Transepidermal water loss (TEWL)

[0255] The physiological parameter transepidermal water loss (TEWL; unit: g / m2 / h) was tested and evaluated on the dorsal skin on day 5 during the IMQ psoriasis experiment using a Tewameter (TM300, Courage and Khazaka, Cologne, Germany). TEWL is a common laboratory parameter for evaluating skin dysfunction present in psoriatic skin. TEWL can be used as a diagnostic marker in clinical practice to accurately assess disease severity in psoriasis. The physiological parameter TEWL showed increased transepidermal water loss on day 5 in the psoriatic dorsal skin of IMQ control mice compared with healthy skin of control mice (Figure 30).

[0256] Neither the test compound nor the technical control etanercept had a significant effect on the newly tested parameter transepidermal water loss (TEWL), although a trend towards a reduction by SCFAs could be observed (Figure 31).

[0257] body weight

[0258] Body weight was measured daily in all mice throughout each study. Oral treatment with either apremilast (25 mg / kg twice daily) or SFA002 (fixed dose twice daily) began with disease induction on day 0. Etanercept (10 mg / kg subcutaneously every 3 days) served as a technical control. Healthy and IMQ control groups did not receive placebo treatment.

[0259] As is known, IMQ induces a slight weight loss of approximately 10% within the first 2-3 days (Figure 30). Neither test compound showed any effect on weight loss in the psoriatic skin of IMQ-treated mice treated with apremilast or SCFA (Figure 31). Regarding animal health observations, SCFA was well tolerated throughout the study, but mice treated with 50 mg / kg / day apremilast exhibited decreased activity, ruffled fur, and a slightly hunched posture.

[0260] On day 6, after assessment of disease severity and ear thickness, the animals were sacrificed, blood was collected from the vena cava, and the right ear of each mouse was harvested for potential ex vivo analysis of inflammatory markers (e.g., cytokines, elastase activity). Ears were frozen in liquid nitrogen and stored at -80°C. In addition, punch biopsies (8 mm diameter, SmithKline Beecham Ltd, UK) were obtained from the dorsal skin, which were also frozen in liquid nitrogen and stored at -80°C.

[0261] Statistical analysis of the data was performed using GraphPad PRISM software. One-way analysis of variance (ANOVA) was performed, and pairwise comparisons with the IMQ disease control group (using Dunnett's test) were performed as a multiple comparison method. Statistical significance was determined by a p-value ( * :p<0.05, ** :p<0.01, *** :p<0.005, **** :p<0.001).

[0262] Example 5: Treatment of skin disorders with short-chain fatty acids Various assays were designed and tested in the mouse imiquimod (IMQ)-induced psoriasis model, as shown and described in Figures 33-37. The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs was evaluated in the mouse imiquimod (IMQ)-induced psoriasis model.

[0263] Imiquimod (IMQ)-induced psoriasis model

[0264] The mouse IMQ-induced psoriasis (IMQ Ps) model was prepared as described in Example 4.

[0265] Before treatment began on the day of disease induction (day 0), mice were randomized into respective groups based on body weight. To evaluate the anti-inflammatory effects of the two test compounds in murine IMQ psoriasis, mice were treated twice daily (BID) by oral gavage with 2.5 mg / kg, 5 mg / kg, and / or 7 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) or a fixed or low dose of SCFA (in ddH2O), starting on day 0.

[0266] In these experiments, the fixed dose of SCFA administered was 120 mg / kg / day of Ca-propionate and 2,146 mg / kg / day of a mixture of Ca-butyrate and Mg-butyrate, and the low dose of SCFA administered was 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a mixture of salts (Ca-butyrate and Mg-butyrate).

[0267] Psoriasis Severity Score

[0268] Disease severity scores were assessed daily as described in Example 4.

[0269] During the study, parameters including disease severity scores (erythema, scaling, thickening) were assessed in psoriatic dorsal skin.

[0270] Treatment with the PDE4 inhibitor apremilast at 10 mg / kg / day and 14 mg / kg / day suppressed the severity of psoriasis in IMQ-treated mice within the first 4 days of the study, but the anti-inflammatory effect was not maintained until the end of the study on day 6 (Figures 33 and 34). Treatment with low-dose SCFA suppressed the severity of psoriasis in IMQ-treated mice within the first 4 days of the study, but the anti-inflammatory effect was not maintained until the end of the study on day 6 (Figure 33). However, treatment with a fixed dose of SCFA significantly reduced disease severity scores throughout the study, including days 5 and 6 (Figure 34).

[0271] Cytokine analysis - multiplex assay Human pro-inflammatory cytokines (e.g., TNFα, IL-17A, and IL-23) in each mouse were measured by multiplex ELISA in dorsal skin biopsies taken 6 days after the IMQ psoriasis challenge (Figures 35-37).

[0272] Example 6: Combined treatment of skin disorders using short chain fatty acids Various assays are designed and tested in the imiquimod (IMQ)-induced psoriasis model in mice.

[0273] Imiquimod (IMQ)-induced psoriasis model

[0274] The mouse IMQ-induced psoriasis (IMQ Ps) model is prepared as described in Example 4.

[0275] Before starting treatment on the day of disease induction (day 0), mice are randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two test compounds in mouse IMQ psoriasis, starting from day 0, mice are treated by oral gavage twice daily (BID) with 2.5mg / kg, 5mg / kg, and / or 7mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) or low dose SCFA (in ddH2O).Healthy controls and IMQ disease controls are orally treated with vehicle alone in parallel.All treatments begin with the first application of IMQ on day 0.

[0276] In these experiments, the fixed doses of SCFA administered were 120 mg / kg / day of Ca-propionate and 2,146 mg / kg / day of Ca-butyrate and Mg-butyrate, and the low doses of SCFA administered were 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0277] Psoriasis Severity Score

[0278] Disease severity scores are assessed daily as described in Example 4.

[0279] During the study, the severity of the disease (including erythema, scaling, and thickening) is assessed daily on the affected dorsal skin, similar to the severity of psoriasis. Following this, the degree of auricular thickening of the IMQ-treated right ear is also assessed daily.

[0280] The sum score (erythema + scaling + thickening) was named the disease severity score (scale 0–9) and served as a marker of the severity of dorsal skin inflammation. Additionally, ear thickness of the right ear was measured daily using an automated caliper (Bayer AG, Germany).

[0281] During the study, parameters including disease severity score (erythema, scaling, thickening) will be assessed in the psoriatic dorsal skin and the degree of ear thickening in the IMQ-treated right ear.

[0282] body weight

[0283] Body weights are measured daily in all mice for the entire duration of each study, as described in Example 4.

[0284] Cytokine analysis - multiplex assay

[0285] Human pro-inflammatory cytokines (eg, TNFα, IL-17A, and IL-23) in each mouse are measured by multiplex ELISA in dorsal skin biopsies taken 6 days after the IMQ psoriasis challenge.

[0286] Example 7: Combined treatment of skin disorders using short chain fatty acids Various assays were designed and tested in the mouse imiquimod (IMQ)-induced psoriasis model, as shown and described in Figures 38-45. The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs was evaluated in combination therapy versus monotherapy in the mouse imiquimod (IMQ)-induced psoriasis model.

[0287] Imiquimod (IMQ)-induced psoriasis model

[0288] The mouse IMQ-induced psoriasis (IMQ Ps) model was prepared as described in Example 4.

[0289] Before treatment began on the day of disease induction (day 0), mice were randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two compounds in mouse IMQ psoriasis, mice were treated by oral gavage twice daily (BID) with 2.5 mg / kg, 5 mg / kg, or 7 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, a fixed dose of SCFA (in ddH2O) alone, a combination of 2.5 mg / kg apremilast and a fixed dose of SCFA, a combination of 5 mg / kg apremilast and a fixed dose of SCFA, or a combination of 7 mg / kg apremilast and a fixed dose of SCFA.Healthy controls and IMQ disease controls were orally treated with vehicle alone in parallel.All treatments began with the first application of IMQ on day 0.

[0290] In these experiments, the SCFAs administered were 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0291] thickened ears

[0292] Disease severity scores were assessed daily from the induction of psoriasis by IMQ application (day 0) until the end of the study (day 6). The degree of ear thickness of the IMQ-treated right ear was measured daily using an automatic caliper (Bayer AG, Germany) as described in Example 4.

[0293] Furthermore, SCFA significantly suppressed ear skin thickening by day 5 (Figure 37). Ear thickness was also suppressed by medium and high doses of apremilast by day 5. Low doses of apremilast did not exhibit any inhibitory effect on ear thickness (Figures 38 and 39). Combination therapy did not exhibit additive or synergistic effects on ear skin thickening compared with the corresponding doses of apremilast or fixed doses of SCFA monotherapy (Figures 35-41). However, significant reductions in ear thickness were observed with combination treatment compared with apremilast monotherapy for all tested doses from day 4 to day 6 (Figures 38 and 39).

[0294] body weight

[0295] Body weights were measured daily in all mice throughout the duration of each study, as described in Example 4.

[0296] As is known, IMQ induces a slight weight loss within the first few days (Figures 42-45). Apremilast and SCFAs, both in combination and alone, did not show a positive effect on treatment-induced weight loss compared to vehicle-treated IMQ-diseased controls (Figures 42-45).

[0297] Regarding animal health observations, all test doses of SCFA and apremilast, or combination treatments, were well tolerated throughout the study period.

[0298] Example 8: Combined treatment of skin disorders using short chain fatty acids Various assays are designed and tested in a mouse imiquimod (IMQ)-induced psoriasis model.The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs is evaluated in combination with monotherapy in a mouse imiquimod (IMQ)-induced psoriasis model.

[0299] Imiquimod (IMQ)-induced psoriasis model

[0300] The mouse IMQ-induced psoriasis (IMQ Ps) model is prepared as described in Example 4.

[0301] Before starting treatment on the day of disease induction (day 0), mice are randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two compounds in mouse IMQ psoriasis, mice are treated by oral gavage twice daily (BID) with 2.5mg / kg, 5mg / kg, or 7mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, a fixed dose of SCFA (in ddH2O) alone, a combination of 2.5mg / kg apremilast and a fixed dose of SCFA, a combination of 5mg / kg apremilast and a fixed dose of SCFA, or a combination of 7mg / kg apremilast and a fixed dose of SCFA.Healthy controls and IMQ disease controls are orally treated with vehicle alone in parallel.All treatments begin with the first application of IMQ on day 0.

[0302] In these experiments, the SCFAs administered were 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0303] Psoriasis Severity Score

[0304] Disease severity scores are assessed daily as described in Example 4.

[0305] During the study, the severity of the disease (including erythema, scaling, and thickening) is assessed daily on the affected dorsal skin, similar to the severity of psoriasis. Following this, the degree of auricular thickening of the IMQ-treated right ear is also assessed daily.

[0306] All IMQ-control mice developed a psoriatic phenotype in the dorsal skin over the study period, subsequently showing increased ear thickness as well as elevated disease severity scores and increased dorsal skin thickness. The pro-inflammatory cytokines TNFα, IL-17A, and IL-23 were increased in the psoriatic dorsal skin of IMQ-treated mice compared with healthy control skin.

[0307] The effect on psoriasis severity in IMQ-treated mice after treatment with the PDE4 inhibitor apremilast alone at 5 mg / kg / day, 10 mg / kg / day, or 14 mg / kg / day, a fixed dose of SCFA alone, and the combination of the PDE4 inhibitor apremilast at 5 mg / kg / day, 10 mg / kg / day, or 14 mg / kg / day with a fixed dose of SCFA will be evaluated for anti-inflammatory effects.

[0308] Additionally, combination treatment with escalating doses of apremilast plus a fixed dose of SCFA will be evaluated for additive / synergistic effects compared to monotherapy with SCFA or monotherapy with an equal dose of apremilast.

[0309] skin thickening

[0310] The effect on psoriasis severity in IMQ-treated mice after treatment with the PDE4 inhibitor apremilast alone at 5 mg / kg / day, 10 mg / kg / day, or 14 mg / kg / day, a fixed dose of SCFA alone, and the combination of the PDE4 inhibitor apremilast at 5 mg / kg / day, 10 mg / kg / day, or 14 mg / kg / day with a fixed dose of SCFA will be assessed in terms of skin thickening of psoriatic dorsal and ear skin.

[0311] Additionally, combination treatment with increasing doses of apremilast plus a fixed dose of SCFA will be evaluated for additive / synergistic effects compared to monotherapy with SCFA or an equivalent dose of apremilast on suppressing ear thickness and reducing dorsal skin thickness.

[0312] body weight

[0313] Body weights were measured daily in all mice throughout the duration of each study, as described in Example 4.

[0314] Cytokine analysis - multiplex assay

[0315] Human pro-inflammatory cytokines (eg, TNFα, IL-17A, and IL-23) in each mouse were measured by multiplex ELISA in dorsal skin biopsies taken 6 days after the IMQ psoriasis challenge.

[0316] Regarding animal health observations, all test doses of SCFA and apremilast, or combination treatments, are well tolerated throughout the study.

[0317] Example 9: Combined treatment of skin disorders using short chain fatty acids Various assays were designed and tested in the mouse imiquimod (IMQ)-induced psoriasis model, as shown and described in Figures 46-49. The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs was evaluated in combination therapy versus monotherapy in the mouse imiquimod (IMQ)-induced psoriasis model.

[0318] Imiquimod (IMQ)-induced psoriasis model

[0319] A murine IMQ-induced psoriasis (IMQ Ps) model was prepared as described in Example 4. IMQ psoriasis was characterized by the rapid induction of skin inflammation, including skin erythema, skin scaling, and acanthosis, accompanied by immune cell infiltration, which is pathologically and histologically similar to human psoriasis.

[0320] Before treatment begins on the day of disease induction (day 0), mice are randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two compounds in mouse IMQ psoriasis, mice are treated by oral gavage twice daily (BID) with 25 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, a fixed dose of SCFA (in ddH2O) alone, or a combination of 25 mg / kg apremilast and a fixed dose of SCFA.Healthy controls and IMQ disease controls are orally treated with vehicle alone in parallel.All treatments begin with the first application of IMQ on day 0.

[0321] In these experiments, the fixed dose of SCFAs included 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0322] skin scales

[0323] In a separate evaluation of skin scaling, one of the disease severity score parameters, the combination treatment significantly (p<0.001) reduced dorsal skin scaling from day 3 to the end of the study (Figure 46). SFA002 and apremilast monotherapy were also able to suppress skin scaling from day 3 to day 5. Cumulative assessment of skin scaling throughout the study period showed significant and similar beneficial effects of all treatments, with p-values ​​of p<0.01 for apremilast, SFA002, and combination therapy (apremilast + SFA002) (Figure 48). However, at the end of the study (d6), only the apremilast + SFA002 combination approach continued to show a significant reduction (approximately 50%) in skin scaling compared to all IMQ-induced comparison groups, including apremilast alone (Figure 47).

[0324] body weight

[0325] Body weights were measured daily in all mice throughout the duration of each study, as described in Example 4.

[0326] As is known, IMQ induces a slight weight loss within the first 2-3 days (Figure 49). Apremilast and SCFAs, both in combination and alone, did not show a positive effect on treatment-induced weight loss compared to vehicle-treated IMQ-diseased controls (Figure 49).

[0327] Regarding animal health observations, all test doses of SCFA and apremilast, or combination treatments, were well tolerated throughout the study period.

[0328] Example 10: Combination treatment of skin disorders using short chain fatty acids Various assays are designed and tested in a mouse imiquimod (IMQ)-induced psoriasis model.The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs is evaluated in combination with monotherapy in a mouse imiquimod (IMQ)-induced psoriasis model.

[0329] Imiquimod (IMQ)-induced psoriasis model

[0330] The mouse IMQ-induced psoriasis (IMQ Ps) model is prepared as described in Example 4.

[0331] Before starting treatment on the day of disease induction (day 0), mice are randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two compounds in mouse IMQ psoriasis, mice are treated by oral gavage twice daily (BID) with 25 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, a fixed dose of SCFA (in ddH2O) alone, or a combination of 25 mg / kg apremilast and a fixed dose of SCFA.Healthy controls and IMQ disease controls are orally treated with vehicle alone in parallel.All treatments begin with the first application of IMQ on day 0.

[0332] In these experiments, the SCFAs administered were 120 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0333] Psoriasis Severity Score

[0334] Disease severity scores are assessed daily as described in Example 4.

[0335] During the study, the severity of the disease (including erythema, scaling, and thickening) is assessed daily on the affected dorsal skin, similar to the severity of psoriasis. Following this, the degree of auricular thickening of the IMQ-treated right ear is also assessed daily.

[0336] All IMQ-control mice developed a psoriatic phenotype in the dorsal skin over the study period, subsequently showing increased ear thickness as well as elevated disease severity scores and increased dorsal skin thickness. The pro-inflammatory cytokines TNFα, IL-17A, and IL-23 were increased in the psoriatic dorsal skin of IMQ-treated mice compared with healthy control skin.

[0337] The effect on psoriasis severity in IMQ-treated mice after treatment with 50 mg / kg / day of the PDE4 inhibitor apremilast alone, a fixed dose of SCFA alone, and a combination of 50 mg / kg / day of the PDE4 inhibitor apremilast and a fixed dose of SCFA will be evaluated for anti-inflammatory effects.

[0338] Additionally, combination treatment with escalating doses of apremilast plus a fixed dose of SCFA will be evaluated for additive / synergistic effects compared to monotherapy with SCFA or monotherapy with an equal dose of apremilast.

[0339] skin thickening

[0340] The effect on psoriasis severity in IMQ-treated mice after treatment with 50 mg / kg / day of the PDE4 inhibitor apremilast alone, a fixed dose of SCFA alone, and a combination of 50 mg / kg / day of the PDE4 inhibitor apremilast and a fixed dose of SCFA is assessed in terms of skin thickening in psoriatic dorsal and ear skin.

[0341] Additionally, combination treatment with increasing doses of apremilast plus a fixed dose of SCFA will be evaluated for additive / synergistic effects compared to monotherapy with SCFA or an equivalent dose of apremilast on suppressing ear thickness and reducing dorsal skin thickness.

[0342] body weight

[0343] Body weights were measured daily in all mice throughout the duration of each study, as described in Example 4.

[0344] Cytokine analysis - multiplex assay

[0345] Human pro-inflammatory cytokines (eg, TNFα, IL-17A, and IL-23) in each mouse are measured by multiplex ELISA in dorsal skin biopsies taken 6 days after the IMQ psoriasis challenge.

[0346] Regarding animal health observations, all test doses of SCFA and apremilast, or combination treatments, are well tolerated throughout the study.

[0347] Example 11: Treatment of Skin Disorders with Short Chain Fatty Acids Various assays were designed and tested in the LPS animal model of inflammation, as shown and described in Figure 50. Plasma TNF-α levels were assessed at 6 and 26 hours after LPS. Administration of SCFAs demonstrated significant and rapid downregulation of TNF-α within 26 hours after treatment (Figure 50).

[0348] Example 12: Combination Treatment of Skin Disorders with Short Chain Fatty Acids Various assays were designed and tested in the mouse imiquimod (IMQ)-induced psoriasis model, as shown and described in Figures 51-70. The anti-inflammatory activity of the PDE4 inhibitor apremilast and SCFAs was evaluated in combination therapy versus monotherapy in the mouse imiquimod (IMQ)-induced psoriasis model.

[0349] Imiquimod (IMQ)-induced psoriasis model

[0350] A murine IMQ-induced psoriasis (IMQ Ps) model was prepared using female Balb / c mice (8 weeks old at the time of ordering, approximately 19-20 g, Charles River, Sulzfeld, Germany; n=10 mice / group, except for healthy controls, n=4) as described in Example 4 (Figure 51).

[0351] Before starting treatment on the day of disease induction (day 0), mice are randomized into respective groups based on body weight.To evaluate the anti-inflammatory effects of the two compounds in mouse IMQ psoriasis, mice are treated by oral gavage twice daily (BID) with one of the following: (1) 12 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, (2) 25 mg / kg apremilast (in sterile water containing 0.5% CMC / 0.025% Tween® 80; m / m / v) alone, (3) a fixed dose of SCFA (in ddH2O) alone, (4) 12 mg / kg apremilast and a fixed dose of SCFA in combination, (5) 25 mg / kg apremilast and a fixed dose of SCFA in combination.Healthy controls and IMQ disease controls are orally treated with vehicle alone in parallel. Etanercept (10 mg / kg subcutaneously every 3 days) was used as technical control. All treatments start on day 0 with the first application of IMQ.

[0352] In these experiments, the SCFAs administered were 60 mg / kg / day of Ca-propionate and 1,100 mg / kg / day of a salt mixture (Ca-butyrate and Mg-butyrate).

[0353] IMQ psoriasis is characterized by the rapid induction of skin inflammation, including skin erythema, scaling, and acanthosis, accompanied by immune cell infiltration, and is pathologically and histologically similar to human psoriasis.

[0354] Psoriasis Severity Score

[0355] Disease severity scores were assessed daily in IMQ-treated mice as described in Example 4. During the study, parameters including disease severity scores (erythema, scaling, thickening) were assessed in psoriatic dorsal skin (Figures 52-56).

[0356] The reduction in psoriasis severity scores after treatment with 12 mg / kg apremilast monotherapy did not reach significance on days 4 and 5 (Figures 55 and 56). However, treatment with 25 mg / kg apremilast monotherapy reduced psoriasis severity scores in IMQ-treated mice on day 4 of the study (p<0.05), and these effects were maintained at the end of the study on day 6 (Figures 52-53 and Figures 55-56).

[0357] Treatment with the fixed dose of SCFAs and 25 mg / kg apremilast combination significantly reduced disease severity scores throughout the study, including days 4 (p<0.0001) and 5 (p<0.0001) (Figures 52-53 and Figures 55-56). On days 4 and 5, the fixed dose of SCFAs and 25 mg / kg apremilast combination therapy demonstrated additive or synergistic effects on reducing disease severity scores compared to 25 mg / kg apremilast monotherapy (Figures 55 and 56).

[0358] Cumulative assessment of disease severity scores over the study period showed a significant beneficial effect for fixed-dose SCFA and 25 mg / kg apremilast combination therapy with a p-value of p<0.001 (Figure 54). Of all IMQ-induced comparator groups tested, only fixed-dose SCFA and 25 mg / kg apremilast combination treatment demonstrated a significant reduction in cumulative disease severity scores (Figure 54).

[0359] skin scales

[0360] Skin scaling, one of the disease severity score parameters, was assessed in IMQ-treated mice (Figures 57-59).

[0361] Treatment with 25 mg / kg apremilast monotherapy significantly inhibited skin scaling on days 5 (p<0.05) and 6 (p<0.01) (Figures 58 and 59). Treatment with a fixed dose of SCFA in combination with 25 mg / kg apremilast significantly inhibited skin scaling on days 5 (p<0.005) and 6 (p<0.01) (Figures 58 and 59).

[0362] On day 5 of the study, treatment with 25 mg / kg apremilast alone significantly reduced dorsal skin scaling (p<0.05), and combination treatment with a fixed dose of SCFAs and 25 mg / kg apremilast further reduced dorsal skin scaling (p<0.005) (Figures 57 and 59). On day 5, combination therapy with a fixed dose of SCFAs and 25 mg / kg apremilast demonstrated additive or synergistic effects on reducing skin scaling compared to 25 mg / kg apremilast monotherapy (Figure 59).

[0363] Treatment with fixed dose SCFA monotherapy or fixed dose SCFA in combination with 12 mg / kg apremilast significantly inhibited skin scaling (p<0.05) by day 6 (Figures 57-59). Reduction in skin scaling after treatment with 12 mg / kg apremilast monotherapy did not reach significance by day 6 (Figure 58).

[0364] thickened ears

[0365] Ear thickening, one of the disease severity score parameters, was evaluated in IMQ-treated mice (Figures 60 and 61). The degree of ear thickening in the IMQ-treated right ear was measured daily using an automated caliper (Bayer AG, Germany) as described in Example 4.

[0366] Treatment with a fixed dose of SCFA alone and combination therapy of a fixed dose of SCFA with 25 mg / kg of apremilast significantly inhibited ear skin thickening on day 6 (p<0.01) (Figure 61). Ear thickness was also inhibited by treatment with a fixed dose of SCFA in combination with 12 mg / kg of apremilast on day 6 (p<0.05) (Figure 61). However, treatment with either monotherapy dose of apremilast (12 mg / kg and 25 mg / kg) did not have any inhibitory effect on ear thickness on day 6 (Figure 61).

[0367] Combination therapy with fixed doses of SCFA and apremilast showed additive or synergistic effects in reducing ear skin thickening compared to apremilast monotherapy at the corresponding doses (Figures 60 and 61).

[0368] body weight

[0369] Body weights were measured daily in all mice throughout the duration of each study, as described in Example 4.

[0370] As is known, IMQ induces a slight weight loss within the first 2-3 days (Figure 62). Apremilast and SCFAs, both in combination and alone, did not show a positive effect on treatment-induced weight loss compared to vehicle-treated IMQ disease controls (Figure 62).

[0371] Regarding animal health observations, all test doses of SCFA and apremilast, or combination treatments, were well tolerated throughout the study period.

[0372] Embodiment

[0373] The following non-limiting embodiments provide illustrative examples of the present disclosure, but do not limit the scope of the disclosure.

[0374] Embodiment 1. A method of treating a condition, the method comprising: a) administering to a subject in need thereof a first pharmaceutical composition, the first pharmaceutical composition comprising a therapeutically effective amount of a compound that is a short chain fatty acid or a pharmaceutically acceptable salt thereof; and b) administering to the subject a second pharmaceutical composition, the second pharmaceutical composition comprising a therapeutically effective amount of a phosphodiesterase 4 (PDE4) inhibitor.

[0375] Embodiment 2. The method of embodiment 1, wherein the condition is a skin disorder.

[0376] Embodiment 3 The method of embodiment 1 or 2, wherein the condition is psoriasis.

[0377] Embodiment 4. The method of any one of embodiments 1-3, wherein the condition is an autoimmune disorder.

[0378] Embodiment 5. The method of any one of embodiments 1-4, wherein the short chain fatty acid is butyric acid.

[0379] Embodiment 6. The method of any one of embodiments 1-5, wherein the short chain fatty acid is propionic acid.

[0380] Embodiment 7. The method of any one of embodiments 1-6, wherein the compound is butyric acid or a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition further comprises an additional short chain fatty acid or a pharmaceutically acceptable salt thereof, wherein the additional short chain fatty acid is propionic acid or a pharmaceutically acceptable salt thereof.

[0381] Embodiment 8 The method of any one of embodiments 1 to 7, wherein the PDE4 inhibitor is apremilast.

[0382] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the therapeutically effective amount of a PDE4 inhibitor is from about 10 mg to about 15 mg.

[0383] Embodiment 10. The method of any one of embodiments 1 to 9, wherein the first pharmaceutical composition further comprises vitamin D3 in an amount of about 50 IU to about 200 IU.

[0384] Embodiment 11. The method of any one of embodiments 1 to 10, wherein the first pharmaceutical composition is formulated for oral administration.

[0385] Embodiment 12. A method of treating a condition, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a first pharmaceutical composition comprising at least one SCFA and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective to treat the condition in combination with the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA, and the reduced amount of the second therapy is less than the amount of the second therapy that is therapeutically effective for the condition in the absence of the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA.

[0386] Embodiment 13 The method of embodiment 12, wherein the condition is a skin disorder.

[0387] Embodiment 14 The method of embodiment 12 or 13, wherein the condition is psoriasis.

[0388] Embodiment 15. The method of any one of embodiments 12-14, wherein the condition is an autoimmune disorder.

[0389] Embodiment 16. The method of any one of embodiments 12-15, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof.

[0390] Embodiment 17. The method of any one of embodiments 12-16, wherein the first pharmaceutical composition comprises propionic acid or a pharmaceutically acceptable salt thereof.

[0391] Embodiment 18. The method of any one of embodiments 12-17, wherein the first pharmaceutical composition comprises at least two SCFAs.

[0392] Embodiment 19. The method of any one of embodiments 12-18, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

[0393] Embodiment 20. The method of any one of embodiments 12-19, wherein the first pharmaceutical composition comprises an inorganic magnesium salt.

[0394] Embodiment 21. The method of any one of embodiments 12-20, wherein the first pharmaceutical composition comprises vitamin D3.

[0395] Embodiment 22 The method of any one of embodiments 12-21, wherein the second therapy comprises a PDE4 inhibitor.

[0396] Embodiment 23 The method of embodiment 22, wherein the PDE4 inhibitor is apremilast.

[0397] Embodiment 24 The method of any one of embodiments 12-23, wherein the second therapy exhibits synergy with the first pharmaceutical composition.

[0398] Embodiment 25 The method of any one of embodiments 12-24, wherein the reduced amount of the second therapy comprises administering to the subject a reduced dose of the second therapy.

[0399] Embodiment 26 The method of any one of embodiments 12-25, wherein the reduced amount of the second therapy comprises administering the second therapy to the subject less frequently.

[0400] Embodiment 27 The method of any one of embodiments 12-26, wherein the reduced amount of the second therapy comprises administering a reduced dose of the second therapy to the subject less frequently.

[0401] Embodiment 28 The method of any one of embodiments 12-27, wherein said treating comprises causing a reduction in psoriatic lesions in said subject.

[0402] Embodiment 29. The method of any one of embodiments 12-28, wherein said treating comprises causing clearance of psoriatic lesions in said subject.

Claims

1. 1. A method of treating a condition, said method comprising: a. administering a first pharmaceutical composition to a subject in need thereof, wherein the first pharmaceutical composition comprises a therapeutically effective amount of a compound that is a short chain fatty acid or a pharmaceutically acceptable salt thereof; b. administering to the subject a second pharmaceutical composition, wherein the second pharmaceutical composition comprises a therapeutically effective amount of a phosphodiesterase 4 (PDE4) inhibitor; A method comprising:

2. 10. The method of claim 1, wherein the condition is a skin disorder.

3. 3. The method of claim 1 or 2, wherein the condition is psoriasis.

4. The method of any one of claims 1 to 3, wherein the condition is an autoimmune disorder.

5. The method according to any one of claims 1 to 4, wherein the short-chain fatty acid is butyric acid.

6. The method according to any one of claims 1 to 5, wherein the short-chain fatty acid is propionic acid.

7. 7. The method of any one of claims 1 to 6, wherein the compound is butyric acid or a pharmaceutically acceptable salt thereof, and the first pharmaceutical composition further comprises an additional short chain fatty acid or a pharmaceutically acceptable salt thereof, wherein the additional short chain fatty acid is propionic acid or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the PDE4 inhibitor is apremilast.

9. 9. The method of any one of claims 1 to 8, wherein the therapeutically effective amount of a PDE4 inhibitor is from about 10 mg to about 15 mg.

10. 10. The method of any one of claims 1 to 9, wherein the first pharmaceutical composition further comprises vitamin D3 in an amount of about 50 IU to about 200 IU.

11. The method of any one of claims 1 to 10, wherein the first pharmaceutical composition is formulated for oral administration.

12. 1. A method of treating a condition, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a first pharmaceutical composition comprising at least one SCFA and a reduced amount of a second therapy, wherein the reduced amount of the second therapy is therapeutically effective to treat the condition in combination with the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA, and the reduced amount of the second therapy is less than the amount of the second therapy that is therapeutically effective for the condition in the absence of the therapeutically effective amount of the first pharmaceutical composition comprising the at least one SCFA.

13. 13. The method of claim 12, wherein the condition is a skin disorder.

14. 14. The method of claim 12 or 13, wherein the condition is psoriasis.

15. The method of any one of claims 12 to 14, wherein the condition is an autoimmune disorder.

16. 16. The method of any one of claims 12 to 15, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof.

17. 17. The method of any one of claims 12 to 16, wherein the first pharmaceutical composition comprises propionic acid or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 12 to 17, wherein the first pharmaceutical composition comprises at least two SCFAs.

19. 19. The method of any one of claims 12 to 18, wherein the first pharmaceutical composition comprises butyric acid or a pharmaceutically acceptable salt thereof and propionic acid or a pharmaceutically acceptable salt thereof.

20. 20. The method of any one of claims 12 to 19, wherein the first pharmaceutical composition comprises an inorganic magnesium salt.

21. The method of any one of claims 12 to 20, wherein the first pharmaceutical composition comprises vitamin D3.

22. 22. The method of any one of claims 12 to 21, wherein the second therapy comprises a PDE4 inhibitor.

23. 23. The method of claim 22, wherein the PDE4 inhibitor is apremilast.

24. 24. The method of any one of claims 12 to 23, wherein the second therapy exhibits synergy with the first pharmaceutical composition.

25. 25. The method of any one of claims 12-24, wherein the reduced amount of a second therapy comprises administering to the subject a reduced dose of the second therapy.

26. 26. The method of any one of claims 12-25, wherein the reduced amount of a second therapy comprises administering the second therapy to the subject less frequently.

27. 27. The method of any one of claims 12-26, wherein the reduced amount of a second therapy comprises administering a reduced dose of the second therapy to the subject less frequently.

28. 28. The method of any one of claims 12 to 27, wherein said treating comprises causing a reduction in psoriatic lesions in said subject.

29. 29. The method of any one of claims 12 to 28, wherein said treating comprises causing clearance of psoriatic lesions in said subject.

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