阅读说明：本技术 包含15-氧代-epa或15-氧代-dgla的组合物及其制备和使用方法 (Compositions comprising 15-oxo-EPA or 15-oxo-DGLA and methods of making and using same ) 是由 M·曼库 J·克莱麦克斯 D·考夫兰 于 2016-05-12 设计创作，主要内容包括：本公开提供15-氧代-EPA和15-氧代-DGLA、包含15-氧代-EPA和/或15-氧代-DGLA的组合物以及通过施用15-氧代-EPA和/或15-氧代-DGLA来在有此需要的受试者中治疗和/或预防纤维化、皮肤病症、炎症、肾病或肾功能障碍的方法。(The present disclosure provides 15-oxo-EPA and 15-oxo-DGLA, compositions comprising 15-oxo-EPA and/or 15-oxo-DGLA, and methods of treating and/or preventing fibrosis, a skin disorder, inflammation, kidney disease, or kidney dysfunction in a subject in need thereof by administering 15-oxo-EPA and/or 15-oxo-DGLA.)

1. A (5Z,8Z,11Z,13E,17Z) -15-oxoeicosa-5, 8,11,13, 17-pentaenoic acid ("15-oxo-EPA").

2. A composition comprising from about 0.1g to about 4g of (5Z,8Z,11Z,13E,17Z) -15-oxoeicosa-5, 8,11,13, 17-pentaenoic acid ("15-oxo-EPA").

3. A pharmaceutical composition comprising (5Z,8Z,11Z,13E,17Z) -15-oxoeicosa-5, 8,11,13, 17-pentaenoic acid ("15-oxo-EPA") and a pharmaceutically acceptable excipient.

4. A (8Z,11Z,13E) -15-oxoeicosa-8, 11, 13-trienoic acid ("15-oxo-DGLA").

5. A composition comprising from about 0.1g to about 4g of (8Z,11Z,13E) -15-oxoeicosa-8, 11, 13-trienoic acid ("15-oxo-DGLA").

6. A pharmaceutical composition comprising (8Z,11Z,13E) -15-oxoeicosa-8, 11, 13-trienoic acid ("15-oxo-DGLA") and a pharmaceutically acceptable excipient.

7. A method of treating and/or preventing fibrosis, inflammation, kidney disease or renal dysfunction in a subject in need thereof, the method comprising administering to the subject a compound, composition or pharmaceutical composition of any one of the preceding claims.

8. The method of claim 7, wherein the fibrosis is associated with an organ or tissue selected from the group consisting of: lung, liver, heart, mediastinum, bone marrow, retropertineneum (retropertoneum), skin, intestine, joint, reproductive organs, and combinations thereof.

9. The method of claim 7 or claim 8, wherein the fibrosis is liver fibrosis.

10. The method of any one of claims 7-9, wherein the fibrosis is associated with nonalcoholic fatty liver disease (NAFLD).

11. The method of any one of claims 7 to 10, wherein NAFLD Activity Score (NAS) in the subject is reduced following administration of the composition, optionally:

wherein the NAS is reduced in the subject compared to baseline, or

Wherein the subject is undergoing fibrosis treatment and the NAS is reduced in the subject compared to a second subject who has not been administered the composition, wherein optionally a placebo has been administered to the second subject, and/or wherein the second subject is optionally undergoing fibrosis treatment, and

optionally wherein the fibrosis treatment is continued during administration of the compound, composition or pharmaceutical composition.

12. The method of claim 11, wherein the fibrosis treatment comprises administration of a Hepatitis C Virus (HCV) non-antiviral agent, an HCV antiviral agent, a Hepatitis B Virus (HBV) non-antiviral agent, an HBV antiviral agent, a primary biliary cirrhosis agent, an alcoholic hepatitis agent, a primary sclerosing cholangitis agent, a NASH agent, an autoimmune hepatitis agent, a pulmonary fibrosis agent, a cystic fibrosis agent, a renal fibrosis agent, a skin fibrosis agent, a myelofibrosis agent, an eosinophilic esophagitis agent, an anti-TGF- β agent, an anti-CTGF agent, a recombinant human serum amyloid P agent, an anti-IL-4 agent, an anti-IL-5 agent (e.g., mepolizumab (mepolizumab)), an anti-IL-13 agent, a neurochemical receptor agent, an anti-IL-17A agent, Hh or Hh (r) an SMO antagonist, a CCR5 antagonist, a CCR4 cytostatic agent, CCR4, a, CXCR4 antagonists, anti-CXCR 4 agents, CXCR3 antagonists, anti-CCL 17 agents, NOX inhibitors, copaxone (copaxone), adiponectin, AMPK agonists, Y-cassette binding protein-1, myofibroblast recruitment inhibitors, anti-Th 17 MMP inducers, anti-extracellular matrix deposition compounds, adenosine receptor antagonists, microrna (mir) agents, stem cells, tenofovir (tenofovir), anti-collagen cross-linking agents (e.g., semtuzumab (simtuzumab), moglycaezumab (mogamulizumab)), or angiotensin II receptor blockers (ARBs) selected from the group consisting of valsartan (valsartan), telmisartan (telmisisartan), losartan (losartan), irbesartan (irbesartan), azilsatan (azilsartan), eprosartan (eprosartan), olmesartan (olmesartan), or any combination thereof.

13. The method of any one of claims 7-12 wherein the 15-oxo-EPA, the composition comprising 15-oxo-EPA, the pharmaceutical composition comprising 15-oxo-EPA, the 15-oxo-DGLA, the composition comprising 15-oxo-DGLA, or the pharmaceutical composition comprising 15-oxo-DGLA is administered orally.

14. The method of any one of claims 7-13, wherein the 15-oxo-EPA or the 15-oxo-DGLA is the only active ingredient in the composition.

15. The method of any one of claims 11-13, wherein the composition further comprises an additional agent for affecting the fibrosis treatment.

16. The method of any one of claims 7-15, further comprising identifying the subject as having fibrosis prior to administering the 15-oxo-EPA, the composition comprising 15-oxo-EPA, the pharmaceutical composition comprising 15-oxo-EPA, the 15-oxo-DGLA, the composition comprising 15-oxo-DGLA, or the pharmaceutical composition comprising 15-oxo-DGLA.

17. The method of any one of claims 7-16 further comprising identifying the subject as having an increased risk of developing fibrosis prior to administering the 15-oxo-EPA, the composition comprising 15-oxo-EPA, the pharmaceutical composition comprising 15-oxo-EPA, the 15-oxo-DGLA, the composition comprising 15-oxo-DGLA, or the pharmaceutical composition comprising 15-oxo-DGLA.

18. The method of claim 16 or claim 17, wherein the identifying step comprises determining a NAS associated with the subject, optionally wherein the NAS associated with the subject is at least 3.

19. The method of any one of claims 16-18, wherein the identifying step comprises screening for a genetic mutation in a nucleic acid molecule associated with the subject.

20. The method of any one of claims 16-19, wherein the identifying step comprises obtaining an analysis of blood and/or serum associated with the subject.

21. The method of any one of claims 16 to 20, wherein the identifying step comprises examining a tissue associated with the subject, optionally wherein the tissue is a histological tissue sample associated with the subject.

22. The method of any one of claims 18 to 21, further comprising determining a second, lower NAS value associated with the subject after administering the composition for a period of time.

23. The compound, composition, pharmaceutical composition, or method of any one of the preceding claims, wherein the 15-oxo-EPA or the 15-oxo-DGLA is in free acid form.

24. The compound, composition, pharmaceutical composition, or method of any preceding claim, wherein the 15-oxo-EPA or the 15-oxo-DGLA is in an esterified form,

optionally wherein the esterified form is an alkyl ester form,

optionally wherein the esterified form is a triglyceride form.

25. The compound, composition, pharmaceutical composition, or method of any one of the preceding claims, wherein the 15-oxo-EPA or the 15-oxo-DGLA is in the ethyl ester form.

26. The method of any one of claims 7 to 25, wherein the inflammatory disease is selected from acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis.

Technical Field

The present invention provides (5Z,8Z,11Z,13E,17Z) -15-oxoeicosa (oxocosa) -5,8,11,13, 17-pentaenoic acid (also known as 15-oxo-EPA) and (8Z,11Z,13E) -15-oxoeicosa-8, 11, 13-trienoic acid (also known as 15-oxo-DGLA), compositions, formulations and dosage units comprising 15-oxo-EPA or 15-oxo-DGLA and methods of treating or preventing fibrosis (e.g., liver fibrosis), skin disorders, inflammation, kidney disease or kidney function disorders by administering 15-oxo-EPA or 15-oxo-DGLA (or pharmaceutical compositions comprising the same) to a subject in need thereof.

Disclosure of Invention

In some embodiments, the present disclosure provides methods of treating and/or preventing fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or renal dysfunction in a subject in need thereof, the method comprising administering to the subject a composition comprising 15-oxo-EPA.

In some embodiments, the present disclosure provides a method of treating fibrosis in a subject undergoing fiber therapy, the method comprising administering to the subject a composition comprising 15-oxo-EPA.

In some embodiments, the present disclosure provides a composition for treating and/or preventing fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or renal dysfunction in a subject in need thereof, wherein the composition comprises an effective amount of 15-oxo-EPA.

In some embodiments, the present disclosure provides the use of 15-oxo-EPA (or a pharmaceutical composition comprising 15-oxo-EPA) for the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or kidney dysfunction.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising 15-oxo-EPA.

In some embodiments, the present disclosure provides methods of treating and/or preventing fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or renal dysfunction in a subject in need thereof, the method comprising administering to the subject a composition comprising 15-oxo-DGLA.

In some embodiments, the present disclosure provides methods of treating fibrosis in a subject undergoing fibrosis treatment, the method comprising administering to the subject a composition comprising 15-oxo-DGLA.

In some embodiments, the present disclosure provides a composition for treating and/or preventing fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or renal dysfunction in a subject in need thereof, wherein the composition comprises an effective amount of 15-oxo-DGLA.

In some embodiments, the present disclosure provides the use of 15-oxo-DGLA (or a pharmaceutical composition comprising 15-oxo-DGLA) for the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or kidney dysfunction.

In some embodiments, the present disclosure provides pharmaceutical compositions comprising 15-oxo-DGLA.

Other features and advantages of the techniques disclosed herein will become apparent from the following detailed description.

Detailed Description

In one embodiment, the present disclosure provides compositions comprising 15-oxo-EPA, 15-oxo-DGLA, or a combination thereof, and methods of using the compositions to treat and/or prevent fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or kidney dysfunction in a subject in need thereof.

15-oxo-EPA has the general structure and IUPAC name shown in formula (I):

15-oxo-EPA can be synthesized from eicosapentaenoic acid (EPA) according to methods known in the art. As used herein, the term "15-oxo-EPA" may refer to 15-oxo-EPA and/or derivatives thereof (R ≠ H) in its free acid form, such as a pharmaceutically acceptable ester, conjugate or salt (R is an ion) consistent with formula (I), or a mixture of any of the foregoing. In some embodiments, 15-oxo-EPA is used in the free acid form (i.e., R ═ H). Alternatively, a pharmaceutically acceptable ester or salt of 15-oxo-EPA is used in certain embodiments of the present disclosure. In some embodiments, 15-oxo-EPA is C_1-4Alkyl esters in the form of, for example, methyl ester (R ═ CH)₃) Or ethyl ester (R ═ CH)₂CH₃) Form (a).

As used herein, "EPA" refers to eicosa-5, 8,11,14, 17-pentaenoic acid, also known as 20: 5n-3, omega-3 fatty acids. EPA is readily available from commercial sources.

15-oxo-DGLA has the general structure and IUPAC name shown in formula (II):

15-oxo-DGLA can be synthesized from dihomo-gamma-linolenic acid (DGLA) according to methods known in the art. As used herein, the term "15-oxo-DGLA" may refer to 15-oxo-DGLA in its free acid form and/or its derivatives (R ≠ H), such as a pharmaceutically acceptable ester, conjugate, or salt consistent with formula (I) (R is an ion), or a mixture of any of the foregoing. In some embodiments, 15-oxo-DGLA is used in the free acid form (i.e., R ═ H). Alternatively, a pharmaceutically acceptable ester or salt of 15-oxo-DGLA is used in certain embodiments of the present disclosure. In some embodiments, 15-oxo-DGLA is C_1-4Alkyl esters in the form of, for example, methyl ester (R ═ CH)₃) Or ethyl ester (R ═ CH)₂CH₃) Form (a).

As used herein, "DGLA" refers to eicosa-8, 11, 14-trienoic acid, also known as 20: 3n-6, omega-6 fatty acids. DGLA is readily available from commercial sources.

Accordingly, in one aspect of the present disclosure, there is provided a method of treating and/or preventing fibrosis in a subject comprising administering to the subject a therapeutically effective amount of 15-oxo-EPA or a composition comprising 15-oxo-EPA.

Thus, in another aspect of the present disclosure, there is provided a method of treating and/or preventing fibrosis in a subject comprising administering to the subject a therapeutically effective amount of 15-oxo-DGLA or a composition comprising 15-oxo-DGLA.

The present disclosure provides 15-oxo-EPA or compositions comprising 15-oxo-EPA for use in the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease or renal dysfunction.

The present disclosure also provides 15-oxo-DGLA or a composition comprising 15-oxo-DGLA for use in the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease, or renal dysfunction.

The present disclosure provides for the use of 15-oxo-EPA, or a composition comprising 15-oxo-EPA, in the manufacture of a medicament for the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease or renal dysfunction.

The present disclosure provides use of 15-oxo-DGLA or a composition comprising 15-oxo-DGLA in the manufacture of a medicament for the treatment and/or prevention of fibrosis (e.g., liver fibrosis), a skin disorder, inflammation, kidney disease or kidney dysfunction.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of 15-oxo-EPA. 15-oxo-EPA may be the only active ingredient (e.g., API) in pharmaceutical compositions and methods and uses as described herein. 15-oxo-EPA may be the only active ingredient. Alternatively, 15-oxo-EPA may be co-formulated or co-administered with another agent or agents for the treatment and/or prevention of fibrosis. If an additional active agent or agents are to be used, the 15-oxo-EPA may be co-formulated as a single dosage unit, or the 15-oxo-EPA and the additional fibrotic therapeutic agent may be formulated as two to more dosage units for coordinated, combined or concomitant administration.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of 15-oxo-DGLA. 15-oxo-DGLA may be the only active ingredient (e.g., API) in the pharmaceutical compositions and methods and uses as described herein. 15-oxo-DGLA may be the only active ingredient. Alternatively, 15-oxo-DGLA may be co-formulated or co-administered with another agent or agents for the treatment and/or prevention of fibrosis. If an additional active agent or agents are to be used, 15-oxo-DGLA may be co-formulated as a single dosage unit, or 15-oxo-DGLA and the additional fibrotic therapeutic agent may be formulated as two to more dosage units for coordinated, combined or concomitant administration.

The present disclosure also provides formulations of 15-oxo-EPA and formulations comprising 15-oxo-EPA and methods of using these formulations to treat and/or prevent fibrosis (e.g., liver fibrosis), skin disorders, inflammation, kidney disease, or kidney dysfunction.

The present disclosure also provides formulations of 15-oxo-DGLA and formulations comprising 15-oxo-DGLA and methods of using these formulations to treat and/or prevent fibrosis (e.g., liver fibrosis), skin disorders, inflammation, kidney disease, or kidney dysfunction.

The present disclosure also provides a pharmaceutical composition for oral delivery comprising 15-oxo-EPA. The composition may comprise a pharmaceutically acceptable excipient. 15-oxo-EPA may be in any of the forms discussed herein. 15-oxo-EPA may be present in one or more divided dosage units in an amount of from about 1mg to about 10,000 mg.

The present disclosure also provides a pharmaceutical composition for oral delivery comprising 15-oxo-DGLA. The composition may comprise a pharmaceutically acceptable excipient. 15-oxo-DGLA may be in any of the forms discussed herein. 15-oxo-DGLA may be present in one or more separate dosage units in an amount of from about 1mg to about 10,000 mg.

15-oxo-EPA

In one embodiment, the composition of the present disclosure comprises 15-oxo-EPA as an active ingredient. As used herein, the term "15-oxo-EPA" refers to 15-oxo-EPA in its free acid form and/or pharmaceutically acceptable esters, conjugates or salts thereof, or mixtures of any of the foregoing. 15-oxo-EPA can be synthesized by means known in the art. In one example, as shown in scheme 1, 15-oxo-EPA can be synthesized from EPA in a 2-step process:

reaction scheme 1

In step 1, EPA (1) is converted to its corresponding 15(S) -hydroxy compound (compound 2) (15- (S) -HEPE) using the reagents oxygen, borax, L-cysteine and the appropriate concentration of the specific enzyme LPX 1. In step 2, MnO is used in Dichloromethane (DCM)₂Oxidizing the 15- (S) -HEPE (compound 2) obtained from step 1 to obtain 15-oxo-EPA.

Derivatives of 15-oxo-EPA may be used instead, although the term "derivatives of 15-oxo-EPA" does not include any derivative compound lacking the oxo group of 15-oxo-EPA. The term "pharmaceutically acceptable" in this context means that the substance does not cause unacceptable toxicity to the subject or interact with other components of the composition.

In one embodiment, 15-oxo-EPA is in the form of an ester, such as an ethyl ester (also referred to herein as E-15-oxo-EPA or ethyl-15-oxo-EPA). In some embodiments, 15-oxo-EPA comprises C of 15-oxo-EPA₁-C₅An alkyl ester. In another embodiment, the 15-oxo-EPA comprises 15-oxo-EPA methyl ester, 15-oxo-EPA propyl ester, or 15-oxo-EPA butyl ester.

In another embodiment, the 15-oxo-EPA comprises lithium 15-oxo-EPA, a mono-, di-or triglyceride of 15-oxo-EPA or any other ester or salt of 15-oxo-EPA, or the free acid form of 15-oxo-EPA.

In various embodiments, the present disclosure provides pharmaceutical compositions, e.g., orally deliverable compositions, comprising 15-oxo-EPA. In one embodiment, the composition comprises a therapeutically effective amount of 15-oxo-EPA. In one embodiment, the pharmaceutical composition comprises from about 0.1% to about 99%, from about 1% to about 95%, from about 5% to about 90% by weight of 15-oxo-EPA.

In one embodiment, the pharmaceutical composition comprises about at least about 70%, at least about 80%, or at least about 90% by weight of 15-oxo-EPA. In one embodiment, the pharmaceutical composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% by weight of 15-oxo-EPA.

In another embodiment, 15-oxo-EPA is present in the compositions of the present disclosure in the following amounts: about 1mg to about 10,000mg, 25mg to about 7500mg, about 25mg to about 5000mg, about 50mg to about 3000mg, about 75mg to about 2500mg, or about 100mg to about 1000mg, for example, about 25mg, about 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 1025mg, about 500mg, about 525mg, about 550mg, about 875mg, 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 107mg, about 1075mg, about 1050mg, about 1000mg, about 107mg, about 1075mg, about 107mg, about 1000mg, about 1075mg, about 1000mg, about 200mg, about 100mg, about 1mg, about 24 mg, about 102 mg, about 1mg, about 24 mg, about 102 mg, about 24 mg, about 102 mg, about 24 mg, about 102 mg, about 1mg, about 24 mg, about 102 mg, about 24 mg, about 1mg, about 102 mg, about 24 mg, about 1mg, about 24 mg, about 1mg, about 24 mg, about 1mg, about 24 mg, about 102 mg, about 1mg, about 102 mg, about 24 mg, about 1mg, about 102 mg, about 24 mg, about 102 mg, about 1mg, about 102 mg, about 1mg, about 102 mg, about 1mg, about 102 mg, About 1275mg, about 1300mg, about 1325mg, about 1350mg, about 1375mg, about 1400mg, about 1425mg, about 1450mg, about 1475mg, about 1500mg, about 1525mg, about 1550mg, about 1575mg, about 1600mg, about 1625mg, about 1650mg, about 1675mg, about 1700mg, about 1725mg, about 1750mg, about 1775mg, about 1800mg, about 1825mg, about 1850mg, about 1875mg, about 1900mg, about 1925mg, about 1950mg, about 1975mg, about 2000mg, about 2025mg, about 2050mg, about 2075mg, about 2100mg, about 2125mg, about 2170 mg, about 2175mg, about 2200mg, about 2225mg, about 220 mg, about 2275mg, about 2300mg, about 2325mg, about 2320 mg, about 2375mg, about 2425mg, about 2150mg, about 2525mg, about 2775mg, about 2675mg, about 2775mg, about 1000mg, about 2775mg, about 1000mg, about 24 mg, about 1000mg, about 500mg, about 24 mg, about 500mg, about, About 2900mg, about 2925mg, about 2950mg, about 2975mg, about 3000mg, about 3025mg, about 3050mg, about 3075mg, about 3100mg, about 3125mg, about 3150mg, about 3175mg, about 3200mg, about 3225mg, about 3250mg, about 3275mg, about 3300mg, about 3325mg, about 3350mg, about 3375mg, about 3400mg, about 3425mg, about 3450mg, about 3475mg, about 3500mg, about 3525mg, about 3550mg, about 3575mg, about 3600mg, about 3625mg, about 3650mg, about 3675mg, about 3700mg, about 3750mg, about 3775mg, about 3800mg, about 3825mg, about 3850mg, about 3875mg, about 3900mg, about 3925mg, about 4050mg, about 405 mg, about 3775mg, about 37440 mg, about 410 mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 4175mg, about 43440 mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about 4175mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about, About 4525mg, about 4550mg, about 4575mg, about 4600mg, about 4625mg, about 4650mg, about 4675mg, about 4700mg, about 4725mg, about 4750mg, about 4775mg, about 4800mg, about 4825mg, about 4850mg, about 4875mg, about 4900mg, about 4925mg, about 4950mg, about 4975mg, about 5000mg, about 5025mg, about 5050mg, about 5075mg, about 5100mg, about 5125mg, about 5150mg, about 5175mg, about 5200mg, about 5225mg, about 5250mg, about 5275mg, about 5300mg, about 5325mg, about 5350mg, about 5375mg, about 5400mg, about 5450mg, about 5475mg, about 5470 mg, about 5525mg, about 5550mg, about 615 mg, about 5600mg, about 580 mg, about 5875mg, about 6075mg, about 5475mg, about 5775mg, about 6075mg, about 5775mg, about 5925mg, about 5775mg, about 595 mg, about 605775 mg, about 5775mg, about 575mg, about 5775mg, about 6050mg, about 575mg, about 5650mg, about 575mg, about 6075mg, about 5675mg, about 6050mg, about 605775 mg, about 5675mg, about 6050mg, about 5675mg, about 5975mg, about 605775 mg, about 6050mg, about 575mg, about 605775 mg, about 595 mg, about 5775mg, about 575mg, about 5775mg, about 575mg, about 595 mg, about 6050mg, about 575mg, about 6050mg, about 5775mg, about 6050mg, about 575mg, about 5775mg, about 5975mg, about 6050mg, about, About 6150mg, about 6175mg, about 6200mg, about 6225mg, about 6250mg, about 6275mg, about 6300mg, about 6325mg, about 6350mg, about 6375mg, about 6400mg, about 6425mg, about 6450mg, about 6475mg, about 6500mg, about 6525mg, about 6550mg, about 6575mg, about 6600mg, about 6625mg, about 6650mg, about 6675mg, about 6700mg, about 6725mg, about 6750mg, about 6775mg, about 6800mg, about 6825mg, about 6850mg, about 6875mg, about 6900mg, about 6925mg, about 6950mg, about 6975mg, about 7025mg, about 7050mg, about 7075mg, about 7100mg, about 7125mg, about 7150mg, about 7175mg, about 7200mg, about 7225mg, about 7755 mg, about 725mg, about 7625mg, about 75765 mg, about 7650mg, about 757775 mg, about 747775 mg, about 760 mg, about 7650mg, about 757775 mg, about 747775 mg, about 7675mg, about 747775 mg, about 7650mg, about 7675mg, about 7650mg, about 7050mg, about 747775 mg, about 7675mg, about 747775 mg, about 7200mg, about 7675mg, about 74735 mg, about 760 mg, about 7675mg, about 747675 mg, about 7675mg, about 747775 mg, about 7650mg, about 7675mg, about 74735 mg, about 74760 mg, about 7675mg, about 747675 mg, about 760 mg, about 747675 mg, about 747775 mg, about 747650 mg, about 74760 mg, about 747675 mg, about 747775 mg, about 747675 mg, about 74760 mg, about 7675mg, about 74770 mg, about 7675mg, About 7775mg, about 7800mg, about 7825mg, about 7850mg, about 7875mg, about 7900mg, about 7925mg, about 7950mg, about 7975mg, about 8000mg, about 8025mg, about 8050mg, about 8075mg, about 8100mg, about 8125mg, about 8150mg, about 8175mg, about 8200mg, about 8225mg, about 8275mg, about 8300mg, about 8325mg, about 8350mg, about 8375mg, about 8400mg, about 8425mg, about 8450mg, about 8475mg, about 8500mg, about 8525mg, about 8550mg, about 8600mg, about 8625mg, about 8650mg, about 8675mg, about 8700mg, about 8750mg, about 8775mg, about 900mg, about 8825mg, about 9175mg, about 9375mg, about 9275mg, about 9250mg, about 9275mg, about 919275 mg, about 9375mg, about 919275 mg, about 9175mg, about 9350mg, about 9175mg, about 919275 mg, about 9175mg, about 9375mg, about 9175mg, about 91300 mg, about 9350mg, about 9175mg, about 91300 mg, about 9275mg, about 9375mg, about 9175mg, about 91300 mg, about 9275mg, about 9175mg, about 9275mg, about 91300 mg, about 9275mg, about 9375mg, about 91300 mg, about 9275mg, about 91300 mg, about 9375mg, about 9275mg, about 9175mg, about 9275mg, about 91300 mg, about 9175mg, about 91300 mg, about 9275mg, about 9375mg, about 9175mg, about 9275mg, about 91300 mg, about 9275mg, about 91300 mg, about 9275mg, about 919275 mg, about 91300 mg, about 9275mg, about 919275 mg, about 9275mg, about 91300 mg, about 9375mg, about 91300 mg, about 919275 mg, about 9375mg, about 91300 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9275mg, about 9375mg, about 9275mg, about 9375mg, about 919275 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9375mg, about 91300 mg, about 9275mg, about 919275 mg, about 9175mg, about 9275mg, about 919275 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9275mg, about 919275 mg, about 9275mg, about 9400mg, about 9425mg, about 9450mg, about 9475mg, about 9500mg, about 9525mg, about 9550mg, about 9575mg, about 9600mg, about 9625mg, about 9650mg, about 9675mg, about 9700mg, about 9725mg, about 9750mg, about 9775mg, about 9800mg, about 9825mg, about 9850mg, about 9875mg, about 9900mg, about 9925mg, about 9950mg, about 9975mg, or about 10,000 mg.

In one embodiment, the 15-oxo-EPA present in the compositions of the present disclosure comprises at least 90% by weight of 15-oxo-EPA. The 15-oxo-EPA composition may comprise even higher purity 15-oxo-EPA, for example at least 95% by weight 15-oxo-EPA or at least 97% by weight 15-oxo-EPA, wherein 15-oxo-EPA is any form of 15-oxo-EPA as described herein. The purity (e.g., impurity profile) of 15-oxo-EPA can be further defined by any description of 15-oxo-EPA provided herein.

The amount of 15-oxo-EPA in the pharmaceutical composition and its purity are discussed above. The nature of the essential fatty acids and their synthesis allows the 15-oxo-EPA composition to include moieties from other essential fatty acids in the essential fatty acid metabolic cascade.

In one embodiment, the compositions of the present disclosure comprise no greater than about 10%, no greater than about 9%, no greater than about 8%, no greater than about 7%, no greater than about 6%, no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, no greater than about 1%, or no greater than about 0.5% by weight of other omega-3 fatty acids, including alpha linolenic acid, stearidonic acid, docosahexaenoic acid (DHA), or derivatives thereof. In other embodiments, such other omega-3 fatty acids are substantially absent or absent.

In another embodiment, 15-oxo-EPA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% by weight of all fatty acids present in the compositions of the present disclosure.

Some residual eicosapentaenoic acid may be present from the synthesis of 15-oxo-EPA. No greater than about 10%, no greater than about 9%, no greater than about 8%, no greater than about 7%, no greater than about 6%, no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, no greater than about 1%, or no greater than about 0.5% by weight EPA may be present. Alternatively, EPA is substantially absent or absent in a form that is not modified to oxo.

15-oxo-DGLA

In one embodiment, the composition of the present disclosure comprises 15-oxo-DGLA as an active ingredient. As used herein, the term "15-oxo-DGLA" refers to 15-oxo-DGLA in its free acid form and/or a pharmaceutically acceptable ester, conjugate or salt thereof, or a mixture of any of the foregoing. 15-oxo-DGLA can be synthesized by means known in the art. In one example, as shown in scheme 2, 15-oxo-DGLA can be synthesized from DGLA in a 2-step process:

reaction scheme 2

In step 1, DGLA (Compound 3) is converted to its corresponding 15(S) -hydroxy compound (Compound 4) using the reagents oxygen, borax, L-cysteine and the appropriate concentrations of the particular enzyme LPX 1. In step 2, MnO is used in Dichloromethane (DCM)₂Oxidizing the compound 4 obtained from step 1 to obtain 15-oxo-DGLA.

Derivatives of 15-oxo-DGLA may be used instead, although the term "derivatives of 15-oxo-DGLA" does not include any derivative compound lacking the oxo group of 15-oxo-DGLA. The term "pharmaceutically acceptable" in this context means that the substance does not cause unacceptable toxicity to the subject or interact with other components of the composition.

In one embodiment, 15-oxo-DGLA is in the form of an ester, such as an ethyl ester (also referred to herein as E-15-oxo-DGLA or ethyl-15-oxo-DGLA). In some embodiments, 15-oxo-DGLA comprises C of 15-oxo-DGLA₁-C₅An alkyl ester. In another embodiment, 15-oxo-DGLA comprises methyl 15-oxo-DGLA, 15-oxo-DGLA propyl ester or 15-oxo-DGLA butyl ester.

In another embodiment, 15-oxo-DGLA comprises lithium 15-oxo-DGLA, a monoglyceride, diglyceride, or triglyceride of 15-oxo-DGLA, or any other ester or salt of 15-oxo-DGLA, or the free acid form of 15-oxo-DGLA.

In various embodiments, the present disclosure provides pharmaceutical compositions, e.g., orally deliverable compositions, comprising 15-oxo-DGLA. In one embodiment, the composition comprises a therapeutically effective amount of 15-oxo-DGLA. In one embodiment, the pharmaceutical composition comprises from about 0.1% to about 99%, from about 1% to about 95%, from about 5% to about 90% by weight of 15-oxo-DGLA.

In one embodiment, the pharmaceutical composition comprises about at least about 70%, at least about 80%, or at least about 90% by weight of 15-oxo-DGLA. In one embodiment, the pharmaceutical composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% by weight of 15-oxo-DGLA.

In another embodiment, 15-oxo-DGLA is present in the compositions of the present disclosure in the following amounts: about 1mg to about 10,000mg, 25mg to about 7500mg, about 25mg to about 5000mg, about 50mg to about 3000mg, about 75mg to about 2500mg, or about 100mg to about 1000mg, for example, about 25mg, about 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 275mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, about 450mg, about 1025mg, about 500mg, about 525mg, about 550mg, about 875mg, 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 107mg, about 1075mg, about 1050mg, about 1000mg, about 107mg, about 1075mg, about 107mg, about 1000mg, about 1075mg, about 1000mg, about 200mg, about 100mg, about 1mg, about 24 mg, about 102 mg, about 1mg, about 24 mg, about 102 mg, about 24 mg, about 102 mg, about 24 mg, about 102 mg, about 1mg, about 24 mg, about 102 mg, about 24 mg, about 1mg, about 102 mg, about 24 mg, about 1mg, about 24 mg, about 1mg, about 24 mg, about 1mg, about 24 mg, about 102 mg, about 1mg, about 102 mg, about 24 mg, about 1mg, about 102 mg, about 24 mg, about 102 mg, about 1mg, about 102 mg, about 1mg, about 102 mg, about 1mg, about 102 mg, About 1275mg, about 1300mg, about 1325mg, about 1350mg, about 1375mg, about 1400mg, about 1425mg, about 1450mg, about 1475mg, about 1500mg, about 1525mg, about 1550mg, about 1575mg, about 1600mg, about 1625mg, about 1650mg, about 1675mg, about 1700mg, about 1725mg, about 1750mg, about 1775mg, about 1800mg, about 1825mg, about 1850mg, about 1875mg, about 1900mg, about 1925mg, about 1950mg, about 1975mg, about 2000mg, about 2025mg, about 2050mg, about 2075mg, about 2100mg, about 2125mg, about 2170 mg, about 2175mg, about 2200mg, about 2225mg, about 220 mg, about 2275mg, about 2300mg, about 2325mg, about 2320 mg, about 2375mg, about 2425mg, about 2150mg, about 2525mg, about 2775mg, about 2675mg, about 2775mg, about 1000mg, about 2775mg, about 1000mg, about 24 mg, about 1000mg, about 500mg, about 24 mg, about 500mg, about, About 2900mg, about 2925mg, about 2950mg, about 2975mg, about 3000mg, about 3025mg, about 3050mg, about 3075mg, about 3100mg, about 3125mg, about 3150mg, about 3175mg, about 3200mg, about 3225mg, about 3250mg, about 3275mg, about 3300mg, about 3325mg, about 3350mg, about 3375mg, about 3400mg, about 3425mg, about 3450mg, about 3475mg, about 3500mg, about 3525mg, about 3550mg, about 3575mg, about 3600mg, about 3625mg, about 3650mg, about 3675mg, about 3700mg, about 3750mg, about 3775mg, about 3800mg, about 3825mg, about 3850mg, about 3875mg, about 3900mg, about 3925mg, about 4050mg, about 405 mg, about 3775mg, about 37440 mg, about 410 mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 4175mg, about 43440 mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 4175mg, about 4150mg, about 43440 mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about 4175mg, about 4150mg, about 43440 mg, about 4175mg, about 4150mg, about, About 4525mg, about 4550mg, about 4575mg, about 4600mg, about 4625mg, about 4650mg, about 4675mg, about 4700mg, about 4725mg, about 4750mg, about 4775mg, about 4800mg, about 4825mg, about 4850mg, about 4875mg, about 4900mg, about 4925mg, about 4950mg, about 4975mg, about 5000mg, about 5025mg, about 5050mg, about 5075mg, about 5100mg, about 5125mg, about 5150mg, about 5175mg, about 5200mg, about 5225mg, about 5250mg, about 5275mg, about 5300mg, about 5325mg, about 5350mg, about 5375mg, about 5400mg, about 5450mg, about 5475mg, about 5470 mg, about 5525mg, about 5550mg, about 615 mg, about 5600mg, about 580 mg, about 5875mg, about 6075mg, about 5475mg, about 5775mg, about 6075mg, about 5775mg, about 5925mg, about 5775mg, about 595 mg, about 605775 mg, about 5775mg, about 575mg, about 5775mg, about 6050mg, about 575mg, about 5650mg, about 575mg, about 6075mg, about 5675mg, about 6050mg, about 605775 mg, about 5675mg, about 6050mg, about 5675mg, about 5975mg, about 605775 mg, about 6050mg, about 575mg, about 605775 mg, about 595 mg, about 5775mg, about 575mg, about 5775mg, about 575mg, about 595 mg, about 6050mg, about 575mg, about 6050mg, about 5775mg, about 6050mg, about 575mg, about 5775mg, about 5975mg, about 6050mg, about, About 6150mg, about 6175mg, about 6200mg, about 6225mg, about 6250mg, about 6275mg, about 6300mg, about 6325mg, about 6350mg, about 6375mg, about 6400mg, about 6425mg, about 6450mg, about 6475mg, about 6500mg, about 6525mg, about 6550mg, about 6575mg, about 6600mg, about 6625mg, about 6650mg, about 6675mg, about 6700mg, about 6725mg, about 6750mg, about 6775mg, about 6800mg, about 6825mg, about 6850mg, about 6875mg, about 6900mg, about 6925mg, about 6950mg, about 6975mg, about 7025mg, about 7050mg, about 7075mg, about 7100mg, about 7125mg, about 7150mg, about 7175mg, about 7200mg, about 7225mg, about 7755 mg, about 725mg, about 7625mg, about 75765 mg, about 7650mg, about 757775 mg, about 747775 mg, about 760 mg, about 7650mg, about 757775 mg, about 747775 mg, about 7675mg, about 747775 mg, about 7650mg, about 7675mg, about 7650mg, about 7050mg, about 747775 mg, about 7675mg, about 747775 mg, about 7200mg, about 7675mg, about 74735 mg, about 760 mg, about 7675mg, about 747675 mg, about 7675mg, about 747775 mg, about 7650mg, about 7675mg, about 74735 mg, about 74760 mg, about 7675mg, about 747675 mg, about 760 mg, about 747675 mg, about 747775 mg, about 747650 mg, about 74760 mg, about 747675 mg, about 747775 mg, about 747675 mg, about 74760 mg, about 7675mg, about 74770 mg, about 7675mg, About 7775mg, about 7800mg, about 7825mg, about 7850mg, about 7875mg, about 7900mg, about 7925mg, about 7950mg, about 7975mg, about 8000mg, about 8025mg, about 8050mg, about 8075mg, about 8100mg, about 8125mg, about 8150mg, about 8175mg, about 8200mg, about 8225mg, about 8275mg, about 8300mg, about 8325mg, about 8350mg, about 8375mg, about 8400mg, about 8425mg, about 8450mg, about 8475mg, about 8500mg, about 8525mg, about 8550mg, about 8600mg, about 8625mg, about 8650mg, about 8675mg, about 8700mg, about 8750mg, about 8775mg, about 900mg, about 8825mg, about 9175mg, about 9375mg, about 9275mg, about 9250mg, about 9275mg, about 919275 mg, about 9375mg, about 919275 mg, about 9175mg, about 9350mg, about 9175mg, about 919275 mg, about 9175mg, about 9375mg, about 9175mg, about 91300 mg, about 9350mg, about 9175mg, about 91300 mg, about 9275mg, about 9375mg, about 9175mg, about 91300 mg, about 9275mg, about 9175mg, about 9275mg, about 91300 mg, about 9275mg, about 9375mg, about 91300 mg, about 9275mg, about 91300 mg, about 9375mg, about 9275mg, about 9175mg, about 9275mg, about 91300 mg, about 9175mg, about 91300 mg, about 9275mg, about 9375mg, about 9175mg, about 9275mg, about 91300 mg, about 9275mg, about 91300 mg, about 9275mg, about 919275 mg, about 91300 mg, about 9275mg, about 919275 mg, about 9275mg, about 91300 mg, about 9375mg, about 91300 mg, about 919275 mg, about 9375mg, about 91300 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9275mg, about 9375mg, about 9275mg, about 9375mg, about 919275 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9375mg, about 91300 mg, about 9275mg, about 919275 mg, about 9175mg, about 9275mg, about 919275 mg, about 9275mg, about 91300 mg, about 919275 mg, about 9275mg, about 919275 mg, about 9275mg, about 9400mg, about 9425mg, about 9450mg, about 9475mg, about 9500mg, about 9525mg, about 9550mg, about 9575mg, about 9600mg, about 9625mg, about 9650mg, about 9675mg, about 9700mg, about 9725mg, about 9750mg, about 9775mg, about 9800mg, about 9825mg, about 9850mg, about 9875mg, about 9900mg, about 9925mg, about 9950mg, about 9975mg, or about 10,000 mg.

In one embodiment, 15-oxo-DGLA present in the composition of the present disclosure comprises at least 90% by weight of 15-oxo-DGLA. The 15-oxo-DGLA composition may comprise even higher purity 15-oxo-DGLA, e.g., at least 95% by weight 15-oxo-DGLA or at least 97% by weight 15-oxo-DGLA, wherein 15-oxo-DGLA is any form of 15-oxo-DGLA as described herein. The purity (e.g., impurity profile) of 15-oxo-DGLA can be further defined by any description of 15-oxo-DGLA provided herein.

The amount of 15-oxo-DGLA in the pharmaceutical composition and its purity are discussed above. The nature of essential fatty acids and their synthesis allows 15-oxo-DGLA compositions to include portions from other essential fatty acids in the essential fatty acid metabolic cascade.

In one embodiment, the compositions of the present disclosure comprise no greater than about 10%, no greater than about 9%, no greater than about 8%, no greater than about 7%, no greater than about 6%, no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, no greater than about 1%, or no greater than about 0.5% by weight of other omega-3 fatty acids, including alpha linolenic acid, stearidonic acid, docosahexaenoic acid (DHA), or derivatives thereof. In other embodiments, such other omega-3 fatty acids are substantially absent or absent.

In another embodiment, 15-oxo-DGLA represents at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, or 100% by weight of all fatty acids present in the compositions of the present disclosure.

There may be some residual DGLA from the synthesis of 15-oxo-DGLA. No greater than about 10%, no greater than about 9%, no greater than about 8%, no greater than about 7%, no greater than about 6%, no greater than about 5%, no greater than about 4%, no greater than about 3%, no greater than about 2%, no greater than about 1%, or no greater than about 0.5% by weight DGLA may be present. Alternatively, DGLA in a form that is not modified to oxo is substantially absent or absent.

Additional active agents

In one embodiment, the pharmaceutical composition further comprises at least one or more additional active agents. In one embodiment, the pharmaceutical composition comprises an amount of the additional active agent that is less than the generally accepted therapeutically effective amount of the agent. In one embodiment, the pharmaceutical composition comprises an amount of the additional active agent equal to or greater than the generally recognized therapeutically effective amount of the agent.

In some embodiments, the additional active agent is a Hepatitis C Virus (HCV) non-antiviral agent, an HCV antiviral agent, a Hepatitis B Virus (HBV) non-antiviral agent, an HBV antiviral agent, a primary biliary sclerosing agent, an alcoholic hepatitis agent, a primary sclerosing cholangitis agent, a non-alcoholic steatohepatitis (NASH) agent, an autoimmune hepatitis agent, a pulmonary fibrosis agent, a cystic fibrosis agent, a renal fibrosis agent, a skin fibrosis agent, a myelofibrosis agent, an eosinophilic esophagitis agent, an anti-TGF-beta agent, an anti-CTGF agent, a recombinant human serum amyloid P inhibitor, a pharmaceutical composition comprising a pharmaceutical composition, a,

anti-IL-4 agents, anti-IL-5 agents (e.g., mepolizumab), anti-IL-13 agents, neurochemical receptor agents, anti-IL-17A agents, Hh or Hh (R) SMO antagonists, CCR5 antagonists, CCR4 cell recruitment inhibitors, CXCR4 antagonists, anti-CXCR 4 agents, CXCR3 antagonists, anti-CCL 17 agents, NOX inhibitors, copaxone (copaxone), adiponectin, AMPK agonists, Y-cassette binding protein-1, myofibroblast recruitment inhibitors, anti-Th 17 MMP inducers, anti-extracellular matrix deposition compounds, adenosine receptor antagonists, microRNA (miR) agents, stem cells, tenofovir (tenofovir), anti-collagen cross-linking agents (e.g., Simtuzumab), Mogamulizumab (mogumamab), or a member selected from valsartan, telsartan (valsartan), telistulisartan), losartan (losartan), irrtan (sartan), azilsartan (irtasartan (irssartan), zirtan (irssartan), and combinations thereof, An angiotensin II receptor blocker (ARB) of the group consisting of eprosartan (eprosartan), olmesartan (olmesartan), or any combination of the foregoing.

In one embodiment, the one or more additional active agents comprise, consist essentially of, or consist of telmisartan.

In one embodiment, the present disclosure provides a composition (e.g., a pharmaceutical composition) comprising 15-oxo-EPA and telmisartan as the sole active agents.

In one embodiment, the present disclosure provides a composition (e.g., a pharmaceutical composition) comprising 15-oxo-DGLA and telmisartan as the only active agents.

In one embodiment, the 15-oxo-EPA is co-administered with one or more active agents in a weight ratio of 15-oxo-EPA to the additional agent present in the composition of the present disclosure, or in a weight ratio of 15-oxo-EPA to the additional agent: about 1:1000 to about 1000:1, about 1:500 to about 500:1, about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1: 1.

In one embodiment, 15-oxo-DGLA is co-administered with one or more active agents in a weight ratio of 15-oxo-DGLA to the additional agent present in the composition of the present disclosure, or in a weight ratio of 15-oxo-DGLA to the additional agent: about 1:1000 to about 1000:1, about 1:500 to about 500:1, about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, about 1:5 to about 5:1, about 1:4 to about 4:1, about 1:3 to about 3:1, about 1:2 to about 2:1, or about 1: 1.

Dosage forms

The compositions used in accordance with the present disclosure may be formulated as one or more dosage units. The terms "dose unit" and "dosage unit" herein refer to a portion of a pharmaceutical composition containing an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered from one to more times per day (i.e., from 1 to about 10 times, from 1 to 8 times, from 1 to 6 times, from 1 to 4 times, or from 1 to 2 times) or as many times as necessary to elicit a therapeutic response.

In some embodiments, the compositions of the present disclosure are in the form of orally deliverable dosage forms or units. Non-limiting examples of suitable dosage forms include tablets (e.g., suspension tablets, chewable (bite) suspension tablets, fast-dispersing tablets, chewable tablets, etc.), caplets, capsules (e.g., soft or hard gelatin capsules or HPMC capsules), lozenges, sachets, cachets, troches, pills, suspensions, elixirs, syrups, or any other solid dosage form reasonably suitable for oral administration. The terms "oral delivery" and "orally administering" herein include any form of delivery in which the agent or composition is placed in the mouth of the subject under treatment, whether swallowed or not. Thus, this includes buccal and sublingual administration as well as esophageal (esophageal) administration.

Alternatively, the compositions of the present disclosure may also be formulated for rectal, topical, or parenteral (e.g., subcutaneous, intramuscular, intravenous, and intradermal, or infusion) delivery.

In discussing the amount of 15-oxo-EPA or 15-oxo-DGLA in the compositions of the present disclosure, this may be divided into several dosage forms. The size of oral administration is limited. For example, if 1g to 4g of 15-oxo-EPA or 1g to 4g of 15-oxo-DGLA is administered to a subject per day, this may be up to 4 capsules per 1g of 15-oxo-EPA or 15-oxo-DGLA provided, or up to 8 capsules per 500mg of 15-oxo-EPA or 15-oxo-DGLA provided.

The compositions of the present disclosure may be in liquid form or in dosage unit form for direct consumption, or may be mixed with food or beverages prior to ingestion. Non-limiting examples of suitable liquid dosage forms include solutions, suspensions, elixirs, syrups, liquid aerosols, and the like.

In another embodiment, the composition of the present disclosure comprises one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" herein means any substance, not itself a therapeutic agent, that acts as a carrier or vehicle for delivering the therapeutic agent to a subject or incorporated into a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a unit dose of the composition, and that does not produce unacceptable toxicity or interaction with other components of the composition. By way of example only, a pharmaceutical composition according to the present disclosure may comprise one or more of the following: antioxidant, surfactant, antiseptic, correctant, cosolvent, viscosity assistant, suspending agent and lipophilic phase.

In one embodiment, the pharmaceutical composition comprises one or more antioxidants such as ascorbic acid, palmitic acid, ascorbyl palmitate, alpha-tocopherol, idebenone, ubiquinone, ferulic acid, coenzyme Q10, lycopene, green tea, catechin, epigallocatechin 3-gallate (EGCG), Green Tea Polyphenols (GTP), silymarin, coffee beans, resveratrol, grape seeds, pomegranate extract, wood flavonoids (genisten), pycnogenol, nicotinamide, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), and the like. In one embodiment, the pharmaceutical composition comprises about 0.01 wt% to about 2 wt% antioxidant, e.g., about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.11 wt%, about 0.12 wt%, about 0.13 wt%, about 0.14 wt%, about 0.15 wt%, about 0.16 wt%, about 0.17 wt%, about 0.18 wt%, about 0.19 wt%, about 0.2 wt%, about 0.21 wt%, about 0.22 wt%, about 0.23 wt%, about 0.24 wt%, about 0.25 wt%, about 0.26 wt%, about 0.27 wt%, about 0.28 wt%, about 0.29 wt%, about 0.3 wt%, about 0.31 wt%, about 0.32 wt%, about 0.33 wt%, about 0.35 wt%, about 0.34 wt%, about 0.35 wt%, about 0.08 wt% About 0.38 wt%, about 0.39 wt%, about 0.4 wt%, about 0.41 wt%, about 0.42 wt%, about 0.43 wt%, about 0.44 wt%, about 0.45 wt%, about 0.46 wt%, about 0.47 wt%, about 0.48 wt%, about 0.49 wt%, about 0.5 wt%, about 0.51 wt%, about 0.52 wt%, about 0.53 wt%, about 0.54 wt%, about 0.55 wt%, about 0.56 wt%, about 0.57 wt%, about 0.58 wt%, about 0.59 wt%, about 0.6 wt%, about 0.61 wt%, about 0.62 wt%, about 0.63 wt%, about 0.64 wt%, about 0.65 wt%, about 0.66 wt%, about 0.67 wt%, about 0.68 wt%, about 0.69 wt%, about 0.62 wt%, about 0.63 wt%, about 0.64 wt%, about 0.65 wt%, about 0.66 wt%, about 0.67 wt%, about 0.69 wt%, about 0.72 wt%, about 0.75 wt%, about 0.71 wt%, about 0.73 wt%, about 0.72 wt%, about 0.73 wt%, about 0., About 0.81 wt%, about 0.82 wt%, about 0.83 wt%, about 0.84 wt%, about 0.85 wt%, about 0.86 wt%, about 0.87 wt%, about 0.88 wt%, about 0.89 wt%, about 0.9 wt%, about 0.91 wt%, about 0.92 wt%, about 0.93 wt%, about 0.94 wt%, about 0.95 wt%, about 0.96 wt%, about 0.97 wt%, about 0.98 wt%, about 0.99 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt% of one or more antioxidants.

Method of treatment

The compositions and formulations disclosed herein are useful for treating fibrosis, inflammation and inflammatory disorders, kidney disease, and renal dysfunction. In one embodiment, the fibrosis is associated with an organ or tissue associated with a lung, liver, heart, kidney, one or more eyes, mediastinum, bone marrow, retropertineneum (retroperitoneum), skin, intestine, joint, reproductive organ, or a combination thereof. In some embodiments, the fibrosis is associated with liver tissue.

In some embodiments, the fibrosis is associated with nonalcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD Activity Score (NAS) in the subject is decreased after administration of the composition. In some embodiments, NAS is reduced in the subject compared to baseline. In some embodiments, the NAS is reduced compared to a second subject not administered the composition. In some embodiments, the second subject has been administered a placebo. In some embodiments, the second subject is undergoing a fibrosis treatment.

In some embodiments, the subject is undergoing a fibrosis treatment. In some embodiments, the fibrosis treatment is continued during administration of the composition. In other embodiments, the fibrosis treatment continues to be discontinued during administration of the composition. For example, in some embodiments, the subject is on telmisartan treatment and discontinues telmisartan treatment after beginning a treatment method comprising administering a composition comprising 15-oxo-EPA or 15-oxo-DGLA as disclosed herein.

In some embodiments, the inflammatory disease is selected from acne vulgaris, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, and the like.

In some embodiments, the composition is administered orally. In some embodiments, 15-oxo-EPA or 15-oxo-DGLA is the only active ingredient in the composition. In other embodiments, the composition further comprises an additional agent for affecting treatment. In some embodiments, the additional agent is telmisartan.

In some embodiments, the present disclosure provides a method of treating fibrosis in a subject undergoing fibrosis treatment, the method comprising administering to the subject a composition comprising 15-oxo-EPA. In some embodiments, the fibrosis is associated with an organ or tissue selected from the group consisting of: lung, liver, heart, kidney, eye, mediastinum, bone marrow, retroperitoneal cavity, skin, intestine, joint, reproductive organs and combinations thereof. In some embodiments, fibrosis is liver fibrosis. In some embodiments, the fibrosis is associated with nonalcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD Activity Score (NAS) in the subject is decreased after administration of the composition. In some embodiments, NAS is reduced in the subject compared to baseline. In some embodiments, the NAS is reduced compared to a second subject not administered the composition. In some embodiments, the second subject has been administered a placebo. In some embodiments, the second subject is undergoing a fibrosis treatment. In some embodiments, the fibrosis treatment comprises administration of a HCV non-antiviral agent, a HCV antiviral agent, a HBV non-antiviral agent, a HBV antiviral agent, a primary biliary sclerosing liver sclerosing agent, an alcoholic hepatitis agent, a primary sclerosing cholangitis agent, a NASH agent, an autoimmune hepatitis agent, a pulmonary fibrosis agent, a cystic fibrosis agent, a renal fibrosis agent, a skin fibrosis agent, a myelofibrosis agent, an eosinophilic esophagitis agent, an anti-TGF- β agent, an anti-CTGF agent, a recombinant human serum amyloid P agent, an anti-IL-4 agent, an anti-IL-5 agent (e.g., mepolizumab), an anti-IL-13 agent, a neuro chemoreceptor agent, an anti-IL-17A agent, Hh or Hh (r) SMO antagonist, CCR5 antagonist, CCR4 cytostatic agent, CXCR4 antagonist, anti-CXCR 4 agent, CXCR3 antagonist, anti-CCL 17 agent, NOX inhibitor, anti-cholecystokinin agent, anti-inflammatory agent, anti-TGF-4 agent, anti-IL-beta agent, anti-CTGF agent, anti-IL-13 agent, anti-IL-17A agent, anti-IL-17A agent, Hh agent, and/or anti-IL (r) agent, Copaxone (copaxone), adiponectin, an AMPK agonist, Y-box binding protein-1, a myofibroblast recruitment inhibitor, an anti-Th 17 MMP inducer, an anti-extracellular matrix deposition compound, an adenosine receptor antagonist, a microrna (mir) agent, a stem cell, tenofovir (tenofovir), an anti-collagen cross-linking agent (e.g., stevizumab, mometazumab), or an angiotensin II receptor blocker (ARB) selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, azilsartan, eprosartan, olmesartan, or any combination thereof. In some embodiments, the subject is undergoing a fibrosis treatment. In some embodiments, the fibrosis treatment is continued during administration of the composition. In some embodiments, the second subject is undergoing a fibrosis treatment. In some embodiments, the composition is administered orally.

In some embodiments, the method further comprises identifying the subject as having fibrosis prior to administering the composition comprising 15-oxo-EPA. In some embodiments, the method further comprises identifying the subject as having an increased risk of developing fibrosis prior to administering the composition comprising 15-oxo-EPA. In some embodiments, the identifying step comprises determining a NAS associated with the subject. In some embodiments, the NAS associated with the subject is at least 3. In some embodiments, the step of identifying comprises screening for a genetic mutation in a nucleic acid molecule associated with the subject. In some embodiments, the step of identifying comprises obtaining an analysis of blood and/or serum associated with the subject. In some embodiments, the step of identifying comprises examining a tissue associated with the subject. In some embodiments, the step of examining comprises analyzing a histological tissue sample associated with the subject (e.g., a biopsy).

In some embodiments, the present disclosure provides methods of treating fibrosis in a subject undergoing fibrosis treatment, the method comprising administering to the subject a composition comprising 15-oxo-DGLA. In some embodiments, the fibrosis is associated with an organ or tissue selected from the group consisting of: lung, liver, heart, kidney, eye, mediastinum, bone marrow, retroperitoneal cavity, skin, intestine, joint, reproductive organs and combinations thereof. In some embodiments, fibrosis is liver fibrosis. In some embodiments, the fibrosis is associated with nonalcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD Activity Score (NAS) in the subject is decreased after administration of the composition. In some embodiments, NAS is reduced in the subject compared to baseline. In some embodiments, the NAS is reduced compared to a second subject not administered the composition. In some embodiments, the second subject has been administered a placebo. In some embodiments, the second subject is undergoing a fibrosis treatment. In some embodiments, the fibrosis treatment comprises administration of a HCV non-antiviral agent, a HCV antiviral agent, a HBV non-antiviral agent, a HBV antiviral agent, a primary biliary sclerosing liver sclerosing agent, an alcoholic hepatitis agent, a primary sclerosing cholangitis agent, a NASH agent, an autoimmune hepatitis agent, a pulmonary fibrosis agent, a cystic fibrosis agent, a renal fibrosis agent, a skin fibrosis agent, a myelofibrosis agent, an eosinophilic esophagitis agent, an anti-TGF- β agent, an anti-CTGF agent, a recombinant human serum amyloid P agent, an anti-IL-4 agent, an anti-IL-5 agent (e.g., mepolizumab), an anti-IL-13 agent, a neuro chemoreceptor agent, an anti-IL-17A agent, Hh or Hh (r) SMO antagonist, CCR5 antagonist, CCR4 cytostatic agent, CXCR4 antagonist, anti-CXCR 4 agent, CXCR3 antagonist, anti-CCL 17 agent, NOX inhibitor, anti-cholecystokinin agent, anti-inflammatory agent, anti-TGF-4 agent, anti-IL-beta agent, anti-CTGF agent, anti-IL-13 agent, anti-IL-17A agent, anti-IL-17A agent, Hh agent, and/or anti-IL (r) agent, Copaxone (copaxone), adiponectin, an AMPK agonist, Y-box binding protein-1, a myofibroblast recruitment inhibitor, an anti-Th 17 MMP inducer, an anti-extracellular matrix deposition compound, an adenosine receptor antagonist, a microrna (mir) agent, a stem cell, tenofovir (tenofovir), an anti-collagen cross-linking agent (e.g., stevizumab, mometazumab), or an angiotensin II receptor blocker (ARB) selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, azilsartan, eprosartan, olmesartan, or any combination thereof. In some embodiments, the subject is undergoing a fibrosis treatment. In some embodiments, the fibrosis treatment is continued during administration of the composition. In some embodiments, the second subject is undergoing a fibrosis treatment. In some embodiments, the composition is administered orally.

In some embodiments, the method further comprises identifying the subject as having fibrosis prior to administering the composition comprising 15-oxo-DGLA. In some embodiments, the method further comprises identifying the subject as having an increased risk of developing fibrosis prior to administering the composition comprising 15-oxo-DGLA. In some embodiments, the identifying step comprises determining a NAS associated with the subject. In some embodiments, the NAS associated with the subject is at least 3. In some embodiments, the step of identifying comprises screening for a genetic mutation in a nucleic acid molecule associated with the subject. In some embodiments, the step of identifying comprises obtaining an analysis of blood and/or serum associated with the subject. In some embodiments, the step of identifying comprises examining a tissue associated with the subject. In some embodiments, the step of examining comprises analyzing a histological tissue sample associated with the subject (e.g., a biopsy).

In some embodiments, the methods of the present disclosure result in a decrease in NAS values in the subject. In some embodiments, the method further comprises determining a second, lower NAS value associated with the subject after administering the composition for a period of time.

In one embodiment, the present disclosure provides a method of treating a skin disease or disorder in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising 15-oxo-EPA. Non-limiting examples of skin disorders and diseases include acne, atopic dermatitis, psoriasis, pruritus/pruritus, radiation protection, dry skin, anti-aging, and photoprotection.

In one embodiment, the present disclosure provides a method of treating a skin disease or disorder in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising 15-oxo-DGLA. Non-limiting examples of skin disorders and diseases include acne, atopic dermatitis, psoriasis, pruritus/pruritus, radiation protection, dry skin, anti-aging, and photoprotection.

The term "acne" herein refers to any disease or disorder of the skin that presents with one or more acneiform eruptions such as papules, pustules, cysts, and the like. Non-limiting examples of acne include acne vulgaris, acne necrotica, acne haloacne, acne chloracne, acne occupations, acne oleosa, acne tar, acne vulgaris, acne tropics, acne cosmetology, acne balm, acne keloidalis (acnes keloidalis nuchae), acne mechanistica, acne exfoliata, acne medicamentosa, acne infantis, acne neonatorum, acne conglobata, acne fulminans, acne granularizona (acnes miliaris necrotica), lupus erythematosus (millaris dissemitus fasciei), and other skin disorders associated with acne-like eruptions.

In one embodiment, the present disclosure provides a method of treating or preventing acne associated with propionibacterium acnes (p.acnes) in a subject in need thereof. In one embodiment, the method comprises administering to a subject a composition as disclosed herein.

In one embodiment, the present disclosure provides methods of inhibiting propionibacterium acnes, including, for example, growth, colonization, and/or infection thereof, in a subject in need thereof. In one embodiment, the method comprises contacting propionibacterium acnes with a composition disclosed herein.

In one embodiment, the method further comprises washing the affected area of the skin (and/or the area of the skin that is typically prone to acne-like eruptions) prior to applying the composition. As used herein, the term "washing" generally refers to any method known to those skilled in the art for cleaning the skin, exfoliating the skin, removing dirt, oil, dead skin cells, and the like from the skin.

In one embodiment, the present disclosure provides a method of treating hypertension (e.g., pulmonary hypertension) in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising 15-oxo-EPA as disclosed herein.

In one embodiment, the present disclosure provides a method of treating hypertension (e.g., pulmonary hypertension) in a subject in need thereof, the method comprising orally administering to the subject a pharmaceutical composition comprising 15-oxo-DGLA as disclosed herein.

In one embodiment, the method comprises administering to the subject a pharmaceutical composition as disclosed herein once a day, twice a day, three times a day, or more than three times a day.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and not intended to be limiting.

While the disclosure may be embodied in many different forms, the following description of several embodiments is provided with the understanding that the present disclosure is to be considered an exemplification of the disclosure and is not intended to limit the technology disclosed herein to the specific embodiments illustrated. Headings are provided for convenience only and should not be construed as limiting the technology disclosed herein in any way. Embodiments shown under any heading may be combined with embodiments shown under any other heading.

Unless expressly stated otherwise, numerical values used in the various quantitative values specified in this application are stated as approximations as if the minimum and maximum values within the stated ranges were both preceded by the word "about". In this way, slight variations from the values can be used to achieve substantially the same results as the values. Further, the disclosure of a range is intended as a continuous range including every value between the minimum and maximum values listed, as well as any range that may be formed from such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a listed value by any other listed value. Thus, those skilled in the art will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values set forth herein and that, in all instances, such ratios, ranges, and ranges of ratios are representative of the various embodiments of the present disclosure.

As used herein, "treating" or "treatment" of a disease, disorder or condition includes, at least in part: (1) preventing a disease, disorder, or condition (i.e., causing clinical symptoms of a disease, disorder, or condition) from occurring in a mammal exposed to or susceptible to a disease, disorder, or condition, but which has not experienced or exhibited symptoms of a disease, disorder, or condition; (2) inhibiting a disease, disorder or condition, i.e., preventing or reducing the occurrence of a disease, disorder or condition or clinical symptoms thereof; (3) alleviating the disease, disorder or condition, i.e., causing regression of the disease, disorder or condition or clinical symptoms thereof. The term "prevention" in relation to a given disease or disorder means: if not, preventing the onset of disease development, preventing the development of disease and disorder in a subject who may be susceptible to the disorder or disease but has not been diagnosed as having the disorder or disease, and/or preventing the further development of disease/disorder if already present.

As used herein, "effective amount" refers to the amount of active composition required to give a therapeutic effect to a subject. As used herein, "therapeutically effective amount" refers to an amount of an agent or compound to be administered that is sufficient to alleviate to some extent one or more symptoms of the disease, disorder, or condition being treated. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, in some embodiments, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms without adverse side effects. In some embodiments, an appropriate "effective amount" in any individual case is determined using techniques such as dose escalation studies. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. In other embodiments, an "effective amount" of a compound disclosed herein, such as a compound of formula (a) or formula (I), is an amount effective to achieve a desired pharmacological effect or therapeutic improvement without undue adverse side effects. In other embodiments, it is understood that the "effective amount" or "therapeutically effective amount" will vary from subject to subject due to differences in metabolism, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. The term "pharmaceutically acceptable" in this context means that the substance does not cause unacceptable toxicity to the subject or interact with other components of the composition.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and use the agents of the present disclosure and practice the claimed methods. The following working examples are provided to facilitate the practice of the present disclosure and should not be construed as limiting the remainder of the disclosure in any way.