Compositions comprising 15-oxo-EPA or 15-oxo-DGLA and methods of making and using the same

Abstract

To provide compositions for treating and / or preventing fibrosis, skin disorders, inflammation, kidney disease or renal dysfunction.SOLUTION: Provided is a composition comprising 15-oxo-EPA. Also provided is a composition comprising 15-oxo-DGLA.SELECTED DRAWING: None

Description

[Technical field]

[0001] Claiming priority This application is a continuation of U.S. Provisional Patent Application No. 62 / 160,863, filed May 13, 2015. No. 6,313,992, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure includes 15-oxo-EPA or 15-oxo-DGLA (5Z,8Z, 11Z,13E,17Z)-15-Oxoicosano-5,8,11,13,17-pentaenoic acid 15-Oxo-EPA (also called 15-oxo-EPA) and (8Z,11Z,13E)-15-oxo Soycosa-8,11,13-trienoic acid (also called 15-oxo-DGLA) composition , formulations, and dosage units, and 15-oxo-EPA or 15-oxo-DGLA (or a pharmaceutical composition containing same) to a subject in need thereof. Treating or preventing fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction To provide a method for prevention. Summary of the Invention

[0003] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, and the like. in a subject in need of treatment and / or prevention of rheumatoid arthritis, kidney disease, or renal dysfunction, A method for doing so is provided, which comprises administering to a subject a composition comprising 15-oxo-EPA. This includes:

[0004] In some embodiments, the present disclosure provides a method for treating fibrosis in a subject receiving a fibrosis therapy. The present invention provides a method for treating an allergy to 15-oxo-EPA, the method comprising administering to a subject a composition comprising 15-oxo-EPA. This includes:

[0005] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, and the like. In one embodiment, there is a need for compositions for treating and / or preventing kidney disease, kidney disease, or kidney dysfunction. The composition is provided to a subject, the composition comprising an effective amount of 15-oxo-EPA.

[0006] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis) in a subject. 15-O-carboxamide for treating and / or preventing skin disorders, inflammation, kidney disease, or kidney dysfunction The present invention provides uses of 15-oxo-EPA (or pharmaceutical compositions containing 15-oxo-EPA).

[0007] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 15-oxo-EPA. Provide.

[0008] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, and the like. in a subject in need of treatment and / or prevention of rheumatoid arthritis, kidney disease, or renal dysfunction, A method for doing so is provided, the method comprising administering to a subject a composition comprising 15-oxo-DGLA. This includes:

[0009] In some embodiments, the present disclosure provides a method for treating fibrosis in a subject receiving a fibrosis therapy. The present invention provides a method for treating a pulmonary artery disease, the method comprising administering to a subject a composition comprising 15-oxo-DGLA. This includes:

[0010] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, and the like. In one embodiment, there is a need for compositions for treating and / or preventing kidney disease, kidney disease, or kidney dysfunction. The composition is provided in a subject, the composition comprising an effective amount of 15-oxo-DGLA.

[0011] In some embodiments, the present disclosure provides a method for treating fibrosis (e.g., liver fibrosis) in a subject. 15-O-carboxamide for treating and / or preventing skin disorders, inflammation, kidney disease, or kidney dysfunction The present invention provides uses of 15-oxo-DGLA (or pharmaceutical compositions containing 15-oxo-DGLA).

[0012] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 15-oxo-DGLA. provide.

[0013] Other features and advantages of the techniques disclosed herein are set forth in the detailed description below. It will become clear from this. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] In one embodiment, the present disclosure provides 15-oxo-EPA, 15-oxo-DGLA, or or a combination thereof, and a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, in a subject in need of treatment and / or prevention of renal disease, kidney disease, or renal dysfunction, and a method for using the same.

[0015] 15-oxo-EPA has the general structure and IUPAC name shown in formula (I): [ka]

[0016] 15-Oxo-EPA can be prepared by the synthesis of eicosapentaenoic acid according to methods known in the art. As used herein, "15-oxo-EP The term "A" refers to 15-oxo-EPA in its free acid form, and / or to 15-oxo-EPA of formula (I) or a pharma- ceutically acceptable ester, conjugate, or salt thereof, which corresponds to any of the above. It can also refer to its derivatives (R ≠ H) (R is an ion), such as mixtures of any of the above. In embodiments, 15-oxo-EPA is used in the free acid form (i.e., R=H). Alternatively, a pharma- ceutically acceptable ester or salt of 15-oxo-EPA may be used in the present invention. In certain embodiments, 15-oxo-E PA is available in the methyl ester (R=CH3) or ethyl ester (R=CH2CH3) forms. C etc. 1~4 It is in the form of an alkyl ester.

[0017] As used herein, "EPA" refers to 20:5n-3, an omega-3 fatty acid. EPA is the abbreviation for eicosa-5,8,11,14,17-pentaenoic acid, also known as It is readily available through supply sources.

[0018] 15-Oxo-DGLA has the general structure and IUPAC name shown in formula (II): . [ka]

[0019] 15-Oxo-DGLA can be prepared by the synthesis of dihomo-ganglionic acid according to methods known in the art. As used herein, "15-hydroxytryptamine" refers to a compound that can be synthesized from malonoleic acid (DGLA). The term "15-oxo-DGLA" refers to 15-oxo-DGLA in its free acid form, and / or or a pharma- ceutically acceptable ester, conjugate, or salt conforming to formula (I), It may refer to any of the above derivatives (R≠H) (where R is an ion), such as mixtures of any of the above. In some embodiments, 15-oxo-DGLA is in the free acid form (i.e., Alternatively, a pharma- ceutical acceptable ester of 15-oxo-DGLA may be used. In some embodiments, the compound or salt thereof is used in the present disclosure. , 15-oxo-DGLA is available as a methyl ester (R = CH3) or an ethyl ester (R =CH2CH3) form of C 1~4 It is in the form of an alkyl ester.

[0020] As used herein, "DGLA" refers to 20:3n-6, an omega-6 fatty acid. DGLA is the commonly known eicosa-8,11,14-trienoic acid. can be easily obtained through

[0021] Accordingly, in one embodiment of the present disclosure, a method for treating and / or preventing fibrosis in a subject is provided. A method is provided for administering a therapeutically effective amount of 15-oxo-EPA or 15-oxo-EPA to a subject. The method includes administering to a subject a composition comprising the

[0022] In another aspect of the disclosure, a method of treating and / or preventing fibrosis in a subject is provided. and a therapeutically effective amount of 15-oxo-DGLA or a composition comprising 15-oxo-DGLA. This includes administering an agent to a subject.

[0023] The present disclosure relates to a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction. 15-oxo-EPA or 15-oxo- A composition comprising EPA is provided.

[0024] The present disclosure also relates to a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney function. 15-Oxo-DGLA or 15-O-DGLA for use in the treatment and / or prevention of disorders A composition comprising oxo-DGLA is provided.

[0025] The present disclosure relates to a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction. 15-oxo-EPA or 15-oxo-EPA in the manufacture of a medicament for treating and / or preventing Uses of compositions comprising 5-oxo-EPA are provided.

[0026] The present disclosure relates to a method for treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction. 15-oxo-DGLA or Uses of compositions comprising 15-oxo-DGLA are provided.

[0027] In another aspect, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of 15-oxo-EPA. 15-Oxo-EPA is used in the pharmaceutical compositions and methods described herein. In some applications, it may be the only active ingredient (e.g., API). PA may be the only active ingredient. Alternatively, 15-oxo-EPA may be used to treat fibrosis. For co-formulation or co-administration with another drug or drugs for the treatment and / or prevention If additional active agent(s) are to be used, 1 The 5-oxo-EPA may be co-formulated as a single dosage unit or may be combined with the 15-oxo -EPA and an additional fibrosis medication are approved for coordinated, co-administration, or simultaneous administration. -May be formulated as multiple dosage units.

[0028] In another aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of 15-oxo-DGLA. 15-oxo-DGLA is provided in the pharmaceutical compositions and methods described herein. In some methods and uses, it may be the only active ingredient (e.g., API). 15-oxo-DGLA may be the only active ingredient. Alternatively, 15-oxo-DGLA may be Co-formulation or co-administration with another agent(s) for treating and / or preventing fibrosis Additional active agent(s) may be used. In this case, 15-oxo-DGLA may be co-formulated as a single dosage unit or 15 -Oxo-DGLA and the additional fibrosis medication are administered in a coordinated, concomitant, or simultaneous manner It may be formulated as a two or multiple dose unit for administration.

[0029] The present disclosure also provides formulations of 15-oxo-EPA, formulations comprising 15-oxo-EPA, Treating and / or treating fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction and methods of using these formulations to treat or prevent the development of inflammatory bowel disorders.

[0030] The present disclosure also provides formulations of 15-oxo-DGLA and formulations containing 15-oxo-DGLA. and to treat and treat fibrosis (e.g., liver fibrosis), skin disease, inflammation, kidney disease, or kidney dysfunction. and methods of using these formulations to treat and / or prevent the development of inflammatory bowel disorders.

[0031] The present disclosure further provides a pharmaceutical composition for oral delivery comprising 15-oxo-EPA. The composition may include a pharma- ceutically acceptable excipient. 15-Oxo-EPA , or in any form discussed herein. 15-oxo-EPA is present in an amount of about 1 mg It may be present in one or more divided dosage units in an amount of up to about 10,000 mg.

[0032] The present disclosure further provides a pharmaceutical composition for oral delivery comprising 15-oxo-DGLA. The composition may include a pharma- ceutically acceptable excipient. A may be in any form as discussed herein. 15-oxo-DGLA is about It may be present in one or more separate dosage units in amounts from 1 mg to about 10,000 mg.

[0033] 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 its free acid form. 15-oxo-EPA, and / or pharma- ceutically acceptable esters, conjugates, or 15-Oxo-EPA refers to any of the compounds, salts, or mixtures of any of the above. In one embodiment, 15-oxo- EPA can be synthesized from EPA in a two-step process as shown in Scheme 1. . Scheme 1. [ka]

[0034] In step 1, EPA (1) uses appropriate concentrations of the reagents, oxygen, borax, and L-cysteine. and the specific enzyme LPX1 to produce the corresponding 15(S)-hydroxy compounds ( Compound 2) (15-(S)-HEPE) is converted into Step 2. 15-(S)-HEPE (compound 2) obtained from Oxidation with nO2 gives 15-oxo-EPA.

[0035] Derivatives of 15-oxo-EPA may be used instead, however, the term "15-oxo-EP The term "derivative of A" refers to any derivative lacking the oxo group of 15-oxo-EPA. The term "pharmaceutical acceptable" in this context means that the substance does not result in unacceptable toxicity to the subject or interactions with other components of the composition. This means that there is no

[0036] In one embodiment, 15-oxo-EPA is in the form of an ester, such as the ethyl ester. (Herein, E-15-oxo-EPA or ethyl-15-oxo-E In some embodiments, 15-oxo-EPA is 15-oxo- In another embodiment, the 15-oxo-EPA is a C1-C5 alkyl ester. So-EPA is 15-oxo-EPA methyl ester, 15-oxo-EPA propyl ester. ester, or 15-oxo-EPA butyl ester.

[0037] In another embodiment, the 15-oxo-EPA is lithium 15-oxo-EPA, molybdenum Mono-, di-, or triglyceride 15-oxo-EPA, or 15-oxo-EPA This includes any other ester or salt, or the free acid form of 15-oxo-EPA.

[0038] In various embodiments, the present disclosure provides pharmaceutical compositions comprising 15-oxo-EPA, e.g. In one embodiment, the composition comprises a therapeutically effective amount of 15 In one embodiment, the pharmaceutical composition contains about 0.1% to about 9% by weight of 1,2,3,4-oxo-EPA. 9%, about 1% to about 95%, about 5% to about 90% 15-oxo-EPA.

[0039] In one embodiment, the pharmaceutical composition comprises at least about 70%, at least about 80%, by weight %, or at least about 90% 15-oxo-EPA. The pharmaceutical composition may comprise at least about 50%, at least about 60%, at least about 70%, It contains at least about 80%, or at least about 90% 15-oxo-EPA.

[0040] In another embodiment, 15-oxo-EPA is from about 1 mg to about 10,000 mg, 5mg~about 7500mg, about 25mg~about 5000mg, about 50mg~about 5000mg, About 50 mg to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1 000 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg g, approx. 150mg, approx. 175mg, approx. 200mg, approx. 225mg, approx. 250mg, approx. 27 5mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, about 425mg, approx. 450mg, approx. 475mg, approx. 500mg, approx. 525mg, approx. 550mg , about 575mg, about 600mg, about 625mg, about 650mg, about 675mg, about 700 mg, about 725mg, about 750mg, about 775mg, about 800mg, about 825mg, about 8 50mg, about 875mg, about 900mg, about 925mg, about 950mg, about 975mg, About 1000mg, about 1025mg, about 1050mg, about 1075mg, about 1100mg, About 1025mg, about 1050mg, about 1075mg, about 1200mg, about 1225mg, Approx. 1250mg, approx. 1275mg, approx. 1300mg, approx. 1325mg, approx. 1350mg, About 1375mg, about 1400mg, about 1425mg, about 1450mg, about 1475mg, Approx. 1500mg, approx. 1525mg, approx. 1550mg, approx. 1575mg, approx. 1600mg, 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, about 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg, About 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg, About 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, About 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, About 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, About 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg, About 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, About 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, About 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, About 5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg, About 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg, About 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg, About 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg, About 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600 mg, About 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about 5725 mg, About 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg, about 5850 mg, About 5875 mg, about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, About 6000 mg, about 6025 mg, about 6050 mg, about 6075 mg, about 6100 mg, About 6125 mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225 mg, About 6250 mg, about 6275 mg, about 6300 mg, about 6325 mg, about 6350 mg, About 6375 mg, about 6400 mg, about 6425 mg, about 6450 mg, about 6475 mg, About 6500 mg, about 6525 mg, about 6550 mg, about 6575 mg, about 6600 mg, About 6625 mg, about 6650 mg, about 6675 mg, about 6700 mg, about 6725 mg, About 6750 mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg, About 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg, About 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about 7100 mg, About 7125 mg, about 7150 mg, about 7175 mg, about 7200 mg, about 7225 mg, About 7250 mg, about 7275 mg, about 7300 mg, about 7325 mg, about 7350 mg, About 7375 mg, about 7400 mg, about 7425 mg, about 7450 mg, about 7475 mg, About 7500 mg, about 7525 mg, about 7550 mg, about 7575 mg, about 7600 mg, About 7625 mg, about 7650 mg, about 7675 mg, about 7700 mg, about 7725 mg, About 7750 mg, about 7775 mg, about 7800 mg, about 7825 mg, about 7850 mg, About 7875 mg, about 7900 mg, about 7925 mg, about 7950 mg, about 7975 mg, About 8000 mg, about 8025 mg, about 8050 mg, about 8075 mg, about 8100 mg, About 8125 mg, about 8150 mg, about 8175 mg, about 8200 mg, about 8225 mg, About 8250 mg, about 8275 mg, about 8300 mg, about 8325 mg, about 8350 mg, About 8375 mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg, About 8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg, Approximately 8625mg, approximately 8650mg, approximately 8675mg, approximately 8700mg, approximately 8725mg, Approx. 8750mg, approx. 8775mg, approx. 8800mg, approx. 8825mg, approx. 8850mg, Approximately 8875mg, approximately 8900mg, approximately 8925mg, approximately 8950mg, approximately 8975mg, approx. 9000mg, approx. 9025mg, approx. 9050mg, approx. 9075mg, approx. 9100mg, Approx. 9125mg, approx. 9150mg, approx. 9175mg, approx. 9200mg, approx. 9225mg, Approx. 9250mg, approx. 9275mg, approx. 9300mg, approx. 9325mg, approx. 9350mg, Approx. 9375mg, approx. 9400mg, approx. 9425mg, approx. 9450mg, approx. 9475mg, Approximately 9500mg, approximately 9525mg, approximately 9550mg, approximately 9575mg, approximately 9600mg, Approximately 9625mg, approximately 9650mg, approximately 9675mg, approximately 9700mg, approximately 9725mg, Approximately 9750mg, approximately 9775mg, approximately 9800mg, approximately 9825mg, approximately 9850mg, Approximately 9875mg, approximately 9900mg, approximately 9925mg, approximately 9950mg, approximately 9975mg, Or present in the compositions of the present disclosure in an amount of about 10,000 mg.

[0041] In one embodiment, the 15-oxo-EPA present in the composition of the present disclosure is at least The 15-oxo-EPA composition contains up to 90% by weight of 15-oxo-EPA. 15-oxo-EPA, e.g., at least 95% by weight of 15-oxo-EPA or can contain at least 97% by weight of 15-oxo-EPA, A is any form of 15-oxo-EPA as described herein. The purity of EPA may be determined according to any of the descriptions of 15-oxo-EPA provided herein. Thus, the impurity profile may be further defined (eg, impurity profile).

[0042] Above, the amount of 15-oxo-EPA in the pharmaceutical composition and its purity are discussed. The properties of essential fatty acids and their synthesis are shown to be important in the treatment of essential fatty acid metabolism. Such may include moieties from other essential fatty acids in the saccade.

[0043] In one embodiment, the composition of the present disclosure comprises alpha linolenic acid, stearidonic acid, docosahexaenoic acid, and glycerin. About 10% or less by weight of dihexaenoic acid (DHA), or derivatives thereof, about 9% Below, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about Contains no more than 2%, no more than about 1%, or no more than about 0.5% of other omega-3 fatty acids. In embodiments, such other omega-3 fatty acids are substantially absent or absent. Does not exist.

[0044] In another embodiment, 15-oxo-EPA is present in the composition of the present disclosure. 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% of all fatty acids.

[0045] Some residual eicosapentaenoic acid from the synthesis of 15-oxo-EPA may be present. Approximately 10% or less by weight, approximately 9% or less, approximately 8% or less, approximately 7% or less, approximately 6% or less, approximately 5% EPA is less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% Alternatively, there is substantially no EPA in a form that is not modified into the oxo form, Or not.

[0046] 15-Oxo-DGLA In one embodiment, the composition of the present disclosure contains 15-oxo-DGLA as an active ingredient. As used herein, the term "15-oxo-DGLA" refers to its free acid form. 15-oxo-DGLA in the form of, and / or pharma- ceutically acceptable esters, conjugates , or a salt thereof, or a mixture of any of the above. , can be synthesized via methods known in the art. Oxo-DGLA can be prepared from DGLA in a two-step process as shown in Scheme 2. It can be synthesized. Scheme 2. [ka]

[0047] In step 1, DGLA (compound 3) is mixed with appropriate concentrations of the reagents oxygen, borax, and L- Cysteine ​​and its corresponding 15(S)-hydroxylase using the specific enzyme LPX1. In step 2, the compound obtained from step 1 is converted to compound 4. 4 is oxidized with MnO2 in dichloromethane (DCM) to give 15-oxo-D Get GLA.

[0048] Derivatives of 15-oxo-DGLA may be used instead, but are referred to as "15-oxo-D The term "derivatives of GLA" refers to any compound that lacks the oxo group of 15-oxo-DGLA. The term "pharmaceutically acceptable" in this context does not include derivative compounds thereof. The substance may exhibit unacceptable toxicity to the subject or interactions with other components of the composition. This means not letting go.

[0049] In one embodiment, 15-oxo-DGLA is in the form of an ester, such as the ethyl ester. (Herein, E-15-oxo-DGLA or ethyl-15-oxo In some embodiments, 15-oxo-DGLA is In another embodiment, the compound comprises a C1-C5 alkyl ester of 15-oxo-DGLA. 15-oxo-DGLA is 15-oxo-DGLA methyl ester, 15-oxo-D Contains GLA propyl ester, or 15-oxo-DGLA butyl ester.

[0050] In another embodiment, the 15-oxo-DGLA is lithium 15-oxo-DGLA. , mono-, di-, or triglyceride 15-oxo-DGLA, or 15-oxo-D Any other ester or salt of GLA, or the free acid form of 15-oxo-DGLA include.

[0051] In various embodiments, the present disclosure provides pharmaceutical compositions comprising 15-oxo-DGLA, e.g. For example, an orally deliverable composition is provided. In one embodiment, the composition comprises a therapeutically effective amount of In one embodiment, the pharmaceutical composition comprises about 0.1% to about 5-oxo-DGLA by weight. Contains about 99%, about 1% to about 95%, or about 5% to about 90% 15-oxo-DGLA.

[0052] In one embodiment, the pharmaceutical composition comprises at least about 70%, at least about 80%, by weight %, or at least about 90% 15-oxo-DGLA. The pharmaceutical composition comprises at least about 50%, at least about 60%, at least about 70%, by weight It contains at least about 80%, or at least about 90% 15-oxo-DGLA.

[0053] In another embodiment, 15-oxo-DGLA is from about 1 mg to about 10,000 mg, 25mg~approx. 7500mg, approx. 25mg~approx. 5000mg, approx. 50mg~approx. 5000mg , about 50 mg to about 3000 mg, about 75 mg to about 2500 mg, or about 100 mg to about 1000 mg, for example, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150mg, about 175mg, about 200mg, about 225mg, about 250mg, about 2 75mg, about 300mg, about 325mg, about 350mg, about 375mg, about 400mg, Approximately 425mg, approximately 450mg, approximately 475mg, approximately 500mg, approximately 525mg, approximately 550mg g, approx. 575mg, approx. 600mg, approx. 625mg, approx. 650mg, approx. 675mg, approx. 70 0mg, 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 1025mg, about 1050mg, about 1075mg, about 1200mg, about 1225mg , about 1250mg, 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 2000 mg, about 2025 mg, about 2050 mg, about 2075 mg, about 2100 mg , about 2125 mg, about 2150 mg, about 2175 mg, about 2200 mg, about 2225 mg , about 2250 mg, about 2275 mg, about 2300 mg, about 2325 mg, about 2350 mg , about 2375 mg, about 2400 mg, about 2425 mg, about 2450 mg, about 2475 mg , about 2500 mg, about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg , about 2625 mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg , about 2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg , about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975 mg , about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg , about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg , about 3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg , about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475 mg , about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about 3600 mg , about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg, about 3725 mg , about 3750 mg, about 3775 mg, about 3800 mg, about 3825 mg, about 3850 mg , about 3875 mg, about 3900 mg, about 3925 mg, about 3950 mg, about 3975 mg , about 4000 mg, about 4025 mg, about 4050 mg, about 4075 mg, about 4100 mg , about 4125 mg, about 4150 mg, about 4175 mg, about 4200 mg, about 4225 mg , about 4250 mg, about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg , about 4375 mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg , about 4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg , about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725 mg , about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg , about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg , about 5000 mg, about 5025 mg, about 5050 mg, about 5075 mg, about 5100 mg , about 5125 mg, about 5150 mg, about 5175 mg, about 5200 mg, about 5225 mg , about 5250 mg, about 5275 mg, about 5300 mg, about 5325 mg, about 5350 mg , about 5375 mg, about 5400 mg, about 5425 mg, about 5450 mg, about 5475 mg , about 5500 mg, about 5525 mg, about 5550 mg, about 5575 mg, about 5600 mg , about 5625 mg, about 5650 mg, about 5675 mg, about 5700 mg, about 5725 mg , about 5750 mg, about 5775 mg, about 5800 mg, about 5825 mg, about 5850 mg , about 5875 mg, about 5900 mg, about 5925 mg, about 5950 mg, about 5975 mg , about 6000 mg, about 6025 mg, about 6050 mg, about 6075 mg, about 6100 mg , about 6125 mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225 mg , about 6250 mg, about 6275 mg, about 6300 mg, about 6325 mg, about 6350 mg , about 6375 mg, about 6400 mg, about 6425 mg, about 6450 mg, about 6475 mg , about 6500 mg, about 6525 mg, about 6550 mg, about 6575 mg, about 6600 mg , about 6625 mg, about 6650 mg, about 6675 mg, about 6700 mg, about 6725 mg , about 6750 mg, about 6775 mg, about 6800 mg, about 6825 mg, about 6850 mg , about 6875 mg, about 6900 mg, about 6925 mg, about 6950 mg, about 6975 mg , about 7000 mg, about 7025 mg, about 7050 mg, about 7075 mg, about 7100 mg , about 7125 mg, about 7150 mg, about 7175 mg, about 7200 mg, about 7225 mg , about 7250 mg, about 7275 mg, about 7300 mg, about 7325 mg, about 7350 mg , about 7375 mg, about 7400 mg, about 7425 mg, about 7450 mg, about 7475 mg , about 7500 mg, about 7525 mg, about 7550 mg, about 7575 mg, about 7600 mg , about 7625 mg, about 7650 mg, about 7675 mg, about 7700 mg, about 7725 mg , about 7750 mg, about 7775 mg, about 7800 mg, about 7825 mg, about 7850 mg , about 7875 mg, about 7900 mg, about 7925 mg, about 7950 mg, about 7975 mg , about 8000 mg, about 8025 mg, about 8050 mg, about 8075 mg, about 8100 mg , about 8125 mg, about 8150 mg, about 8175 mg, about 8200 mg, about 8225 mg , about 8250 mg, about 8275 mg, about 8300 mg, about 8325 mg, about 8350 mg , about 8375 mg, about 8400 mg, about 8425 mg, about 8450 mg, about 8475 mg , about 8500 mg, about 8525 mg, about 8550 mg, about 8575 mg, about 8600 mg , about 8625 mg, about 8650 mg, about 8675 mg, about 8700 mg, about 8725 mg , about 8750 mg, about 8775 mg, about 8800 mg, about 8825 mg, about 8850 mg , about 8875 mg, about 8900 mg, about 8925 mg, about 8950 mg, about 8975 mg , about 9000mg, about 9025mg, about 9050mg, about 9075mg, about 9100mg , about 9125mg, about 9150mg, about 9175mg, about 9200mg, about 9225mg , about 9250mg, about 9275mg, about 9300mg, about 9325mg, about 9350mg , about 9375mg, 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.

[0054] In one embodiment, the 15-oxo-DGLA present in the composition of the present disclosure is at least The 15-oxo-DGLA composition contains 90% by weight of 15-oxo-DGLA. Higher purity 15-oxo-DGLA, e.g., at least 95% by weight 15-oxo-D GLA or at least 97% by weight of 15-oxo-DGLA, Oxo-DGLA is any form of 15-oxo-DGLA described herein. The purity of 15-oxo-DGLA is as described herein for 15-oxo-DGLA. The composition may be further defined by any of the following (e.g., impurity profile):

[0055] The above discusses the amount of 15-oxo-DGLA in the pharmaceutical composition and its purity. The properties of essential fatty acids and their synthesis indicate that 15-oxo-DGLA compositions are effective in replacing essential fatty acids. Such fatty acids may include moieties from other essential fatty acids in the metabolic cascade.

[0056] In one embodiment, the composition of the present disclosure comprises alpha linolenic acid, stearidonic acid, docosahexaenoic acid, and glycerin. About 10% or less by weight of dihexaenoic acid (DHA), or derivatives thereof, about 9% Below, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about Contains no more than 2%, no more than about 1%, or no more than about 0.5% of other omega-3 fatty acids. In embodiments, such other omega-3 fatty acids are substantially absent or absent. Does not exist.

[0057] In another embodiment, 15-oxo-DGLA is the major component present in the composition of the present disclosure. 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% of all fatty acids.

[0058] Some residual DGLA from the synthesis of 15-oxo-DGLA may be present. Approximately 10% or less, approximately 9% or less, approximately 8% or less, approximately 7% or less, approximately 6% or less, approximately 5% or less, approximately 4% or less % or less, about 3% or less, about 2% or less, about 1% or less, or about 0.5% DGLA. Alternatively, there is substantially no DGLA in a form that is not modified into the oxo form, or do not have.

[0059] Additional activators In one embodiment, the pharmaceutical composition comprises at least one additional active agent(s). In one embodiment, the pharmaceutical composition further comprises a commonly recognized In one embodiment, the pharmaceutical composition comprises an amount of the additional active agent that is less than a therapeutically effective amount. Addition of an additional dose equal to or greater than the generally recognized therapeutically effective amount for that drug. The amount of active agent included.

[0060] In some embodiments, the additional active agent is a non-Hepatitis C virus (HCV) antiviral agent. antiviral drugs, HCV antiviral drugs, non-antiviral drugs for hepatitis B virus (HBV), antiviral drugs for HBV Illness drugs, primary biliary cirrhosis drugs, alcoholic hepatitis drugs, primary sclerosing cholangitis drugs, non-alcoholic Nonalcoholic fatty liver disease (NASH) agents, autoimmune hepatitis agents, pulmonary fibrosis agents, cystic fibrosis agents, renal Fibrosis drugs, skin fibrosis drugs, myelofibrosis drugs, eosinophilic esophagitis drugs, anti-TGF-β drugs, anti-CTGF drugs agents, recombinant human serum amyloid P agents, anti-IL-4 agents, anti-IL-5 agents (e.g., Mepoliz mab), anti-IL-13 agent, neurochemical receptor agent, anti-IL-17A agent, Hh or Hh(R )SMO antagonist, CCR5 antagonist, CCR4 cell recruitment inhibitor, CXCR 4 antagonist, anti-CXCR4 agent, CXCR3 antagonist, anti-CCL17 agent, NO X inhibitor, copaxone, adiponectin, AMPK agonist, Y box binding protein Protein-1, myofibroblast mobilization inhibitor, anti-Th17 MMP inducer, anti-extracellular matrix deposition compounds, adenosine receptor antagonists, microRNA (miR) drugs, stem cells, tenofovir, anti-collagen cross-linking drugs (e.g., simtuzumab, mogamulizumab), or Rusartan, telmisartan, losartan, irbesartan, azilsartan, eprosa angiotensin II receptor blocker selected from the group consisting of olmesartan, olmesartan, ARB), or any combination of the above.

[0061] In one embodiment, the one or more additional active agent(s) includes telmisartan , consisting essentially of or consisting of.

[0062] In one embodiment, the present disclosure provides a method for the preparation of a terpenoid comprising administering to a subject a composition comprising 15-oxo-EPA and a terpenoid as the only active agent. and misartan.

[0063] In one embodiment, the present disclosure provides a combination of 15-oxo-DGLA and tetracycline as the only active agents. and lumisartan.

[0064] In one embodiment, the 15-oxo-EPA and one or more active agent(s) are or from about 1:1000 to about 1000:1, from about 1:500 to about 500:1, approx. 1:100 to approx. 100:1, approx. 1:50 to approx. 50:1, approx. 1:25 to approx. 2 5:1, approx. 1:10 to approx. 10:1, approx. 1:5 to approx. 5:1, approx. 1:4 to approx. 4:1, approx. 1:3 ~about 3:1, about 1:2 to about 2:1, or about 1:1 15-oxo-EPA:additional drug The agents are co-administered in a weight ratio of

[0065] In one embodiment, the 15-oxo-DGLA and one or more active agent(s) are or from about 1:1000 to about 1000:1, from about 1:500 to about 1:1000:1, About 500:1, about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, approx. 1:10 to approx. 10:1, approx. 1:5 to approx. 5:1, approx. 1:4 to approx. 4:1, approx. 1: 3 to about 3:1, about 1:2 to about 2:1, or about 1:1 15-oxo-DGLA:addition The drugs are co-administered in a weight ratio of:

[0066] Dosage Form Compositions for use in accordance with the present disclosure may be formulated as one or more dosage units. The terms "dosage unit" and "dosage unit" herein refer to a single dose that provides a therapeutic effect. A dosage unit refers to a quantity of a pharmaceutical composition containing an amount of a therapeutic agent suitable for administration. One to multiple times per day (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 times), or as many times as needed to produce a therapeutic response.

[0067] In some embodiments, the compositions of the present disclosure are administered in orally deliverable dosage forms or units. Non-limiting examples of suitable dosage forms include tablets (e.g., suspension tablets). tablets, chewable tablets, fast dispersing tablets, chewable tablets, etc.), capsules capsules (e.g., soft or hard gelatin capsules or HPMC capsules); Lozenges, packets, cachets, troches, pellets, suspensions, elixirs, syrups, and or any other solid dosage form reasonably adapted for oral administration. The terms "oral delivery" and "oral administration" refer to any drug that is administered orally, whether or not it is swallowed. This includes any form of delivery in which the agent or composition is placed in the mouth of the subject being treated. This includes buccal and sublingual administration, as well as esophageal administration.

[0068] Alternatively, compositions of the present disclosure can also be administered rectally, topically, or parenterally (e.g., subcutaneously, intramuscularly). The compositions may be formulated for intravenous, intradermal, or infusion (intravenous, intradermal, or intradermal) delivery.

[0069] Considering the amount of 15-oxo-EPA or 15-oxo-DGLA in the compositions of the present disclosure, In some cases, it may be divided into several dosage forms. For example, subjects may receive 1 to 4 g of 15-oxo-EPA or 1 to 4 g of 15-oxo-EPA per day. If 4g of 15-oxo-DGLA is to be administered, this will be a maximum of 4 capsules, each containing 1 g of 15-oxo-EPA or 15 -Providing oxo-DGLA or up to 8 capsules each containing 500 mg Provide 5-oxo-EPA or 15-oxo-DGLA.

[0070] The compositions of the present disclosure may be in the form of liquid dosage forms or dosage units for direct absorption. Alternatively, they may be mixed with food or drink prior to ingestion. Non-exclusive examples include suspensions, elixirs, syrups, and liquid aerosol formulations. can be done.

[0071] In another embodiment, the compositions of the present disclosure include one or more pharma- ceutically acceptable excipients. As used herein, the term "pharmaceutically acceptable excipient" refers to any vehicle that is suitable for delivery of a therapeutic agent to a subject. or be added to a pharmaceutical composition to facilitate its handling. or improves storage characteristics or allows for the formation of unit doses of the composition, or and does not result in unacceptable toxicity or interactions with other components in the composition. By way of example only, any substance that is not a therapeutic agent in accordance with the present disclosure The pharmaceutical composition may contain additives such as antioxidants, surfactants, preservatives, flavoring agents, co-solvents, viscosity aids, suspension aids, and a lipophilic phase.

[0072] In one embodiment, the pharmaceutical composition comprises ascorbic acid, palmitic acid, palmitic acid a Scorbyl, α-tocopherol, idebenone, ubiquinone, ferulic acid, coenzyme Q10, lycopene, green tea, catechin, epigallocatechin 3-gallate (EGCG), green tea Polyphenols (GTP), silymarin, coffee berry, resveratrol, grape seed , Pomegranate Extract, Genisten, Pycnogenol, Niacinamide, Butyric Hydroxide One or more of the following: butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA) In one embodiment, the pharmaceutical composition comprises from about 0.01% by weight to about 2% by weight of the above antioxidants. % antioxidant, e.g., about 0.01%, about 0.02%, about 0.03%, about 0 .04% by weight, approximately 0.05% by weight, approximately 0.06% by weight, approximately 0.07% by weight, approximately 0.08% by weight Amount%, approx. 0.09 wt%, approx. 0.1 wt%, approx. 0.11 wt%, approx. 0.12 wt%, approx. 0 .13% by weight, approximately 0.14% by weight, approximately 0.15% by weight, approximately 0.16% by weight, approximately 0.17% by weight Amount%, approx. 0.18 wt%, approx. 0.19 wt%, approx. 0.2 wt%, approx. 0.21 wt%, approx. 0 .22wt%, approx. 0.23wt%, approx. 0.24wt%, approx. 0.25wt%, approx. 0.26wt Amount%, approx. 0.27 wt%, approx. 0.28 wt%, approx. 0.29 wt%, approx. 0.3 wt%, approx. 0 .31% by weight, approximately 0.32% by weight, approximately 0.33% by weight, approximately 0.34% by weight, approximately 0.35% by weight Amount%, approx. 0.36 wt%, approx. 0.37 wt%, approx. 0.38 wt%, approx. 0.39 wt%, approx. 0.4% by weight, approximately 0.41% by weight, approximately 0.42% by weight, approximately 0.43% by weight, approximately 0.44% by weight Amount%, approx. 0.45 wt%, approx. 0.46 wt%, approx. 0.47 wt%, approx. 0.48 wt%, approx. 0.49% by weight, approximately 0.5% by weight, approximately 0.51% by weight, approximately 0.52% by weight, approximately 0.53% by weight Amount%, approx. 0.54 wt%, approx. 0.55 wt%, approx. 0.56 wt%, approx. 0.57 wt%, approx. 0.58% by weight, approximately 0.59% by weight, approximately 0.6% by weight, approximately 0.61% by weight, approximately 0.62% by weight Amount%, approx. 0.63 wt%, approx. 0.64 wt%, approx. 0.65 wt%, approx. 0.66 wt%, approx. 0.67% by weight, approximately 0.68% by weight, approximately 0.69% by weight, approximately 0.7% by weight, approximately 0.71% by weight Amount%, approx. 0.72 wt%, approx. 0.73 wt%, approx. 0.74 wt%, approx. 0.75 wt%, approx. 0.76% by weight, approximately 0.77% by weight, approximately 0.78% by weight, approximately 0.79% by weight, approximately 0.8% by weight Amount%, approx. 0.81 wt%, approx. 0.82 wt%, approx. 0.83 wt%, approx. 0.84 wt%, approx. 0.85% by weight, approximately 0.86% by weight, approximately 0.87% by weight, approximately 0.88% by weight, approximately 0.89 Weight%, approx. 0.9wt%, approx. 0.91wt%, approx. 0.92wt%, approx. 0.93wt%, approx. 0.94% by weight, approximately 0.95% by weight, approximately 0.96% by weight, approximately 0.97% by weight, approximately 0.98 Weight%, approx. 0.99% by weight, approx. 1% by weight, approx. 1.1% by weight, approx. 1.2% by weight, approx. 1.3% by weight Amount%, approx. 1.4% by weight, approx. 1.5% by weight, approx. 1.6% by weight, approx. 1.7% by weight, approx. 1.8% by weight %, about 1.9% by weight, or about 2% by weight of one or more antioxidants.

[0073] Treatment method The compositions and formulations disclosed herein are useful in treating fibrosis, inflammation and inflammatory disorders, kidney disease and renal disease. In one embodiment, the fibrosis may be used in the treatment of dysfunction of the lungs, liver, heart, kidney, or other organs. , one or more of the eyes, mediastinum, bone marrow, retroperitoneum, skin, intestine, joints, reproductive organs, or any combination thereof In some embodiments, fibrosis is associated with an organ or tissue associated with Associated with liver tissue.

[0074] In some embodiments, the fibrosis is caused by non-alcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD Activity Score (NAS) is In some embodiments, the NAS is reduced in the patient after administration of the In some embodiments, the NAS is reduced in the patient compared to the line. In some embodiments, the composition is administered to a second subject, and the first subject is not administered the composition. and the second subject receives a placebo. The elephant is undergoing fibrosis therapy.

[0075] In some embodiments, the subject is undergoing a fibrosis therapy. In another embodiment, the fibrosis therapy is continued during administration of the composition. Therapy is interrupted during administration of the composition. For example, in some embodiments, the subject is 15-oxo-EPA or 15-oxo-EPA disclosed herein. After initiating a treatment method including administration of a composition containing 5-oxo-DGLA, telmisartan The therapy is interrupted.

[0076] In some embodiments, the inflammatory disease is, inter alia, acne vulgaris, asthma, autoimmune diseases. , autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammation reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and interstitial Interstitial cystitis.

[0077] In some embodiments, the composition is administered orally. 15-oxo-EPA or 15-oxo-DGLA is the only active ingredient in the composition. In another embodiment, the composition further comprises an additional agent for affecting therapy. In some embodiments, the additional agent is telmisartan.

[0078] In some embodiments, the present disclosure provides a method for treating fibrosis in a subject receiving a fibrosis therapy. The present invention provides a method for treating an allergy to 15-oxo-EPA, the method comprising administering to a subject a composition comprising 15-oxo-EPA. In some embodiments, the fibrosis is in the lungs, liver, heart, kidneys, mediastinum, bone, or the like. The tissue is selected from the group consisting of the spinal cord, the retroperitoneum, the skin, the intestine, the joints, the reproductive organs, and combinations thereof. In some embodiments, the fibrosis is associated with an organ or tissue in which fibrosis occurs. In some embodiments, the fibrosis is caused by non-alcoholic fatty liver disease (NAFLD). In some embodiments, the NAFLD Activity Score (NAS) is In some embodiments, the NAS is reduced in the patient following administration of the composition. In some embodiments, the NAS is reduced in the patient as compared to the baseline. The composition is administered to a second subject, and the first subject is administered the composition to a third subject. and the second subject receives a placebo. The subject is undergoing a fibrosis therapy. In some embodiments, the fibrosis therapy is Non-antiviral drugs, HCV antiviral drugs, HBV non-antiviral drugs, HBV antiviral drugs, Drugs for primary biliary cirrhosis, alcoholic hepatitis, primary sclerosing cholangitis, NASH, autoimmune Hepatitis drugs, pulmonary fibrosis drugs, cystic fibrosis drugs, renal fibrosis drugs, skin fibrosis drugs, bone marrow fibrosis drugs, acidophilic Drugs for globuloesophagitis, anti-TGF-β drugs, anti-CTGF drugs, recombinant human serum amyloid P drugs, anti-I L-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 ists, CCR4 cell recruitment inhibitors, CXCR4 antagonists, anti-CXCR4 agents, CXC R3 antagonists, anti-CCL17 agents, NOX inhibitors, copaxone, adiponectin, AMPK agonist, Y-box binding protein-1, myofibroblast mobilization inhibitor, anti-Th 17 MMP inducers, anti-extracellular matrix deposition compounds, adenosine receptor antagonists , microRNA (miR) drugs, stem cells, tenofovir, anti-collagen cross-linking drugs (e.g., Simtuzumab, mogamulizumab), or valsartan, telmisartan, losartan, Selected from the group consisting of irbesartan, azilsartan, eprosartan, and olmesartan angiotensin II receptor blockers (ARBs) or any combination of the above In some embodiments, the subject is receiving a fibrosis therapy. In some embodiments, the fibrosis therapy is continued during administration of the composition. In some embodiments, the second subject is undergoing a fibrosis therapy. In some embodiments, the composition is administered orally.

[0079] In some embodiments, the method comprises administering a composition comprising 15-oxo-EPA. In some embodiments, the method further comprises identifying the subject as having fibrosis prior to the administration of the antibody. The method further comprises treating the subject with a composition comprising 15-oxo-EPA prior to administering the composition to the subject. In some embodiments, the determining step further comprises identifying the patient as being at high risk of developing a disease. In some embodiments, the method includes determining the NAS relative to a control. In some embodiments, the NAS associated with the specific step is at least 3. involves screening for genetic mutations in nucleic acid molecules associated with a subject. In one embodiment, the determining step comprises obtaining an analysis of blood and / or serum associated with the subject. In some embodiments, the identifying step includes obtaining a tissue sample relative to a control. In some embodiments, the step of testing comprises testing the Histology involves analyzing tissue samples (eg, biopsies).

[0080] In some embodiments, the present disclosure provides a method for treating fibrosis in a subject receiving a fibrosis therapy. The present invention provides a method for treating a pulmonary artery disease, the method comprising administering to a subject a composition comprising 15-oxo-DGLA. In some embodiments, the fibrosis is in the lungs, liver, heart, kidneys, mediastinum, Selected from the group consisting of bone marrow, retroperitoneal cavity, skin, intestine, joints, reproductive organs, and combinations thereof In some embodiments, the fibrosis is associated with liver fibrosis. In some embodiments, the fibrosis is caused by non-alcoholic fatty liver disease (NAFL). D). In some embodiments, the NAFLD Activity Score (NAS) is associated with: In some embodiments, the NAS is reduced in the patient after administration of the composition. In some embodiments, the NAS is reduced in the patient compared to baseline. In some embodiments, the inflammatory response is reduced in a subject compared to a second subject who is not administered the composition. In some embodiments, the second subject is administered a placebo. The subject is undergoing a fibrosis therapy. In some embodiments, the fibrosis therapy is V non-antiviral drugs, HCV antiviral drugs, HBV non-antiviral drugs, HBV antiviral drugs, Primary biliary cirrhosis drugs, alcoholic hepatitis drugs, primary sclerosing cholangitis drugs, NASH drugs, autoimmune diseases Infectious hepatitis drugs, pulmonary fibrosis drugs, cystic fibrosis drugs, renal fibrosis drugs, skin fibrosis drugs, myelofibrosis drugs, Drugs for eosinophilic esophagitis, anti-TGF-β drugs, anti-CTGF drugs, recombinant human serum amyloid P drugs, anti IL-4 agents, anti-IL-5 agents (e.g., mepolizumab), anti-IL-13 agents, neurochemical receptors drugs, anti-IL-17A agents, Hh or Hh(R)SMO antagonists, CCR5 antagonists agonists, CCR4 cell recruitment inhibitors, CXCR4 antagonists, anti-CXCR4 agents, CX CR3 antagonist, anti-CCL17 agent, NOX inhibitor, copaxone, adiponectin , AMPK agonist, Y-box binding protein-1, myofibroblast mobilization inhibitor, anti-T h17 MMP inducer, anti-extracellular matrix deposition compound, adenosine receptor antagonist stromal, microRNA (miR) drugs, stem cells, tenofovir, anti-collagen cross-linking drugs (e.g. , simtuzumab, mogamulizumab), or valsartan, telmisartan, or losartan , irbesartan, azilsartan, eprosartan, and olmesartan Angiotensin II receptor blockers (ARBs) of choice, or any of the above In some embodiments, the subject is receiving a fibrosis therapy. In some embodiments, the fibrosis therapy is continued during administration of the composition. In some embodiments, the second subject is undergoing a fibrosis therapy. In one embodiment, the composition is administered orally.

[0081] In some embodiments, the method comprises administering a composition comprising 15-oxo-DGLA. In some embodiments, the method further comprises identifying the subject as having fibrosis prior to administering the therapeutic agent to the subject. The method further comprises administering to the subject a composition comprising 15-oxo-DGLA, the ... In some embodiments, the method further includes identifying a patient as being at high risk for developing the disease. In some embodiments, the step includes determining the NAS relative to a control. The NAS associated with the subject is at least 3. In some embodiments, The screening involves screening for genetic mutations in nucleic acid molecules associated with a subject. In some embodiments, the identifying step comprises analyzing blood and / or serum associated with the subject. In some embodiments, the determining step includes obtaining a control-associated In some embodiments, the step of examining the tissue comprises examining the tissue in association with a control. This includes analyzing a histological tissue sample (e.g., a biopsy) obtained.

[0082] In some embodiments, the methods of the disclosure reduce NAS levels in a subject. In some embodiments, the method comprises administering the composition to the subject for a period of time. and determining a second lower NAS value associated with the

[0083] In one embodiment, the present disclosure provides a method for treating a skin condition or skin disorder in a subject in need of treatment. The present invention provides a method for doing so, comprising administering to a subject a pharmaceutical composition comprising 15-oxo-EPA. Non-limiting examples of skin diseases and conditions include acne, acne vulgaris, and acne scars. These include eczema, psoriasis, pruritus / itch, radiation protection, dry skin, anti-aging, and photoprotection. Can be obtained.

[0084] In one embodiment, the present disclosure provides a method for treating a skin condition or skin disorder in a subject in need of treatment. The present invention provides a method for doing so, comprising administering to a subject a pharmaceutical composition comprising 15-oxo-DGLA. Non-limiting examples of skin diseases and skin conditions include acne, For eczema, psoriasis, pruritus / itch, radiation protection, dry skin, anti-aging, and photoprotection Some examples include:

[0085] As used herein, the term "acne" refers to a skin condition characterized by one or more acne-like lesions, such as papules, pustules, or cysts. Acne refers to any disease or disorder of the skin that affects the skin. Non-limiting examples of acne include acne vulgaris, acne necrosis, and acne ulcers. Acne vera, halogenacne, chloracne, occupational acne, oily acne, tar acne, summer acne, tropical acne Sexual acne, cosmetic acne, pomade acne, nuchal keloid acne, mechanical acne, skin peeling acne Acne, drug-induced acne, childhood acne, neonatal acne, acne conglobata, acne fulminans, miliary necrotizing acne, Lupus miliaris disseminated faciens, and other skin diseases associated with acneiform eruptions.

[0086] In one embodiment, the present disclosure provides a method for treating or preventing acne associated with P. acnes. In one embodiment, the method comprises the steps of: The method includes administering a composition disclosed herein to a subject.

[0087] In one embodiment, the present disclosure provides methods for determining, for example, the proliferation, colonization, and / or infection of and a method for inhibiting P. acnes, including the inhibition of P. acnes, in a subject in need thereof. In one embodiment, the method includes contacting P. acnes with a composition disclosed herein. This includes making the

[0088] In one embodiment, the method includes treating the affected area (and / or generally) of the skin prior to administering the composition. The term "acne-like rash" as used herein further includes cleansing the skin of areas prone to acne-like rashes. When used in a skin care product, the term "washing" generally refers to cleansing the skin, washing the skin, It is a great way to exfoliate the skin and remove dirt, oil, dead skin cells, etc. This refers to any method known to the practitioner.

[0089] In one embodiment, the present disclosure provides a method for treating hypertension (e.g., pulmonary hypertension). The present invention also provides a method for doing so in a subject having a 15-oxidase inhibitor as disclosed herein. The method includes orally administering to a subject a pharmaceutical composition comprising so-EPA.

[0090] In one embodiment, the present disclosure provides a method for treating hypertension (e.g., pulmonary hypertension). The present invention also provides a method for doing so in a subject having a 15-oxidase inhibitor as disclosed herein. The method includes orally administering to a subject a pharmaceutical composition containing so-DGLA.

[0091] In one embodiment, the method is administered once per day, twice per day, three times per day, or or more than four times per day, .

[0092] Unless otherwise specified, all technical and scientific terms used herein are intended to be understood as being within the scope of the present disclosure. The terms used herein have the same meaning as commonly understood by a person skilled in the relevant art. Although methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure, preferred Methods and materials are described below. All publications, patent applications, patent applications and other materials mentioned herein are incorporated by reference in their entirety. Xu, and other references are expressly incorporated by reference in their entireties. In all cases, the present specification, including definitions, controls. In addition, the materials, methods, and The examples are illustrative only and are not intended to be limiting.

[0093] While the present disclosure may be embodied in various forms, the following are some embodiments. The description of the present disclosure is to be considered as an example of the present disclosure, and the technology disclosed in this specification It is understood that the present invention is not intended to limit the present invention to the particular embodiments illustrated. Headings are provided for convenience only and do not necessarily represent or imply any change in the disclosure herein. The embodiments illustrated under any heading should not be construed as limiting the scope of the invention. The embodiments may be combined with embodiments illustrated under any other heading.

[0094] The use of numerical values ​​for the various quantitative values ​​specified in this application is by no means intended, unless expressly indicated otherwise. Assuming that both the minimum and maximum values ​​within the stated ranges are preceded by the term "about." , are stated as approximations. In this way, it is possible to achieve results substantially identical to those stated. In order to achieve this, slight variations from the stated values ​​may be used. Also, the disclosure of ranges is All values ​​between the minimum and maximum values ​​listed, as well as values ​​that may be formed by such values. Any range is intended as a continuous range, including any range. Also, any recited numerical value can be combined with any other Any and all ratios that can be formed by dividing the enumerated values ​​(and any such Such ratio ranges are disclosed herein. Thus, one of ordinary skill in the art can easily The ranges, ranges, and ratio ranges may be derived expressly from the numerical values ​​presented herein, and in all cases It is understood that such ratios, ranges, and ratio ranges represent various embodiments of the present disclosure. You will understand.

[0095] As used herein, "treating" or "treating" a disease, disorder, or condition. "Treatment" means, at least in part, (1) preventing a disease, disorder, or condition; That is, the clinical symptoms of a disease, disorder, or condition are not observed after exposure to the disease, disorder, or condition. A person who is susceptible to or has contracted a disease, disorder, or condition but has not yet experienced symptoms of the disease, disorder, or condition. (2) not causing disease, disorder, or injury in a mammal that does not exhibit the disease, disorder, or injury; The objective of the present invention is to prevent a condition, i.e., to prevent the onset of a disease, disorder, or condition, or its clinical symptoms. (3) halting or reducing a disease, disorder, or condition; and, i.e., causing regression of a disease, disorder, or condition, or its clinical symptoms. The term "prevention" with respect to a given disease or disorder includes the to prevent the onset of disease, or to prevent the onset of disease ... A disease or disorder occurs in a subject who has not yet been diagnosed with the disease or disorder. Prevent the onset of further disease / disease if already present It means to prevent.

[0096] As used herein, an "effective amount" refers to the amount of a compound required to confer a therapeutic effect on a subject. As used herein, a "therapeutically effective amount" refers to the amount of active compound required for treatment. alleviate to some extent one or more of the symptoms of the disease, disorder, or condition being treated In some embodiments, the results are indicative of a disease. Reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other part of a biological system. For example, in some embodiments, an "effective amount" for therapeutic use is is required to provide a clinically significant reduction in disease symptoms without undue adverse side effects. is the amount of a composition comprising a compound disclosed herein that is In any individual case, an appropriate "effective amount" may be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. The "effectiveness" of the compounds disclosed herein, such as compounds of formula (A) or formula (I), "Amount" refers to an amount sufficient to achieve the desired pharmacological effect or therapeutic improvement without undue adverse side effects. In another embodiment, the amount is an amount effective to treat a subject's metabolism, age, weight, general condition, or other characteristics. Depending on the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician, It is understood that an "effective amount" or a "therapeutically effective amount" will vary from subject to subject. The term "pharmaceutical acceptable" means that the substance does not have unacceptable toxicity to a subject. Or it means that it does not cause any interaction with other components of the composition.

[0097] Without further elaboration, it is understood that one of ordinary skill in the art can, using the preceding description and the illustrative examples below, The disclosed agents can be made and used to practice the claimed methods. The following examples are provided to facilitate the practice of the disclosure and are intended to provide Nothing in this document should be construed as limiting in any way the remainder of the disclosure. The present application provides the following invention. (Configuration 1) (5Z,8Z,11Z,13E,17Z)-15-OXOICOSA-5,8,11,13 , 17-pentaenoic acid ("15-oxo-EPA"). (Configuration 2) Approximately 0.1g to 4g of (5Z,8Z,11Z,13E,17Z)-15-oxoecosamine - Compositions containing 5,8,11,13,17-pentaenoic acid ("15-oxo-EPA") . (Configuration 3) (5Z,8Z,11Z,13E,17Z)-15-OXOICOSA-5,8,11,13 , 17-pentaenoic acid ("15-oxo-EPA"), and a pharma- ceutically acceptable excipient; 23. A pharmaceutical composition comprising: (Configuration 4) (8Z,11Z,13E)-15-oxoicosa-8,11,13-trienoic acid ("1 5-oxo-DGLA). (Configuration 5) About 0.1g to about 4g of (8Z,11Z,13E)-15-oxoicosa-8,11,1 A composition comprising 3-trienoic acid ("15-oxo-DGLA"). (Configuration 6) (8Z,11Z,13E)-15-oxoicosa-8,11,13-trienoic acid ("1 5-oxo-DGLA") and a pharma- ceutical acceptable excipient. (Configuration 7) Patients in need of treatment and / or prevention of fibrosis, inflammation, kidney disease, or kidney dysfunction A method for carrying out the same in an object, comprising the steps of: The method comprises administering to the subject a pharmaceutical composition comprising administering to said subject a (Configuration 8) The fibrosis may affect the lungs, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestines, joints, reproductive organs, and and combinations thereof. Method of posting. (Configuration 9) The method of any one of claims 7 to 8, wherein the fibrosis is liver fibrosis. (Configuration 10) The fibrosis is associated with nonalcoholic fatty liver disease (NAFLD), 2. The method according to any one of claims 1 to 11. (Configuration 11) The NAFLD activity score (NAS) is reduced in the subject following administration of the composition. and optionally, the NAS is reduced in the subject compared to baseline; or The subject is undergoing a fibrosis therapy and the NAS has not been administered the composition. is reduced in said subject as compared to a second subject, said second subject optionally being treated with placebo. and / or the second subject is optionally receiving a fibrosis therapy; Optionally, the fibrosis therapy is continued during administration of the compound, composition, or pharmaceutical composition. The method according to any one of aspects 7 to 10, (Configuration 12) The fibrosis therapy includes a non-HCV antiviral drug, an HCV antiviral drug, , non-antiviral drugs for hepatitis B virus (HBV), antiviral drugs for HBV, primary biliary cirrhosis Drugs, Alcoholic Hepatitis Drugs, Primary Sclerosing Cholangitis Drugs, NASH Drugs, Autoimmune Hepatitis Drugs, Pulmonary Fibroblasts Fibrosis drugs, cystic fibrosis drugs, renal fibrosis drugs, skin fibrosis drugs, myelofibrosis drugs, eosinophilic esophagitis drugs, Anti-TGF-β drugs, anti-CTGF drugs, recombinant human serum amyloid P drugs, anti-IL-4 drugs, anti-I L-5 drugs (e.g., mepolizumab), anti-IL-13 drugs, neurochemical receptor drugs, anti-IL-17 Drug A, Hh or Hh(R)SMO antagonist, CCR5 antagonist, CCR 4 Cell mobilization inhibitors, CXCR4 antagonists, anti-CXCR4 drugs, CXCR3 antagonists Streptococcus aureus, anti-CCL17 drugs, NOX inhibitors, copaxone, adiponectin, AMPK agonists Streptococcus erythroblastus, Y-box binding protein-1, myofibroblast mobilization inhibitor, anti-Th17 MMP inducer Conductive agents, anti-extracellular matrix deposition compounds, adenosine receptor antagonists, microR NA (miR) drugs, stem cells, tenofovir, anti-collagen cross-linking drugs (e.g., simtuzumab, mogamulizumab), or valsartan, telmisartan, losartan, or irbesartan angiogenic agent selected from the group consisting of azilsartan, eprosartan, and olmesartan Administration of tensin II receptor blockers (ARBs), or any combination of the above 12. The method of claim 11, comprising: (Configuration 13) The 15-oxo-EPA, the composition containing 15-oxo-EPA, 15-oxo- The pharmaceutical composition containing EPA, the 15-oxo-DGLA, The composition comprising, or the pharmaceutical composition comprising, 15-oxo-DGLA is administered orally. The method according to any one of aspects 7 to 12, (Configuration 14) The 15-oxo-EPA or the 15-oxo-DGLA is the only component in the composition. 14. The method according to any one of aspects 7 to 13, wherein the active ingredient is (Configuration 15) The composition further comprises an additional agent for influencing the fibrosis therapy. 14. The method according to any one of 1 to 13. (Configuration 16) The 15-oxo-EPA, the composition containing 15-oxo-EPA, 15-oxo- The pharmaceutical composition containing EPA, the 15-oxo-DGLA, or the pharmaceutical composition comprising 15-oxo-DGLA, Any one of configurations 7 to 15, further comprising identifying the subject as having fibrosis. The method described. (Configuration 17) The 15-oxo-EPA, the composition containing 15-oxo-EPA, 15-oxo- The pharmaceutical composition containing EPA, the 15-oxo-DGLA, or the pharmaceutical composition comprising 15-oxo-DGLA, The method according to any one of claims 7 to 16, further comprising identifying the subject as being at high risk for developing fibrosis. 2. The method according to claim 1 . (Configuration 18) The identifying step includes determining a NAS associated with the subject, and optionally, 18. The method of claim 16 or 17, wherein the NAS associated with the subject is at least 3. Law. (Configuration 19) The identifying step may include screening for genetic mutations in nucleic acid molecules associated with the subject. 19. The method according to any one of aspects 16 to 18, further comprising: (Configuration 20) The identifying step may include obtaining an analysis of blood and / or serum associated with the subject. 20. The method according to any one of claims 16 to 19, comprising: (Configuration 21) The identifying step may include examining tissue associated with the subject, and optionally, 21. The method according to any one of claims 16 to 20, wherein the tissue is a histological tissue sample associated with the subject. Method of posting. (Configuration 22) A second, lower N associated with the subject after administering the composition over a period of time. 22. The method of any one of claims 18 to 21, further comprising determining an AS value. (Configuration 23) The 15-oxo-EPA or the 15-oxo-DGLA is in the free acid form. 23. The compound, composition, pharmaceutical composition, or method according to any one of claims 1 to 22. (Configuration 24) The 15-oxo-EPA or the 15-oxo-DGLA is in an esterified form. the law of nature, Optionally, the esterified form is an alkyl ester form; 24. Any of claims 1 to 23, wherein the esterified form is a triglyceride form. 2. The compound, composition, pharmaceutical composition, or method according to claim 1. (Configuration 25) The 15-oxo-EPA or the 15-oxo-DGLA is in the ethyl ester form. The compound, composition, pharmaceutical composition, or method according to any one of claims 1 to 24, . (Configuration 26) The inflammatory disease is acne vulgaris, asthma, autoimmune disease, autoinflammatory disease, celiac disease. , chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis sarcoidosis, transplant rejection, vasculitis, and interstitial cystitis. 26. The method according to any one of claims 7 to 25.

Claims

1. (5Z,8Z,11Z,13E,17Z)-15-oxoicosane-5,8,11,13 15-Oxo-EPA (17-Pentaenoic Acid), xo-EPA is present in the composition in an amount of 0.1% to 99% by weight of the total weight of the composition. The composition.

2. (8Z,11Z,13E)-15-oxoicosa-8,11,13-trienoic acid ("1 15-oxo-DGLA" ("15-oxo-DGLA"), wherein the composition The composition is present in the composition in an amount of 0.1% to 99% by weight of the total weight of the composition.

3. For treating and / or preventing fibrosis, inflammation, kidney disease, or kidney dysfunction in a subject.

3. A composition for use in a method for treating a vascular endothelial disorder comprising administering to a patient a therapeutically effective amount of a therapeutically effective amount of a vascular endothelial disorder comprising administering to a patient a therapeutically effective amount of a vascular endothelial disorder.

4. The fibrosis may affect the lungs, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestines, joints, reproductive organs, and and combinations thereof. The composition described.

5. The composition of claim 3 or 4, wherein the fibrosis is liver fibrosis.

6. Claims 3 to 5, wherein the fibrosis is associated with non-alcoholic fatty liver disease (NAFLD). The composition according to any one of claims 1 to 5.

7. The composition of claim 1 or 2, wherein the composition is formulated for oral administration.

8. The 15-oxo-EPA or the 15-oxo-DGLA is the only component in the composition. The composition according to any one of claims 1 to 7, wherein the active ingredient is

9. The composition further comprises an additional agent for affecting the fibrosis therapy.

9. The composition according to any one of claims 1 to 8.

10. The 15-oxo-EPA or the 15-oxo-DGLA is in the free acid form. The composition according to any one of claims 1 to 9.

11. The 15-oxo-EPA or the 15-oxo-DGLA is in an esterified form. the law of nature, Optionally, the esterified form is an alkyl ester form; Optionally, the esterified form is a triglyceride form.

2. The composition described in item 1.

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