Omega-7 fatty acid berberine salt and methods of uses thereof

Abstract

The disclosure provides omega-7 fatty acid berberine salts and uses thereof.

Description

PCT APPLICATIONOMEGA-7 FATTY ACID BERBERINE SALT AND METHODS OF USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 665,569 filed June 28, 2024; which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Berberine (5 ,6-dihydro-9, 10-dimethoxybenzo [g] - 1 ,3 -benzodioxolo [5 ,6-a]quinolizinium), an isoquinoline alkaloid isolated from Rhizoma Copiidis. has had a long history of medicinal use in China to treat various gastrointestinal diseases. Berberine is found in a variety of plants as Berberis, Hydrastis canadensis, Xanthorhiza simplicissima, Phellodendron amurense, Coptis chinensis, Tinospora cordifolia, Argemone mexicana, and Eschscholzia californica. In the past two decades, in vitro and in vivo studies have demonstrated the efficacy of berberine when used alone or as a combination for diabetes, dyslipidemia, cancer, neuroprotection, and cardiovascular diseases. Currently, berberine can be obtained commercially in the form of chloride, sulfate, or tannate salt, with berberine hydrochloride having been used in almost all previous studies. The low bioavailability of berberine in the current available forms makes its applications for the treatment of chronic and systemic disease very challenging.BRIEF DESCRIPTION OF THE DRAWINGS

[0003] FIG. 1 shows the ’HNMR graph of berberine palmitoleic acid salt.

[0004] FIG. 2 shows the ’HNMR graph of berberine palmitoleic acid salt and its overlay with palmitoleic acid.

[0005] FIG. 3 shows the mean plasma concentration (ng / mL) or Berberine in male SD rats after PO administration of berberine palmitoleic acid salt and berberine HC1 at 50 mpk.SUMMARY

[0006] Disclosed herein is an omega-7 fatty acid berberine salt.

[0007] In some embodiments, the omega-7 fatty acid has the following formula: CH3-(CH2)5-CH=CH- (CH2)n-CC>2H; wherein n is 3-15.

[0008] In some embodiments, the omega-7 fatty acid has the following formula: CH3-(CH2)5-CH=CH- CH=CH-(CH2)m-CC>2H; wherein m is 3-13.

[0009] In some embodiments, the omega-7 fatty acid is 5 -dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca- 9,11-dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid.

[0010] In some embodiments, the omega-7 fatty acid is palmitoleic acid.

[0011] In some embodiments, the omega-7 fatty acid is vaccenic acid.

[0012] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0013] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0014] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0015] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0016] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0017] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0018] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0019] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0020] Also disclosed herein is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one omega-7 fatty acid berberine salt.

[0021] In some embodiments, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH-(CH2)n-CC>2H; wherein n is 3-15.

[0022] In some embodiments, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH-CH=CH-(CH2)m-CO2H; wherein m is 3-13.

[0023] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is 5 -dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11- octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15- docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

[0024] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

[0025] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

[0026] In some embodiments, the at least one omega-7 fatty acid salt is one disclosed herein.

[0027] Also disclosed herein is a nutraceutical composition comprising at least one excipient and at least one omega-7 fatty acid berberine salt.

[0028] In some embodiments, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH-(CH2)n-CC>2H; wherein n is 3-15.

[0029] In some embodiments, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH-CH=CH-(CH2)m-CO2H; wherein m is 3-13.

[0030] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that 5-dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11- octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15- docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

[0031] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

[0032] In some embodiments, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

[0033] In some embodiments, the at least one omega-7 fatty acid salt is one disclosed herein.

[0034] Also disclosed herein is a method for treating a disease or disorder, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0035] In some embodiments, the disease or disorder is a metabolic disorder.

[0036] In some embodiments, the metabolic disorder is diabetes, diabetic complications, dyslipidemia, obesity, metabolic syndromes, pre-diabetes, fatty liver, NAFLD, MASH, and NASH.

[0037] In some embodiments, the disease or disorder is heart disease.

[0038] In some embodiments, the disease or disorder is neurodegenerative diseases.

[0039] In some embodiments, the disease or disorder is chronic inflammation.

[0040] Also disclosed herein is a method for increasing the levels of HDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0041] Also disclosed herein is a method for lowering the levels of LDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0042] Also disclosed herein is a method for maintaining healthy cholesterol and / or blood sugar levels in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0043] Also disclosed herein is a method for maintaining body weight or promoting healthy body weight in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.INCORPORATION BY REFERENCE

[0044] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTIONDefinitions

[0045] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0046] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0047] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0048] ‘ ‘Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0049] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.Berberine Salts

[0050] Described herein are omega-7 fatty acid berberine salt.

[0051] Omega-7 fatty acids, mainly palmitoleic acid (Cl 6: 1 n-7) and vaccenic acid (Cl 8: 1 n-7), belong to the group designated monounsaturated fatty acids (MUFA). Currently, products rich in omega-7 fattyacids are typically obtained from plant sources, such as sea buckthorn (Hippophae rhamnoids) and macadamia nut oil (Macadamia integrifolia), as well as animal sources such as mink oil. Omega-7 fatty acids can turn on the body’s energy control system and manage the body’s metabolism. Specifically, omega-7 can help with the process of burning fat and sugar molecules. These fatty acids can also prevent fats and sugars from storing up in the body.

[0052] In some embodiments, the omega-7 fatty acid berberine salt has improved absorption compared to berberine chloride.

[0053] In some embodiments, the omega-7 fatty acid berberine salt has enhanced lipophilicity which may result in improved membrane permeability.

[0054] In some embodiments, the omega-7 fatty acid berberine salt may be absorbed lymphatically.

[0055] In some embodiments, the omega-7 fatty acid berberine salt may bypass first-pass metabolism in the liver.

[0056] In some embodiments, the omega-7 fatty acid berberine salt forms micelle in the intestine which could result in better dissolution.

[0057] In some embodiments, the omega-7 fatty acid berberine salt may reduce P-gp efflux of berberine.

[0058] In some embodiments, the omega-7 fatty acid berberine salt may have a lower hydration shell and faster diffusion in the small intestine.

[0059] In some embodiments, the omega-7 fatty acid has the following formula: CH3-(CH2)5-CH=CH- (CIDn-CChH; wherein n is 3-15. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15.

[0060] In some embodiments, the omega-7 fatty acid has the following formula: CH3-(CH2)5-CH=CH- CH=CH-(CH2)m-CC>2H; wherein m is 3-13. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13.

[0061] In some embodiments, the omega-7 fatty acid is 5 -dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca- 9,11-dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid. In some embodiments, the omega-7 fatty acid is palmitoleic acid. In some embodiments, the omega-7 fatty acid is vaccenic acid.

[0062] In some embodiments, disclosed herein is a berberine omega-7 fatty acid salt. In some embodiments, the salt is a monohydrate. In some embodiments, the salt is a dihydrate. In some embodiments, the salt is a anhydrous.

[0063] In some embodiments, disclosed herein is a berberine palmitoleic acid salt. In some embodiments, the berberine palmitoleic acid salt is a monohydrate. In some embodiments, the berberinepalmitoleic acid salt is a dihydrate. In some embodiments, the berberine palmitoleic acid salt is anhydrous.

[0064] In some embodiments, a salt described herein has a certain purity. In some embodiments, a berberine salt described herein has a purity of at least 70%. In some embodiments, a berberine salt described herein has a purity of at least 80%. In some embodiments, a berberine salt described herein has a purity of at least 85%. In some embodiments, a berberine salt described herein has a purity of at least 90%. In some embodiments, a berberine salt described herein has a purity of at least 95%. In some embodiments, a berberine salt described herein has a purity of at least 99%. In some embodiments, a berberine salt described herein has a purity of at least 99.9%.%. In some embodiments, the berberine salt is berberine palmitoleic acid salt.

[0065] In some embodiments, disclosed herein is a composition comprising one or more berberine salts. In some embodiments, the composition comprises berberine palmitoleic acid salt. In some embodiments, the composition comprises one more berberine omega-7 fatty acid salt. In some embodiments, the composition comprises two or more berberine salts.

[0066] In some embodiments, a salt described herein contains a water content. In some embodiments, a berberine salt described herein has a water content of at most 10% by weight. In some embodiments, a berberine salt described herein has a water content of at most 5% by weight. In some embodiments, a berberine salt described herein has a water content of at most 3% by weight. In some embodiments, a berberine salt described herein has a water content of at most 1% by weight.

[0067] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0068] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0069] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0070] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0071] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0072] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0073] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:

[0074] In some embodiments, the omega-7 fatty acid berberine salt has the following structure:Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0075] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0076] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1,respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes, such as3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, one or more -CH3 in a compound disclosed herein has been replaced by a -CDs.

[0077] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Solvates

[0078] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0079] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Method of Use

[0080] Disclosed herein is a method for treating a disease or disorder, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0081] In some embodiments, the disease or disorder is a metabolic disorder. In some embodiments, the metabolic disorder is diabetes, diabetic complications, dyslipidemia, obesity, metabolic syndromes, prediabetes, fatty liver, NAFLD, MASH, and NASH.

[0082] In some embodiments, the disease or disorder is heart disease.

[0083] In some embodiments, the disease or disorder is neurodegenerative diseases.

[0084] In some embodiments, the disease or disorder is chronic inflammation.

[0085] Also disclosed herein is a method for increasing the levels of HDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0086] Also disclosed herein is a method for lowering the levels of LDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0087] Also disclosed herein is a method for enhancing the secretion of GLP-1, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0088] Also disclosed herein is a method for activating the GLP-1 receptors, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a pharmaceutical composition disclosed herein.

[0089] Also disclosed herein is a method for maintaining healthy cholesterol and / or blood sugar levels in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0090] Also disclosed herein is a method for maintaining body weight or promoting healthy body weight in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0091] Also disclosed herein is a method for maintaining a healthy gut microbiome in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0092] Also disclosed herein is a method for promoting healthy blood sugar metabolism in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0093] Also disclosed herein is a method for supporting metabolic health in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0094] Also disclosed herein is a method for supporting cardiovascular health in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0095] Also disclosed herein is a method for supporting gastrointestinal health in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0096] Also disclosed herein is a method for supporting and maintaining healthy respiratory tract mucus membranes in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.

[0097] Also disclosed herein is a method for supporting healthy cholesterol levels in a subject, the method comprising administering an omega-7 fatty acid berberine salt disclosed herein or a nutraceutical composition disclosed herein.Dosing

[0098] In certain embodiments, the compositions containing the salt described herein are administered for therapeutic treatments. In certain embodiments, the compositions containing the salt described herein are administered as a dietary supplement. In certain therapeutic applications, the salts or compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by any suitable methods. In some embodiments, the salts or compositions are administered to a healthy individual. In some embodiments, the salts or compositions are administered to an individual that is overweight. In some embodiments, the salts or compositions are administered to an individual that is obese. In some embodiments, a berberine salt described herein is administered to an individual in an amount of 0.001 mg to 5000 mg.

[0099] Salts and compositions described herein can be administered to an individual through oral administration or any other suitable administration method.Pharmaceutical Compositions / Nutraceutical compositions

[0100] Provided herein are pharmaceutical or nutraceutical compositions comprising at least one omega- 7 fatty acid berberine salt disclosed herein. Pharmaceutical or nutraceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.

[0101] Disclosed herein is a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one omega-7 fatty acid berberine salt.

[0102] In some embodiments of the pharmaceutical composition, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH- (C Dn-CCEH; wherein n is 3-15.

[0103] In some embodiments of the pharmaceutical composition, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH- CH=CH-(CH2)m-CC>2H; wherein m is 3-13.

[0104] In some embodiments of the pharmaceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is 5-dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9- hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

[0105] In some embodiments of the pharmaceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

[0106] In some embodiments of the pharmaceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

[0107] In some embodiments of the pharmaceutical composition, the composition comprises at least one omega-7 fatty acid salt disclosed herein.

[0108] Also disclosed herein is a nutraceutical composition comprising at least one excipient and at least one omega-7 fatty acid berberine salt.

[0109] In some embodiments of the nutraceutical composition, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH- (CH2)n-CC>2H; wherein n is 3-15.

[0110] In some embodiments of the nutraceutical composition, the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH- CH=CH-(CH2)m-CC>2H; wherein m is 3-13.

[0111] In some embodiments of the nutraceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that 5-dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9- hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

[0112] In some embodiments of the nutraceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

[0113] In some embodiments of the nutraceutical composition, the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

[0114] In some embodiments of the nutraceutical composition, the composition comprises at least one omega-7 fatty acid salt disclosed herein.EXAMPLESExample 1: Preparation of the Berberine Palmitoleic acid (POA, Omega 7) salt

[0115] The berberine palmitoleic acid salt was prepared from palmitoleic acid (of various purities) and a salt of berberine (where X is an appropriate negative counter ion). Palmitoleic acid (0.538 mmol, 98% purity) was dissolved in ethanol (0.6 mL) and sodium carbonate (0.269 mmol) in water (2.4 mL). The mixture was agitated for 30 mins and then added to a clear solution of berberine chloride (0.269 mmol) in water (1.5 mL). The resulting reaction mixture was agitated at 60 °C for 16 h and then cooled to 25 °C at a rate of 10 degrees per hour and allowed to age for another 16 h. The resulting precipitate was collected by filtration and washed with water (1 mL X 2) and dried under 40 °C (122 mg, 52% yield).'HNMR analysis

[0116] The ’HNMR of the berberine palmitoleic acid (Omega 7) salt and its overlay with the ’HNMR of the starting palmitoleic acid are shown in FIG. 1 and FIG. 2. All the hydrogens were assigned and labeled. A clear chemical shift of the C-5 hydrogens on the palmitoleic acid from the starting free acid (2.25 ppm) to the salt product (2. 14 ppm) was observed. This is the result of the formation of the salt complex.Example 2: Purity and Quantitation

[0117] The quantitation analytical methods were validated using product synthesized from 98% pure palmitoleic acid. The observed values of each component (berberine, palmitoleic acid, and water) matched perfectly with the theoretical values of a dihydrate, with a total purity of 100.54% as shown in table 1.TABLE 1*: When 98% pure palmitoleic acid was used. Dried under vacuum for 8h at 40 °C.

[0118] When 77% pure palmitoleic acid was used, the values of the product were shown in table 2, which also closely matched those of the dihydrate, with a total purity of 92.11%. The remaining 7.89% (100%-92. 11%) are berberine salts formed with the other fatty acids present in the starting palmitoleic acid.TABLE 2**: Palmitoleic acid used was 77% pureExample 3: Pharmacokinetics (PK) studies of the berberine palmitoleic acid (Omega 7) salt

[0119] The pharmacokinetic properties of orally administered berberine palmitoleic acid salt in rats, relatively to berberine chloride and palmitoleic acid alone was investigated to see if there was any improvements in exposure. A dose of 50 mg / kg in rats to mimic a commonly used 500 mg a day dosing in humans was selected. A standard vehicle (0.5% MC) was selected to avoid formulation-specific influences. The AUC and Cmax of berberine chloride were low. The berberine palmitoleic acid salt showed a dramatic 19X and 7X improvement in Cmax and AUC respectively, over those of berberine chloride. It is long believed that berberine’s poor absorption / exposure is a major factor limiting its therapeutic potential. With a 7-fold improvement in AUC, This salt has the potential to greatly enhance the therapeutic usefulness of berberine.TABLE 3* : normalized** Aggregated results from four studies

[0120] Maximum Concentration (Cmax): The peak concentration of a drug in a biological fluid (like plasma) after administration.

[0121] Time to Reach Maximum Concentration (Tmax): The time it takes to achieve the peak drug concentration (Cmax) after administration.Area Under the Concentration-Time Curve (AUC): Represents the overall drug exposure in the body over a specific period and indicates the total amount of drug that reached systemic circulation.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. An omega-7 faty acid berberine salt.

2. The omega-7 faty acid berberine salt of claim 1, wherein the omega-7 faty acid has the following formula: CH3-(CH2)5-CH=CH-(CH2)n-CC>2H; wherein n is 3-15.

3. The omega-7 faty acid berberine salt of claim 1, wherein the omega-7 faty acid has the following formula: CH3-(CH2)5-CH=CH-CH=CH-(CH2)m-CO2H; wherein m is 3-13.

4. The omega-7 faty acid berberine salt of claim 1, wherein the omega-7 fatty acid is 5 -dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11- octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid.

5. The omega-7 faty acid berberine salt of claim 1, wherein the omega-7 fatty acid is palmitoleic acid.

6. The omega-7 faty acid berberine salt of claim 1, wherein the omega-7 faty acid is vaccenic acid.

7. The omega-7 faty acid berberine salt of claim 1 having the following structure:

8. The omega-7 faty acid berberine salt of claim 1 having the following structure:

9. The omega-7 faty acid berberine salt of claim 1 having the following structure:

10. The omega-7 faty acid berberine salt of claim 1 having the following structure:

11. The omega-7 faty acid berberine salt of claim 1 having the following structure:

12. The omega-7 faty acid berberine salt of claim 1 having the following structure:

13. The omega-7 faty acid berberine salt of claim 1 having the following structure:

14. The omega-7 faty acid berberine salt of claim 1 having the following structure:

15. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and at least one omega-7 fatty acid berberine salt.

16. The pharmaceutical composition of claim 15, wherein the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CHs- ClDs- CH=CH-(CH2)n-CC>2H; wherein n is 3-15.

17. The pharmaceutical composition of claim 15, wherein the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CHs- C Ds- CH=CH-CH=CH-(CH2)m-CO2H; wherein m is 3-13.

18. The pharmaceutical composition of claim 15, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is 5-dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9-hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca-9, 11- dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

19. The pharmaceutical composition of claim 15, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

20. The pharmaceutical composition of claim 15, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

21. The pharmaceutical composition of claim 15, comprising at least one omega-7 fatty acid salt selected from a salt of any one of claims 7-14.

22. A nutraceutical composition comprising at least one excipient and at least one omega-7 fatty acid berberine salt.

23. The nutraceutical composition of claim 22, wherein the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH-(CH2)n- CO2H; wherein n is 3-15.

24. The nutraceutical composition of claim 22, wherein the at least one omega-7 fatty acid berberine salt comprises an omega-7 fatty acid having the following formula: CH3-(CH2)5-CH=CH- CH=CH-(CH2)m-CC>2H; wherein m is 3-13.

25. The nutraceutical composition of claim 22, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that 5-dodecenoic acid, 7-tetradecenoic acid, palmitoleic acid (9- hexadecenoic acid), vaccenic acid (11 -octadecenoic acid), rumenic acid (octadeca-9, 11 -dienoic acid), paullinic acid (13-eicosenoic acid), 15-docosenoic acid, or 17-tetracosenoic acid, or any combination thereof.

26. The nutraceutical composition of claim 22, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is palmitoleic acid.

27. The nutraceutical composition of claim 22, wherein the at least one omega-7 fatty acid comprises an omega-7 fatty acid that is vaccenic acid.

28. The nutraceutical composition of claim 22, comprising at least one omega-7 fatty acid salt selected from a salt of any one of claims 7-14.

29. A method for treating a disease or disorder, the method comprising administering an omega-7 fatty acid berberine salt of any one of claims 1-14 or a pharmaceutical composition of any one of claims 15-21.

30. The method of claim 29, wherein the disease or disorder is a metabolic disorder.

31. The method of claim 30, wherein the metabolic disorder is diabetes, diabetic complications, dyslipidemia, obesity, metabolic syndromes, pre-diabetes, fatty liver, NAFLD, MASH, and NASH.

32. The method of claim 29, wherein the disease or disorder is heart disease.

33. The method of claim 29, wherein the disease or disorder is neurodegenerative diseases.

34. The method of claim 29, wherein the disease or disorder is chronic inflammation.

35. A method for increasing the levels of HDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt of any one of claims 1-14 or a pharmaceutical composition of any one of claims 15-21.

36. A method for lowering the levels of LDL cholesterol, the method comprising administering an omega-7 fatty acid berberine salt of any one of claims 1-14 or a pharmaceutical composition of any one of claims 15-21.

37. A method for maintaining healthy cholesterol and / or blood sugar levels in a subject, the method comprising administering an omega-7 fatty acid berberine salt of any one of claims 1-14 or a nutraceutical composition of any one of claims 22-28.

38. A method for maintaining body weight or promoting healthy body weight in a subject, the method comprising administering an omega-7 fatty acid berberine salt of any one of claims 1-14 or a nutraceutical composition of any one of claims 22-28.

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