Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
  • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics

Definitions

• ⁇ -3 polyunsaturated and other fatty acid salts have poor solubility in aqueous solution. This prevents intravenous administration of ⁇ -3 fatty acids to the tissue in which they have much of their therapeutic effect, i.e. the circulatory system. Further, this poor solubility increases the difficulty of combining ⁇ -3 fatty acids with food, drink and nutraceuticals.
• gastrointestinal tract into systemic circulation Another hallmark of such preparations is the rapid rate at which they are absorbed into the systemic circulation resulting in a high concentration of the active agent in the blood.
• water soluble preparations are especially suitable for parenteral administration, for example, intravenous administration.
• ⁇ -3 polyunsaturated fatty acids are susceptible to lipid oxidation. This oxidation leads to formation of undesirable fishy and rancid off-flavors that prevent such products from being palatable.
• Increasing the solubility of ⁇ -3 polyunsaturated fatty acids avoids the need for emulsions when trying to add these fatty acids to food.
• the oil-water interface of emulsions greatly influences oxidation of ⁇ -3 polyunsaturated fatty acids. Its removal would prevent much oxidation.
• solubility of ⁇ -3 polyunsaturated fatty acids in the aqueous phase would allow the ⁇ -3 polyunsaturated fatty acids greater access to aqueous soluble anti-oxidants that would prevent oxidation of the fatty acids.
• solubility fatty acid salts particularly ⁇ - 3 fatty acid salts.
• a method of increasing the concentration of a fatty acid in aqueous solution comprising combining the anion fatty acid with a cation that increases the solubility of the fatty acid in aqueous solution.
• the fatty acid is eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA).
• the cation is metformin, piperazine, meglumine or lysine.
• the maximum concentration of the fatty acid is greater than 15 or ⁇ g/mL in the plasma of the mammalian subject. In other embodiments, the maximum concentration of the fatty acid is greater than 10 ⁇ g/mL and less than 100 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 50 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 40 ⁇ g/mL; greater than 15 ⁇ g/mL and less than 40 ⁇ g/mL; or greater than 15 ⁇ g/mL and less than 35 ⁇ g/mL in the plasma of the mammalian subject.
• the disclosure provides a composition comprising a salt of a fatty acid comprising a fatty acid and a cation, wherein the salt of the fatty acid has a solubility in aqueous solution greater than 50 and less than 1000 mg/mL; greater than 100 and less than 1000 mg/mL; greater than 50 and less than 500 mg/mL or greater than 100 and less than 500 mg/mL.
• the solubility of the fatty acid salt in aqueous solution is 50 to 100 times the solubility of the ethyl ester of the fatty acid.
• the maximum concentration of the fatty acid is greater than 10 ⁇ g/mL or 15 ⁇ g/mL in the plasma of the mammalian subject.
• the maximum concentration of the fatty acid is greater 10 ⁇ g/mL and less than 100 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 50 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 40 ⁇ g/mL; greater than 15 ⁇ g/mL and less than 40 ⁇ g/mL; or greater than 15 ⁇ g/mL and less than 35 ⁇ g/mL in the plasma of the mammalian subject.
• the maximum concentration of the fatty acid is at least two times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form. In other embodiments, the maximum
• concentration of the fatty acid is at least 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form.
• the fatty acid is eicosapentaenoic acid (EPA) or
• DHA docosahexaenoic acid
• the cation is metformin, piperazine, meglumine or lysine.
• the maximum concentration of the fatty acid is two times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form.
• the maximum concentration of the fatty acid is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form.
• the area under the curve from time zero to 24 hours of the fatty acid is greater than 90, 100 or 120 ⁇ g*h/mL in the plasma of the mammalian subject. In certain embodiments, the area under the curve from time zero to 24 hours of the fatty acid is greater than 100 or 120 ⁇ g*h/mL in the plasma of the mammalian subject.
• the area under the curve from time zero to 24 hours of the fatty acid is greater than 90 ⁇ g*h/mL and less than 160 ⁇ g*h/mL; greater than 100 ⁇ g*h/mL and less than 150 ⁇ g*h/mL; or greater than 110 ⁇ g*h/mL and less than 150 ⁇ g*h/mL in the plasma of the mammalian subject.
• the fatty acid is eicosapentaenoic acid (EPA) or
• DHA docosahexaenoic acid
• the cation is metformin, piperazine, meglumine or lysine.
• the disclosure also a method of treating atrial fibrillation, comprising intravenously administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising piperazine, meglumine or lysine salts of EPA or DHA.
• the effective amount is between 5-100 mg/kg of the subject's body weight per day.
• the subject is cardiopathic or is affected by coronary ischemia, cardiac insufficiency, cardiac decompensation or diabetic pathology concomitant with cardiopathy.
• the disclosure also provides a method of reducing the probability of an occurrence of a major cardiovascular event in a subject who is affected by atrial fibrillation, comprising intravenously administering to a subject in need thereof an effective amount of a
• the effective amount is between 5-100 mg/kg of the subject's body weight per day.
• the subject is cardiopathic or is affected by coronary ischemia, cardiac insufficiency, cardiac decompensation or diabetic pathology concomitant with cardiopathy.
• the subject who is affected by atrial fibrillation has not undergone a previous infarct episode.
• the disclosure also provides an intravenous dosage form comprising a salt of a fatty acid comprising a fatty acid and a cation, wherein the salt of the fatty acid concentration of greater than 50 and less than 1000 mg/mL; greater than 100 and less than 1000 mg/mL; greater than 50 and less than 500 mg/mL or greater than 100 and less than 500 mg/mL.
• the solubility of the fatty acid salt is 50 to 100 times the solubility of the ethyl ester of the fatty acid.
• the maximum concentration of the fatty acid is greater than 10 ⁇ g/mL in the plasma of the mammalian subject.
• the maximum concentration of the fatty acid is greater than 15 or ⁇ g/mL in the plasma of the mammalian subject. In other embodiments, the maximum concentration of the fatty acid is greater than 10 ⁇ g/mL and less than 100 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 50 ⁇ g/mL; greater than 10 ⁇ g/mL and less than 40 ⁇ g/mL; greater than 15 ⁇ g/mL and less than 40 ⁇ g/mL; or greater than 15 ⁇ g/mL and less than 35 ⁇ g/mL in the plasma of the mammalian subject.
• the fatty acid is eicosapentaenoic acid (EPA) or
• DHA docosahexaenoic acid
• the cation is metformin, piperazine, meglumine or lysine.
• the maximum concentration of the fatty acid is two times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form.
• the maximum concentration of the fatty acid is at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times greater in the plasma of a mammalian subject than when the same amount of fatty acid is administered to the mammalian subject in the ethyl ester form.
• the disclosure also provides an intravenous dosage form comprising a salt of a fatty acid comprising a fatty acid and a cation, wherein when 52 mg/kg of the salt of the fatty acid is administered to a mammalian subject the area under the curve from time zero to 24 hours of the fatty acid is greater than 90 ⁇ g*h/mL in the plasma of the mammalian subject. In certain embodiments, the area under the curve from time zero to 24 hours of the fatty acid is greater than 100 or 120 ⁇ g*h/mL in the plasma of the mammalian subject.
• the area under the curve from time zero to 24 hours of the fatty acid is greater than 90 ⁇ g*h/mL and less than 160 ⁇ g*h/mL; greater than 100 ⁇ g*h/mL and less than 150 ⁇ g*h/mL; or greater than 110 ⁇ g*h/mL and less than 150 ⁇ g*h/mL in the plasma of the mammalian subject.
• the fatty acid is eicosapentaenoic acid (EPA) or
• DHA docosahexaenoic acid
• the cation is metformin, piperazine, meglumine or lysine.
• the disclosure also provides a nutraceutical, food product or drink product comprising a salt of a fatty acid wherein the fatty acid is eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA).
• the cation of the salt is metformin, piperazine, meglumine or lysine.
• the disclosure also provides a method of making a fatty acid supplemented nutraceutical, food product or drink product comprising mixing an aqueous solution of a fatty acid comprising a fatty acid and a cation wherein the fatty acid is eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA).
• EPA eicosapentaenoic acid
• DHA docosahexaenoic acid
• the cation is metformin, piperazine, meglumine or lysine.
• the cation is metformin, piperazine, meglumine or lysine.
• the fatty acid the concentration of the fatty acid in the aqueous solution is between greater than 50 and less than 1000 mg/mL; greater than 100 and less than 1000 mg/mL; greater than 50 and less than 500 mg/mL or greater than 100 and less than 500 mg/mL.
• the solubility of the fatty acid salt is 50 to 100 times the solubility of the ethyl ester of the fatty acid.
• the fatty acid piperazine salt of EPA or DHA can comprise a compound of the structural Formula I, II, III, IV, V, VI, VII or VIII:
• X " is an anion of a pharmaceutically acceptable acid compound, or a mixture
• Figure 1 is a line graph showing mean plasma metformin concentrations ⁇ g/mL) rats administered a single oral dose of metformin EPA or metformin HCl plotted against time. 3 male and 3 female rats were used for each time point.
• Figure 2 is a line graph showing mean plasma metformin concentrations ⁇ g/mL) in male and female rats administered a single oral dose of metformin EPA, metformin HC1, EPA FFA or EPA ethyl ester plotted against time.
• Figure 3 is a line graph showing the same data as Figure 3 where the plasma metformin levels are shown in log 10 scale.
• Figure 4 is a line graph showing mean plasma EPA concentrations ⁇ g/mL) in rats administered a single oral dose of metformin EPA, EPA FFA or EPA ethyl ester plotted against time. 3 male and 3 female rats were used for each time point.
• Figure 5 is a line graph showing mean plasma metformin concentrations ⁇ g/mL) in male and female rats administered a single oral dose of metformin EPA, metformin HC1, EPA FFA or EPA ethyl ester plotted against time.
• Figure 6 is a line graph showing the same data as Figure 5 where the plasma EPA levels are shown in log 10 scale.
• the disclosure provides salts of fatty acids with high solubility and bioavailability.
• High solubility of the fatty acids allows for them to be better absorbed when administered orally to subjects and allows for intravenous administration of these fatty acids at higher dosages. Further, the high solubility and bioavailability of these fatty acid salts allows them to be easily used as additives to food and nutraceuticals.
• the fatty acids are ⁇ -3 polyunsaturated fatty acids
• ⁇ -3 polyunsaturated fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
• Cations that are used to form fatty acid salts include metformin, piperazine, meglumine and lysine. Examples of fatty acid salts made with these cations are provided below.
• Metformin eicosapentaenoate is represented below:
• Metformin docosahexaenoate is represented below:
• piperazine salts of EPA and DHA as well as meglumine salts of EPA and DHA.
• a compound of Formula I is provided herein:
• the compound of Formula I and II are, respectively, the mono-salt of EPA with piperazine and the mono-salt of DHA with piperazine.
• X " is a pharmaceutically acceptable counter anion.
• the pharmaceutically acceptable counter anion can derived from acid compounds listed in Table 1, pp 406 - 407, Handbook of Pharmaceutical Salts, P. Heinrich Stahl Camille G. Wermuth (Eds.), incorporated by reference herein.
• the pharmaceutically acceptable counter anion is selected from mineral acids, such as hydrochloric acid, hydrobromic acid, and phosphoric acid.
• the pharmaceutically acceptable counter anion is selected from carboxylic acids, poly-carboxylic acids, and poly-hydroxy carboxylic acids, such as acetic acid, propionic acid, succinic acid, maleic acid, malic acid, tartaric acid, lactic acid, citric acid, and benzoic acid.
• the pharmaceutically acceptable counter anion is selected from sulfonic acids and hydroxyl-sulfonic acids, including, but not limited to, methanesulfonic acid, isethionic acid, ethanesulfonic acid, 2 -hydro xy- ethanesulfonic acid, and benzenesulfonic acid.
• the pharmaceutically acceptable counter anion is selected from amino acids, including, but not limited to, glycine, alanine, lysine, arginine, aspartic acid, or glutamic acid.
• X " is an omega-3 polyunsaturated acid, such as eicosapentaenoic acid or docosahexaenoic acid.
• hydrochloride salt of Formula V the hydrobromide salt of Formula V
• the phosphate salt of Formula V the phosphate salt of Formula V
• the sulfate salt of Formula V the hydrochloride salt of Formula V
• hydrochloride salt of Formula VI the hydrobromide salt of Formula VI, the phosphate salt of Formula VI, and the sulfate salt of Formula VI.
• the present invention also relates to compounds of the Formula V and Formula VI wherein X " is a pharmaceutically acceptable counter anion derived from naturally occurring amino acids.
• X " is a pharmaceutically acceptable counter anion derived from naturally occurring amino acids.
• the amino acids include, but are not limited to, glycine, alanine, lysine, and glutamic acid.
• the compounds of Formula I, II, III, IV, V, VI, VII, or VIII also include isomers and enantiomers wherever it is applicable.
• solvates e.g., hydrates of the compounds of Formula I, II,
• solvate refers to any form of the compounds of the invention that are bound by a non-covalent bond to another molecule (such as a polar solvent). Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. When the solvent is water, the solvate formed is a hydrate.
• Example hydrates include hemihydrates, mono hydrates, dihydrates, etc.
• the compounds of Formula I, II, III, IV, V, VI, VII, or VIII are crystalline, which is useful not only for drug delivery purposes, but is also useful in the preparation of pharmaceutical formulations, and will improve general handling,
• the crystalline form of the compound of Formula I, II, III, IV, V, VI, VII, or VIII is in a particular polymorph form.
• polymorphism The ability of a substance to exist in more than one crystal form is defined as polymorphism; the different crystal forms of a particular substance are referred to as "polymorphs.”
• polymorphism is affected by the ability of a molecule of a substance to change its conformation or to form different intermolecular or intra-molecular interactions, particularly hydrogen bonds, which is reflected in different atom arrangements in the crystal lattices of different polymorphs.
• morphology which refers to the external shape of the crystal and the planes present, without reference to the internal structure. Crystals can display different morphology based on different conditions, such as, for example, growth rate, stirring, and the presence of impurities.
• PUFAs and esters of PUFAs are practically insoluble in water. In fact, they form soap-like emulsions when mixed with water. Therefore, the potential to derive optimum therapeutic benefits of PUFAs should be markedly facilitated by delivery of water soluble PUFAs.
• the compounds of the present invention are markedly more water soluble to achieve high oral absorption and to enable the preparation of intravenous dosage forms.
• Fatty acid salts according to the disclosure are able to be diluted in aqueous solution at high concentrations.
• the fatty acid salts described herein have a solubility in aqueous solution greater than 50 and less than 1000 mg/mL; greater than 100 and less than 1000 mg/mL; greater than 50 and less than 500 mg/mL; greater than 100 and less than 500 mg/mL in solution.
• fatty acid salts described herein have a solubility in aqueous solution of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg/mL.
• the fatty acid salts have solubility in aqueous solution that is 50-100 times greater than the solubility of the ethyl ester of the fatty acid.
• the solubility of fatty acid salts is 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 times greater than the solubility of the ethyl ester of the fatty acid.
• the fatty acid salts described herein have high bioavailability when administered to human subjects.
• the maximum plasma concentration (Cmax), dose normalized maximum plasma concentration (Cmax/dose), area under the curve from time zero to 24 hours (AUC(0-24)), dose normalized area under the curve (AUC/dose), or average plasma concentration are higher for a given dose of fatty acid salt described herein, than for fatty acid salts described in the prior art.
• metformin EPA when metformin EPA is administered to a mammalian subject at 52 mg/kg it produces a Cmax of between 10 ⁇ g/mL and 50 ⁇ g/mL of EPA.
• metformin EPA when metformin EPA is administered to a mammalian subject at 52 mg/kg it produces a Cmax of between 10 ⁇ g/mL and 40 ⁇ g/mL; 10 ⁇ g/mL and 30 ⁇ g/mL; 10 ⁇ g/mL and 20 ⁇ g/mL ⁇ ⁇ , 10 ⁇ g/mL and 15 ⁇ g/mL; 15 ⁇ g/mL and 50 ⁇ g/mL; 15 ⁇ g/mL and 40 ⁇ g/mL ⁇ ⁇ , 15 ⁇ / ⁇ and 30 ⁇ g/mL; 15 ⁇ / ⁇ and 20 ⁇ g/ L ⁇ , 20 ⁇ / ⁇ and 50 ⁇ g/mL ⁇ , 20 ⁇ / ⁇ and 40 ⁇ g/ L
• the Cmax is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 ⁇ g/mL of EPA in plasma of the mammalian subject.
• the Cmax of EPA is 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• the Cmax is between 2 and 10, 3 and 8 or 4 and 6 times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• the Cmax is about 5 times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• metformin EPA when metformin EPA is administered to a mammalian subject at 104 mg/kg it produces a Cmax of between 10 ⁇ g/mL and 50 ⁇ g/mL of EPA in plasma of the mammalian subject. In other embodiments, when metformin EPA is administered to a mammalian subject at 104 mg/kg it produces a Cmax of between 10 ⁇ g/mL and 40 ⁇ g/mL; 10 ⁇ g/mL and 30 ⁇ g/mL; 10 ⁇ g/mL and 20 ⁇ g/mL; 10 ⁇ g/mL and 15 ⁇ g/mL; 15 ⁇ g/mL and 50 ⁇ g/mL; 15 ⁇ g/mL and 40 ⁇ g/mL; 15 ⁇ g/mL and 30 ⁇ g/mL; 15 ⁇ g/mL and 20 ⁇ g/mL; 20 ⁇ g/mL and 50 ⁇ g/mL; 20 ⁇ g/mL and 40 ⁇ g
• the Cmax is at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 ⁇ g/mL of EPA in plasma of the mammalian subject.
• the Cmax of EPA is 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• the Cmax is between 2 and 10, 3 and 8 or 4 and 6 times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• the Cmax is about 5 times the Cmax of EPA from the same dose of the ethyl ester of the fatty acid.
• metformin EPA when metformin EPA is administered to a mammalian subject at 52 mg/kg it produces a AUC(0-24) of between 90 ⁇ g*h/mL and 200 ⁇ g*h/mL of EPA in plasma of the mammalian subject.
• metformin EPA when metformin EPA is administered to a mammalian subject at 52 mg/kg it produces a AUC(0-24) of between 90 ⁇ g*h/mL and 180 ⁇ g*h/mL; 90 ⁇ g*h/mL and 160 ⁇ g*h/mL; 90 ⁇ g*h/mL and 140 ⁇ g*h/mL; 90 ⁇ g*h mL and 120 ⁇ g*h mL; 90 ⁇ g*h mL and 100 ⁇ g*h mL; 110 ⁇ g*h mL and 200 ⁇ g*h/mL; 110 ⁇ g*h/mL and 180 ⁇ g*h/mL; 110 ⁇ g*h/mL and 160 ⁇ g*h/mL; 110 ⁇ g*h/mL and 140 ⁇ g*h mL; 110 ⁇ g*h/mL and 120 ⁇ g*h/mL; 130 ⁇ g*h mL and 200 ⁇ g*h
• the AUC(0-24) is at least 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 ⁇ *1 ⁇ / ⁇ of EPA in plasma of the mammalian subject.
• the AUC(0-24) of EPA is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid.
• the AUC(0-24) is between 1.5 and 8, 2 and 6 or 3 and 4 times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid. In other embodiments, the AUC(0-24) is about 2 times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid.
• metformin EPA when metformin EPA is administered to a mammalian subject at 104 mg/kg it produces a AUC(0-24) of between 150 ⁇ g*h/mL and 300 ⁇ g*h/mL of EPA in plasma of the mammalian subject.
• metformin EPA when metformin EPA is administered to a mammalian subject at 104 mg/kg it produces a AUC(0-24) of between 150 ⁇ g*h/mL and 300 ⁇ g*h/mL; 150 ⁇ g*h/mL and 280 ⁇ g*h/mL; 150 ⁇ g*h/mL and 260 ⁇ g*h/mL; 150 ⁇ g*h/mL and 240 ⁇ g*h/mL; 150 ⁇ g*h/mL and 220 ⁇ g*h/mL; 150 ⁇ g*h/mL and 200 ⁇ g*h mL; 150 ⁇ g*h/mL and 180 ⁇ g*h/mL; 150 ⁇ g*h mL and 160 ⁇ g*h/mL; 170 ⁇ g*h mL and 300 ⁇ g*h/mL; 170 ⁇ g*h mL and 280 ⁇ g*h/mL; 170 ⁇ g*h/
• the AUC(0-24) is at least 150, 100, 110, 120, 130, 140, 150, 160, 170, 180, 1150, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290 or 300 ⁇ g*h/mL of EPA in plasma of the mammalian subject.
• the AUC(0-24) of EPA is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid.
• the AUC(0- 24) is between 1.5 and 8, 2 and 6 or 3 and 4 times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid. In other embodiments, the AUC(0-24) is about 2 times the AUC(0-24) of EPA from the same dose of the ethyl ester of the fatty acid.
• the bioavailability of the above dosages are the result of oral administration. In other embodiments, the bioavailability of the above dosages are the result of intravenous administration.
• This disclosure provides methods for the use of polyunsaturated fatty acids of the ⁇ -3 series for the preparation of a drug useful in the primary prevention of a major cardiovascular event in subjects who have not undergone previous infarct episodes, wherein the fatty acids comprise eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) and/or at least one pharmaceutically acceptable derivative thereof, in quantities greater than or equal to 25 wt % on the total fatty acid weight.
• the polyunsaturated fatty acids of the ⁇ -3 series are administered intravenously.
• the disclosure also provides intravenous dosage forms of fatty acid salts as well as methods of using these intravenous dosage forms for the treatment of disease in mammalian subjects.
• the dosage forms can include ⁇ -3 polyunsaturated fatty acids, ⁇ -3 polyunsaturated fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
• Cations that are used to form fatty acid salts include metformin, piperazine, meglumine and lysine. Examples of fatty acid salts made with these cations are provided above.
• intravenous dosage forms can contain fatty acids at a concentration greater than 50 and less than 1000 mg/mL; greater than 100 and less than 1000 mg/mL; greater than 50 and less than 500 mg/mL; greater than 100 and less than 500 mg/mL in solution.
• the intravenous dosage forms can contain concentrations of fatty acids of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg/mL.
• the fatty acid salts have solubility in aqueous solution that is 50-100 times greater than the solubility of the ethyl ester of the fatty acid.
• the solubility of fatty acid salts is 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 times greater than the solubility of the ethyl ester of the fatty acid.
• the fatty acids are ⁇ -3 polyunsaturated fatty acids.
• the fatty acids are EPA or DHA. The total daily dosages of EPA and DHA can range from 5 to 1000 mg/kg.
• the total daily dosage can range between 5, 10, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 950 mg/kg and 10, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 and 1000 mg/kg.
• These intravenous dosage forms can be administered 1-10 times daily.
• these intravenous dosage forms are used for the treatment, prevention or alleviation of symptoms associated with atrial fibrillation.
• polyunsaturated fatty acids of the ⁇ -3 series means those long-chain polyunsaturated fatty acids, generally C16-C24, containing fish oils, in particular those having a C20-C22 chain, which are predominant in purification processes.
• examples of these polyunsaturated fatty acids of the ⁇ -3 series include EPA and DHA.
• mammalian subject refers to rodents, livestock, primates or pets. Rodents include rats, mice or rabbits. Livestock include sheep, goats, llamas, camels, cattle, or buffalo. Primates include monkeys, apes or humans. Pets include dogs or cats.
• major cardiovascular event refers to particular those events which involve reversible or irreversible cardiovascular damage, such as infarct of the myocardium and of individual coronary branches, death from cardiac causes, sudden death, etc., besides to infarct, broadly speaking, ictus etc., and those conditions prodromal to such major events, such as myocardial fibrillation, atrial and/or ventricular fibrillation, etc. Said major cardiovascular events are usually induced by various cardio circulatory and
• cardiorespiratory pathologies such as coronary ischemic illness not displayed by previous infarct episodes, and by serious hypoxic/anoxic states caused by a sudden lack of oxygen (for example during anesthesia, surgery, etc.), possibly in the presence of conditions which contemplate an increase in the oxygen requirement, (accentuated physical stress, drug abuse, acute hypertensive crises, etc.) and analogous acute and chronic pathologies due to cardiac defects of electrical and/or mechanical type.
• Atrial fibrillation is a form of cardiac arrhythmia. Symptoms associated with atrial fibrillation include rapid heart rate, irregular heart rate, palpitations, exercise intolerance, angina, shortness of breath, edema, stroke, transient ischemic attack, fainting and congestive heart failure. Atrial fibrillation can be associated with central sleep apnea, left atrial enlargement, mitral stenosis, hypertension, coronary artery disease, mitral regurgitation, hypertrophic cardiomyopathy, pericarditis, congenital heart disease, previous heart surgery, lung diseases, excessive alcohol consumption, hyperthyroidism, carbon monoxide poisoning, Friedrich's ataxia or rheumatoid arthritis.
• the subjects affected by pathologies of the cardiocirculatory and cardiorespiratory system are representative of subjects definable at various levels as cardiopaths, by being affected, for example, by coronary ischemia detectable by coronarography, scintigraphy of the myocardium, electrocardiogram (ECG) under stress, etc., against which interventions of revascularization (angioplasty) or other possible pharmacological or invasive treatments have been proposed, and of subjects affected by electrical hyperexcitability of the myocardium cells, disorder of the diffusion of electrical excitement or of electrical conduction
• polyunsaturated fatty acids of the ⁇ -3 series is particularly indicated if the occurrence of a major event is predicted, such as an infarct, in particular of the myocardium, death from a cardiological cause, or sudden death, and where such an occurrence takes place in cardiopathic subjects affected, for example, by coronary ischemia, arrhythmia, atrial and/or ventricular fibrillation, electrical hyperexcitability of the myocardium cells, disorder of the diffusion of electrical excitement or of electrical conduction of the myocardium, or cardiac disorders of mechanical type, for example cardiac insufficiency or cardiac decompensation, possibly affected by diabetic pathology concomitant with the cardiopathy.
• a major event such as an infarct, in particular of the myocardium, death from a cardiological cause, or sudden death, and where such an occurrence takes place in cardiopathic subjects affected, for example, by coronary ischemia, arrhythmia, atrial and/or ventricular fibrillation, electrical hyperexcitability of
• the content of EPA and/or DHA and/or of the at least one derivative thereof is between 50% and 100%, in particular between 75% and 95%, and more preferably about 85% by weight on the total fatty acid weight.
• the preferred EPA and/or DHA derivatives are selected from the corresponding C1 -C3 alkyl esters and/or from their salts with metformin, piperazine, meglumine and lysine.
• the invention relates to a method for the primary prevention of a major cardiovascular event in subjects who have not undergone previous infarct episodes, comprising the administration of an effective dose of a drug comprising polyunsaturated fatty acids of the ⁇ -3 series as hereinbefore described.
• the method of the invention is indicated whenever the occurrence of a major cardiac event is predicted such as an infarct, in particular of the myocardium, death from a cardiological cause or sudden death.
• compositions including food, drink, and nutraceutical products that are supplemented with ⁇ -3 polyunsaturated fatty acid salt forms described herein.
• These fatty acids can be supplied in aqueous solution through formation of the fatty acid salts described herein.
• These fatty acids can also be used to supplement food, drink, and nutraceutical products in solid form.
• the formation of these fatty acid salts allows for higher concentrations of fatty acids to be formed in aqueous solution. Forming higher concentration aqueous solutions of ⁇ -3 polyunsaturated fatty acids can be used to decrease their oxidation. When not in aqueous solution, ⁇ -3 polyunsaturated fatty acids are often supplied as emulsions.
• Emulsions allow for enhanced oxidation of ⁇ -3 polyunsaturated fatty acids along the oil-water interface. Further, emulsions can prevent antioxidants that are soluble in aqueous solution from preventing oxidation of ⁇ -3 polyunsaturated fatty acids in the organic phase. Oxidation of ⁇ -3 polyunsaturated fatty acids can make supplemented food, drink, and nutraceutical unpalatable.
• the disclosure provides food, drink and nutraceuticals supplemented with aqueous solutions of fatty acid salts, described above.
• the fatty acid salts described herein can be incorporated into food or drink.
• foods/drinks there is no specific limitation on the foods/drinks to which the fatty acid salts described herein can be incorporated.
• foods/drinks include processed foods based on meat, poultry meat, fish/shellfish and the like; soup; seasonings including sweetener and the like; rice seasonings; instant foods; frozen foods; snacks; various types of functional foods such as supplements, nutritional drinks and the like; canned foods; dairy products; confectionery such as chewing gum, candy, gummy candy, chocolate, baked sweets and the like; ice cream; soft drinks such as tea, coffee, cocoa, fruit juice, sports drink, carbonated drink, vegetable drink and the like; liquors; soya milk; lactic acid bacteria beverages; and chlorophyll juice.
• the amount of the fatty acid salts described herein added to the food or drink varies in accordance with the type of food or drink and the amount that one wishes to supplement a diet with one or more fatty acids, particularly ⁇ -3 fatty acids, and the method of applying the composition described herein, the method of use and the like.
• the composition described herein is generally used in an amount of about 0.000001 to 20% by weight, and more preferably in an amount of about 0.00001 to 10% by weight, with respect to the food/drink.
• the fatty acid salts described herein can be incorporated into nutraceutical products to be used as a fatty acid supplement, particularly ⁇ -3 fatty acids.
• nutraceutical products into which the fatty acid salts can be incorporated.
• the nutraceutical products include liquid, granular, and powdery substances.
• the amount of the fatty acid salt described herein varies in accordance with the amount of fatty acid that is desired in the nutraceutical, the type of nutraceutical product and the method of applying nutraceutical.
• the fatty acid salt described herein is generally used in an amount of about 0.000001 to 20% by weight, and more preferably in an amount of about 0.00001 to 10% by weight, with respect to the pharmaceutical product.
• Nutraceuticals further include mouse washes, various types of dentifrices, chewing gum, candy, tablets, capsules, mouth sprays, and films.
• AUC(0-24) Area under the curve from time zero to 24 hours
• Example 1 Determination of plasma pharmacokinetic data of test substances in male and female rats following a single dose oral administration.
• Serial blood samples (approximately 0.3 mL) were obtained via a jugular vein catheter from the animals in each group at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose. Derived plasma samples were stored frozen at approximately -70°C until shipment to BASi, Inc. Results
• TP- 101 is an ionic salt that dissociates into EPA free fatty acid and metformin.
• Plasma EPA levels in rats administered a 52 mg/kg oral dose of TP-101 (Group 1) were markedly higher than EPA levels following either a 40 mg/kg oral dose of EPA FFA (Group 4) or a 40 mg/kg oral dose of EPA ethyl ester (Group 5).
• Mean Cmax values were 23.6 ⁇ 14.10, 13.6 ⁇ 9.16 and 4.65 ⁇ 1.320 ⁇ g/mL for Groups 1, 4 and 5, respectively.
• Mean AUC (0-24) values were 133 ⁇ 39.1 , 89.9 ⁇ 24.00 and 47.8 ⁇ 12.00 ⁇ g*h mL, respectively.
• Plasma metformin levels for the 52 mg/kg dose of TP-101 were similar to the levels following the 20 mg/kg oral dose of metformin HCl.
• the 104 mg/kg dose of TP-101 resulted in mean AUC(0-24) metformin levels approximately two-fold higher than the 52 mg/kg dose.
• Lot/Batch No. Lot 30 Jan 2012; expiration date: 12 Feb 2012 and Lot 1
• TP-101 - 5.2 mg/mL On 31 Jan 2012, 130.00 mg of TP-101 was transferred into a glass beaker, 21 mL of deionized water was added and the preparation was stirred/mixed for 32 minutes. The pH of the preparation was measured at 10.1 and then adjusted to 8.2 by the addition of 0.1 mL of 0.1N HC1. The preparation was brought to a final volume of 25 mL with the addition of 3.9 mL of deionized water. The final formulation appeared as a homogeneous, cloudy, off- white liquid and was transferred to a prelabeled amber glass bottle and stored at room temperature.
• TP-101 - 10.4 mg/mL On 31 Jan 2012, 260.01 mg of TP-101 was transferred into a glass beaker, 21 mL of deionized water was added and the preparation was stirred/mixed for 26 minutes. The pH of the preparation was measured at 9.9 and then adjusted to 8.3 by the addition of 0.2 mL of 0.1N HC1. The preparation was brought to a final volume of 25 mL with the addition of 3.8 mL of deionized water. The final formulation appeared as a homogeneous, cloudy, off- white liquid and was transferred to a prelabeled amber glass bottle and stored at room temperature.
• Group 3 Metformin HC1 - 2 mg/mL: On 1 Feb 2012, 50.08 mg of Metformin HC1 was transferred into a glass beaker, 21 mL of deionized water was added and the preparation was stirred/mixed for 25 minutes. The pH of the preparation was measured at -5.5. The preparation was brought to a final volume of 25 mL with the addition of 4 mL of deionized water. The final formulation appeared as a clear, colorless liquid and was transferred to a prelabeled amber glass bottle and stored at room temperature.
• EPA FFA - 4 mg/mL On 1 Feb 2012, 100.80 mg of EPA FFA was transferred into a glass beaker, 21 mL of deionized water was added and the preparation was stirred/mixed for 15 minutes. The pH of the preparation was measured at -4.5. The preparation was brought to a final volume of 25 mL with the addition of 4 mL of deionized water. The final formulation appeared as a homogeneous, cloudy liquid and was transferred to a prelabeled amber glass bottle and stored at room temperature.
• Gender 15 males and 15 females
• Age Range Males: 9 to 10 weeks; Females: 13 to 14 weeks. Records of dates of birth for animals used in this study will be retained in the Calvert archives.
• Body Weight Range 241 to 300 g at time of dosing
• the rat is a standard rodent species used in preclinical pharmacokinetic studies of new chemical entities and different test article formulations. 1 Thirty animals were considered to be the minimum number necessary to properly perform this parallel oral pharmacokinetic discovery-type study involving five distinct test article formulations. Three animals per sex per group permitted the generation of descriptive statistical analysis.
• Water was available ad libitum to each animal. The water is routinely analyzed for contaminants as per Calvert SOPs. No contaminants were known to be present in the water at levels that would be expected to interfere with the results of this study. Results of the water analysis are maintained in the Calvert archives.
• Animals were manually assigned to the study and study groups based on body weight and catheter patency. Animals were assigned a permanent identification number and then ear tagged.
• the oral route was selected by the Sponsor as this is the potential route of administration in humans.
• the dose levels were selected by the Sponsor based on previously published metformin and EPA toxicity data.
• Body weight was determined on the day of test article administration just prior to dosing.
• the actual dose administered to the animal was the difference between the loaded and unloaded dosing syringe weights.
• Serial blood samples were obtained from each animal by a jugular vein catheter and then transferred into pre-labeled tubes containing K 2 EDTA anticoagulant. Just before each blood sampling timepoint, blood was withdrawn from the jugular vein catheter (a volume slightly larger than the catheter tubing void volume) and discarded. A blood sample (approximately 0.3 mL) was then obtained from the catheter using a syringe with blunted needle and the sample was immediately transferred into a blood collection tube containing anticoagulant. Following each 0.3 mL blood sample collection, the catheter was flushed with an anticoagulant solution in sterile saline (a volume slightly larger than the catheter tubing void volume).
• Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose. Collected blood samples were gently inverted several times and stored on chill packs protected from light until centrifugation.
• Plasma samples were centrifuged at -1500 g for 15 minutes at +4 °C within 30 minutes of collection. Derived plasma was split into two aliquots; one aliquot contained 50 ⁇ ⁇ and the other contained the remainder of the plasma sample.
• Plasma aliquots tubes were labeled with the Calvert study number, treatment group number, species, animal number, dose level/route, date of collection, time of collection, and sample type. Samples were placed immediately on dry ice until stored frozen at approximately -70 °C.
• TP-101 52 or 104 mg/kg
• metformin HCl 20 mg/kg
• EPA FFA 40 mg/kg
• EPA ethyl ester 40 mg/kg
• TP-101 is an ionic salt that dissociates into EPA free fatty acid and metformin. Animals appeared normal at all blood sampling timepoints through 24 hours post-dose following each administration. All blood samples were collected at their targeted times and derived plasma samples were stored frozen until shipment to BASi, Inc. for analysis.
• Plasma metformin concentrations plotted as a function of time are presented in Figures 1-3.
• Plasma metformin concentration-time profiles following a single 52 mg/kg oral dose of TP-101 to rats in Group 1 (52 mg/kg is an equivalent dose of 20 mg/kg metformin HC1), a 104 mg/kg dose of TP-101 to rats in Group 2, or a 20 mg/kg oral dose of metformin HC1 to rats in Group 3 demonstrated a bi-phasic decline through 24 hours post-dose following a Tmax at -0.5 to 0.7 hours.
• the mean terminal phase half-life (Tl/2) calculated using the 4 hour, 8 hour and 24 hour timepoints was slightly longer for the TP-101 dose groups (-5.1 to 6.3 hours) versus the metformin HC1 dose group (-3.4 hours).
• Group 1 and Group 3 mean Cmax (Group 1 - 1.87 + 0.511 ⁇ g/mL; Group 3 - 2.32 + 0.333 ⁇ g/mL) and AUC(0-24) values (Group 1 - 5.01 + 0.397 ⁇ g*hr/mL; Group 3 - 5.18 + 0.484 ⁇ g*h/mL) were similar.
• Plasma metformin concentrations following a 104 mg/kg oral dose of TP-101 (Group 2) were approximately two-fold higher than were observed for Groups 1 and 3 with mean Cmax and AUC (0-24) values of 4.26 + 1.200 ⁇ g/mL and 11.6 + 2.34 ⁇ g*h/mL, respectively.
• Plasma EPA levels in the rats administered a 52 mg/kg oral dose of TP-101 were higher than concurrent levels following either a 40 mg/kg oral dose of EPA FFA or a 40 mg/kg oral dose of EPA ethyl ester.
• Mean Cmax values were 23.6 + 14.10, 13.6 + 9.16 and 4.65 + 1.320 ⁇ g/mL for Groups 1, 4 and 5, respectively.
• Mean AUC(0-24) values were 133 + 39.1, 89.9 + 24.00 and 47.8 + 12.00 ⁇ g*h/mL, respectively.
• Mean AUC(0-24) values following a 104 mg/kg oral dose of TP-101 (Group 2) were -60% higher than the 52 mg/kg dose.
• TP-101 52 mg/kg and 104 mg/kg oral doses of TP-101 were well tolerated by Sprague Dawley rats.
• Exposure to EPA was greater after an oral dose of TP-101 than after an equivalent oral dose of EPA, FFA or EPA ethyl ester.
• Plasma EPA levels following a 52 mg/kg oral dose of TP-101 were markedly higher than EPA levels following 40 mg/kg oral doses of EPA FFA or EPA ethyl ester.
• Plasma EPA AUC(0-24) following a 104 mg/kg oral dose of TP-101 was approximately 60% higher than measured for the 52 mg/kg dose.
• Plasma metformin AUC(0-24) values following a 52 mg/kg oral dose of TP-101 and a 20 mg/kg oral dose of metformin HC1 were similar and increased proportionately following a 104 mg/kg oral dose of TP-101.

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