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JP-2026514545-A - Menaquinone-9 nanoparticles and treatment method

JP2026514545AJP 2026514545 AJP2026514545 AJP 2026514545AJP-2026514545-A

Abstract

This application discloses a composition comprising nanoparticles of vitamin K2 and a method of using the same. In one embodiment, a composition is provided comprising nanoparticles (or nano-sized particles) of water-soluble vitamin K2, wherein the nanoparticles have an average particle size of about 0.1 nm to 1,000 nm. In one embodiment, the vitamin K2 is MK-9 (menaquinone-9) and/or MKH2-9 (menaquinol-9). In another embodiment, the nanoparticles have an average particle size of 200 nm, 175 nm, 150 nm, 125 nm, 115 nm, 100 nm, 90 nm, less than 80 nm, or less than 75 nm. In another embodiment, the composition is a stable composition.

Inventors

  • ルディ， ジョン エム．

Assignees

  • エピゾン， インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20240322

Claims (20)

  1. A composition comprising water-soluble vitamin K2 nanoparticles, wherein the nanoparticles have an average particle size of approximately 0.1 nm to 1,000 nm.
  2. The composition according to claim 1, wherein the vitamin K2 is MK-9 (menaquinone-9) or menaquinol-9 (MKH2-9).
  3. The composition according to claim 2, wherein the vitamin K2 is MK-9.
  4. The composition according to any one of claims 1 to 3, wherein the nanoparticles have an average particle size of 200 nm, 175 nm, 150 nm, 125 nm, 115 nm, 100 nm, 90 nm, less than 80 nm, or less than 75 nm.
  5. The composition according to any one of claims 1 to 4, wherein the nanoparticles are prepared using a homogenizer selected from the group consisting of a rotor stator homogenizer, a bead mill homogenizer, or a mortar and pestle homogenizer.
  6. Poloxamer 188, Polysorbate 80, Polysorbate 20, Vit E-TPGS (TPGS), TPGS-1000, TPGS-750-M, Solutol HS15, PEG-40 Hydrogenated Castor Oil, PEG-35 Castor Oil, PEG-8 Caprylic/Capric Glyceryl, PEG-32 Glyceryl Laurate, PEG-32 Glyceryl Palmitostearate, Polysorbate 85, Polyglyceryl-6 Dioleate, Sorbitan Monooleate, Capmul The composition according to any one of claims 1 to 5, further comprising at least one emulsifier selected from the group consisting of MCM, Maisine 35-1, glyceryl monooleate, glyceryl monolinoleate, PEG-6 oleate, PEG-6 linoleate, oleic acid, linoleic acid, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 diisostearate, and lecithin.
  7. The composition according to claim 6, wherein the emulsifier is selected from polysorbate 80, Vit E-TPGS, Solutol HS15, PEG-40 hydrogenated castor oil, and PEG-35 castor oil.
  8. The composition according to any one of claims 1 to 7, further comprising at least one bioavailability activator selected from the group consisting of medium-chain fatty acids, omega-3 fatty acids, capric acid, caprylic acid, alkyl glycosides, chitosan, trimethylated chitosan, ethylene glycol tetraacetic acid, ethylenediamine tetraacetic acid, salicylic acid, genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one) and pharmaceutically acceptable salts thereof.
  9. A composition according to any one of claims 1 to 8, comprising nano-suspended material in water.
  10. The composition according to any one of claims 1 to 9, wherein the nano-suspended material is at least five times more soluble than commercially available, unhomogeneized vitamin K2.
  11. The composition according to claim 10, wherein the vitamin K2 is MK-9.
  12. The composition according to claim 10 or 11, wherein the nano-suspended vitamin K2 is carried out at a concentration of 0.01 mg/mL in water.
  13. The composition according to claim 10 or 11, wherein the nano-suspended material is present in an aqueous solution in the simulated feeding intestinal fluid (FeSSIF).
  14. The composition according to claim 13, wherein the solubility is determined after 10 minutes in FeSSIF.
  15. A composition according to any one of claims 1 to 14, further comprising pharmaceutically acceptable additives, and effective for the treatment of vitamin K-related conditions such as osteoporosis or arteriosclerosis.
  16. A method for treating a disease selected from the group consisting of neurodegenerative diseases, retinopathy, polyarthritis rheumatica, atherosclerosis, amyotrophic lateral sclerosis, cerebral ischemia, cataracts, systemic infections, pathologies associated with skin aging and tissue aging, pathologies associated with mitochondrial dysfunction, and cachexia associated with nutritional deficiencies, wherein the treatment results in an increase in the lifespan of the mammal, and the method comprises administering a therapeutically effective amount of the composition described in any one of claims 1 to 15.
  17. A method for treating a mammal having a disease selected from the group consisting of vitamin K deficiency, osteoporosis, proliferative disorders, and cardiovascular diseases, comprising the step of administering to the mammal a therapeutically effective amount of the composition described in any one of claims 1 to 15.
  18. A method for treating or preventing osteoporosis and/or osteopenia, comprising the step of administering a therapeutically effective amount of the composition according to any one of claims 1 to 15 to a patient in need of treatment.
  19. A method for treating, preventing, slowing, stopping, and/or reversing calciphylaxis in a mammal requiring treatment, prevention, slowing, cessation, and/or reversal of its progression, comprising the step of administering to the mammal a therapeutically effective amount of the composition according to any one of claims 1 to 15 and a pharmaceutically acceptable additive to prevent, slow, stop, or reverse calciphylaxis.
  20. The method according to claim 19, wherein the mammal has distal calciphylaxis and/or central calciphylaxis.

Description

Related applications: This application relates to U.S. Provisional Application No. 63/447,312, filed on 21 February 2023. Field of Invention The present invention relates to menaquinone-9 nanoparticles, compositions and formulations thereof for treating diseases related to vitamin K. Background of the Invention Vitamin K is known as a group of structurally similar fat-soluble vitamins. Vitamin K2 (or vitamin K2) or menaquinone has nine related compounds that can be subdivided into short-chain menaquinones (such as menaquinone-4 or MK-4) and long-chain menaquinones (such as MK-7, MK-8, MK-9 to MK-14). The vitamin includes phylloquinone (K1), menaquinone (K2), and menadione (K3). Plants synthesize vitamin K1, while bacteria can produce a range of vitamin K2 forms, including the conversion of K1 to K2 by bacteria in the small intestine. Vitamin K3 is a synthetic version of the vitamin and, due to its toxicity, is prohibited for human use by the U.S. Food and Drug Administration. It has been established that taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in humans compared to those not taking these antibiotics. A diet low in vitamin K also lowers the body's vitamin K levels. Vitamin K1 is preferentially used by the liver as a clotting factor. Vitamin K2 is preferentially used in the brain, vascular structures, breasts, and kidneys. Vitamin K2 contributes to the production of myelin and sphingolipids (fat essential for brain health), protecting the brain from oxidative damage. Vitamin K2, such as MK-4, promotes bone health by stimulating the production of connective tissue in bones. In animals, vitamin K2, the primary storage form, has several subtypes, which differ in the length of the isoprenoid group or the residues in the side chain. These vitamin K2 homologs are called menaquinones and are characterized by the number of isoprenoid residues in their side chains. For example, MK-4 has four isoprene residues in its side chain and is the most common type of vitamin K2 in animal products. MK-4 is usually synthesized from vitamin K1 in certain animal tissues (arterial walls, pancreas, and testes) by replacing the phytyl group with an unsaturated geranyl group containing four isoprene units. Unlike MK-4, MK-7 is not produced by human tissue. MK -7 can be converted from phylloquinone ( K1 ) in the colon by E. coli bacteria. MK-4 and MK-7 are marketed in the United States as nutritional supplements for bone health. MK-4 has been shown to reduce the incidence of fractures. In Japan, since 1995, MK-4 at a daily dose of 45 mg has been approved by the Ministry of Health for the prevention and treatment of osteoporosis. Cardiovascular disease (CVD) is established as the leading cause of death in patients with chronic kidney disease (CKD). Compared to the general population, the risk of death due to CVD is approximately 10 to 20 times higher in CKD patients receiving hemodialysis. Furthermore, vascular calcification and associated arteriosclerosis have been demonstrated to be frequently associated with the development of CVD. Therefore, the methods of treatment disclosure can be applied to the treatment of peripheral artery disease. In addition, CKD patients receiving dialysis have a three times higher risk of fractures, including vertebral fractures and other types of fractures. Vitamin K, including menaquinone-9 or MK-9, is present in low concentrations in a normal diet. A direct correlation between the level of vitamin K in a patient's blood and the incidence of vascular calcification, bone density, and bone strength has also been established. Therefore, the supplemental use of vitamin K, such as MK-9 and/or MKH2-9 (MK-9/MKH2-9), as nanoparticle formulations disclosed herein, can increase bone mineralization or bone mineral density, providing significant clinical benefits, in part, by reducing vascular calcification observed depending on the degree of arteriosclerosis. These can aid in the treatment or prevention of CVD and bone disease in patients with CKD. In one embodiment, a disclosed method for administering MK-9 as nanoparticles can be used in patients with CKD, etc., for the treatment or reduction of vascular calcification, for increasing bone mineral density, and for the treatment, mitigation, or prevention of bone disease. In food, vitamin K1 is established to be bound to the chloroplast membrane of green leafy vegetables. MK-4, derived from the conversion of menadione, a synthetic analog of vitamin K, is found in animal products such as eggs and meat. Long-chain menaquinones such as MK-7, MK-8, and MK-9 are found in fermented foods such as cheese, curd, and sauerkraut. The effect of long-chain MK-n, such as MK-7, on normal blood clotting is also established to be higher and longer-lasting than that of vitamin K1 and MK-4. MK-7 has also been shown to have a longer half-life in serum compared to MK-4 and yields superior carboxylation grade osteocalcin compared to vita