Dihydromyricetin hot melt extrusion formulations and methods for forming them

Abstract

Compositions including dihydromyricetin (DHM) and methods for forming them through hot melt extrusion.

1 . A dihydromyricetin (DHM) formulation, comprising:
 dihydromyricetin (DHM) and   a matrix material.   
     
     
         2 . The DHM formulation of  claim 1 , wherein the matrix material comprises a polymer selected from the group consisting of hydroxypropyl methyl cellulose (HPMC), cellulose ester, cellulose acrylate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose propionate succinate, hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, carboxymethyl ethylcellulose (CMEC), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), hydroxypropyl methylcellulose propionate phthalate, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), hydroxypropyl methylcellulose propionate trimellitate, cellulose acetate succinate (CAS), methyl cellulose acetate succinate (MCAS), carboxymethylcellulose, carboxymethylcellulose salt, sodium carboxymethylcellulose, a cellulose polymer, and combinations. 
     
     
         3 . The DHM formulation of  claim 1 , wherein the matrix material comprises a polymer selected form the group consisting of polyethylene oxide (PEO), a polyoxyethylene-polyoxypropylene block copolymer (a poloxamer), a polyoxyethylene alkyl ether, a polyoxyethylene castor oil, a low molecular-weight oligomer of polyethylene glycol, an ethylene glycol-vinyl glycol copolymer, a polyoxyethylene castor oil, an ethoxylated castor oil, a polyoxyl hydrogenated castor oil, a polyoxyl 40 hydrogenated castor oil, a polyethoxylated sorbitan, polyoxyethylene sorbitan monooleate, and combinations. 
     
     
         4 . The DHM formulation of  claim 1 , wherein the matrix material comprises polyvinyl pyrrolidone (PVP). 
     
     
         5 . The DHM formulation of  claim 1 , wherein the matrix material comprises poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA). 
     
     
         6 . The DHM formulation of  claim 1 , wherein the matrix material comprises a polymer selected from the group consisting of poly(methyl methacrylate) (PMMA), low molecular weight poly(methyl methacrylate), polymethacrylate, methacrylic acid copolymers, a polymethacrylate derivative, poly(methacrylic acid-co-methyl methacrylate) 1:1, poly(methacrylic acid-co-methyl methacrylate) 1:2, poly(methacrylic acid-co-ethyl acrylate) 1:1, and combinations. 
     
     
         7 . The DHM formulation of  claim 1 , wherein the matrix material comprises a polymer selected from the group consisting of polycaprolactam, polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-glycolic acid) (PLGA), and combinations. 
     
     
         8 . The DHM formulation of  claim 1 , wherein the matrix material comprises a material selected from the group consisting of a wax, low melting point waxes such as carnauba wax, starch, starch derivatives, sugars, sugar alcohols, leucine, lipids, a polyol, a polyether, fructose, glucose, lactose, mannitol, trehalose, sucrose, raffinose, maltitol, lactitol, sorbitol, xylitol, erythritol, xylose, acorbose, melezitose, galactose, melibrose, isomaltose, a natural sugar extracts, malt beet sugar, corn sugar, high-fructose corn syrup, a sugar oligomers, polydextrose and dextrans with molecular weights less than 10,000 Daltons, a polyol, glycerol, sorbitol, ethylene glycol, propylene glycol, butanediol, polymeric derivatives of vitamin E, poly(propylene), and combinations. 
     
     
         9 . The DHM formulation of  claim 1 , further comprising a plasticizer. 
     
     
         10 . The DHM formulation of  claim 9 , wherein the plasticizer comprises a plasticizer selected from the group consisting of triacetin, citrate ester, triethyl citrate, acetyl triethyl citrate, tributyl citrate, and combinations. 
     
     
         11 . The DHM formulation of  claim 9 , wherein the plasticizer comprises a plasticizer selected from the group consisting of low molecular weight polyols having aliphatic hydroxyls, poly(propylene glycol), low molecular weight poly(ethylene oxide) having an average molecular weight of less than about 500,000 Da, poly(ethylene glycol), D-alpha tocopheryl PEG 1000 succinate (TPGS), low molecular-weight polyethylene glycol, propylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, triethylene glycol, tetraethylene glycol, mono propylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycolate, vitamin E, and pressurized CO 2 . 
     
     
         12 . The DHM formulation of  claim 1 , further comprising a permeabilizer. 
     
     
         13 . The DHM formulation of  claim 12 , wherein the permeabilizer comprises caprylic acid, a caprylate salt, and/or sodium caprylate. 
     
     
         14 . The DHM formulation of  claim 12 , wherein the permeabilizer comprises a permeabilizer selected from the group consisting of a fatty acid, a saturated fatty acid, and/or a fatty acid complexed with a cation, such as a metal cation, a metal divalent cation, a magnesium divalent cation, a calcium divalent cation, a zinc divalent cation, an iron divalent cation, a metal trivalent cation, an iron trivalent cation, a fatty acid salt, a fatty acid metallic soap, and combinations. 
     
     
         15 . The DHM formulation of  claim 1 , further comprising an antioxidant. 
     
     
         16 . The DHM formulation of  claim 1 , further comprising a coactive selected from the group consisting of glutathione, L-cysteine, N-acetyl cysteine (NAC), Prickly Pear extract, Milk Thistle, ginger toot, vitamin B, vitamin C, vitamin E, an electrolyte, a sugar, and combinations. 
     
     
         17 . The DHM formulation of  claim 1 , further comprising a pH buffering agent. 
     
     
         18 . The DHM formulation of  claim 17 , wherein the pH buffering agent is selected from the group consisting of an acidic pH buffering agent, citric acid, a citrate salt, a sodium citrate, a potassium citrate, calcium citrate, and combinations. 
     
     
         19 . The DHM formulation of  claim 1 ,
 wherein the DHM is not solubilized or dissolved by an aqueous solution having a pH of at most 3.5 and   wherein the DHM is solubilized or dissolved by an aqueous solution having a pH of at least 5.5.   
     
     
         20 . The DHM formulation of  claim 1 , wherein the DHM comprises at least 20 wt % of the powder. 
     
     
         21 . The DHM formulation of  claim 1 , wherein the crystallinity of the DHM is at most 10%. 
     
     
         22 . The DHM formulation of  claim 1 , wherein the DHM formulation is homogeneous. 
     
     
         23 . A dosage form, comprising
 the DHM formulation of  claim 1 , and   an enteric coating that encapsulates the DHM formulation.   
     
     
         24 . The dosage form of  claim 23 , wherein the enteric coating is selected from the group consisting of a polymeric coating and a methacrylate copolymer coating. 
     
     
         25 . A dosage form, comprising
 the DHM formulation of  claim 1  in a powder form, and   an aqueous liquid or a gel,   wherein the DHM formulation in a powder form is mixed with or suspended in the aqueous liquid or the gel.   
     
     
         26 . The DHM formulation of  claim 1 ,
 wherein the matrix material is poly(vinyl pyrrolidone-co-vinyl acetate) (PVP-VA) and   wherein the DHM comprises at least 20 wt % of the DHM formulation.   
     
     
         27 . A method for forming the dihydromyricetin (DHM) formulation of  claim 1 , comprising:
 mixing the dihydromyricetin (DHM) and the matrix material to form a compounding mixture;   processing the compounding mixture in an extruder to form an extrudate; and   collecting the extrudate as the dihydromyricetin (DHM) formulation.   
     
     
         28 . The method of  claim 27 , wherein an operating temperature of the extruder is less than a melting temperature of the dihydromyricetin (DHM). 
     
     
         29 . A method for reducing hangover symptoms, comprising
 administering the dihydromyricetin (DHM) formulation of  claim 1  to a patient suffering from hangover symptoms,   so that the patient's hangover symptoms are reduced.   
     
     
         30 . The dihydromyricetin (DHM) formulation of  claim 1  for use in preventing an alcohol use disorder, preventing alcoholism, treating an alcohol use disorder, treating alcoholism, or treating an alcohol overdose. 
     
     
         31 . The dihydromyricetin (DHM) formulation of  claim 1  for use in increasing antioxidant capacity, neuroprotection, preventing Alzheimer's disease, treating Alzheimer's disease, inhibiting inflammation, protecting the kidney, protecting the liver, preventing or treating cancer, ameliorating a metabolic disorder, preventing diabetes, treating diabetes, or treating a bacterial infection.