U.S. patent application number 16/683387 was filed with the patent office on 2020-05-14 for dihydromyricetin hot melt extrusion formulations and methods for forming them.
The applicant listed for this patent is Robert K. POWELL PRUD'HOMME. Invention is credited to Nicholas CAGGIANO, Vikram PANSARE, Brooks POWELL, Robert K. PRUD'HOMME.
Application Number | 20200147032 16/683387 |
Document ID | / |
Family ID | 70551482 |
Filed Date | 2020-05-14 |
United States Patent
Application |
20200147032 |
Kind Code |
A1 |
PRUD'HOMME; Robert K. ; et
al. |
May 14, 2020 |
DIHYDROMYRICETIN HOT MELT EXTRUSION FORMULATIONS AND METHODS FOR
FORMING THEM
Abstract
Compositions including dihydromyricetin (DHM) and methods for
forming them through hot melt extrusion.
Inventors: |
PRUD'HOMME; Robert K.;
(Princeton, NJ) ; POWELL; Brooks; (Houston,
TX) ; PANSARE; Vikram; (Princeton, NJ) ;
CAGGIANO; Nicholas; (Princeton, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PRUD'HOMME; Robert K.
POWELL; Brooks
PANSARE; Vikram
CAGGIANO; Nicholas |
Princeton
Houston
Princeton
Princeton |
NJ
TX
NJ
NJ |
US
US
US
US |
|
|
Family ID: |
70551482 |
Appl. No.: |
16/683387 |
Filed: |
November 14, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62767208 |
Nov 14, 2018 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/06 20130101; A61K
9/10 20130101; A61K 9/1617 20130101; A61K 9/0095 20130101; A61K
47/38 20130101; A61K 9/0053 20130101; A61K 45/06 20130101; A61K
31/352 20130101; A61K 9/146 20130101; A61K 9/4866 20130101; A61K
47/10 20130101; A61K 47/32 20130101; A61K 9/2846 20130101; A61K
9/1647 20130101 |
International
Class: |
A61K 31/352 20060101
A61K031/352; A61K 9/06 20060101 A61K009/06; A61K 9/10 20060101
A61K009/10; A61K 9/28 20060101 A61K009/28; A61K 9/16 20060101
A61K009/16 |
Claims
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.sub.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.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/767,208, filed Nov. 14, 2018, which is hereby
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention pertains to compositions including
dihydromyricetin (DHM) and methods for forming them, including hot
melt extrusion.
BACKGROUND
[0003] Alcohol is a constituent of medicines, foods, and beverages
that provides both beneficial and detrimental effects on human
beings. Alcohol can refer to ethyl alcohol (ethanol), which is the
common form of consumable alcohol found in alcoholic beverages,
e.g., such as beer, wine, and liquor. During consumption, alcohol
is rapidly absorbed from the stomach and small intestine into the
bloodstream, from which it can affect several organs, including the
brain, heart, pancreas, and liver. Alcohol can act as a depressant
to the central nervous system (CNS). For example, alcohol
interferes with the brain's communication pathways, which affects
brain functionality that manifests in cognitive and behavioral
changes, e.g., such as a person's ability to think, focus, and
move, as well as his/her mood and behavior. Alcohol can cause
inflammation and damage to the liver, e.g., consistent heavy
drinking can cause chronic liver problems. For example, heavy
drinking can lead to steatosis (e.g., fatty liver), infection
(e.g., alcoholic hepatitis), fibrosis, and cirrhosis. More
commonly, even a single instance of light to moderate to heavy
alcohol consumption can result in what is commonly known as an
`alcohol hangover`. A hangover refers to an array of physical
symptoms that affect a person shortly after ingesting alcohol,
e.g., within hours of consumption. The symptoms of a hangover
include, for example, one or more of thirst, fatigue and/or
weakness, headache and/or muscle aches, dizziness/faintness, loss
of appetite, poor and/or decreased sleep, nausea and/or stomach
pain (e.g., which can include vomiting), and elevated heart rate. A
hangover is considered to be one of the most widely experienced
negative consequences of consuming ethanol.[1]
SUMMARY OF INVENTION
[0004] In an embodiment of the invention, a dihydromyricetin (DHM)
formulation includes dihydromyricetin (DHM) and a matrix material.
The matrix material can include a polymer. For example, the polymer
can be 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/or
combinations.
[0005] The polymer can also be 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/or combinations.
[0006] In an embodiment of the invention, the matrix material
includes polyvinyl pyrrolidone (PVP). In an embodiment of the
invention, the matrix material includes poly(vinyl
pyrrolidone-co-vinyl acetate) (PVP-VA).
[0007] The matrix material can include a polymer. The polymer can
be 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/or combinations. The polymer can also be polycaprolactam,
polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid
(PGA), poly(lactic-glycolic acid) (PLGA), and/or combinations.
[0008] The matrix material can include a material, such as 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.
[0009] The DHM formulation can further include a plasticizer. The
plasticizer can include a plasticizer, for example, triacetin,
citrate ester, triethyl citrate, acetyl triethyl citrate, tributyl
citrate, and combinations. The plasticizer can also be 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/or
pressurized CO.sub.2.
[0010] The DHM formulation can further include a permeabilizer. The
permeabilizer can include caprylic acid, a caprylate salt, and/or
sodium caprylate. The permeabilizer can also include a
permeabilizer such as 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.
[0011] The DHM formulation can further include an antioxidant. The
DHM formulation can further include a coactive such as 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.
[0012] The DHM formulation can further include a pH buffering
agent. The pH buffering agent can be an acidic pH buffering agent,
citric acid, a citrate salt, a sodium citrate, a potassium citrate,
calcium citrate, and/or combinations.
[0013] In an embodiment of the invention, in the DHM formulation,
the DHM is not solubilized or dissolved by an aqueous solution
having a pH of at most 3.5, and the DHM is solubilized or dissolved
by an aqueous solution having a pH of at least 5.5. In an
embodiment of the invention, the DHM comprises at least 20 wt % of
the powder. In an embodiment of the invention, the crystallinity of
the DHM is at most 10%. In an embodiment of the invention, the DHM
formulation is homogeneous.
[0014] In an embodiment of the invention, a dosage form includes
the DHM formulation and an enteric coating that encapsulates the
DHM formulation. The enteric coating can be a polymeric coating or
a methacrylate copolymer coating.
[0015] In an embodiment of the invention, a dosage form includes
the DHM formulation of in a powder form and an aqueous liquid or a
gel. The DHM formulation can be in a powder form which is mixed
with or suspended in the aqueous liquid or the gel.
[0016] In an embodiment of the invention, in the DHM formulation,
the matrix material is poly(vinyl pyrrolidone-co-vinyl acetate)
(PVP-VA) and the DHM comprises at least 20 wt % of the DHM
formulation.
[0017] In an embodiment of the invention, a method for forming the
dihydromyricetin (DHM) includes: 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.
The operating temperature of the extruder can be less than the
melting temperature of dihydromyricetin (DHM).
[0018] In an embodiment of the invention, a method for reducing
hangover symptoms includes: administering the dihydromyricetin
(DHM) formulation to a patient suffering from hangover symptoms, so
that the patient's hangover symptoms are reduced.
[0019] In an embodiment of the invention, the dihydromyricetin
(DHM) formulation can be used in preventing an alcohol use
disorder, preventing alcoholism, treating an alcohol use disorder,
treating alcoholism, or treating an alcohol overdose.
[0020] In an embodiment of the invention, the dihydromyricetin
(DHM) formulation can be used 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.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Embodiments of the invention are discussed in detail below.
In describing embodiments, specific terminology is employed for the
sake of clarity. However, the invention is not intended to be
limited to the specific terminology so selected. A person skilled
in the relevant art will recognize that other equivalent parts can
be employed and other methods developed without parting from the
spirit and scope of the invention. All references cited herein are
hereby incorporated by reference in their entirety as if each had
been individually incorporated.
[0022] An embodiment of the present invention includes a method to
improve the bioavailability of the molecule dihydromyricetin (DHM)
through the process known as hot melt extrusion (HME) to form a hot
melt extruded formulation. This method can include processing by
HME of a combination of materials including DHM, additional
beneficial molecules (e.g., co-actives), polymeric excipients,
plasticizers, and permeability-enhancing compounds
(permeabilizers). The final form of the product may comprise
powders, granules, or tablets to be used in further
formulations.
[0023] The present invention can provide a hot-melt extrusion
method and resultant formulation including a beneficial amount of
DHM, additional beneficial molecules, polymeric excipients,
plasticizers, and permeability-enhancing compounds. Improvements in
bioavailability and pharmacokinetic parameters of DHM can be
associated with this formulation method.
[0024] In an embodiment, the formulation may be processed further
in forms beyond powders, granules, and tablets for administration
by various routes either by self-administration or administration
by any number of routes known to a skilled artisan. In some
embodiments, the formulation may be well suited to oral
administration routes.
[0025] Thomson, et al. (U.S. Pat. No. 3,239,370) discusses a method
and process for coating substrates with films of molten random
copolymer of ethylene and carboxylic acid. The polymer is hot melt
extruded through a slit die to provide the film that is applied to
a substrate in molten form before cooling into a solid state. [9]
Schippers, et al. (U.S. Pat. No. 3,410,938) discusses processing
thermoplastic polymers by conveying them down the barrel of a hot
metal extruder by screw extrusion to remove trapped gases within
the polymer and generate various morphologies of the polymer being
processed.[10] McGinity, et al. (U.S. Pat. No. 6,488,963B1)
discusses hot melt extrudable pharmaceutical formulations, which
include therapeutic molecules dispersed within a high molecular
weight poly(ethylene oxide) (PEO) matrix and may include
plasticizers. [11] Miller, et al. (U.S. Pat. No. 9,504,658, U.S.
Ser. No. 11/718,620) discusses dispersions of fine drug particles
within polymeric and/or lipophilic polymeric matrices, e.g., of
PEO, which can include other hydrophilic polymers, e.g.,
hydroxypropyl methylcellulose (HPMC) and polyvinyl acetate (PVA),
that are processed by HME. [12] Alderman, et al. (U.S. Pat. No.
4,678,516) discusses a method for prolonging the release of
therapeutically active molecules by dispersing them within a
thermoplastic polymeric matrix consisting of hydroxypropyl
methylcellulose (HPMC) and plasticizers. [13] Brough, et al. (U.S.
Pat. No. 8,486,423, U.S. Ser. No. 12/196,154) discusses a method of
dispersing pharmaceutically relevant active ingredients (APIs) into
homogeneous composites, including thermoplastic polymers that can
molecularly dissolve the API or provide a matrix for dispersion of
fine particles of the API, that can be further processed by hot
melt extrusion. [14] Fischer, et al. (U.S. Pat. No. 8,298,581, U.S.
Ser. No. 10/550,685) discusses a matrix composition for the
delivery of APIs as oral formulations and a double-coating process
including a polymer from the PEO group and a polymer from a
copolymer of ethylene oxide and propylene oxide.[15] Yang, et al.
(U.S. Pat. No. 8,603,514, U.S. Ser. No. 11/775,484) and Fuisz, et
al. (US Pat. Applic. Pub. 2007-0281003 A1, U.S. Ser. No.
11/674,223) discuss pharmaceutically relevant compositions for the
formation of films containing one or more entrapped APIs and other
excipients or plasticizers in a polymeric matrix by HME.[16, 17]
Bernstein, et al. (U.S. Pat. No. 6,730,322B1) discusses the
integration of hydrophobic components into a microsphere polymeric
matrix to alter the release characteristics of entrapped drugs.
McAllister, et al. (US Pat. Applic. Pub. 2003-0049311 A1,
10/060,603) and McAllister, et al. (U.S. Pat. No. 7,842,308, Ser.
No. 10/470,439) discuss pharmaceutical formulations for injection
molding and polymeric matrices for film formation.[18-20]
Dihydromyricetin (DHM)
[0026] Dihydromyricetin (DHM), a flavonoid compound isolated from
the Hovenia plant can "sober-up" rats inebriated with alcohol[2],
prevent predisposed rats from becoming alcoholics[2], return
alcoholic rats to baseline levels of alcohol consumption[2], reduce
hangover symptoms[2], and prevent fetal alcohol spectrum disorders
in the offspring of rats exposed to significant amounts alcohol
during pregnancy.[2] DHM can be dissolved in a solvent, such as
dimethylsulfoxide (DMSO). DHM can be complexed with a metal, such
as a divalent alkali earth metal, divalent magnesium (Mg(II),
Mg.sup.+2), a divalent transition metal, divalent iron (Fe(II),
Fe.sup.+2), divalent copper (Cu(II), Cu.sup.+2), a trivalent
transition metal, or trivalent iron (Fe(III), Fe').
[0027] DHM has unique physicochemical properties including low
solubility, high hydroxyl functional group content, and unknown
thermal stability, rendering the processing of DHM and other
flavonoids under hot melt extrusion (HME) conditions difficult.
[0028] DHM demonstrates pharmacological properties for successful
medical treatment of alcohol use disorders (AUDs)[21-23]. Given
limited available pharmacotherapies for AUDs and these being
limited by low patient compliance, because of the adverse effects
they may cause, therapies for the treatment of AUDs should be
advanced, e.g., through DHM therapeutic strategies. [24]
[0029] In addition to DHMs potential for the treatment of AUDs,
which, without being bound by theory, may be achieved through DHM's
inhibiting the effect of alcohol on GABA.sub.A receptors
(GABA.sub.ARs) in the brain, DHM and the Hovenia plant it is
isolated from have shown efficacy in mitigating liver
injuries[25-27], decreasing alcohol and acetaldehyde concentrations
in the blood via enhancing ADH and ALDH activity[28, 29], and
eliminating alcohol-induced excessive free radicals.[30] DHM has
been observed to have oxidative stress-mediating activity, i.e.,
increase antioxidant capacity for scavenging reactive oxygen
species, which may result in neuroprotective, nephroprotective
(kidney protecting), and hepatoprotective (liver protecting)
effects, which may ameliorate, for example, the effects of
hypobaric hypoxia, side effects of the chemotherapeutic agent
cisplatin, and detrimental effects of ethanol. DHM may have a
neuroprotective role in Alzheimer's and Parkinson's diseases. DHM
can also inhibit inflammation. DHM can also have anticancer
activity and regulate cell proliferation and apoptosis. DHM can
mediate metabolism, and may be useful in ameliorating certain
metabolic disorders, such as diabetes, weight gain, hyperlipidemia,
and atherosclerosis. DHM exhibits antibacterial activity (Li, H. et
al., "The Versatile Effects of Dihydromyricetin in Health",
Evidence Based Complementary & Alternative Medicine 2017, Art.
ID 1 053617).
[0030] A DHM formulation designed to reduce alcohol's negative
effects when taken after alcohol consumption is covered under U.S.
Pat. No. 9,603,830 B2 (granted on Mar. 28, 2017) and is sold in the
US under the brand name Thrive+.RTM..
[0031] Despite promising results in rats, one challenge in
translating DHM's efficacy to humans in a commercially viable way
is DHM's oral bioavailability of less than 5% [31]. DHM can have
poor stability. DHM is a BCS class IV drug limited by having the
properties of low solubility and low permeability. In the context
of successfully commercialized drugs, DHM requires large doses for
efficacy. Because DHM is a naturally occurring organic compound
isolated from an herb, a DHM formulation can be classified as a
food (or dietary supplement) under the Dietary Products
designation.
[0032] This invention addresses the problem of poor bioavailability
and stability of DHM through the use of hot melt extrusion (HME).
By dispersing DHM within a set of excipients using HME, e.g.,
excipients which are preferably chiefly polymeric, DHM can have
higher supersaturation, and may exhibit increased bioavailability,
be released more slowly upon ingestion, and exhibit enhanced
dissolution and release kinetics, longer sustained release, higher
concentrations, and improved stability with respect to low pH
gastric juices and enzymes, which can cause degradation and
quenching of DHM activity, than when administered in a pure form.
Furthermore, the DHM HME formulation may possess improved ability
to penetrate intestinal barriers, to allow DHM to reach the
bloodstream more effectively and efficiently.
Hot Melt Extrusion
[0033] Hot melt extrusion (`HME`) is an industrial process that can
be used to create uniform polymer products such as tubes, sheets,
and foams.[3-7] HME can be employed to disperse active
pharmaceutical ingredients (APIs) within solid polymer matrices.
[3, 5, 6] In this process, an API and polymer excipient(s) are fed
into an extruder. These are then conveyed by single or
double-screws down the barrel of the device while undergoing
melting, mixing, dispersing, and finally cooling processes.
[0034] HME can be used to confer improved bioavailability and API
dissolution in a final application. A limitation of HME is that the
active compound and excipient(s) are subjected to elevated
temperatures which may prompt or accelerate degradation of an
API.
[0035] The term "hot-melt extrudable" refers to a compound or
formulation that may be hot-melt extruded. A hot-melt extrudable
polymer is one that is sufficiently rigid for an intended use at
standard ambient temperature and pressure, but is capable of
deformation or forming a liquid or semi-liquid state under elevated
heat or pressure.
[0036] In an embodiment of the invention, a composition for
hot-melt extrusion does not include a plasticizer. In another
embodiment of the invention, a composition for hot-melt extrusion
includes one or more plasticizers. Although the process according
to the invention has been called a hot-melt extrusion, other
equivalent and similar processes such as injection molding, hot
dipping, melt casting, and compression molding may be used. By
using any of these methods, the formulation may be shaped as needed
according to the desired mode of administration, e.g. powders,
tablets, pills, lozenges, suppositories, capsules and the like. The
hot-melt extrusion process employed in some embodiments of the
invention is conducted at an elevated temperature, i.e., the
heating zone(s) of the extruder is above room temperature (about
20.degree. C.). An operating temperature range should be selected
that minimizes the degradation or decomposition of the therapeutic
compound (e.g., DHM) during processing. For example, the operating
temperature range can be in the range of from about 60.degree. C.
to about 160.degree. C. and can be set for one or more extruder
heating zone(s).
[0037] In a hot-melt extrusion (HME) process according to the
invention an effective amount of therapeutic compound(s) is mixed
with matrix polymer(s), a plasticizer, such as polyethylene glycol
(PEG), permeability-enhancers, and/or other excipients. Other
components may be added for various embodiments of the invention.
The mixture is then placed in the extruder hopper and passed
through the heated area of the extruder at a temperature which
melts or softens the matrix polymer, excipient(s), and/or
plasticizer, if present, to form a matrix throughout which the
therapeutic compound is dispersed. The molten or softened mixture
then exits via a die, or other such element, at which time the
mixture (now called the extrudate) begins to harden. Since the
extrudate is still warm or hot upon exiting the die, it may be
easily shaped, molded, chopped, ground, shaped into beads, cut into
strands, tableted, or otherwise processed to the desired physical
form. The extruder used to practice the invention may be any
commercially available or custom-built model equipped to handle dry
feed and having a solid conveying zone, one or multiple heating
zones, and an extrusion die. A two-stage Single Screw extruder,
such as that manufactured by C. W. Brabender Instruments
Incorporated (NJ), is one such apparatus. It can be advantageous
for the extruder to possess multiple separate temperature
controllable heating zones.
[0038] Several conditions may be varied during the extrusion
process to arrive at a particularly advantageous formulation. Such
conditions include, by way of example, formulation composition,
feed rate, operating temperature, extruder screw RPM, residence
time, die configuration, heating zone length, and/or extruder
torque and/or pressure.
[0039] For example, the extrusion conditions may be selected to
produce a formulation that is a homogeneous, e.g., DHM is
homogeneously dispersed in a matrix material or in a combination of
matrix material(s), plasticizer(s), and/or permeabilizer(s).
[0040] HME can produce various forms of solid dispersions. These
may include, but are not limited to, pharmaceutically-relevant
dosage forms, such as powders, pellets, cylinders, tubes, granules,
and flakes. These can be processed further into a desired
morphology with desired surface characteristics.
[0041] In an embodiment of the present invention, the use of hot
melt extrusion in the preparation of pharmaceutical dosage forms to
effectively deliver DHM has several advantages. HME is scalable,
e.g., it can be used at the lab scale, the pilot plant scale, and
to mass produce large quantities of product. It allows for DHM to
be formulated with a wide variety of excipient(s) and
plasticizer(s) to allow for maximum effectiveness as needed for
various administration routes. Furthermore, HME can be solvent
free, thus reducing the need for a subsequent solvent removal step
and reducing the potential for solvent-induced toxicity.[7]
[0042] The invention includes, but is not limited to, a combination
of materials including the active ingredient DHM and/or other
flavonoids, additional active molecules and co-actives,
permeability enhancers, excipients (including matrix materials),
plasticizers, and an enteric coating. In an embodiment, the HME
dosage form includes dihydromyricetin (DHM) and a coactive, such as
L-cysteine, N-acetyl cysteine (NAC), Prickly Pear extract, Milk
Thistle, ginger root, vitamin B, vitamin C, vitamin E, an
electrolyte, a sugar, an antioxidant, and/or glutathione.
Permeability-Enhancers
[0043] A permeability-enhancer or permeabilizer is an agent that
enhances the permeation of a drug compound through the epithelial
cell layer in the gastrointestinal (GI) tract and, hence, enhances
the amount of drug entering the bloodstream. Permeability-enhancers
have been reviewed by Aungst and Whitehead[32-35]. The list of
agents presented by Aungst in Table I and Whitehead in Table I are
incorporated into this patent in their entirety.
[0044] Examples of permeability-enhancers are fatty acids, a
saturated fatty acid, caprylic acid, a caprylate salt, sodium
caprylate, a fatty acid complexed with a cation, such as a metal
cation, a metal divalent cation, a magnesium (Mg(II), Mg.sup.+2),
calcium (Ca(II), Ca.sup.+2), or zinc divalent cation (Zn(II),
Zn.sup.+2), iron divalent cation (Fe(II), Fe.sup.+2), a metal
trivalent cation, iron trivalent cation (Fe(III), Fe.sup.+3), a
fatty acid salt, a fatty acid metallic soap, and combinations of
these. For example, capric acid and its salts are permeabilizers
that are currently clinically approved for use in an ampicillin
suppository. The caprates and other long-chain saturated fatty
acids and their salts can be incorporated into the hot melt
extrusion (HME) process. Their hydrophobicity can be enhanced by
complexing them, for example, with divalent cations such as those
of magnesium (Mg(II), Mg.sup.+2), calcium (Ca(II), Ca.sup.+2), or
zinc, divalent iron, or trivalent iron. Permeabilizers are optional
additions to the formulation. When they are used, the mass ratios
of permeabilizer to DHM in the hot melt extruded formulation
(extrudate) produced can range from 1:100 to 100:1.
Excipients and Matrix Materials
[0045] Excipients and matrix materials are defined as materials
that aid in the formulation, stability, and/or release
characteristics of the active molecule DHM. For example,
homopolymers, copolymers, and amphiphilic copolymers can be used as
excipients and matrix materials. The matrix material can constitute
from 0.1 wt % to 99 wt % of the combined mass of the active
agent(s) and excipients by weight of the final solid form. When it
is desirable for the matrix material to prevent aggregation of the
active domains into larger aggregates, the matrix material can
constitute more than 20% or more than 40% of the combined mass of
the active agent(s) and matrix material.
[0046] Exemplary excipients and matrix materials include low
melting point waxes such as carnauba wax, cellulose, methyl
cellulose, ethyl cellulose, polyvinylpyrrolidone (PVP) and its
copolymers such as polyvinylpyrrolidone-vinyl acetate (PVP-VA),
poly(ethylene-co-vinyl acetate), various grades of polyethylene
glycol (PEG), polyethylene oxide (PEO), cellulose esters, cellulose
acrylates, cellulose derivatives, polymethacrylate,
polymethacrylate derivatives, polyoxyethylene-polyoxypropylene
block copolymers (also referred to as poloxamers),
hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC),
HPMC derivatives, polylactic acid (PLA), poly(glycolide) (PGA), and
poly(lactide-co-glycolide) (PLGA), poly(caprolactone) (PCL),
starch, starch derivatives, sugars, sugar alcohols, waxes, leucine,
lipids, carboxymethylcellulose, sodium carboxymethylcellulose,
carboxymethylcellulose salts, hydroxyethylcellulose, methacrylic
acid copolymers, poly(methyl methacrylate) (PMMA), and ethylene
glycol-vinyl glycol copolymer.
[0047] Examples of excipients and matrix materials include
polyoxyethylene alkyl ethers, polyoxyethylene castor oils,
polycaprolactam, hydroxypropyl methyl cellulose acetate succinate
(HPMCAS), hydroxypropyl methyl cellulose propionate succinate,
hydroxypropyl methyl cellulose phthalate (HPMCP), 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 (HPMC), 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), poly(methacrylic acid-co-methyl methacrylate) 1:1
(e.g., Eudragit.RTM. L100, Evonik Industries AG), poly(methacrylic
acid-co-methyl methacrylate) 1:2 (e.g., Eudragit.RTM. S100),
poly(methacrylic acid-co-ethyl acrylate) 1:1 (e.g., Eudragit.RTM.
L100-55), a polyol, a polyether, a cellulosic polymer, sugars and
sugar alcohols, for example, fructose, glucose, lactose, mannitol,
trehalose, sucrose, raffinose, maltitol, lactitol, sorbitol,
xylitol, erythritol, xylose, acorbose, melezitose, galactose,
melibrose, and isomaltose, natural sugar extracts, for example,
malt beet sugar, corn sugar, high-fructose corn syrup, sugar
oligomers, such as polydextrose and dextrans with molecular weights
less than 10,000 Daltons, polyols such as glycerol, sorbitol,
ethylene glycol, propylene glycol, butanediol, and other oligomers,
low molecular-weight oligomers, such as low molecular weight
polyethylene glycol and low molecular weight poly(methyl
methacrylate), ethoxylated castor oil, polyoxyl hydrogenated castor
oil, polyoxyl 40 hydrogenated castor oil, polymeric derivatives of
vitamin E, polyethoxylated sorbitan, and polyoxyethylene sorbitan
monooleate.
[0048] The excipients and matrix materials can include amphiphilic
block copolymers, for example, polystyrene-block-polyethylene
glycol (PS-b-PEG), polylactic acid-block-polyethylene glycol
(PLA-b-PEG), and poly(lactic-co-glycolic acid)-block-polyethylene
glycol (PLGA-b-PEG).
[0049] Examples of excipients and matrix materials include
derivatives of the above, copolymers of the above, and combinations
of the above.
[0050] In an embodiment, the matrix material includes components
with a molecular weight of less than 1,000,000 Daltons (Da), less
than 100,000 Daltons, less than 10,000 Daltons, less than 5000
Daltons, or less than 2000 Daltons.
[0051] The matrix material can include a polymer. A polymer is
formed of several monomer units bound to each other. For example, a
polymer can be a linear polymer, a branched polymer, or a cyclic
polymer. In a cyclic polymer, a set of monomers can be bound to
each other to form a ring. In a noncyclic polymer, there is no set
of monomers that are bound to each other to form a ring (although
atoms within a given monomer unit of the polymer still may be in a
ring structure, e.g., a cyclopentyl, furan, furanose, cyclohexyl,
pyran, pyranose, benzene, or saccharide structure). For example,
cyclodextrin is a cyclic polysaccharide. By contrast, cellulose is
a linear polysaccharide formed of several hundred to many thousands
of D-glucose monomers. Gum arabic includes arabinogalactan, formed
of arabinose and galactose monomers.
[0052] Certain polymeric excipients and matrix materials marketed
under trade names by manufacturers may include the following:
BASF: Povidones, copovidones, methacrylic acid copolymers, ethylene
glycol-vinyl glycol copolymers, Poloxamer 407, Poloxamer 188, poly
ethylene glycols, polyoxyl 40 hydrogenated castor oils, and
polymeric derivatives of vitamin E marketed by BASF under trade
names SOLUPLUS, KOLLIDON VA 64, KOLLIDON 12 PF, KOLLIDON 17 PF,
KOLLIDON 30, KOLLIDON 90 F, KOLLIDON SR, KOLLICOAT MAE 100P,
KOLLICOAT IR, KOLLICOAT PROTECT, KOLLIPHOR P 407, KOLLIPHOR P407
MICRO, KOLLIPHOR P188, KOLLIPHOR P188 MICRO, KOLLISOLV PEG,
KOLLIPHOR RH 40, KOLLIPHOR TPGS. The Dow Chemical Company: Polymers
with trade names METHOCEL, ETHOCEL, POLYOX, and AFFINISOL marketed
by the Dow Chemical Company. Evonik Corporation: Polymers with
trade names EUDRAGIT.RTM. (methacrylates) and RESOMER, marketed by
Evonik Corporation. Ashland: Polymers with trade names AquaSolve
hypromellose acetate succinate, Aqualon ethylcellulose, Aqualon
sodium carboxymethylcellulose, Aquarius control film coating
systems, Aquarius prime film coating systems, Aquarius protect film
coating systems, Aquarius film coating systems, Aquarius preferred
film coating systems, Benecel methylcellulose and hypromellose,
Blanose sodium carboxymethylcellulose, CAVAMAX native
cyclodextrins, Cavitron cyclodextrin, CAVASOL cyclodextrin, Klucel
hydroxypropylcellulose, Natrosol hydroxyethylcellulose, Pharmasolve
N-methyl-2-pyrrolidone, Plasdone S-630 copovidone, Plasdone
povidone, and Polyplasdone crospovidone (cross linked polyvinyl
N-pyrrolidone) marketed by Ashland Global Holdings Inc.
[0053] The foregoing lists of materials are not intended to
indicate that all of these materials are equivalent and/or equally
suitable.
[0054] The polymer matrix material can have a glass transition
temperature (Tg) of at least 50.degree. C., 60.degree. C.,
70.degree. C., 80.degree. C., 90.degree. C., 100.degree. C.,
110.degree. C., 115.degree. C., 120.degree. C., 125.degree. C.,
130.degree. C., 150.degree. C., 175.degree. C., 200.degree. C., or
250.degree. C. For example, hydroxypropyl methyl cellulose acetate
succinate (HPMCAS) has a glass transition temperature (Tg) of about
120.degree. C.
[0055] The polymer matrix material may be selected to adjust the
formulation's release profile, e.g., to adjust the rate at and
duration of time over which the formulation releases an active
pharmaceutical ingredient (API), such as DHM.
[0056] In an embodiment, polymers, such as one or more of those
listed above, may also be incorporated as enteric coatings which
coat a final tablet form of a DHM hot-melt extruded (HME)
formulation and provide additional stability or sustained release
benefits. For example, including an enteric coating in the
formulation may alter the formulation's release profile, e.g., may
alter the rate at and duration of time over which the formulation
releases an active pharmaceutical ingredient (API), such as DHM.
For example, the enteric coating may be a methacrylate copolymer
coating.
Plasticizer
[0057] The term "plasticizer" includes compounds capable of
plasticizing the polymeric excipients, including the polymer matrix
material, used. The plasticizer may lower the glass transition
temperature or softening point of the excipient(s) in order to
allow for lower processing temperature, extruder torque, and
pressure during the hot-melt extrusion (HME) process. Plasticizers,
such as PEG and low molecular weight PEO, can broaden the average
molecular weight of the polymeric excipients used, thereby lowering
the glass transition temperature or softening point of the
composition being extruded. Plasticizers can reduce the viscosity
of a polymer melt, thereby allowing for lower processing
temperature and extruder torque during hot-melt extrusion. A
plasticizer may impart advantageous physical properties to the
extruded formulation. As used herein, the term "low molecular
weight PEO" means poly(ethylene oxide) homopolymer having an
average molecular weight less than about 500,000.
[0058] In an embodiment according to the invention, the composition
that undergoes hot melt extrusion (HME) and the extruded
formulation do not include a plasticizer. In an embodiment
according to the invention, the composition that undergoes hot melt
extrusion (HME) and the extruded formulation include a
plasticizer.
[0059] Including a plasticizer in the formulation may alter the
formulation's release profile, e.g., may alter the rate at and
duration of time over which the formulation releases an active
pharmaceutical ingredient (API), such as DHM. Increasing the amount
of plasticizer in the formulation may increase the release rate of
the therapeutic compound (API, e.g., DHM). A combination of
plasticizers may be used in the composition to be extruded and the
extruded formulation.
[0060] Plasticizers that may be used in an embodiment of the
invention include, by way of example and without limitation, low
molecular weight polymers, oligomers, copolymers, oils, small
organic molecules, low molecular weight polyols having aliphatic
hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene
glycol), multi-block polymers, single block polymers, low molecular
weight poly(ethylene oxide) (e.g., having an average molecular
weight of less than about 500,000 Da), and poly(ethylene
glycol).
[0061] Plasticizers that may be used in an embodiment of the
invention include, but are not limited to triacetin, citrate ester,
vitamin E, D-alpha tocopheryl PEG 1000 succinate (TPGS), molecular
surfactants, low molecular-weight polyethylene glycol, pressurized
CO.sub.2, propylene glycol, 1,2-butylene glycol, 2,3-butylene
glycol, styrene, a glycol, triethylene glycol, tetraethylene glycol
and other poly(ethylene glycol) compounds, 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, triethyl
citrate, acetyl triethyl citrate, tributyl citrate, and allyl
glycolate.
[0062] Examples of plasticizers include derivatives of the above,
copolymers of the above, and combinations of the above.
[0063] The foregoing lists of materials are not intended to
indicate that all of these materials are equivalent and/or equally
suitable.
[0064] The amount of plasticizer used in the formulation may affect
the formulation's properties. The amount of plasticizer selected
for use in the composition for HME and the formulation produced can
will depend upon the plasticizers composition, physical properties,
effect upon the excipient(s), interaction with other components of
the formulation, ability to solubilize the therapeutic compound,
and/or other factors.
Composition of the Components
[0065] In some embodiments, DHM constitutes at least 0.1 wt %, 1 wt
%, 2 wt %, 3 wt %, 5 wt %, 7 wt %, 10 wt %, 15 wt %, 20 wt %, 25 wt
%, 30 wt %, 35 wt %, 40 wt %, 50 wt %, 55 wt %, 60 wt %, 70 wt %,
80 wt %, 90 wt %, 95 wt %, 98 wt %, or 99 wt % of the HME
formulation, relative to the total mass of the formulation,
including all other excipients and matrix materials.
[0066] In some embodiments, the concentration of all other
components, and particularly excipients and matrix materials, in
the formulation may range from 0.001 wt % to 0.01 wt %, or from
0.01 wt % to 0.1 wt %, or from 0.1 wt % to 1 wt %, or from 1 wt %
to 10 wt %, or from 10 wt % to 99.9 wt %, depending on the desired
release profile, the pharmacological activity and toxicity of the
therapeutic compound, such as DHM and any coactive, and other such
considerations.
Administration
[0067] The resulting formulations of embodiments of the present
invention are useful and suitable for delivery in animals and
humans and may be administered by a variety of methods. Such
methods include, by way of example and without limitation: oral,
nasal, buccal, rectal, ophthalmic, otic, urethral, vaginal, or
sublingual dosage administration. Such methods of administration
and others contemplated within the scope of the present invention
are known to the skilled artisan. In vivo stability of the present
formulation may vary according to the physiological environment to
which it is exposed and the matrix material, excipients, and
plasticizer used. Therefore, the necessity for or frequency of
readministration may be different for various formulations.
[0068] The formulation of the present invention may be provided in
a variety of ways, for example, powder, tablet, and capsule dosage
forms. Additional components that would not significantly prohibit
the hot-melt extrusion (HME) process may be added to the
formulation prior to hot-melt extrusion. That is, such additional
components should still allow for formulation using the hot-melt
extrusion process.
[0069] For oral, buccal, and sublingual administration, the
formulation may be in the form of a gel cap, caplet, tablet,
capsule, suspension, or powder. Alternatively, the formulation may
be in the form of a mixture with or suspension in, e.g., a
DHM-containing powder according to an embodiment of the invention
mixed with or suspended in, a consumable (edible) liquid (e.g., an
aqueous liquid, such as water), such as a drink or liquid
concentrate. Alternatively, the formulation may be in the form of a
mixture with or suspension in, e.g., a DHM-containing powder
according to an embodiment of the invention mixed with or suspended
in, an edible gel. For rectal administration, the formulation may
be in the form of a suppository, ointment, enema, tablet, or cream
for release of compound into the intestines, sigmoid flexure,
and/or rectum.
[0070] In solid dosage forms, the compounds can be combined with
conventional carriers, for example, one or more of the following:
binders, such as acacia, corn starch, or gelatin; disintegrating
agents, such as corn starch, guar gum, potato starch, or alginic
acid; lubricants, such as stearic acid or magnesium stearate; and
inert fillers, such as lactose, sucrose, or corn starch.
[0071] It is contemplated that either one or a combination of
long-acting, sustained-release, controlled-release, and/or or
slow-release dosage forms may be used in the present invention.
This may be desirable, if continuous exposure of an animal or a
human to the active ingredient(s) (e.g., DHM) is the desired
outcome. The polymers and formulations useful in this case can
include derivatized cellulosic polymers of the type described in
the Dow Chemical Company Technical Bulletin "Using Dow Excipients
for Controlled Release of Drugs in Hydrophilic Matrix Systems",
2006 and marketed under the trade name METHOCEL (methylcellulose
and hydroxypropyl methylcellulose (HPMC) polymers). The course and
duration of administration of and the dosage requirements for the
formulation of the present invention will vary according to the
animal or human being treated, the formulation used, the method of
administration used, the severity of the condition being treated,
the co-administration of other drugs, and other factors.
[0072] Increased bioavailability can be achieved using HME
processing by tuning the interactions between the drug (e.g., DHM)
and the HME polymer. For example, the drug (e.g., DHM) can be
substantially soluble in the molten polymer phase, which can
include one or more excipient(s) and/or plasticizers, such that
upon cooling and solidification, that drug is prevented from
substantially crystallizing. Capturing the drug (e.g., DHM) in an
amorphous, or non-crystalline-associated state (which can be a
high-energy state), can result in a higher dissolution level or a
supersaturation level, when dissolved in vitro or in vivo.
Thermodynamic reasons for this increase in solubility have been
discussed by Hu, Johnson & Williams.[36]
[0073] Commercially supplied pure DHM can be entirely (100%) or
nearly entirely crystalline.
[0074] The crystallinity of the DHM in the hot-melt extruded (HME)
formulation can be qualitatively assessed or quantitatively
measured by techniques, such as polarized light microscopy (PLM),
differential scanning calorimetry (DCS), and powder X-ray
diffraction (P-XRD). The DHM in the hot-melt extruded (HME)
formulation can have a crystallinity of less than or equal to 90%,
80%, 60%, 50%, 40%, 30%, 20%, 25%, 20%, 15%, 10%, 7%, 5%, 3%, 2%,
or 1%. The DHM in the hot melt extruded formulation (extrudate) can
be amorphous.
Dissolution/Kinetics Studies
[0075] In an embodiment, the DHM in the hot melt extrusion
formulation (extrudate) does not dissolve in and/or is not
solubilized by an aqueous solution having a pH of at most (i.e.,
less than or equal to) 4.8, 4.5, 4, 3.5, 3.2, 3, 2.7, 2.5, 2.3, 2,
1.8, 1.5, or 1. The chyme that is expelled by the stomach, through
the pyloric valve, has a pH of approximately 2. Gastric juices lead
to material in the stomach having a pH in the range of from 1.5 to
3.5, and this low pH in the stomach and the enzymes active in the
stomach at this low pH may result in degradation of DHM and
quenching of DHM activity.
[0076] In an embodiment, the DHM in the hot-melt extruded (HME)
formulation dissolves in and/or is solubilized by water (pH of 7)
and/or an aqueous solution having a pH of at least (i.e., greater
than or equal to) 5, 5.3, 5.5, 5.8, 6, 6.2, 6.5, 6.7, 7, 7.2, or
7.5. Bile released into the duodenum and/or pancreatic secretions
of sodium bicarbonate increase the pH of the chyme. For example,
the pH of chyme and material in the intestine (bowel) can range
from 5.5 to 7, for example, can be 7. The dissolution and/or
solubilization of the DHM in the hot melt extruded formulation in
the intestine, for example, the small intestine, can result in the
DHM being absorbed by the wall of the intestine, for example, the
wall of the small intestine, and into the blood.
[0077] For example, hydroxypropyl methyl cellulose acetate
succinate (HPMCAS) is insoluble in an aqueous solution of acidic
(low) pH, but is soluble in an aqueous solution of neutral or
alkaline (high) pH. Therefore, a hot-melt extruded (HME)
formulation including HPMCAS and DHM can retain the DHM at an
acidic (low) pH, e.g., a pH of 3.5 or less, but release the DHM at
a neutral or alkaline (high) pH, e.g., a pH of 7 or greater.
[0078] A pH buffering agent can be included in such a hot-melt
extruded (HME) formulation.
[0079] Inclusion of an acidic component in such a hot-melt extruded
(HME) formulation, such as an acidic pH buffering agent (i.e., a
buffering agent that maintains an acidic pH, a pH of less than 7),
e.g., citric acid or a citrate salt (e.g., a sodium citrate, a
potassium citrate, calcium citrate, and/or combinations), can
stabilize an aqueous solution formed with the hot-melt extruded
(HME) formulation, so that the DHM is not released into the aqueous
solution or so that the release of the DHM into the aqueous
solution is delayed.
[0080] The polymer matrix material can be selected, so that it is
moderately soluble (e.g., from 0.01 g/100 mL to 3 g/100 mL, or from
0.1 g/100 mL to 1 g/100 mL) in water. Moderate solubility in water
allows the polymer matrix material to dissolve in the body of an
organism and release the DHM.
[0081] The dissolution and release kinetics of DHM are studied
under different conditions; three protocols are described as
follows. [37]
[0082] Release Kinetics in Vitro: Simulated gastric fluid (FaSSGF)
and intestinal fluids (FaSSIF and FeSSIF) are prepared according to
the manufacturer's instructions. Dissolution tests are performed
with hot-melt extruded (HME) DHM-containing powders or tablets with
the appropriate controls.
[0083] Release under Gastric Conditions: DHM-containing hot melt
extruded (HME) powder samples are suspended in prewarmed FaSSGF
(37.degree. C.) to achieve a drug (DHM) concentration of roughly
10-100.times. the previously determined equilibrium solubility in
the FaSSGF fluid (e.g., 75 .mu.g/mL) by pipetting up and down
vigorously multiple times. The samples are incubated for the
duration of the study (e.g., 30 min) at 37.degree. C. (NesLab
RTE-111 bath circulator, Thermo Fisher Scientific, Waltham, Mass.)
without agitation to mimic physiological gastric conditions and
transition time in the stomach. Aliquots can be taken, for example,
at 1, 5, 10, 15, 30, 60, 120, and 360 min. To analyze the free DHM
concentration, each aliquot can be centrifuged at 28000 g for 5 min
to pellet suspended particles. The supernatant is frozen and
lyophilized; the remaining solids are reconstituted in, for
example, 2:8 THF (tetrahydrofuran):acetonitrile to dissolve DHM and
precipitate out lipids and salts from the release media. The
samples are then diluted as appropriate to fall within the
detection range and analyzed by high-performance liquid
chromatography (HPLC), with the mobile phase as 80:20
H.sub.2O:acetonitrile (each with 0.05% trifluoroacetic acid), and
with detection with UV-Vis at 290 nm. The concentration of DHM is
then calculated based on a calibration curve.
[0084] Release under Intestinal Conditions: DHM-containing hot melt
extruded (HME) powder samples are suspended in prewarmed
(37.degree. C.) Fed State Simulated Intestinal Fluid (FeSSIF) or
Fasted State Simulated Intestinal Fluid (FaSSIF) to achieve a drug
(DHM) concentration of roughly 10-100.times. the previously
determined equilibrium solubility in the FeSSIF or FaSSIF fluid by
pipetting up and down vigorously multiple times. The equilibrium
solubility of crystalline DHM in FeSSIF was measured to be about
140 .mu.g/mL, and the equilibrium solubility of crystalline DHM in
FaSSIF is about 50 .mu.g/mL. Aliquots are taken at, for example, 1,
5, 10, 15, 30, 60, 120, and 360 min and centrifuged at, for
example, 28000 g for 10 min. The supernatant is frozen and
lyophilized; the remaining solids are reconstituted in, for
example, 2:8 THF (tetrahydrofuran):acetonitrile to dissolve DHM and
precipitate out lipids and salts from the release media. The
samples are then diluted as appropriate to fall within the
detection range and analyzed by HPLC, with the mobile phase as
80:20 H.sub.2O:acetonitrile (each with 0.05% trifluoroacetic acid),
and with detection with UV-Vis at 290 nm. The concentration of DHM
is then calculated based on a calibration curve.
[0085] FaSSIF is a biorelevant intestinal media representing the
fasted state intestinal fluid, and FeSSIF is another biorelevant
intestinal media representing the fed state intestine fluid. FaSSIF
and FeSSIF have different compositions. For example, components of
FaSSIF include 3 mM taurocholate, 0.75 mM phospholipids, 148 mM
sodium, 106 mM chloride, and 29 mM phosphate, while components of
FeSSIF include 15 mM taurocholate, 3.75 mM phospholipids, 319 mM
sodium, 203 mM chloride, and 144 mM acetic acid. In in vivo tests,
the presence of food changes the pH and composition of fats and
surfactants in the intestinal fluid. FaSSIF has a higher pH (6.5)
than FeSSIF (5.0) and has lower levels of fat.
[0086] The intestine can be the site of absorption for oral dosage
forms, thus understanding the solubility of a drug or active
ingredient in the intestinal fluid can be important.
[0087] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fasted state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 15 minutes over that of pure DHM.
[0088] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fed state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 15 minutes over that of pure DHM.
[0089] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fasted state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 30 minutes over that of pure DHM.
[0090] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fed state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 30 minutes over that of pure DHM.
[0091] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fasted state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 60 minutes over that of pure DHM.
[0092] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fed state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 60 minutes over that of pure DHM.
[0093] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fasted state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 120 minutes over that of pure DHM.
[0094] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fed state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 120 minutes over that of pure DHM.
[0095] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fasted state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 360 minutes over that of pure DHM.
[0096] For example, the dissolution kinetics of DHM in a hot-melt
extruded (HME) formulation in an embodiment of the present
invention in in vitro dissolution tests in simulated fed state
fluid can be increased by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%,
100%, or 250% after 360 minutes over that of pure DHM.
Animal PK Studies
[0097] DHM-containing samples (e.g., hot-melt extruded (HME)
formulations in an embodiment of the present invention) can be
administered (e.g., through oral gavage) to an animal (e.g., a rat
or a mouse) at 10 mg DHM/kg body weight, 75 mg DHM/kg body weight,
or another dosage in an in vivo study, and a pharmacokinetic study
can be carried out to evaluate animal pharmacokinetics. The plasma
concentration of DHM can be determined, for example, using a Waters
Acquity ultra performance liquid chromatography system equipped
with an electrospray ionization mass spectrometry system (Waters,
Milford, Mass.), in accordance with a previous report [38], or an
equivalent analytical analysis system.
[0098] An animal dosed with a hot melt extrusion formulation
containing DHM according to the present invention can show
increased blood maximum concentrations, relative to dosing with
pure DHM powder, of 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 100%,
250%. The area under the curve (AUC) for 24 hours can be increased
by 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 100%, 250% over the value
associated with dosing with pure DHM powder.
[0099] Several nonlimiting Aspects of the invention are set forth
below.
Aspect 1. A dihydromyricetin (DHM) formulation, comprising:
[0100] dihydromyricetin (DHM) and
[0101] a matrix material,
[0102] wherein the DHM is dispersed within the matrix material
and
[0103] wherein the matrix material is a solid.
Aspect 2. The DHM formulation of Aspect 1, wherein the matrix
material comprises a polymeric matrix material. Aspect 3. The DHM
formulation of any one of Aspects 1 through 2, wherein the matrix
material comprises cellulose and/or a cellulose derivative. Aspect
4. The DHM formulation of any one of Aspects 1 through 3, wherein
the matrix material comprises hydroxypropyl methyl cellulose
(HPMC). Aspect 5. The DHM formulation of any one of Aspects 1
through 4, wherein the matrix material comprises a material
selected from the group consisting of 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. Aspect 6. The DHM formulation of any one of Aspects 1
through 5, wherein the matrix material comprises polyethylene oxide
(PEO). Aspect 7. The DHM formulation of any one of Aspects 1
through 6, wherein the matrix material comprises a material
selected from the group consisting of
polyoxyethylene-polyoxypropylene block copolymers (also referred to
as poloxamers), polyoxyethylene alkyl ethers, polyoxyethylene
castor oils, a low molecular-weight oligomer of polyethylene
glycol, an ethylene glycol-vinyl glycol copolymer, polyoxyethylene
castor oils, ethoxylated castor oil, polyoxyl hydrogenated castor
oil,polyoxyl 40 hydrogenated castor oil, polyethoxylated sorbitan,
polyoxyethylene sorbitan monooleate, and combinations. Aspect 8.
The DHM formulation of any one of Aspects 1 through 7, wherein the
matrix material comprises a material selected from the group
consisting of polyvinyl pyrrolidone (PVP) and poly(vinyl
pyrrolidone-co-vinyl acetate) (PVP-VA). Aspect 9. The DHM
formulation of any one of Aspects 1 through 8, wherein the matrix
material comprises a material selected from the group consisting of
poly(methyl methacrylate) (PMMA), low molecular weight poly(methyl
methacrylate), polymethacrylate, methacrylic acid copolymers,
polymethacrylate derivatives, 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. Aspect 10. The DHM formulation of any one of Aspects
1 through 9, wherein the matrix material comprises a material
selected from the group consisting of polycaprolactam,
polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid
(PGA), poly(lactic-glycolic acid) (PLGA), and combinations. Aspect
11. The DHM formulation of any one of Aspects 1 through 10, 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. Aspect 12. The DHM formulation
of any one of Aspects 1 through 11, further comprising a
plasticizer. Aspect 13. The DHM formulation of Aspect 12, 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) (e.g., having an average molecular weight of
less than about 500,000 Da), and 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 and
other poly(ethylene glycol) compounds, 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, and combinations. Aspect 14. The DHM formulation of any
one of Aspects 12 and 13, wherein the plasticizer comprises a
plasticizer selected from the group consisting of triacetin,
vitamin E, pressurized CO.sub.2, citrate ester, triethyl citrate,
acetyl triethyl citrate, tributyl citrate, and combinations. Aspect
15. The DHM formulation of any one of Aspects 12 through 14,
wherein the plasticizer comprises a plasticizer selected from the
group consisting of a low molecular weight polymer, an oligomer, a
copolymers, an oil, a small organic molecule, an ester-type
plasticizer, a multi-block polymer, a single block polymer, a
molecular surfactant, styrene, a glycol, a glycol ether, and
combinations. Aspect 16. The DHM formulation of any one of Aspects
1 through 15, further comprising a permeabilizer. Aspect 17. The
DHM formulation of Aspect 16, wherein the permeabilizer comprises
caprylic acid, a caprylate salt, and/or sodium caprylate. Aspect
18. The DHM formulation of any one of Aspects 16 and 17, 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. Aspect 19. The DHM
formulation of any one of Aspects 1 through 18, further comprising
a coactive. Aspect 20. The DHM formulation of Aspect 19, wherein
the coactive comprises an antioxidant. Aspect 21. The DHM
formulation of any one of Aspects 19 and 20, wherein the coactive
is glutathione. Aspect 22. The DHM formulation of any one of
Aspects 19 through 21, wherein the coactive is L-cysteine. Aspect
23. The DHM formulation of any one of Aspects 19 through 22,
wherein the coactive is selected from the group consisting of
N-acetyl cysteine (NAC), Prickly Pear extract, Milk Thistle, ginger
toot, vitamin B, vitamin C, vitamin E, and combinations. Aspect 24.
The DHM formulation of any one of Aspects 19 through 23, wherein
the coactive comprises an electrolyte and/or a sugar. Aspect 25.
The DHM formulation of any one of Aspects 1 through 24, further
comprising a pH buffering agent. Aspect 26. The DHM formulation of
Aspect 25, wherein the pH buffering agent is an acidic pH buffering
agent. Aspect 27. The DHM formulation of Aspect 26, wherein the
acidic pH buffering agent comprises citric acid, a citrate salt, a
sodium citrate, a potassium citrate, calcium citrate, and/or
combinations. Aspect 28. The DHM formulation of any one of Aspects
1 through 27, wherein the DHM is not solubilized or dissolved by an
aqueous solution having a pH of at most 3.5. Aspect 29. The DHM
formulation of any one of Aspects 1 through 28, wherein the DHM is
not solubilized or dissolved by an aqueous solution having a pH of
at most 2. Aspect 30. The DHM formulation of any one of Aspects 1
through 29, wherein the DHM is solubilized or dissolved by an
aqueous solution having a pH of at least 5.5. Aspect 31. The DHM
formulation of any one of Aspects 1 through 29, wherein the DHM is
solubilized or dissolved by water or an aqueous solution having a
pH of at least 7. Aspect 32. The DHM formulation of any one of
Aspects 1 through 31, wherein the DHM comprises at least 5 wt % of
the powder. Aspect 33. The DHM formulation of any one of Aspects 1
through 31, wherein the DHM comprises at least 20 wt % of the
powder. Aspect 34. The DHM formulation of any one of Aspects 1
through 31, wherein the DHM comprises at least 40 wt % of the
powder. Aspect 35. The DHM formulation of any one of Aspects 1
through 31, wherein the DHM comprises at least 55 wt % of the
powder. Aspect 36. The DHM formulation of any one of Aspects 1
through 35, wherein the crystallinity of the DHM is at most 20%
Aspect 37. The DHM formulation of any one of Aspects 1 through 35,
wherein the crystallinity of the DHM is at most 10%. Aspect 38. The
DHM formulation of any one of Aspects 1 through 35, wherein the
crystallinity of the DHM is at most 5%. Aspect 39. The DHM
formulation of any one of Aspects 1 through 35, wherein the
crystallinity of the DHM is at most 2%. Aspect 40. The DHM
formulation of any one of Aspects 1 through 35, wherein the DHM is
amorphous. Aspect 41. The DHM formulation of any one of Aspects 1
through 40, wherein the DHM formulation is homogeneous and/or
molecularly dispersed. Aspect 42. A dosage form, comprising
[0104] the DHM formulation of any one of Aspects 1 through 41,
and
[0105] an enteric coating that encapsulates the DHM
formulation.
Aspect 43. The dosage form of Aspect 42, wherein the enteric
coating is a polymeric coating. Aspect 44. The dosage form of
Aspect 42, wherein the enteric coating is a methacrylate copolymer
coating. Aspect 45. The dosage form of any one of Aspects 42
through 44, wherein the dosage form is a capsule, tablet, or pill.
Aspect 46. A dosage form, comprising
[0106] the DHM formulation of any one of Aspects 1 through 41 in a
powder form, and
[0107] an aqueous liquid,
[0108] wherein the DHM formulation in a powder form is mixed with
or suspended in the liquid.
Aspect 47. A dosage form, comprising
[0109] the DHM formulation of any one of Aspects 1 through 41 in a
powder form, and
[0110] a gel,
[0111] wherein the DHM formulation in a powder form is mixed with
or suspended in the gel.
Aspect 48. The DHM formulation of Aspect 1,
[0112] wherein the matrix material is polyethylene oxide (PEO),
and
[0113] wherein the DHM comprises at least 5 wt % of the DHM
formulation.
Aspect 49. The DHM formulation of Aspect 1,
[0114] wherein the matrix material is hydroxypropyl methylcellulose
(HPMC), and
[0115] wherein the DHM comprises at least 5 wt % of the DHM
formulation.
Aspect 50. A method for forming a dihydromyricetin (DHM)
formulation of any one of Aspects 1 through 41, Aspect 48, and
Aspect 49 or the dosage form according to any one of Aspects 42
through 47, comprising:
[0116] mixing the dihydromyricetin (DHM) and the matrix material to
form a compounding mixture;
[0117] processing the compounding mixture in an extruder to form an
extrudate; and
[0118] collecting the extrudate as the dihydromyricetin (DHM)
formulation.
Aspect 51. The method of Aspect 50, further comprising grinding the
extrudate into a powder. Aspect 52. The method of Aspect 51,
further comprising filling the powder into a capsule or pressing
the powder into a tablet. Aspect 53. The method of Aspect 50,
comprising,
[0119] mixing the dihydromyricetin (DHM) and polyethylene oxide
(PEO) as the matrix material to form the compounding mixture;
[0120] wherein the weight ratio of DHM to PEO is 5:95,
[0121] processing the compounding mixture in the extruder to form
the extrudate; and
[0122] collecting the extrudate as the dihydromyricetin (DHM)
formulation.
Aspect 54. The method of Aspect 50, comprising,
[0123] mixing the dihydromyricetin (DHM) and hydroxypropyl
methylcellulose (HPMC) as the matrix material to form the
compounding mixture;
[0124] wherein the weight ratio of DHM to HPMC is 5:95,
[0125] processing the compounding mixture in the extruder to form
the extrudate; and
[0126] collecting the extrudate as the dihydromyricetin (DHM)
formulation.
Aspect 55. The dihydromyricetin (DHM) formulation of any one of
Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage form
according to any one of Aspects 42 through 47 for use as a
medicament. Aspect 56. The dihydromyricetin (DHM) formulation of
any one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the
dosage form according to any one of Aspects 42 through 47 for use
in reducing hangover symptoms. Aspect 57. The dihydromyricetin
(DHM) formulation of any one of Aspects 1 through 41, Aspect 48,
and Aspect 49 or the dosage form according to any one of Aspects 42
through 47 for use in preventing an alcohol use disorder. Aspect
58. The dihydromyricetin (DHM) formulation of any one of Aspects 1
through 41, Aspect 48, and Aspect 49 or the dosage form according
to any one of Aspects 42 through 47 for use in preventing
alcoholism. Aspect 59. The dihydromyricetin (DHM) formulation of
any one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the
dosage form according to any one of Aspects 42 through 47 for use
in treating an alcohol use disorder. Aspect 60. The
dihydromyricetin (DHM) formulation of any one of Aspects 1 through
41, Aspect 48, and Aspect 49 or the dosage form according to any
one of Aspects 42 through 47 for use in treating alcoholism. Aspect
61. The dihydromyricetin (DHM) formulation of any one of Aspects 1
through 41, Aspect 48, and Aspect 49 or the dosage form according
to any one of Aspects 42 through 47 for use in treating an alcohol
overdose. Aspect 62. The dihydromyricetin (DHM) formulation of any
one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage
form according to any one of Aspects 42 through 47 for use in
increasing antioxidant capacity. Aspect 63. The dihydromyricetin
(DHM) formulation of any one of Aspects 1 through 41, Aspect 48,
and Aspect 49 or the dosage form according to any one of Aspects 42
through 47 for use in neuroprotection. Aspect 64. The
dihydromyricetin (DHM) formulation of any one of Aspects 1 through
41, Aspect 48, and Aspect 49 or the dosage form according to any
one of Aspects 42 through 47 for use in preventing Alzheimer's
disease. Aspect 65. The dihydromyricetin (DHM) formulation of any
one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage
form according to any one of Aspects 42 through 47 for use in
treating Alzheimer's disease. Aspect 66. The dihydromyricetin (DHM)
formulation of any one of Aspects 1 through 41, Aspect 48, and
Aspect 49 or the dosage form according to any one of Aspects 42
through 47 for use in inhibiting inflammation. Aspect 67. The
dihydromyricetin (DHM) formulation of any one of Aspects 1 through
41, Aspect 48, and Aspect 49 or the dosage form according to any
one of Aspects 42 through 47 for use in protection of the kidney.
Aspect 68. The dihydromyricetin (DHM) formulation of any one of
Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage form
according to any one of Aspects 42 through 47 for use in protection
of the liver. Aspect 69. The dihydromyricetin (DHM) formulation of
any one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the
dosage form according to any one of Aspects 42 through 47 for use
in preventing or treating cancer. Aspect 70. The dihydromyricetin
(DHM) formulation of any one of Aspects 1 through 41, Aspect 48,
and Aspect 49 or the dosage form according to any one of Aspects 42
through 47 for use in ameliorating a metabolic disorder. Aspect 71.
The dihydromyricetin (DHM) formulation of any one of Aspects 1
through 41, Aspect 48, and Aspect 49 or the dosage form according
to any one of Aspects 42 through 47 for use in preventing diabetes.
Aspect 72. The dihydromyricetin (DHM) formulation of any one of
Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage form
according to any one of Aspects 42 through 47 for use in treating
diabetes. Aspect 73. The dihydromyricetin (DHM) formulation of any
one of Aspects 1 through 41, Aspect 48, and Aspect 49 or the dosage
form according to any one of Aspects 42 through 47 for use in
treating a bacterial infection. Aspect 74. Use of the
dihydromyricetin (DHM) formulation of any one of Aspects 1 through
41, Aspect 48, and Aspect 49 in the manufacture of a medicament for
reducing hangover symptoms. Aspect 75. Use of the dihydromyricetin
(DHM) formulation of any one of Aspects 1 through 41, Aspect 48,
and Aspect 49 in the manufacture of a medicament for preventing an
alcohol use disorder, preventing alcoholism, treating an alcohol
use disorder, treating alcoholism, and/or treating an alcohol
overdose. Aspect 76. Use of the dihydromyricetin (DHM) formulation
of any one of Aspects 1 through 41, Aspect 48, and Aspect 49 in the
manufacture of a medicament for neuroprotection, preventing
Alzheimer's disease, and/or treating Alzheimer's disease. Aspect
77. Use of the dihydromyricetin (DHM) formulation of any one of
Aspects 1 through 41, Aspect 48, and Aspect 49 in the manufacture
of a medicament for ameliorating a metabolic disorder, preventing
diabetes, and/or treating diabetes. Aspect 78. Use of the
dihydromyricetin (DHM) formulation of any one of Aspects 1 through
41, Aspect 48, and Aspect 49 in the manufacture of a medicament for
increasing antioxidant capacity, inhibiting inflammation,
protecting the kidney, protecting the liver, preventing and/or
treating cancer, and/or treating a bacterial infection. Aspect 79.
The DHM formulation of any one of Aspects 1 through 41, Aspect 48,
and Aspect 49, so that mixing of the DHM formulation with a solvent
results in a concentration of DHM dissolved in the solvent that is
at least 20%, 50%, 70%, 100%, 200%, 400%, or 900% greater than the
equilibrium concentration of crystalline DHM dissolved in the
solvent. Aspect 80. The DHM formulation of Aspect 79, wherein the
solvent is an aqueous solvent. Aspect 81. The DHM formulation of
Aspect 79, wherein the solvent is an aqueous solvent of pH in the
range of 4.5 to 7.0. Aspect 82. The DHM formulation of Aspect 79,
wherein the solvent is an aqueous solvent of pH in the range of 4.5
to 7.0 and comprising sodium at a concentration of from 100 mM to
400 mM. Aspect 83. The DHM formulation of Aspect 79, wherein the
solvent is an aqueous solvent of pH in the range of 4.5 to 7.0 and
comprising sodium at a concentration of from 100 mM to 400 mM and a
surfactant at a concentration of from 0.01 wt % to 2 wt %. Aspect
84. The DHM formulation of Aspect 79, wherein the solvent is an
aqueous solvent of pH in the range of 4.5 to 7.0 and comprising
sodium at a concentration of from 100 mM to 400 mM and a nonionic
surfactant at a concentration of from 0.05 wt % to 1.5 wt %. Aspect
85. The DHM formulation of Aspect 79, wherein the solvent is fed
state simulated intestinal fluid (FeSSIF). Aspect 86. The DHM
formulation of Aspect 79, wherein the solvent is fed state
simulated intestinal fluid (FeSSIF) further comprising polysorbate
at a concentration of about 1 wt %. Aspect 87. The DHM formulation
of Aspect 79, wherein the solvent is fasted state simulated
intestinal fluid (FaSSIF). Aspect 88. The DHM formulation of Aspect
79, wherein the solvent is fasted state simulated intestinal fluid
(FaSSIF) further comprising polysorbate at a concentration of about
1 wt %.
EXAMPLES
[0127] The following example(s) provide descriptions of embodiments
of the invention. It is recognized that departures from the
disclosed embodiment may be made within the scope of the invention
and that obvious modifications will occur to a person skilled in
the art. The claims and specification should not be construed to
unduly narrow the full scope of protection to which the invention
is entitled.
Example 1: Preparation of a DHM--Poly(Ethylene Oxide) Hot-Melt
Extruded (HME) Formulation
[0128] An amount of dihydromyricetin (DHM) sufficient to provide an
effective amount of the formulation may be mixed with a known
amount of polyethylene oxide (PEO) polymer. The weight ratio of DHM
to polymer may be about 5:95. The mixture may then be placed into
an extruder hopper. The extruder used should include a
solids-conveying mechanism (e.g., a screw or twin screws) that
extends from the hopper through a heating zone to the extrusion
die. The mixture is passed through the heated extruder at a
temperature range which may be from about 100.degree. C. to about
140.degree. C., as set by the temperature setting of the extruder
heating zone, so that melting or softening of the PEO occurs. Upon
exiting the die, the extrudate (PEO/DHM) may be chopped to the
desired length. The extrudate may then be, for example, ground to a
powder and filled into a capsule or pressed into a tablet.
Example 2: Preparation of a DHM--Cellulosic Hot-Melt Extruded (HME)
Formulation
[0129] An amount of dihydromyricetin (DHM) sufficient to provide an
effective amount of the formulation may be mixed with a known
amount of cellulose-derived AFFINISOL.TM. HPMC HME hydroxypropyl
methylcellulose (HPMC) polymer of low to medium molecular
weight.
[0130] The weight ratio of DHM to polymer may be about 5:95. The
mixture may then be placed into an extruder hopper. The extruder to
be used should include a solids-conveying mechanism (e.g., a screw
or twin screws) that extends from the hopper through a heating zone
to the extrusion die. The mixture is passed through the heated
extruder at a temperature range which may be from about 100.degree.
C. to about 155.degree. C., as set by the temperature setting of
the extruder heating zone, so that the polymer is sufficiently
melted or softened. Upon exiting the die, the extrudate (HPMC/DHM)
may be chopped to the desired length. The extrudate may then be,
for example, ground to a powder, filled into a capsule, or pressed
into a tablet.
Example 3: Preparation of a DHM--Poly(Vinylpyrrolidone-Co-Vinyl
Acetate) (PVP-VA) Hot-Melt Extruded (HME) Formulation
[0131] An amount of dihydromyricetin (DHM) sufficient to provide an
effective amount of the formulation was mixed with a known amount
of poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA). The PVP-VA
used was BASF Kollidon VA 64, which is an amorphous copolymer
having 60% vinylpyrrolidone and 40% vinyl acetate, a molecular
weight of about 45,000 g/mol, and a glass-transition temperature
(Tg) measured to be 109.degree. C. The DHM and PVP-VA were mixed
and ground by hand in a mortar and pestle to form a physical
mixture that was fed to an extruder. A HAAKE Mini-Lab II extruder
having a chamber volume of 7 cm.sup.3, counter-rotating twin
screws, and an internal recirculation channel was used.
Approximately 5 g of the physical mixture of DHM and PVP-VA was
loaded into the extruder. The mixture was passed through the heated
extruder at about 160.degree. C., with the extruder operated at
30-50 rpm. Approximately 5 min loading time, 5 min recirculation
time, and 5 min unloading time were used. The extrudate was then
collected as the dihydromyricetin (DHM) formulation.
[0132] In the exemplary extrudate produced, the drug (DHM) loading
in the extrudate was 20 wt %, i.e., the weight ratio of DHM:PVP-VA
was 20:80. (For example, in other cases, the weight ratio of DHM to
PVP-VA may be about 5:95, 10:90, 30:70, 40:60, 50:50, 60:40, or
80:20.)
[0133] The DHM/PVP-VA (20/80) extrudate from this hot melt
extrusion (HME) was darker brown and uniform in color and somewhat
opaque, indicating that the DHM was uniformly dispersed in the
extrudate. The glass-transition temperature (Tg) of this DHM/PVP-VA
(20/80) HME extrudate was 126.degree. C. The PVP-VA in the
DHM/PVP-VA (20/80) extrudate was amorphous.
[0134] In comparison, extruded PVP-VA polymer (without DHM) was
lighter brown in color and more translucent. The Tg of this
extruded PVP-VA polymer was measured to be 108.degree. C., the same
as the bulk PVP-VA (BASF Kollidon VA64) copolymer, indicating that
extrusion did not change the Tg of the polymer. The PVP-VA in the
extrudate was amorphous.
[0135] The melting temperature (point) Tm of DHM is approximately
240.degree. C.-256.degree. C., for example, about 240.degree. C.
Thus, the operating temperature of the extruder, about 160.degree.
C. was less than the melting temperature of the DHM. Without being
bound by theory, the DHM was thought to have dissolved into the
molten PVP-VA polymer in the extruder.
[0136] The Tg of DHM is inferred to be less than 120.degree. C.
That is, a spray dried dispersion (SDD) of DHM and hydroxypropyl
methylcellulose acetate succinate (HPMCAS) exhibited an
intermediate Tg less than the Tg of HPMCAS (.about.120.degree. C.),
so that the Tg of DHM is inferred to be less than the Tg of
HPMCAS.
[0137] Thus, the Tg of the DHM/PVP-VA (20/80) HME extrudate
(126.degree. C.) was greater than the Tg of the DHM (less than
120.degree. C.) and was greater than the Tg of the PVP-VA matrix
(about 108.degree. C.).
Example 4: Characterization of DHM Release from a DHM--Matrix
Hot-Melt Extruded (HME) Formulation
[0138] In vitro release data may be obtained to allow comparison of
the concentration of DHM in a liquid yielded by starting
crystalline DHM material with the concentration of DHM in a liquid
yielded by a DHM--matrix HME formulation over a time period, such
as a 6-hour time period with sampling timepoints at 1, 5, 10, 15,
30, 60, 120, and 360 minutes.
[0139] For example, the release study may be performed in fed state
simulated intestinal fluid (FeSSIF), with or without 1% v/v Tween
20 (Polysorbate 20) having been added. The fluid may be maintained
at a temperature of 37.degree. C. for the duration of the
experiment. For each study, the starting crystalline DHM material
or the HME formulation may be loaded into a separate volume of
prepared FeSSIF fluid at a concentration substantially greater than
the equilibrium solubility of DHM in FeSSIF (140 .mu.g/mL). For
example, the starting crystalline DHM material or the HME
formulation may be loaded into the prepared FeSSIF fluid at a DHM
concentration of 1400 .mu.g/mL, 10 times the equilibrium solubility
of crystalline DHM in FeSSIF, or at a DHM concentration of 7 mg/mL,
50 times the equilibrium solubility of DHM in FeSSIF. (The excess
DHM loaded into the release media enables detection and
quantitation of potentially supersaturated dissolved DHM
concentrations that a given formulation may provide.) At the
completion of the release studies, the HME formulation may be found
to produce a supersaturated DHM concentration that is greater than
that of the crystalline DHM.
[0140] Such release studies may establish that the HME formulation
will release a concentration of dissolved DHM into a patient's
intestine that is greater than the concentration of dissolved DHM
released by crystalline DHM. The greater concentration of dissolved
DHM released into the patient's intestine may result in the HME
formulation promoting uptake of DHM into the overall system (body)
of the patient that is greater than the DHM uptake when crystalline
DHM is administered, by way of an increased concentration driving
force of the DHM across the membrane of the intestine.
[0141] The embodiments illustrated and discussed in this
specification are intended only to teach those skilled in the art
the best way known to the inventors to make and use the invention.
Nothing in this specification should be considered as limiting the
scope of the present invention. All examples presented are
representative and non-limiting. The above described embodiments of
the invention may be modified or varied, without departing from the
invention, as appreciated by those skilled in the art in light of
the above teachings. It is therefore to be understood that, within
the scope of the claims and their equivalents, the invention may be
practiced otherwise than as specifically described.
REFERENCES
[0142] 1. Powell, B. A. R., COMPOSITIONS AND METHODS FOR PREVENTING
AND RECOVERY FROM DETRIMENTAL EFFECTS OF ALCOHOL CONSUMPTION, U.S.
Pat. No. 9,603,830, (Mar. 28, 2017), THRIVEPLUS LLC: USA. [0143] 2.
Shen, Y., et al., Dihydromyricetin As a Novel Anti Alcohol
Intoxication Medication. The Journal of Neuroscience, 2012. 32(1):
p. 390-401. [0144] 3. Breitenbach, J., Melt extrusion: from process
to drug delivery technology. European Journal of Pharmaceutics and
Biopharmaceutics, 2002. 54(2): p. 107-117. [0145] 4. Chokshi, R.
and H. Zia, Hot-melt extrusion technique: a review. Iranian Journal
of Pharmaceutical Research, 2010: p. 3-16. [0146] 5. Crowley, M.
M., et al., Pharmaceutical applications of hot-melt extrusion: part
I. Drug development and industrial pharmacy, 2007. 33(9): p.
909-926. [0147] 6. Maniruzzaman, M., et al., A review of hot-melt
extrusion: process technology to pharmaceutical products. ISRN
pharmaceutics, 2012. 2012. [0148] 7. Patil, H., R. V. Tiwari, and
M. A. Repka, Hot-Melt Extrusion: from Theory to Application in
Pharmaceutical Formulation. AAPS PharmSciTech, 2015. 17(1): p.
20-42. [0149] 8. Liang, J., R. Olsen, and I. Spigelman, Methods of
treating alcohol intoxication, alcohol use disorders, and alcohol
abuse which comprise the administration of dihydromyricetin, in
Google Patents. 2012, The Regents of the University of California.
[0150] 9. Thomson, J. E., J. John V. Landry, and M. W. Zembal,
HOT-MELT EXTRUSION COATING OF RANDOM COPOLYMER OF ETHYLENE AND
MONO-CARBOXYLIC ACID, in Google Patents. 1966, The Dow Chemical
Company: USA. [0151] 10. Schippers, H. and Remscheid-Lennep,
APPARATUS FOR HOT MELT EXTRUSION, in Google Patents, U. PTO,
Editor. 1968, Barmer Maschinenfabrik Aktiengesellschaft
Wuppertal-Oberbarmen, Germany. [0152] 11. McGinity, J. W. and F.
Zhang, Hot-melt extrudable pharmaceutical formulation in Google
Patents, U. PTO, Editor. 2002, University of Texas System: USA.
[0153] 12. Miller, D. A., et al., STABILIZED HME COMPOSITION WITH
SMALL DRUG PARTICLES, in Google Patents. 2008, BOARD OF REGENTS,
THE UNIVERSITY OF TEXAS SYSTEM, Austin, Tex. (US): USA. [0154] 13.
Alderman, D. A. and T. D. Wolford, Sustained release dosage form
based on highly plasticized cellulose ether gels, in Google
Patents. 1987, The Dow Chemical Company: USA. [0155] 14. Brough,
C., et al., THERMOKINETIC MIXING FOR PHARMACEUTICAL APPLICATIONS,
in Google Patents. 2009, BOARD OF REGENTS, THE UNIVERSITY OF TEXAS
SYSTEM, Austin, Tex. (US): USA. [0156] 15. Fischer, G., et al.,
MATRIX COMPOSITIONS FOR CONTROLLED DELIVERY OF DRUG SUBSTANCES, in
Google Patents. 2007, EGALET A/S, Vaerlose (Denmark): USA. [0157]
16. Yang, R. K., et al., UNIFORM FILMS FOR RAPID DISSOLVE DOSAGE
FORM INCORPORATING TASTE-MASKING COMPOSITIONS, in Google Patents.
2008, MONOSOLRX LLC, Portage, Ind. (US): USA. [0158] 17. Fuisz, R.
C., et al., POLYMER-BASED FILMS AND DRUG DELIVERY SYSTEMS MADE
THEREFROM, in Google Patents. 2007: USA. [0159] 18. Bernstein, H.,
et al., MATRICES FORMED OF POLYMER AND HYDROPHOBC COMPOUNDS FOR USE
IN DRUG DELIVERY, in Google Patents, U. PTO, Editor. 2004,
Acusphere, Inc., Cambridge, Mass. (US): USA. [0160] 19.
MacAllister, S. M., et al., Pharmaceutical Formulation, in Google
Patents. 2004, SMITHKLINE BEECHAM CORPORATION. [0161] 20.
McAllister, S. M., et al., PHARMACEUTICAL FORMULATION, in Google
Patents. 2003, GLAXOSMITHKLINE. [0162] 21. Davies, D. L., et al.,
Recent advances in the discovery and preclinical testing of novel
compounds for the prevention and/or treatment of alcohol use
disorders. Alcoholism: Clinical and Experimental Research, 2013.
37(1): p. 8-15. [0163] 22. Liang, J., et al., Dihydromyricetin
prevents fetal alcohol exposure-induced behavioral and
physiological deficits: the roles of GABAA receptors in
adolescence. Neurochemical research, 2014. 39(6): p. 1147-1161.
[0164] 23. Shen, Y., et al., Dihydromyricetin as a novel
anti-alcohol intoxication medication. Journal of Neuroscience,
2012. 32(1): p. 390-401. [0165] 24. Ji, Y., J. Li, and P. Yang,
Effects of fruits of Hovenia dulcis Thunb on acute alcohol toxicity
in mice. Zhong yao cai=Zhongyaocai=Journal of Chinese medicinal
materials, 2001. 24(2): p. 126-128. [0166] 25. Fang, H.-L., et al.,
Treatment of chronic liver injuries in mice by oral administration
of ethanolic extract of the fruit of Hovenia dulcis. The American
journal of Chinese medicine, 2007. 35(04): p. 693-703. [0167] 26.
Hase, K., et al., Hepatoprotective Effect of Hovenia dulcis THUNB.
on Experimental Liver Injuries Induced by Carbon Tetrachloride or
D-Galactosamine: Lipopolysaccharide. Biological and pharmaceutical
Bulletin, 1997. 20(4): p. 381-385. [0168] 27. Ji, Y., et al.,
Effects of Hovenia dulcis Thunb on blood sugar and hepatic glycogen
in diabetic mice. Zhong yao cai=Zhongyaocai=Journal of Chinese
medicinal materials, 2002. 25(3): p. 190-191. [0169] 28. Okuma, Y.,
et al., Effect of extracts from Hovenia dulcis Thunb. alcohol
concentration in rats and men administered alcohol. Journal of
Japanese Society of Nutrition and Food Science (Japan), 1995.
[0170] 29. WANG, X.-y. and Z.-t. JIANG, RESEARCH PROGRESS IN
NATURAL ANTIOXIDANT DIHYDROMYRICETIN [J]. Food Research and
Development, 2007. 2: p. 056. [0171] 30. Zhang, X., et al.,
Scavenging effect of dihydromyricetin on the free radicals by ESR.
Modern Food Science and Technology, 2010. 26(10): p. 1040-1042,
1070. [0172] 31. Liu, B., et al., Characterization and antioxidant
activity of dihydromyricetin-lecithin complex. European Food
Research and Technology, 2009. 230(2): p. 325-331. [0173] 32.
Aungst, B. J., Absorption enhancers: applications and advances. The
AAPS journal, 2012. 14(1): p. 10-18. [0174] 33. Thanou, M., J.
Verhoef, and H. Junginger, Oral drug absorption enhancement by
chitosan and its derivatives. Advanced drug delivery reviews, 2001.
52(2): p. 117-126. [0175] 34. Whitehead, K., N. Karr, and S.
Mitragotri, Safe and effective permeation enhancers for oral drug
delivery. Pharmaceutical research, 2008. 25(8): p. 1782-1788.
[0176] 35. Whitehead, K. and S. Mitragotri, Mechanistic analysis of
chemical permeation enhancers for oral drug delivery.
Pharmaceutical research, 2008. 25(6): p. 1412-1419. [0177] 36. Hu,
J., K. P. Johnston, and R. O. Williams, Nanoparticle Engineering
Processes for Enhancing the Dissolution Rates of Poorly Water
Soluble Drugs. Drug development and industrial pharmacy, 2004.
30(3): p. 233-245. [0178] 37. Zhang, Y., et al., Design and
Solidification of Fast-Releasing Clofazimine Nanoparticles for
Treatment of Cryptosporidiosis. Molecular pharmaceutics, 2017.
14(10): p. 3480-3488. [0179] 38. Onoue, S., et al.,
Self-micellizing solid dispersion of cyclosporine A with improved
dissolution and oral bioavailability. Eur J Pharm Sci, 2014. 62: p.
16-22.
* * * * *