High molecular weight, lipophilic, orally ingestible bioactive agents in formulations having improved bioavailability
Orally ingestible bioactive agents are disclosed which contain a triglyceride matrix and one or more polyphenols that improve the bioavailability of the bioactive agent. In particular non-limiting examples, the bioactive agent is a ubiquinone (such as Coenzyme Q), the triglyceride matrix is a soybean oil matrix, and the composition further includes additional anti-oxidants.
1 . An oral dosage composition of a high molecular weight, lipophilic, bioactive agent, comprising:
a biologically effective amount of the bioactive agent;
a lipid matrix in which the bioactive agent is suspended, wherein the lipid matrix comprises about 85%-90% of the composition by weight; and
a sufficient amount of a polyphenol to improve gastrointestinal absorption of the bioactive agent when the dosage form is orally administered.
2 . The composition of claim 1 , wherein the lipid matrix comprises a triglyceride matrix that is a liquid at body temperature.
3 . The composition of claim 2 , wherein the triglyceride matrix comprises a soybean lipid matrix.
4 . The composition of claim 1 , wherein the bioactive agent has a molecular weight of at least 200.
5 . The composition of claim 4 , wherein the bioactive agent comprises one or more of a steroid; a steroid antagonist; a non-steroidal anti-inflammatory agent; an anti-hypertensive agent; an antioxidant; an anti-epileptic agent; an antibiotic; an antiviral agent; an anticancer agent; a neuroprotective agent; an anti-depressive agent; an enzyme; a coenzyme; a protein; a globulin; a vitamin; a retinoid; an immunological agent; a nucleotide; a lectin; or a growth factor.
6 . The composition of claim 3 , wherein the triglyceride lipid matrix comprises a mixture of refined soybean oil; mono-, di- and triglycerides, and polyglycerol oleate and/or polyglycerol dioleate.
7 . The composition of claim 6 , wherein the di- and triglycerides are glycerides having side chains with 16 to 18 carbons.
8 . The composition of claim 1 wherein the polyphenol comprises one or more of:
l) resveratrol;
m) Polygonum cuspidatum extract;
n) green tea extract;
o) grape extract;
p) grape seed extract;
q) blackberry extract;
r) blueberry extract;
s) cranberry extract;
t) elderberry extract;
u) black current extract; or
v) oolong tea extract.
9 . The composition of claim 1 wherein the polyphenol or mixture of polyphenols comprises one ore more of a di- and/or trihydroxyphenyl compound chosen from:
a) catechins and substituted catechins;
b) flavanols;
c) flavondiols;
d) theaflavins;
e) thearubigens;
f) anthocyanidin and substituted anthocyanidins;
g) rutin and substituted rutin;
h) tannins; or
i) genistein and substituted genisten.
10 . The composition of claim 9 , wherein the polyphenol comprises a catechin and/or substituted catechin.
11 . The composition of claim 10 , wherein the catechin and/or substituted catechin comprises one or more of epicatechin, epicatechin gallate (ECG), epigallocatechin (EGC), epigallocatechin gallate (EGCG), or gallocatechin.
12 . The composition of claim 9 , wherein the polyphenol comprises one or more flavonols.
13 . The composition of claim 12 , wherein the flavonol comprises one or more of quercetin, kampferol, or myricetin.
14 . The composition of claim 1 , wherein the bioactive agent comprises a Coenzyme Q in either its reduced form (ubiquinone) or oxidized form (ubiquinol).
15 . The composition of claim 8 , wherein the polyphenol comprises Polygonum cuspidatum extract.
16 . The composition of claim 8 , wherein the polyphenol comprises resveratrol.
17 . The composition of claim 1 , further comprising an anti-oxidant other than the polyphenol or bioactive agent.
18 . The composition of claim 17 , wherein the anti-oxidant comprises one or more of Vitamin A, Vitamin E (tocopherol), Vitamin K, Copper, Zinc, Iron, Selenium, beta-carotene, eriodictyol, camosic acid, carnosol, rosmarinic acid, caffeic acid, coumaric acid, cinnamic acid, Coenzyme Q, Probucol, astaxanthin, lycopene, alpha-lipoate, and urate.
19 . The composition of claim 1 , wherein the bioactive agent comprises Coenzyme Q10, the polyphenol comprises Polygonum cuspidatum extact, and the lipid matrix comprises a mixture of refined soybean oil; mono-, di- and triglycerides, and polyglycerol oleate and/or polyglycerol dioleate.
20 . The composition of claim 19 , further comprising an anti-oxidant other than the Coenzyme Q10 or the polyphenol.
21 . The composition of claim 20 , wherein the anti-oxidant comprises tocopherol.
22 . The composition of claim 1 , comprising, by weight, about 8-10% bioactive agent, less than about 1% polyphenol, and about 85-90% lipid matrix.
23 . The composition of claim 1 , further comprising 2-3% of an anti-oxidant other than the bioactive agent and polyphenol.
24 . A method of improving absorption of a high molecular weight, lipophilic, bioactive agent in the gastrointestinal tract, the method comprising orally administering to a subject the composition of claim 1 .
25 . The method of claim 24 , comprising administering the composition of claim 2 .
26 . The method of claim 25 , comprising administering the composition of claim 3 .
27 . The method of claim 26 , comprising administering the composition of claim 4 .
28 . The method of claim 27 , comprising administering the composition of claim 5 .
29 . The method of claim 28 , comprising administering the composition of claim 6 .
30 . The method of claim 29 , comprising administering the composition of claim 17 .
31 . The method of claim 24 , comprising administering the composition of claim 19 .
32 . The composition of claim 18 , wherein the anti-oxidant comprises a pharmaceutically acceptable salt or ester of the anti-oxidant.
33 . The composition of claim 21 , wherein the tocopherol comprises a pharmaceutically acceptable ester of tocopherol.
34 . The composition of claim 1 , consisting of:
the biologically effective amount of the bioactive agent;
the lipid matrix in which the bioactive agent is suspended; and
the sufficient amount of the polyphenol to improve gastrointestinal absorption of the bioactive agent when the dosage form is orally administered.