IMPLANTS FOR RELEASE OF LIPOPHILIC OR AMPHIPHILIC PHARMACEUTICAL SUBSTANCES
Implants are described which comprise lipophilic pharmaceutical substances. Excipients are used which provide appropriate and controllable/tunable release of the lipophilic drug from the matrix of the implant. The implants can be implanted into a patient for release of the pharmaceutical substances. Methods of making and using such implants are also described.
1 . An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance is a lipophilic pharmaceutical substance comprising a lipophilic moiety.
2 . The implant of claim 1 , wherein the implant is a subcutaneous implant.
3 . The implant of claim 1 , wherein in an aqueous environment over a defined period of time, at least about 50% more of the pharmaceutical substance is released from the implant as is released from a comparable implant lacking the excipient.
4 . The implant of claim 3 , wherein the defined period of time is about 6 hours, about 24 hours, about 72 hours, or about 7 days.
5 . The implant of claim 3 or claim 4 , wherein the aqueous environment is selected from an aqueous solution, a sub-dermal location in a test animal, or a sub-dermal location in a human.
6 . The implant of claim 3 or claim 4 , wherein the aqueous environment comprises an aqueous solution comprising about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na 2 HPO 4 , and about 1.8 mM KH 2 PO 4 at about pH 7.4 and about 37° C.
7 . The implant of any one of claims 1 - 4 , wherein the excipient comprises a compound selected from the group consisting of sugar alcohols and biodegradable polymers.
8 . The implant of any one of claims 1 - 7 , wherein the excipient comprises a compound selected from the group consisting of sugar alcohols.
9 . The implant of any one of claims 1 - 7 , wherein the excipient comprises a compound selected from the group consisting of mannitol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, fucitol, galactitol, iditol, inositol, sorbitol, volemitol, isomalt, lactitol, and maltitol.
10 . The implant of any one of claims 1 - 7 , wherein the excipient comprises mannitol.
11 . The implant of any one of claims 1 - 7 , wherein the excipient comprises a compound selected from the group consisting of biodegradable polymers.
12 . The implant of any one of claims 1 - 7 , wherein the excipient comprises poly(lactic-co-glycolic) acid (PLGA).
13 . The implant of claim 1 , wherein the lipophilic pharmaceutical substance comprises a lipid.
14 . The implant of claim 13 , wherein the lipid is selected from the group consisting of a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a phospholipid, and a steroid.
15 . The implant of claim 1 , wherein the lipophilic pharmaceutical substance comprises a lipidated peptide.
16 . The implant of claim 1 , wherein the lipophilic pharmaceutical substance comprises a fatty acid.
17 . The implant of claim 1 , wherein the lipophilic pharmaceutical substance comprises a fatty acid covalently conjugated to a peptide.
18 . The implant of claim 17 , wherein the lipophilic pharmaceutical substance comprising a fatty acid covalently conjugated to a peptide comprises liraglutide.
19 . The implant of claim 1 , wherein the matrix comprises a non-biodegradable polymer.
20 . The implant of claim 19 , wherein the non-biodegradable polymer comprises a polymer selected from the group consisting of: ethylene vinyl acetate, polyolefins, polyethylenes, polypropylenes, polybutylenes, polyolefin copolymers, ethylene-methacrylic acid, ethylene-acrylic acid, vinyl aromatic polymers, polystyrene, vinyl aromatic copolymers, styrene-isobutylene copolymers, butadiene-styrene copolymers, polyvinyl alcohols, polyacetals, chloropolymers, polyvinyl chloride (PVC), fluoropolymers, polytetrafluoroethylene (PTFE), polyesters, polyethyleneterephthalate (PET), polyester-ethers, polyamides, nylon-6, nylon-6,6; polyethers, polyamide ethers, silicones, polyurethanes, polyurethane copolymers, polycarbonates,polycarbonate-based polyurethanes, and a mixture or copolymer of any of the foregoing.
21 . The implant of claim 19 , wherein the non-biodegradable polymer comprises ethylene vinyl acetate.
22 . An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance forms micelles in aqueous solution.
23 . The implant of claim 22 , wherein the aqueous solution is phosphate buffered saline (PBS) between about pH 7 and about pH 8.
24 . An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance is amphiphilic.
25 . An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance has been co-lyophilized with the excipient to form a pharmaceutical substance-excipient mixture prior to incorporation of the pharmaceutical substance-excipient mixture into the matrix.
26 . The implant of claim 25 , wherein the pharmaceutical substance is selected from the group consisting of:
a pharmaceutical substance which comprises a lipophilic moiety;
a pharmaceutical substance which forms micelles in aqueous solution; and
a pharmaceutical substance which is amphiphilic.
27 . The implant of claim 25 , wherein the pharmaceutical substance is liraglutide.
28 . The implant of any one of claims 25 - 27 , wherein the excipient is a sugar alcohol.
29 . The implant of claim 28 , wherein the sugar alcohol is mannitol.
30 . The implant of any one of claims 1 - 29 , wherein the matrix is ethylene vinyl acetate (EVA).
31 . The implant of any one of claims 1 - 30 , wherein the excipient:pharmaceutical substance ratio ranges from about 5:1 to about 1:10 by weight.
32 . The implant of claim 31 , wherein the excipient:pharmaceutical substance ratio ranges from about 1:1 to about 1:6 by weight.
33 . The implant of any one of claims 1 - 32 , wherein the weight ratio of matrix to (pharmaceutical substance+excipient) ranges from about 10:1 to about 1:4.
34 . The implant of claim 33 , wherein the weight ratio of matrix to (pharmaceutical substance+excipient) ranges from about 5:1 to about 1:3.
35 . The implant of any one of claims 1 - 34 , wherein the excipient comprises mannitol.
36 . The implant of any one of claims 1 - 34 , wherein the excipient comprises poly(lactic-co-glycolic acid) (PLGA).
37 . A subcutaneous implant comprising:
about 40% to about 60% by weight of ethylene vinyl acetate, and
about 60% to about 40%% by weight of a mannitol:liraglutide mixture,
wherein the mannitol:liraglutide mixture comprises about 10% to about 30% by weight mannitol and about 90% to about 70% by weight of liraglutide.
38 . A subcutaneous implant comprising:
about 50% by weight of ethylene vinyl acetate, and
about 50% by weight of a mannitol:liraglutide mixture, wherein the mannitol:liraglutide mixture comprises about 20% by weight mannitol and about 80% by weight of liraglutide.
39 . The implant of any one of claims 1 - 38 , wherein the implant is about 1 cm to about 5 cm long and about 1 mm to about 3 mm in diameter.
40 . The implant of any one of claims 1 - 39 , wherein the implant is a subcutaneous implant.
41 . The implant of any one of claims 1 - 40 , wherein the implant is prepared by hot melt extrusion.
42 . The implant of any one of claims 1 - 41 , wherein the implant is dip-coated.
43 . The implant of claim 42 , wherein the implant is dip-coated with ethylene vinyl acetate.
44 . The implant of claim 42 , wherein the implant is dip-coated with ethylene vinyl acetate by dipping the implant into a 1% solution of EVA prepared in dichloromethane (DCM).