STENTS HAVING CONTROLLED ELUTION
Provided herein is a device comprising a stent and a coating on the stent; wherein the coating comprises at least one polymer and at least one active agent; wherein at least part of the active agent is in crystalline form.
1 . A device comprising
a. a stent comprising a cobalt-chromium alloy; and
b. a coating on the stent; wherein the coating comprises at least one polymer and at least one crystalline active agent;
wherein the level of active agent degradation after two weeks incubation in a serum-supplemented cell culture medium at 37° C. is significantly reduced for the device as compared to a device comprising a metal cobalt-chromium stent and a coating comprising at least one polymer and at least one amorphous active agent.
2 . A device comprising
a. a stent comprising a cobalt-chromium alloy; and
b. a coating on the stent; wherein the coating comprises at least one polymer and at least one crystalline active agent;
wherein the coating disassociates from the stent following implantation of the device in a first artery of an animal and spreads within the vessel wall creating coating deposits in the neointima.
3 . The device of claim 2 ,
wherein there are, on average, fewer than twenty inflammatory cells associated with stent struts of the stent at 3 days following implantation of a single stent in a first artery of an animal.
4 . The device of claim 2 ,
wherein when said device is implanted in an overlapping manner with a second device in a first artery of an animal wherein the second device comprises
a. a second stent comprising a cobalt-chromium alloy; and
b. a coating on the second stent; wherein the coating comprises at least one polymer and at least one crystalline active agent;
there are, on average, fewer than twenty inflammatory cells associated with stent struts of the first stent at 3 days following implantation in the overlapping region of the overlapping devices.
5 . The device of claim 2 , wherein the crystalline active agent is at least one of: 50% crystalline, at least 75% crystalline, at least 90% crystalline.
6 . The device of claim 2 , wherein the crystalline active agent comprises pharmaceutical agent comprising at least one polymorph of the possible polymorphs of the crystalline structures of the pharmaceutical agent.
7 . The device of claim 2 , wherein the polymer comprises a bioabsorbable polymer.
8 . (canceled)
9 . (canceled)
10 . (canceled)
11 . (canceled)
12 . The device of claim 2 , wherein the polymer is selected from the group: PLGA, a copolymer comprising PLGA (i.e. a PLGA copolymer), a PLGA copolymer with a ratio of about 40:60 to about 60:40, a PLGA copolymer with a ratio of about 70:30 to about 90:10, a PLGA copolymer having a weight average molecular weight of about 25 kD, a PLGA copolymer having a weight average molecular weight of about 31 kD, PGA poly(glycolide), LPLA poly(1-lactide), DLPLA poly(d1-lactide), PCL poly(e-caprolactone) PDO, poly(dioxolane) PGA-TMC, 85/15 DLPLG p(d1-lactide-co-glycolide), 75/25 DLPLG, 65/35 DLPLG, 50/50 DLPLG, TMC poly(trimethylcarbonate), poly(anhydrides) such as p(CPP:SA) poly(1,3-bis-p-(carboxyphenoxy)propane-co-sebacic acid), and a combination thereof.
13 . The device of claim 2 , wherein the stent is formed from a material comprising the following percentages by weight: about 0.05 to about 0.15C, about 1.00 to about 2.00Mn, about 0.04Si, about 0.03P, about 0.3S, about 19.0 to about 21.0Cr, about 9.0 to about 11.0Ni, about 14.0 to about 16.00 W, about 3.0Fe, and Bal. Co.
14 . The device of claim 2 , wherein the stent is formed from a material comprising at most the following percentages by weight: about 0.025C, about 0.15Mn, about 0.15Si, about 0.015P, about 0.01S, about 19.0 to about 21.0Cr, about 33 to about 37Ni, about 9.0 to about 10.5Mo, about 1.0Fe, about 1.0Ti, and Bal. Co.
15 . The device of claim 2 , wherein the stent is formed from a material comprising a platinum chromium alloy or magnesium alloy.
16 . (canceled)
17 . The device of claim 2 , wherein the stent has a thickness of from about 50% to about 90% of a total thickness of the device.
18 . The device of claim 2 , wherein the coating has a total thickness of from about 5 μm to about 50 μm.
19 . The device of claim 2 , wherein the device has an active agent content of from about 5 μg to about 500 μg.
20 . (canceled)
21 . The device of claim 2 , wherein the active agent comprises a macrolide immunosuppressive (limus) drug.
22 . The device of claim 21 , wherein the macrolide immunosuppressive drug comprises one or more of: rapamycin, biolimus (biolimus A9), 40-O-(2-Hydroxyethyl)rapamycin (everolimus), 40-O-Benzyl-rapamycin, 40-O-(4′-Hydroxymethyl)benzyl-rapamycin, 40-O-[4′-(1,2-Dihydroxyethyl)]benzyl-rapamycin, 40-O-Allyl-rapamycin, 40-O-[3′-(2,2-Dimethyl-1,3-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin, (2′:E, 4 ′S)-40-O-(4′,5′-Dihydroxypent-2′-en-1′-yl)-rapamycin, 40-O-(2-Hydroxy)ethoxycarbonylmethyl-rapamycin, 40-O-(3-Hydroxy)propyl-rapamycin, 40-O-(6-Hydroxy)hexyl-rapamycin, 40-O-[2-(2-Hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-( 2 -Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethylrapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotarolimus), picrolimus, novolimus, myolimus, and salts, derivatives, isomers, racemates, diastereoisomers, prodrugs, hydrate, ester, or analogs thereof.
23 . The method of claim 24 ,
wherein the level of active agent degradation after two weeks incubation in a serum-supplemented cell culture medium at 37° C. is significantly reduced for the device as compared to a device comprising a metal cobalt-chromium stent and a coating comprising at least one polymer and at least one amorphous active agent.
24 . A method comprising
providing a device comprising
a stent comprising a cobalt-chromium alloy; and
a coating on the stent; wherein the coating comprises at least one polymer and
at least one crystalline active agent; and
implanting the device in an animal,
wherein the coating disassociates from the stent following implantation of the device in a first artery of the animal and spreads within the vessel wall creating coating deposits in the neointima.
25 . The method of claim 24 ,
wherein there are, on average, fewer than twenty inflammatory cells associated with stent struts of the stent at 3 days following implantation of a single stent in a first artery of the animal.
26 . The method of claim 24 ,
wherein when said device is implanted in an overlapping manner with a second device in a first artery of an animal wherein the second device comprises
a. a second stent comprising a cobalt-chromium alloy; and
b. a coating on the second stent; wherein the coating comprises at least one polymer and at least one crystalline active agent;
there are, on average, fewer than twenty inflammatory cells associated with stent struts of the first stent at 3 days following implantation in the overlapping region of the overlapping devices.
27 - 44 . (canceled)