HK1109066B

HK1109066B - Radiopaque polymeric stents

Info

Publication number: HK1109066B
Application number: HK07114308.1A
Authority: HK
Inventors: J．B．科恩; D．博利卡尔; J．策尔廷格; A．F．佩内尔; D．K．布兰多姆; E.施米德
Original assignee: 罗格斯州立大学
Priority date: 2004-08-13
Filing date: 2004-09-27
Publication date: 2013-11-22

Description

Radiopaque polymeric stents

RELATED APPLICATIONS

Priority of U.S. provisional application No. US60/601,743 filed 2004, 8/13/2004 under 35u.s.c. § 119(e), the disclosure of which is incorporated herein by reference.

Technical Field

Preferred embodiments of the present invention relate to polymeric medical devices, such as stents. More specifically, the polymer compositions disclosed herein comprise iodine-containing tyrosine-derived biphenols, optionally in combination with other groups, such as dicarboxylic acids and/or poly (alkylene oxides), such that stents made from these polymer compositions are bioabsorbable and radiopaque, and exhibit physiomechanical properties consistent with their intended use.

Background

Vascular stents are widely used for a variety of purposes, including, inter alia, for the treatment of heart disease. It has been reported in 1998 that about 6100 million americans have some form of heart disease, which has been the single leading cause of death in the united states since about 1990. One type of heart disease, Coronary Artery Disease (CAD), is characterized, at least in part, by the inhibition of blood flow through the arteries supplying the heart muscle due to the build-up of plaque (arteriosclerosis) in the arteries. There is suspected to be 1 CAD in every 5 deaths in the united states. In 2001, about 1100 million people had new or recurrent myocardial infarction (heart attack due to coronary artery disease). See, for example, the report by American heart association: "Heart and Stroke Statistical Update", 2001, American Heart Association, Dallas, TX. Over 500,000 americans currently receive treatment for coronary artery blockage every year. This number is expected to double in the next 10 years, given the aging population.

Vascular stents generally comprise a mesh tube that is stretched by means of a balloon after being inserted into an artery during angioplasty in order to keep the artery open. Generally, a vascular stent is fixed on a balloon catheter inserted through the femoral artery and advanced to a desired position within the aorta. The balloon is inflated therein, thereby deploying the stent and clinging to the vessel wall to secure it in place.

Most stents are constructed of metals, including, for example, stainless steel or nickel [ Ni ] titanium [ Ti ] memory alloys. While such metallic stents have certain desirable characteristics, such as sufficient radial strength to maintain patency of a subject's artery and radiopacity (so that the implanted stent can be viewed and monitored by radiographic/fluoroscopic examination), there are a number of significant drawbacks to metallic stents. For example, insertion and expansion of a metal stent into an artery tends to further damage the diseased vessel, possibly leading to intimal hyperplasia and further occlusion of the vessel by allowing smooth muscle cells and matrix proteins to grow inward through the stent small connectors. Another drawback associated with the use of metallic stents is that once deployed, they become permanent residents within the vessel wall — their usefulness has disappeared after a long time. In fact, the useful life of stents is estimated to be in the range of about 6-9 months. Since then, it is believed that the long-term pressure and overstretching of the vascular structure by the permanent metal implant promotes in-stent restenosis. Another drawback associated with the use of metallic stents is that the placement of multiple permanent metallic stents into the vessel can be an obstacle to subsequent surgical bypass. In addition, deployment of a first metal stent can be a physical barrier to subsequent delivery of a second stent at a distal site within the same vessel. In contrast to metal stents, bioabsorbable stents do not survive in a vessel for as long as they are useful. In addition, bioabsorbable stents can be used to deliver larger doses of therapeutic agents because the drug and/or bioactive agent coated stent can be on and embedded within the device itself. In addition, such stents may deliver multiple drugs and/or bioactive agents simultaneously or at different times during their life cycle in order to treat a particular aspect or condition of a vascular disease. In addition, bioabsorbable stents also allow for repeated treatment of similar regions of the same vessel.

In addition, a great need remains to develop temporary (bioabsorbable) and radiopaque stents wherein the polymeric materials used to make these stents have desirable metallic qualities (e.g., sufficient radial strength and radiopacity, etc.) while preventing or alleviating the drawbacks or limitations associated with the use of permanent metallic stents.

U.S. Pat. No. 6,475,477 ("the' 477 patent") discloses stents made of radiopaque biocompatible polymers having a hydrolytically unstable backbone and free pendant carboxylic acid groups that promote polymer degradation and resorption. Not only are many of the disclosed polymers less than ideal for use in stents, but polymers having free carboxylic acid groups are prepared from monomers having benzyl-protected free acid moieties that are selectively removed from the polymer by hydrogenolysis in the presence of a palladium catalyst and hydrogen. Although such methods can effectively remove benzyl protecting groups with little or no cleavage of the polymer backbone, the palladium catalysts used therein are relatively expensive and traces of palladium are difficult to remove from the polymer product.

Because the presence of free carboxylic acid groups is a highly desirable feature, new synthetic methods are needed to prepare polymers comprising free carboxylic acid groups and bioabsorbable polymer backbones in order to meet the heretofore unsatisfactory need for bioabsorbable and radiopaque stents having the desirable characteristics of metallic stents.

Summary of The Invention

For the purpose of summarizing the invention, certain aspects, advantages and novel features of the invention have been described herein above. Of course, it is to be understood that not necessarily all such advantages may be achieved in accordance with any particular embodiment of the invention. Thus, the invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught or suggested herein without necessarily achieving another advantage or group of advantages as taught or suggested herein.

In preferred embodiments of the present invention, radiopaque bioabsorbable stents are disclosed. The stent comprises a bioabsorbable polymer containing sufficient halogen atoms to impart intrinsic radiopacity to the stent. The stent may further comprise a structure selected from the group consisting of a plate stent, a braided stent, a self-expanding stent, a metal mesh stent, a deformable stent, and a slide-and-lock stent. In another variation, the stent is balloon-expandable and comprises at least two substantially non-deforming elements arranged to form a tubular member, the non-deforming elements being slidably or rotatably interconnected for expanding the tubular member from a collapsed diameter to an expanded diameter.

In another preferred embodiment of the present invention, a radiopaque, bioabsorbable stent is disclosed comprising a polymer comprising one or more units described by formula I:

wherein each X is independently I or Br, Y1 and Y2 for each biphenol unit are independently in the range of 0 to 4 inclusive, and Y1+ Y2 for each biphenol unit is in the range of 1 to 8 inclusive.

Wherein R and R₂Each independently of the other isAlkyl, aryl or alkylaryl of up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising a free carboxylic acid pendant group;

wherein A is:

wherein R is₃Is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkylaryl group containing up to about 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N;

wherein P is poly (C)₁-C₄Alkylene glycol) units; f is 0 to less than 1 inclusive; g is 0-1 inclusive; and f + g is inclusive of 0 to 1.

Preferably, both iodine and bromine are present as ring substituents. Furthermore, all X groups are preferably ortho-oriented. Y1 and Y2 may be independently 2 or less, and Y1+ Y2 is 1,2, 3 or 4. In another variation, Y1+ Y2 is 2 or 3. All X groups are preferably iodine.

In another variant of the invention, the poly (C)₁-C₄Alkylene glycol) units less than about 75 wt%. In a preferred variant, the poly (C) s₁-C₄Alkylene glycol) units less than about 50 wt%. More preferably poly (C)₁-C₄Alkylene glycol) is a poly (ethylene glycol) having a weight fraction of less than about 40 wt%. Most preferably, the weight fraction of poly (ethylene glycol) units is from about 1 to 25 weight percent. P may independently be C₁-C₄Or C₁-C₄The copolymer of (1).

In another variation of the invention, f may vary between about 0 and 0.5 inclusive. Preferably, f is less than about 0.25. More preferably, f is less than about 0.1. More preferably, f varies from about 0.001 to about 0.08. Most preferably, f varies between about 0.025 to about 0.035.

In another variation of the invention, g is greater than 0 and typically varies between greater than 0 and about 0.5 inclusive. Preferably, g is greater than about 0.1 to about 0.35. More preferably, g is from about 0.2 to about 0.3. More preferably, g varies from about 0.01 to about 0.25. Most preferably, g is from about 0.05 to about 0.15.

In another variant of the invention, R and R₂All contain COOR₁A pendant group; wherein for R, the subgroup R₁Alkyl groups containing 0 to 5 heteroatoms independently from 1 to about 18 carbon atoms selected from O and N; and wherein with respect to R₂In general, the radical R₁Is a hydrogen atom. In another preferred embodiment, each R and R₂Each independently has the following structure:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I, and wherein R is₂Q comprises a free carboxylic acid group and for each R is independently selected from hydrogen and carboxylic acid esters and amides, wherein said esters and amides are selected from alkyl and alkylaryl esters and amides containing up to 18 carbon atoms and esters and amides of biologically active compounds.

In a preferred variant of the invention, R and R₂Each independently has the following structure:

wherein R is₅To compriseAlkyl of up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N, and wherein m is an integer from 1 to 8 inclusive; and wherein for each R₂In the sense that R₁Is hydrogen, and for each R, R₁Independently 1 to about 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N.

In a more preferred variant of the invention, each R and R₂Each independently has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and wherein each R₂R of (A) to (B)₁Is hydrogen, and for each R, R₁Independently an alkyl group containing from 0 to 5 heteroatoms independently selected from O and N, from 1 to about 18 carbon atoms.

Preferably each R of R₁Each of the subgroups is independently an alkyl group of from 1 to about 18 carbon atoms and containing from 0 to 5 heteroatoms selected from O and N. More preferably R of R₁The subgroups are each independently ethyl or butyl.

In another variant of the invention, a is — C (═ O) -. Alternatively, a may be:

wherein R is₃Is C₄-C₁₂Alkyl radical, C₈-C₁₄Aryl or C₈-C₁₄An alkylaryl group. Preference is given to selecting R₃Such that a is a dicarboxylic acid moiety belonging to a naturally occurring metabolite. More preferably R₃Is selected from-CH₂-C(＝O)-、-CH₂-CH₂-C (═ O) -, -CH ═ CH-and (-CH)₂-)_zAnd wherein is an integer from 0 to 8 inclusive. Furthermore, the utility modelPreferably z is an integer between 1 and 8 inclusive.

In another variation of the invention, the scaffold further comprises an effective amount of a therapeutic agent. Preferably the amount is sufficient to inhibit restenosis, thrombosis, plaque formation, plaque rupture and inflammation and/or promote healing. In another variation, the polymer forms a coating on at least a portion of the stent. The polymer coating is preferably adapted to promote a selected biological response.

Another embodiment of the invention discloses a polymer comprising one or more units described by formula I:

wherein each X is independently I or Br, Y1 and Y2 of each diphenol unit are independently from 1 to 4 inclusive, and Y1+ Y2 of each diphenol unit are from 1 to 8 inclusive;

wherein R and R₂Each independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N and R₂Further comprising a free carboxylic acid pendant group; wherein A is:

wherein P is poly (C)₁-C₄Alkylene glycol) units; f ranges from 0 to less than 1; g is the range of 0-1 inclusive; and f + g is inclusive of 0 to 1.

Preferably Y1 and Y2 are independently 2 or less, and Y1+ Y2 is 1,2, 3 or 4. All X groups are also preferably ortho-oriented. In another variation of the polymer of formula I, Y1+ Y2 is 2 or 3. All X groups are preferably iodine.

Preferably poly (C)₁-C₄Alkylene glycol) units less than about 75 wt%. In a preferred variant of the polymer of the formula I, poly (C)₁-C₄Alkylene glycol) units less than about 50 wt%. More preferably, P is a poly (ethylene glycol) unit having a weight fraction of less than about 40 wt%. Most preferably, the weight fraction of poly (ethylene glycol) units is from about 1 to about 25 weight percent. P may independently be C₁-C₄Or C₁-C₄The copolymer of (1).

In another variation of the polymer of formula I, f can vary between about 0 and 0.5 inclusive. Preferably, f is less than about 0.25. More preferably, f is less than about 0.1. More preferably, f varies from about 0.001 to about 0.08. Most preferably, f varies between about 0.025 to about 0.035.

In another variation of the polymer of formula I, g is greater than 0 and typically varies between greater than 0 and about 0.5 inclusive. Preferably, g is greater than about 0.1 to about 0.35. More preferably, g is from about 0.2 to about 0.3. More preferably, g varies from about 0.01 to about 0.25. Most preferably, g is from about 0.05 to about 0.15.

In another variation of the polymer of formula I, R and R₂Each containing COOR₁A pendant group; wherein R of R₁The subgroups are independently alkyl of 1 to about 18 carbon atoms containing 0 to 5 heteroatoms selected from 0 and N; and wherein R₂R of (A) to (B)₁A subgroup is a hydrogen atom. In another preferred embodiment, R and R₂Each independently has the following structure:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-C)H₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I, and wherein for each R₂Q comprises a free carboxylic acid group and for each R is independently selected from hydrogen and carboxylic acid esters and amides, wherein said esters and amides are selected from alkyl and alkylaryl esters and amides containing up to 18 carbon atoms and esters and amides of biologically active compounds.

wherein R is₅Is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N, and wherein m is an integer from 1 to 8 inclusive; and wherein for each R₂In the sense that R₁Is hydrogen, and for each R, R₁Independently 1 to about 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N.

In a more preferred variant of the polymer of the formula I, R and R₂Each independently has the following structure:

wherein j and m are independently integers from 1 to 8 inclusive, wherein R of R is₁Each of the subgroups independently is an alkyl group of from 1 to about 18 carbon atoms containing from 0 to 5 heteroatoms selected from O and N, and wherein R is₂R of (A) to (B)₁A subgroup is a hydrogen atom;

in one variation of the polymer of formula I, R of R is₁The subgroups are each ethyl or butyl.

In another variation of the polymer of formula I, a is-C (═ O) -. Or A is:

in another variation of the polymer of formula I, R₃Is C₄-C₁₂Alkyl radical, C₈-C₁₄Aryl or C₈-C₁₄An alkylaryl group. More preferably R₃Is selected from-CH₂-C(＝O)-、-CH₂-CH₂-C (═ O) -, -CH ═ CH-and (-CH)₂-) z, wherein z is an integer from 0 to 8 inclusive.

A system for treating a site within a body cavity is disclosed. The system comprises a catheter having a deployment device and a radiopaque, bioabsorbable stent, wherein the catheter is adapted to deliver the stent to the site and the deployment device is adapted to deploy the stent. In a preferred embodiment of the system, the catheter is selected from the group consisting of an over-the-wire catheter, a coaxial rapid exchange catheter, and a multiple exchange delivery catheter.

A process for selectively removing tert-butyl esters from hydrolytically unstable polymers to form new polymer compositions with free carboxylic acid groups other than the tert-butyl ester group is disclosed. The process comprises dissolving said hydrolytically unstable polymer in a solvent comprising an amount of acid having a pKa in the range of about 0 to about 4 effective to selectively remove said t-butyl group by acid hydrolysis to form a new polymer composition having free carboxylic acid groups.

Preferably the hydrolytically unstable polymer is soluble in the solvent. In one embodiment, the solvent consists essentially of an acid. In variations, the solvent is selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, and mixtures thereof. The acid may be selected from formic acid, trifluoroacetic acid, chloroacetic acid and mixtures thereof, preferably the acid is formic acid.

In one variation of the method, the hydrolytically unstable polymer comprises one or more units of formula II:

wherein X of each polymer unit is independently Br or I, Y is 0 to 4 inclusive, and R is₄Is an alkyl, aryl or alkylaryl group having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and further contains pendant tertiary butyl ester groups.

In another variation of the process, the hydrolytically unstable polymer is blended with up to about 75 wt% of poly (C)₁-C₄Alkylene glycol). In general, poly (C)₁-C₄Alkylene glycol) less than about 50 wt%. Preferably less than about 40 weight percent poly (ethylene glycol), and more preferably less than about 25 weight percent poly (ethylene glycol). The hydrolytically unstable polymers for stent applications preferably contain a mole fraction of poly (ethylene glycol) of about 0.001 to 0.08.

In another variant of the process, all X groups are ortho-oriented and Y is 1 or 2. Preferably each X is iodine.

In another variation of the method, R₄Is an alkyl group. R₄May have the following structure:

wherein R is₂Independently of each other, contain up to 18 carbon atomsAnd alkyl, aryl or alkylaryl of 0-8 heteroatoms selected from O or N, and further comprising pendent t-butyl esters; and R is_5aAnd R₆Each independently selected from hydrogen and straight and branched chain alkyl groups having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N.

Or, R₂Can be as follows:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I; and Q comprises tert-butyl carboxylate.

In a preferred variant of the process, R₂Has the following structure:

wherein R is₅Is an alkyl group having up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and R is₁Is tert-butyl ester group.

In a more preferred variant of the process, R₂Has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and R₁Is tert-butyl esterAnd (4) a base.

In another variation of the method, R₄Is aryl or alkylaryl. Preferably the units described in formula II comprise biphenol units. More preferably R₄Is an alkylaryl group and the diphenol unit is described by formula III:

wherein X of each polymer unit is independently Br or I, Y1 and Y2 are independently from 1 to 4 inclusive, Y1+ Y2 are from 1 to 8 inclusive, and R of each unit is independently₂Independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising a tertiary butyl ester side group.

In another variation of the method, R₂Comprises the following steps:

In a preferred variant of the process, R₂Has the following structure:

wherein R is₅Is containing up to 18 carbonsAlkyl of atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and R is₁Is tert-butyl ester group.

In a more preferred variant of the process, R₂Has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and R₁Is tert-butyl ester group.

Preferably all X groups are ortho-oriented and Y1+ Y2 is 1,2, 3 or 4. Each X is preferably iodine.

In another variation of the method, the hydrolytically unstable polymer may comprise one or more units defined by formula I:

wherein each X is independently I or Br, Y1 and Y2 of each biphenol unit are independently from 1 to 4 inclusive, and Y1+ Y2 of each biphenol unit is from 0 to 8 inclusive.

Wherein R and R of each unit₂Independently containAlkyl, aryl or alkylaryl of up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising a tertiary butyl ester side group;

wherein A is:

wherein P is poly (C) having a weight fraction of less than about 75 wt%₁-C₄Alkylene glycol) units; f is 0 to less than 1; g is 0-1 inclusive; and f + g is inclusive of the range of 0-1.

More preferably R and R₂May comprise:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I; and wherein with R₂In another aspect, Q comprises a tert-butyl carboxylate, and for each R, Q is independently selected from hydrogen and carboxylic acid esters and amides, wherein the esters and amides are selected from alkyl and alkylaryl esters and amides containing up to 18 carbon atoms and esters and amides of biologically active compounds.

In a preferred variant of the process, R and R₂Independently have the following structure:

wherein R is₅Is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and wherein with respect to R₂In the sense that R₁Is a tert-butyl ester group, and for each R, R₁Independently 1 to about 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N.

In a more preferred variant of the process, R and R₂Independently have the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and wherein for each R, a subgroup R₁A straight or branched chain alkyl group containing 0 to 5 heteroatoms independently selected from O and N and from 1 to about 18 carbon atoms; and with R₂In general, the radical R₁Is a tert-butyl (tB) ester group.

Disclosed are polymers comprising one or more units described by formula II:

wherein X of each polymer unit is independently Br or I, Y is 0 to 4 inclusive, and R is₄Is an alkyl, aryl or alkylaryl group having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N and further contains pendant tertiary butyl ester groups.

Said polymer being blended with up to about 75 wt% of poly (C)₁-C₄Alkylene glycol). In general, poly (C)₁-C₄Alkylene glycol) less than about 50 wt%. Preferably less than about 40 weight percent poly (ethylene glycol), and more preferably less than about 25 weight percent poly (ethylene glycol). The polymer for stent applications preferably contains a mole fraction of poly (ethylene glycol) of about 0.001 to 0.08.

Preferably all X groups are ortho-oriented, Y is 1 or 2, and each X is iodine.

In another variation of the polymer of formula II, R₄Is an alkyl group.

More preferably R₄Has the following structure:

wherein R is₂Independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O or N, and further comprising pendant tertiary butyl ester groups; and R is_5aAnd R₆Each independently selected from hydrogen and straight and branched chain alkyl groups having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N.

More preferably R₂Comprises the following steps:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I; and Q comprises a tert-butyl carboxylate.

In one kind excellenceIn a selected variant, R₂Has the following structure

Wherein R is₅Is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and R is₁Is tert-butyl ester group.

In a more preferred variant, R₂Has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and wherein R is₁Each is a tert-butyl ester group.

In another variation of the polymer of formula II, R₄May be an aryl or alkylaryl group. The units may also comprise biphenol units. In a preferred variant, R₄Are alkylaryl and alkylphenol units described by formula III:

wherein X of each polymer unit is independently Br or I, Y1 and Y2 are independently 0 to 4 inclusive, Y1+ Y2 are independently 0 to 8 inclusive, and R of each unit is independently₂Each independently being an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising tertiary butyl ester side groups. The class of polymers of formula III includes polymers of formula I bearing free carboxylic acid groups, wherein the carboxylic acid groups are protected by t-butyl esters. Also included are compounds of formula IA halogen-containing polymer.

In another variation, R₂Comprises the following steps:

In a preferred variant, R₂Has the following structure:

In a more preferred variant, R₂Has the following structure:

In another variation, the polymer is blended with up to about 75 wt% of poly (C)₁-C₄Alkylene glycol). In general, poly (C)₁-C₄Alkylene oxideBased on the diol) is less than about 50 wt%. Preferably less than about 40 weight percent poly (ethylene glycol), and more preferably less than about 25 weight percent poly (ethylene glycol). The polymer for stent applications preferably contains a mole fraction of poly (ethylene glycol) of about 0.001 to 0.08.

Preferably all X groups are ortho-oriented and Y1+ Y2 is 1,2, 3 or 4Y. Each X is preferably iodine.

In another variation, the hydrolytically unstable polymer may comprise one or more units defined by formula I:

wherein each X is independently I or Br, Y1 and Y2 of each biphenol unit are independently from 0 to 4 inclusive, and Y1+ Y2 of each biphenol unit is from 0 to 8 inclusive.

Wherein R and R of each unit₂Independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising pendant tertiary butyl ester groups;

wherein A is:

More preferably R and R₂May comprise:

In a preferred variant, R and R₂Independently have the following structure:

In a more preferred variant, R and R₂Independently have the following structure:

In a preferred embodiment of the invention, compounds having the structure described by formula IIa are disclosed:

wherein X is Br or I, Y is 0-4 inclusive, and R₄Is an alkyl, aryl or alkylaryl group having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and further contains pendant tertiary butyl ester groups.

Preferably all X groups are ortho-oriented, Y ═ 1,2, 3, or 4, and each X group is iodine.

R₄May be an alkyl group, preferably having the structure:

In a preferred variant of the compound of the formula IIa, R₂Comprises the following steps:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I; and Q comprises a tert-butyl carboxylate group.

In a preferred variant, R₂Has the following structure:

In a more preferred variant, R₂Has the following structure:

In another variation, R is selected for a compound of formula IIa₄Such that the compound comprises diphenol units, preferably according to formula IIIa:

wherein each X is independently Br or I, Y1 and Y2 are independently 0-4 inclusive, Y1+ Y2 are independently 0-8 inclusive, and R is₂Independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising tertiary butyl ester side groups.

In a preferred variant of the diphenols, R₂Comprises the following steps:

In a preferred variant, R₂Has the following structure:

In a more preferred variant, R₂Has the following structure:

wherein j and m are independently inclusiveAnd R is an integer of 1 to 8, and₁is tert-butyl ester group.

In another embodiment of the invention, compounds having the structure:

in another embodiment of the invention, compounds having the structure:

methods of retreating a body lumen are disclosed. The method comprises the following steps: deploying a first device comprising a radiopaque, bioabsorbable stent along a region within the body lumen, wherein the first device resides therein for a first treatment period until the stent is bioresorbable; and deploying a second device after the first treatment period along the region such that the body lumen is retreated.

In one variation of the radiopaque, bioabsorbable stent, the polymer is not naturally occurring. In another variation, the polymer further comprises an amino acid.

Brief Description of Drawings

FIG. 1 depicts an X-ray comparison of a polymer stent of a preferred embodiment of the present invention with a prior art steel stent in a porcine heart;

FIG. 2A depicts poly (I)₂-DTE carbonate) optical micrograph of an enlarged section of the stent;

FIG. 2B is a drawing depicting a poly (I) of another preferred embodiment of the present invention₂-light micrograph of enlarged section of DTE-co-2.5% PEG2K carbonate) scaffold;

FIG. 3 depicts paclitaxel dissolved in PBS containing Tween 20 at 37 deg.C, leaving a poly-DTE-carbonate coating; and is

Figures 4a-b depict X-ray comparisons of radiopaque, bioabsorbable tyrosine triiodinated derivatized polycarbonate films that represent one preferred embodiment of the present invention.

Best mode for carrying out the invention

In preferred embodiments of the present invention, there are disclosed inherently radiopaque bioabsorbable stents comprising bioabsorbable polymers with sufficient halogen atoms to allow visualization of the stent by conventional X-ray fluoroscopy. Also disclosed herein are novel compositions of halogenated bioabsorbable polymers that exhibit uniquely optimized properties and methods of making the same.

Within this framework, a particular challenge is to synthesize polymers containing preselected proportions of repeating units bearing free carboxylic acid groups. It is well known in synthetic polymer chemists that polymers containing free carboxylic acid groups as side chains cannot be synthesized by condensation type polymerization reactions because free carboxylic acid groups have a strong tendency to interfere with most condensation reactions. Thus, an indirect synthetic route is used. First, monomers comprising carboxylic acid groups rendered chemically inert by selective removal of "protecting groups" are prepared as described for peptides in general (Principles of peptidesynthesis, 1984, Springer Verlag, Berlin, Germany) and in particular for the amino acid L-tyrosine. The protected monomers are then subjected to condensation polymerization resulting in the formation of a polymer containing protected carboxylic acid groups. In the final reaction step, the protecting groups are selectively removed without cleaving the polymer backbone and without causing other unwanted structural changes to the polymer. When a polymer is designed to be bioabsorbable, the polymer backbone is intentionally constructed to be readily degradable-making removal of the protecting group without simultaneously damaging the polymer backbone very challenging. Applicants describe herein polymer scaffolds that meet this challenge and result in scaffolds with desirable and unexpected properties.

The optimized polymer used to make the stent should meet at least some of the following criteria:

radiopacity is preferably sufficient to ensure visualization of the stent structure on background of the human breast by standard methods used clinically, i.e. X-ray fluoroscopy;

the scaffold connectors are preferably as thin as possible, preferably 635 microns or less thick, and more preferably 100 microns or less thick, but still strong enough to prevent vessel collapse and crush resistance. According to a preferred embodiment, the stent may exhibit an elastic modulus of about 50,000-500,000PSI and more preferably at least about 200,000PSI and a tensile strength at production of greater than about 1,000PSI and more preferably greater than about 5,000 PSI.

The stent is preferably hemocompatible in order to prevent acute thrombosis. Thus, the device surface is preferably resistant to protein adsorption and platelet/monocyte attachment. In addition, the device surface is ideally conducive to endothelial growth, but impedes smooth muscle cell attachment and growth (which can lead to restenosis).

The scaffold preferably maintains its mechanical strength (e.g., hoop tensile strength) for a period of about 1-24 months, more preferably about 3-18 months, more preferably about 3-12 months, and most preferably about 3-6 months.

The stent preferably has the desired biodegradation and bioresorbable properties such that the stent resides within the body lumen for a period of time such that any stent thereafter, whether bioresorbable, metallic, etc., may be used to reprocess the vessel approximately the same area or to allow other forms of vascular re-intervention, such as a vascular shunt.

The term "stent" is used broadly herein to designate embodiments of the expandable tubular member that are placed in: (1) vascular body lumens (i.e., arterial and/or intravenous), such as coronary, neural, and peripheral vessels, e.g., the kidneys, iliac, femoral, popliteal, subclavian, and carotid arteries; and (2) non-vascular body lumens such as those currently treated, i.e., digestive lumens (e.g., gastrointestinal, duodenal and esophageal, biliary), respiratory lumens (e.g., tracheal and bronchial), and urinary lumens (e.g., urethra); (3) additionally, such embodiments may be used in cavities of other body systems, such as reproductive, endocrine, hematopoietic and/or body wall, musculoskeletal/orthopedic and nervous systems (including otic and ocular applications); and (4) finally, the stent embodiments can be used to expand occluded lumens and to induce occlusion (e.g., in the case of blocking an aneurysm sac).

The term "bioabsorbable" as used herein means that at least some of the polymers and degradation products that undergo biodegradation (by the action of water and/or by chemically degraded enzymes) are eliminated and/or absorbed by the body. The term "radiopaque substance" as used herein is meant to encompass objects or substances that allow visualization of a target by in vivo imaging analysis techniques such as, but not limited to, methods such as radiography, fluoroscopy, other forms of radiation, MRI, electromagnetic energy, structural imaging (such as computer or computerized tomography), and functional imaging (such as ultrasonography). The term "inherently radiopaque substance" as used herein means a polymer that is inherently radiopaque due to the covalent binding of halogen species to the polymer. Thus, the term does not include polymers simply blended with halogenated species or other radiopacity agents, such as metals and complexes thereof.

To meet the important need in the development of bioabsorbable radiopaque stents, applicants have developed certain preferred polymers containing a combination of structural units selected from the group consisting of dicarboxylic acids, halogenated (e.g., iodinated or brominated) derivatives of deaminated tyrosyl-tyrosine and poly (alkylene glycol) s, exhibiting desirable physico-mechanical and physicochemical properties consistent with their use in the manufacture of medical devices, including stents. It is apparent that while applicants have previously described polymers having different properties and combinations of characteristics in U.S. patent No. 6,475,477, applicants have found that the particular polymers of the present invention exhibit a significant and surprising combination of properties that is superior to the above polymers and are particularly well suited for use in implantable medical devices. Accordingly, the stent described in the preferred embodiment of the present invention: (a) sufficient radiopacity to be visualized by conventional X-ray fluoroscopy; (b) of sufficient strength to support a medically relevant level of radial compression within arterial or surrounding tissue; (c) having surface properties that minimize fibrinogen adsorption on the polymer surface and thereby reduce the occurrence of acute thrombosis and reduce the likelihood of smooth muscle cell proliferation and adhesion; and (d) have desirable resorption properties that can be tailored to meet the needs of a range of applications requiring stents to exist for different time periods or to elute therapeutic agents.

While applicants do not wish to be bound by or to be bound by any particular theory of operation, applicants believe that the beneficial combination of properties associated with the medical devices of the present invention are due, at least in part, to certain properties of the polymers of formula I from which the devices are made. In particular, applicants believe that a particular level of halogen (e.g., iodine) substitution, a particular ratio of the deaminated tyrosyl-tyrosine alkyl ester and deaminated tyrosyl-tyrosine used, and a particular amount and molecular weight of poly (alkylene glycol) (e.g., poly (ethylene glycol); PEG ") units incorporated into a preferred polymer provide a significantly superior combination of properties.

The term "ortho-oriented" as used herein is used to denote the orientation of a halogen atom relative to a phenoxyalcohol group.

It is also understood that the various polymeric formulae provided to represent polymeric structures may include homopolymers and heteropolymers, including stereoisomers. Homopolymer is used herein to denote a polymer composed of all of the same type of monomers. Heteropolymers, as used herein, are intended to mean polymers composed of two or more monomers of the type that are impermeable, also known as copolymers. Heteropolymers or copolymers can be of the type known as block, random, and alternating. Further, with respect to the various polymer formulas provided, the products of embodiments of the present invention can be comprised of homopolymers, heteropolymers, and/or blends of such polymers.

Preferred polymers

Accordingly, one aspect of the present invention provides a halogen-substituted polymer comprising one or more units described by formula I:

wherein each X is independently I or Br, Y1 and Y2 of each diphenol unit are independently from 0 to 4 inclusive, and Y1+ Y2 of each diphenol unit is from 1 to 8.

Wherein R and R₂Each independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R₂Further comprising a free carboxylic acid pendant group;

wherein A is:

wherein P is poly (C)₁-C₄Alkylene glycol) units; f is 0 to less than 1; g is 0-1 inclusive; and f + g is inclusive of the range of 0-1.

In a preferred variant of formula I, both iodine and bromine are present in the ring substituent. In other preferred variations, all X groups are ortho-oriented. Preferably Y1 and Y2 are independently 2 or less, and Y1+ Y2 is 1,2, 3 or 4, and more preferably 2 or 3. In a more preferred embodiment of formula I, all X groups are iodine.

In a preferred variant of formula I, P, i.e. poly (C)₁-C₄Alkylene glycol) less than about 75 wt%, and more preferably less than about 50 wt%. The poly (alkylene glycol) preferably has a molecular weight of 10,000 or less than 10,000. In an even more preferred embodiment, the poly (C)₁-C₄Alkylene glycol) is a poly (ethylene glycol) having a weight fraction of less than about 40 wt% and most preferably from about 1 to 25 wt%. It is understood that P may independently be C₁-C₁And C₁-C₄The copolymers, the latter of which may be represented in any combination.

In preferred embodiments, f may vary from about 0 to about 0.5, more preferably f is less than about 0.25 and more preferably less than about 0.1. In a more preferred variation, f can vary from greater than about 0.001 to about 0.08, and most preferably from about 0.025 to about 0.035.

In a preferred embodiment of formula I, g is greater than 0 and generally varies from about 0 to about 0.5. More preferably, g is greater than about 0.1 to about 0.35, and more preferably g is about 0.2 to about 0.3. In a more preferred variation, g may vary from about 0.01 to about 0.25, and more preferably from about 0.05 to about 0.15.

In other preferred variants of formula I, R and R₂All contain COOR₁A pendant group; wherein for each R, the subgroup R₁Alkyl groups containing 0 to 5 heteroatoms independently from 1 to about 18 carbon atoms selected from O and N; and wherein with respect to R₂In general, the radical R₁Is a hydrogen atom.

In other preferred variants of formula I, R and R₂Each independently has the following structure:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I; and wherein with R₂The sub-groups Q, in turn, comprise free carboxylic acid groups and, for each R, are independently selected from hydrogen and carboxylic acid esters and amides selected from alkyl and alkylaryl esters and amides containing up to 18 carbon atoms and esters and amides of biologically and pharmaceutically active compounds.

wherein R is₅Is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N; and wherein m is an integer from 1 to 8 inclusive; and wherein with respect to R₂In general, the radical R₁Is a hydrogen atom, and for each R, R₁Independently 1 to about 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N.

In a more preferred variant of formula I, R and R₂Each independently has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and R is₂In general, the radical R₁Is a hydrogen atom, and for each R, R₁Independently 1 to about 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N. Preferably R of R₁Each of the subgroups is independently an alkyl group of from 1 to about 18 carbon atoms and containing from 0 to 5 heteroatoms selected from O and N, and more preferably ethyl or butyl.

In other preferred variations of formula I, a is-C (═ O) -. In another preferred variant of formula I, a is:

wherein R is₃Is C₄-C₁₂Alkyl radical, C₈-C₁₄Aryl or C₈-C₁₄An alkylaryl group. Preference is given to selecting R₃Such that A is a dicarboxylic acid belonging to a naturally occurring metaboliteAn acid moiety. More preferably R₃Is selected from-CH₂-C(＝O)-、-CH₂-CH₂-C (═ O) -, -CH ═ CH-and (-CH)₂-)_zWherein z is an integer between 0 and 8 inclusive, and more preferably between 1 and 8.

In other preferred embodiments of the invention, polymers comprising one or more units described by formula II are disclosed:

wherein X of each polymer unit is independently Br or I, Y is 1-4 inclusive, and R is₄Is an alkyl, aryl or alkylaryl group having from 1 to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N, and further includes pendent t-butyl esters.

When R is₄When alkyl, it preferably has the structure:

wherein R is₂As defined herein for aspects of formula II, including all disclosed variations; and R is_5aAnd R₆Each independently selected from hydrogen and straight and branched chain alkyl groups having up to 18 carbon atoms and 0-8 heteroatoms independently selected from O and N.

The hydrolytically unstable polymer is optionally blended with up to about 75 wt% of poly (C)₁-C₄Alkylene glycol). In general, poly (C)₁-C₄Alkylene glycol) less than about 50 wt%. Preferably less than about 40 weight percent poly (ethylene glycol), and more preferably less than about 25 weight percent poly (ethylene glycol). The hydrolytically unstable polymers for stent applications preferably contain a mole fraction of poly (ethylene glycol) of about 0.001 to 0.08.

Selection of preferred R₄Aryl or alkylaryl species such that the unit depicted in formula II is a diphenol. In an even more preferred class, R₄The phenolic ring is iodinated or brominated to give a radiopaque polymer.

In other preferred embodiments of the present invention, polymers comprising one or more diphenol units described by formula III are disclosed:

wherein X, Y1, Y2 and R₂The same as described herein for formula III, including all disclosed variations, and Y1+ Y2 is between 0 and 8 inclusive. The polymer is optionally blended with up to about 75 wt% of poly (C)₁-C₄Alkylene glycol). In general, poly (C)₁-C₄Alkylene glycol) less than about 50 wt%. Preferably less than about 40 weight percent poly (ethylene glycol), and more preferably less than about 25 weight percent poly (ethylene glycol). The hydrolytically unstable polymers for stent applications preferably contain a mole fraction of poly (ethylene glycol) of about 0.001 to 0.08.

The class of polymers of formula III includes polymers of formula I bearing free carboxylic acid groups, wherein the carboxylic acid groups are protected by t-butyl esters. The polymers of formula I may also be halogen-free. Thus, polymers of formula I are disclosed, wherein X, Y1, Y2, R, R₂P, A, f and g are the same as described above for formula I, including all disclosed variations except for R₂Is protected by a tert-butyl group and Y1+ Y2 may also be equal to 0.

The present invention thus also includes t-butyl protected polymers of formulas I, II and III having heretofore unknown uses in the preparation of polymers having a hydrolytically unstable backbone and pendant carboxylic acid groups and t-butyl protected monomers for polymerizing polymers.

A preferred embodiment of the invention discloses monomers having the structure described by formula IIa:

R₄May be an alkyl group, preferably having the structure:

wherein R is₂And variations thereof are the same as described above for formula IIa; and R is_5aAnd R₆Each independently selected from hydrogen and straight and branched chain alkyl groups having up to 18 carbon atoms and 0-8 heteroatoms selected from O and N.

wherein each X is independently Br or I, Y1 and Y2 are independently 0-4 inclusive, Y1+ Y2 are independently 0-8 inclusive, and R is₂And variations thereof are the same as described above for formula IIIa.

In another preferred embodiment of the invention, the following monomers are described:

compound 001:

compound 002:

compound 003

Compound 004:

compound 005

In certain embodiments of the invention, the polymers of this aspect of the invention need not be inherently radiopaque, for example, where radiopacity is not a desirable feature or where radiopacity is delivered through a non-polymeric component of the stent (e.g., a coated metal stent). Regardless of the importance of radiopacity, the polymer need not also contain a poly (alkylene glycol) block (e.g., PEG).

In certain preferred embodiments of formula I, including polymers containing a tert-butyl protected free carboxylic acid group, R of R₁Is ethyl or butyl, and R₃is-CH₂-CH₂-or-CH₂-CH₂-CH₂-CH₂-. It is further understood that the formula I is provided schematically and the polymer structures represented are random copolymers with respect to the P position, such that different subunits may occur in random order throughout the polymer backbone, except where a is always attached to P or the phenol ring.

For all depicted polymers of the present invention, when a is carbonyl (C ═ O), the resulting polymer comprises polycarbonates. When A is:

time of flight

The resulting polymer comprises polyarylate. The polymers of the formulae II and II also include polycarbonates and polyarylates and any other polymers which can be polymerized from monomers having two terminal-OH groups, and in particular any polymers which can be polymerized from diphenols. Polyarylates of formulae II and III include polymers of the dicarboxylic acids disclosed for the preparation of polyarylates of formula I.

In certain preferred embodiments, it is understood that alkyl groups may be branched (such as isopropyl or tert-butyl) or straight-chain and may contain heteroatoms, such as O, N and S.

It is to be understood that the formula I is provided schematically and the polymer structures represented are random copolymers with respect to the P position, such that different subunits may occur in random order throughout the polymer backbone, except where a is preferably attached to P or the phenol ring.

In embodiments where formula I defines a polyarylate, R₃Preferably a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkyl radical containing up to about 18 carbon atomsAryl radical. In certain preferred embodiments, R₃Is a straight or branched chain alkyl group containing from about 2 to about 12 carbon atoms. R₃The groups may be substituted with any suitable functional group that does not or does not tend to cross-react with other monomeric compounds during polymerization, or otherwise significantly interfere with the formation of the polymers of the present invention by polymerization as described below. In certain preferred embodiments, R is selected₃Such that the polyarylate A-moieties in formula I are derived from dicarboxylic acids that are naturally occurring metabolites or highly biocompatible compounds. For example, in certain embodiments, R is selected₃Such that the polyarylate A-moieties in formula I are derived from intermediate dicarboxylic acids of the cellular respiratory pathway known as the Krebs cycle. Such dicarboxylic acids include alpha-ketoglutaric acid, succinic acid, fumaric acid, maleic acid, and oxaloacetic acid. Other preferred biocompatible dicarboxylic acids include sebacic acid, adipic acid, oxalic acid, malonic acid, glutaric acid, pimelic acid, suberic acid, and azelaic acid. According to said another mode, R₃More preferably selected from-CH ═ CH-and (-CH)₂-)_zWherein z is an integer between 0 and 8 inclusive, preferably between 2 and 8.

Among the preferred aromatic dicarboxylic acids are terephthalic acid, isophthalic acid and bis (p-carboxyphenoxy) alkanes such as bis (p-carboxyphenoxy) propane.

P in formula I is a poly (alkylene glycol), and preferably a poly (ethylene glycol) block/unit, which generally has a molecular weight of less than about 10,000 per unit. More typically, the poly (ethylene glycol) blocks/units have a molecular weight of less than about 4000/unit. The molecular weight is preferably from about 1000 to about 2000 per unit.

The same poly (alkylene glycol) and preferred species thereof may optionally be copolymerized with the polymers of formulae II and III.

The mole fraction of poly (ethylene glycol) units in preferred embodiments of formula I can vary from 0 to less than 1, typically from about 0 to about 0.5. More preferably, f is less than about 0.25 and more preferably less than about 0.1. In a more preferred variation, f can vary from greater than about 0.001 to about 0.08 inclusive, and most preferably from about 0.025 to about 0.035. The same mole fractions apply to the polymers of formulae II and III when copolymerized with poly (alkylene glycol).

As illustrated in formula I, and unless otherwise stated, the mole fractions reported herein are based on the total molar amount of diphenol carboxylate monomer units, diphenol free carboxylic acid units, and poly (alkylene glycol) units in the polymer units of formula I.

Applicants have recognized that the mole fraction of free carboxylic acid units, such as DT units, in the polymers of the invention can be adjusted in accordance with the invention to also adjust the degradation/reabsorbability of devices made from such polymers. For example, applicants recognized that while a polymer containing about 35% free acid carboxylic acid units (mole fraction 0.35) was 90% resorbed in about 15 days, polymers with lower amounts of free carboxylic acid had the desired longer life in vivo. Furthermore, by adjusting the amount of free carboxylic acid in the polymer in different ways throughout the preferred mole fraction range, the resulting polymer can be adapted for use in a variety of applications requiring different device lifetimes. In general, the higher the mole fraction of free carboxylic acid units, the shorter the lifetime of the device in vivo, and more suitable such devices are for applications requiring shorter lifetimes. In certain embodiments, if a lifetime of 6 months or more is required, then a polymer of free carboxylic acid units in the presently preferred range tends to be desirable. According to a preferred embodiment, the mole fraction of repeat units in formula I derived from the free acid carboxylic acid is in the range of about 0 to about 0.5, more preferably g is greater than about 0.1 to about 0.35, and more preferably g is about 0.2 to about 0.3. In a more preferred variation, g may vary from about 0.01 to about 0.25, and most preferably from about 0.05 to about 0.15.

Applicants have also recognized that the glass transition temperature of the polymer increases with increasing mole fraction of halogenated and free carboxylic acid units. Higher poly (alkylene oxide) weight percentages are generally used in polymers having higher levels of iodination and/or higher mole fractions of free carboxylic acid units in order to maintain the glass transition temperature of the polymer within a range deemed acceptable by those skilled in the art of polymer scaffold design.

In certain preferred embodiments, the copolymers of the present invention have a weight average molecular weight (Mw) of from about 20,000 to about 500,000, preferably from about 50,000 to about 300,000, and more preferably from about 75,000 to about 200,000. Copolymer polydispersity (P)_d) Values range from about 0.5 to about 10, more preferably from about 1.5 to 2.5, and most preferably about 2. The corresponding number average molecular weight (Mn) of the polymers of the invention can be calculated using the following formula:

Mn＝Mw/P_d

thus, the Mn value of the copolymers of the present invention is from about 10,000 to about 250,000, more preferably from about 25,000 to about 150,000, and even more preferably from about 37,500 to about 100,000. Molecular weights were determined by Gel Permeation Chromatography (GPC), against polystyrene standards, and without further calibration.

It will further be understood that the polymers of certain preferred embodiments of the present invention include not only polymers from which stents (or other medical devices) are made, but also precursor polymers bearing tertiary butyl protected carboxylic acid groups, i.e., polymers of formula I, wherein R is₂R of (A) to (B)₁Is a tert-butyl group.

Stent and stent system

In a preferred embodiment of the present invention, an inherently radiopaque, biocompatible, bioabsorbable stent is disclosed. The stent comprises a tubular member and further comprises any of the polymers described above, wherein the tubular member comprises a structure selected from the group consisting of a plate stent, a braided stent, a self-expanding stent, a metal mesh stent, a deformable stent, and a slide-and-lock stent. In certain embodiments, the polymer is a coating on a metal stent. More preferably, the stent is balloon expandable and comprises at least two substantially non-deforming elements arranged to form the tubular member, the non-deforming elements being slidably or rotatably interconnected for expanding the tubular member from the collapsed diameter to the expanded diameter. In another variation, the tubular member comprises a series of slidably engaged radial elements and at least one locking structure that allows the radial elements to slide unidirectionally from a first collapsed diameter to a second expanded diameter.

A collapsed stent secured to a delivery catheter is referred to herein as a stent system. Catheters include, but are not limited to, wire-over catheters, coaxial rapid-exchange designs, and multiple-exchange delivery platforms, such as Medtronic Zipper Technology. Such catheters may include: examples of catheters such as those described in the following references: U.S. Pat. nos. US4,762,129 and 5,232,445 to Bonzel and 4,748,982 to Yock; US5,496,346; US5,626,600; US5,040,548; US5,061,273; US5,350,395; US5,451,233 and US5,749,888. In addition, the catheter may include: examples of catheters such as those described in the following references: US patent US4,762,129; US5,092,877; US5,108,416; US5,197,978; US5,232,445; US5,300,085; US5,445,646; US5,496,275; US5,545,135; US5,545,138; US5,549,556; US5,755,708; US5,769,868; US5,800,393; US5,836,965; US5,989,280; US6,019,785; US6,036,715; US5,242,399; US5,158,548; and US6,007,545. The disclosures of the above-referenced patents are incorporated herein by reference in their entirety.

The catheter may be dedicated to various purposes, such as generating an ultrasound effect, an electric field, a magnetic field, light and/or a temperature effect. The heating duct may include: such as those described in US5,151,100, US5,230,349, US6,447,508 and US6,562,021 and WO9014046a 1. The infrared-emitting catheter may include: such as those described in US5,910,816 and US5,423,321. The disclosures of the above-referenced patents are incorporated herein by reference in their entirety.

Stents produced in accordance with preferred aspects of the present invention may have any design suitable for the intended application (e.g., slide-and-lock stents, plate stents (sometimes referred to as jelly roll stents), deformable stents, and self-expanding stents). The stent of the present invention is preferably designed to be easily implanted into an artery or tissue of an animal, such as a human, and to be expandable and/or adapted to maintain the artery open after opening the artery by a medical procedure, such as angioplasty. Examples of suitable stent designs for use in the present invention include "slide-and-anchor" stents, including those described in the following references: US patent US6,033,436; US6,224,626 and US6,623,521 and pending US application US 10/897,235 filed on 21/7/2004; these documents are incorporated herein by reference.

Other suitable designs suitable for use herein include those conventionally applied to metallic and polymeric stents, including various mesh, jelly-roll, plate, zigzag, and helical coil designs, such as the deformable stent of Palmaz in, for example, U.S. patent No. 4,733,665 and the successors thereof having controllable expansion and pressure-dependent deformation of the prosthetic portion under an excessive elastic limit. Other stent designs include the following and their successors: lau, US patent 5,344,426; U.S. patents US5,549,662 and US5,733,328 to Fordenbacher; U.S. patents US5,735,872 and US5,876,419 to Carpenter; U.S. patent No. US5,741,293 to Wijay; ryan, US patent US5,984,963; U.S. patents US5,441,515 and US5,618,299 to Khosravi; US patent US5,059,211 to Stack; US5,306,286 and US5,527,337; U.S. patent US5,443,500 to Sigwart; U.S. patent No. US5,449,382 to Dayton; U.S. patent US6,409,752 to Boatman et al.

The preferred embodiments of the present invention described herein relate generally to expandable medical implants for maintaining support of a body lumen. Over the years, various stent types have been proposed. Although the stent structure may vary significantly, virtually all stents can expand from a collapsed condition having a small diameter to an expanded condition having a larger diameter. In the case of collapse, the stent is typically delivered to the treatment site via a catheter, through a blood vessel or other body lumen. Upon reaching the treatment site, the stent radially expands to an implantable size to support the vessel wall. Expansion of the stent from the collapsed condition to the expanded condition can be performed in different ways. Various types of stents are described below based on their structure and manner of expansion. For additional information, various types of stents are described in the following documents: balcon et al, "Recommendations on StentManual, Implantation and Ultilization," European Heartjournal (1997), vol.18, 1536. 1547; and Phillips et al, "the sinter's notewood," Physician's Press (1998), Birmingham, Michigan; the disclosures of these documents are incorporated herein in their entirety by reference.

Balloon expandable stents are fabricated in the collapsed condition and expanded to the desired diameter using a balloon. During delivery, a balloon-expandable stent is typically secured to the exterior of an inflatable balloon positioned along the distal portion of the catheter. After reaching the treatment site, the stent is expanded from a collapsed condition to an expanded condition by inflating the balloon. The stent is typically expanded to a diameter greater than or equal to the inner diameter of the body lumen. The expandable stent structure may be held in the expanded state by mechanically deforming the stent, as taught, for example, in U.S. patent 4,733,665 to Palmaz. Alternatively, the balloon expandable stent may be held in the expanded state by engaging the stent walls with one another, as disclosed in, for example, Kramer, U.S. patent No. 4,740,207, Beck et al, U.S. patent No. 4,877,030, and Derbyshire, U.S. patent No. 5,007,926. In addition, the stent may be held in the expanded state by unidirectional occlusion of the stent wall with the endothelium in which the stent is grown, as shown in U.S. patent No. US5,059,211 to Stack et al.

The term "radial strength" as used herein describes the external pressure that a stent can withstand without causing clinically significant damage. Balloon expandable stents are commonly used in coronary arteries because of their high radial strength to ensure patency of the vessel. During deployment within the body lumen, the inflation of the balloon may be adjusted to expand the stent to a particular desired diameter. Thus, balloon expandable stents may be used in applications where precise placement and sizing is important. Balloon expandable stents are also commonly used in direct stenting, where the vessel is not pre-expanded prior to stent deployment. In the direct stenting procedure, however, expansion of the inflatable balloon dilates the vessel and also expands the stent.

One of the first self-expanding stents used clinically is the braided "WallStent" described by WallStent in U.S. patent No. 4,954,126. WallStent generally comprises a metal mesh in the form of a chinese finger glove. Such a sheath may provide a braided stent that is not superelastic, but still technically belongs to the family of self-expanding stents. Another example of a self-expanding stent is disclosed in U.S. patent No. 5,192,307 to Wall, wherein the stent-like prosthesis is formed of a polymer or sheet metal that is expandable or contractible for placement. Such a stent may be biased in the open position and may be locked in the closed position. Alternatively, it may be biased toward the closed position and locked in the open position. In the former case, a pin may be used to hold the stent in the collapsed state. Such pins are removed to allow the stent to assume the expanded state. One or more hooks may be formed in the wall to lock the bracket. The hooks engage complementary recesses formed in the opposing walls to mechanically interlock the rolled panels forming the stent.

The heat expandable stent is substantially similar to a self-expanding stent. However, this type of stent applies heat to create expansion of the stent structure. Stents of this type are formed from shape memory alloys, such as nitinol. Other types of heat-expandable stents may be formed from tin-coated, heat-expandable coils. A heat-expandable stent may be delivered to an affected area on a catheter capable of receiving a heated fluid. Heated saline or other fluid may pass through the portion of the catheter where the stent is located, thereby transferring heat to the stent and causing the stent to expand.

Ideally, the stent is balloon expandable to provide precise placement and sizing at the treatment site. It is also desirable that such stents have sufficient radial strength to maintain patency of the lumen when subjected to large external forces. It is also desirable that such stents be configured to exhibit little or no longitudinal foreshortening during radial expansion. It is also desirable that such stents be sufficiently flexible along the longitudinal axis to conform to the curved shape of the body lumen. It is also desirable that such stents have a capacity to conform to the interior of a body lumen.

While various stent configurations, including, but not limited to, plate stents, braided stents, self-expanding stents, wire mesh stents, deformable stents and slide-and-lock stents are well known in the art, it is to be understood that this description is illustrative only and should not be taken in any way as limiting the invention. Indeed, the radiopaque bioabsorbable polymers described herein may be applied to a variety of other stent designs known in the art. In addition, the general concepts described herein also include various applications of the invention and modifications thereof as would occur to those skilled in the art.

Certain preferred embodiments relate to expandable slide-and-lock stents having multiple components. The assembly has a plurality of sliding and locking elements that permit the radial-like element to slide unidirectionally from the collapsed diameter to the expanded/deployed diameter, but resist radial recoil from the expanded diameter. One advantage is that the stent design elements of the assembly and interlock can be varied to tailor the functional characteristics of strength, compliance, radius of curvature at deployment to expansion ratios. In certain preferred embodiments, the stent comprises a polymer as described in formula I, such that the stent comprises a radiopaque bioabsorbable material suitable for ablating over time. In certain embodiments, the stent is used as a therapy delivery platform.

Certain embodiments relate to radially expandable stents for opening or expanding a targeted area within a body lumen. In certain embodiments, the assembled stent comprises a tubular member having a longitudinal axial length and a radial axial diameter, and is sized for insertion into a body lumen. The length and diameter of the tubular member can be varied considerably to facilitate deployment in different selected target lumens depending on the number and configuration of the structural elements described below. The tubular member may be adjusted from at least a first collapsed diameter to at least a second expanded diameter. One or more detent elements and gripping elements or tabs are incorporated into the structural elements of the tubular member, thereby reducing recoil (i.e., collapse from an expanded diameter to a more collapsed diameter) to a minimum of less than about 5%.

The tubular member of certain embodiments has a "through lumen," which is defined as any structural element that does not have a lumen extending into the collapsed or expanded diameter. Furthermore, the tubular member has smooth edges to minimize damage from edge effects. The tubular member is preferably thin-walled (wall thickness depending on the material selected less than about 635 to less than about 100 microns) and flexible (e.g., less than about 0.01 newton force per millimeter of deflection) to facilitate delivery to small vessels and through tortuous vasculature. The thin-walled design also minimizes the risk of blood turbulence and thus thrombus formation. The thin profile of the expanded tubular member of certain embodiments also facilitates more rapid endothelialization of the stent.

The wall of the tubular member contains at least one assembly comprising a series of sliding and locking radial elements. Preferably, the plurality of modules are connected in the longitudinal axis by a connecting element coupling at least some of the radiating elements between adjacent modules. The radioactive elements are arranged within each assembly in order to define the periphery of the tubular member. Each radial element within the assembly is preferably a discrete unitary structure comprising one or more circumferential ribs bowed radially inwardly to form part of the overall circumference of the tubular member. At least one of the ribs in each of the radiating elements has one or more braking elements aligned along the length of the rib. At least some of the radiating elements also have at least one articulation mechanism to slidably engage the radiating elements from adjacent circumferential offsets. In one aspect of the invention, the articulating mechanism includes a tab for engaging a detent element arranged along a slidable engagement adjacent rib. The articulation between the tabs from one radial element and the detent elements from an adjacent radial element allows a locking or ratcheting structure to be formed whereby adjacent radial elements can slide circumferentially away from each other but are substantially prevented from sliding circumferentially toward each other. Thus, the tubular member can be radially expanded from a smaller diameter to a larger diameter, and rebound to the smaller diameter is minimized by the locking arrangement. The amount of spring back for an application can be tailored by adjusting the size and spacing between the braking elements along the rib. Preferably, the rebound is less than about 5%.

Certain aspects of stent embodiments are disclosed in U.S. patents US6,033,436/US 6,224,626 and US6,623,521, both to Steinke et al; each of these documents is incorporated herein in its entirety by reference.

Although a stent formed from a single unitary element has been described above as having particular mechanical features that lock the stent in an expanded condition, various other "slide and lock" configurations may be used. For example, other suitable locking structures may be found in: lau, US patent 5,344,426; U.S. patents US5,735,872 and US5,876,419 to Carpenter; U.S. patent No. US5,741,293 to Wijay; ryan, US patent US5,984,963; U.S. patents US5,441,515 and US5,618,299 to Khosravi; US patent US5,306,286 to Stack; U.S. patent US5,443,500 to Sigwart; U.S. patent No. US5,449,382 to Dayton; U.S. patent US6,409,752 to Boatman et al. Each of these references is incorporated herein by reference. Furthermore, many of the sliding and locking structures disclosed in the above-mentioned patents may be adapted to stent embodiments incorporating slidable interconnecting elements of the type described above.

Therapeutic agents and stent coatings

In another preferred variation of the invention, the stent further comprises a therapeutic agent (e.g., a pharmaceutical and/or biological agent) in an amount sufficient to exert the selected therapeutic effect. The term "agent" as used herein includes substances intended to alleviate, treat or prevent the stimulation of a specific physiological (metabolic) response. The term "biological agent" as used herein includes any substance having structural and/or functional activity in a biological system including, but not limited to: organ, tissue or cell based derivatives; cells, viruses, vectors, nucleic acids (animals, plants, microorganisms and viruses), both natural and recombinant and synthetic, of any sequence and size; antibodies, polynucleotides, oligonucleotides, cdnas, oncogenes, proteins, peptides, amino acids, lipoproteins, glycoproteins, lipids, carbohydrates, polysaccharides, lipids, liposomes or other cellular components or organelles such as receptors and ligands. Furthermore, the term "biological agent" as used herein includes viruses, sera, toxins, antitoxins, vaccines, blood components or derivatives, allergen products or similar products or arsine or its derivatives (or any trivalent organic arsenic-containing compound) which may be used in the prevention, treatment or cure of human diseases or injuries (each 351(a) part of Public Health Service Act (42u.s.c.262 (a)). furthermore, the term "biological agent" may include 1) a "biomolecule" or synthetic analogue, antibody, tissue or cell line of such a molecule as used herein, including bioactive peptides, proteins, carbohydrates, vitamins, lipids or nucleic acids produced by and purified from natural or recombinant organisms; 2) "genetic material", as used herein, includes nucleic acids (deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)), genetic components, genes, factors, alleles, operons, structural genes, regulatory genes, operators, gene complements, genomes, genetic codes, codons, anticodons, messenger RNA (mrna), transfer RNA (trna), ribosomal extrachromosomal genetic components, cytoplasmic genes, plasmids, transposons, gene mutations, gene sequences, exons, introns; and 3) "processed biologicals" as used herein, such as cells, tissues or organs that are manipulated. The therapeutic agent may also include vitamins or minerals or other natural elements.

The amount of therapeutic agent is preferably sufficient to inhibit restenosis or thrombosis or to affect some other condition of the tissue into which the stent is placed, such as healing of vulnerable plaque and/or preventing rupture or stimulating endothelialization. According to a preferred embodiment of the invention, the active agent may be selected from antiproliferative, anti-inflammatory, anti-matrix metalloproteinase and lipid lowering agents, agents that alter cholesterol, antithrombotic agents and antiplatelet agents. In certain preferred embodiments of the stent, the therapeutic agent is contained within the stent, as the active agent may be blended or mixed with the polymer by other means known to those skilled in the art. In other preferred embodiments of the stent, the therapeutic agent may be delivered from a polymeric coating on the surface of the stent. In another preferred variation, the therapeutic agent is delivered through a non-polymeric coating. In other preferred embodiments of the stent, the therapeutic agent is delivered from at least one region or surface of the stent. The therapeutic agent can be chemically bound to a polymer or carrier used to deliver the therapeutic agent from at least one portion of the stent, and/or the therapeutic agent can be chemically bound to a polymer comprising at least one portion of the stent body. In a preferred embodiment, more than one therapeutic agent may be delivered.

In addition to stents that can deliver therapeutic agents, for example, biopolymers such as the repulsing agent (repellant) phosphorylcholine on the stent, the stent may also be coated with other predetermined bioabsorbable polymers to promote the intraluminal biological response required for certain clinical effects. In addition, the coating may be used to mask the surface characteristics of the polymers included in the stent embodiments. The coating may be selected from a broad class of biocompatible bioabsorbable polymers, which may include halogenated and/or non-halogenated, which may or may not include any one or combination of any poly (alkylene glycol). These polymers may include variations in combinations including homopolymers, heteropolymers, stereoisomers, and/or blends of such polymers. These polymers may include, for example, but are not limited to, polycarbonates, polyarylates, poly (ester amides), poly (amide carbonates), trimethylene carbonates, polycaprolactones, polydioxanes, polyhydroxybutyrates, polyhydroxyvalerates, polyglycolides, polylactides, and stereoisomers and copolymers thereof, such as glycolide/lactide copolymers. In a preferred embodiment, the stent is coated with a polymer that exhibits a negative charge that repels the outer membrane of negatively charged red blood cells, thereby reducing the risk of clot formation. In another preferred embodiment, the stent is coated with a polymer that exhibits an affinity for cells (e.g., endothelial cells) to promote healing. In another preferred embodiment, the stent is coated with a polymer that repels attachment and/or proliferation of specific cells, such as arterial fibroblasts and/or smooth muscle cells, in order to reduce restenosis and/or inflammatory cells, such as macrophages.

The therapeutic agent may be incorporated into the bioabsorbable stent and/or coated on at least one region of the stent surface, thereby providing for the localized release of such active agents. In a preferred embodiment, the therapeutic agent is contained in the stent because the active agent is blended or mixed with the polymer by other means known to those skilled in the art. In other preferred embodiments of the stent, the therapeutic agent is delivered from a polymeric coating on the surface of the stent. In another preferred variation, the therapeutic agent is delivered through a non-polymeric coating. In other preferred embodiments of the stent, the therapeutic agent is delivered from at least one region or side of the stent.

Preferred therapeutic agents control restenosis (including neointimal thickening, intimal hyperplasia, and in-stent restenosis or limit vessel smooth muscle cell overgrowth) within the lumen of a vessel in which the stent is placed. Vascular stent applications and other body applications may require different treatments or more than one therapeutic agent.

A variety of compounds are believed to be useful in controlling vascular restenosis and in-stent restenosis. Some of these preferred active agents that improve vascular patency include, but are not limited to, paclitaxel, rapamycin, ABT-578, everolimus, dexamethasone, nitric oxide modulating molecules for endothelial function, tacrolimus, estradiol, mycophenolic acid, C6-ceramide, actinomycin D, and epothilone, as well as derivatives and analogs thereof.

Preferred therapeutic agents may also limit or inhibit thrombosis or affect certain other conditions of the tissue in which the stent is placed, such as healing vulnerable plaque, inhibiting plaque rupture, stimulating endothelialization or limiting other types of cells to proliferate and produce and deposit extracellular matrix molecules. According to a preferred embodiment of the invention, the active agent may be selected from the following drugs, but is not limited to them: antiproliferative agents, anti-inflammatory agents, anti-matrix metalloproteinase agents, and lipid lowering agents, antithrombotic agents, and antiplatelet agents.

In a preferred stent embodiment, the device delivers a therapeutic agent to treat vulnerable plaque lesions, such as an anti-inflammatory, lipid lowering/matrix altering therapeutic agent and/or an antiproliferative. Anti-inflammatory agents may include aspirin (an effective neutralizer of inflammation), losartan (an angiotensin receptor blocker), or pravastatin (a 3-hydroxy-3-methyl-glutaryl-coenzyme a (HMG-CoA) reductase inhibitor). Other deliveries of statins, such as pravastatin and fluvastatin, which are 3-HMG-CoA reductase inhibitors, may reduce (may) interstitial collagen gene expression and reduce matrix metalloprotease (MMP-1, MMP-3 and MMP-9) expression in order to effectively stabilize vulnerable plaque lesions. Local stent delivery of lipid lowering drugs, such as pravastatin may also improve plaque stability.

In a preferred stent embodiment, the device delivers an antiplatelet agent that is inhibited or otherwise acted upon by glycoprotein IIb/IIIa receptors, such as, but not limited to, aspirin, borrelidine (clopidogrel bisulfate), ticlopidine, quotation and dipyridamole. In another preferred stent embodiment, the device delivers antithrombin drugs that act by thrombin inhibition or other means, such as heparin, Low Molecular Weight Heparin (LMWH), polyamines to which dextran sulfate and heparin are covalently bound, heparin-containing polymer coatings for indwelling implants (MEDI-COAT from STS Biopolymers), polyurethane urea/heparin, R-hirudin, hirulog, hirudin/prostacyclin and analogs, argatroban, efegado, and ticks anticoagulant peptide. Additional antithrombotic substances and agents may include, but are not limited to, endothelial cell-derived relaxin, prostaglandin I subtype 2, plasminogen activator inhibitors, tissue plasminogen activator (tPA), abciximab: antiplatelet glycoprotein IIb/IIIa integrin receptor; fibrin and fibrin peptide a; lipid lowering agents, such as omega-3 fatty acids and chrysin (aka TRAP-508) from Chrysalis Vascular Technologies.

Different compounds address other pathological conditions and/or vascular diseases. Some of these therapeutically targeted compounds are agents that treat endothelial damage (e.g., VEGF; FGF); agents that modulate cellular activation and phenotype (e.g., MEF-2& Gax modulators; NFKB antagonists; cell cycle inhibitors); agents that deregulate cell growth (e.g., E2F decoys; RB mutants; cell cycle inhibitors); agents for apoptosis disorders (e.g., inducers of Bax or CPP 32; Bcl-2 inhibitors; integrin antagonists); and agents for aberrant cell migration (e.g., integrin antagonists; PDGF blockers; plasminogen activator inhibitors).

Therapeutic agents coated or incorporated into the stent polymer of embodiments of the present invention may be classified according to their site of action within the host. The following agents are believed to exert their effects extracellularly or at specific membrane receptor sites. They include corticoids and other ion channel blockers; a growth factor; an antibody; a receptor blocker; a fusion toxin; an extracellular matrix protein; peptides or other biomolecules (e.g., hormones, lipids, matrix metalloproteinases, etc.); irradiating; anti-inflammatory agents, including cytokines such as interleukin-1 (IL-1); and tumor necrosis factor alpha (TNF-alpha); gamma interferon (interferon-gamma); and tranilast; they modulate the inflammatory response.

Other classes of active agents exert their effects on the plasma membrane. They include those active agents involved in signaling cascades such as conjugated proteins, membrane-associated and cytosolic protein kinases and effectors, tyrosine kinases, growth factor receptors and adhesion molecules (selectins and integrins).

Certain compounds are active in the cytoplasm and include, for example, heparin, ribozymes, cytotoxins, antisense oligonucleotides, and expression vectors. Other therapeutic approaches are directed to the nucleus. They include gene integration; protooncogenes, particularly those important for cell division; nuclear protein; a cell cycle gene; and a transcription factor.

Can be used as a stent coating and/or incorporated into a bioabsorbable stentOther therapeutic substances for depot formulations include: antibodies, such as ICAM-1 antibodies that inhibit monocyte chemotaxis recruitment and adhesion, macrophage adhesion and related conditions (Yasukawa et al, 1996, Circulation); toxin-based therapies such as chimeric toxins or single toxins that control vascular SMC proliferation (Epstein et al, 1991, Circulation); bFGF-saporin which selectively terminates SMC proliferation in those cells with high FGF-2 receptors (Chen et al, 1995, Circulation); suramin which inhibits migration and proliferation by blocking PDGF-induced and/or mitogen-activated protein kinase (MAPK-AP-1) -induced signaling (Hu et al, Circulation, 1999); belaprost sodium, a chemically stable prostacyclin analogue (PGI), which inhibits intimal thickening and luminal narrowing in coronary arteries₂) (Kurisu et al, Hiroshima J. MedSci, 1997); verapamil, which inhibits neointimal smooth muscle cell proliferation (Brauner et al, JThorac Cardiovasc Surg 1997); agents that block the CD 154 or CD40 receptor may limit the development of atherosclerosis (E Lutgens et al, Nature Medicine 1999); an agent controlling the stress response component or mechanical stress or inhibitory component or heat shock gene response; and anti-chemoattractants for SMC and inflammatory cells.

Additionally or alternatively, the cells may be encapsulated in bioabsorbable microspheres or mixed directly with a polymer or hydrogel. Living cells can be used for the continuous delivery of molecules, such as cytokines and growth factors. Any source of cells may be used in this aspect of the invention. In addition, non-viable cells, or dehydrated cells that can retain their purpose upon rehydration, can be used and preserved. Natural, chemically modified (processed) and/or genetically engineered cells may be used.

The therapeutic agent may be polar or carry a net negative or positive or neutral charge; they may be hydrophobic, hydrophilic or zwitterionic or have a great affinity for water. Release may be by a controlled release mechanism, diffusion, interaction with another active agent delivered by intravenous injection, nebulization, or oral administration. The release may also be performed by applying a magnetic field, an electric field or using ultrasound.

In another aspect of the invention, the scaffold may also incorporate or deliver a hydrogel or other substance, such as Phosphorylcholine (PC) that functions to prevent adhesion of blood cells, blood proteins or molecules, extracellular matrix, or other cell types. The hydrogel can deliver a therapeutic agent.

Synthetic natural (of plant, microbial, viral or animal origin) and recombinant active agents with selected functional or chemical properties for use can be mixed with complementary substances (e.g. anti-thrombotic and anti-restenotic substances; nucleic acids; and lipid complexes). The agent may also be combined with vitamins or minerals. For example, those that act directly or indirectly through interactions or mechanisms include amino acids, nucleic acids (DNA, RNA), proteins or peptides (e.g., RGD peptides), carbohydrate moieties, polysaccharides, liposomes or other cellular components or organelles, such as receptors and ligands.

Genetic means of controlling restenosis include, but are not limited to: applying antisense oligonucleotides to PDGFR- β β mRNA to control PDGF expression; the application of antisense oligonucleotides to the nuclear antigen c-myb or c-myc oncogene (Bauters et al, 1997, Trends CV Med); the use of antisense phosphorothioate oligodeoxynucleotides against cdk 2 kinase (cyclin-dependent kinase) in order to control the cell cycle of vascular smooth muscle cells (Morishita et al 1993, Hypertension); the use of the VEGF gene (or VEGF itself) in order to stimulate reconstructive wound healing, such as endothelialisation and reduction of neointimal growth (Asahara et al 1995); delivering nitric oxide synthase gene (eNOS) to reduce vascular smooth muscle cell proliferation (Von Der Leyen et al, 1995, Proc Natl Acad Sci); the use of adenoviruses expressing plasminogen activator inhibitor-1 (PAI-1) in order to reduce vascular smooth muscle cell migration and thereby reduce restenosis (Carmeliet et al, 1997, Circulation); stimulating apolipoprotein a-1(ApoA1) overexpression in order to rebalance serum levels of LDL and HDL; use of apoptosis gene products to promote cell (e.g., smooth muscle cell) death and cell chemotaxis gene products to regulate cell division (ras inhibition; tumor suppressor protein p53 and Gax homologous gene products overexpressed by p 21); and inhibition of NF-. kappa.B activation (e.g., p65) for the control of smooth muscle cell proliferation (Autieri et al, 1994, Biochem Biophys Res Commun).

Production method

In another aspect of the invention, a method of making an inherently radiopaque, biocompatible, bioabsorbable stent is disclosed. One aspect of the process involves the selective removal of tertiary butyl ester groups from hydrolytically unstable polymers to form new polymer compositions having free carboxylic acid groups instead of the tertiary butyl ester groups. The disclosed method comprises dissolving a hydrolytically unstable polymer having at least one t-butyl ester group in a solvent comprising an acid in an amount effective to selectively remove at least one t-butyl group by acid hydrolysis to form free carboxylic acid groups, the acid having a pKa of about 0 to about 4.

In a preferred embodiment of this, the polymer is soluble in acid and the solvent consists essentially of acid.

In another embodiment, the solvent is selected from the group consisting of chloroform, dichloromethane, tetrahydrofuran, dimethylformamide, and mixtures of two or more thereof. In another variant of the process, the acid is selected from formic acid, trifluoroacetic acid, chloroacetic acid and mixtures of two or more thereof. In a preferred embodiment of the process, the acid is formic acid.

The polymer composition of formula I may be prepared by any number of methods. As noted above, the polymer of formula I is a halogen ring-substituted diphenol polycarbonate or polyarylate comprising defined relative amounts of diphenolate units, diphenol free carboxylic acid units, and poly (alkylene glycol) units. Thus, in a preferred embodiment, wherein the halogen is iodine and the poly (alkylene glycol) unit is poly (ethylene glycol) ("PEG"), the polymer may be prepared by a process comprising the steps of: polymerizing a desired proportion of one or more iodocyclo-substituted diphenol monomer compounds (including the R subgroup from formula I)₁Monomer combination as a tert-butyl ester groupMaterial) and PEG, followed by deprotection reaction to remove the tert-butyl ester protecting group to form the polymer composition of formula I.

Examples of suitable processes for preparing the polycarbonate or polyarylate polymers of the present invention are disclosed in U.S. Pat. Nos. 5,099,060, 5,587,507, 5,658,995, 5,670,602, 6,120,491 and 6,475,477, the disclosures of which are incorporated herein by reference. Other suitable methods, associated catalysts and solvents are well known in the art and are taught in Schnell's Chemistry and Physics of Poly carbonates (Interscience, New York 1964), the teachings of which are incorporated herein by reference.

Polycarbonates may also be prepared by dissolving the diphenol monomer and poly (ethylene glycol) in methylene chloride containing 0.1M pyridine or triethylamine. A solution of phosgene in toluene at a concentration of about 10 to about 25 weight percent and preferably about 20 weight percent is typically added at a constant rate over about 2 hours using a syringe pump or other device. The reaction mixture was quenched by stirring with Tetrahydrofuran (THF) and water, after which the polymer was isolated by precipitation with Isopropanol (IPA). The residual pyridine (if used) is then removed by stirring the THF polymer solution with a strongly acidic resin, such as AMBERLYST 15.

The above process improves upon the prior art process using phosgene gas, which is known to require special handling and also careful co-addition of sodium hydroxide at a controlled rate to maintain the pH of the reaction mixture at 6-8 to prevent polymer backbone degradation. The prior art processes also require a large excess of phosgene, since under the conditions used, a large amount of hydrolysis occurs. The process of the invention may also advantageously provide for a more complete removal of residual pyridine or for the complete replacement of pyridine with triethylamine, which has more favourable toxicity characteristics.

For example, methods of preparing biphenol monomers for producing polymers are disclosed in U.S. Pat. nos. 5,587,507 and 5,670,602. In particular, such references disclose the preparation of non-ester deaminated tyrosyl-tyrosine free carboxylic acids (DTs) and deaminated tyrosyl-tyrosine esters including ethyl (DTE), butyl (DTB), hexyl (DTH), octyl (DTO), benzyl (DTBn) and other esters. For example, an iodo-substituted diphenol monomer may be prepared by coupling two phenol compounds to each other by any of the procedures disclosed herein, wherein one or both of the phenol rings are iodo substituted or a diphenol is formed, which is iodinated after coupling by any suitable iodination method.

As noted above, although any of the above methods are suitable herein, it can be difficult to prepare preferred polycarbonates and polyarylates having pendant free carboxylic acid groups from monomers having free carboxylic acid groups (such as DT monomers) without cross-reacting the free carboxylic acid groups of the monomers with comonomers. However, applicants have found that free acid polymers, including the preferred polymers of the present invention, can be produced from protected polymers in the absence of palladium catalysts as described in detail below, thereby avoiding any of the disadvantages associated with conventional processes. Applicants have found that contrary to the conventional teachings in the art, the use of tert-butyl (tB) as a free acid protecting group can be achieved with great advantage in that these protecting groups can be easily and selectively removed from the polymer without the need for palladium or other difficult to remove catalysts.

The term "selective removal" as used herein means a deprotection reaction wherein more than 99% of all tert-butyl protecting groups are removed and the polymer molecular weight is reduced by less than 10%. Applicants have found that the process of the present invention is capable of removing a tert-butyl protecting group from a provided polymer with a selectivity of about 99.99% or greater than 99.99%, and preferably about 99.995% or greater.

More specifically, preferred polymers of the present invention can be advantageously prepared by the following steps: the iodo-ring substituted alkyl ester monomers are polymerized with poly (ethylene glycol) and a temporarily protected free acid carboxylic acid monomer (monomer in which the free acid functionality is masked with a temporary protecting group) to form polycarbonate or polyarylate polymer units from which the temporary protecting group can be selectively removed to yield the corresponding free carboxylic acid group.

Any of a variety of suitable protection/deprotection methods may be suitable for use in preparing the polymer devices of the present invention, including, for example, methods for converting benzyl carboxylic acid esters to free carboxylic acid moieties as described in U.S. Pat. No. 6,120,491, which is incorporated herein by reference.

Another method that may be used is the novel deprotection method of the present invention, wherein the tert-butyl ester protecting group on the hydrolytically unstable polymer is selectively removed to give a novel polymer with free carboxylic acid groups instead of tert-butyl ester groups. The process contacts a hydrolytically unstable polymer having at least one tertiary butyl ester group with an acid having a pKa of about 0 to about 4 in an amount effective to selectively remove the at least one tertiary butyl group by acid hydrolysis to form a free carboxylic acid group.

Preferred polymer feedstocks have at least one repeat unit comprising a tert-butyl protected free acid. One example of a t-butyl protected polymer suitable for use in the deprotection process of the invention comprises one or more units as described by formula II. Preferred diphenol polymers comprise one or more diphenol units of formula III, and in particular tertiary butyl protected polymers of formula I.

In general, polymers having one or more repeating t-butyl (tB) ester groups to be deprotected according to the methods of the invention can be provided by various methods. When radiopacity is desired, the monomer is suitably ring-iodinated or brominated. Formula II includes polycarbonates and polyarylates, including copolymers thereof with poly (alkylene oxides), which can be prepared as described herein. In certain preferred embodiments, polyarylates or polycarbonates comprising tertiary butyl (tB) ester repeat units are prepared and provided by reacting tertiary butyl ester-protected carboxylate monomers with other monomers.

Formula II also includes poly (amidocarbonates) and poly (esteramides) prepared according to the method described in US patent US6,284,462 using the monomer species disclosed herein having pendant tertiary butyl ester groups, which is incorporated herein by reference. Formula II also includes polyiminocarbonates, which may be prepared, for example, by reacting tert-butyl ester protected carboxylate monomers with other monomers according to the methods disclosed in U.S. patent No. US4,863,735, which is incorporated herein by reference.

Formula II also includes the phosphorus-containing polymers disclosed in U.S. patents US6,238,687 and US5,912,225, which are incorporated herein by reference, which may be prepared, for example, by reacting the monomers disclosed therein with pendant tertiary butyl ester groups with other monomers according to the polymerization methods disclosed therein. The above-referenced aliphatic-aromatic monomers with pendant tertiary butyl ester groups disclosed in U.S. patent No. 6,284,462 can be substituted for tyrosine-derived biphenols to make other polymers of formula II.

Formula II also includes strictly alternating poly (alkylene oxide ether) copolymers that can be prepared, for example, by reacting tert-butyl ester-protected carboxylate monomers with other monomers according to the methods disclosed in U.S. patent No. US6,602,497, which is incorporated herein by reference.

Thus, a polymer having units of formula II wherein R is₄X and Y are as defined herein:

the preparation of monomers is described in the patents referred to herein, see in particular M: U.S. patents US6,284,462, US4,863,735, US6,238,687, US5,912,225 and US6,602,497, the disclosures of which are incorporated herein by reference in their entirety.

Polymers having diphenol units of formulae I and III may be polymerized from diphenol monomers of formula IIIa, R being in the case of formula IIIa₂X, Y1 and Y2 are as defined herein:

the polymer may be contacted with the acid by dissolving the polymer in a solvent containing an effective amount of the acid. Any suitable inert solvent in which the polymer to be deprotected is soluble may be used in the reaction mixture in the steps provided for in the process of the invention. Examples of suitable solvents include chloroform, dichloromethane, THF, dimethylformamide and the like. In certain preferred embodiments, the solvent comprises dichloromethane.

Any suitable weak acid capable of facilitating the removal of the t-butyl protecting group from the carboxylic acid groups of the provided polymer by acidolysis may be used in accordance with the process of the present invention. Examples of certain suitable weak acids include acids having a pKa of about 0 to about 4, including formic acid, trifluoroacetic acid, chloro-acetic acid, and the like. In certain preferred embodiments, the weak acid is formic acid.

With this method, complete deprotection can be achieved with minimal (< 1%) molecular weight reduction. Thus, the amount of weak acid used should be the maximum amount that can be added to the solvent without interfering with the solubility of the polymer. Depending on the particular polymer formulation, complete deprotection can occur within 1-4 days. The polymer is then recovered by precipitation in isopropanol or water. Redissolving in a solvent (free of acid) and reprecipitation can remove any residual acid.

Weak acids can be used as solvents in which the polymer is dissolved. In such cases, deprotection occurs more rapidly within 4-8 hours and eliminates the need for a separate process solvent. In this embodiment, the preferred acid is formic acid. The same precipitation and reprecipitation steps can be used in order to recover and purify the polymer.

The contacting step or components thereof can be carried out under any suitable conditions effective to selectively remove the t-butyl protecting group by acidolysis. One skilled in the art can employ any of a wide variety of acid hydrolysis methods for the contacting step of the present invention to selectively remove the tert-butyl group without undue experimentation. For example, in certain preferred embodiments, the contacting step is carried out at about 25 ℃ and about 1 atm.

In light of the disclosure herein, one skilled in the art can produce a variety of hydrolytically unstable polymers bearing free carboxylic acid groups, and in particular the polymers of the present invention, from corresponding polymers comprising tert-butyl protected free carboxylic acid repeat units, which are useful in a variety of medical devices.

After polymerization and deprotection, suitable post-treatment of the polymers of the preferred embodiments of the present invention can be carried out by any known method in order to produce a variety of stents or other medical devices suitable for different applications. For example, in certain preferred embodiments, the polymers of the present invention are formed into a stent by a process comprising extrusion, compression molding, injection molding, solvent casting, rotational casting, combinations of two or more thereof, and the like. Additionally, the scaffold may include at least one fibrous material, curable material, layered material, and/or woven material.

Such methods may further include two-dimensional fabrication methods such as cutting extruded polymer sheets by laser cutting, etching, mechanical cutting or other methods and assembling the cut parts into a stent, or similar three-dimensional methods to fabricate devices from solid forms. In certain embodiments, the polymer is coated on the surface of an implantable device, particularly a stent, made of the polymer of the present invention or another material, such as a metal. Such coatings may be formed on the stent by techniques such as dipping, spraying, combinations thereof, and the like.

Other applications

The highly beneficial combination of properties associated with the preferred polymers of the present embodiments is well suited for the production of a variety of medical devices, including stents, particularly implantable medical devices that are biocompatible, preferably radiopaque, and have different bioresorption times. For example, applicants have recognized that in certain embodiments, the polymers are suitable for use in the production of implantable devices for orthopedic, tissue engineering, dental applications, wound closure, gastric slotted band (stomachiclap bands), drug delivery, cancer therapy, other cardiovascular applications, non-cardiovascular stents, such as biliary, esophageal, vaginal, pulmonary/bronchial etc. In addition, it is useful for the production of implantable radiopaque discs, plugs and other devices for tracking areas of tissue removal, such as in the removal of cancerous tissue and organ removal, and staples and clips useful for wound closure, tissue adhesion to bone and/or cartilage, hemostasis (homeostasis), tubal ligation, surgical adhesion prevention, and the like. Applicants have also recognized that the polymers of the present invention are well suited for use in the production of various coatings for medical devices, including stents, and particularly implantable medical devices.

Furthermore, in certain preferred embodiments, the polymers of the present invention may be advantageously used in the manufacture of orthopedic devices, including, for example, radiopaque biodegradable screws (interventional screws), radiopaque biodegradable suture anchors, and the like, for applications including correction, prevention, reconstruction, and repair of Anterior Cruciate Ligaments (ACLs), rotator cuff muscle groups/rotator cup muscle groups, and other skeletal deformities.

Other devices that may be advantageously formed from the polymers of the present invention include medical tissue engineering devices. Examples of suitable devices include tissue engineering scaffolds and grafts (such as vascular grafts, grafts or implants for nerve regeneration). The polymers of the present invention may also be used to form various devices effective for closing wounds in the body. For example, biodegradable sutures, clips, staples, barbs, or mesh sutures, implantable organ supports, and the like, may be formed for various surgical, cosmetic applications, and cardiac wound closure.

Various devices for dental applications may be advantageously formed in accordance with preferred aspects of the present invention. For example, devices for guiding tissue regeneration, for alveolar ridge replacement in denture wearers, and for maxillary-facial bone regeneration may benefit from radiopacity, so that the surgeon/dentist can determine placement and continued function of such implants by simple X-ray visualization.

The polymers of the present invention are also useful in the production of gastric suture loops for the treatment of obesity. The production of radiopaque slotted bands enables more effective monitoring of devices within the body and more effective treatment of obesity.

In addition to intravascular stents and non-cardiovascular stents, the polymers of the present invention are useful in many other cardiovascular and vascular devices. For example, valves for replacement repair of heart valves, catheters, and the like, chordae replacement, annuloplasty rings, leaflet repair patches, vascular grafts, vascular catheters, septal defect patches, arterial and venous access closure devices (plugs), and the like may be formed. Furthermore, components of the artificial heart, such as the rough surface/fiber-like layer (bellows pump) may be formed from the polymers of the invention.

The polymers of the present invention are further useful in the production of various therapeutic delivery devices. Such devices may be adapted for use with a variety of therapeutic agents, including, for example, pharmaceutical agents (i.e., drugs) and/or biological agents as described above, including biological macromolecules, genetic material, processed biological material, and the like. Any number of delivery systems capable of delivering therapeutic agents to the body may be manufactured, including therapeutic delivery devices for treating cancer, intravascular problems, dental problems, obesity, infections, and the like. In certain embodiments, any of the above-described devices described herein may be adapted for use as (including any other function of) a therapy delivery device. Controlled therapeutic delivery systems can be prepared in which biologically or pharmaceutically active and/or passive agents are physically embedded or dispersed within a polymer matrix or physically mixed with the polycarbonates or polyarylates of the present invention. Controlled therapy delivery systems can also be prepared by applying the therapeutic agent directly to the surface of a bioabsorbable stent device (including at least one of the polymers of the invention) without using these polymers as a coating, or using other polymers or substances for coating.

One major advantage of using the radiopaque bioabsorbable polymers of the present invention in therapeutic delivery applications is the ease of monitoring the release of the therapeutic agent and the presence of the implantable therapeutic delivery system. Because the radiopacity of the polymer matrix is due to covalent bonding of halogen substituents, the level of radiopacity is directly related to the residual amount of degraded therapeutic delivery matrix that remains on the implant site at any given time after implantation. In preferred embodiments, the rate of release of the therapeutic agent from the degraded therapeutic agent delivery system is related to the resorption rate of the polymer. In preferred embodiments, the direct quantitative determination of the residual degree of radiopacity from degradation in preferred embodiments provides the attending physician with a means to monitor the level of release of the therapeutic agent from the implanted therapeutic delivery system.

The following non-limiting examples illustrate certain aspects of the invention. Unless otherwise stated, all parts and percentages are by weight and all temperatures are in degrees celsius.

Detailed Description

Nomenclature and abbreviations used

The following abbreviations are used to identify the various iodinated compounds. TE represents tyrosine ethyl ester, DAT represents deaminated tyrosine and DTE represents deaminated tyrosyl tyrosine ethyl ester. The polymer obtained by phosgenating the DTE is denoted as poly (DTE carbonate). "I" before the abbreviation means mono-iodination (e.g., ITE means mono-iodinated TE), and I before the abbreviation₂Denotes di-iodination (e.g. I)₂DAT denotes di-iodinated DAT). In DTE, if "I" precedes D, it means iodine is on DAT, and if "I" follows D, it means iodine is on the tyrosine ring (e.g., DI₂TE represents DTE with 2 iodine atoms in the tyrosine ring). The following figures further illustrate this nomenclature.

General Structure of iodinated DTE monomers

R₁＝I，R₂，R₃，R₄＝H；IDTE

R₁，R₂＝I，R₃，R₄＝H；I₂DTE

R₁，R₂＝H，R₃，R₄＝I；DI₂TE

R₁，R₃＝I，R₂，R₄＝H；IDITE

Tension test

The test was performed using an Endura TEC EMS with a suitable load cell, run with WinTest software version 2.22(Minnetonka, MN) and according to ASTM D882-02 standard test method for tensile properties of thin plastic sheets. Briefly, to simulate in vivo conditions, film samples were produced using the thermo-compression Method (Thermal Press Method) using PHI Tulip laboratory pressure (Model Q230) with a calibrated temperature range of 0-315 ℃. The films were hydrated in 7.4pH phosphate buffered saline for 30 minutes and then tested for tensile force while immersed. Data were collected and analyzed using the method according to ASTM D882-02 to obtain the modulus of elasticity, yield point, yield strength, percent elongation at yield tension, maximum tension, and longest elongation.

Resorption test

The use of Abramson et al in "small changes in polymer structure can significantly increase the degradation rate: effect of free carboxylic acid groups on the Properties of tyrosine-derived polycarbonates "-six World Biomaterials Congress Transactions, Society for Biomaterials 26^thThe materials and methods described in Annual Meeting, Abstract 1164(2000) for determining the rate of polymer degradation in vivo and in vitroThe disclosure of which is incorporated herein by reference.

Example 1: 3, 5-diiodo-4-hydroxyphenylpropionic acid (3, 5-di-iodo-desaminotyrosine, I)₂DAT) preparation

50g (0.300mol) of DAT was dissolved in 500mL of 95% ethanol. To the stirred solution was added 146g (0.605mol) of PyICl. The solution was stirred for 30 minutes, at which time the solid slowly dissolved to a pale yellow solution. The solid was added to 2.5 liters of water containing 10g of sodium thiosulfate over 30 minutes. The water was stirred during this addition. An off-white solid was isolated and separated by filtration and washed with several portions of deionized water.

The solid was transferred to a large beaker containing 2L of deionized water and 24g of sodium hydroxide and stirred until dissolved. The filtrate was acidified with 35mL of acetic acid (pH about 4). The white solid formed was isolated by filtration and washed with several portions of water. The moisture barrier rubber was used to squeeze out all the water. The solid was dried under nitrogen and then under vacuum. The dried solid was purified by recrystallization from 1: 2 acetone-water. 50g of crude I are obtained₂DAT and HPLC and¹and H NMR characterization.

Examples 2 and 3: Di-iodo-DTE (I)₂Preparation of DTE):

using similar operating procedures as those disclosed in the literature, by using I₂Preparation of diiodinated monomer (I) by DAT instead of DAT₂DTE). In a typical procedure 53.3g (0.255mol) tyrosine ethyl ester, 104g (0.250mol) I are stirred in a1 liter round bottom flask₂DAT and 3g (0.025mol) of 1-hydroxybenzotriazole with 500mL of tetrahydrofuran. The flask was cooled to 10-18 ℃ in an ice-water bath and 50g (0.255mol) EDCI was added and stirred at 15-22 ℃ for 1 hour. After which it was stirred at ambient temperature for 5 hours. The reaction mixture was concentrated to 250mL and then stirred with 1L of water and 1L of ethyl acetate. The lower aqueous layer was separated and discarded using a separatory funnel. The organic layer was washed with 500mL each of 0.4M HCl, 5% sodium bicarbonate solution and 20% sodium chloride solution in that order. After drying over anhydrous sodium sulfate, the organic layer was concentrated to syrup and purified by reaction withThe hexanes were milled together with stirring. A pale yellow solid was obtained. The product was purified by HPLC and¹and H NMR characterization. Using similar operating procedures, by reacting I₂DAT and commercial tyrosinate tert-butyl ester (TtBu) coupling preparation I₂DTtBu。

Examples 4 and 5: preparation of iodinated tyrosine esters

Preparation of ethyl 3-Iodotyrosine (ITE) and ethyl 3, 5-diiodotyrosine (I) from the corresponding tyrosine iodide by esterification with ethanol and thionyl chloride₂TE). Iodinated tyrosine was prepared by the method of example 1.

Examples 6 to 11: other iodinated diphenol monomers

Many other iodinated monomers were prepared by coupling the following combination of two phenolic reagents, following the procedure of examples 2-3. The monomers prepared are listed below:

DITE: DAT and ITE

IDITE: IDAT and ITE

I₂DTE：I₂DAT and TE

DI₂TE: DAT and I₂TE

I₂DTtB：I₂DAT and TtB

I₂DITE：I₂DAT and ITE

Figures 4a-b show X-ray comparisons of radiopaque bioabsorbable di-iodinated and tri-iodinated tyrosine-derived polycarbonate films. Poly (I2 DITE-co-20% PEG2k) carbonate 114 micron films had optical densities equivalent to human bone. Films of poly (80% I2 DTE-co-20% PEG2k) carbonate had lower optical densities.

Example 12: iodine and poly (ethylene glycol) -containing polymers

I containing 97.5 mol% was prepared as follows₂Polymer of DTE and 2.5% poly (ethylene glycol) with molecular weight of 2000 (poly)(97.5％I₂DTE-co-2.5% PEG2K carbonate)). To a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer, reflux condenser and rubber septum was added 29.7g (0.0488mol) of I₂DTE, 2.5g (0.00125mol) PEG2000 and 215mL dichloromethane. A clear, light yellow solution was obtained upon stirring. To this was added 15.1mL (0.15mol) of pyridine. 30mL of a 20% phosgene in toluene (0.0576mol) solution was placed in an air-tight plastic syringe and added to the reaction flask over a period of 3 hours using a syringe pump. Molecular weight was determined by analyzing an aliquot of the reaction mixture with GPC. Additional phosgene solution (up to 10%) was added to achieve the desired molecular weight. The reaction mixture was quenched with 110mL of tetrahydrofuran and 10mL of water. The polymer was precipitated by adding the reaction mixture to 1.5L of cold 2-propanol in a high speed waring blender. The resulting polymer was triturated with two portions of 0.5L 2-propanol. The particulate polymer particles were isolated by filtration and dried in a vacuum oven.

Examples 13 and 14: preparation of poly (DTE carbonate) and poly (I-DTE carbonate)

By the method of example 12, I was replaced with DTE and I-DTE, respectively₂DTE preparation of poly (DTE carbonate) and poly (I-DTE carbonate).

Example 15: polymers for stent preparation

The following example describes poly (87.5% I) for scaffold preparation₂DTE-total-10% I₂DttBu-co-2.5% PEG2K carbonate). To a three-necked round-bottomed flask equipped with a mechanical stirrer, thermometer, reflux condenser and rubber septum was added 26.6g (0.044mol) of I₂DTE，3.20g(0.005mol)I₂DTtBu, 2.5g (0.00125mol) PEG2000 and 215mL of dichloromethane. A clear, light yellow solution was obtained upon stirring. To this was added 15.1mL (0.15mol) of pyridine. 30mL of a 20% phosgene in toluene solution (0.0576mol) was placed in an air-tight plastic syringe and added to the reaction flask over a period of 3 hours using a syringe pump. Molecular weight was determined by analyzing an aliquot of the reaction mixture with GPC. Additional phosgene solution (up to 10%)) To obtain the desired molecular weight. The reaction mixture was quenched with 110mL of tetrahydrofuran and 10mL of water. The polymer was precipitated by adding the reaction mixture to 1.5L of cold 2-propanol in a high speed waring blender. The resulting gum-like polymer was milled with two portions of 0.5L 2-propanol. The particulate polymer particles were isolated by filtration and dried in a vacuum oven.

Example 16: deprotection of the tert-butyl side chain

To remove the tert-butyl protecting group, 25g of the poly (87.5% I) prepared above were used₂DTE-total-10% I₂DTtBu-co-2.5% PEG2K carbonate) was stirred with 125mL trifluoroacetic acid (TFA) to give a 20% solution. After all the polymer particles had come into solution, stirring was continued at room temperature for 4 hours. The polymer was precipitated by adding the solution to 1 liter of 2-propanol in a high speed waring blender. The resulting polymer particles were triturated twice with 500mL 2-propanol to remove traces of TFA. The product was isolated by filtration, washed with IPA and dried in a vacuum oven at 40 ℃.

Examples 17 to 19: preparation of poly (DTE-co-PEG carbonate)

Following the procedure of example 15, I was replaced with DTE₂-DTE and I₂-DTtBu and substitution of PEG1000 for PEG2000 and adjustment of the stoichiometric amount to increase the PEG molar ratio to prepare poly (DTE-co-5% PEG1k carbonate). Preparation of Poly (I) Using the same procedure₂DTE-co-2.5% PEG 2000-carbonate) and poly (I)₂DTE-co-3.4% PEG 2000-carbonate).

Examples 20 to 25: preparation of poly (DTE-co-DT carbonate)

Prepare poly 63% DTE-co-37% DT carbonate) according to the procedure of example 15, wherein the desired ratio of DTE to DT was obtained without using G and adjusting the stoichiometry. The tert-butyl group was deprotected as in example 16. Also prepared by this method were poly (90% DTE-co-10% DT carbonate), poly (85% DTE-co-15% DT carbonate), poly (83% DTE-co-17% DT carbonate), poly (76% DTE-co-24% DT carbonate), and poly (75% DTE-co-25% DT carbonate).

Example 26: poly (I)₂DTE-Co-2.5 mole% PEG_2kAdipate) preparation

Reacting diphenol I₂DTE (2.97g, 4.87mmol), PEG2000(0.250g, 0.125mmol) and adipic acid (0.731g, 5.04mmol) and 0.4g DPTS (dimethylaminopyridine-p-toluenesulfonate, catalyst) were weighed into a 100mL brown bottle with a Teflon liner cap and 40mL of dichloromethane were added to the bottle and tightly capped. The flask was stirred for 10-15 minutes and then 2.5mL (2.02g, 16mmol) of diisopropylcarbodiimide was added and stirring continued for 2 hours. An aliquot of the sample was withdrawn and analyzed by GPC after appropriate treatment. An Mw of about 100,000 is desirable. Once the desired Mw was reached, 200mL of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried in a stream of nitrogen. The precipitate was then dissolved in 20mL of dichloromethane and precipitated with 200mL of methanol. The polymer was then dried in a nitrogen atmosphere and subsequently dried in a vacuum oven.

Example 27: poly (60% I)₂DTE-total-20% I₂DT-Co-20% PEG_2kAdipate) polymerization

The di-alcoholized component (1.83g, 3.00mmol I)₂DTE，0.638g、1.00mmolI₂DTtB and 2.000g of 1.00mmol PEG2000) and diacid (0.731g, 5mmol adipic acid) and 0.4g DPTS were weighed into a 100mL brown bottle with a Teflon liner cap. To the bottle was added 40ml of dichloromethane and tightly sealed. The flask was stirred for 10-15 minutes and then 2.5mL (2.02g, 16mmol) of diisopropylcarbodiimide was added and stirring continued for 2 hours. An aliquot of the sample was withdrawn and analyzed by GPC after appropriate treatment. An Mw of about 100,000 is desirable. Once the desired Mw was reached, 200mL of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried in a stream of nitrogen. The precipitate was then dissolved in 20mL of dichloromethane and precipitated with 200mL of methanol. The polymer was then dried in a nitrogen atmosphere and subsequently dried in a vacuum oven.

Deprotection of the amino acid: the resulting polymer was dissolved in trifluoroacetic acid (10% w/v) and stirred overnight. On day 2 the polymer was precipitated in isopropanol using a mixer. The polymer was then triturated twice with fresh isopropanol and filtered through a sintered filter between washes. The polymer was then dried in a nitrogen atmosphere and subsequently dried in a vacuum oven.

Example 28: poly (I)₂DTE-Co-2.5 mole% PEG_2kSebacate) preparation

Reacting diphenol I₂DTE (2.98g, 4.89mmol), PEG2000(0.250g, 0.125mmol) and sebacic acid (1.01g, 5.00mmol) and 0.4g DPTS were weighed into a 100mL brown bottle with a Teflon liner cap. To the bottle was added 40ml of dichloromethane and tightly sealed. The flask was stirred for 10-15 minutes and then 2.5mL (2.02g, 16mmol) of diisopropylcarbodiimide was added and stirring continued for 2 hours. An aliquot of the sample was withdrawn and analyzed by GPC after appropriate treatment. An Mw of about 100,000 is desirable. Once the desired Mw was reached, 200mL of 2-propanol was added to the reaction mixture with stirring. The precipitate was collected and dried in a stream of nitrogen. The precipitate was then dissolved in 20mL of dichloromethane and precipitated with 200mL of methanol. The polymer was then dried in a nitrogen atmosphere and subsequently dried in a vacuum oven.

The applicant has carried out a detailed study aimed at finding an optimized polymer composition that can satisfy the above requirements. Key findings are recorded in table 1 below.

Table 1: iodination and Effect of PEG on mechanical Properties

Each time, 5, 7.4pH PBS for 30 min at 37 ℃

(close to significant figures)

Table 1 illustrates poly (DTE carbonic acid)Ester) (formula 1 is defined, in which f is 0, g is 0, X is Y is 0, R is₁Ethyl and a ═ C (═ O) -) is strong enough to be an ideal candidate material for the fabrication of bioabsorbable stents (see column 1). However, such materials do not have radiopacity and are not sufficiently hemocompatible. As described above, the introduction of iodine substituents reduces the mechanical strength of the polymer. Under mono-iodination (column 2, the polymer is still strong enough to be used as a stent material, but does not have sufficient radiopacity to be seen by X-ray fluoroscopy when two iodine atoms are incorporated into the polymer structure, the polymer has sufficient radiopacity but insufficient mechanical strength (column 3). also, when PEG is incorporated into the polymer backbone (f 0.05), the polymer is significantly weaker (column 4). indeed, as little as 5 mol% PEG results in a 50% decrease in the strength and stiffness of the polymer and completely loses the qualification of the corresponding polymer if used as a stent material and itself to be further considered, layered and multi-polymer stent designs can use such polymers for specific design purposes.

Against this background, the applicant has found that the introduction of iodine and a low percentage of PEG into the polymer has a non-obvious and totally unexpected effect on significantly improving the mechanical properties of the polymer (see column 5 of table 1). One skilled in the art of polymer science can confidently predict synergistic effects: since PEG and iodine each individually reduce the mechanical strength of the polymer, the simultaneous incorporation of PEG and iodine within the same polymer should result in a significant reduction in the mechanical strength of the polymer containing iodine and PEG. In contrast to this prediction, the combined incorporation of iodine and PEG had a "counter-synergistic" effect, resulting in a polymer composition superior in strength and hardness to poly (DTE carbonate).

Figure 1 shows that the polymer compositions of column 5 of table 1 actually have sufficient strength to make a fully functional stent and sufficient radiopacity to be visible in an animal heart by X-ray fluoroscopy. Comparison with the clinically used stainless steel stent showed practically the same level of visibility. FIGS. 2A and 2B are optical micrographs ofPolymer compositions containing iodine substituents have been shown to be too brittle to make functional scaffolds. FIG. 2A shows a copolymer of poly (I)₂DTE carbonate) (without PEG) formed stent frame was broken at multiple positions under gentle handling (see arrows). The mechanical strength of the polymer is significantly improved by the simultaneous incorporation of PEG and iodine into the polymer. FIG. 2B shows poly (I)₂DTE-co-2.5% PEG2K carbonate) has sufficient stiffness and ductility to be easily fabricated into a stent. The polymer compositions of column 5 of table 1 thus have sufficient strength and ductility for stent fabrication.

Table 2 explains that DT incorporation has minimal impact on the mechanical properties of the polymer. Although there is a tendency for the strength to drop at yield and break, the elongation and elastic modulus are virtually unchanged-albeit dropping significantly over the device resorption period.

Table 2: effect of DT elements on mechanical Properties and resorption time

(close to significant figures)

Example 29: adsorption of fibrinogen to Polymer surfaces

The time course of adsorption of human fibrinogen to the test polymer and stainless steel surface was determined using a quartz crystal microbalance (QCM-D, Q-Sense AB, model D300, Goeteborg, Sweden) with loss monitoring.

QCM-D is a gravimetric technique and is used to determine the mass of a substance in a liquid attached to a surface in real time. The increased mass associated with the quartz surface results in a decrease in the oscillation frequency of the crystal. In addition, the device can measure mass-induced depletion changes of surface adsorption.

Quartz crystals (Q-Sense, Cat # QSX-301) were spin coated with a polymer solution (1% polymer in methylene chloride). Also included are commercially available quartz crystals coated with thin layer stainless steel (Q-Sense, Cat # QSX-304). To start a typical experiment, the crystals were inserted into a QCM-D instrument and incubated in Phosphate Buffered Saline (PBS) at 37 ℃. After reaching a stable baseline, fibrinogen solution was injected and the mass-induced frequency and loss changes of adsorption were recorded in real time. The fibrinogen solution was incubated until binding saturation was reached (as evidenced by no further significant changes in frequency and consumption values). The fibrinogen free PBS was used for all washing steps to remove unbound fibrinogen from the sensor surface after the adsorption process. Human fibrinogen was purchased from Calbiochem (Cat #341576) and diluted in PBS to a final concentration of 3 mg/mL. All experiments were performed in triplicate, with standard deviations below 12% (standard error averages).

The quartz crystal can be reused up to 10 times by applying the following cleaning procedure: with H in a ratio of 1: 5₂O₂(30％)、NH₄The quartz crystal was treated with a cleaning solution (80 ℃ C., 15 minutes) composed of OH and ultrapure water. Thereafter the crystals were rinsed thoroughly with ultrapure water and blown dry with nitrogen. The crystals were finally exposed to UV and ozone for 15 minutes (UVO cleaner, Jelight Company, Irvine, Calif., USA).

Table 3 summarizes comparative evaluation of different scaffold polymer formulations for in vitro fibrinogen adsorption. Fibrinogen is a key blood protein. The extent of adsorption of fibrinogen on an artificial surface that is in contact with blood is widely regarded as a reliable indicator of the tendency of said surface to be hemocompatible. In general, it is known to those of ordinary skill in the art of biomedical engineering that the lower the level of fibrinogen adsorbed on a material, the higher the hemocompatibility of the material.

Table 3: relative level of fibrinogen adsorbed on the test surface as determined by in vitro quartz microbalance (Q-sense) frequency shift

In terms of table 3, item 1 (stainless steel) represents a clinically used stent material, which is known to have a low level of thrombosis and good blood compatibility. Stainless steel was used as a control and had an acceptable level of fibrinogen adsorption. Item 2 in table 3 is Dacron, a known thrombogenic material limited to clinical use in vascular applications. Dacron had the highest level of fibrinogen adsorption among all the tested materials. Item 3 is poly (DTE carbonate), a base material in the polymer represented by formula I. Its high level of fibrinogen adsorption indicates that this polymer is not an ideal candidate for medical devices that contact blood. The introduction of iodine alone (item 4) or DT units alone (item 5) tends to reduce the level of fibrinogen adsorption, however, this reduction is not sufficient to qualify these polymer compositions as ideal materials for scaffolds.

The above description shows that the simultaneous introduction of iodine, DT and PEG results in a significant reduction of fibrinogen adsorption-at PEG levels still consistent with that required to provide a polymer with mechanical strength. In this general scenario, the applicant provides another surprising observation: comparing items 6 and 7 shows that a very small step-wise increase in the amount of PEG in the polymer composition can have a non-obvious and unpredictable effect on protein adsorption. The fibrinogen adsorption to the polymer composition 6 is low enough that the composition has the quality of being an ideal candidate material for a scaffold, while the additional addition of PEG as low as 0.9 mol% to the polymer composition 7 provides a polymer composition that exhibits superior hemocompatibility to stainless steel for clinical use.

Polymer composition 7 in table 3 explains the key design principle that applicants first recognized: when iodine and PEG are introduced simultaneously into a polymer composition comprised by formula I, a very low molar ratio of PEG is sufficient to significantly reduce the surface adsorption level of fibrin. In combination with the above-described effect of iodine and PEG on the mechanical properties of the polymer composition, applicants have discovered a method to simultaneously optimize the mechanical and biological properties of polymers for stent applications.

Example 30: in vitro drug elution kinetics

The release of drug from certain polymers is determined based on physicochemical characteristics and solvent extraction at 37 ℃, a "sink" state and conditions of agitation to ensure dissolution uniformity. The therapeutic substance (e.g., drug) in a polymer (see table below) can be coated on the surface of a polymer film, a metal stent or on a metal surface and can be embedded or blended with the polymer prior to lamination.

The membrane is sized to fit drug loading and quantitative detection limits. Typical procedures may include extraction or precipitation of the compound followed by quantification using High Performance Liquid Chromatography (HPLC). A suitable dissolution medium is used, such as 3% Bovine Serum Albumin (BSA) or 35% Tween 20 in Phosphate Buffered Saline (PBS). The dissolution rate was measured from 24 hours to 28 days. After dissolution, the drug content in the membrane and/or the media is analyzed. The mass balance measurements from this HPLC assay were used to calculate the dissolution rate of each drug. For the overall dissolution profile, the percentage of dissolution was calculated by using the amount measured at each time point.

Table 4-test summary of tyrosine-derived polycarbonate coatings

Test material
	Poly (95% I2 DTE-co-5% PEG 1K) carbonate^1，2
Poly (97.5% I2 DTE-co-2.5% PEG2K) carbonate
	Poly (77.5% I2 DTE-co-20% I2 DT-2.5% PEG2K) carbonate
Poly (67.5% I2 DTE-co-30% I2 DT-2.5% PEG2K) carbonate
	Poly (70% I2 DTE-co-20% I2 DT-10% PEG2K) carbonate
Poly (80% I2 DTE-co-20% PEG2K) carbonate

Comparative control Material
	Poly (95% DTE-co-5% PEG 1K) carbonate

¹Only the polymer was coated on the steel stent in order to determine the surface properties of the polymer coating by Scanning Electron Microscopy (SEM).

²Drug-containing polymers were coated on metal stents and tested for biocompatibility and drug elution in an in vivo system, i.e., porcine coronary artery.

Drug elution using various polymers coated on the surface of the polymer or embedded within the polymer and pressed into a film showed drug elution. Figure 3 shows that the elution of drugs from poly-DTE-carbonates can be adjusted by changing the polymers containing iodine on the DAT ring and by adding PEG to the backbone of the polymer. SEM studies confirmed that the polymer coated directly on the steel stent adhered to it and remained intact after stent deployment. SEM also confirmed that the polymer-drug coated on the steel or polymer stent adhered to it and remained intact after stent deployment. The drug-containing polymers coated on metal and polymer stents showed biocompatibility in porcine coronary arteries when tested for 28 days in vivo and demonstrated a reduction in restenosis (compared to drug-uncoated stents) due to the presence of antiproliferative drug elution and performing its action.

The foregoing description of the preferred embodiments is to be considered as illustrative and not restrictive, and the invention is defined by the appended claims. As will be readily appreciated, numerous variations and combinations of the features set forth above may be employed without departing from the present invention as set forth in the claims. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications are intended to be included within the scope of the following claims.

Claims

1. A radiopaque, bioabsorbable stent comprising a bioabsorbable polymer containing sufficient halogen atoms to impart intrinsic radiopacity to the stent, the polymer comprising one or more units of formula I

Wherein each X is independently I or Br, Y1 and Y2 for each biphenol unit are independently 0 to 4 inclusive, and Y1+ Y2 for each biphenol unit is between greater than 0 to 8,

wherein R and R₂Each independently an alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and 0-8 heteroatoms selected from O and N, and R2 further comprises free carboxylic acid pendant groups;

wherein A is:

wherein R is₃Is a saturated or unsaturated, substituted or unsubstituted alkyl, aryl or alkylaryl group containing up to 18 carbon atoms and from 0 to 8 heteroatoms selected from O and N;

wherein P is poly (C)₁-C₄Alkylene glycol) units; f is from 0.0001 to less than 0.25; g is 0.01-0.25; and f + g is in the range of 0 to 1 inclusive.

2. The stent of claim 1, wherein the stent further comprises a structure selected from the group consisting of a plate stent, a braided stent, a self-expanding stent, a metal mesh stent, a deformable stent, and a slide-and-lock stent.

3. The stent of claim 1, wherein the stent is balloon expandable and comprises at least two substantially non-deforming elements arranged to form a tubular member, the non-deforming elements being slidably or rotatably interconnected for expanding the tubular member from a collapsed diameter to an expanded diameter.

4. The scaffold of claim 1, wherein both iodine and bromine are present as ring substituents.

5. The scaffold of claim 1, wherein all X groups are ortho-oriented, which is used to denote the orientation of a halogen atom relative to a phenoxyalcohol group.

6. The stent of claim 1, wherein Y1 and Y2 are independently 2 or less than 2 and Y1+ Y2 is 1,2, 3, or 4.

7. The stent of claim 1, wherein Y1+ Y2 is 2 or 3.

8. The scaffold of claim 1, wherein all X groups are iodine.

9. The stent of claim 1, wherein the poly (C)₁-C₄Alkylene glycol) units less than 75 wt%.

10. The stent of claim 1, wherein the poly (C)₁-C₄Alkylene glycol) units less than 50 wt%.

11. The stent of claim 1, wherein the poly (C)₁-C₄Alkylene glycol) is a poly (ethylene glycol) having a weight fraction of less than 40 wt%.

12. The stent of claim 1, wherein the weight fraction of poly (ethylene glycol) units is 1 to 25 wt%.

13. The stent of claim 1, wherein f is less than 0.1.

14. The stent of claim 1, wherein f varies between 0.001-0.08.

15. The stent of claim 1, wherein f varies between 0.025-0.035.

16. The stent of claim 1, wherein g is between 0.05 and 0.15.

17. The stent of claim 1, wherein R and R₂All contain COOR₁A pendant group; wherein for R, the subgroup R₁Alkyl containing 0 to 5 heteroatoms independently from 1 to 18 carbon atoms selected from O and N; and wherein with respect to R₂In general, the radical R₁Is a hydrogen atom.

18. The stent of claim 1, wherein R and R₂Each independently has the following structure:

wherein R is₇Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) a; wherein R is₈Selected from-CH ═ CH-, -CHJ₁-CHJ₂-and (-CH)₂-) n; wherein a and n are independently 0 to 8 inclusive; and J₁And J₂Independently is Br or I, and wherein R is₂The subgroup Q, in turn, comprises free carboxylic acid groups and is selected, for each R, from hydrogen and carboxylic acid esters and amides selected from alkyl and alkylaryl esters and amides containing up to 18 carbon atoms.

19. The stent of claim 1, wherein R and R₂Each independently has the following structure:

wherein R is₅Is an alkyl group containing up to 18 carbon atoms and 0 to 5 heteroatoms selected from O and N, and wherein m is an integer from 1 to 8 inclusive; and wherein with respect to R₂In general, the radical R₁Is hydrogen, and for each R, a subgroup R₁Independently 1 to 18 carbonsAn alkyl group of atoms containing 0 to 5 heteroatoms selected from O and N.

20. The stent of claim 1, wherein R and R₂Each independently has the following structure:

wherein j and m are independently an integer from 1 to 8 inclusive, and wherein with respect to R₂In general, the radical R₁Is a hydrogen atom, and for each R, R₁Independently 1 to 18 carbon atoms, containing 0 to 5 heteroatoms selected from O and N.

21. The scaffold of claim 20, wherein for R, a subgroup R₁Each independently an alkyl group containing 1 to 18 carbon atoms and at least one oxygen atom.

22. The scaffold of claim 20, wherein for R, a subgroup R₁Each independently is ethyl or butyl.

23. The scaffold of claim 1, wherein a is a-C (═ O) -group.

24. The stent of claim 1, wherein a is:

wherein R is₃Is C₄-C₁₂Alkyl radical, C₈-C₁₄Aryl, or C₈-C₁₄An alkylaryl group.

25. The stent of claim 24, wherein R is selected₃Such that a is part of a dicarboxylic acid belonging to a naturally occurring metabolite, such dicarboxylic acid being selected from the group consisting of α -ketoglutaric acid, succinic acid, fumaric acid, maleic acid and oxaloacetic acid, sebacic acid, adipic acid, oxalic acid, malonic acid, glutaric acid, pimelic acid, suberic acid and azelaic acid.

26. The stent of claim 24, wherein R₃Is selected from-CH₂-C(＝O)-、-CH₂-CH₂-C (═ O) -, -CH ═ CH-and (-CH)₂-)_z(ii) a And wherein z is an integer between 0 and 8 inclusive.

27. The stent of claim 26, wherein R₃Is (-CH)₂-)_zWherein z is an integer from 1 to 8 inclusive.

28. The stent of claim 1 or 4, further comprising an effective amount of a therapeutic agent.

29. The stent of claim 28, wherein the amount is sufficient to inhibit restenosis, thrombosis, plaque formation, plaque rupture and inflammation and/or promote healing.

30. The stent of claim 1 or 4, wherein the polymer forms a coating on at least a portion of the stent.

31. A system for treating a site within a body lumen, comprising a catheter having a deployment device and the stent of claim 1 or 4, wherein the catheter is adapted to deliver the stent to the site and the deployment device is adapted to deploy the stent.

32. The system of claim 31, wherein the catheter is selected from the group consisting of a wire outer catheter, a coaxial rapid exchange catheter, and a multiple exchange delivery catheter.

33. The stent of claim 1, wherein the polymer is not naturally occurring.

34. The scaffold of claim 1, wherein the polymer further comprises an amino acid.