Biologically absorbable coatings for implantable devices based on poly(ester amides) and methods for fabricating the same

ES 2 297 530 T3

DESCRIPTION

Biologically absorbable coatings for implantable devices based on polyester amides and methods for making the same.

Background

1. Field of the invention

This invention relates to coatings for drug delivery devices such as vascular stents that deliver drugs and methods for producing the same.

2. Description of the state of the art

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure to treat heart disease. A catheter assembly having a balloon portion is percutaneously introduced into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the portion of the balloon is positioned through the occlusive lesion. Once in position through the lesion, the balloon is inflated to a predetermined size to radially compress the atherosclerotic plaque of the lesion to reshape the lumen wall. The balloon is then deflated to a smaller profile to allow the catheter to be removed from the patient's vasculature.

A problem associated with the above procedure includes the formation of intimal flaps or tears in the arterial lining that can fold and occlude the duct after the balloon is deflated. In addition, thrombosis and restenosis of the artery may develop several months after the procedure, which may require another angioplasty procedure or bypass surgery. To reduce partial or total occlusion of the artery by folding the arterial lining and to reduce the chances of thrombosis and restenosis development, a stent is implanted in the lumen to maintain vascular patency.

Stents are used not only as a mechanical intervention but also as a vehicle to provide drug therapy. As a mechanical intervention, the stents act as scaffolds, to physically hold open and, if desired, to expand the wall of the passageway. Typically, stents can be compressed so that they can be inserted through small blood vessels via catheters and then expanded to a larger diameter once they are in the desired location. Examples in the patent literature describing stents that have been applied in PTCA procedures include the stents illustrated in US Pat. 4,733,655 issued to Palmaz, US Patent No. 4,800,882 issued to Gianturco, and US Patent No. 4,886,062 issued to Wiktor.

Drug therapy can be achieved by inserting drugs into the stents. Medicated stents enable local delivery of a therapeutic substance to the desired site. To provide an effective concentration to the treated site, systemic administration of such a drug often produces toxic or adverse side effects for the patient. Local delivery is a preferred treatment method because smaller total drug levels are delivered compared to systemic dosages, but they are concentrated at a specific site. Therefore local supply produces fewer side effects and achieves more favorable results. One proposed method of introducing drugs into stents involves the use of a polymeric carrier spread over the surface of a stent. A solution including solvent, a polymer dissolved in the solvent, and a therapeutic substance dispersed in the mixture is applied to the stent. The solvent is allowed to evaporate, leaving on the surface of the stent a coating of the polymer and the therapeutic substance impregnated in the polymer.

Polyester amides as described in US Patent No. 6,503,538 to Chu et al., Are a category of polymers well suited for stent coatings. Polyester amides are highly biocompatible and are an effective matrix for drug delivery. However, improvements can be made to the properties of polyester amides. For example, the polyester amides described by Chu et al. Are too soft and sticky which causes these polyester amides to adhere to the surface of the balloon. Furthermore, the polyester amides described by Chu et al. Tend to flow during ethylene oxide (ETO) sterilization. Accordingly, there is a need for polyester amides that include units derived from monomers identical or similar to those in US Pat. 6,503,538 with improved toughness, an increased ability to adhere to balloon surfaces, and a higher degree of drag resistance during an ETO sterilization process.

Summary

A medical article is provided comprising an implantable substrate having a coating, the coating including the polymeric product of the reaction between a diol diamine and a dicarboxylic acid wherein the diol diamine comprises a structure of

ES 2 297 530 T3

<td>RO</td><td>0 R</td>

<td>1 il</td><td>II 1</td>

<td>CH — C — 0-</td><td>- (CH₂) _x—O — C — CH — NH₂</td>

in which:

R is hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, or ethylene amide, and x is an integer between 2 and 16.

wherein the polymeric product comprises a structure of

Γ O GOLD OR

II II 1 II II 1 c— (CH₂) _Y—C — NH — CH —- C — O —- (CH₂) _x—O — C — CH — NH

<img file="ES2297530T3_D0001.tif" />

in which:

R is hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, or ethylene amide, and x is an integer between 2 and 16 and is an integer between 0 and 16, and n is an integer between 35 and 1,100.

The diol-diamine can be a condensation product of an amino acid and a diol. Examples of amino acids that can be used to prepare diol diamine include glycine, alanine, valine, isoleucine, leucine, phenylalanine, methionine, asparagine, glutamine, proline, and mixtures thereof. Examples of diols that can be used to make the diol diamine include ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol and 1,12-dodecanediol and mixtures thereof. Examples of dicarboxylic acids that can be used to react with dioldiamine include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, undecanedioic acid, dodecanedioic acid, brazilian acid. , tetradodecanedioic acid, pentadecanedioic acid, tapsic acid, and mixtures thereof.

A medical article is provided comprising an implantable substrate having a coating, the coating including a condensation copolymer having the formula

O GOLD OR

II II I II II I - [C— (CH₂)_Y—C — NH — CH — C — O— {CH₂), .— O — C-CH — M-i]., - in which R is selected from a group consisting of hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, and ethylene amide ; x is an integer that has a value between 2 and 16; y is an integer that has a value between 0 and 16; and n is an integer that has a value between 35 and 1,100.

A medical article is provided comprising an implantable substrate having a coating, the coating including a condensation copolymer having a formula

OO Oo

II II IIII

- [C- (CH₂)_k-CN ----- CH — C — O— (CH₂)_K—O — C — CHN] „IIII

H₂C-CH₂-CH₂ h₂c — ch₂—Ch₂ where x is an integer that has a value between 2 and 16; y is an integer that has a value between 0 and 16; and n is an integer that has a value between 35 and 1,100.

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A method of manufacturing a medical article is provided, the method includes synthesizing a condensation copolymer and forming a coating comprising the copolymer on at least a portion of an implantable substrate, the synthesis of the copolymer being the reaction of a diol diamine with a dicarboxylic acid, in which the diol-diamine comprises a structure of

ROOR

I II II I

HjN — CH — C — O— &lt;CH₂)_x—O — C — CH — NH₂ in which:

R is hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, or ethylene amide, and x is an integer between 2 and 16;

wherein the polymeric product comprises a structure of

<img file="ES2297530T3_D0002.tif" />

in which:

R is hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, or ethylene amide, x is an integer between 2 and 16 and is an integer between 0 and 16, and n is an integer between 35 and 1,100.

A method of manufacturing a medical article is provided, the method includes synthesizing a condensation copolymer and forming a coating comprising the copolymer on at least a portion of an implantable substrate, wherein the condensation copolymer has a formula

O GOLD OR

II II I II II I wherein R is selected from a group consisting of hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl, methylene amide, and ethylene amide; x is an integer that has a value between 2 and 16; y is an integer that has a value between 0 and 16; and n is an integer that has a value between 35 and 1,100.

A method of manufacturing a medical article is provided, the method includes synthesizing a condensation copolymer and forming a coating comprising the copolymer on at least a portion of an implantable substrate, wherein the condensation copolymer has a formula

0 Oo

II II IIII - [C— (CH₂)_r—C — N ---- CH-CO- (CH_:), - OC-CHN]

IIII

H₂C — CHj — CH₂ H₂C — CH₂—CH₂ where x is an integer that has a value between 2 and 16; y is an integer that has a value between 0 and 16; and n is an integer that has a value between 35 and 1,100.

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Detailed description

1. Terms and definitions

The following definitions apply:

The term "biologically absorbable" coatings and / or polymers is defined as coatings and / or polymers that can completely degrade, dissolve and / or erode when exposed to bodily fluids such as blood and are gradually reabsorbed, absorbed and / or removed by the body. The dissolution process and eventual absorption and removal of the coating and / or polymer can be brought about, for example, by hydrolysis, enzymatic action, oxidation, phagocytosis, metabolic processes, mass or surface erosion or the like.

When referring to "biologically absorbable" stent coatings and / or polymers that form such stent coatings, it is understood that after the process of degradation, dissolution, erosion, absorption and / or resorption is complete, no coating on the stent.

The term "polyester amide" or "PEA" is defined as a polymer that has at least one ester bond (I) and at least one amide bond (II):

OR

II or

II —NH — C— (Π)

The term "condensation copolymer" is defined as a copolymer that is a product of a polycondensation process of two monomers. "Polycondensation" is defined according to the definition used by IUPAC (the "International Union for Pure and Applied Chemistry". The IUPAC defines "polycondensation" as a polymerization process in which the growth of polymer chains is carried out by condensation reactions between molecules of all degrees of polymerization (Definition 3.7).

2. Embodiments of the invention

A coating for an implantable medical device, such as a stent, in accordance with embodiments of the present invention, can be a multilayer structure that can include any of the following four layers or any combination thereof:

(a) an initial coat;

(b) a drug-polymer layer (also referred to as a "reservoir" or "reservoir layer"), comprising a condensation copolymer and a drug or alternatively a non-polymeric drug layer;

(c) a top coat layer; and / or (d) a topcoat layer.

Any of the layers of the stent coating can be formed on the stent by dissolving the condensation copolymer or a mixture of condensation copolymers in a solvent or a mixture of solvents and applying the resulting copolymer solution to the stent by spraying or dipping the stent into the solution. After the solution has been applied to the stent, the coating dries allowing the solvent to evaporate. The drying process can be sped up if drying is carried out at a high temperature.

To incorporate a drug into the reservoir layer, the drug can be combined with the copolymer solution that is applied to the stent as described above. Alternatively, to make a polymer-free reservoir, the drug can be dissolved in a suitable solvent or solvent mixture and the resulting drug solution can be applied to the stent by spraying or dipping the stent into the drug solution.

Instead of introducing the drug as a solution, the drug can be introduced as a colloidal system, such as a suspension in an appropriate solvent phase. To prepare the suspension, the drug can be dispersed in the solvent phase using conventional techniques used in colloidal chemistry. Depending on various factors,

ES 2 297 530 T3 for example, the nature of the drug, those skilled in the art can select the solvent to form the solvent phase of the suspension, as well as the amount of drug to be dispersed in the solvent phase. The suspension can be mixed with a condensation copolymer solution and the mixture can be applied to the stent as described above. Alternatively, the drug suspension can be applied to the stent without mixing with the copolymer solution.

The drug-polymer layer can be applied directly to at least part of the stent surface to serve as a reservoir for at least one active agent or a drug that is incorporated into the reservoir layer. The initial layer can be applied between the stent and the reservoir to improve adhesion of the drug-polymer layer to the stent. The topcoat layer can be applied over at least a portion of the reservoir layer and serves as a rate limiting membrane that helps control the rate of drug release. In one embodiment, the topcoat layer can be essentially free of any active agent or drug. If the topcoat layer is used, the optional topcoat layer can be applied over at least a portion of the topcoat layer for additional control of the drug release rate and to improve the biocompatibility of the coating, for example to provide antithrombotic and / or non-contaminating properties to the surface of the coating. Without the topcoat layer, the topcoat layer can be deposited directly onto the deposit layer.

In one embodiment, any or all of the layers of the stent coating can be made of a condensation copolymer that is biologically beneficial and biologically degradable, erodible, absorbable, and / or resorbable. In another embodiment, only the outermost layer of the coating can be limited to said polymer.

To illustrate in more detail, in the stent coating having the four layers described above (i.e., the initial, the reservoir layer, the top coating layer, and the final coating layer), the outermost layer is the layer A topcoat that is made from a condensation copolymer that is biologically degradable, erodible, absorbable, and / or resorbable. In this case, optionally, the rest of the layers (that is, the initial, the deposit layer and the upper coating layer) can also be made of a biologically degradable condensation copolymer; and the copolymer can be the same or different in each layer.

If the topcoat layer is not used, the topcoat layer can be the outermost layer and is prepared from a biologically degradable condensation copolymer. In this case, optionally, the rest of the layers (ie the initial and the reservoir layer) can also be made of a biologically degradable condensation copolymer; and the copolymer can be the same or different in each of the three layers.

If neither the topcoat layer nor the topcoat layer are used, the stent coating can have two layers, the initial layer and the deposit layer. In this case, the deposition layer is the outermost layer of the stent coating and can be prepared from a biologically degradable condensation copolymer. Optionally, the initial can also be made of a biologically degradable condensation copolymer. The two layers can be prepared from the same or different materials.

Biologically absorbable condensation copolymers that can be used to prepare any of these stent coating layers include polyester amides (PEA). Synthetic techniques that can be used to obtain PEAs are described below. Generally, PEAs are products of the reaction between a group A precursor-reagent and a group B precursor-reagent. According to embodiments of this invention, the group A reagent precursors include various diol diamines, and the group B reagent precursors include various dicarboxylic acids. In some embodiments the coating can be free of any particular polyester amide.

The reactive precursors of groups A and B are characterized as follows.

A. Group A reagents - Diol-Diamines

The diol-diamines comprising the reagent-precursors (hereinafter "reagents") of group A that can be used in accordance with the embodiments of the present invention are chemical compounds having a general formula (III):

<img file="ES2297530T3_D0003.tif" />

where R can be hydrogen, methyl, isopropyl, sec-butyl, isobutyl, benzyl, methyl mercaptoethyl (CH₂-CH₂-SCH₃), methylene amide (CH₂-CO-NH₂) or ethylene amide (CH₂-CH₂-CO-NH₂); and x can be an integer between 2 and 16.

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The reagents described by formula (III) are diol diamines that can be synthesized by condensing an amino acid and a diol. The synthesis can be carried out under conditions that favor the esterification of the amino acid by the carboxyl group of the amino acid. The reaction can be carried out under dehydration conditions that include an anhydrous environment and an elevated temperature, for example about 50 ° C. The reaction can be catalyzed by a strong acid or base, for example, p-toluenesulfonic acid. Anhydrous conditions can be obtained by removing the water by azeotropic distillation of the reaction solvent, for example toluene or benzene.

The diol that can be used to prepare the diol-diamines having the formula (III) has the formula OH- (CH₂)_XOH, where x has been defined above. Representative examples of diols that can be used include ethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,7-heptanediol, 1,8-octanediol , 1,9-nonanediol, 1,10-decanediol, 1,11-undecanediol and 1,12-dodecanediol or mixtures thereof.

The amino acid that can be used to prepare diol diamines having the formula (III) have the formula H₂NCHR-COOH, where R is defined above. Some amino acids that can be used are summarized in Table 1.

TABLE 1

<td rowspan="2">No.</td><td rowspan="2">R</td><td colspan="2">Amino acid (H₂N-CHR-COOH)</td>

<td>Formula</td><td>Name</td>

<td> 1</td><td>H</td><td>H2N-CHR-COOH</td><td>glycine (aminoethanoic acid)</td>

<td> 2</td><td>ch₃</td><td>ch₃I h₂n-ch-cooh</td><td>Alanine (2-aminopropanoic acid)</td>

<td> 3</td><td>/ -C3H7</td><td>ch₃-ch-ch₃I h₂n-ch-cooh</td><td>valine (2-amino-3-methyl butyric acid)</td>

<td> 4</td><td>sec-C4H₉</td><td>CHr — CH₂—CH — CH₃I H₂N — CH — COOH</td><td>isoleucine (2-amino-3-methyl pentanoic acid)</td>

<td> 5</td><td>/ -C4H9</td><td>ch₃I ch₃-ch-ch₂l h₂n-ch-cooh</td><td>leucine (2-amino-4-methyl pentanoic acid)</td>

<td> 6</td><td>C₆H₅-CH2</td><td>CéHs-CHz I h₂n-ch-cooh</td><td>phenylalanine (2-amino-3-phenylpropanoic acid)</td>

<td> 7</td><td>(CH₂) 2-S-CH₃</td><td>CHt-CH₂-S-CH₃I h₂n-ch-cooh</td><td>methionine (a-amino-γmercaptobutyric acid)</td>

<td> 8</td><td>CH2-CO-NH2</td><td>CHg — CO — NH₂I h₂n-ch-cooh</td><td>asparagine (2,4-diamino-4-oxobutanoic acid)</td>

<td> 9</td><td>(CH₂) 2-CO-NH₂</td><td>CH₂—CH₂—-CO — ÑH₂I h₂n-ch-cooh</td><td>glutamine (2,5-diamino4-oxopentaenoic acid)</td>

In addition to the amino acids listed in Table 2, other amino acids may alternatively be used eg proline (2-pyrrolidine carboxylic acid).

One amino acid or two different amino acids can be used to synthesize diol diamines having the formula (III). If an amino acid is used, two molar equivalents of the amino acid per one molar equivalent of a diol described above can be used. If two different amino acids are used, one molar equivalent of the first amino acid and one molar equivalent of the second amino acid per one molar equivalent of a diol can be used.

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B. Group B Reagents - Dicarboxylic Acids

Group B reagents comprising dicarboxylic acids that can be used to synthesize the biologically absorbable condensation copolymers according to embodiments of the present invention are chemical compounds having a general formula (IV):

OO

II ll (iv)

HO — C— (CH₂) y — C — OH where y can be an integer between 0 and 16. Some examples of dicarboxylic acids described by formula (IV) that can be used are summarized in Table 2. The mixtures of the carboxylic acids present in Table 2 can also be used, if desired.

TABLE 2

<td rowspan="2">No.</td><td rowspan="2">Y</td><td colspan="2">Dicarboxylic Acid (HOOC- (CH₂)_V-COOH)</td>

<td>Formula</td><td>Name</td>

<td> 1</td><td> 0</td><td>HOOC-COOH</td><td>oxalic acid (ethanedioic)</td>

<td> 2</td><td> 1</td><td>HOOC-CH₂-COOH</td><td>malonic (propanedioic)</td>

<td> 3</td><td> 2</td><td>HOOC- (CH₂)₂-COOH</td><td>succinic acid (butanedioic)</td>

<td> 4</td><td> 3</td><td>HOOC- (CH₂)₃-COOH</td><td>glutaric acid (pentanedioic)</td>

<td> 5</td><td> 4</td><td>HOOC- (CH₂)₄-COOH</td><td>adipic acid (hexanedioic)</td>

<td> 6</td><td> 5</td><td>HOOC- (CH₂)₅-COOH</td><td>pimelic (heptanedioic) acid</td>

<td> 7</td><td> 6</td><td>HOOC- (CH₂)₆-COOH</td><td>suberic acid (octanedioic)</td>

<td> 8</td><td> 7</td><td>HOOC- (CH₂)₇-COOH</td><td>azelaic (nonanedioic) acid</td>

<td> 9</td><td> 8</td><td>HOOC- (CH₂)₈-COOH</td><td>sebacic acid (decanedioic)</td>

<td> 10</td><td> 9</td><td>HOOC- (CH₂)₉-COOH</td><td>nonane-1,9-dicarboxylic acid (undecanedioic)</td>

<td> 11</td><td> 10</td><td>HOOC- (CH₂) io-COOH</td><td>decane-1,10-dicarboxylic acid (dodecanedioic)</td>

<td> 12</td><td> 11</td><td>HOOC- (CH₂) i- | -COOH</td><td>brazilian acid (tridecanedioic)</td>

<td> 13</td><td> 12</td><td>HOOC- (CH₂) i₂-COOH</td><td>dodecane-1,12-dicarboxylic acid (tretradecanedioic)</td>

<td> 14</td><td> 13</td><td>HOOC- (CH₂)₁₃-COOH</td><td>tridecane-1,13-dicarboxylic acid (pentanedecanedioic)</td>

<td> 15</td><td> 14</td><td>HOOC- (CH₂)₁₄-COOH</td><td>tapsic acid (hexadecanedicoic)</td>

As mentioned above, to synthesize the PEAs, at least one reagent from group A can be reacted with at least one reagent from group B. Coupling of the diol-diamines directly with the dicarboxylic acids can be carried out using acids or catalysis under conditions dehydration. To perform the coupling process with fewer side reactions, the dicarboxylic acid can be pre-activated with a carbodiimide, such as 1,3-dicyclohexylcarbodiimide (DCC), or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC). Alternatively, instead of a dicarboxylic acid, a derivative thereof may be used, such as diacid chloride, diacid bromide, or derivative of p-nitrophenol.

ES 2 297 530 T3

According to one embodiment, as a result of the synthesis, biologically absorbable PEAs having a general formula (V) can be obtained:

O OROO R

Ii II I IIII I - [C— (CH₂)_Y—C — NH — CH — C “O— (CH₂)_X—O — C — CH — NH]_n- (V) where R, x and y are as defined above, and n is an integer having a value between about 35 and about 1,100, for example between 90 and 650.

According to another embodiment, if the amino acid used is proline, biologically absorbable PEAs having a general formula (VI) oo Oo can be obtained.

II II IIII - [C— (CH₂)_Y—C — N ----- CH-CO- (CH₂)_K-OC-CH ----- N]_n-(SAW)

IIII h₂c-ch₂-ch₂ h₂c-ch₂-ch₂ where x, y and n are as defined above.

An example of the process of synthesis of polyester amides having the general formula (V), can be the synthesis of polyester amide based on alanine, adipic acid, and 1,6-hexanediol according to the following procedure.

First, two equivalents of L-alanine in the benzene solution can be combined with one equivalent of 1,6-hexanediol and with at least two equivalents of p-toluenesulfonic acid. Instead of benzene, toluene or chloroform can be used if desired. The mixture can be heated to reflux and azeotropic distillation can be used using a Dean-Stark trap to remove generated water. As a result, the di-ptoluenesulfonic acid salt of bis- (L-alanine) -1,6-hexylene diester (monomer 1) can be obtained.

The adipic acid can then be activated by reacting one equivalent of adipoyl chloride with two equivalents of p-nitrophenol, in tetrahydrofuran (THF) solution, with at least two equivalents of triethylamine to obtain di-p-nitrophenyl adipate (monomer 2). Instead of THF, diethyl ether or p-thioxane can be used if desired. Monomer 1 and Monomer 2 can have a stoichiometry as close to 1: 1 as possible to achieve high molecular weights.

Finally, one equivalent of monomer 1 can be reacted with one equivalent of monomer 2 and at least two equivalents of triethylamine in dry N, N-dimethylacetamide (DMAC). Alternatively, dimethylformamide (DMF) or dimethylfulsphoxide (DMSO) can be used in place of DMAC. The ratio of monomers 1 and 2 can be, but is not required, 1: 1. Generally the molar ratio of the two monomers is within 10% of each, depending on the desired molecular weight of the final polymer. The ratio can deviate from 1: 1, but in the case of deviation, the polymer has a lower molecular weight.

After combining the reagents at room temperature, the mixture can be heated, with stirring, at about 80 ° C for about 16 hours. The viscous reaction mixture can be cooled to room temperature, diluted with an amount of alcohol (such as methanol or ethanol) at least equal to the volume of the reaction, and poured into water. As a result, the final polymer, co-poly- [N, N'-adipoyl-bis- (L-alanine) -1,6-hexylene diester] can be produced. The precipitated polymer can be isolated, washed with water, and dried under vacuum.

A layer of the stent coating can contain any amount of the biologically absorbable condensation copolymers described above or a mixture of more than one such copolymer. If less than 100% of the layer is prepared from the biologically absorbable condensation copolymers described above, the remainder may comprise alternative copolymers. It is preferred that the alternative polymer is biodegradable but can also be non-biodegradable. Examples of alternative polymers that can be used include polyacrylates, such as poly (butyl methacrylate), poly (ethyl methacrylate), and poly (ethyl methacrylate-co-butyl methacrylate), and fluorinated polymers and / or copolymers such as poly (vinylidene fluoride), and poly (vinylidene fluoride-co-propene fluoride), poly (N-vinylpyrrolidone), poly (hydroxyvalerate), poly (L-lactic acid), polycaprolactone, poly (lactide-co-glyoride), poly (hydroxybutyrate), poly (hydroxybutyrate-co-valerate), polydioxanone, polyorthoester, polyanhydride, poly (glycolic acid), poly (D, L-lactic acid), poly (glycolic acid-trimethylene carbonate), polyphosphoester, polyurethane polyphosphoester, poly (amino acids), cyanoacrylates, poly (trimethylene carbonate), poly (iminocarbonate), copoly (ether-esters), polyalkylene oxalates, polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,

ES 2 297 530 T3 starch, collagen and hyaluronic acid), polyurethane, silicones, polyesters, polyolefins, polyisobutyrene and ethylene-alphaolefin copolymers, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), copolymers of vinyl monomers with each other and olefins, for example, poly (ethylene-co-vinyl alcohol) (EVAL), ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins and ethylene-vinyl acetate copolymers ; polyamides (such as Nylon 66 and polycarprolactam), alkyd resins, polycarbonate, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose acetate butyrate, cellophane, cellulose, cellulose propionate, cellulose ethers and carboxymethyl cellulose.

Representative examples of some suitable solvents for preparing stent coatings include DMAC, DMF, THF, 100% absolute ethanol, cyclohexanone, xylene, toluene, acetone, i-propanol, methyl ethyl ketone, propylene glycol monomethyl ether, methyl butyl ketone , ethyl acetate, n-butyl acetate and dioxane. Some solvent mixtures can also be used. Representative examples of mixtures include:

(1) DMCA and methanol (for example at 50:50 by mass of the mixture);

(2) water, i-propanol and DMAC (for example a 10: 2: 87 mixture by mass);

(3) i-propanol and DMAC (for example mixtures 80:20, 50:50 or 20:80 by mass);

(4) acetone and cyclohexanone (for example mixtures 80:20, 50:50 or 20:80 by mass);

(5) acetone and xylene (for example a 50:50 mixture by mass);

(6) acetone, FLUX REMOVER AMS and xylene (eg a 10:50:40 mixture by mass); and (7) 1,1,2-trichloroethane and chloroform (eg, an 80:20 mixture by mass).

FLUX REMOVER AMS is the trade name for a solvent manufactured by Teach Spray, Inc., of Amarillo, Texas that comprises approximately 93.7% of a mixture of 3,3-dichloro-1,1,1,2,2- pentafluoropropane and 1,3-dichloro-1,1,2,2,3-pentafluoropropane and the remainder of methanol, with trace amounts of nitromethane. Those skilled in the art will select the appropriate solvent or solvent mixture to dissolve a particular polymer.

The therapeutic substance that can be used in the reservoir layer can include any substance capable of exerting a therapeutic or prophylactic effect for a patient. The therapeutic substance can include small molecular substances, peptides, proteins, oligonucleotides, and the like. The therapeutic substance can be designed, for example, to inhibit the activity of vascular smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and / or proliferation of smooth muscle cells or to inhibit restenosis.

Examples of therapeutic substances that can be used include antiproliferative substances such as actinomycin D or derivatives and analogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wisconsin or COSMEGEN available from Merck). Synonyms for actinomycin D include dactinomycin, actinomycin IV, actinomycin Ii, actinomycin X_i and actinomycin Ci. The active agent can also be within the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antiallergic and antioxidant substances. Examples of such antineoplastics and / or antimitotics include paclitaxel (for example TAXOL® from Bristol-Myers Squibb Co., Stamford, Conn.), Docetaxel (for example Taxotere®, from Aventis SA, Frankfurt, Germany), methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (for example Adriamycin® from Pharmacia &amp; Upjohn, Peapack NJ) and mitomycin (for example Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombin include sodium heparin, low-molecular-weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin, and prostacyclin analogs, dextran, D-chloromethyl-pro-argone (antichloromethane-pro-argone synthetic), dipyramidol, platelet glycoprotein IIb / IIIa membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as ANGIOMAX (Biogen, Inc., Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopectin, angiotensin converting enzyme inhibitors, such as captopril (for example Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), Cilazapril or lisinopril (for example Prinivil® and Prinzide® from Merck &amp; Co., Inc., Whitehouse Station, NJ); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3 fatty acid), histamine antagonists, lovastatin (an HMG-CoA reductase inhibitor, a cholesterol-lowering drug, trade name Mevacor® from Merck &amp; Co., Inc., Whitehouse Station, NJ), monoclonal antibodies (such as those specific for platelet-derived growth factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is potassium permirolast. Other therapeutic substances or agents that may be appropriate include interferon alpha, genetically engineered epithelial cells, tacrolimus, dexamethasone, and rapamycin, and structural derivatives or functional analogs thereof, such as 40-O- (2-hydroxy) ethyl-rapamycin (known as EVEROLIMUS trademark available from Novartis) 40-O- (3-hydroxy) propyl-rapamycin, 40O- [2- (2-hydroxy) ethoxy] ethyl-rapamycin and 40-O-tetrazole-rapamycin.

ES 2 297 530 T3

The coatings and methods of the present invention have been described with reference to a stent such as an expandable balloon or a self-expanding stent. However, the use of the liner is not limited to stents and the liner can also be used with a number of different medical devices. Examples of the implantable medical device, which may be used in conjunction with the embodiments of this invention, include stents / grafts, grafts (eg, aortic grafts), artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, coronary axis shunts, and shunts. endocardiac (eg FINELINE and ENDOTAK, available from Guidant Corporation). The underlying structure of the device can be of virtually any design. The device may be made of a metallic material or an alloy, such as, but not limited to, cobalt-chromium alloys (eg ELGILOY), stainless steel (316L), "MP35N", "MNP20N", ELASTINITE (Nitinol) , tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as for example platinoiridium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys or combinations thereof. Devices made from bioabsorbable or biostable polymers can also be used with embodiments of the present invention. In some embodiments, the device, for example the stent, can be prepared from the copolymers of the invention.

"MP35N" and "MP20N" are trademarks of cobalt, nickel, chromium and molybdenum alloys available from Standard Press Steel Co. of Jenkintown, Pennsylvania. "MP35N" is made up of 35% cobalt, 35% nickel, 20% chromium and 10% molybdenum. "MP20N" is made up of 50% cobalt, 20% nickel, 20% chromium and 10% molybdenum.

3. Examples

The following examples are provided to illustrate additional embodiments of the present invention.

Example 1

A copolymer, co-poly- {N, N'-sebacoyl-¿/ s- (L-Leucin) -1,6-hexylene diester}, having the formula (VII) can be synthesized and used to practice the invention :

CH3-CH-CH3

CH3-CH-CH3

I

O CH₂ (VII)

II I

OO CH₂ OR

Β II I II - [C— (CH2) 8r^-C ~ NH- ~ CH — C — O— (CHzjff — Ch-C^-CH — NH]_n- where n can be between 85 and 95, for example 90.

To synthesize the copolymer (VII) a diol-diamine of the family having the formula (III) can be reacted with a dicarboxylic acid of the family having the formula (IV).

The diol-diamine substance can be the di-p-toluenesulfonic acid salt of b / s- (L-leucine) -1,6-hexylene diester and can be synthesized by condensation of L-leucine with 1,6-hexanediol using a ptoluenesulfonic acid catalyst.

The dicarboxylic acid substance can be the di-p-nitrophenyl derivative of sebacic acid and can be synthesized by condensation of p-nitrophenol with sebacoyl chloride. Conditions for the synthesis of diol diamine and dicarboxylic acid can be determined by those skilled in the art.

The synthesis of the copolymer (VII) can be carried out according to the following procedure. About 100.3 grams (0.15 mole) of the di-p-toluenesulfonic acid salt of b / s- (L-leucine) -1,6-hexylene diester can be mixed with about 105 mL of dry DMAC and made React with approximately 66.67 g (0.15 mole) of di-p-nitrophenyl sebacinate. The reagents can be combined in a one liter round bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and an oil bath warmed to room temperature.

Then about 46.2 ml (0.33 mole) of dry triethylamine can be added to the flask with stirring, the temperature of the reaction mixture can be increased to about 80 ° C, and the solution can be stirred for about 10 hours. The viscous reaction mixture can then be cooled to room temperature, diluted with about 250 ml of ethanol, and slowly added to about 2 liters of deionized water with stirring. The polymer can then be isolated by filtration, resuspended in approximately 1 liter of deionized water, and isolated again by filtration. The resuspension and filtration process can be repeated. Finally, the polymer can be dried at about 30 ° C under reduced pressure overnight.

ES 2 297 530 T3

Example 2

A copolymer, co-poly- {N, N'-sebacoyl-bis- (L-Leucin) -1,4-butylene diester}, having the formula (VII) can be synthesized and used to practice the invention:

<td></td><td>ch₃-ch-ch₃ 1</td><td>CHj — CH-CH₃ 1</td><td></td>

<td> 0</td><td>1 0 ch₂ OR</td><td>1 0 ch₂</td><td>(VIII)</td>

<td>II</td><td>II 1 II</td><td>II 1</td><td></td>

- [C- (CH₂) 8-C-NH-CH-CO- (CH2) 4-0-C-CH-NH]_nwhere n can be between 140 and 160, for example 150.

Copolymer (VIII) can be synthesized in the same way as copolymer (VII) described in Example 1, except that the 1,4-butanediol derivative can be used instead of the 1,6-hexanediol derivative. Specifically, the following synthesis procedure can be used.

About 99.13 g (0.15 mole) of the di-p-toluenesulfonic acid salt of bis- (L-leucine) -1,4-butylene diester can be mixed with about 150 mL of dry DMAC and reacted with about 66.67 g (0.15 mole) of di-p-nitrophenyl sebacinate. The reagents can be combined in a one liter round bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and an oil bath warmed to room temperature.

Then about 46.2 ml (0.33 mole) of dry triethylamine can be added to the flask with stirring, the temperature of the reaction mixture can be increased to about 80 ° C, and the solution can be stirred for about 12 hours. The viscous reaction mixture can then be cooled to room temperature, diluted with about 250 ml of ethanol, and slowly added to about 2 liters of deionized water with stirring. The polymer can then be isolated by filtration, resuspended in approximately 1 liter of deionized water, and isolated again by filtration. The resuspension and filtration process can be repeated. Finally, the polymer can be dried at about 30 ° C under reduced pressure overnight.

Example 3

A copolymer, co-poly- {N, N'-adipoyl-bis- (L-Leucin) -1,4-butylene diester}, having the formula (IX) can be synthesized and used to practice the invention:

CH3-CH-CH3

<img file="ES2297530T3_D0004.tif" />

<img file="ES2297530T3_D0005.tif" />

<img file="ES2297530T3_D0006.tif" />

OO CH₂ OR

II II I II

- [C .- &lt;CH₂) 4-C-NH-CH-C-0- {CH₂) 4-0-C-CH-NH] n where n can be between 140 and 160, for example 150.

Copolymer (IX) can be synthesized in the same way as copolymer (VIII) described in Example 2, except that adipic acid can be used instead of sebacic acid. Specifically, the following synthesis procedure can be used.

About 99.13 g (0.15 mole) of the di-p-toluenesulfonic acid salt of bis- (L-leucine) -1,4-butylene diester can be mixed with about 76 mL of dry DMAC and reacted with about 58.2 g (0.15 mole) of di-p-nitrophenyl adipate. The reagents can be combined in a one liter round bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and an oil bath warmed to room temperature.

Then about 46.2 ml (0.33 mole) of dry triethylamine can be added to the flask with stirring, the temperature of the reaction mixture can be increased to about 80 ° C, and the solution can be stirred for about 10 hours. The viscous reaction mixture can then be cooled to room temperature, diluted with about 220 ml of ethanol, and slowly added to about 2 liters of deionized water with stirring. The polymer can then be isolated by filtration, resuspended in approximately 1 liter of

ES 2 297 530 T3 deionized water and isolated again by filtration. The resuspension and filtration process can be repeated. Finally, the polymer can be dried at about 30 ° C under reduced pressure overnight.

Example 4

A copolymer, co-poly- {N, N'-adipoyl-is- (L-alanin) -1,4-butylene diester}, having the formula (X) can be synthesized and used to practice the invention:

oo ch₃ oo ch

II II I IIII I - [C— (CH₂) 4 — C — NH — CH — C — O— {CHi) 4 — O — C — CH — NH]_n- (X) where n can be between 250 and 300, for example 275.

To synthesize the copolymer (X), a diol-diamine substance from a family having the formula (III) can be reacted with a dicarboxylic acid substance from a family having the formula (IV).

The diol-diamine substance can be the di-p-toluenesulfonic acid salt of Is- (L-alanin) -1,4-butylene diester and can be synthesized by condensation of L-alanine with 1,4-butanediol using a ptoluenesulfonic acid catalyst.

The dicarboxylic acid substance can be the di-p-nitrophenyl derivative of adipic acid and can be synthesized by condensation of p-nitrophenol with adipoyl chloride. The conditions for the synthesis of the diol diamine and dicarboxylic acid substances can be determined by those skilled in the art.

The synthesis of the copolymer (X) can be carried out according to the following procedure. About 86.4 g (0.15 mole) of the di-p-toluenesulfonic acid salt of Is- (L-alanin) -1,4-butylene diester can be mixed with about 72 mL of dry DMAC and reacted with about 58.2 g (0.15 mole) of di-p-nitrophenyl adipate. The reagents can be combined in a one liter round bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and an oil bath warmed to room temperature.

Then about 46.2 ml (0.33 mole) of dry triethylamine can be added to the flask with stirring, the temperature of the reaction mixture can be increased to about 80 ° C, and the solution can be stirred for about 16 hours. The viscous reaction mixture can then be cooled to room temperature, diluted with about 205 ml of ethanol, and slowly added to about 2 liters of deionized water with stirring. The polymer can then be isolated by filtration, resuspended in approximately 1 liter of deionized water, and isolated again by filtration. The resuspension and filtration process can be repeated. Finally, the polymer can be dried at about 30 ° C under reduced pressure overnight.

Example 5

A first composition can be prepared by mixing the following components:

(a) about 2.0% by mass of co-poly-N, N'-sebacoyl-is- (L-Leucin) -1,4-butylene diester, the copolymer having the formula (VIII); and (b) the rest ethanol, absolute (100%).

The first composition can be applied to the surface of a small bare 12mm VISION stent (available from Guidant Corporation). The coating can be sprayed and dried to form an initial coat. A sprayer having a 0.014 round nozzle maintained at room temperature with a 2.5 psi (0.17 atm) supply pressure and an atomization pressure of approximately 15 psi (1.2 atm) can be used. Approximately 20 pg of the coating can be applied per spray pass. Between spray passes the stent can dry for approximately 10 seconds in a jet of air at approximately 50 ° C. Approximately 110 pg of wet coating can be applied. Stents can be fired at approximately 50 ° C for approximately one hour, producing an initial layer consisting of approximately 100 pg of the copolymer (VII).

A second composition can be prepared by mixing the following components:

(a) about 2.0% by mass of the copolymer of formula (VIII);

(b) about 2.0% by mass EVEROLIMUS; and (c) the remainder absolute ethanol.

ES 2 297 530 T3

The second composition can be applied over the dry start coat, using the same spray technique and the same equipment that was used to apply the start coat, to form the drug-polymer layer. About 120 pg of wet coating can be applied followed by drying and baking at about 50 ° C for about 1 hour, to produce a dry drug-polymer layer having a solid content of about 110 pg.

A third composition can be prepared by mixing the following components:

(a) about 2.0% by mass of the copolymer of formula (VIII); and (b) the remainder, absolute ethanol.

The third composition can be applied over the dry polymeric drug layers, using the same spray technique and equipment used to apply the initial and drug-polymer layers, to form a topcoat layer. About 200 pg of wet coating can be applied followed by drying and baking at about 50 ° C for about 1 hour, to produce a dry topcoat layer having a solid content of about 200 pg.