CN101467921B - Method for producing bracket for eluting medicament - Google Patents

Abstract

The invention relates to a method of producing drug-eluting stents. The drug-eluting stent has a distensible tubular body formed by connected filaments, areas of the top side, the side surface and the internal surface and a drug-eluting polymer coating of the selected drug. The method comprises a. placing the tubular body of the stent on a fastener which contacts with the internal surface of the tubular body to fasten the stent body, so that the fastener making the tubular body rotate in an axial direction; b. placing a guide tube on the position near the tubular body on the fastener, when the stent rotates on the fastener and moves in an axial direction relative to the guide pipe, a drug-polymer solution with a viscosity of 2-2000 centipoise contained in a pressure accumulator communicated with the guide tube being coated directly from the guide pipe to the top side area of the filaments sent through the guide pipe; and c. controlling the moving speed of the guide tube relative to the filaments stent and the transferring speed of materials from the guide tube to the accumulator, therefore, the drug-polymer solution can be only coated on the top side area and the side surface area of the stent.

Description

The production method of bracket for eluting medicament

The application is the application number submitted on April 24th, 2003 the dividing an application for the international application of " polymer composition that contains macrocyclic triene compound " that be PCT/US2003/012746, denomination of invention; This application gets into the China national stage on October 25th, 2004, and application number is 03809309.x.

Invention field:

The present invention relates to the production method of bracket for eluting medicament; Said support has the distensible tubular body that is formed by the filament that connects; And the medicament elution polymer coating that has end face, side and inner surface section and contain selected amount medicine; Said method comprises that (a) is placed on the support tubular body on the clip; Through clip is contacted with the inner surface of tubular body stake body is blocked with clip so that tubular body is rotated vertically with clip, (b) with clip on the tubular body position adjacent place a conduit; When support rotates on clip and moves axially with respect to conduit; Through this conduit can with viscosity be the 2-2000 centipoise and be included in pressurized reservoir that conduit is connected in drug-polymer solution directly from conduit be coated in the top surface areas of stake body filament and (c) the control conduit with respect to the translational speed of stent filaments and material through conduit from the bin transmitting speed, thereby make medicine-polymer solution only be painted on the end face and the lateral side regions of support.

Background of invention:

Rapamycin is a macrocyclic triene compound, and isolated streptomycete (streptomyces hygroscopicus) extracts (people such as Vezina, J.Antibiot. from the pedotheque of eastern island at first 28: 721 (1975); U.S. Patent number: 3,929,992; 3,993,749).Rapamycin has following molecular structure:

Former antifungal (the United States Patent (USP): 3 that is used as of rapamycin; 929; 992), find that subsequently it also is effective activating agent for other disease and disease, comprise being used to treat cancer and tumor (United States Patent (USP): 4; 885,171), be used to prevent experimental immune disease (EAE and adjuvant arthritis; Martel, R., Can.J.Physio1., 55: the propagation (Morris, R., J.Heart Lung Transplant, 11 (pt.2) (1992)) of 48 (1977), inhibition of transplant rejection (United States Patent (USP) 5,100,899) and inhibition smooth muscle cell.

Yet this chemical compound is restricted as the application of medicine extremely low and variable bioavailability and the very high toxicity owing to it.In addition, rapamycin only is slightly soluble in water, like 20mg/ml, therefore is difficult to be mixed with the stable compositions that is suitable for sending in the body.For overcoming these problems, the prodrug and the derivant of chemical compound are synthesized out.Through 31 and 40 formation glycinates, propionic ester, the pyrrolidinyl butyrate with the rapamycin structure, this prodrug (United States Patent (USP): 4,650,803) on the books.4,316,885), acetal derivatives (United States Patent (USP): 5 the prior art ester has been put down in writing the derivant of multiple rapamycin, comprises monoacyl and diacyl derivant (United States Patent (USP):; 151,413), monosilane ether (United States Patent (USP): 5,120; 842), hydroxy ester (United States Patent (USP): 5,362,718); And alkyl, aryl, alkenyl and alkynyl derivatives (United States Patent (USP): 5,665,772; 5,258,389; 6,384,046; WO97/35575).

Summary of the invention

On the one hand, the present invention includes the polymer composition that is used for macrocyclic triene compound is delivered to individual intravital target spot.Said composition contains: (i) polymeric substrate of 20-70% weight and the (ii) macrocyclic triene compound of 30-80% weight, and this chemical compound has following structural formula:

Wherein R is CH ₂-X-OH, X are the alkyl that contains the straight or branched of 6-10 carbon atom.When said compositions is placed to target spot and cells contacting, can make the amount of taking in the chemical compound in the target cell effectively obviously more than the same polymeric substrate that contains rapamycin or everolimus (everolimis) macrocyclic triene compound.

In one embodiment, said composition is used to treat solid tumor, inflammation or the wound of target spot, and is made up of the suspension of injectable microgranule, can be through localizing in the target spot injection.

In another embodiment, the polymeric substrate in the compositions is formed by biodegradable polymer.

In another embodiment, compositions is used to treat solid tumor, inflammation or the wound of target spot, and is the form by the patch of polymeric substrate and compound formation.Medicated patches is placed the surface of organizational structure, the for example outer or inner surface of the outer surface of organ or tumor or blood vessel.

Said composition also can be used for treating the tissue or the wound of inflammation, and polymeric substrate wherein is the form of the ointment that is used for smearing at the tissue that needs are arranged.

Said composition also is used in the vascular damaged position and suppresses restenosis, and compositions wherein comprises the entrained coating of part that contacts with blood vessel wall in the expansible intravascular stent.

In another embodiment, said composition is used for sending macrocyclic triene compound to the cell of mucomembranous surface.Polymeric substrate in the compositions has a mucosa-adherent face coat, is suitable for being placed on the mucosal tissue place.

In any or all these purposes, in one embodiment, chemical compound has following structure: wherein R is CH ₂-X-OH, X are the straight chained alkyls that contains 6-10 carbon atom.In another embodiment, R is CH ₂-X-OH, X are the straight chain group that contains 6 carbon atoms.

In another embodiment, polymeric substrate is by the biodegradable polymer compositions.The instance of biodegradable polymer comprises: polylactic acid, polyglycolic acid and their copolymer.Suitable polylactic acid comprises: gather-the l-lactide, gather-d-lactide and gathering-the dl-lactide.

In another embodiment, the initial concentration of macrocyclic triene compound is the 35-80% (weight) of total composition weight.

Through below in conjunction with the accompanying drawing detailed description of the present invention, these and other purpose of the present invention and characteristics will be clearer.

Summary of drawings

Fig. 1 is half-logarithmic function figure of the relative acetone concentration (equilibrium water) of relative hydrophobicity (Rm value) of several kinds of chemical compounds.Solid circles is a 40-O-hydroxyl heptyl; Open squares is everolimus (a 40-O-hydroxyethyl rapamycin); Solid diamond is a rapamycin; Hollow triangle is a paclitaxel; Filled squares is a dexamethasone.

Fig. 2 and Fig. 3 have shown the endovascular stent with metal filament that forms according to one embodiment of the invention, and Fig. 2 is the contraction state of support; Fig. 3 is the expansion state of support.

Fig. 4 is the transverse section wiry enlarged drawing of the support floating coat of Fig. 2.

Fig. 5 is the transverse section enlarged drawing of the degradable polymer support of a coating.

Fig. 6 A and 6B are the sketch maps that is applicable to the polymer coating method of producing the polymer coating support.

Fig. 7 shows that the biodegradable polymer support is installed in the conduit that is used to deliver to vascular site.

Fig. 8 A and 8B are the functional arrangements that discharges everolimus from the support that has polymer coating.

Fig. 9 is the cross-sectional view after support is inserted vascular site.

Figure 10 A-10C inserts the angiological histology section of naked metal rack after 28 days.

Figure 11 A-11C inserts the angiological histology section of wire rack mount after 28 days that contains polymer coating.

Figure 12 A-12C and 13A-13C insert the angiological histology section of polymer coating wire rack mount after 28 days that contains everolimus.

Figure 14 is angiological histology's section of an amplification, and wherein the filament of the visible used support of Figure 12 A-12C covers with new tissue on this filament, forms the blood vessel wall of healing.

Figure 15 is various supports when inserting back 28 days, the narrow area and the functional arrangement of injury tolerance.

Figure 16 shows a correction function figure, and the Y axle is an injury tolerance, the ratio of B/A when the X axle is inserted for support (sacculus/tremulous pulse).

Figure 17 be medicine total amount (μ g) relative time that discharges of the polymeric substrate (gathering-dl-lactic acid) from support (hour) functional arrangement.Solid circles is represented everolimus (40-O-hydroxyethyl rapamycin); Solid square is represented 40-O-hydroxyl heptyl rapamycin.

Detailed Description Of The Invention

I, definition:

" rapamycin " in this use refers to the chemical compound with following structure:

This chemical compound is also referred to as " sirolimus ".

" the substituted rapamycin of 40-O-hydroxy alkyl " chemical compound is meant 40 hydroxyl in the rapamycin compounds is replaced formed chemical compound with hydroxy alkyl.For example, 40-O is modified, with (CH ₂) ₇OH replaces the hydrogen on the hydroxyl just to produce 40-O-hydroxyl heptyl rapamycin.

" everolimus " refers to have the chemical compound of following structure:

Wherein R is CH ₂CH ₂OH (hydroxyl ethane base).

" effective dose " is meant is enough to the dosage that therapeutical effect is provided to the disease of being treated or disease.This meeting is along with patient, disease, institute treat and change, but be easy to confirmed by related disease or the peculiar clinical marker of disease.As: after support was implanted, the area of back cross section of growth of new tissue in support was implanted in measurement and because the stretching of the excessive expansion of sacculus makes the area of the damage of blood vessel that the clinical marker of restenosis just is provided.With the active drug of doses on tumor locus, the minimizing of tumor or the stable clinical labelling that oncotherapy just is provided.Will observe the effectiveness of the continuity of situation that organ moving or allograft about the clinical marker of organ transplantation or vascular transplant.For the wound of skin, clinical marker is the variation of observing redness, granulation formation or Fibrotic inflammation labelling.Increase for prostate, clinical marker is exactly to keep watch on any minimizing that ureter stops up recurrence.

II, polymer composition

The present invention relates to a kind of polymer composition, said composition contains the substituted rapamycin compounds of 40-O-hydroxy alkyl (C7-C11).Below discussed, rapamycin and its bioavailability of many derivants are very low, and this has limited its application as medicine.In the present invention, some 40-O-hydroxy alkyl rapamycin derivative can provide the bioavailability of improvement in allocating polymer architecture into the time when contacting with the tissue of being treated.The rapamycin compounds that is used in the polymer is the chemical compound that has carried out following modification in the position of 40-O:

Wherein R is CH ₂-X-OH, X are the straight or branched alkyl that contains 6-10 carbon atom.In the one of which embodiment, X is the straight or branched alkyl that contains 6-10 carbon atom, and perhaps, in another embodiment, X contains 7-11 carbon atom.In a preferred embodiment, X is the straight chained alkyl that contains 6 carbon atoms.Wherein R is CH ₂-X-OH, X are that the chemical compound of the alkyl of 6,7,8,9,10 carbon is called 40-O-hydroxyl heptyl, 40-O-hydroxyl octyl group, 40-O-hydroxyl nonyl, 40-O-hydroxyl decyl and 40-O-hydroxyl undecyl in this article respectively.

Fig. 1 is the half-logarithmic function figure that shows the relative hydrophobicity (Rm value) of several drugs.Rm be used to weigh hydrophobicity (people such as Biagi G.., J.Medicinal Chem., 18(9): 873 (1975); Ichihaski, people such as T., Pharm.Res., 11 (4): 508 (1994)).The Rm value is used general Biagi method, confirms with anti-phase-thin layer chromatography technology.The method is between polar mobile phase and nonpolar immobile phase, to distribute the chemical compound of test.The relative mobility of surveying each chemical compound gets the Rm value.Reverse chromatograms adopts the single octadecane modified silica-gel thin layer chromatography dish (Alltech63077) of HPTLC-RP18F.Mobile phase is made up of the solution (v/v) of the various concentration of water and acetone.Under ultraviolet light 254nm, observe.See Fig. 1, below result's (RM value) of several kinds of chemical compounds: solid circles is represented 40-O-hydroxyl heptyl rapamycin; Open squares is everolimus (a 40-O-hydroxyethyl rapamycin); Solid diamond is a rapamycin; Hollow triangle is a paclitaxel; Filled squares is a dexamethasone.See the Y y-intercept value of each chemical compound of table-1.

Table-1

Chemical compound	Y y-intercept value 1
		40-O-hydroxyl heptyl rapamycin	4.667
40-O-hydroxyethyl rapamycin (everolimus)	3.966
		Rapamycin	3.860
Paclitaxel	2.659
		Dexamethasone	2.341

¹The linear regression analysis of being done by Fig. 1 data draws

The Y values of intercept is a logarithm, so the hydrophobicity of 40-O-hydroxyl heptyl rapamycin is approximately big 7 times than 40-O-hydroxyethyl rapamycin (everolimus); 40-O-hydroxyethyl rapamycin is approximately big 1 times than rapamycin.With these data is that the water miscible relatively order that the basis obtains several kinds of chemical compounds is: dexamethasone＞＞paclitaxel＞＞＞rapamycin＞everolimus＞＞＞＞＞40-O-hydroxyl heptyl rapamycin

With respect to 40-O-hydroxyl heptyl rapamycin, the solubility of rapamycin and everolimus is more close each other, and this bioavailability of two kinds is also more close so.Because 40-O-hydroxyl heptyl rapamycin water solublity is very low, makes its bioavailability poor, also just be difficult to control its preparation, so also just can not be selected as medicine.But, will confirm that as following the 40-O-hydroxy alkyl derivant of this chemical compound and rapamycin can be mixed with the medicine that is used in treatment site administration.

Therefore, on the one hand, the invention provides a kind of polymer composition that the substituted rapamycin compounds of 40-O-hydroxy alkyl (C7-C11) is sent in patient's body site that is used for.This polymer composition generally contains the selected polymer of 20-70% weight and the substituted rapamycin compounds of 40-O-hydroxy alkyl of 30-80% weight.Perhaps, said composition can contain the selected polymer of 30-70% weight and the substituted rapamycin compounds of 40-O-hydroxy alkyl of 30-70% weight.

Mention as top, can adopt multiple polymers and prescription thereof, below will discuss several concrete examples in more detail.Usually, polymer composition plays a kind of effect of drug-reservoir, and it contains chemical compound and after putting into target spot, discharges chemical compound.

Polymer beads

A kind of exemplary polymer compositions exists with the polymer beads form, and this granule can be through being put in the organism alive with a certain instrument such as tube injection or deposition.Polymer beads can be many micropores, macropore or not have the hole that it can store dissolves the very poor 40-O-rapamycin compounds of aqueous.

Porous polymer particles has many continuous holes, and particulate appearance is reached in these holes, makes outside the granule to be connected with interior space.The bin that the granule that can make is used to form this macropore is described in United States Patent (USP): 5,135,740, and this draws and is reference.In brief, be exactly through polymerization, like liquid-liquid system suspension polymerisation, generate porous granule.Usually, be shaped on the solution of monomer and polymerization catalyst earlier, this solution is water insoluble; Add a kind of dissolve in this solution but water-fast atent solvent in solution; This solution suspends in aqueous solution, and the additive of surfactant and dispersant class is arranged in the general aqueous solution, to promote suspension or emulsifying.In case the discontinuous granule of hoping forms, and through heating or shining the activating reaction agent polyreaction is proved effective.In case polymerization is accomplished, and generates solid granule, granule is solid, ball-type, loose structure.Because polymer generates around inert fluid, thereby, forming porous network, atent solvent has occupied particulate hole as pore forming agent.This hole agent then is removed.

The macropore granule can make through solvent evaporation biodegradable or not biodegradable polymer.Solvent evaporation technology: 1, need the polymer of evaporation dissolved in an organic solvent, then with solution cross monochlor(in)ate sodium crystallization (hoping the size crystalline particle) layer (see solemn Buddhist nun, wait the people, Bao Er's wood .. agate is special. the research magazine 37: 413-42, (1997).Solvent is generally through evaporative removal, and the polymer that the obtains sodium chloride that leaches under water produces the porous polymer store body.2 or, the sodium chloride crystalline solid is dispersed in the polymer solution, stirs to obtain the isostatic peptizaiton of sodium chloride crystalline solid; Dispersion dropwise is pressed against in the non-solvent then, and stir make polymer beads be deposited to sodium chloride crystal around.Solid-state polymer beads through filter or centrifugal filtration after be dipped in the water to leach sodium chloride, obtain porous polymer store body.Sodium chloride can use any nontoxic, water-soluble salt or low-molecular-weight, water-soluble polymer to substitute.

Porous compounds can load one or more medicine so that contain chemical compound in the polymer in the granule forming process or after forming.For example, form the process that the back loads medicine at granule: at a solubilized medical compounds, but can not in the solvent of dissolve polymer dissolve medicine, put into polymer, stir and make granule and drug solvent mixing, drug solns is produced free-pouring powder by granule absorption.Granule is removed solvent on demand.

The another kind of polymer beads that can make is a non-porous particle, as: microcapsule body and microparticle, its chemical compound can or be dispersed in wherein by bag.Microcapsule and microparticle (are seen example, Bark, R.W., the release of control biological assistant, New York, John Willie sons &, 1987 in pharmacy and medicine conduction industry by well-known; Lei Nada .V and Hao Linge, M., the medicine conducting system, CRC publishes, and 1996).Wrapped up by the membrane for polymer shell around the store body of microcapsule as coagent.Microparticle is that the treatment auxiliary agent is disperseed the triangular web of whole particle.Yet, in these two definition, also have many forms, as: the microcapsule cohesion, these forms also are suitable for here.

Available biodegradable or non-biodegradation polymer are processed microcapsule body and microparticle.Microcapsule can be processed through SOME METHODS, comprise polymerization, solvent evaporation and physics between cohesion, interface compression (Bark, R.W., control biological assistant release, New York, & mountain, John Willie this, 1987).The microparticle preparation has many methods, and straightforward procedure disperses the polymeric film of treatment auxiliary agent to wear into suitable dimensions containing.Another method is the pharmaceutical auxiliary agent granule from the polymer solution dispersing dry.The detailed procedure of the seal compression of biological activity auxiliary agent is at United States Patent (USP) 4,675,189 with patent application 2 0010033868, be incorporated herein by reference here.

The particle form of polymer is multiple and changes.General choice criteria is that polymer can hold 40-O-hydroxyl-alkyl rapamycin.The example of these polymer includes but not limited to: gather (d; L-lactic acid), gather (l-lactic acid), gather (d-lactic acid), methacrylate polymers, like polybutyl methacrylate etc., ethylene-vinyl alcohol copolymer (EVOH), 6-caprolactone, ethyl vinyl hydroxylating acetas (EVA), polyvinyl alcohol (PVA), polyethylene glycol oxide (PEO), polyesteramide and its copolymer and mixture.All these polymer all are useful on the safety and the low inflammation history of systemic circulation.Generally the 40-O-hydroxyl-alkyl rapamycin compounds by polymer that accounts for 20-70% weight and 30-80% combines to form polyblend.

No matter granule is porose and atresia, differs greatly dimensionally, and diameter range is from the 0.1-100 micron, and only is from the 0.5-40 micron. these granules can be used as clean granule use or process glue, slurry, ointment, ointment or viscous liquid and are used to target.

Polymer composition of the present invention can be disperseed or be placed on the target place polymer composition is contacted with the body tissue at target place.To contact with destination organization only be a kind of of the many application of polymer beads to mixture in fact, and polymer can carry hydrophobic compound and form thin film, sheet, slurry, cream or glue and be placed on or be dispersed in the purpose place.For example: a polymer sheet that simply is loaded with 40-O-hydroxyl-alkyl rapamycin compounds can be placed in the surface of the body tissue that needs treatment.This tissue surface can be blood vessel, organ, tumor or body surface injured or that hindered.

The mucosa-adherent polymer composition

Another form of polymer composition, polymer composition are by the polymer liner that the mucoadhesive characteristic is arranged, to be placed on the position that connects mucosal tissue.Mucosa position at health refers to: in the blind pipe of eyes, the oral cavity, nose, rectum, vagina, periodontal, intestinal and colon.The mucosa conducting system is showed and to be taken bonding to mucosal tissue of the mucosa polymer that contains chemical compound.

Various polyblends are used to do the mucosa conductor.Especially, make mucoadhesive have hydrophilic and hydrophobic dual nature with 40-O-hydroxy alkyl rapamycin.Binding agent be colloid, gel and hydroxy-methyl cellulose at the intravital mixture of a sticking polymerization, be adhered to oral mucous membrane.Other have hydrophilic and hydrophobic mucoadhesive as comprising: gather (methyl vinyl ether/maleic anhydride) and gel, be dispersed in the ointment and contain dispersed polyethylene as mineral oil and (see United States Patent (USP): 4,948,580).Another hydrophilic and draining system are at United States Patent (USP) 5,413, and 702 have narration, and the polysiloxanes and that has promptly disclosed a pasty state dissolves the water polymeric material.

In the present invention, polymer composition has mucoadhesive polymers lining and 40-O-of the present invention hydroxyl-alkyl rapamycin compounds.The mucosa polymers compositions is put into the surface that connects mucosa by conduction, and chemical compound is gone out to get into mucosal tissue by eluting from polymer then.Can adopt the sticking patch of polymer, be put into sticking patch by the surface of treated tissue.Tissue can be an organ, a blood vessel, the body surface that tumor maybe need be treated.

Endovascular stent

Another purposes of polymer composition of the present invention is the polymer coating on an expansible intravascular stent.Fig. 2 and 3 is sketch maps of a stent with coating in blood vessel, and coating is the polymer composition that contains the substituted rapamycin compounds of 40-O-.In these figure, show the contraction state (Fig. 2) and the expansion state (Fig. 3) of support 20.Support comprises structural member or structure 22 and an external coating that carries and discharge chemical compound, below will do with reference to Fig. 3 and Fig. 4 and further describe.

In Fig. 2 and embodiment shown in Figure 3, stake body is the tube-like pieces that linked to each other through filament by a plurality of, like part 24 and 26 compositions.Each part has distensible Z type sawtooth or sinusoidal configuration.Each part body is through axial connector, and for example the crest with adjacent component is connected with the connector 28,30 that trough links to each other.Be appreciated that this structure makes support be expanded to expansion state (as shown in Figure 3) from contraction state (as shown in Figure 2), and the length of support is constant or a little change arranged.Simultaneously, less relatively connection makes that support can be crooked between the peak valley of adjacent tubular part.This characteristic is imported into vascular site particular importance with contraction state for support in conduit or on the conduit.Support has the typical contraction state diameter (Fig. 2) of a 0.5-2mm, more preferably 0.71-1.65mm, and length is 5-100mm.In the expansion state (see figure 3) of support, the diameter of support is 2 times of its contraction state at least, even can reach 8-9 doubly.Therefore, can be expanded to diameter radially at the support of 0.7-1.5mm be 2-8mm or bigger selected expansion state for contracted state diameter.

It is known having such support by the stake body that links to each other, distensible tube-like piece constitutes, and WO99/07308 is said like the PCT publication No., and this patent application and the application belong to same applicant, and introduces this paper as a reference.Other example is recorded in United States Patent (USP) 6,190, and in 406,6,042,606,5,860,999,6,129,755 or 5,902,317, these patents are introduced this paper as a reference.Perhaps, the structural member of support also possibly be successive spiralled wire band structure, that is, stake body is to be made up of single successive silk ribbon appearance spiral.The basic demand of stake body is when being positioned over vascular injury site, can expand; And can apply the coating of drug at its outer surface, can be in the blood vessel wall (as: middle film, adventitia and the endodermis of tissue) of blood vessel target spot internal layer with drug conveying contained in the coating.Preferably, stake body also has netted or open architecture, allows endotheliocyte to pass support and grows from outside to inside.

On scaffolding thread, scribble the coating of releasable medicaments; This coating by polymeric matrix be distributed in the substituted rapamycin compounds of intramatrical 40-O-hydroxy alkyl and form; Being used in several weeks at least, generally is 4-8 week, continues sometimes 2-3 month or discharges medicine from support in longer period.

Fig. 4 has shown the scaffolding thread 24 with coating 32 with the sectional mode of amplifying; Said coating has covered all faces of filament fully, i.e. top (forming the filament side of stake body outer surface), bottom (forming the filament side of stake body inner surface) and relative filament side.Will further discuss as following, the thickness of coating is generally the 3-30 micron, and this thickness depends on the character of the matrix material that constitutes coating and the relative quantity of polymeric matrix and reactive compound.It is desirable to, coating is thin as much as possible, as 15 microns or littler, so that support is minimum at the profile of vascular injury site.

The thickness of going up (outward) face coat also should be even relatively, with the medicine that the promotes release uniform distribution at target spot.The method that on scaffolding thread, produces the coating of relative uniform thickness is discussed below.

Fig. 4 has shown at scaffolding thread and has been coated with interlayer has one layer of polymeric bottom 34.The purpose of bottom is to help the stake body filament and be coated with the bonding of interlayer, promptly stablizes the coating on the filament.Below can see, valuable especially when this function contains the anti-restenosis compounds (as: chemical compound of 35-80% weight) of high percentage ratio in forming the polymeric substrate of coating.A kind of example of bottom polymer is a parylene, and it is in order to connect the polymeric substrate by biodegradable gathering-the dl-lactide forms.Other polymer base coat that is suitable for is ethylene-vinyl alcohol copolymer (EVOH), paryLAST ^TM, parylene, polysiloxanes, TEFLON ^TMWith other fluoropolymer, they can be deposited on metal support surface through plasma coated, other coating or depositing technology.Underlayer thickness is generally the 1-5 micron.

The polymer that forms ground can be any biocompatible polymeric material, and the chemical compound that is wherein comprised can discharge through diffusion and/or the degraded through polymeric matrix.Two kinds of known nondegradable polymer that are used for the coating ground are polymethyl methacrylate, ethylene-vinyl alcohol copolymer.Preparation is applicable to that the method for these polymer of stake body is described among US2001/0027340A1 and the WO00/145763, and these two pieces applications are introduced this paper as a reference.Usually, it is about 20-40% weight that the medicine that adds polymer is limited the quantity of.

Biodegradable polymer particularly gathers-the dl-lactide, also is suitable as coating ground material.In one the embodiment in the present invention, coating is biodegradable gathering-dl-lactide polymer ground, promptly gathers-the dl-lactic acid polymer, and its reactive compound that can hold up to 80% (dry weight) is dispersed in the polymeric substrate.More general, coating contains the reactive compound of 35-80% dry weight and the polymer of 20-65% dry weight.Exemplary coating contains the polymeric matrix of 25-50% dry weight and the reactive compound of 50-75% weight.Following description is seen in polymer and the synthetic detailed description of medicine about being used to be deposited on the scaffolding thread.

A kind of preferred coating is formed by the macro ring triolefin immunosuppressive compounds of the gathering of 25-50% weight-dl-lactide polymer ground and 50-75% weight, and coating layer thickness is the 3-15 micron.Bottom is a parylene, and thickness is the 1-5 micron.In this embodiment, it is long that the content of chemical compound is equivalent to 15 μ g medicine/mm supports.

In another embodiment, coating is formed by the degradable of 15-35% weight or the substituted rapamycin compounds of 40-O-hydroxy alkyl of nondegradable polymeric substrate and 65-85% weight.Coating layer thickness is preferably the 10-30 micron, and support can also contain the polymer base coat of 1-5 micron, like the parylene bottom.In this embodiment, it is long that the content of chemical compound is equivalent to about 15 μ g medicine/mm supports.

Coating can also contain second kind of bioactivator, and this bioactivator can effectively be treated related disease or disease or treated any second kind of disease that possibly occur.For example: if the substituted rapamycin of 40-O-hydroxy alkyl is used to treat restenosis, just can contain second kind can for example possibly be stimulated blood-related events the blood coagulation that form reduce to minimum or improved the bioactivator of the healing of blood vessel injury by the existence of former blood vessel injury or support.The example of second kind of activating agent comprises the thrombolytics of anti-platelet agents, fibrinolytic agent or solvable crystal form, but or the NO donor of stimulating endothelial cell healing and control smooth muscle cell growth.The instance of anti-platelet agents, fibrinolytic agent or thrombolytics is heparin, aspirin, hirudin, ticlopidine, eptifibatide, urokinase, streptokinase, tissue plasminogen activator (TPA) or their mixture.If the substituted rapamycin of 40-O-hydroxy alkyl is used as antitumor agent, then can comprise the second kind of activating agent that is usually used in chemotherapy of tumors.The example of second kind of chemotherapeutics comprises: paclitaxel, platinum compounds, cytosine arabinoside, 5-fluorouracil, teniposide, etoposide, methotrexate, amycin etc.The content of second activating agent in bracket coating provides the length in the period of treatment benefit to decide by this activating agent of needs.Second activating agent can be included in according to known method and prepare to be coated in the coating formula on the stake body filament.

Biodegradable stents

In another embodiment, stake body and polymer coating constitute by biodegradable polymers, are absorbed fully through the certain hour support.Support is a distensible helical mount preferably, and it has the stake body (not having diagram) that is formed by the spiral shape filament.At United States Patent (USP) 4,990, put down in writing the self expandable helical mount that is used for implantable intravascular in 155, draw at this and be reference.

Helical mount can prepare with preformed support, and the final expansion diameter of preform support is slightly larger than the intravascular space size intended with this helical mount treatment (for coronary artery 3.5mm external diameter (OD) ± 1mm) commonly.Usually, support can prepare through following mode: the support under the mold expansion state serves as that the stubborn support of axle makes it be in contraction state or radially presses support to be in contraction state by it with the major axis of support again, delivers to blood vessel on the catheter tip so that be installed in.The gross thickness of support is preferably the 100-1000 micron, and total length is 0.4-10cm.In fact, an important advantage of the type Biodegradable stents is, relatively long support, surpasses the support of 3cm like length, can easily send into and be placed on vascular injury site.

Form the existing report of method (United States Patent (USP) 6,080,177) of balloon-expandable stent about woollen yarn knitting silk with biodegradable polymers (as gathering-the l-lactide).Also there is a kind of device of form to be used to discharge medicine (U.S. 5,733,327).

A kind of polymeric material that preferably is used to form support is to gather-l-or gather-dl-lactide (United States Patent (USP) 6,080,177).As stated, stake body and coating can be one, become an expansible silk support that in entire bracket, contains anti-restenosis compounds.Perhaps, biodegradable coating can be coated onto in the ready-formed biodegradable body, sees the description of following second portion for details.By the latter, stake body can by a kind of biodegradable polymers as gather-the l-lactide forms, coating by second kind of polymer as gather-the dl-lactide polymer forms.Coating is if be coated onto on the stent preform, and then coating has and essentially identical composition of above description and thickness characteristics.

Fig. 5 has shown a filament, the cross-sectional view of for example spiral silk ribbon in the Biodegradable stents of just having described, and it has stake body and the coating that forms respectively.The biodegradable stent filaments 36 that has shown an inside among the figure all scribbles biodegradable coating 38 in its all sides.A kind of exemplary coating by gather-the dl-lactide forms, and contains the 40-O hydroxyalkyl-rapamycin of 20-40% weight and the polymeric substrate of 60-80% weight.In another embodiment, coating contains the chemical compound of 45-75% weight and the polymeric substrate of 25-55% weight.

Biodegradable support has a special advantages; Be exactly with a whole blood vessel of device treatment; It both can be used in combination with the sacculus plasty in case when having big obstruction to exist the predilation blood vessel, also can be used as preventative implant and put into the high-risk patient body that possibly stop up in the future.Because support is fully biodegradable, it can be as " all-metal clothing ", to be that the bracket for eluting medicament of a string containing metal ground is influence that the patient is later to do the chance that non-complex is performed the operation at blood vessel.

As above said, can on coating, mix second kind of activating agent, be used for discharging from coating in the certain hour in hope after the implantation.Perhaps, if used second kind of activating agent,, then can second kind of activating agent be incorporated in the stake body filament if be coated onto the inner surface that the coating of stake body does not cover stake body.The coating process about the wire rack mount body in following second portion narration also is applicable to the polymer filament stake body.

The bracket coating method

With reference to accompanying drawing, Fig. 5 A and 5B are the sketch maps of bracket coating technology of the present invention in more detail.Dissolve polymer obtains polymer solution 40 in compatible solvent.With the substituted chemical compound of 40-O-with, if necessary, second kind of activating agent adds in the polymer solution with homogeneous solvent or different solvents with the form of suspension or solution.Whole mixture is placed pressurized reservoir 42.Be connected with a liquid force (forcing) pump 44 on the bin.

Force (forcing) pump can adopt any source pressure, as long as can push away solution transfer tube 46 to mixed solvent with the speed of a design.Known as accurate feeding system field, force (forcing) pump 44 is by microcontroller (not having diagram) control.For example: such microcontroller can contain 4-axle autofeed device (4-Axis Dispensing Robot; Model is I&J500-R and I&J750-R; Can be from FairLawn, the I&J Fisnar company of NJ obtains, and it can exchange the interface through RS-232C and controlled by PC; Or accurate feeding system such as Automove A-400, it is from the Asymtek of Canadian Ka Ersibai.A suitable software program that is used to control the RS232C interface can be from comprising the Fluidmove system, and it also can be obtained by the Asymtek of Canadian Ka Ersibai.

Link to each other with bin 42, what for example link to each other with the bottom of bin is solution conduit 48, and it is transferred to solvent mixture on the surface of support.But pressurized reservoir 42 and conduit 48 are installed in one movably (not having diagram) on the support, and it can make the solvent conduit move with small step-length, for example every step 0.2mm, or move (shown in arrow X1 in scheming) along the long axis direction of support continuously.The movable supporting frame of pressurized reservoir 42 and conduit 46 also can be shifted to the tip (far-end) of conduit or away from the surface of filament along the direction shown in the Y1 with small step-length.

The support of coating is not stuck on the clip of rotation, and clip has at least an end to contact with the inner surface of support.Drive clip through motor support is rotated with small angle vertically, like each 0.5 degree, so that the outmost surface of supporting structure can be by catheter coatings, this is well known in the art.If desired, support also can rotate continuously.Accurately the method for the low quantity of fluid conduction device in location is known in X-Y-Z solvent feeding system field, can be used for the present invention.

The activity of liquid force (forcing) pump, liquid conduits X1 and Y1 are to be controlled by digitial controller and computer software to location and support R1 to the location; Quantitative like this solution accurately is coated onto the needed place of rack surface; Then; Solvent can be evaporated, the polymer and the active agent coating of the remaining hardening of rack surface.Usually with the quantitative changeization of solvent, its scope 2-2000 centipoise possibly be the 300-700 centipoise to the viscosity of solvent mixture usually.Perhaps, can conduit be fixed on fixed position, support also can move the completion coating process along its long axis direction except that rotating.

The X-Y-Z positioning table and movably support can purchase from I&J Fisnar.The solution conduit size is the rustless steel syringe of 18-28 metering specification preferably, and being connected with can blocked adapter.This conduit can be from RI, and the EFD company of East Providence obtains.See the entry needle selection guide of the special purposes of EFD.Preferred entry needle is again that granule or condensed material are filled in subscription number " not having pool that passivation stainless pin, length 1/4 " quick point-to-point injection from 5118-1/4-B to 5121-1/4-B "; Subscription number is " oval stainless pin is smeared condensed slurry, sealant and epoxy material on the flat ribbon deposit " of 51150VAL-B again; Again subscription number from 5121-TLC-B to 5125-TLC-B " anti-cyanoacrylate condenses and the control of additional deposition is provided for low-viscosity (mobile) liquid.Embossing and lining teflon ".A kind of disposable pressurized solution bin also can obtain from EFD, and stock 1000Y5148 is to 1000Y 5152F.Being used for another kind of syringe needle of the present invention is capillary glass tube, and the about 0.0005-0.002 inch of internal diameter, can obtain catalog number (Cat.No.) 15401-560 " little blood cell is than solvent pipe ", length 60mm, internal diameter 0.5-0.6mm by 0.001 inch according to appointment in the VWR catalogue.

Under Bunsen burner, pipe is further stretched, and obtains being used for the size of the hope of accurate coated polymeric/drug/solvent mixture.The programmable micro controller and the XYZ platform that are used to operate motor can obtain from Asymtek company.The present invention comprises that also the more than one liquid feeding pipe of use forms coating jointly; Or in same coating process, use more than onely to be equipped with different entry needles or to contain the solution of different viscosities or by the removable solution storage storage of the different chemical agent of multiple solution composition.Clip and stepping motor system can be from NJ, and the Edmund Scientific of Barrigton buys.

As stated, coating directly is coated in the outer supporting surface of support usually, possibly cover or not cover the whole of support inner surface or (or many) part, and the situation of covering depends on how to control above-described coat system of the present invention, shown in Fig. 6 A and 6B.Back figure is top and the lateral side regions that is coated with filament 50 with coating material 52.Perhaps, coating or coating mix also can directly be coated onto the inner surface of support.A thin guide pin can pass one or more indentation, there (that is: window) of cradle wall, thereby makes coating mix directly be coated onto the position that the support inner surface is hoped.Use the method, just can realize being coated onto the interior and outside of filament with the different coating material that contains the different pharmaceutical composition.For example, the filament external surface coating can contain the substituted rapamycin compounds of 40-O-, one of second activating agent carried above the coating on inner surface of filament can contain or the substituted rapamycin compounds of another kind of 40-O-.If support has enough big diameter, thin " L-type " guide pin can be inserted into support along the long axis direction of support open end is with the coating on inner surface with support.

Being used for polymer of the present invention comprises but is not limited in: gather (d; L-lactic acid), gather (l-lactic acid), gather (d-lactic acid), ethylene-vinyl alcohol copolymer (EVOH), 6-caprolactone, ethyl vinyl hydroxylating acetas (EVA), polyvinyl alcohol (PVA), polyethylene glycol oxide (PEO) and its copolymer and mixture, be dissolved in chloroform or acetone or other solvents that is suitable for.All these polymer all are useful on the safety and the low inflammation history of systemic circulation.

A kind of non-polymer coating also can be used for the present invention, as connect the substituted rapamycin compounds of 40-O-that is coated onto metal support surface through ion.

The coat system of use describing, can find to the rack surface coating go up, side or the inside all be feasible.Through the suitable ratio of careful selective solvent and polymer, can adjust the viscosity of solution, thereby some solution can be moved down along the side of pillar, and before solidifying, occupy lower surface, see Fig. 6 B.Through the time of staying of control conduit near bracket edge, the amount that polymer is coated onto bracket edge or bottom will be increased and decreased.In the embodiment depicted in fig. 4, at first will be coated onto rack surface 24, then solvent evaporation fallen by the bottom 34 usefulness coat system of the present invention of straight polymer and solvent composition.Coat the second layer polymer coating 32 that contains bioactivator then.

As stated, second activating agent also can be added in the mixture of polymers.As: the heparin of crystal form can be added in the coating.The heparin crystal fine grainization is about the 1-5 micron to granularity, and the form with suspension adds in the polymer solution then.When according to technology coating of the present invention, the suitable form of heparin is that those show bioactive crystalline state in mammal, comprises heparinate (that is: heparin sodium and low molecular weight heparin and salt thereof).When drug release type support is placed into blood vessel wall, as shown in Figure 9, begin dissolving near the heparin crystal of the polymer-coated surface of solidifying, increased the hole of polymer.When polymer slowly dissolves, more heparin and bioactivator are released with controlled way.

Yet, referring to Fig. 9, it should be noted that, always need be at the support coating on inner surface.For example, increased the corrugated conduction profile of support, made in little endovascular operability to diminish at the support coating on inner surface.And directly by the blood flow flushing through support, the drug wastage that causes the release of support inner surface is in systemic circulation for inner surface behind the implantable intravascular.So in Fig. 4 and embodiment shown in Figure 5, polymer that solidifies and activating agent major part are painted on the outside of the circumference of stent support, secondly are on the side.In a preferred embodiment, only the polymer of minimum and activating agent are painted on the inner surface of support.If need, also can have at least a part of support inner surface not coated or exposed.

In addition, the coating of Fig. 4 and Fig. 5 also can be coated onto the surface of scaffolding thread selectively.The thickness of coating should be corresponding with the volume of the bioactivity coatings that is used for organizing.The coating that limits some scopes is favourable, because the height damage of the coating of these scopes can cause putting support the time.

Earlier coat bottom equably, contain the bonding of bioactivator coating and support, and/or help to be stabilized in the polymer coating on the support with promotion on the surface of support.Initial coating can be used any method coating known in the art, or with accurate feeding of the present invention system coating.Use the different polymer material to be coated with initial coating also in the present invention, as using parylene (gathering (two chloro-right-xylene)), or any other can make metal substrate and the coating that contains bioactivator can fine adherent material.Parylene (gathering (two chloro-right-xylene)) can adopt plasma deposition or vapor deposition techniques, and this technology is (seeing United States Patent (USP) 6,299,604) well known in the art.In one embodiment of the invention, the discontinuous or continuous coating that contains heparin is coated in the inner surface of support, and the coating that contains the above-mentioned anti-proliferative drugs of the present invention is coated in rack outer surface.

Have high drug/polymer ground ratio when need on the metal rack ground, forming, when accounting for the coating of coating weight 40-80%, be preferably in and be coated with a bottom on the scaffolding thread and stablize and securely coating is bonded on the ground like medicament contg.Before the deposited coatings material, bottom can further handle through swelling in a kind of suitable solvent, and solvent can be for example acetone, chloroform, xylene or their mixture.This method has been described in embodiment 5, be used to prepare have high everolimus/gather-support of dl-lactide ratio.

Wherein, on scaffolding thread, form the parylene bottom through plasma deposition processes, then with this bottom swelling in xylene, last deposited coatings material.This method can be used for producing and gathering-contain the coating of 50% medicine or 75% medicine in the dl-lactide polymer ground, and coating layer thickness is merely the 5-10 micron.

As stated, use support that coat system of the present invention produces totally biodegradable also within the scope of the invention.Elder generation can be with feeding system injection of polymer in this groove with " C-shape " spiral groove tubular preforms of support shape system making of open-top.The external diameter of prefabricated component is open, so that polymer can be placed in the prefabricated component, uses a passage of syringe usually, if need also can have a plurality of; And set up the edge of support uniformity simultaneously, because polymer can receive the restriction of prefabricated component.Prefabricated component dissolves in a kind of solvent, but consequent Biodegradable stents is insoluble to this solvent.After the solvent of injection of polymer and polymer solution has been evaporated, can assembly be put into the solution of solubilized prefabricated component, discharge complete supporting structure.The representational raw material that is used to prepare prefabricated component is a sucrose, and it can process the prefabricated component shape of hope with the injection molding technology of standard.The representative solvents of prefabricated component is a water.

III, method for using

The substituted rapamycin compounds of 40-O-hydroxy alkyl can be used for treating any disease that rapamycin and everolimus are responded.This comprises any disease relevant with wound healing, for example relates to the postoperative wound healing of blood vessel or transplant operation; Tumor disease in this disease, directly is put into cancer location to polymer composition for example on the solid tumor.Inflammation is treated with the substituted rapamycin derivative of the also available 40-O-hydroxy alkyl of infection.In addition, this chemical compound also can be used in the arterial vascular treatment, especially restenosis.Chemical compound is fitted on the polymeric substrate that is used for site administration in the body of individuality, and exemplary polymeric substrate prescription as stated.The polymer composition that is coated onto the polymer coating on the expandable stent is specially adapted to treat restenosis.

About the treatment of blood vessel injury, can reduce have local vascular to damage or the danger and/or the degree of patient's restenosis of vascular occlusion risk with the polymer composition that contains the substituted rapamycin compounds of 40-O-hydroxy alkyl.Typical blood vessel injury is to cause when in angiography procedures, opening the inaccessible blood vessel of part such as coronary artery or peripheral arterial.In angiography, foley's tube is put in the occlusion, and sacculus far-end inflation and exit one or repeatedly forces inaccessible blood vessel to be opened.The expansion of this blood vessel relates in particular to the surface injury of blood vessel wall, and the speckle on it is moved, and often causes local wound, be enough to make blood vessel in time past and produce cell proliferation and closed reaction again.Strange, the incidence rate of restenosis and the order of severity frequent with angiography in the degree that is pulled of related blood vessel relevant.Particularly excessively be stretched to 35% or when higher, the occurrence frequency of restenosis is very high and often be very serious, i.e. vascular occlusion.

Support is placed the far-end of conduit with its contraction state, can in catheter lumen, perhaps place the far-end of sacculus with its contraction state.Then distal end of catheter is directed to injury region or potential closing point and discharges support from conduit; For example, if support is the self expandable type, discharge support to the site with tripwire; Perhaps; On sacculus, make the support expansion, contact with blood vessel wall up to support through inflated, thereby with support implantable intravascular wall tissue.

Fig. 7 has shown the support of a fully biodegradable and support has been inserted the blood vessel such as the IC conduit of cardiovascular system.The support 53 that has shown the part relaxation state among the figure is called " medicine helical mount ".This support is the screw type support of self expandable, is formed and is contained one or more bioactivators by polylactic acid.

This helical mount is processed with described prefabricated component, and the final expansion diameter of prefabricated component is set to the intravascular space size that is slightly larger than with this helical mount treatment.After removing prefabricated component, make it arrive small radii, compress its total length to one like this slidably under the sheath, make the transmission diameter of spiral be approximately 1/3 (under body temperature) of final expansion diameter through the two ends of medicine helical mount are twisted in the other direction.The thickness of medicine helical mount enough little (about 25-125 micron) makes it be easy to bend to littler radius, forms the spiral of the compression suitable with the internal diameter of sheath.Sheath is placed on the conduit 55 slidably, and this conduit is suitable for the support of compressive state is imported target blood.Sheath 54 has a grip 56 at its near-end, and through it, the operator of angioplasty can pull back sheath when catheter tip arrives the appropriate location of blood vessel, thereby discharges the medicine spiral fully.

Conduit 55 central authorities have a diameter to be about 0.014 " inner chamber, having pliable and tough most advanced and sophisticated 58 seal wire 57 can slide within it.Conduit also has a Lu Er hub 59, is used to connect inner chamber to Y joint and haemostatic valve, and this is the angioplasty known.The external diameter scope that the conduit of sheath is slidably arranged is in 2-4F (french size); If the treatment peripheral arterial can be bigger.

Because the medicine helical mount is a fully biodegradable, it does not influence the chance that the patient accepts uncomplicated vascular operation later on, unlike the all-metal clothing.Neural and vascular applications fields at some; Naked metal spiral support is put into blood vessel and is produced thromboembolism through regular meeting, or even entirely shuts, and surprisingly; Have been found that; Disclosed biocompatible polymer in the structure and gathered (dl-lactic acid) (PDLA) and composition thereof, the suitable mechanical strength blood vessel with support blood vessels shaping postoperative damage can be provided, and not produce thromboembolism; Therefore be the exemplary materials that is used for production medicine helical mount of the present invention.

Support in a single day go into the position promptly begin release of active compounds in the cell of blood vessel inner layer to suppress cell proliferation.Fig. 8 A shows the kinetics that everolimus discharges from two supports, and each support has the coating (square of blacking) of about 10 micron thick.Drug release kinetics is to obtain through support being immersed in 25% the alcoholic solution, and this solution can be accelerated the speed that medicine discharges from bracket coating greatly.Expected drug release kinetics in the curve chart display body, but the experience time to grow many.

Fig. 8 B demonstration discharges the figure of everolimus from the polymer coating on the metal rack.A top sets of curves shows the drug release of the coating that directly is coated onto the metal surface.Below a sets of curves (show slowly discharge) be through being coated with one deck parylene bottom or primary coating earlier at metal support surface, and then coating obtains from the teeth outwards.Can find out, scribble bottom the mechanical adhesion of coating and rack surface is increased that the decomposition of biodegradable coating is slowed down, and drug release also slows down.When the strong adherent bracket coating of needs to stand bracket for eluting medicament in conduit and/or blood vessel during bending operation during repeatedly wearing and tearing; And/or need support to insert the back to slow down when prolonging the treatment to Atherosclerosis inserting speed that fraction medicine discharges, such structure is useful.

Fig. 9 shows a cross-sectional view, can see the angiosomes 60 of having implanted a support 62 among the figure, and the coating silk of said support is silk 64 coatings 66 for example.This figure shows that reactive compound is discharged into vascular wall area on every side from each zone.Through after a while, the smooth muscle cell of the blood vessel wall of formation begins in support or passes the support net or the growth of spiral space, forms at last to swallow up the two-sided successive inner cell layer of support.If it is successful that support is implanted, later on will be less than 50% in the inaccessible degree of the blood vessel of backing positions, the cross-sectional diameter that promptly in blood vessel, keeps channel of blood flow is when implanting 50% of the expandable stent diameter at least.

Like the described pig restenosis animal model of people such as Schwartz (" sacculus postangioplasty restenosis--the multiplicative model of the practicality of a porcine coronary "; Circulation 82: (6) 2190-2200; Nineteen ninety December) in the test carried out confirmed the ability of support restriction extent of restenosis of the present invention; And this support is superior to existing and through the superiority of support of test, and especially to the case of serious blood vessel damage, i.e. the stretching of blood vessel is greater than 35% case.Research is summed up in embodiment 4.

In brief, the degree of several kinds of supports restenosiss after implanting 28 days has been compared in research, and support comprises: the polymer coating support of naked metal rack, polymer coating support, the rapamycin that comprises high or low concentration and everolimus.

The table 1 of embodiment 4 shows that rapamycin (Rapa-height or Rapa-are low) and everolimus (C-height or C-are low) support have significantly reduced the level of restenosis, and the restenosis of high dose everolimus support is minimum.In low damage zooscopy, obtained same result's (table 2).

Figure 10 A-10C is a support transverse section legend of implanting back 28 days new intimas of naked metal S-support (obtaining from the Biosensores International Inc of california Bewport Beach).Figure 11 A-11C is the example that the neointima of polymer coating (no medicine) S-support forms.Figure 12 A-12C and Figure 13 A-13C are that the neointima of everolimus/polymer coating support forms.Generally speaking, the healing of blood vessel that the everolimus coating bracket is treated is good, and endodermis is set up good, and 28 days blood vessels heal fully and reach the blood vessel stable state.Figure 14 is a blood vessel transverse section of amplifying 91 times, shows the endodermis that support is implanted the interior healing of lumen of vessels in back 28 days and set up.

Photo shows that the best combination of eliminating restenosis at 28 days is C-height or C-U high (seeing embodiment 4), and they contain 325mg and 275mg everolimus respectively on the long support of 18.7mm.The young pig of outbreed is followed up a case by regular visits to 28 days data prediction, compare with naked metal rack (S-support) in the market, restenosis rate reduces 50%.Data show that also on same support/polymer transmission platform, everolimus is superior to or is equivalent at least the 180mg rapamycin.Form metric analysis (embodiment 4) is supported these results.

Figure 15 shows " best fit " linear regression curve of selecting to be coated onto the drug dose in the polymer on the S-support, and injury tolerance narrow area when following up a case by regular visits to is relevant." narrow area " is an accurate index that the neointima of being confirmed by the form metric analysis forms.Can find out that on scheming only high-load everolimus coating bracket relative damage degree increases demonstration negativity slope in the sample sets of test.This analyzes the high coating of prompting C-possibly control restenosis in the coronary artery of damage, this is in fact irrelevant with injury tolerance.Other coating formula all can not show this unique property.

Figure 16 shown in zoopery, excessively stretched by the sacculus relation of (through sacculus/to the tremulous pulse ratio, promptly (B/A ratio) measured) and blood vessel injury of blood vessel.This data show to cause the blood vessel injury of highly control with the angioplasty sacculus of overdistension be the rational exact method that in pig model, causes measurable and known blood vessel injury.

Figure 17 is that a PDLLA polymer coating from metal rack discharges the everolimus (curve chart of filled circles and 40-O-hydroxyalkyl replacement rapamycin (solid positive square).Curve is to be measured from polymer by relative time to be discharged into the chemical compound amount ethanol and the water solution of (25/75 compares) and to obtain.The amount of the 40-O-hydroxyalkyl replacement rapamycin that in the time of 8 hours, discharges approximately is 1.7 times of everolimus; Time after 8 hours, release 40-O hydroxyalkyl replacement rapamycin is 1.5 times of everolimus approximately.We can say thus; At room temperature, replace 1.5 times of speed that polymer composition that rapamycin compounds forms discharges chemical compound in ethanol/water speed is the mixture release chemical compound formed of polymer and everolimus at least by polymer liner and 40-O-hydroxyalkyl.

From aforementioned, can see that this invention can be satisfied a plurality of purposes, and multiple characteristics are arranged.This polymer architecture contains RM value actual specific everolimus or the RM value height of rapamycin that the 40-O-hydroxyalkyl replaces the polymer architecture of rapamycin compounds, so can be placed in the impact point that a quilt is treated.When being placed to the tissue that needs treatment, such mixture of polymers contacts; The 40-O-hydroxyalkyl replaces rapamycin compounds can be discharged into tissue from polymeric liner; It can treat any disease that rapamycin and everolimus can be treated, and comprising: tumor, inflammation, infection, wound healing, graft-rejection and restenosis.Also can treat those polymer can local placements needs the place of treating, like wound, tumor or restenosis, inflammation or infection place.

Embodiment

The each side of for example clear support manufacturing of the present invention of following examples and use.But the present invention is not limited only to these scopes.

Embodiment 1

The preparation of everolimus and derivant thereof

Synthesizing of steps A, 2-(tert-butyl group dimethylsilyl) ethoxy-ethanol (TBS ethylene glycol)

Anhydrous THF of 154ml and 1.88g NaH are stirred in the 500ml round-bottomed flask that is having condenser under the blanket of nitrogen.In flask, adding 4.4ml does not have water glycol, stirs and generates a large amount of precipitate after 45 minutes.In flask, add the 11.8g tert-butyl chloro-silicane and continued vigorous stirring 45 minutes.The mixture that forms is poured in the 950ml ether.With 420ml salt washing ether, solution is used dried over sodium sulfate.Product is concentrated through the vacuum evaporation ether, fill silicagel column through flash chromatography with 27 * 5.75cm then and carry out purification, with hexane/Et ₂O (75: 25v/v) solvent system eluting.With product 0 ℃ of preservation.

Synthesizing of step B, 2-(tert-butyl group dimethylsilyl) ethoxy-ethanol triflate (TBS ethylene glycol Trif)

Under blanket of nitrogen and the vigorous stirring, with 4.22g TBS ethylene glycol and 5.2g 2, the 6-lutidines mixes in the 100ml double-neck flask of condenser is housed.In 35-45 minute, slowly add the 10.74g trifluoromethanesulfanhydride anhydride, generate yellow-brownish solution.Add 1ml saline then and finish reaction, solution is with 100ml salt washing 5 times, and final pH value is 6-7.Solution is used dried over sodium sulfate, evaporate dichloromethane in a vacuum and concentrate.Product is filled silicagel column through flash chromatography with 24 * 3cm carry out purification, with hexane/Et ₂O (85: 15v/v) solvent system eluting, preserve down at 0 ℃ then.

Synthesizing of step C, 40-O-[2-(tert-butyl group dimethylsilyl) oxygen base] ethyl-rapamycin (TBS Rap)

In the 50ml flask, with 400mg rapamycin, 10ml toluene and 1.9ml 2, the 6-lutidines mixes and is incorporated in 55-57 ℃ of stirring down.In the barrier film bottle of another 3ml, add 1ml toluene, add 940 μ l 2 again, the 6-lutidines then adds the TBS ethylene glycol Trif of 2.47g.Be added to the mixture in the bottle in the flask of 50ml, reaction was under agitation carried out 1.5 hours.In reaction flask, add 480 μ L 2 again, 6-lutidines and the 1.236g TBS ethylene glycol Trif that other adds continued stirring reaction 1 hour.Add 480 μ L 2 at last again, 6-lutidines and 1.236g TBS ethylene glycol Trif are in mixture, with mixture restir 1-1.5 hour.The brown solution that generates is filtered with the vacuum fritted glass filter.Removed up to all colours with the crystalloid precipitate of toluene wash.Use the saturated NaHCO of 60ml then ₃Solution washing is filtrated 2 times, and then washes with salt.Solution is used dried over sodium sulfate, vacuum concentration.With a small amount of hexane/EtOAc (40: 60v/v) dissolution with solvents product, with 33 * 2cm fast silica gel chromatogram column purification, with same solvent elution.Solvent removed in vacuo is deposited product under 5 ℃.

The synthesis technique of step D, 40-O-(2-hydroxyl) ethyl-rapamycin (everolimus)

To the heat resistant glass dish (fill it up with in 150 * 75mm) ice and be placed on the agitator disk.Add low amounts of water.Earlier in a little vial with the TBS-rapamycin of 8ml dissolve with methanol 60-65mg.The HCl that in bottle, adds 0.8ml 1N with solution stirring 45 minutes, adds the saturated NaHCO of 3ml then ₃Aqueous solution neutralizes.In solution, add 5ml saline, add 20ml EtOAc then, produce biphase mixture.Mix biphase, the reuse separatory funnel water layer of draining.Remaining solution uses the salt washing to be 6-7 up to final pH, uses dried over sodium sulfate then.Remove sodium sulfate with fritted glass filter, vacuum is steamed and is desolventized then.The concentrate that obtains is dissolved in the EtOAc/ methanol (97: 3), uses 23 * 2cm fast silica gel chromatogram column purification then, with same solvent elution.Solvent removed in vacuo is deposited product under 5 ℃.

Embodiment 2

Be prepared in and gather-d, contain the support of everolimus in the l-lactide coating

At room temperature with the gathering-d of 100mg, the l-lactide is dissolved in 2ml acetone.The 5mg everolimus is placed in the bottle, adds 400 μ L lactide solution.With the lactide solution of the syringe pump accurate feeding 10 μ L drug of microprocessor control end face to stent strut.On support, produce the single polymers layer of uniform drug after the solvent evaporation.

With same method 15 μ L solution are coated onto the end face and the side of stent strut, produce and be coated in stent strut top and lateral signal layer coating.

Embodiment 3

, contain in the l-lactide coating on the support of everolimus and discharge medicine from gathering-d external

Coating bracket is put into the phosphate buffer that contains 25%ETOH of 2ml pH 7.4, with 0.05% (w/v) Hydrazoic acid,sodium salt anticorrosion and with temperature maintenance at 37 ℃, make up vitro drug release.Regularly extract whole buffer out and take a sample, put into new buffer (unlimited deposition) simultaneously with volume to carry out the medicine measurement.Fig. 8 illustrates the drug release situation that is coated with the similar support of single polymers coating with the method from 2.

Embodiment 4

Animal is implanted experiment

The safety of A, pig and the QCA result of dose study

It is the blood vessel of major injury that bracket for eluting medicament is treated the challenging disease of tool, because the increase of known blood vessel injury degree directly causes the increase of restenosis (neointima formation) degree.Experiment is carried out pig on one's body, and the target vessel that coating stent of medicine is implanted is with angioplasty sacculus major injury (the excessive tensile damage of blood vessel on average about 36%).This causes seriously tearing and stretching of tunica intima layer and intermediate layer, causes the exuberant restenosis of blood vessel behind the implant frame 28.In this way, can be in the Different Weight ratio of medicine and medicine and the polymer of the various various dose of assessment on same metal rack/polymer platform relative effectiveness after support is implanted 28 days to the minimizing restenosis.

The test platform abbreviation:

" bare bracket " refers to the naked wavy metal ring support of 18.7mm (that is " the S-support ", made by BiosensorsIntl.Inc in the market);

" C-is high " refers to the support of 18.7mm, in PDLA (gathering-dl-lactic acid) polymer coating, contains the everolimus of 325mg.

" C-is low " refers to the support of 18.7mm, in the PDLA polymer coating, contains the 180mg everolimus.

" rapamycin-Gao " refers to the support of 18.7mm, in the PDLA polymer coating, contains the 325mg rapamycin.

" rapamycin-low " refers to the support of 18.7mm, in the PDLA polymer coating, contains the 180mg rapamycin.

The support that " C-U is high " refers to 18.7mm contains 275mg everolimus (weight ratio of medicine and polymer is 37%) in PDLA polymer coating as thin as a wafer.

" C-U is low " refers to the support of 18.7mm, in PDLA polymer coating as thin as a wafer, contains 180mg everolimus or equivalent (weight ratio of medicine and polymer is 37%).

" polymer support " refers to only to have the S-support of the 18.7mm of PDLA polymer coating.

" B/A ": the sacculus and the arterial vascular ratio of final expansion, the expression blood vessel is by excessive tensile degree.

" average inner chamber loss (MLL) ": the measurement bracket inner chamber is 3 times during implantation, and the meansigma methods of 3 secondary data deducts the poor of 3 times are measured when following up a case by regular visits to radiography meansigma methods, has reflected the formation amount of neointima in the support.

Method:

To be implanted to the young pig (also implantable still block tower piglets continue above 28 days) of outbreed by the bracket for eluting medicament that the wire screen support (being the S-support) and the polymer coating of wavy rings are formed, the everolimus or the rapamycin of coating use various dose.When implanting, measure the blood vessel diameter of implant frame front and back with QCA (quantitatively coronary angiography).At 28 days or in the longer time of following table regulation, before euthanasia, animal is cooked radiography again at rack area.

After the scheme euthanasia of animal by permission, take out the heart of animal, inject coronary artery with the formalin pressurization.The coronary artery segment that contains support is excised from the surface of heart to be fixed on the acrylic plastics plate subsequently, cuts out the transverse section with diamond saw.The acryhic material that contains each 50 micron thick of blood vessel most proximal end, centre, distal-most end is cut into slices through being installed in after the optical finish on the microscopical slide plate.

Take out the high-resolution picture of the blood vessel transverse section that is installed on the slide plate with a microscope that has a digital camera.Image is done the tissue morphology analysis by following program.

Use a computer image processing system Image Pro Plus 4.0 through carry out the analysis of tissue morphology based on the A.G.Heinze microscope of PC system.

1, average cross-section area and inner chamber thickness (by the area of inner membrance/neointima-inner chamber limit delimitation); Neointima (at inner chamber and interior elastic thin layer is the area between IEL, when IEL disappears, then is inner chamber and residual intermediate coat or the area between outer elastic thin layer EEL); Middle (area between IEL and EEL); Blood vessel size (, but not comprising outer membrane area) by the area of EEL delineation; Outer membrane area (at peripheral adventitial tissue, the area between fatty tissue and cardiac muscle and the EEL).

2, injury tolerance.For quantizing the degree of blood vessel injury, use the length of tearing and measuring the scoring that is the basis with the different blood vessel wall construction.Injury tolerance is calculated as follows:

The IEL that 0=is complete;

1=IEL is slightly torn, and has exposed table middle level (less damage);

2=IEL is torn by moderate, has exposed darker middle level (moderate incision);

3-EEL is torn, and has exposed skin.mm ²

Following table is result's (measuring because the average inner chamber loss that restenosis produces) that QCA analyzes.Data show in following table " neointima area " row blood vessel that takes off from pig when following up a case by regular visits to and the morphological analysis result of support

Table 1 " high damage " result of experiment

The device explanation	(B/A) than (on average)	Follow up a case by regular visits to the time	Average inner chamber loss (mm)	Neointima area (mm 2)	Support number
						Naked metal rack	1.33	28	1.69	5.89	31，39，40，45，47，50
The polymer coating support	1.36	28	2.10	5.82	32，41，43，48，51，60
						RAPA-is high	1.39	28	1.07	3.75	42，44，49，65，69，73
RAPA-is low	1.42	28	0.99	2.80	52，56，61，64，68，72
						C-is high	1.37	28	0.84	3.54	54，55，59，63
C-is low	1.36	28	1.54	3.41	53，57，58，62，66，70，74
						C-U is high	1.36	28	0.85	2.97	67，75，92，103

B, low damage research:

For further confirming the optimal dose of everolimus in minor injury's blood vessel; Especially to the patient of simple coronary artery disease and single untreated pathological changes, implant the everolimus bracket for eluting medicament and cause moderate to arrive low excessive tensile damage (about 15%).Carry out 30 days experiment with farm pigs, the You Kata piglets is implanted 3 months safety research with growing up.Angiographic results is following:

The QCA result of table 2 " low damage " experiment

The device explanation	(B/A) ratio	Natural law after the implantation	Average inner chamber loss (mm)	Neointima area (mm 2)	Support number
						Naked metal rack	1.14	28	0.95	2.89	20，22，26，29
Naked metal rack	1.13	90			76，80，84，87，91
						C-U is high	1.15	28	0.60	2.14	94，96，98，102
C-U is low	1.09	28	0.49	2.26	93，95，97，100，101
						C-U is high	1.15	90			77，81，85，86，90

The indication of above data, the low or C-U high dose of the C-U of everolimus can reduce neointima formation 45-48% in being low to moderate the blood vessel of Moderate lesion.

C, morphometric Analysis

Area of section with area of section total in each support of computer measurement and the new organization (neointima) that in support, forms calculates narrow area percentage.Mean vascular injury tolerance, neointima area and the narrow area percentage of every kind of medicine and polymer formulators (each support is measured three slice, thin pieces, averages) is presented in the following table.

Table 3 " high damage " experimental result

The device explanation	Injury tolerance	Follow up a case by regular visits to the time	Neointima area (mm 2)	Narrow area (%)	Support number
						Naked metal rack	1.9	28	5.89	0.72	31，39，40，45，47，50
The polymer coating support	2.11	28	5.82	0.70	32，41，43，48，51，60
						RAPA-is high	2.10	28	3.75	0.55	42，44，49，65，69，73
RAPA-is low	1.90	28	2.80	0.43	52，56，61，64，68，72
						C-is high	1.89	28	3.54	0.38	54，55，59，63
C-is low	2.1	28	3.41	0.53	53，57，58，62，66，70，74
						C-U is high	2.13	28	2.97	0.45	67，75，92，103

Morphometric Analysis is the accurate method of the height of restenosis in the measurement bracket in the porcine coronary model.In the model of height damage, the high prescription of C-forms at the height injury experiment produces minimum flow in the time of 28 days neointima; And the highest degree of injury of C-U Gao Zuyou, but still can keep the narrow area that hangs down percentage ratio--0.45.Therefore, these data have independently confirmed the discovery that QCA analyzes, and supporting human experimentation preferably to fill a prescription should be that C-U is high.

D, histologic analysis

C-U height and rapamycin-low lantern slide are to an experienced cardiopathology man, inflammation, cellulose protein, the endothelialization situation of the new intravascular space that heals in blood vessel cross section are examined closely.Do not find that the histology's variation that is caused by rapamycin and everolimus FirebirdTM has different.Generally speaking, blood vessel has formed intact its balance of endodermis recovery in the time of 28 days, reaches healing fully.Figure 14 is a blood vessel transverse section example that amplifies 91 times, shows the healing of support implantation intravascular space after 28 days and the foundation of endodermis.

E, with the comparison of having delivered the result

People such as Carter have delivered rapamycins coating support result of experiment on one's body pig of using Palmaz Schatz metal rack.Following table is the result of the Carter that delivered and the comparison of Biosensors experimental result:

Table-4

The device explanation	Blood vessel excessively stretch (%)	Average back wall losses (mm)	Standard deviation (mm)	Neointima area of section (mm 2)
					The naked metal pair of S-support shines	33.5％±9.2％	1.80	±0.5	7.6
The S-support only is coated with polymer	34.9％±4.8％	2.02	±0.8	8.5
					S-support polymer/rapamycin (325mg)	32.9％±10.1％	0.66	±0.2	(3.27 contrast-57%)
S-support polymer/everolimus (325mg)	36.8％±8.5％	0.74	±0.3	(3.61 contrast-50%)
					PS support BARE ＊Contrast	10-20％	1.19	---	4.5
The PS support only is coated with polymer	10-20％	1.38	---	5.0
					PS rapamycin FirebirdTM * 166mg	10-20％	0.70	---	(2.9 contrast-33.5%)
PS rapamycin FirebirdTM * 166mg (slow release)	10-20％	0.67	---	(2.8 contrast-37.7%)
					PS rapamycin FirebirdTM ＊450mg	10-20％	0.75	---	(3.1 contrast-31.1%)

Embodiment 5

The preparation of high medicament contg support

On the long metal wavy rings support of commercially available 14.6mm (the S-support of Biosensors Intl, wavy rings design), coat parylene " C " bottom of about 2 micron thick earlier with plasma deposition technology.The support that will scribble parylene then is placed in the xylene and spends the night at ambient temperature.Gather-d l-lactic acid storing solution through what the polylactic acid (PDLA) with 100mg was dissolved in the 2ml acetone that preparation contains 50 μ g/ μ L PDLA.

In order to prepare medicine and polymer ratio is 50% coating bracket, and the 5mg everolimus is dissolved in 100 μ L PDLA storing solutions.Other adds 20 μ L acetone to promote the dispersion of solution.From xylene, take out support, dip in solvent dried carefully.At the outer surface feed of each support 5.1 μ L coating solutions altogether.Support is at room temperature dry and place the exsiccator dried overnight.Make each support in 212 μ g PDLA, contain 212 μ g everolimuses thus.

In order to prepare medicine and polymer ratio is 75% coating bracket, and the 5mg everolimus is mixed with 33.3 μ L PDLA storing solutions.Other adds 33.3 μ L acetone makes the mixture dissolving.As described above takes out support and dips in dried from xylene.At the outer surface feed of each support 2.8 μ L coating solutions altogether.Support is at room temperature dry and place the exsiccator dried overnight.Make each support in 70 μ g PDLA, contain 212 μ g everolimuses thus.

The everolimus of finished product support/PDLA coating layer thickness is about 5 microns, or presents shallow milky outward appearance, and this coating firmly is connected with the side smooth distribution and with the metal mainstay surface at end face.

Claims (3)

1. produce the method for bracket for eluting medicament, said support has the distensible tubular body that is formed by the filament that connects, and the medicament elution polymer coating that has end face, side and inner surface section and contain selected amount medicine, and said method comprises

(a) the support tubular body is placed on the clip, stake body is blocked with clip through clip is contacted with the inner surface of tubular body, so that tubular body is rotated vertically with clip,

(b) with clip on the tubular body position adjacent place a conduit; When support rotates on clip and moves axially with respect to conduit; Through this conduit can with viscosity be the 2-2000 centipoise and be included in pressurized reservoir that conduit is connected in drug-polymer solution directly be coated in the top surface areas of stake body filament from conduit

(c) the control conduit passes through the transmission of conduit from bin with respect to the material that moves and control of stent filaments, thereby makes medicine-polymer solution only be painted on the end face and the lateral side regions of support.

2. the described method of claim 1, wherein used drug-polymer solution comprises the macro ring trienes medicine of 40-80 weight % and the polylactic acid polymer of 20-60 weight % in the step (b).

3. the described method of claim 2 wherein applied support earlier before medicament-polymer solution applies with polymer base coat.

Images