CN105246521A - Crosslinked coatings delivered via balloon - Google Patents

Abstract

The present invention relates to systems for and corresponding methods of delivering a therapeutic agent to a vessel wall of a body lumen by providing a compound capable of being crosslinked after intraluminal release onto a vessel wall so that the therapeutic agent is temporarily retained at the site of delivery by the crosslinked compound.

Description

Via the cross-linked coating that sacculus is sent

Invention field

Theme of the present disclosure relates to from interventional medical device delivering therapeutic agents.More specifically, theme of the present disclosure relates to and uses the cross-linked compound that can be cross-linked in blood vessel wall from expandable members such as sacculus (balloon) delivering therapeutic agents.

background of invention

Atherosclerosis is the arterial vascular syndrome of impact.It causes the chronic inflammatory in the wall of tremulous pulse to respond, and its major part is due to the accumulation of lipid, macrophage, foam cell and in arterial wall, forms speckle caused.Atherosclerosis is commonly referred to arteriosclerosis, although the pathophysiology of disease itself manifests several dissimilar pathological changes, scope is from fibrosis to being full of lipid (lipidladen) to calcification.Angioplasty relates to the blood vessel interventional technique making the blood vessel of the obstruction usually caused by atherosclerosis machinery broadening.

In angioplasty procedures, the conduit with closely folding sacculus is inserted in the vascular system of patient, and the logical vasotropic position narrowed, use expansion fluid (being generally the solution of angiography contrast media) by inflation to fixed dimension at this point.Percutaneous coronary gets involved (PCI), is commonly referred to Coronary angioplasty, is the narrow treatment procedure coronarius being used for the treatment of the heart usually found in coronary heart disease.

In contrast, peripheral blood vessel plasty, is commonly referred to Percutaneous Transluminal Angioplasty (PTA), refers to that the machinery of the blood vessel of utilization except coronary artery is broadening.PTA is generally used for treating leg most, and especially, ilium, external iliac, surperficial femur are with the tremulous pulse of popliteal tremulous pulse narrows.PTA also can treat the narrow of vein and other blood vessels.

Determine after angioplasty, although will successfully make blood vessel broaden, sometimes rebound or spasm and experience suddenly closed due to acute after inflation or expansion through the blood vessel wall for the treatment of.Get involved cardiologist by do for blood vessel support with prevent acute rebound with vasospasm solve this problem.Support (stent) is a kind of device, is generally metal tube or support (scaffold), is inserted in blood vessel, opens to keep blood vessel at postangioplasty.

Although the appearance of support eliminates many complication of unexpected vessel sealing after angioplasty procedures, doing support about in six months, can form narrowing again of blood vessel, this is the situation being called restenosis.Find that the damage of restenosis to angioplasty procedures has response, and it is characterized in that the growth of smooth muscle cell-formed similar with the scar on damaging.As a kind of scheme, develop the generation again that bracket for eluting medicament solves narrowed blood vessels.An example of bracket for eluting medicament is metal rack, and described metal rack has applied the medicine of known disturbances restenosis process.The potential defect of some drugs FirebirdTM is called after-poppet thrombosis, and this is the event that blood clot is formed in support.

Drug coat sacculus it is believed that it is the viable option of bracket for eluting medicament in treatment atherosclerosis.Restenosis in the patient of assessment medicine coated spheres capsule and implantation of drug-eluting stent and major adverse cardiac event (such as heart attack, bypass (bypass), repeat narrow or dead) ratio research in, compared with the patient (wherein restenosis be 20.8% and MACE ratio is 22.0%) with implantation of drug-eluting stent, only experience 3.7% restenosis and 4.8%MACE with the patient of medicine coated spheres capsule treatment.(see, PEPCADII studies, Rotenburg, Germany).

Although drug coat sacculus is viable option, and as PEPCADII institute proposes, may have the effect larger than bracket for eluting medicament in some cases, but due to period of contact very short between drug coat balloon surface and blood vessel wall, there is challenge in drug coat sacculus.The drug delivery time period of drug coat sacculus is different from the drug delivery time period of controlled release drug FirebirdTM, it typically is several weeks to the several months.Specifically, for coronary artery, sacculus only may be inflated and be less than one minute, and usually expands only 30 seconds.Therefore, the medicine of effective therapeutic dose must be transferred to blood vessel wall at 30 seconds to a minutes section.For peripheral vasculature, admissible Bulking Time can be greater than one minute, but still with a minute measurement.Therefore, because need short Bulking Time, the time of medicine or coating transfer is therefore shorter, so there is challenge for the drug delivery carried out via drug coat sacculus especially--and one is just being retained in the challenge do not presented in the bracket for eluting medicament in the vascular system of patient once implantation.

Each embodiment having proposed drug coat sacculus solves these demands, comprises the sacculus with the therapeutic agent directly arranged in balloon surface and the sacculus with various protection sheath (protectivesheaths).But not every embodiment all causes effective response in reduction sacculus and/or the post-traumatic restenosis of bare mental stents.

In addition, retaining the dose in blood vessel wall after inflation and coating are released into site of delivery is expect.Organize reservation will depend on several factor, comprise the preparation of the characteristic sum sacculus coating of therapeutic agent.This type of retains and will allow larger topical remedy's picked-up, thus improves therapeutic effect, and reduces systemic exposure in therapeutic agent.

Therefore, still to need and the object of disclosed theme relates to coating composition for drug delivery balloon and corresponding method, it allows the reservation being strengthened the coating of site of delivery by the coating of chemical modification site of delivery.

summary of the invention

The object of disclosed theme and advantage will be described in the following description, and be obvious according to the following description, and the practice by disclosed theme be learnt.By printed instructions herein and claim and by accompanying drawing in the method and system specifically noted, will realize and obtain the additional advantage of disclosed theme.

In order to realize these and other advantages, and according to the object of disclosed theme, as implemented and extensively describing, disclosed theme comprise for by therapeutic agent delivery to the system and method for the blood vessel wall of body cavity.According to disclosed theme, system comprises the expandable members with far-end, near-end and active section between the two, along the cross-linked compound that can be cross-linked after intracavity is released in blood vessel wall arranged at least partially of described active section, and along described active section part arrange in case intracavity be released into blood vessel wall after the temporarily stored at least one therapeutic agent of being crosslinked property compound.

In some embodiments of disclosed theme, described therapeutic agent is selected from antithrombotic agents, anticoagulant, anti-platelet agents, anti-lipid agent, thrombolytics, antiproliferative, antiinflammatory, Inhibiting proliferation agent, smooth muscle cell inhibitors, antibiotic, growth factor receptor inhibitors, cell adhension inhibitors, cell adhesion promoter, cell growth inhibition medicine, antimitotic agent, antifibrin agent (antifibrins), antioxidant, antineoplastic agent, promote the medicament that endotheliocyte recovers, antiallergic material, viral vector, nucleic acid, monoclonal antibody, antisense compounds, oligonucleotide, cell permeation enhancers, radiopaque medium labelling, HMGCoA reductase inhibitor, prodrug and combination thereof.

According to an aspect of theme of the present disclosure, cross-linked compound can be arranged as the coating on expandable members, the skin such as containing one or more therapeutic agents.Additionally or alternatively, expandable members can have the outer surface containing bank, and described bank contains the cross-linked compound for intracavity release.Alternately or simultaneously, expandable members can have the hole of the part along active section, and described cross-linked compound is discharged by described hole.One or more therapeutic agents can also be positioned at described bank or hole, for intracavity release upon inflation.

In certain embodiments, cross-linked compound is cross-linked by heat treatment.Described compound can at the temperature crosslink of 37 degrees Celsius or more.The compound of this type of embodiment can be selected from the polymer (silk-elastin-likeprotein-basedpolymers) based on silk-Elastin-like proteins, pluronic F127, Pluronic F68, poly-N-isopropyl acrylamide (" poly-NIPAAM "), NIPAAM-acrylic copolymer (polyNIPAAM-co-acrylicacid), PEG-PEG-PLA-PEG, PLGA-PEG, PLGA, the extracellular matrix dissolved, self-assembling peptides, hydroxypropyl emthylcellulose or its combination.Also thermal source can be provided by the system of these embodiments, the compound in blood vessel wall is heated above the temperature of 37 degrees Celsius after intraluminal delivery.

In other embodiments of the present invention, cross-linked compound is cross-linked by melting heat process.The cross-linked compound of this type of embodiment can be cross-linked being equal to or less than about 37 degrees Celsius.The compound of these embodiments can be selected from poly-(6-caprolactone), poly-(ortho esters) and polyanhydride.Also can provide thermal source by the system of these embodiments, so that temperature compound being heated above 37 degrees Celsius is used for discharging in balloon cavity, and cools subsequently and be cross-linked in blood vessel wall.

In other embodiments, cross-linked compound of the present invention is cross-linked by solvation.The compound of these embodiments can be selected from poly-(esteramides), lactic acid-ethanol copolymer (" PLGA "), poly-DL-lactide (" PDLLA "), PLLA (" PLLA "), PLGA-Polyethylene Glycol (" PEG ")-PLGA, PLLA-PEG-PLLA and combination thereof.Suitable solvent for these embodiments comprises N-Methyl pyrrolidone, dimethyl sulfoxine and dichloromethane.In this embodiment, solvent and cross-linked compound along the active section independent delivery of expandable members, such as, in above-mentioned bank, and respectively as coatings applications, and can combine in site of delivery.

In other embodiments of disclosed theme, cross-linked compound is shear sensitive, so as remove be released into the relevant shearing of blood vessel wall with the expansion of site of delivery and/or intracavity after be cross-linked.The cross-linked compound of these embodiments can be selected from hyaluronate sodium, sodium alginate and some lightly crosslinked hydrogel, such as lightly crosslinked sodium alginate, lightly crosslinked hyaluronate sodium/methylcellulose admixture, or its combination.

For some other embodiment, providing can at the internally crosslinked cross-linked compound of pH scope of about 6.8 to about 7.4.The cross-linked compound of these embodiments can be selected from acid-soluble collagen, chitosan, polyacrylic acid or its combination.

In other embodiments of disclosed theme, cross-linked compound is by being cross-linked with the chemical reaction of the second compound.Described second compound is along the layout at least partially of the active section of expandable members.The cross-linked compound of these embodiments can be selected from PEGN-hydroxysuccinimide (" NHS ") ester, PEG acrylate, PEG amine, PEG mercaptan, hyaluronic acid acrylate sodium (sodiumhyaluronateacrylate), hyaluronic acid mercaptan, fibrin and methacrylate modified acrylate.The compound of these embodiments can be selected, to be chemical reaction in the environment with predetermined pH scope.In one aspect, predetermined pH is at least about 6.8.

In other embodiments of disclosed theme, cross-linked compound passes through photoactivated cross-linking.The cross-linked compound of these embodiments can be selected from 2-hydroxyl-1-[4-(hydroxyl-oxethyl) phenyl]-2-methyl isophthalic acid-acetone, PEG acrylate, methacrylate modified alginate (methacrylatemodifiedalginate), methacrylate modified hyaluronic acid and combination thereof.The system of this type of embodiment can comprise light source so that by photoactivated cross-linking compound.The second compound by photoactivated cross-linking also can be arranged along the active section of expandable members.

Also having in other embodiments, cross-linked compound can be cross-linked by ionomer.Suitable cross-linked compound can be selected from sodium alginate, pectin, aloe pectin and combination thereof.Second compound can optionally arrange the active section of described expandable members at least partially, and wherein said second compound is selected from calcium chloride, barium chloride and combination thereof.By this way, described second compound is dissociated into corresponding component ion so that the cross-linked compound of crosslinked site of delivery.

In addition, disclosed theme comprises therapeutic agent delivery to the method for the blood vessel wall of body cavity.Described method comprises the system provided corresponding to above-mentioned embodiment, described expandable members is positioned in body cavity, inflating inflatable component is to contact blood vessel wall for cross-linked compound intracavity is released into blood vessel wall, and cross-linked compound is cross-linked in blood vessel wall, the compound that one or more therapeutic agents are crosslinked temporarily is retained in blood vessel wall.

accompanying drawing is sketched

Figure 1A is the schematic diagram of a representative foley's tube according to disclosed theme.Figure 1B is the schematic cross-section end-view (cross-sectionalendview) got along the line A-A in Figure 1A.Fig. 1 C is the schematic cross-section end-view got along the line B-B in Figure 1A.

Fig. 2 is disclosed for being represented by the schematic side elevation of therapeutic agent delivery to the method for body cavity, and wherein Fig. 2 A is narrow arterial vascular schematic side elevation; Fig. 2 B is the schematic side elevation of the same vessel after the expandable members conduit of insertion Fig. 1; Fig. 2 C is the schematic side elevation of blood vessel after the intracavity of expandable members catheter expansion and therapeutic agent and cross-linked compound discharges; And Fig. 2 D has the schematic side elevation of the blood vessel of cross-linked compound crosslinked in blood vessel wall after being expandable members catheter expansion.

Fig. 3 is that the schematic cross-section of method disclosed in Fig. 2 represents, wherein Fig. 3 A is narrow arterial vascular schematic cross section; Fig. 3 B is the schematic cross section of the same vessel after the expandable members conduit of insertion Fig. 1; Fig. 3 C is the schematic cross section of blood vessel after the intracavity of expandable members catheter expansion and therapeutic agent and cross-linked compound discharges; And Fig. 3 D has the schematic cross section of the blood vessel of cross-linked compound crosslinked in blood vessel wall after being expandable members catheter expansion.

describe in detail

Now with detailed reference to the embodiment of disclosed theme.The detailed description of the system of the theme disclosed in combination is described described method and corresponding steps.

The method and system presented herein can be used for therapeutic agent delivery to the blood vessel wall of body cavity.Therapeutic agent is applied to the blood vessel wall of body cavity by the mode that disclosed theme is particularly suitable for promoting therapeutic agent to be retained in site of delivery.

Disclosed theme provides blood vessel wall therapeutic agent being applied to body cavity, the system and the correlation method that by cross-linked compound, therapeutic agent are retained in site of delivery thus.Delivery system and correlation method via expandable members by therapeutic agent delivery to body cavity.Expandable members deposits therapeutic agent and cross-linked compound by the brought into temporary contact of the blood vessel wall with body cavity.Crosslinked cross-linked compound after being delivered to body cavity as disclosed herein, to promote therapeutic agent in the reservation of site of delivery and to send.

According to an aspect of disclosed theme, provide for by therapeutic agent delivery to the system of the blood vessel wall of body cavity.Described system comprises the expandable members with far-end, near-end and active section between the two.Expandable members have along its active section arrange at least partially for upon inflation from expandable members intracavity release cross-linked compound.The cross-linked compound of described system can be released into after in blood vessel wall at intracavity and be cross-linked.Expandable members also comprise along its active section a part arrange in case after intracavity is released into blood vessel wall the temporarily stored at least one therapeutic agent of being crosslinked property compound.

According to another aspect of invention required for protection, provide therapeutic agent delivery to the method for the blood vessel wall of body cavity.Described method provides the system comprising the expandable members with far-end, near-end and active section between the two.Along the cross-linked compound arranged at least partially of the active section of expandable members, and along described active section part arrange in case intracavity be released into blood vessel wall after the temporarily stored at least one therapeutic agent of being crosslinked property compound.Described expandable members is positioned in body cavity, then expands to contact blood vessel wall for cross-linked compound intracavity is released into blood vessel wall.Cross-linked compound is cross-linked in blood vessel wall with the temporarily stored at least one therapeutic agent of cross-linking compounds being used to be delivered to blood vessel wall.

The detailed each side with reference to disclosed theme now.Detailed description in conjunction with system provided herein, drawings and Examples is described by the method for disclosed theme.

Unless otherwise defined, what all technology used herein and scientific terminology and disclosed theme those of ordinary skill in the field understood usually has identical meanings.Although the method identical or equivalent with method as herein described or material or material may be used for during it implements, suitable method and material being described below.

It should be noted that term " one/kind (a) " entity or " one/kind (an) " entity refer to one/kind or multiple/kind of this entity.Therefore, term "/kind (a) ", " one/kind (an) ", " one/kind or multiple/kind " and " at least one/kind " are used interchangeably in this article.Term " comprises ", " comprising " and " having " be also used interchangeably.In addition, term " amount " and " level " are also interchangeable, and can be used for describing concentration or specified quantitative.In addition, term " is selected from " the one or more members referred in group listed later, comprises the mixture (namely combining) of two or more members.

Term " about " or " approximately " mean in the acceptable range of error of the occurrence determined such as those of ordinary skill in the art, and it will depend in part on this value and how to measure or to determine, that is, the restriction of measuring system.Such as, according to the practice of this area, " about " can mean at 3 or more than in 3 standard deviations.Or " about " is gratifying shows maximum +/-20% of definite value or the scope of maximum +/-10% or maximum +/-5% or maximum +/-1%.Or specifically about system or process biology, this term can mean in the order of magnitude of value, or in 5 times, or in 2 times.About pharmaceutical composition, term " about " refers to the acceptable scope of the quality control standard for the product ratified by supervision department.

The method and system presented can be used for therapeutic agent delivery to the blood vessel wall of experimenter.The method and system presented herein also can be used for manufacturing and assembling armarium such as drug coat foley's tube.Although the application of disclosed theme reference treatment agent, should be understood that, as expected, various coating, comprises polymer coated, therapeutic or matrix coating, can be applicable to each surface of armarium.

With reference to figure 1, for the purpose of illustration and not limitation, schematically Figure 1A and 1B is shown according to the exemplary of the balloon catheter device of disclosed theme.As described in Figure 1A and 1B, balloon catheter device 10 generally includes to be had near-end and has the conduit axle 12 of the prolongation of far-end and the expandable members be positioned at closest to the far-end of conduit axle or sacculus 30.According to disclosed theme, crosslinked source 50 is applied to the active section of foley's tube at least partially.Balloon-expandable has the outer surface and inner surface arranged at the distal portions of conduit axle.

For the purpose of illustration and not limitation, display has the elongate catheter axle 12 of the arranged in co-axial alignment comprising outer tubular member 14 and inner tubular member 16.Outer tubular member 14 is limited to the expansion chamber 20 arranged between the proximal part of conduit axle 12 and distal portions.Such as, and as shown in figure 1b, the coaxial relation between inner tubular member 16 and outer tubular member 14 limits annular expansion chamber 20.Expandable members 30 is communicated with expansion chamber 20 fluid.Expansion chamber between the two under stress to expandable members 30 delivering fluids, and can set up negative pressure to extract fluid out from expandable members 30.Therefore expandable members 30 can expand and shrink.The conduit extended is made certain size and is arranged for being sent by bending anatomical structure, and can comprise guidewire lumen 22 further, and described guidewire lumen 22 allows it to send along wire 18.As shown in figure 1b, inner tubular member 16 is defined for the guidewire lumen 22 of wire 18.Although Figure 1A and 1B illustrates that guidewire lumen has along wire (over-the-wire) (OTW) structure, guidewire lumen can be set to fast-exchange (RX) structure, this is well-known in the art.Similarly, described axle may be provided in multi-cavity component, or the composition of two or more tubular elements, as known in the art.

As described further in Figure 1A, expandable members or sacculus 30 have far-end 32, near-end 34 and active section between the two " L ".The expandable members implemented herein has the interior chamber 36 be communicated with inflatable chamber 20 fluid of extending shaft 12.Any multiple suitable expandable members structure and shape can be used, as further described below.

According to disclosed theme, at least one therapeutic agent 40 is along the layout at least partially of the active section " L " of expandable members 30.Described active section can be institute's selections of described active section or the whole of described active section at least partially.In addition, described at least partially can with reference to the pattern on the surface of described active section, such as ring, point, linear or curve section or another design.Described at least one therapeutic agent can be arranged along the part of the active section of expandable members to allow any suitable mode being released into blood vessel wall from expandable members.Such as, described at least one therapeutic agent can as coatings applications to the outer surface of expandable members.Additionally or alternatively, described expandable members can provide bank or similar surface character with containing therapeutic agent for from its release.In addition, hole or passage can limit along the part of active section, for discharging therapeutic agent from its infusion type.Described at least one therapeutic agent (such as, can not mixed other components) separately and is arranged, or combines with suitable additive (such as surfactant, plasticizer etc.) and arrange.In addition, and as further described below, described at least one therapeutic agent can combine cross-linked compound 60 and arranges and be used for sending.Such as, described therapeutic agent can as on cross-linked compound layer layer application, and/or described therapeutic agent can suitably time mix with cross-linked compound.

Further according to disclosed theme, cross-linked compound is along the layout at least partially of expandable members.After endoceliac expandable members expands, described cross-linked compound is transferred to chamber wall from the outer surface of expandable members.By this way, when being transferred to body cavity from expandable members or afterwards, cross-linked compound can be cross-linked, described therapeutic agent is retained in site of delivery.As therapeutic agent, as open in detail further below, cross-linked compound can various suitable mode be arranged along the part of active section.Such as, and unrestricted, cross-linked compound can as coatings applications to the outer surface of expandable members, and/or can be limited in bank of limiting in outer surface etc.In addition, cross-linked compound can be arranged and to send from described expandable members for the hole by expandable members limits, passage etc.

In addition, and as schematic representation in Fig. 1, crosslinked source 50 can be provided, to send or to be cross-linked to by cross-linked compound 60 after discharging in blood vessel wall (if needs) from expandable members.Cross-linked compound 60 to be used will be depended on, as further described below in crosslinked source 50.The example in this type of crosslinked source can include, but not limited to thermal source, light source and/or send the independent source of solvent or cross-linking agent, as further described below.Although the crosslinked source 50 described herein is provided at the expandable members for delivering therapeutic agents 40 and/or cross-linked compound 60, but will be appreciated that, crosslinked source 50 can and expandable members interval provide, or when expect or suitable time can be provided on independent conduit.

With reference now to various cross-linking compounds, layout, technology and crosslinked source.Should be understood that, this type of example, when expect and suitable time, can combine and/or exchange.

For the purpose of illustration and not limitation, cross-linked compound can be arranged on the outer surface of expandable members as coating.As mentioned above, the coating of expandable members may further include the skin containing at least one therapeutic agent.In addition or alternately, therapeutic agent can combine with cross-linked compound or be mixed into the coating on the outer surface of expandable members.After expandable members expands, the coating containing at least one therapeutic agent is transferred to body lumen wall.If therapeutic agent is arranged as independent skin, then described cross-linking compounds is disposed on the therapeutic agent in blood vessel wall.Cross-linked compound is cross-linked subsequently, therapeutic agent is temporarily retained in site of delivery.Site of delivery can be, such as, stenotic lesion, although described position can be any suitable body cavity expecting delivering therapeutic agents.

The unrestriced object in order to understand, this process schematically illustrates in figs. 2 and 3.Fig. 2 A and 3A shows artery stenosis blood vessel.Introduce according to expandable members 30 of the present invention, as shown in Fig. 2 B and 3B.Expandable members 30 expands as shown in Fig. 2 C and 3C, therapeutic agent 40 and cross-linked compound 60 are delivered to blood vessel wall.Particularly, and with reference to the above-mentioned embodiment with the skin of therapeutic agent and the lower floor of cross-linked compound, therapeutic agent 40 is transferred to blood vessel wall, and cross-linked compound 60 is disposed on the therapeutic agent in blood vessel wall.Then cross-linked compound 60 can use the suitable crosslinked source 50 of (when desired) on conduit on expandable members or independent that is arranged in be cross-linked.As in Fig. 2 D and 3D describe, therefore cross-linked compound 60 is retained in blood vessel wall after removal expandable members, and then therapeutic agent 40 can be adsorbed on site of delivery.

Although use coating above with reference on expandable members, extra and/or alternative technology can be used for arranging therapeutic agent and/or cross-linking compounds along a part for active section.Such as, and as herein implement, expandable members can have the outer surface with bank or similar characteristics that the part along the active section of described component limits.Therefore cross-linked compound can be arranged for the intracavity release in bank.After expandable members expands, cross-linked compound and/or at least one therapeutic agent discharge from bank and are transferred to the blood vessel wall of body cavity.Such as, cross-linked compound can be arranged in first group of bank, and therapeutic agent can be arranged in second group of bank.Or cross-linked compound can mix with the ground floor in bank or be arranged as the ground floor in bank, and therapeutic agent can be arranged as the second layer in bank identical with cross-linking compounds.

In addition or alternately, infusion techniques can be used for sending cross-linked compound and/or therapeutic agent.Such as, expandable members can have along the part of active section the hole or passage that are defined in wherein, and wherein said cross-linked compound and/or at least one therapeutic agent are arranged to be discharged by the intracavity in described hole.After expandable members expands, cross-linked compound and/or at least one therapeutic agent can be extruded, or discharge additionally by hole or passage and be transferred to the blood vessel wall of body cavity.Cross-linked compound and therapeutic agent can be arranged to be discharged by separate openings, or are mixed for being sent together by same holes.

One skilled in the art will appreciate that at least one therapeutic agent can combine cross-linked compound and send, wherein one or more therapeutic agents are trapped in cross-linking compounds after cross-linking.When desired, therefore one or more therapeutic agents can be released into blood vessel wall along with the time.In addition or alternately, one or more therapeutic agents can be sent according to the exemplary provided, be limited to blood vessel wall to be crosslinked material or to be forced into blood vessel wall.

According to disclosed theme, cross-linked compound can be cross-linked by heat treatment." heat treatment " typically refers to heat energy from external source or be endogenously transferred to cross-linked compound.The suitable compound be cross-linked by heat treatment comprises, but be not limited to, based on the extracellular matrix of the polymer of silk-Elastin-like proteins, pluronic F127, Pluronic F68, poly-NIPAAM, NIPAAM-acrylic copolymer, PEG-PEG-PLA-PEG, PLGA-PEG, PLGA, dissolving, self-assembling peptides, hydroxypropyl emthylcellulose and combination thereof.This type of heat cross-linking compound can be equal to or higher than about 37 degrees Celsius usually, such as passes through on expandable members or the thermal source of disposed adjacent, is cross-linked.

This type of heat cross-linking compound is favourable because only have a kind of compound to need for crosslinked, although extra additive or potential reaction compound can use, required really.About the limiting examples of silk-Elastin-like proteins polymer, cross-linked compound passes through, and such as, one of above-mentioned example technique is sent, and be cross-linked in site of delivery, irreversibly to crystallize into beta sheet configuration by the heated filament on expandable members or other suitable thermals source subsequently.This type of stable crosslinked configuration provides cross-linked compound and the improvement of therapeutic agent in blood vessel wall retains.About another limiting examples of pluronic F127, cross-linked compound can be liquid in room temperature and in body temperature gelation.Catheter delivery and expand after, body temperature gelatine allow compound be retained in site of delivery.

According to the Additional embodiments of disclosed theme, cross-linked compound can be cross-linked by melting heat process.As used herein " melting heat process " typically refers to the heat fusing of polymer in vivo or in ex vivo.Suitable melting heat polymer is crosslinked when they solidify again subsequently.Melting heat cross-linked compound includes but not limited to gather (6-caprolactone), poly-(ortho esters), polyanhydride and combination thereof.This type of melting heat cross-linked compound can be cross-linked being equal to or less than about 37 degrees Celsius.As herein implement, the crosslinked source for this type of melting heat cross-linked compound can comprise thermal source, and described thermal source is in the temperature sending and be heated above by melting heat cross-linked compound before discharging about 37 degrees Celsius from expandable members.By this way, and with reference to the limiting examples of poly-(6-caprolactone), cross-linked compound can be sent higher than the form of the polymer melt of the Tm of about 60 degrees Celsius, or In Situ Heating is to higher than the temperature of about 60 degrees Celsius.After being released into blood vessel wall from expandable members, then cross-linked compound solidifies at body temperature and is cross-linked, and is retained in site of delivery to allow compound.

Also having in other embodiments according to disclosed theme, cross-linked compound passes through photoactivated cross-linking.As used herein " photoactivation " to typically refer in delivery process or afterwards the light of suitable wavelength and intensity or electromagnetic energy (the visible or ultraviolet portion of such as electromagnetic spectrum) is applied to cross-linked compound.PEG diacrylate and 2-hydroxyl-1-[4-(hydroxyl-oxethyl) phenyl]-2-methyl isophthalic acid-acetone (Irgacure2959 can be included, but not limited to by the suitable cross-linked compound of photoactivated cross-linking ^?).The appropriate light activator of this compounds includes, but not limited to ultraviolet light.When cross-linked compound is by photoactivated cross-linking, crosslinked source is provided as the assembly of light source as catheter cartridge part, or as independent conduit tube component.

According in other embodiments of disclosed theme, cross-linked compound is cross-linked by solvation.As used herein " solvation " typically refers to before sending, in process or introduces afterwards by solvent or be applied to cross-linked compound.The suitable cross-linked compound crosslinked by solvation includes, but are not limited to: poly-(esteramides) (" PEA "), PLGA, PDLLA, PLLA, PLGA-PEG-PLGA, PLLA-PEG-PLLA, N-Methyl pyrrolidone, dimethyl sulfoxine, dichloromethane and combination thereof.Therefore the easy solubilizing hydrophobic medicine of this compounds can be favourable in some indication.By with medicine carrying Solvents Solvent cross-linked compound, can form at site of balloon inflation the cross-linked formulations being incorporated to and expecting hydrophobic drug.The unrestriced mode by example, according to some exemplary of the present invention, PEA can be delivered to the blood vessel wall of body cavity according to delivery system as herein described, and uses N-Methyl pyrrolidone to be cross-linked by solvation to be formed in the cross-linked formulations that the blood vessel wall of site of delivery retains.In this exemplary embodiment, crosslinked source can be for solvent being released into the one or more hole of cross-linked compound or combining with cross-linked compound.

Also having in other embodiments according to disclosed theme, the cross-linked compound provided is shear sensitive, so that crosslinked after removal shear stress.Such as, the removal of shear stress can occur after cross-linked compound intracavity is released into blood vessel wall.Suitable shear sensitive cross-linked compound includes but not limited to: hyaluronate sodium (such as, Healon5 ^?) and sodium alginate, and some lightly crosslinked hydrogel, such as lightly crosslinked sodium alginate and hyaluronate sodium methylcellulose admixture and combination thereof.The gelation immediately after removal is sheared of these compounds, therefore can be retained in the blood vessel wall of site of delivery.When expecting photo-crosslinking before sending, can before lightly crosslinked compound being incorporated to the system provided, instead of in vivo, realize that this type of is tentatively crosslinked.

According in other embodiments of disclosed theme, can cross-linked compound be selected, be cross-linked when being exposed to the environment within the scope of the pH of about 6.8 to about 7.4 with box lunch.Acid-soluble collagen, chitosan, polyacrylic acid and combination thereof is included, but not limited at the internally crosslinked suitable cross-linked compound of the pH scope of about 6.8 to about 7.4.The unrestriced mode by example, acid recombined collagen can be delivered to the blood vessel wall of body cavity according to embodiment provided herein.After contacting with the neutral body pH of blood vessel wall, acid collagen protein solution neutralizes and gelation, and therapeutic agent is trapped in wherein.The collagen solution of gelatine is retained in the blood vessel wall of site of delivery, and therapeutic agent is trapped in wherein.

Also having in other embodiments according to disclosed theme, cross-linked compound is by being cross-linked with the chemical reaction of one or more added compound.Can added compound be selected so as with the first cross-linked compound chemical reaction.These added compound can along the release at least partially of layout and/or the active section from expansible elements at least partially of the active section of expansible elements.By the mode of example, added compound can be arranged in Topcoating or basic unit.In addition or alternately, the bank that added compound can limit from expandable members or hole release, with above-mentioned solvent based seemingly.In expandable members expansion with after compressing coating for blood vessel wall, by cross-linked compound and extra one or more compound mechanicals mixing, to promote mixture being cross-linked in blood vessel wall.Or added compound can be sent via the second balloon-expandable or via the bank in the first sacculus or passage.

By the mode implemented, and as described below, the chemical crosslinking compound for being sent temporarily to retain one or more therapeutic agents by sacculus comprises hydrophilic polymer, peptide hydrogel, carbohydrate hydrogel and combination thereof.Suitable hydrophilic polymer for chemical crosslinking comprises, but be not limited to, Polyethylene Glycol (" PEG "), PLLA-PEG-PLLA copolymer, PLDA-PEG-PLDA copolymer, PLGA-PEG-PLGA copolymer, PEG-PLLA copolymer, PEG-PLDA copolymer, PEG-PLGA copolymer and combination thereof.Alginate, hyaluronic acid, collagen protein, laminin，LN, poly-l-lysine, fibrin, Fibrinogen, gelatin and combination thereof is comprised for the suitable peptide of chemical crosslinking and carbohydrate Hydrogel Component.

In addition, hydrophilic polymer, peptide and carbohydrate Hydrogel Component, and can be functionalized to promote chemical crosslinking with reactive functional groups.Suitable functional group comprises, but be not limited to, mercaptan, vinyl, amino, acrylate, methacrylate, aldehyde, vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan), succinimido, N-Hydroxysuccinimide base, nitrophenolate (nitrophenolate) and carbohydrazide part.According to some embodiments of disclosed theme, cross-linked compound reactive functional groups is functionalized.In Additional embodiments, cross-linked compound and one or more compounds extra all use reactive functional groups functionalized.Again further in embodiment, only have one or more compound reactive functional groups extra functionalized.

In some embodiments of disclosed theme, cross-linked compound is cross-linked by Michael addition reaction.Such as, cross-linked compound can be functionalized with nucleophile, and added compound is with electrophile functionalized.When cross-linked compound and added compound contact with each other (such as, as mentioned above, by from hole infusion and/or by after inflation mechanical mixture) time, Michael addition reaction original position between nucleophilic compound and electrophilic compound occurs, to form cross-linked composite in the blood vessel wall at the position of inflation.Michael reaction carries out relatively soon, and the order of magnitude is several seconds to several hours, and is correspondingly very suitable for in-situ cross-linked so that therapeutic agent is retained in blood vessel wall.

In Additional embodiments, cross-linked compound can be cross-linked by forming disulfide bond in the oxidation reaction.Such as, can be used in oxidizing condition the thiol residue forming disulfide bond functionalized for cross-linked compound.Added compound can be promote that original position forms the oxidative compound of disulfide bond.

Select one or more compounds extra, so as in the environment with predetermined pH (it is at least about 6.8 in certain embodiments) with the first cross-linked compound chemical reaction.In some embodiments (including but not limited to the crosslinked embodiment wherein expecting relative fast velocity), added compound can be provided with priming reaction functional group.The unrestriced mode by example, can provide alkaline buffer in the bank on sacculus or the passage in sacculus, to accelerate the crosslinked of cross-linked compound by the deprotonation of initial nucleophilic functional group.In certain embodiments, this buffer has the pH of about 7.0 to about 10.0.

The unrestriced mode by example, according to some embodiment of disclosed theme, cross-linked compound is the PEG polymer be made up of multi-arm PEG monomer, and wherein each PEG arm nucleophilic functional group is functionalized.There is provided the added compound be made up of PEG polymer, described PEG polymer is made up of multi-arm PEG monomer, and wherein each PEG arm Qin electricity functional group is functionalized.By the mode of example, suitable nucleophilic functional group includes, but not limited to mercaptan, amino, hydroxyl and CO-NH_NH2 group, and suitable Qin electricity functional group includes, but not limited to acrylate, vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan) and N-hydroxy-succinamide group.In some embodiments, the cross-linking chemistry reaction between polymer causes forming biodegradable covalent bond, such as ester bond.Such as, the reaction of PEG-acrylate and PEG-mercaptan causes forming thioester bond, and it is easily hydrolyzed in vivo.

In some embodiments, multi-arm PEG cross-linked compound has 1 to 16 arm, and has straight chain, pectination, side chain or star configuration.PEG cross-linked compound also can have the molecular weight of about 2 to 40kDa.In Additional embodiments, extra multi-arm PEG cross-linked compound has 1 to 16 arm, and has straight chain, pectination, side chain or star configuration, and has the molecular weight of 2 to 40kDa.

In further embodiment, cross-linked compound is multi-arm PEG as above, and added compound is peptide or carbohydrate polymer.In this type of exemplary, PEG-NHS ester is delivered to body cavity as cross-linked compound, and gelatin provides as added compound.Gelatin, such as, arranges along expandable members, and with PEG-NHS ester chemical reaction so that gelation in position, to promote that cross-linked compound is temporarily retained in site of delivery.In further embodiment, cross-linked compound is with the functionalized carbohydrate of reactive functional groups.The unrestriced mode by example, bridging property carbohydrate can be hyaluronic acid acrylate sodium, hyaluronic acid-mercaptan or methacrylate modified alginate.

According in other embodiments of disclosed theme, the cross-linked compound provided is cross-linked by ionomer.Such as, the second compound can be provided, to realize the ionomer of cross-linked compound, and can arrange along a part for the active section of expandable members.The suitable cross-linked compound crosslinked by ionomer includes, but are not limited to: sodium alginate, pectin, aloe pectin, alginate conjugate, comprise alginate-collagen protein and alginate layer Fibronectin, and combination.The second suitable compound for ionomer includes but not limited to: calcium chloride, barium chloride, calcium chloride and combination thereof.By this way, and as above-mentioned solvent execution, separately compound as separates layers and/or can pass through via a point perforate infusion, and mechanical mixture after expanding, or the expandable members by separating, and sends.

Various suitable therapeutic agent can be sent by system and method disclosed herein.According to disclosed theme, and for the purpose of illustration and not limitation, therapeutic agent or medicine can comprise any multiple suitable antiproliferative, antiinflammatory, antitumor agent, anti-platelet agents, anticoagulant, antifibrin agent, antithrombotic agent, antimitotic agent, antibiotic, anti-allergic agent and anti-oxidant compounds.Therefore, therapeutic agent can be, be not limited to equally, the inorganic or organic compound of synthesis, albumen, peptide, polysaccharide and other sugar, lipid, DNA and RNA nucleotide sequence, antisense oligonucleotide, antibody, receptors ligand, enzyme, adhesin polypeptide, coagulant comprise streptokinase and tissue plasminogen activator, antigen, hormone, somatomedin, ribozyme and retroviral vector.

As used herein term " antiproliferative " means for cytostatic medicament, such as chemotherapeutics.Some limiting examples of anti-proliferative drugs comprise taxanes, paclitaxel, Docetaxel and protaxel.Antiproliferative can be antimitotic.As used herein term " antimitotic agent " means for suppressing or affecting cell division, the thus usual medicament participating in fissional process and do not occur.A subclass of antimitotic agent comprises vinca alkaloids.The illustrative examples of vinca alkaloids includes but not limited to vincristine, paclitaxel, etoposide, nocodazole, indirubin and anthracycline derivative, comprises, such as daunorubicin, daunomycin and plicamycin.Other subclass of antimitotic agent comprise resisting mitosis alkylating agent; comprise; such as tauromustine, bofumustine and fotemustine, and resisting mitosis metabolite, comprise such as methotrexate, fluorouracil, 5-bromouracil deoxyribose, 6-nitrogen cytidine and cytosine arabinoside.Resisting mitosis alkylating agent changes DNA by covalency, RNA or albumen and affect cell division, suppresses that DNA replication dna, rna transcription, RNA translate thus, albumen synthesis or above-mentioned combination.The example of antimitotic agent includes, but not limited to paclitaxel.As used herein, paclitaxel comprises alkaloid itself and its naturally occurring form and derivant, and its synthesis and semisynthetic form.

Anti-platelet agents is treatment entity, worked by following manner: (1) suppresses platelet adhesion to surface, usual thrombosis surface, (2) anticoagulant, (3) suppress platelet activation, or the combination that (4) are above-mentioned.Hematoblastic activation is such process, by this process, platelet from static, inactive state be converted into wherein platelet experience by with thrombosis surface contact and the state of many metamorphosis of inducing.These changes comprise the change of platelet shape, along with the formation of pseudopodium, with the combination of membrane receptor, and the secretion of micromolecule and albumen (comprising such as ADP and platelet factor 4).The anti-platelet agents serving as the inhibitor of platelet adhesion comprises, but be not limited to, the peptide based on RGD (Arg-Gly-Asp) of the combination of Eptifibatide, tirofiban, suppression and gpIIbIIIa or avb3, block the antibody, the anti-palatelet-selectin antibody that are combined with gpIIaIIIb or avb3, anti-E-Selectin antibody, blocks palatelet-selectin or E-Selectin and is bonded to its compound of aglucon, orotic acid and anti-vWF antibody separately.The medicament of the platelet aggregation of ADP mediation is suppressed to include but not limited to disagregin and cilostazol.

As discussed above, at least one therapeutic agent can be antiinflammatory.The limiting examples of antiinflammatory comprises prednisone, dexamethasone, dexamethasone acetate, hydrocortisone, estradiol, triamcinolone, Mo Meitasong, fluticasone, Clobetasol and nonsteroidal anti-inflammatory, comprise, such as acetaminophen, ibuprofen, naproxen, adalimumab and sulindac.Arachidonic acid metabolite prostacyclin or prostacyclin analogue are the examples of vasoactive antiproliferative.Other examples of these medicaments comprise the medicament that blocking-up cytokine activity or the T suppression cell factor or chemotactic factor are bonded to the pro-inflammatory signal that homoreceptor is transduceed with the T suppression cell factor or chemotactic factor.The representative example of these medicaments includes but not limited to anti-IL1, anti-IL2, anti-IL3, anti-IL4, anti-IL8, anti-IL15, anti-IL18, anti-MCP1, anti-CCR2, anti-GM-CSF and anti-TNF antibody.

Anti-thrombotic agents comprises and can carry out the chemistry of intervening and biological entities in any stage of condensation approach.The example of concrete entity includes, but not limited to the micromolecule of the activity of inhibitive factor Xa.In addition, directly or indirectly can suppress the heparinoid type medicament of FXa and thrombin, comprise, such as heparin, heparin sulfate, low molecular weight heparin, comprise, such as, have the compound of trade mark Clivarin and the oligosaccharide of synthesis, comprise, such as, there is the compound of trade mark Arixtra.Also comprise direct thrombin inhibitor, comprise, the peptide mimics of the binding site of the Phe-Pro-Arg Fibrinogen substrate of such as melagatran, ximelagatran, argatroban, Inogatran and thrombin.The another kind of antithrombotic agents that can send is factor Ⅴ II/VIIa inhibitor, comprises, such as anti-factor Ⅴ II/VIIa antibody, rNAPc2 and tissue factor pathway inhibitor (TFPI).

Thrombolytics, may be defined as the medicament helping degraded thrombosis (grumeleuse), because the effect of cracking grumeleuse can help to disperse to be captured in the platelet in thrombosis fibrin matrix, so thrombolytics also can be used as adjuvant.The representative example of thrombolytics includes, but not limited to urokinase or recombinaton urokinase, prourokinase or Recombinant Pro-urokinase, tissue plasminogen activator or its recombinant forms and streptokinase.

In addition, described therapeutic agent comprises cytostatic agent.As used herein term " cytostatic agent " means to alleviate cell proliferation, allow cell migration and the medicament of not inducing cytotoxic.For the purpose of illustration and not limitation, these cytostatic agents comprise, macrolide antibiotics, Zuo Tamosi, sirolimus, rapamycin, everolimus, biolimus, myolimus, novolimus, CCI-779 (temsirolimus), deforolimus, merilimus, sirolimus derivant, tacrolimus, pimecrolimus, its derivant and analog, any macrolide immunosuppressive drug and combination thereof.Other treatment agent comprises cytotoxic drug, comprises, and such as, cell death inducer, comprises TGF, and topoisomerase enzyme inhibitor, comprises, 10-hydroxycamptothecine, irinotecan and amycin.

The example of anti-inflammatory agent comprises steroidal and NSAID (non-steroidal anti-inflammatory drug) (NSAID) such as, but is not limited to, clobetasol, alclofenac, alclometasone dipropionate, algestone acetonide (algestoneacetonide), alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, Antril (Synergen), anirolac (anirolac), anitrazafen, azapropazone, balsalazide disodium, bendazac, Benoxaprofen, benzydamine hydrochloride, bromelain, broperamole, budesonide, carprofen, cicloprofen, cinnopentazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, propanoic acid cloticasone, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone, dexamethasone dipropionate, dexamethasone acetate, dexamethasone phosphate, momentasone, cortisone, cortisone acetate, hydrocortisone, prednisone, prednisolone acetate, betamethasone, betamethasone acetate, diclofenac potassium, diclofenac sodium, two acetic acid diflorasones, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxine, drocinonide, endrisone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, Bufemid, fenclofenac, fenclorac, fendosal, it is grand to put forth energy a handkerchief, fentiazac, flazalone, L-6400, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, propanoic acid halogen Beta rope, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, Ibuprofen Piconol, ilonidap, indomethacin, Indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, Isoxepac, isoxicam, ketoprofen, sieve non-imidazole hydrochlorate, lornoxicam, Lotepredenol etabonate, meclofenamate sodium, meclofenamic acid, Meclorisone Dibutyrate, mefenamic acid, mesalazine, meseclazone, methylprednisolone suleptanate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochlorate, sodium pentosanpolysulfate, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, citric acid proxazole, rimexolone, romazarit, salcolex, Salnacedin, salsalate, Sanguinarium Chloride chloride (sanguinariumchloride), seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, Talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine (tetrydamine), tiopinac, neopentanoic acid tixocortol, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (aspirin), salicylic acid, corticosteroid, glucocorticoid, tacrolimus and pimecrolimus.

In addition or alternately, described medicament can comprise other compounds or additive, such as excipient, bonding agent, plasticizer, solvent, surfactant, additive, filler etc.The example of possible compound comprises polyvinylpyrrolidone, gelatin, maltodextrin, starch, hydroxypropyl emthylcellulose, glycerol, Polyethylene Glycol, polysorbate, tween, poloxamer, Vitamin E tocopherol polyethanediol succinate (" TPGS "), fatty alcohol, fatty acid ester, tocopherol and phospholipid.In some embodiments, when desired, these additives can be selected to regulate the rate of dissolution of crosslinked rear cross-linking compounds.In one embodiment, therapeutic agent can provide in liquid form or be dissolved in applicable solvent.In further embodiment, treatment preparation provides as microgranule, and is blended in applicable carrier, for applying as fluid.

Although describe disclosed theme herein in some exemplary, those skilled in the art will recognize that and can carry out various changes and improvements when not deviating from its scope to disclosed theme.In addition, although the independent characteristic of disclosed theme embodiment can be discussed or shows in the figure of an embodiment in this article, and do not show in other embodiments, but should be apparent that, the independent characteristic of an embodiment can with one or more feature of another embodiment or with the characteristics combination from multiple embodiment.

Except following claimed specific embodiments, disclosed theme also relates to any other other embodiments that may combine with following claimed additional characteristic feature and those disclosed above.Therefore, present in dependent claims and above disclosed special characteristic can in the scope of disclosed theme otherwise combination with one another, make disclosed theme should be regarded as also being specifically related to have any other other embodiments that may combine.Therefore, in order to the purpose of illustration and description presents the above description of the particular of disclosed theme.Itself and not intended to be are detailed or are not intended to disclosed theme to be limited to those disclosed embodiments.

Various foley's tube and sacculus construct are known and are applicable to use according to disclosed theme.For the purpose of illustration and not limitation, expandable members is made up of polymeric material, (compliant), immalleable (non-compliant) that described polymeric material is such as submissive or half submissive (semi-compliant) polymeric material or polymer blend (such as, the mixture of polymer).In one embodiment, polymeric material is submissive, such as, but not limited to polyamide/polyether block copolymer (being commonly referred to PEBA or polyether block amide).In some embodiments, the polyamide of block copolymer is connected by amide or ester bond with polyethers section.Polyamide-block can be selected from various aliphatic series known in the art or aromatic polyamides.In some embodiments, polyamide is aliphatic.Some limiting examples comprise nylon 12, nylon 11, nylon 9, nylon 6, nylon 6/12, nylon 6/11, nylon 6/9 and nylon 6/6.In some embodiments, polyamide is nylon 12.Polyether block can be selected from various polyethers known in the art.Some limiting examples of polyethers section comprise poly-(tetramethylene ether), tetramethylene ether, Polyethylene Glycol, polypropylene glycol, poly-(pentamethylene ether) and poly-(hexa-methylene ether).Also commercially available PEBA material can be utilized, such as, such as, the PEBAX material supplied by Arkema (France).Known in the art for being formed the various technology of sacculus by polyamide/polyether block copolymer.This type of example a kind of is disclosed in the U.S. Patent number 6,406,457 of Wang, and its content is incorporated to by reference.

In extra embodiment, balloon material is formed by polyamide.In some embodiments, polyamide has sizable hot strength, tolerates pin-holing (pin-holing), even after folding and unfolding, and it is normally scratch resistant, such as be disclosed in the U.S. Patent number 6 of Pinchuk, 500,148 those, its disclosure is incorporated to herein by reference.Some limiting examples being applicable to the polyamide material of sacculus comprise nylon 12, nylon 11, nylon 9, nylon 69 and nylon66 fiber.In some embodiments, polyamide is nylon 12.Polyester for building other suitable materials of immalleable sacculus, such as poly-(PETP) (PET), Hytrel thermoplastic polyester and polyethylene.

In extra embodiment, sacculus is formed by polyurethane material such as TECOTHANE (Thermedics).TECOTHANE is the thermoplastic aromatic's polyether-polyurethane from the synthesis of methylene diisocyanate (MDI), polytetramethylene ether diol (PTMEG) and BDO chain extender.TECOTHANE grade 1065D is suitable, and has the Shore hardness of 65D, the fracture rate elongation of about 300%, and the high tensile of about 10,000psi surrenders (yield).But can use other suitable grades, comprise TECOTHANE 1075D, it has the Shore D hardness of 75.Other suitable submissive polymeric materials comprise ENGAGE, and (DuPontDowElastomers (ethylene alpha-olefin polymer) and EXACT (ExxonChemical), is thermoplastic polymer both it.Other suitable submissive materials include but not limited to resilient silicone, latex and urethanes.

Submissive material can carry out crosslinked or not be cross-linked, and this depends on balloon material needed for embody rule and feature.Some polyurethane balloons material is not cross-linked.But other suitable materials such as polyolefin polymer ENGAGE and EXACT can be cross-linked.By the crosslink material making sacculus submissive, final inflated balloon size can be controlled.Conventional crosslinking technological can be used, comprise heat treatment and electron beam exposure.After crosslinked, initial press, expansion and preshrinking, sacculus is expanded to reproducible diameter in a controlled manner by response to the given bulbs of pressure subsequently, and avoids support (if for stent delivery system) excessive expansion to less desirable major diameter thus.

In one embodiment, sacculus arranges polymer (such as silicone-polyurethane copolymer) by low stretching and is formed.In some embodiments, silicone-polyurethane is ether urethanes, more specifically, it is aliphatic ether urethanes, such as PURSILAL575A and PURSILAL10 (PolymerTechnologyGroup) and ELAST-EON3-70A (Elastomedics), it is silicone polyether urethane copolymers, more specifically, is aliphatic ether urethanes copolymerized siloxanes (cosiloxanes).In an alternative embodiment, low stretching arranges polymer is diene polymer.Multiple suitable diene polymer can be used, such as, but not limited to isoprene such as AB and ABA poly-(styrene-b-isoprene), poly-(styrene-b-butadiene) the such as styrene butadiene styrene (SBS) and styrene butadiene ribber (SBR) of neoprene, AB and ABA and 1，4-polybutadiene.In some embodiments, diene polymer is isoprene, comprises isoprene copolymer and isoprene block copolymer such as poly-(styrene-b-isoprene).Suitable isoprene is styrene isoprene styrene block copolymer (SIS), such as can derive from Kraton, the Kraton1161K of Inc.But, multiple suitable isoprene can be used, comprise the HT200 that can derive from ApexMedical, the KratonR310 that can derive from Kraton and the isoprene (that is, 2-methyl isophthalic acid, 3-butadiene) of DupontElastomers can be derived from.The neoprene grade that can be used for disclosed theme comprises the HT501 that can derive from ApexMedical and can derive from the neoprene of DupontElastomers (namely, polychlorobutadiene), comprise neoprene G, W, the T and category-A type that can derive from DupontElastomers.

According to another aspect of disclosed theme, change the outer surface of sacculus.In this respect, balloon surface can comprise the surface of textured, coarse surface, space (voids), ridge column structure (spines), passage, dimple (dimples), hole or microcapsule or its combination, as described below.

In the further embodiment of disclosed theme, sacculus is formed by porous elastic material, and described porous elastic material has at least one space formed in the wall of balloon surface.Such as, the whole cross section of sacculus can contain multiple space.Or multiple space can along institute's selections distribution of sacculus outer surface.Such as unrestricted, multiple space can only distribute along the working section (workingsection) of sacculus.Space is limited to the open space in the outer surface of sacculus.In some embodiments, cross-linked compound and/or therapeutic agent disperse in the space that the multiple spaces by the cross section across sacculus outer surface limit.

In operation, after inflation, therapeutic agent, cross-linked compound or crosslinked source discharge or discharge from hole.In this respect, the hardness of the polymeric material of balloon surface, particularly void indentation enough flexible being enough to allows after inflation, discharge the therapeutic agent and/or coating that contain in multiple space.That discharges is released in lumen of vessels containing the coating of therapeutic agent or is released into around with in the tissue contacting dilatation balloon.

In an alternate embodiment, sacculus can comprise two concentric sacculus of nested configuration.In certain embodiments, cross-linked compound and/or therapeutic agent are disposed between two concentric sacculus.Or bridging property catalyst is disposed between two concentric sacculus.Therefore, the space between two concentric sacculus; One is interior sacculus, and another is outer sacculus, serves as bank.In this respect, protuberance can comprise the perforate for discharging crosslinked source such as solvent as disclosed above or cross-linking agent or discharge cross-linked compound and/or therapeutic agent after inside and outside concentric inflation.Such as, as the US6 of Hektner, 991, described in 617, it is incorporated to herein its disclosure by reference.In another embodiment, sacculus can comprise setting with the longitudinal protuberance forming ridge in balloon surface.As the U.S. Patent number 7,273 of Wang, described in 417, its whole disclosure is incorporated to herein by reference, and the long filament (filaments) that ridge can be separated by the circumference equidistant intervals around sacculus is formed.But, or the ridge of greater or lesser number can be used.Longitudinal ridge can be encapsulated wholly or in part by the polymeric material of sacculus.

In the still further embodiment of disclosed theme, sacculus can comprise microcapsule on its outer surface.In this respect, microcapsule arranges to comprise crosslinked source and/or cross-linked compound and/or therapeutic agent.After inflation, be positioned at the tissue of the microcapsule contact arterial wall on the surface of sacculus.Or microcapsule can be formed in the wall of balloon surface.Broken and/or diffuse into arterial wall from microcapsule by microcapsule, cross-linked compound and/or therapeutic agent can discharge from microcapsule.Method disclosed in the U.S. Patent number 5,1023,402 of Dror or the U.S. Patent number 6,129,705 of Grantz and the patent wherein quoted, can manufacture microcapsule, described patent is incorporated to herein by reference with its entirety separately.

According in the Additional embodiments of disclosed theme, change the surface of expandable members or sacculus, to promote that crosslinked source and/or cross-linked compound and/or therapeutic agent are deposited in balloon surface with in balloon wall film.The appropriate technology changed for this type of is disclosed in, and such as, the U.S. Patent Publication No. 2008/0113081 of the people such as Hosseiny, it is incorporated to herein by reference with its entirety.

It will be apparent to those skilled in the art that and can carry out various change and change in the method and system of disclosed theme, and do not depart from the spirit or scope of disclosed theme.Therefore, be intended to disclosed theme and be included in the modifications and variations of enclosing within the scope of claim and its equivalent.

Claims (amendment according to treaty the 19th article)

1. by therapeutic agent delivery to the system of the blood vessel wall of body cavity, it comprises:

A () has the expandable members of far-end, near-end and active section between the two;

B () is along first compound for being discharged by its intracavity after described expandable members expansion arranged at least partially of described active section;

C () is along second compound arranged at least partially of the active section of described expandable members; Described second compound can with described first compound crosslink; With

D at least one therapeutic agent that () arranges along the part of described active section;

Wherein said first compound and described second compound are configured to after described expandable members is for distended blood vessel wall crosslinked, to make described therapeutic agent temporarily be retained in described blood vessel wall.

2. the system of claim 1, wherein said first compound is arranged to the coating on described expandable members.

3. the system of claim 1, wherein said expandable members has the outer surface containing the bank be limited to wherein or hole along the part of described active section, and described second compound is arranged to intracavity release in described bank or hole.

4. the system any one of aforementioned claim, wherein said at least one therapeutic agent and described first compound combination.

5. the system any one of aforementioned claim, wherein said first compound and described second compound through selecting in case have at least 6.8 pH environment in be chemically reactive.

6. the system of claim 2, wherein said first compound is arranged to the basic unit's coating on described expandable members, and described second compound is arranged to the coating in described basic unit coating.

7. the system any one of aforementioned claim, wherein said at least one therapeutic agent is arranged to the skin of described expandable members.

8. the system any one of aforementioned claim, one or both in wherein said first compound and described second compound is selected from following hydrophilic polymer: PEG, the copolymer of PLLA and PEG, the copolymer of PLDA and PEG, the copolymer of PLGA and PEG, the copolymer of PEG, PLLA and PLDA, the copolymer of PEG, PLLA and PLGA, the copolymer of PEG, PLDA and PLGA, and combination.

9. the system any one of aforementioned claim, wherein said first compound is PEG, and described second compound is selected from PEG, peptide hydrogel and carbohydrate hydrogel, optionally, wherein said peptide hydrogel is selected from collagen protein, laminin，LN, poly-l-lysine, fibrin, Fibrinogen, gelatin and combination thereof, or described carbohydrate hydrogel is selected from alginate, hyaluronic acid and combination thereof.

10. the system any one of aforementioned claim, one or both reactive functional groups in wherein said first compound and described second compound is functionalized, optionally, wherein said functional group is selected from hydroxyl, carbohydrazide, NHS, acrylate, methacrylate, amine, mercaptan and vinylsulfone group and combination thereof.

The system of 11. claim 10, wherein said first compound is functionalized by one or more nucleophilic functional group, and described second compound is functionalized with one or more Qin electricity functional groups.

The system of 12. claim 11, wherein said first compound is PEG, and described second compound is PEG.

The system of 13. claim 10, wherein said first compound is functionalized PEG, and described second compound is selected from gelatin, hyaluronate and alginate.

The system of 14. claim 3, comprises the alkaline buffer arranged for the release of intracavity in bank further.

Claims (15)

1. by therapeutic agent delivery to the system of the blood vessel wall of body cavity, it comprises:

A () has the expandable members of far-end, near-end and active section between the two;

B (), along the cross-linked compound for being discharged by its intracavity after described expandable members expansion arranged at least partially of described active section, described cross-linked compound can be cross-linked after intracavity is released in blood vessel wall; With

C () arranges so that by the temporarily stored at least one therapeutic agent of described cross-linked compound after intracavity is released into described blood vessel wall along the part of described active section.

2. the system of claim 1, wherein said cross-linked compound is arranged on described expandable members as coating, and optionally, wherein said coating comprises the skin comprising described at least one therapeutic agent.

3. the system of claim 1, wherein said expandable members has the outer surface containing the bank be limited to wherein along the part of described active section, described cross-linked compound is arranged to intracavity release in bank, optionally, wherein said at least one therapeutic agent is arranged to intracavity release in bank.

4. the system of claim 1, wherein said expandable members has along the part of described active section the hole be limited to wherein, described cross-linked compound is arranged to by discharging in described vestibule, and optionally, wherein said at least one therapeutic agent is arranged to by discharging in described vestibule.

5. the system any one of aforementioned claim, wherein said at least one therapeutic agent and described cross-linked compound combine.

6. the system any one of aforementioned claim, wherein said cross-linked compound is cross-linked by heat treatment, optionally, wherein said cross-linked compound be equal to or higher than about 37 degrees Celsius be cross-linked, further optionally, wherein said cross-linked compound is selected from based on the extracellular matrix of the polymer of silk-Elastin-like proteins, pluronic F127, Pluronic F68, poly-NIPAAM, NIPAAM-acrylic copolymer, PEG-PEG-PLA-PEG, PLGA-PEG-PLGA, dissolving, self-assembling peptides, hydroxypropyl emthylcellulose and combination thereof.

7. the system of claim 1-5, wherein said cross-linked compound is cross-linked by melting heat process, optionally, wherein said cross-linked compound be equal to or less than about 37 degrees Celsius be cross-linked, and described system comprises thermal source by described cross-linked compound heating further higher than about 37 degrees Celsius, further optionally, wherein said cross-linked compound is selected from poly-(6-caprolactone), poly-(ortho esters), polyanhydride and combination thereof.

8. the system of claim 1-5, wherein said cross-linked compound is cross-linked by solvation, optionally, wherein said cross-linked compound is selected from poly-(esteramides), PLGA, PDLLA, PLLA, PLGA-PEG-PLGA, PLLA-PEG-PLLA, N-Methyl pyrrolidone, dimethyl sulfoxine, dichloromethane and combination thereof.

9. the system of claim 1-5, wherein said cross-linked compound is shear sensitive, so that crosslinked after removal is released into the relevant shearing of described blood vessel wall to intracavity, optionally, wherein said cross-linked compound is selected from hyaluronate sodium, sodium alginate, with lightly crosslinked hydrogel, comprise lightly crosslinked sodium alginate, hyaluronate sodium methylcellulose admixture and combination thereof.

10. the system of claim 1-5, wherein said cross-linked compound is crosslinked within the scope of the pH of about 6.8 to about 7.4, and optionally, wherein said cross-linked compound is selected from acid-soluble collagen albumen, chitosan, polyacrylic acid and combination thereof.

The system of 11. claim 1-5, wherein said cross-linked compound is cross-linked by reacting with second compound chemistry arranged at least partially of the active section along described expandable members, optionally, wherein said cross-linked compound is selected from PEGNHS ester, PEG acrylate, PEG amine, PEG sulfur alcohol, hyaluronic acid acrylate sodium, hyaluronate-sulfur alcohol, fibrin, methacrylate modified acrylate and combination thereof, and described second compound in the environment with predetermined pH with the first cross-linked compound chemical reaction, and further optionally, wherein said predetermined pH is at least about 7.

The system of 12. claim 1-5, wherein said cross-linked compound passes through photoactivated cross-linking, described system comprises light source further, optionally, wherein said cross-linked compound is PEG diacrylate, and further optionally, wherein said system comprises second compound arranged at least partially of the active section along described expandable members, described second compound is selected from 2-hydroxyl-1-[4-(hydroxyl-oxethyl) phenyl]-2-methyl isophthalic acid-acetone, PEG acrylate, methacrylate modified alginate, methacrylate modified hyaluronic acid and combination thereof.

The system of 13. claim 1-5, wherein said cross-linked compound is cross-linked by ionomer, optionally, wherein said cross-linked compound is selected from sodium alginate, pectin, aloe pectin and combination thereof, and further optionally, wherein said system comprises second compound arranged at least partially of the active section along described expandable members, and described second compound is selected from calcium chloride, barium chloride and combination thereof.

System any one of 14. aforementioned claim, wherein said at least one therapeutic agent is selected from antithrombotic agents, anticoagulant, anti-platelet agents, anti-lipid agent, thrombolytics, antiproliferative, antiinflammatory, Inhibiting proliferation agent, smooth muscle cell inhibitors, antibiotic, growth factor receptor inhibitors, cell adhension inhibitors, cell adhesion promoter, antimitotic agent, antifibrin agent, antioxidant, antineoplastic agent, promote the medicament that endotheliocyte recovers, antiallergic material, viral vector, nucleic acid, monoclonal antibody, antisense compounds, oligonucleotide, cell permeation enhancers, radiopaque medium labelling, HMGCoA reductase inhibitor, prodrug and combination thereof.

15. by therapeutic agent delivery to the method for the blood vessel wall of body cavity, it comprises:

System any one of aforementioned claim is provided;

Expandable members is positioned in body cavity;

Described expandable members is expanded to contact described blood vessel wall for cross-linked compound intracavity is released into described blood vessel wall; With

Make the described cross-linked compound in described blood vessel wall and be cross-linked, for delivery to described blood vessel wall by the temporarily stored at least one therapeutic agent of described cross-linked compound.