CN102657900A - Medicine balloon based on hydrogen bond effects and coating method thereof - Google Patents

Abstract

The invention relates to the medical instrument field, and concretely relates to a medicine balloon based on a hydrogen bond effect. The medicine balloon comprises a balloon surface and a medicine coating containing active medicines, wherein the balloon surface is processed or modified to have hydrophilic groups, and the hydrogen bond effects exist between the balloon surface and the medicine coating. The invention also relates to a coating method of the medicine balloon. The hydrogen bond effects which increase the adhesion force between the medicine coating and the balloon surface guarantee the ductility of the coating, and are benefit for loading the medicines on the balloon surface.

Description

A kind of medicinal balloon and coating process thereof based on hydrogen bond action

Technical field

The present invention relates to medical instruments field.More specifically, the present invention relates to a kind of medicinal balloon and coating process thereof based on hydrogen bond action.

Background technology

Since the seventies in last century, the sacculus plasty is widely used in treating the angiostenosis that is caused by atherosclerosis in tube chamber.Though the immediate treatment effect of sacculus plasty is satisfactory, its postoperative complication is the incidence rate height of restenosis particularly, limits it in Clinical Application.

The endovascular stent plasty is narrow positions implant frame (can be bare bracket or drug stent) in balloon expandable; Support can significantly reduce the acute or subacute ischemia complication of interventional therapy to the restenosis that anti-angiogenic layering and elastical retraction are caused.Yet clinical effectiveness analysis for many years shows that still there are some complication in this technology, and for example inflammation, tunica intima are torn, vascular endothelial proliferation etc., thereby possibly cause vascular restenosis.

The medication coat sacculus is the emerging means that are used for intracavitary therapy that occur in recent years, and it has avoided medicine to continue the endothelialization obstacle that contact is caused, medication coat sacculus or shown good prospect based on its naked metal rack of medication coat sacculus.

(name of product: SeQuent Please) so far, existing a plurality of medicinal balloons go on the market in Europe to release first generation medicinal balloon from Bei Lang.The crucial part of medicinal balloon is how to realize the effective adhesive that has between medication coat and the balloon surface.If the cohesive force between medication coat and the balloon surface is less, then sacculus is prone to come off in folding process, or in implanting the course of conveying of lesions, loses, or in contact expansion process before with target lesion tissue, breaks and come off and be flushed away.A research focus of current medicinal balloon is the coating process of development novel medicament.

The application people relates to a kind of sacculus dilating catheter of carrying medicaments for the patent application No.200910084768.0 (publication number CN101549186) of Tiandihexie Science and Technology Co. Ltd., Beijing.Said sacculus dilating catheter comprises sacculus and is coated in the multiple medicine on the sacculus, it is characterized in that, a kind of in the said medicine is probucol.Because probucol not only can increase medicine greatly by the absorbance of blood vessel inner cell; Can also reduce the loss of other medicine in the blood transport process simultaneously; The described sacculus dilating catheter that carries multiple medicine of this application is compared with existing sacculus dilating catheter; The better effects if of its prevention and treatment restenosis is particularly suitable for treating the intrastent restenotic lesions of blood vessels such as coronary artery, carotid artery, renal artery, perhaps replaces existing drug stent; Treat that constitutional pathological changes stenosis is lighter clinically, the slight disease of narrow blood vessel negligible amounts etc.One of the coated medicament that focuses on of this patent application is a probucol, and unexposed or the hint through hydrogen bond action power medicine and additive firmly are coated in balloon surface.

The application people relates to the medication coat that a kind of alleviating vascular restenosis is coated in the foley's tube balloon surface for the patent application No.200710150413.8 (publication number CN101264347) of Tianjin Baichang Medical Equipment Science & Technology Co., Ltd., particularly a kind ofly alleviates the postoperative vascular restenosis is coated in balloon surface in the foley's tube with the minimizing radical damage medication coat.This medication coat is made up of the medicine of 1%-99% and the pharmaceutical carrier of 1%-99%, and described medicine can be selected single plant mixing, list kind or the multiple anti-oxidation medicine of anti-oxidation medicine, multiple anti-oxidation medicine and mixing of anti-angiogenic restenosis class drug regimen.And adopt mixing or layering coating method medicine to be coated in equably on the surface of air bag, through local application, can alleviate effectively and reduce because of the final realization treatment of the damage of radical pair human body cell and tissue behind myocardial ischemia-reperfusion cardiac dysfunction.The combination that focuses on medicine and carrier of this patent application, and unexposed or the processing of hint balloon surface or modification and interpolation low-molecular-weight hydrophilic additive.

The application people relates to a kind of medicinal balloon catheter and preparation method thereof for the patent application No.201010121627.4 (publication number CN101785900A) of Chengdu dimension moral medical apparatus and instruments Co., Ltd.The sacculus outer surface of this medicinal balloon catheter is for having concavo-convex nonplanar structure.This medicinal balloon catheter adopts Ultra-Violet Laser grinding sacculus outer surface, the sacculus outer surface is formed have concavo-convex nonplanar structure.Because contactless, the no processing heat characteristics of laser grinding, processed balloon still keeps original intensity.This medicinal balloon catheter since the sacculus outer wall surface for having concavo-convex nonplanar structure; Therefore medicine absorption storage capability is obtained the improvement of essence; The one, the amount of absorption medicine greatly increases, and the 2nd, through in the process that arrives diseased region, the medicine that can keep as far as possible being adsorbed on the sacculus outer wall can not washed loss by the blood in the blood vessel to the medicine of sacculus absorption in blood vessel; Can effectively be transported to diseased region, play the efficacious therapy effect through sacculus.This medicinal balloon catheter not only can be applicable to coronary heart disease, and the various diseases that also narrows down applicable to other various pipelines is like the narrow and obstruction of artery of lower extremity that causes owing to diabetes.Focusing on of this patent application, for improving drug loading, the sacculus outer surface of said medicinal balloon catheter is for having concavo-convex nonplanar structure.

The application people relates to a kind of novel foley's tube that carries medicament microcapsule for the patent application No.200920268650.9 (publication number CN201524344U) of Donguan Dikai Precision Pipe Co., Ltd..This foley's tube is by proximal tube, distal tube, sacculus, medicament microcapsule and most advanced and sophisticated flexibly the composition, and sacculus is the folding sacculus of a Memorability, and uses special infiltration technology medicament microcapsule to be wrapped in the gauffer inner surface of collapsible sacculus.Wherein, collapsible sacculus can be two lobes, three lobes, the folding sacculus of five lobes, but the medicine of medicament microcapsule parcel is the Chinese medicine extract of treatment of vascular restenosis, like the Radix Salviae Miltiorrhizae water extract, after concentrating, adds corresponding adjuvant, processes powder shape medicament microcapsule.This utility model has to strengthen carries drug targeting property, can accurately locate, regularly slowly discharge medicine, has realized the purpose of long-acting treatment, fundamentally the advantages such as generation of treatment of vascular restenosis.This utility model focus on adopting the folding packaging medicine.

In order to improve the performance of medicinal balloon, prior art has carried out improving design from many aspects such as medicine and balloon structure.Yet, still need from other aspects, for example balloon surface and medicine combines the seeking breakthrough mouth.

Summary of the invention

The present invention provides a kind of medicinal balloon based on hydrogen bond action; Comprise balloon surface and the medicine layer that contains active medicine; Wherein said balloon surface makes it be with hydrophilic radical, and has hydrogen bond action between said balloon surface and the said medicine layer through handling or modifying.

Make it have more hydrophilic groups through active medicine being carried out structural modification; And/or further contain the additive of being with hydrophilic radical through medicine layer; Make and have hydrogen bond action between balloon surface and the medicine layer; Thereby the increase cohesive force keeps the ductility of coating, and is beneficial to the load of medicine in balloon surface.

The present invention also provides a kind of medicinal balloon coating process based on hydrogen bond action, comprising: balloon surface is handled or modified, make it to have hydrophilic radical; The additive of active medicine and optional band hydrophilic radical is dissolved in forms mixed solution in the organic solvent; With mode mixed solution is coated to balloon surface, forms medication coat through spraying or dipping.

According to the present invention, for balloon surface, under the prerequisite of the physics and chemistry that does not influence the balloon material matrix, mechanical property, its surface is handled or modified, make it to have hydrophilic radical, increase hydrophilic.The nylon that said balloon material is known for this research field personnel, Pebax, macromolecular materials such as polyethylene.

Preferably, surface modification of low temperature plasma is carried out on the expandable balloon surface, balloon material is introduced various hydrophilic groups such as amino, hydroxyl, carboxyl at material surface after ammonia, oxygen, water Cement Composite Treated by Plasma.

Preferably, balloon material is placed ozone atmosphere, make its surface introduce one deck peroxide reactive group.

Preferably, utilizing high-energy radiations such as a, β, gamma-rays and x ray to make material surface or body produce free radical or Ionized active center, is that reaction site is carried out glycerol polymerization or idol with the active group, makes the surface have hydrophilic group.

Preferably, utilize ultraviolet light or visible light (wavelength 200-800nm) irradiation material surface, make material surface produce the polymerization activity center, thereby introduce corresponding hydrophilic functional group.

Preferably, apply such as electronegative property resins such as polycarboxylic acids or polycarboxylic acid derivants, form the resin bed of band hydrophilic radical in balloon surface.

Preferably, said polycarboxylic acids can be selected from one or more of polymer, starch, cellulose, alginic acid, pectin etc. of acrylic acid, methacrylic acid, maleic acid, aspartic acid or glutamic acid.

Preferably, said active medicine is a fat-soluble medicine.Preferably, said fat-soluble medicine is selected from one or more in cancer therapy drug, anticoagulant, microorganism immunosuppressant and other the anti-restenosis medicaments, includes but not limited to paclitaxel, rapamycin or derivatives thereof etc.

Said cancer therapy drug selects one or more in white methotrexate, purine class, miazines, plant bases, epothilones, Radix Tripterygii Wilfordii series compound, antibiotic (particularly actinomycin D), hormone, the antibody curing cancer drug.Preferably, said plant alkaloid kind anti-cancer drugs thing is a paclitaxel.

Said anticoagulant is selected from heparin, aspirin, hirudin, colchicine, antiplatelet GP IIb/IIIa receptor and ties in the anti-agent one or more, and said antiplatelet GP IIb/IIIa receptor is tied anti-agent and is selected from tirofiban, abciximab, the eptifibatide one or more.

Said microorganism immunosuppressant is selected from Ciclosporin A, tacrolimus and homologue, takes off spergualin, among the bacterial strain FR900523 of the bacterial strain FR900520 of enzyme phenolic acid fat, rapamycin and derivant thereof, streptomycete kind, streptomycete kind, daclizumab, pentanamide, Kanglemycin C, spergualin, prodigiosin 25c, tranilast, myriocin, ciclosporin C, bredinin, Mycophenolic Acid, brefeldin A, ketone corticosteroid one or more.

Said other anti-restenosis medicaments be selected from batimastat, inhibitors of metalloproteinase, 17 beta estradiols, NO donor, 2-chlorine Deoxyadenosine, 2-deoxycoformycin, Fen Gemode, wheat examine phenol sodium, ring spore A derivative I SA (TX) 247, Ai Saibu can, in the Zenapax, basiliximab, anti-thymus globulin, everolimus, methotrexate, Nei Aolaer, cyclophosphamide, brequinar sodium, leflunomide, mizoribine one or more.

Preferably, said active medicine carries out chemical constitution to it and modifies under the prerequisite that does not influence drug effect, as through esterification, amidatioon, salify modification, ring formation or open loop modification etc. to drug molecular structure, makes the pharmaceutical chemistry structure have more hydrophilic group.

Preferably, said additive mainly is a hydrophilic organics hydrophilicity, includes but not limited to contain hydroxyl-OH, amino-NH₂, amide groups-CONH-, sulfonic group-SO₃The Organic substance soluble in water of one or more functional groups of carboxylic acids such as H, carboxylic acid group-COOH.

Preferably, said additive is water miscible, less than non-ionic water-soluble polymer of 50000 etc., includes but not limited to PVP, PEG (Mn＜5000), PEO, Tween20, PEO-PPO-PEO, PVA, polyureas, polyester etc. like molecular weight.

Preferably, said additive is the bio-soluble plasticiser, and except that cohesive force improved, plasticiser also can increase the ductility of coating, prevents the embrittlement of sacculus at folding or expansion process floating coat.Said additive comprises but is not limited to triethyl citrate, citric acid three own esters, cyclohexane extraction-1, one or more of 2-dicarboxylic acids dinonyl, ethyl lactate, benzyl alcohol, citric acid, three acetic anhydride oils and fatss etc.

Preferably; Said additive is materials such as monosaccharide, polysaccharide, cellulose; Some monosaccharide can reduce the hygroscopicity influence that the hygroscopicity additive produces active medicine; Some anion polysaccharide can also increase the adhesive attraction between medicine and the cell, and some water-soluble cellulose can increase the strength and toughness of coating.Said additive comprises but is not limited to glucosan, sulfonation glucosan, hyaluronate sodium, hyaluronic acid, pectin, mannitol, methylcellulose, vinyl cellulose, hydroxypropyl cellulose etc.

Preferably, the weight ratio of said active medicine and additive is 1: between the 0.01-50.Preferably, weight ratio is 1: between the 0.1-3.

Preferably; Said active medicine and additive are dissolved in and form mixed solution in the organic solvent, and said organic solvent includes but not limited to the mixture of one or more and water of methanol, ethanol, acetone, oxolane, dimethyl formamide, isopropyl alcohol, acetonitrile, ethyl acetate etc.

Preferably, described medication coat can be coated on the balloon surface through the mode of spraying or dipping.

In a specific embodiment; Expandable balloon of the present invention surface is provided with the medicine layer of being made up of active medicine and additive, wherein before pharmaceutical pack is layed onto balloon surface, balloon surface is handled or is modified; Make it be with hydrophilic radical; Select hydrophilic additive simultaneously, thereby utilize the hydrogen bond action between balloon surface and the additive, increase the cohesive force between medicine layer and the balloon surface.In another embodiment; Under the prerequisite that does not influence drug effect; Active medicine is directly carried out chemical constitution to be modified; Make its pharmaceutical chemistry structure have more hydrophilic group, thereby utilize the hydrogen bond action between balloon surface and the active medicine, increase the cohesive force between medicine and the balloon surface.To a kind of embodiment in back, if desired, can add above-mentioned various additive in the medicine layer, its effect also can be expected.

Description of drawings

In order more clearly to describe technical scheme of the present invention, will combine accompanying drawing to briefly introduce below.Obviously, these accompanying drawings only are some specific embodiment that the application puts down in writing, and do not mean it is limited.

Fig. 1 illustrates the optics Electronic Speculum figure of the medicinal balloon a of embodiment 1; With

Fig. 2 illustrates the optics Electronic Speculum figure of the medicinal balloon b of embodiment 1.

The specific embodiment

In order further to understand the present invention, will combine embodiment that preferred version of the present invention is described below.These descriptions just illustrate feature and advantage of the present invention, and unrestricted protection scope of the present invention.

Embodiment 1

The paclitaxel of 75mg, the citric acid of 30mg three own esters, (acetone: water=7.5: 1), ultrasonic 10min forms finely dispersed mixed solution to be dissolved in 4ml acetone and aqueous solution.

Above-mentioned solution is sprayed on respectively on the nylon based sacculus (3.0*20) that 5 surfaces do not process, makes drug loading reach 3 μ g/mm²About, oven dry, folding, obtain medicinal balloon a.

Above-mentioned solution is sprayed on 5 respectively carries out the nylon based balloon surface (3.0*20) that plasma oxygen is handled 5min in advance, make drug loading reach 3 μ g/mm²About, oven dry, folding, obtain medicinal balloon b.

Through the electron microscopic observation sacculus, find that medicinal balloon a has a little medicine obscission in the sacculus folding process, when folding sacculus a was reexpanded out, the sacculus burst also had medicine obscission (as shown in Figure 1); Medicinal balloon b no medicine in folding process comes off, the back balloon surface that reexpands out smooth evenly (as shown in Figure 2).

Embodiment 2

The nylon based sacculus is carried out ozonation treatment 10min, balloon surface is had-the O-O group; With the paclitaxel of 75mg and the PEG of 45mg (Mw＜5000) be dissolved in 4ml acetone and ethanol (acetone: form mixed liquor ethanol=3: 1), with above-mentioned solution spraying in balloon surface, oven dry, folding, can obtain medicinal balloon.

Embodiment 3

The nylon based sacculus is carried out X ray handle 3min; With the rapamycin of 75mg and the PEG of 45mg (Mw＜5000) be dissolved in 4ml acetone and ethanol (acetone: form mixed liquor ethanol=3: 1), with above-mentioned solution spraying in balloon surface, oven dry, folding, can obtain medicinal balloon.

Embodiment 4

Utilize the irradiation under ultraviolet ray Pebax base balloon surface 5min of wavelength for 400nm; With the glycerol of the rapamycin of 37.5mg and 30mg be dissolved in 2-4ml acetone and water (acetone: form mixed liquor water=7.5: 1), with above-mentioned solution spraying in balloon surface, oven dry, folding, can obtain medicinal balloon.

Embodiment 5

Under the room temperature, Pebax base sacculus is soaked in the acrylic acid aqueous solution of 1mol/L among the 10min vacuum drying; With the PVP of the rapamycin of 75mg and 30mg be dissolved in 4ml acetone and water (acetone: form mixed liquor water=7.5: 1), with above-mentioned solution spraying in balloon surface, oven dry, folding, can obtain medicinal balloon.

No medicine comes off in the medicinal balloon folding process of embodiment 2-5, and the back balloon surface that reexpands out is smooth evenly, has obtained the effect same with the medicinal balloon b of embodiment 1.

The explanation of above embodiment just is used for helping to understand core concept of the present invention.Should be pointed out that for those of ordinary skill in the art, under the prerequisite that does not break away from the principle of the invention, can also carry out some improvement and modification, but these improvement and modify also fall in the scope that claim of the present invention asks for protection the present invention.

Claims (9)

1. medicinal balloon based on hydrogen bond action; Comprise balloon surface and the medicine layer that contains active medicine; Wherein said balloon surface makes it be with hydrophilic radical, and has hydrogen bond action between said balloon surface and the said medicine layer through handling or modifying.

2. the medicinal balloon of claim 1, wherein said medicine layer also contains the additive of being with hydrophilic radical.

3. claim 1 or 2 medicinal balloon, wherein said active medicine is modified through chemical constitution, under the situation that does not influence drug effect, has more hydrophilic radical.

4. each medicinal balloon of aforementioned claim, wherein the material of sacculus is selected from nylon, Pebax and polyethylene.

5. each medicinal balloon of aforementioned claim, wherein said active medicine is a fat-soluble medicine, includes but not limited to paclitaxel, rapamycin or derivatives thereof.

6. medicinal balloon coating process based on hydrogen bond action comprises:

Balloon surface is handled or modified, make it to have hydrophilic radical;

The additive of active medicine and optional band hydrophilic radical is dissolved in forms mixed solution in the organic solvent;

Mode through spraying or dipping is coated to balloon surface with mixed solution, forms medication coat.

7. the method for claim 6, the step of wherein balloon surface being handled or modifying is selected from:

(1) surface modification of low temperature plasma is carried out on the expandable balloon surface, balloon material is introduced amino, hydroxyl, carboxylated hydrophilic group at material surface after ammonia, oxygen, water Cement Composite Treated by Plasma;

(2) balloon material is placed ozone atmosphere, make its surface introduce one deck peroxide reactive group;

(3) utilizing a, β, gamma-rays and x ray to make material surface or body produce free radical or Ionized active center, is that reaction site is carried out glycerol polymerization or coupling with the active group, makes the surface have hydrophilic group;

(4) utilize ultraviolet light or radiation of visible light material surface, make material surface produce the polymerization activity center, thereby introduce corresponding hydrophilic functional group; With

(5) apply electronegative property resin polycarboxylic acids or polycarboxylic acid derivant in balloon surface, form the resin bed of band hydrophilic radical.

8. claim 6 or 7 method, wherein said additive contain for (1)-OH ,-NH₂,-CONH-,-SO₃H ,-Organic substance soluble in water of one or more functional groups of COOH; Preferred molecular weight includes but not limited to PVP, PEG (Mn＜5000), PEO, Tween 20, PEO-PPO-PEO, PVA, polyureas, polyester less than 50000 non-ionic water-soluble polymer; (2) bio-soluble plasticiser includes but not limited to triethyl citrate, citric acid three own esters, cyclohexane extraction-1,2-dicarboxylic acids dinonyl, ethyl lactate, benzyl alcohol, citric acid, three acetic anhydride greasy one or more; And/or (3) monosaccharide, polysaccharide and cellulose, include but not limited to glucosan, sulfonation glucosan, hyaluronate sodium, hyaluronic acid, pectin, mannitol, methylcellulose, vinyl cellulose, hydroxypropyl cellulose.

9. each method of claim 6-8, the weight ratio between wherein said active medicine and the additive is 1: between the 0.01-50, be preferably 1: between the 0.1-3.

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