CN103611212A - Drug balloon preparation method - Google Patents
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Abstract
The invention relates to a drug balloon preparation method. The method includes performing hydrophilic pretreatment on the surface of a balloon; adhering a first water-soluble additive solution on the surface of the balloon to obtain a modified balloon, wherein the first water-soluble additive solution contains at least one of hydroxy, amino and carboxyl; brushing drug crystals on the surface of the modified balloon, or rolling the modified balloon on the drug crystals until the drug crystals adhered on the surface of the modified balloon reach needed weight, and obtaining the drug balloon after drying, wherein a preparation method of the drug crystals include adding a second water-soluble additive in a mixed solution of a drug, an organic solvent and water, stirring for dissolving, standing, filtering, and drying to obtain the drug crystals, and the second water-soluble additive contains at least one of hydroxy, carboxyl and amino and has effect of dispersing, plastifying and improving cellular affinity. The drug balloon preparation method is simple, efficient, stable, simple and convenient in operation and quick.
Description
Technical field
The present invention relates to the preparation method of medical apparatus and instruments, refer in particular to a kind of preparation method of medicinal balloon.
Background technology
Coronary heart disease is one of modal heart disease, refers to the myocardial dysfunction or the organic disease that because of coronary stricture, blood supply insufficiency, cause, therefore claim again ischemic cardiomyopathy.Its cause of disease be the coronary artery tube wall formation atheromatous plaque due to supply heart itself cause lumen of vessels narrow due to heart change.
At present, coronary heart disease mainly contains Drug therapy, interventional therapy and three kinds of therapeutic schemes of Cardiac Surgery bypass surgery.Drug therapy is the most basic treatment, once patient makes a definite diagnosis, Drug therapy will maintain all the life.But when medication effect is good enough or invalid, should not do as early as possible coronary angiography, Coronary Artery Lesions is made to detailed evaluation, then according to patient's Coronary Artery Lesions situation, determine whether to select interventional therapy or bypass surgery.Bypass surgery is reliable for effect, but needs open chest surgery, and wound is larger, and recovery time is longer.Interventional therapy wound is little, recovery is fast, can eliminate rapidly coronary stricture, alleviate myocardial ischemia, and shortcoming is that cost is large.
The blood vessels such as coronary artery are in the postoperative vascular restenosis problem that occurs of interventional therapy, it is the puzzlement to clinical interventional technique, new technique-medicine-coated balloon (the Drug Coated Balloons that had occurred in the last few years the postoperative vascular restenosis of prevention interventional therapy, be called for short: DCB), obtained good clinical application effect.
Medicine-coated balloon is the novel therapeutic sacculus drug release technology growing up on the interventional technique bases such as balloon dilatation or Balloon Angioplasty, it is by anti-proliferative medicine, as paclitaxel, coating is in balloon surface, when sacculus arrive lesion vessels wall softened, expansion, while contacting with blood vessel wall inner membrance, by tearing, blood vessel wall inner membrance pressurization discharge fast, the technology of diversion medicaments in local vessel wall, medicine plays the effect of anti-angiogenic neointimal hyperplasia in part, thus the vascular restenosis after prevention vascular procedure.
Medicine intravasation tissue has three kinds of approach: one, inflation medicine discharges from coating surface, makes medicine dissolve and enter in endo cell fast under the effect of cosolvent; Two, inflation tear portion inner membrance, medicine enters the gap of tearing from balloon surface coating shedding, thereby plays the long-term drug action that slowly discharges; Three, medicament contact vascular wall tissue, contacts with the esterophilic site of cell, and sticks on cell wall, and at this moment blood is difficult to medicine to wash away, thereby plays the effect of long-term release drug effect.
If the adhesion between the medicine of balloon surface and sacculus a little less than, medicine easily enters targeting moiety at sacculus and even in course of conveying, easily by blood, is washed away; Medicine can not fully contact fully adhesive bond of ，Qie Yu vascular tissue esterophilic site with target vessel tissue, measure less; Medicine and target vessel organize esterophilic site adhesion time too short; Above factor all can cause medicine to be difficult to be organized Cell uptake, can not play good bioavailable degree.That is to say, the factor that affects medicinal balloon bioavailable degree mainly contains three: 1. the adhesion of medication coat and balloon surface; 2. the number of medicine and cells of vascular wall esterophilic point Exposure; 3. medicine sticks to the time length on vascular wall tissue.
Therefore, be necessary to provide a kind of preparation method of medicinal balloon to improve the bioavailable degree of medicine.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of method that technique is prepared medicinal balloon of brushing of using, the coating medicine carrying technique of can either provide easy, quick, dose is controlled, make medicine firmly stick in balloon surface, reduce the loss of medicine in course of conveying, can improve again medicine and arrive the bioavailable degree after targeting moiety, increase the long-term drug action of medicine.
Solving the technical scheme that technical problem of the present invention adopts is: a kind of preparation method of medicinal balloon is provided, and this preparation method comprises the following steps:
Balloon surface is carried out to hydrophilic pretreatment;
The first water-soluble additives solution is attached in balloon surface, obtains modification sacculus;
In this modification balloon surface, brush medicine crystal, or, by this modification sacculus roll-in on medicine crystal, until be attached to the medicine crystal of described modification balloon surface, reach required weight, after being dried, obtain this medicinal balloon;
The preparation of described medicine crystal comprises: in the mixed solution of medicine, organic solvent and water, add the second water-soluble additives, and stirring and dissolving, standing, filter dry making;
Described the first water-soluble additives contains at least one in hydroxyl, amino, carboxyl, utilizes the intermolecular larger Van der Waals force of medicine and the first water-soluble additives, reaches the effect that increases medicine and balloon surface adhesion property; Described the second water-soluble additives contains at least one in hydroxyl, carboxyl, amino, and has dispersion, plasticising, the effect of raising cellular affinity.
Compared with prior art, the present invention possesses following advantage:
(1) preparation method of the present invention is before whitewashing coating to balloon surface, first carry out surface modification pretreatment, balloon surface hydrophilic is improved, and the binding ability between the first water-soluble additives strengthens, and then improve the bond strength between balloon surface and drug-loaded layer, make balloon surface carry enough medicines;
(2) the present invention first applies the first water-soluble additives in balloon surface before carrying medicament, and follow-up drug solution is disperseed better in balloon surface, and crystallization is more even;
(3) the present invention is by controlling kind, consumption and the concentration of the second water-soluble additives, synergism with temperature, mode, time in drug crystallization process, reach the object of controlling taxol drug crystal crystal formation and particle diameter, the drug crystal forms of the medicinal balloon area load of preparation is regular, moderate dimensions, had both guaranteed that the dose that balloon surface is carried arrived targeting moiety more fast and effectively; Also the bioavailable degree of medicine and the effect that discharges for a long time drug effect have been improved greatly;
(4) the medicinal balloon coating that prepared by the present invention firmly, even, dose is accurately controlled, is conducive to reduce medicine and by blood, rinsed the loss rate causing in course of conveying;
(5) preparation technology of the present invention is simple, efficient, stable, easy and simple to handle, quick.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described, in accompanying drawing:
Fig. 1 is undressed balloon surface shape appearance figure.
The balloon surface shape appearance figure of Fig. 2 for processing through alcoholization.
Fig. 3 is the balloon surface shape appearance figure through Low Temperature Plasma Treating.
Fig. 4 is medicine crystal SEM(500 times) photo.
Fig. 5 is balloon surface coating pattern SEM(1000 times after whitewashing coating process processing) photo.
Fig. 6 is balloon surface coating pattern SEM(2000 times after whitewashing coating process processing) photo.
Fig. 7 is the pig arteria coronaria drug release kinetics curve comparison diagram of the embodiment of the present invention 1～6 and commercially available prod.
The specific embodiment
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
The invention provides a kind of preparation method of medicinal balloon, this preparation method comprises the following steps:
Balloon surface is carried out to hydrophilic pretreatment;
The first water-soluble additives solution is attached in balloon surface, obtain modification sacculus, described the first water-soluble additives contains at least one in hydroxyl, amino, carboxyl, utilize the intermolecular larger Van der Waals force of medicine and the first water-soluble additives, reach the effect that increases medicine and balloon surface adhesion property;
In this modification balloon surface, brush medicine crystal, or, by this modification sacculus roll-in on medicine crystal, until be attached to the medicine crystal of described modification balloon surface, reach required weight, after being dried, obtain this medicinal balloon; The preparation method of described medicine crystal comprises: in the mixed solution of medicine, organic solvent and water, add the second water-soluble additives, and stirring and dissolving, standing, filter dry making; Described the second water-soluble additives contains at least one in hydroxyl, carboxyl, amino, and has dispersion, plasticising, the effect of raising cellular affinity.
Preferably, this hydrophilic pretreatment is that low-temperature plasma is processed or alcoholization is processed, this low-temperature plasma is processed and is comprised: selecting gas purity is 90～99.9999% nitrogen, oxygen, argon and/or helium, in temperature, be-40～10 ℃, air pressure is under 1～100Pa, to carry out plasma treatment 5 seconds～30 minutes; This alcoholization is processed and is comprised: it is in 1～99% alcoholic solution that sacculus is immersed to volumetric concentration, at the temperature of 30～70 ℃, under the condition that is 40～100KHz ultrasonic 5～100 minutes, takes out and is dried in frequency.
Preferably, the concentration of this mixed solution Chinese medicine is 5～60mg/ml; The concentration of this first water-soluble additives solution is 1～100mg/ml; This first water-soluble additives is that molecular weight ranges is at nonionic micromolecular compound or the oligomer of 200～5000D, this second water-soluble additives be molecular weight ranges at the organic micromolecule compound of 50～1000D, the concentration in this mixed solution is 5～80mg/ml.
Preferably, this first water-soluble additives is selected from one or more in Polyethylene Glycol, polylysine, poloxamer, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol oxide or polyacrylate.
Preferably, this second water-soluble additives is selected from Tween 80, mannitol, sorbitol, potassium sorbate, tryptophan, methionine, L-Phe, phenylalanine, leucine, L-threonine, Valine, ILE, glutamic acid, lysine or amino acid derivatives, sodium benzoate, salicylic acid, sodium aminosalicylate, sodium ferulate, meglumine, nicotiamide, acetamide, vitamin A
1, vitamin A
2, vitamin A
3, vitamin B
1, vitamin B
2, vitamin B
3, vitamin C
1, vitamin C
2, vitamin C
3or one or more in para-amino benzoic acid.
Preferably, this medicine is that anti-neointimal hyperplasia medicine, anticoagulation medicine, the antiplatelet that is used for the treatment of vascular restenosis adheres to medicine, anti-infectives, antibacterials or antitumor drug.
Preferably, this medicine is selected from one or more of rapamycin and derivant, dexamethasone, paclitaxel, taxol, class Ramulus et folium taxi cuspidatae, docetaxel, probucol, colchicine, heparin, warfarin sodium, vitamin K antagon, aspirin, prostaglandin, salvianolic acid, nitric acid lipid drug, aspisol, persantin, ampicillin, cephamycin, sulfadiazine, streptomycin sulfate, chitosan and derivant thereof, cefoxitin, nalidixan, pipemidic acid, daunorubicin, amycin, carboplatin, macrolide apoplexy due to endogenous wind.
Preferably, this organic solvent is selected from diox, dimethyl formamide, dimethyl sulfoxide, N-Methyl pyrrolidone, acetonitrile, N, at least one in N-dimethyl acetylamide, oxolane, acetone, methanol, ethanol, butanols or normal heptane, in the mixture of this organic solvent and water, the volume ratio of organic solvent and water is 99～50:1～50.
Preferably, this standing temperature is-30～30 ℃, and the time is 5～24 hours.
Preferably, described paclitaxel is the regular crystal of long rod shape, and particle diameter is 1～4 micron, and grain length is 20～40 microns.
By a plurality of embodiment, illustrate below the aspect such as performance and preparation method thereof of medicinal balloon.
In following examples, all use high performance liquid chromatography (HPLC) to carry out the medicament contg test of medicinal balloon, test condition is: chromatographic column model is Kromasil C18, aperture 5 μ m, cylinder sizes 200mm * 4.6mm; Mobile phase is methanol: acetonitrile: water=1:2:2; Column temperature is 30 ℃; Detection wavelength is 227nm; Flow velocity is 1ml/ minute.
Embodiment 1
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Employing low-temperature plasma is processed, and the model of selecting Yantai Jin Ying Science and Technology Ltd. to produce is GDR-200PR plasma cleaner, selects nitrogen, temperature-40 ℃, and output is 500W, and frequency is 50MHz, and the processing time is 15 minutes, and air pressure is 100Pa;
(2) PEG2000 is dissolved in ethanol/water (volume ratio 99:1) and obtains 40mg/ml solution, the inflated that step (1) is obtained expands to 8atm, immerses in above-mentioned solution 1 minute, naturally dries, and obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 40mg/ml in the mixed solution of methanol/water (volume ratio is 85:15), in the above-mentioned paclitaxel solution of 10ml, add 250mg sodium benzoate 10 revs/min of stirring and dissolving, under room temperature standing 24 hours, filter to obtain solid, naturally dry, obtain medicine crystal, be long rod shape regular, approximately 1～3 micron of particle diameter, approximately 30 microns of grain lengths;
(4) the modification balloon surface that obtains in step (2) is brushed the medicine crystal that step (3) obtains, and weighs and repeats to brush 4 times until reach required drug weight, naturally dry, and flap coiling, packaging sterilizing, obtains medicinal balloon I.
After measured, the medicinal balloon content of taxol of embodiment 1 preparation is 545 μ g, and calculating surperficial paclitaxel unit are content is 2.89 μ g/mm
2.
The computing formula of required dose is: M=(C * S)/W; Wherein,
M: required total dose, unit is g;
C: the medicine density of balloon surface, unit is μ g/mm
2, scope is 1～5 μ g/mm
2;
S: balloon surface Ji， unit is mm
2;
W=drug quality/(drug quality+the second water-soluble additives quality).
Fig. 1 is undressed balloon surface shape appearance figure, and its surface is very smooth.
The balloon surface shape appearance figure of Fig. 2 for processing through alcoholization, can find out that its surface becomes coarse, and specific surface area increases, and hydrophilic improves.
Fig. 4 is 500 times of SEM collection of illustrative plates of taxol drug crystal, can find out its regular crystal forms.
Fig. 5 is 1000 times of SEM collection of illustrative plates of balloon surface coating pattern after whitewashing coating, can find out medicinal balloon face coat regular crystal forms prepared by the present invention, be of a size of 20～30 microns.
Fig. 6 is the 2000 times of SEM collection of illustrative plates of balloon surface coating pattern after whitewashing coating.
Embodiment 2
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Employing low-temperature plasma is processed, and selects oxygen, temperature-20 ℃, and output is 1000W, and frequency is 10MHz, and the processing time is 10 minutes, and air pressure is 50Pa;
(2) by the poloxamer188 20mg/ml solution that obtains soluble in water, the inflated that step (1) is obtained expands to 6atm, immerses in above-mentioned solution 2 minutes, and 50 ℃ of blast heatings obtain modification sacculus to dry in 30 minutes;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 20mg/ml in the mixed solution of oxolane/water (volume ratio is 99:1), in the above-mentioned paclitaxel solution of 10ml, add 350mg acetamide 50 revs/min of stirring and dissolving, standing 5 hours in-30 ℃, filter to obtain solid, under room temperature, air blast is dried, and obtains medicine crystal, is long rod shape regular, approximately 3～5 microns of particle diameters, approximately 20 microns of grain lengths;
(4) the modification balloon surface obtaining in step (2) is brushed the medicine crystal that step (3) obtains, and weighs and lays equal stress on overcoating 3 times until reach required drug weight, and 60 ℃ of heating are extremely dried for 60 minutes, and flap is reeled, and packaging sterilizing, obtains medicinal balloon II.
Fig. 3, for the balloon surface shape appearance figure through Low Temperature Plasma Treating, can find out that its surface becomes coarse, and specific surface area increases, and balloon surface hydrophilic improves.
After measured, the medicinal balloon content of taxol of embodiment 2 preparations is 595 μ g, and calculating surperficial unit are content is 3.15 μ g/mm
2.
Embodiment 3
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Employing low-temperature plasma is processed, and selects nitrogen, temperature-20 ℃, and output is 2000W, and frequency is 25Hz, and the processing time is 30 minutes, and air pressure is 1Pa;
(2) polylysine is dissolved in and in ethanol, obtains 60mg/ml solution, the sacculus flap that step (1) is obtained is reeled, with Hamilton MOD710SYR100 μ lNR type syringe (eastern happy nature gene life sciences company, China) above-mentioned solution is dripped and is applied on sacculus, naturally dry, obtain modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 15mg/ml in the mixed solution of dimethyl sulfoxide/water (volume ratio is 70:30), in the above-mentioned paclitaxel solution of 10ml, add 400mg lysine 10 revs/min of stirring and dissolving, at-5 ℃ standing 24 hours, filter to obtain solid, 40 ℃ of heating are extremely dried for 60 minutes, obtain medicine crystal, are long rod shape regular, approximately 1～3 micron of particle diameter, approximately 40 microns of grain lengths;
(4) the modification balloon surface obtaining in step (2) is brushed the medicine crystal that step (3) obtains, weigh and repeat to brush 5 times until reach required drug weight, under 1000Pa vacuum, be heated to 60 ℃ dry, flap is reeled, packaging sterilizing, obtains medicinal balloon III.
After measured, the medicinal balloon content of taxol of embodiment 3 preparations is 515 μ g, and calculating surperficial unit are content is 2.73 μ g/mm
2.
Embodiment 4
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Employing low-temperature plasma is processed, and selects nitrogen, 10 ℃ of temperature, and output is 50W, and frequency is 100MHz, and the processing time is 5 seconds (S), and air pressure is 10Pa;
(2) polyacrylate is dissolved in the mixed solvent that ethanol/water volume ratio is 55:45 and obtains 1mg/ml solution, the inflated that step (1) is obtained expands to 10atm, immerses in above-mentioned solution 1 minute, naturally dries, and obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 5mg/ml in the mixed solution of N-Methyl pyrrolidone/water (volume ratio is 60:40), in the above-mentioned paclitaxel solution of 10ml, add 500mg sodium aminosalicylate 100 revs/min of stirring and dissolving, standing 24 hours in 30 ℃, filter to obtain solid, under 1000Pa vacuum, be heated to 60 ℃ and be dried, obtain medicine crystal, be long rod shape regular, approximately 5～8 microns of particle diameters, approximately 35 microns of grain lengths;
(4) the modification balloon surface that obtains in step (2) is brushed the medicine crystal that step (3) obtains, and weighs and repeats to brush 5 times until reach required drug weight, and dry in 40 ℃ of heating 60 minutes, flap is reeled, and packaging sterilizing, obtains medicinal balloon IV.
After measured, the medicinal balloon content of taxol of embodiment 4 preparations is 489 μ g, and calculating surperficial unit are content is 2.60 μ g/mm
2.
Embodiment 5
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Employing low-temperature plasma is processed, and selects nitrogen, 10 ℃ of temperature, and output is 2000W, and frequency is 10MHz, and the processing time is 30 minutes, and air pressure is 100Pa;
(2) polyethylene glycol oxide (PEO) is dissolved in the mixed solution of normal heptane/water (volume ratio is 1:99) and obtains 100mg/ml solution, the inflated that step (1) is obtained expands to 8atm, immerse in above-mentioned solution 1 minute, naturally dry, obtain modification sacculus;
(3) paclitaxel is dissolved in to N, in the mixed solution of N-dimethyl acetylamide/water (volume ratio is 90:10), prepare the paclitaxel solution of 60mg/ml, in the above-mentioned paclitaxel solution of 10ml, add 800mg mannitol 50 revs/min of stirring and dissolving, under room temperature standing 24 hours, filter to obtain solid, under 10Pa vacuum, be heated to 60 ℃ dry, obtain medicine crystal, be long rod shape regular, approximately 3～5 microns of particle diameters, approximately 35 microns of grain lengths;
(4) the modification balloon surface obtaining in step (2) is brushed the medicine crystal that step (3) obtains, and weighs and lays equal stress on overcoating 4 times until reach required drug weight, in 40 ℃ of heating, within 60 minutes, is dried, and flap is reeled, and packaging sterilizing, obtains medicinal balloon V.
After measured, the medicinal balloon content of taxol of embodiment 5 preparations is 425 μ g, and calculating surperficial unit are content is 2.26 μ g/mm
2.
Embodiment 6
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Adopt alcoholization to process, it is in 75% alcoholic solution that clean nylon balloons is dipped into volumetric concentration, in 45 ℃, and ultrasonic 90 minutes of 90KHz;
(2) PEG400 is dissolved in ethanol/water (50:50) and obtains 100mg/ml solution, the sacculus that step (1) is obtained immerses in above-mentioned solution 2 minutes, naturally dries, and obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 50mg/ml in the mixed solution of dimethyl formamide/water (volume ratio is 85:15), in the above-mentioned paclitaxel solution of 10ml, add 300mg Tween 80 10 revs/min of stirring and dissolving, at-30 ℃ standing 5 hours, filter to obtain solid, room temperature air blast is dried, and obtains medicine crystal, is long rod shape regular, approximately 1～4 micron of particle diameter, approximately 35 microns of grain lengths;
(4) modification inflated step (2) being obtained expands to 8atm, and the medicine crystal obtaining in its surface brushing step (3) is weighed and repeated and brushes until reach required drug weight, naturally dry and spend the night, flap is reeled, and packaging sterilizing, obtains medicinal balloon VI.
After measured, the medicinal balloon content of taxol of embodiment 6 preparations is 520 μ g, and calculating surperficial unit are content is 2.76 μ g/mm
2.
Embodiment 7
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Adopt alcoholization to process, it is in 90% alcoholic solution that clean nylon balloons is dipped into volumetric concentration, in 50 ℃, and ultrasonic 20 minutes of 60KHz;
(2) polyvinyl pyrrolidone (PVP) is dissolved in ethanol (10:90) and obtains 50mg/ml solution, the sacculus that step (1) is obtained immerses in above-mentioned solution 1 minute, repeat to soak 3 times, and each 5 seconds, naturally dry, obtain modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 55mg/ml in the mixed solution of acetonitrile/water (volume ratio is 75:25), in the above-mentioned paclitaxel solution of 10ml, adds 150mg vitamin C
1and 100 revs/min of stirring and dissolving, under room temperature standing 10 hours, filter to obtain solid, naturally dry, obtain medicine crystal, be long rod shape regular, approximately 1～3 micron of particle diameter, approximately 30 microns of grain lengths;
(4) modification sacculus flap step (2) being obtained is reeled, and on its surface, brushes the medicine crystal that step (3) obtains, and weighs and repeats to brush 2 times until reach required drug weight, 40 ℃ of blast heatings 60 minutes, flap is reeled, and packaging sterilizing, obtains medicinal balloon VII.
After measured, the medicinal balloon content of taxol of embodiment 7 preparations is 581 μ g, and calculating surperficial unit are content is 3.08 μ g/mm
2.
Embodiment 8
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Adopt alcoholization to process, it is in 99% alcoholic solution that clean nylon balloons is dipped into volumetric concentration, in 70 ℃, and ultrasonic 15 minutes of 45KHz;
(2) PEG800 is dissolved in methanol/water (80:20) and obtains 20mg/ml solution, the sacculus that step (1) is obtained immerses in above-mentioned solution, repeats to soak 5 times, and each 5s, dries naturally, obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 80mg/ml in the mixed solution of normal heptane/water (volume ratio is 60:40), in the above-mentioned paclitaxel solution of 10ml, add 500mg nicotiamide 50 revs/min of stirring and dissolving, at-10 ℃ standing 20 hours, filter to obtain solid, room temperature air blast is dried, and obtains medicine crystal, is long rod shape regular, approximately 8～10 microns of particle diameters, approximately 30 microns of grain lengths;
(4) the modification sacculus flap that step (2) obtained is reeled, on medicine crystal roll-in 5 times to reaching required drug weight, vacuum 120Pa be heated to 50 ℃ dry, flap is reeled, packaging sterilizing, obtains medicinal balloon VIII.
After measured, the medicinal balloon content of taxol of embodiment 8 preparations is 553 μ g, and calculating surperficial unit are content is 2.94 μ g/mm
2.
Embodiment 9
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Adopt alcoholization to process, it is in 99% alcoholic solution that clean nylon balloons is dipped into volumetric concentration, in 60 ℃, and ultrasonic 100 minutes of 40KHz;
(2) polyvinyl alcohol (PVA) is dissolved in the mixed solution that ethanol/water volume ratio is 99:1 and obtains 1mg/ml solution, the inflated that step (1) is obtained expands to 20atm, immerses in above-mentioned solution, repeat to soak 5 times, each 5s, dries naturally, obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 5mg/ml in the mixed solution of diox/water (volume ratio is 55:45), in the above-mentioned paclitaxel solution of 10ml, add 50mg para-amino benzoic acid 100 revs/min of stirring and dissolving, at-30 ℃ standing 5 hours, filter to obtain solid, naturally dry, obtain medicine crystal, be long rod shape regular, approximately 1～3 micron of particle diameter, approximately 35 microns of grain lengths;
(4) modification inflated step (2) being obtained expands to 8atm, on its surface, brush the medicine crystal that step (3) obtains, weigh and repeat to brush 3 times until reach required drug weight, vacuum 10Pa is heated to 60 ℃ and is dried, flap is reeled, packaging sterilizing, obtains described medicinal balloon IX.
After measured, the medicinal balloon content of taxol of embodiment 9 preparations is 461 μ g, and calculating surperficial unit are content is 2.45 μ g/mm
2.
Medicinal balloon by nylon balloons for the preparation for the treatment of angiostenosis.
(1) pretreatment is carried out in nylon balloons surface; Adopt alcoholization to process, it is in 1% alcoholic solution that clean nylon balloons is dipped into volumetric concentration, in 30 ℃, and ultrasonic 5 minutes of 100KHz;
(2) PEG2000 being dissolved in to ethanol/water volume ratio is in 1:99, to obtain 100mg/ml solution, and the sacculus that step (1) is obtained immerses in above-mentioned solution, repeats to soak 5 times, and each 5s, dries naturally, obtains modification sacculus;
(3) paclitaxel is dissolved in to the paclitaxel solution of preparing 60mg/ml in the mixed solution of acetone/water (volume ratio is 50:50), in the above-mentioned paclitaxel solution of 10ml, add 800mg sodium benzoate 50 revs/min of stirring and dissolving, at 30 ℃ standing 24 hours, filter to obtain solid, naturally dry, obtain medicine crystal, be long rod shape regular, approximately 1～3 micron of particle diameter, approximately 40 microns of grain lengths;
(4) modification inflated step (2) being obtained expands to 20atm, on its surface, brush the medicine crystal that step (3) obtains, weigh and repeat and brush until reach required drug weight, vacuum 120Pa is heated to 55 ℃ and is dried, flap is reeled, packaging sterilizing, obtains described medicinal balloon X.
After measured, the medicinal balloon content of taxol of embodiment 10 preparations is 536 μ g, and calculating surperficial unit are content is 2.85 μ g/mm
2.Adopt commercially available Cotavance medicinal balloon (Beyer Co., Ltd, Germany) in contrast, carry out respectively following performance test.
Dry spreading performance test
Evaluation operation example 1～6 is prepared contingent paclitaxel loss in the process of expansion of sacculus respectively, the adhesive capacity for side reflection medication coat in balloon surface.Evaluation methodology: medicinal balloon is filled in test tube to 6～12 normal atmospheres, rock 40 seconds, take out, measure the content of falling into the paclitaxel in test tube with HPLC.Result is as shown in table 1.
Dose test in body
Respectively the medicinal balloon of embodiment 1～6 preparation is carried out to dose test in body.Concrete grammar is: large to about March, the pig of heavily about 30kg is punctured through right femoral artery by standard angiography, first, with the sacculus that rustless steel bare bracket is housed, is delivered to behind arteria coronaria position, expands, and then shrinks and recalls, for doing sampling labelling; Then with being contained in supravasal medicinal balloon sample, send in animal arteria coronaria position; Respectively after short-term (15～30 minutes) and long-term (24h, 72,120h), sampling, and with scheduled volume methanol extraction so that concentration > 50%, under room temperature ultrasonic 30 minutes and after centrifugal 10 minutes, by HPLC, measure extract, to determine the paclitaxel amount of losing in paclitaxel amount that vascular tissue absorbs and blood flow.The results are shown in Table 1.
Table 1 medicinal balloon the performance test results
Remarks: in table 1, data are means standard deviation.
As shown in Table 1:
(1) known by data in table 1, medicinal balloon prepared by the present invention paclitaxel dose loss in dry expansion and blood flow is all less, and standard deviation is less, illustrates that medicinal balloon of the present invention is functional, process stabilizing, is more conducive to medicine and enters histiocytic long-term absorption after target vessel.
(2) according to general knowledge known in this field, the less correspondence of dry enlargement loss it lose also littlely in blood flow, and meanwhile, the dose of intravasation tissue is also just more, and the paclitaxel amount that long-term vascular tissue absorbs is also more; Cotavance compares with Bayer, of the present inventionly whitewash medicinal balloon (I～VI) prepared by coating process), its dry expansion dose loss is less, side light the combination of medication coat of the present invention and balloon surface more firm, simultaneously, the dose that short-term (0.5h) vascular tissue absorbs is more, has directly illustrated that the dose of intravasation tissue is also more, and the paclitaxel bioavailable degree that its long-term vascular tissue absorbs is also higher.
(3) medicinal balloon that prepared by preparation method of the present invention is not when expanding, and the content of taxol losing in blood flow is also less, and coating adhesion-tight of the present invention is described, effectively reduced the loss that medicine is washed away by blood flow in blood transport process.
(4) medicinal balloon of preparing by method of the present invention, after its shortterm effect 0.5h, the content of taxol that vascular tissue absorbs is higher than the medicinal balloon of Bayer, sacculus arrival targeting moiety be described after medicine can from balloon surface, discharge in vascular wall tissue more quickly.
(5) in conjunction with shown in Fig. 7, medicinal balloon prepared by the inventive method, compare with Bayer Cotavance medicinal balloon, after difference long term 24h, 72h, 120h, the content of taxol that vascular tissue absorbs is all higher than the latter, illustrate that medicine can more preferably stick on vascular wall tissue, thereby reach the effect of long-term drug effect, improved the bioavailability of medicine.
To sum up, with the present invention, whitewash medicinal balloon prepared by coating and in pharmacokinetics animal experiment, show medicine and there is prolonged stay in the effect of target vascular therapy, improved bioavailability, thereby restenosis is had to good inhibitory action.
In the present invention, owing to adopting the first crystallization of the taxol drug mode of load again, compare with the mode that first applies recrystallize of traditional preparation method, in crystallization process, the change of temperature, time and mode is more flexible, can control crystal formation and the size of paclitaxel crystal, therefore the drug crystal forms of the medicinal balloon area load of preparation is regular, moderate dimensions, improve the unit are drug loading of sacculus simultaneously, both guaranteed that the dose that balloon surface is carried arrived targeting moiety more fast and effectively; Also the bioavailable degree of medicine and the effect that discharges for a long time drug effect have been improved greatly.
Secondly, added the first water-soluble additives and the second water-soluble additives, before carrying medicament, first in balloon surface, applied the first water-soluble additives, follow-up drug solution can be disperseed better in balloon surface, crystallization is more even; And by controlling kind, consumption and the concentration of the second water-soluble additives, and with drug crystallization process in temperature, mode, the synergism of time, reach the object of controlling taxol drug crystal crystal formation and particle diameter.
Again, surface hydrophilicity pretreatment makes follow-up load more easy, preparation method of the present invention is before whitewashing coating to balloon surface, first it is carried out to modification pretreatment, make balloon surface become more hydrophilic, the first water-soluble additives also can better be sprawled and come in balloon surface, bonding state is better, bond strength is higher, and then improves the bond strength between balloon surface and drug-loaded layer, makes balloon surface drug loading amount high.
Therefore, the present invention compared with prior art, has the following advantages:
(1) preparation method of the present invention is before whitewashing coating to balloon surface, first carry out surface modification pretreatment, balloon surface hydrophilic is improved, and the binding ability between the first water-soluble additives strengthens, and then improve the bond strength between balloon surface and drug-loaded layer, make balloon surface carry enough medicines;
(2) the present invention first applies the first water-soluble additives in balloon surface before carrying medicament, and follow-up drug solution is disperseed better in balloon surface, and crystallization is more even;
(3) the present invention is by controlling kind, consumption and the concentration of the second water-soluble additives, synergism with temperature, mode, time in drug crystallization process, reach the object of controlling taxol drug crystal crystal formation and particle diameter, the drug crystal forms of the medicinal balloon area load of preparation is regular, moderate dimensions, had both guaranteed that the dose that balloon surface is carried arrived targeting moiety more fast and effectively; Also the bioavailable degree of medicine and the effect that discharges for a long time drug effect have been improved greatly;
(4) the medicinal balloon coating that prepared by the present invention firmly, even, dose is accurately controlled, is conducive to reduce medicine and by blood, rinsed the loss rate causing in course of conveying;
(5) preparation technology of the present invention is simple, efficient, stable, easy and simple to handle, quick.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. a preparation method for medicinal balloon, is characterized in that, this preparation method comprises the following steps:
Balloon surface is carried out to hydrophilic pretreatment;
The first water-soluble additives solution is attached in balloon surface, obtains modification sacculus;
In this modification balloon surface, brush medicine crystal, or, by this modification sacculus roll-in on medicine crystal, until be attached to the medicine crystal of described modification balloon surface, reach required weight, after being dried, obtain this medicinal balloon;
The preparation of described medicine crystal comprises: in the mixed solution of medicine, organic solvent and water, add the second water-soluble additives, and stirring and dissolving, standing, filter dry making;
Described the first water-soluble additives contains at least one in hydroxyl, amino, carboxyl, utilizes the intermolecular larger Van der Waals force of medicine and the first water-soluble additives, reaches the effect that increases medicine and balloon surface adhesion property; Described the second water-soluble additives contains at least one in hydroxyl, carboxyl, amino, and has dispersion, plasticising, the effect of raising cellular affinity.
2. the preparation method of medicinal balloon as claimed in claim 1, it is characterized in that: this hydrophilic pretreatment is that low-temperature plasma is processed or alcoholization is processed, this low-temperature plasma is processed and is comprised: selecting gas purity is 90～99.9999% nitrogen, oxygen, argon and/or helium, in temperature, be-40～10 ℃, air pressure is under 1～100Pa, to carry out plasma treatment 5 seconds～30 minutes; This alcoholization is processed and is comprised: it is in 1～99% alcoholic solution that sacculus is immersed to volumetric concentration, at the temperature of 30～70 ℃, under the condition that is 40～100KHz ultrasonic 5～100 minutes, takes out and is dried in frequency.
3. the preparation method of medicinal balloon as claimed in claim 1, is characterized in that: the concentration of this mixed solution Chinese medicine is 5～60mg/ml; The concentration of this first water-soluble additives solution is 1～100mg/ml; This first water-soluble additives is that molecular weight ranges is at nonionic micromolecular compound or the oligomer of 200～5000D, this second water-soluble additives be molecular weight ranges at the organic micromolecule compound of 50～1000D, the concentration in this mixed solution is 5～80mg/ml.
4. the preparation method of medicinal balloon as claimed in claim 3, is characterized in that: this first water-soluble additives is selected from one or more in Polyethylene Glycol, polylysine, poloxamer, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol oxide or polyacrylate.
5. the preparation method of medicinal balloon as claimed in claim 3, is characterized in that: this second water-soluble additives is selected from Tween 80, mannitol, sorbitol, potassium sorbate, tryptophan, methionine, L-Phe, phenylalanine, leucine, L-threonine, Valine, ILE, glutamic acid, lysine or amino acid derivatives, sodium benzoate, salicylic acid, sodium aminosalicylate, sodium ferulate, meglumine, nicotiamide, acetamide, vitamin A
1, vitamin A
2, vitamin A
3, vitamin B
1, vitamin B
2, vitamin B
3, vitamin C
1, vitamin C
2, vitamin C
3or one or more in para-amino benzoic acid.
6. the preparation method of medicinal balloon as claimed in claim 1, is characterized in that: this medicine is that the anti-neointimal hyperplasia medicine, anticoagulation medicine, the antiplatelet that are used for the treatment of vascular restenosis adhere to medicine, anti-infectives, antibacterials or antitumor drug.
7. the preparation method of medicinal balloon as claimed in claim 1, it is characterized in that: this medicine is selected from rapamycin and derivant thereof, dexamethasone, paclitaxel, taxol, class Ramulus et folium taxi cuspidatae, docetaxel, probucol, colchicine, heparin, warfarin sodium, vitamin K antagon, aspirin, prostaglandin, salvianolic acid, nitric acid lipid drug, aspisol, persantin, ampicillin, cephamycin, sulfadiazine, streptomycin sulfate, chitosan and derivant thereof, cefoxitin, nalidixan, pipemidic acid, daunorubicin, amycin, carboplatin, one or more of macrolide apoplexy due to endogenous wind.
8. the preparation method of medicinal balloon as claimed in claim 1, it is characterized in that: this organic solvent is selected from diox, dimethyl formamide, dimethyl sulfoxide, N-Methyl pyrrolidone, acetonitrile, N, at least one in N-dimethyl acetylamide, oxolane, acetone, methanol, ethanol, butanols or normal heptane, in the mixture of this organic solvent and water, the volume ratio of organic solvent and water is 99～50:1～50.
9. the preparation method of medicinal balloon as claimed in claim 1, is characterized in that: this standing temperature is-30～30 ℃, and the time is 5～24 hours.
10. the preparation method of medicinal balloon as claimed in claim 7, is characterized in that: described paclitaxel is the regular crystal of long rod shape, and particle diameter is 1～10 micron, and grain length is 20～40 microns.
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