CN106237330A - Compound medicine and medicine carrying sacculus for arteries pathological changes expansion medicine carrying sacculus - Google Patents
Compound medicine and medicine carrying sacculus for arteries pathological changes expansion medicine carrying sacculus Download PDFInfo
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- CN106237330A CN106237330A CN201610612700.5A CN201610612700A CN106237330A CN 106237330 A CN106237330 A CN 106237330A CN 201610612700 A CN201610612700 A CN 201610612700A CN 106237330 A CN106237330 A CN 106237330A
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Abstract
The invention discloses a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus and medicine carrying sacculus, compound medicine includes raw material: for treating the lipophilic active medicine of arteries pathological changes, medicine built agent, solvent, active medicine and medicine built agent mass ratio are 1.2 4.8；The gross mass of active medicine and medicine built agent and the mass volume ratio of solvent are 8 20 (g/l)；Medicine built agent is hydrophilic surfactant active；Solvent is the mixed solution of non-polar solven miscible with water or non-polar solven miscible with water and water.Medicine carrying sacculus includes the sacculus with folding valve structure, and balloon surface is attached with medication coat, and medication coat includes active medicine and medicine built agent.Compound medicine rate of release of the present invention is fast, active medicine component is not reunited and balloon surface uniform adhesion, is not easily formed blood vessel embolism；In medicine carrying sacculus, active medicine balances with the cohesive force of balloon surface, and medicine is effectively transported to target location and the release that can accelerate medicine and absorption.
Description
Technical field
The invention belongs to pharmaceutical technology field, relate to a kind of compound medicine and medicine carrying sacculus, particularly relate to a kind of for moving
The compound medicine of arteries and veins vascular lesion expansion medicine carrying sacculus and medicine carrying sacculus.
Background technology
Arteries pathological changes (inaccessible, calcification, narrow etc.) it is that vascular disease occurs one of main causes of death, mesh
Before for this disease primary treatment regimen be: 1, lesion vessels is bridged by surgical operation；2, blood vessel intervention support plasty,
Support is implanted at lesion vessels；3, blood vessel gets involved Balloon Angioplasty, uses inflatable ball ductus bursae, lesion vessels is carried out ball
Capsule is expanded so that lesion vessels recovers original lumen diameter.Wherein, second and third method little because of its wound, recover fast, curative effect
Significantly, the most increasingly welcome by doctor and patient.
Second method is used to implant support, although to compare for solving atherosclerosis and narrow the providing of Ink vessel transfusing
Good solution, makes therapeutic efficiency greatly improve, but there is Ink vessel transfusing and in-stent restenosis, to thin vessels, bifurcated vessels
And the shortcoming such as the therapeutic effect of in situ pathological changes etc. is undesirable, rise year by year owing to accepting the patient populations of PCI treatment, support occurs
The absolute quantity of the patient of restenosis is the biggest.
When using the third method to expand, because using pressure the highest, the blood vessel wall that may result in pathological changes ruptures, and quilt
Extruding is displaced in surrounding tissue.The blood vessel wall processed by the method generally occurs as soon as what thickness increased in a few weeks or months
Situation, is similar to form cicatrix.As a result, due to the progress of arteriosclerosis, these blood vessels soon will be the narrowest (restenosis).Cause
This, restenosis is a serious difficult medical problem and causes medical expense to raise and patient suffering.
The method used currently for restenosis includes: the expansion again of simple sacculus, orientation speckle rotary-cut art, turnery
Art, intravascular brachytherapy and repetition stenter to implant etc., existing bare ball capsule and drug stent all have some limitations, naked
The restenosis rate of sacculus is higher, and drug stent is the best for the therapeutic effect of thin vessels and bifurcated vessels, and both fails
Show its preferable effectiveness or safety.
For above-mentioned knotty problem, recently propose to use medicine expansion of balloon catheter, by anti-proliferate drug coat at ball
Ductus bursae surface, sacculus moment expansion so that medicine fast transfer to blood vessel wall also sticks in blood vessel wall, so that medicine is sent out
Wave long term effect effect.But, the medicine of this method transfer is difficult in blood vessel wall for a long time, keeps biology enduringly
Effect and drug effect.Reason is that the cohesive force between medication coat and balloon surface is less, and medicine can be by defeated before inserting lesion
Send conduit, the friction of blood vessel wall and swiftly flowing blood to wash away, thus medicine can be caused to lose in a large number；Due to antiproliferative pharmaceutical
Thing is insoluble in water, and medicine is slow by histiocyte, and medicine bioavailability is low.It addition, the medication coat on foley's tube
Granule is easily reunited and is lumpd, and easily causes blood vessel embolism after coming off.
Summary of the invention
The technical problem to be solved in the present invention is, for the drawbacks described above of prior art, it is provided that a kind of compound medicine, multiple
Medicine rate of release is fast, prevent active medicine component reunion and balloon surface uniform adhesion, be not easily formed blood vessel embolism.
The present invention to solve the technical problem that further and be, it is provided that a kind of active medicine is flat with the cohesive force of balloon surface
Weighing apparatus so that medicine is effectively transported to the medicine carrying sacculus of target location and the release that can accelerate medicine and absorption.
The technical solution adopted for the present invention to solve the technical problems is:
A kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material: be used for treating arteries
The lipophilic active medicine of pathological changes, medicine built agent, solvent, wherein active medicine and medicine built agent mass ratio are 1.2-4.8；
The gross mass of active medicine and medicine built agent and the mass volume ratio of solvent are 8-20；Described medicine built agent is hydrophilic table
Face activating agent；Described solvent is the mixed solution of non-polar solven miscible with water or non-polar solven and water.
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, the most described active medicine and medicine
Built agent mass ratio is 1.5-4.8.
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, the most described active medicine and medicine
The gross mass of built agent and the mass volume ratio of solvent are 10-15 (g/l).
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, and the most described active medicine is Ramulus et folium taxi cuspidatae
Alcohol, rapamycin, paclitaxel derivant or rapamycin derivative.
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, and the most described medicine built agent is Portugal
One or more in grape amine substance, acetamide, sorbitol, PEG100 etc..
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, and the most described Fructus Vitis viniferae amine substance is
N-methyl-D-glucose methylamine, N-methyl-D-glucose ethamine or caprylyl-N-methyl glucose osamine.
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, and the most described solvent is methanol, second
At least one in alcohol, acetone, ethyl acetate, DMSO, DMF；Or described solvent be methanol, ethanol, acetone, ethyl acetate,
At least one in DMSO, DMF and the mixed mixed solution of water.
Described expands in the compound medicine of medicine carrying sacculus for arteries pathological changes, and the most described solvent is methanol, second
At least one in alcohol, DMSO, or described solvent to be that at least one in methanol, ethanol, DMSO is mixed with water mix
Solution.
A kind of medicine carrying sacculus, including the sacculus of folding valve structure, is attached with medication coat in balloon surface, and medication coat includes
Active medicine and medicine built agent；Described active medicine is the lipophilic active medicine for treating arteries pathological changes；Described
Medicine built agent is hydrophilic surfactant active.
In described medicine carrying sacculus, in the most described medication coat, medicine built agent parcel or interval active drug particles.
In compound medicine of the present invention, active medicine is lipophilic drugs medicative to arteries pathological changes, medicine
Built agent is hydrophilic surfactant active.Wherein, selecting lipophilic drugs is to avoid hydrophilic medicament to be dissolved in water, conveying to lose
Big problem, but owing to the reunion poor, mutual of the cohesive force of lipophilic drugs Yu balloon surface is difficult to dispersion, also need cooperation to make
Use medicine built agent, medicine built agent function as the viscous of surfactant regulation lipophilic active medicine and balloon surface
Knot dynamic balance, accelerates release and the absorption of medicine simultaneously, and the hydrophilelipophile material of medicine built agent first can be with lipotropy
Active medicine (rapamycin or paclitaxel etc.) combines, it is therefore prevented that the medicine that lipophilic active drug molecule is mutually assembled and caused
Coating is lumpd, and reduces the surface tension of balloon surface material simultaneously so that lipophilic active medicine is with balloon surface equably
Adhere to；Meanwhile, medicine built agent plays the effect of physical separation between lipophilic active medicine crystal granule, adds lipotropy
The specific surface area of active drug particles, increases the dissolubility in intercellular substance, thus be conducive to contacting blood during
Immersional wetting, promotes that medicine discharges during foley's tube inserts target site the most rapidly, accelerates medicine and arrives targeting
The lipid bilayer of pathological tissues cell membrane；Thus accelerate medicine diffusion in tissue and lipophilic active medicine is greatly facilitated
Absorption by target vessel pathological tissues cell.Finally, so that in clinical course or afterwards that active medicine is the most direct
Be transported to targeting diseased tissue area, foley's tube should be fast in effective and efficient mode at required target position simultaneously
Discharge active medicine fastly, make it possible to quickly infiltrate into target tissue, and stick in blood vessel wall, play drug effect for a long time,
To treat arteriovascular diseases.
Using medicine built agent another one important function is to reduce the risk of blood vessel embolism, owing to active medicine is at sacculus
Easily reuniting caking in surface, is washed intravasation after dropping in conveying, and the problem that can cause blood vessel embolism, the present invention uses medicine
Built agent, medicine built agent plays the effect of physical separation between lipophilic active medicine crystal granule, decreases active medicine
Reunite, decrease the risk of blood vessel embolism.
The medicine carrying sacculus of the present invention, for active medicine is transported to the target site of blood vessel or tube chamber, medication coat covers
On the outer surface of foley's tube.Owing to have employed active medicine and medicine built agent so that medication coat with catheter sheath
Friction and when being washed away by swiftly flowing blood, difficult drop-off and cause substantial amounts of loss.Medicine built agent accelerates activity
Medicine rate of release from sacculus so that active medicine discharged within the shortest period and rapid osmotic enters disease sites
The tissue at place, thus improve active medicine absorbance in the illing tissue of vascular system or other body lumens, can solve
Certainly the medication amount in Clinical practice course of conveying is lost and after balloon expandable, medicine is reprinted to the quick of target lesion position.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described, in accompanying drawing:
Fig. 1 is that the compound medicine of the embodiment of the present invention is in balloon surface view；
Fig. 2 a-2c be compound medicine of the present invention make medicine carrying sacculus respectively 500 times, 1000 times, under 2000 times of Electronic Speculum
Aspect graph；
Fig. 3 a-3c is that existing medicine makes medicine carrying sacculus respectively 500 times, 1000 times, shape under 2000 times of Electronic Speculum
State figure；
Fig. 4 a-4d respectively embodiment of the present invention 4 make the balloon expandable of medicine carrying sacculus before radiography figure, balloon expandable time make
After shadow figure, balloon expandable at once radiography figure, within 28 days, follow up a case by regular visits to radiography figure；
Radiography when Fig. 5 a-5d respectively comparative example 1 medicine makes radiography figure, balloon expandable before the balloon expandable of medicine carrying sacculus
Figure, after balloon expandable at once radiography figure, within 28 days, follow up a case by regular visits to radiography figure；
Fig. 6 is medicine carrying sacculus sectional view of the present invention.
Detailed description of the invention
In order to be more clearly understood from the technical characteristic of the present invention, purpose and effect, now comparison accompanying drawing describes in detail
The detailed description of the invention of the present invention.
A kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material: be used for treating arteries
The lipophilic active medicine of pathological changes, medicine built agent, solvent, wherein active medicine and medicine built agent mass ratio are 1.2-4.8；
Owing to compound medicine coats on sacculus repeatedly or soaks, then active medicine is required very with medicine built agent mass ratio
Wide in range, in the range of 1.2-4.8, it is all suitable for the present invention.The most described active medicine and medicine built agent mass ratio are 1.5-4.8.
The gross mass of active medicine and medicine built agent and the mass volume ratio of solvent are 8-20 (g/l)；The most described work
Property medicine and the gross mass of medicine built agent and the mass volume ratio of solvent be 10-15 (g/l).
Described medicine built agent is hydrophilic surfactant active；The most described medicine built agent is Fructus Vitis viniferae amine substance, second
One or more in amide, sorbitol, PEG100 etc..The most described Fructus Vitis viniferae amine substance is N-methyl-D-glucose first
Amine, N-methyl-D-glucose ethamine or caprylyl-N-methyl glucose osamine.Said medicine built agent role is identical,
In the following examples, can arbitrarily replace.
Described solvent is the mixed solution of non-polar solven miscible with water or non-polar solven and water.Preferably institute
Stating solvent is at least in methanol, ethanol, acetone, ethyl acetate, DMSO (dimethyl sulfoxide), DMF (dimethylformamide)
Kind；Or described solvent is that at least one in methanol, ethanol, acetone, ethyl acetate, DMSO, DMF is mixed with water to be mixed
Solution.The most described solvent is at least one in methanol, ethanol, DMSO, or described solvent is methanol, ethanol, DMSO
In at least one with the mixed mixed solution of water.Above-mentioned solvent role is identical, in the following embodiments, permissible
Arbitrarily replace.
The compound medicine of the present invention is for treating arteries pathological changes, along with the development for the treatment of technology, medicine
Also there is respective change, but as long as be all suitable for the present invention for treating the lipophilic active medicine of arteries pathological changes.Preferably institute
Stating active medicine is paclitaxel, rapamycin or taxol.
By immersion, spraying etc., above-mentioned compound medicine is made medicine carrying sacculus as shown in Figure 6, and medicine carrying sacculus includes rolling over lobe
The sacculus 100 of structure.Sacculus 100 surface is carried out fold process, i.e. sacculus 100 surface being carried out rolls over lobe and obtains rolling over valve structure ball
Capsule, folding lobe makes sacculus 100 cross section be star structure, it is easy to rolling.Folding lobe quantity can set according to actual needs.Permissible
Folding 2-6 lobe；More preferably 3 lobes, 6 lobes.Medication coat 200, medication coat 200 is had to include active medicine in sacculus 100 surface attachment
The crystal formed with medicine built agent, active medicine and medicine built agent is attached to sacculus 100 surface；Described active medicine is for using
Lipophilic active medicine in treatment arteries pathological changes；Described medicine built agent is hydrophilic surfactant active.
In described medicine carrying sacculus, in the most described medication coat 200, medicine built agent parcel or interval active medicine
Grain, thus the medication coat caking preventing lipophilic active drug molecule from mutually assembling and causing, medicine built agent reduces simultaneously
The surface tension of balloon surface material so that lipophilic active medicine is uniformly adhered with balloon surface；Reduce active medicine
Reunite, decrease the risk of blood vessel embolism.
Medicine carrying sacculus, for active medicine is transported to the target site of blood vessel or tube chamber, treats blood vessel or intraluminal narrow
Narrow, prevent inner membrance or epithelial proliferation；Blood vessel refers to coronary artery, peripheral arterial blood vessel or cerebral artery vessel；Tube chamber refer to esophagus,
Air flue, intestinal, biliary tract, urinary tract, prostate or nicergoline road.
Hereinafter use specific embodiment, detailed description technical scheme:
Embodiment 1, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug taxol 30mg
Medicine built agent PEG100 20mg
Solvent acetone 4.25ml, water 2ml.
By 30mg paclitaxel, 20mgPEG100, it is dissolved in the mixed solvent of 4.25ml acetone and 2ml water and is prepared as mixing
Solution；Periphery foley's tube (diameter 6.0mm, long 60mm) balloon portion is dipped in mixed solution, takes out, be dried.Through 10
Secondary repeatedly soaking, dried medicine carrying sacculus, is 3.86 μ g/mm in the HPLC detection drug density obtained in medication coat2。
The material of foley's tube is one or more in nylon, nylon elastomer, PU, Pebax, PET or polyethylene.
Embodiment 2, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug taxol 50mg
Medicine built agent N-methyl-D-glucose ethamine 10.42mg
Solvent acetone 6ml, water 1ml.
By 50mg paclitaxel, 10.42mg N-methyl-D-glucose ethamine, the mixing being dissolved in 6ml acetone and 1ml water is molten
Agent is prepared as mixed solution；Periphery foley's tube (diameter 6.0mm, long 60mm) balloon portion is dipped in mixed solution,
Take out, be dried.Repeatedly soak through 10 times, dried medicine carrying sacculus, obtain the drug density in medication coat in HPLC detection
It is 3.17 μ g/mm2。
Embodiment 3, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug rapamycin 60mg
Medicine built agent N-methyl-D-glucose ethamine 20mg
Solvent methanol 6.7ml.
By 60mg rapamycin, 20mg N-methyl-D-glucose ethamine, it is dissolved in 6.7ml methanol solution；By periphery
Foley's tube (diameter 6.0mm, long 60mm) balloon portion is dipped in mixed solution, takes out, and is dried.Repeatedly soak through 12 times,
Dried medicine carrying sacculus, is 4.78 μ g/mm in the HPLC detection drug density obtained in medication coat2。
Embodiment 4, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug rapamycin 20mg
Medicine built agent N-methyl-D-glucose methylamine 8.8mg, sorbitol 8mg
Etoh solvent 2.4ml and water 1ml.
By 20mg rapamycin, 8.7mg N-methyl-D-glucose methylamine and 8mg sorbitol, be dissolved in 2.4ml ethanol and
In the mixed solution of 1ml water；Mixed solution and sprayed is coated with and puts on periphery foley's tube (diameter 6.0mm, long 60mm) balloon surface
On, it is dried.Through repetitious spraying, dried medicine carrying sacculus, obtain the drug density in medication coat in HPLC detection
It is 2.95 μ g/mm2。
Embodiment 5, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug taxol 25mg
Medicine built agent acetamide 16.7mg
Solvent ethyl acetate 2.8ml.
By 25mg paclitaxel, 16.7mg acetamide, it is dissolved in 2.8ml ethyl acetate；By solution drop coating in periphery sacculus
In conduit (diameter 6.0mm, long 60mm) balloon surface, it is dried.After drop coating the most repeatedly, it is dried to obtain medicine carrying sacculus, examines in HPLC
Recording the drug density in medication coat is 1.78 μ g/mm2。
Embodiment 6, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active medicine taxol 25mg
Medicine built agent caprylyl-N-methyl glucose osamine 20mg
Solvent DMF 2.25ml.
Embodiment 7, a kind of compound medicine for arteries pathological changes expansion medicine carrying sacculus, including raw material:
Lipophilic active drug rapamycin 25mg
Medicine built agent acetamide 16.7mg
Solvent DMSO 2.8ml.
Comparative example 1
By 24mg paclitaxel, 28mg Iopromide, it is dissolved in 7ml ethanol solution；Solution drop coating is led in periphery sacculus
In pipe (diameter 6.0mm, long 60mm) balloon surface, it is dried.Through drop coating the most repeatedly, it is dried after executing, is coated with in HPLC detection
Layer drug density is 3.64 μ g/mm2。
Comparative example 2
50mg paclitaxel is dissolved in the mixed solution of 4.25ml acetone and 2ml water；By solution drop coating in periphery sacculus
In conduit (diameter 6.0mm, long 60mm) balloon surface, it is dried.Through drop coating the most repeatedly, it is dried after executing, obtains in HPLC detection
Coating drug density is 5.2 μ g/mm2。
Morphologic observation
As it is shown in figure 1, be compound medicine in balloon surface view, active medicine is graininess, medicine built agent
It is liquid with solvent, active medicine is wrapped up, serve the interval action of lipophilic drugs crystal grain, increase drug particles ratio
Surface area.
As shown in figs. 2 a-2 c, it is that medicine built agent of the present invention makes medicine carrying sacculus, forms medication coat in balloon surface and divide
Not at 500 times, 1000 times, aspect graph under 2000 times of Electronic Speculum.As shown in figs 3 a-3 c, it is that existing medicine paclitaxel is made
Medicine carrying sacculus, forms medication coat respectively at 500 times, 1000 times, aspect graph under 2000 times of Electronic Speculum in balloon surface.From figure
Seeing, after compound medicine of the present invention makes medicine carrying sacculus, the crystal formation of the medication coat of formation becomes bar-shaped or needle-like, and granular size is moderate
(about 20 μm), is evenly distributed, most significantly combines between granule loosely, do not reunite.And medicine individually makes in prior art
With paclitaxel, after being coated in sacculus, the crystal formation of crystallization is chaotic, particle diameter difference is big, it is obvious to reunite.
Course of conveying loss simulation test
Carry out course of conveying with the target vessel of artificial blood vessel in simulation use system and want immeasurable loss simulation test, test
Before balloon expandable expands, i.e. foley's tube inserts and moves to the medication amount loss during target site.
Respectively the compound medicine of embodiment 1～5 and the medicine of comparative example 1～2 preparation are made medicine carrying sacculus, by medicine carrying ball
Ductus bursae inserts in in-vitro simulated blood vessel model.Simulated blood vessel device systems carried and 120 seconds flotation times, does not expands
, then take out foley's tube.Utilize HPLC to analyze medicine remaining on foley's tube, calculate the loss of course of conveying medication amount.
HPLC test condition is: Japan's Shimadzu LC-20A high performance liquid chromatograph, chromatographic column: Aglilent ZOBAX SB-C18 4.6
× 250mm, 5um, flow phase: methanol: acetonitrile: water=230:360:410, column temperature: 30 DEG C, and UV-detector detects wavelength
227nm, flow velocity: 1.0ml/min.
HPLC measurement result is as shown in table 1:
Table 1 course of conveying loss simulation test result
Table 1 result shows: compared with comparative example 1, and the foley's tube of the present invention is moving to the mistake in Intertherapy site
Obvious much less is wanted in medication amount loss in journey.And with only use active medicine and without effect compared with the comparative example 2 of medicine built agent
Fruit becomes apparent from.Illustrating that the cohesive force between the medication coat of the present invention and foley's tube is relatively big, medicine carrying sacculus arrives target lesion
Remain in dose in balloon surface during position more, be more beneficial for medicine and efficiently discharge.
Drug disposition release test
In rabbit body, ventral aorta row medicine carrying balloon dilatation carries out drug release test.
New Zealand white rabbit, about 6 months big, body weight about 3kg.Respectively by compound medicine and the comparative example 1～2 of embodiment 1～5
Medicine carrying sacculus made by the medicine of preparation, by medicine carrying foley's tube from femoral artery puncture mouth position, is delivered to after ventral aorta ball
Capsule is charged to about 6atm.Expansion time 60～120 seconds, blood stream is kept to wash away 10 minutes, then by foley's tube release and withdraw
Take out, collect target vessel tissue.By tissue extraction and HPLC, test and protect on the medicament contg in target vessel tissue and sacculus
The remaining dose stayed, ibid, result is as shown in table 2 for test condition.
The in-vitro simulated test result of table 2
As shown in Table 2: compared with comparative example 1, ventral aorta vasodilation in the medicine carrying foley's tube rabbit body of the present invention
After, the amount of medicine fast transfer to blood vessel wall substantially wants many.And with only use active medicine and right without any medicine built agent
Ratio 2 is compared difference and is become apparent from.Illustrate that the present invention has the release characteristics of quick medicament, and high potency drugs transfer ability.
Microgranule is tested
Simulated blood vessel model system in vitro, tests medicine carrying sacculus particles from getting loose level.
Respectively the compound medicine of embodiment 1～5 and the medicine of comparative example 1～2 preparation are made medicine carrying sacculus, by medicine carrying ball
Ductus bursae inserts in in-vitro simulated blood vessel model.In simulated blood vessel device systems, it is delivered to target vascular therapy position, keeps conveying
120 seconds time, then foley's tube is pressurized to 6atm, expands time 60～120 seconds, release, then take out foley's tube.Target
Blood vessel end is collected medicine carrying sacculus and is washed away the granule got off.Then the size detecting come off granule on particulate instrument is big
Little, particle diameter distribution and quantity.Result is as shown in table 3.
Table 3. particles from getting loose is added up
As shown in Table 3: compared with comparative example 1, the medicine carrying foley's tube analog systems in vitro that medicine of the present invention is made expands
Zhang Hou, particles from getting loose substantially to lack in each particle diameter distributed number.And with only use active medicine and without any medicine built agent
Comparative example 2 compare effect and become apparent from.Illustrate that present invention medicine on sacculus has less particles from getting loose, the microgranule come off
Particle diameter is less.Further illustrate during clinical drug of the present invention uses and there is safer performance.
Zoopery
Ilium/tremulous pulse overdistension medicine carrying sacculus in pig body, 28 days later evaluation ball expansion section blood vessels, downstream vascular occlusion, with
And the phenomenon such as downstream tissue ischemic necrosis.
Experimental subject: health pig, about 3 months big, 30～35kg weights.
Experimental procedure: as a example by embodiment 4 and comparative example 1, prepares compound medicine and the comparative example 1 of embodiment 4 respectively
Medicine make medicine carrying sacculus, by medicine carrying foley's tube from carotid puncture mouth position, with the help of DSA contrast apparatus, will
Medicine carrying foley's tube is pressurized to about 6atm to sacculus, after expanding 3 minutes after being delivered to left and right ilium/femoral artery.Withdraw from medicine carrying sacculus
Conduit, sews up puncture orifice.Follow up a case by regular visits to after 28 days, use DSA radiography, observe target vessel and downstream blood vessel occlusion condition.
As compound medicine that Fig. 4 a-4d is the embodiment of the present invention 4 makes radiography figure, sacculus before the balloon expandable of medicine carrying sacculus
During expansion after radiography figure, balloon expandable at once radiography figure, within 28 days, follow up a case by regular visits to radiography figure；Such as the balloon expandable that Fig. 5 a-5d is comparative example 1
When front radiography figure, balloon expandable after radiography figure, balloon expandable at once radiography figure, within 28 days, follow up a case by regular visits to radiography figure.
Before and after medicine carrying foley's tube femoral artery in pig body of embodiment 4 preparation completes expansion, and within 28 days, follow up a case by regular visits to DSA and make
Shadow shows, target vessel and downstream vascular flow are unobstructed, has no the complication such as narrow, interlayer, obturation；The load of comparative example 1 preparation
Medicine ball ductus bursae is in pig body before femoral artery expansion, and angiography show and all goes well at once after completing expansion, and blood flow is logical
Freely.But following up a case by regular visits to DSA radiography after 28 days show, target vessel section is entirely shut, blood flow cannot be normal through.The visible present invention
The medicine carrying foley's tube of preparation can greatly reduce the incidence rate of vascular occlusion.
From above-mentioned experiment it can be seen that compound medicine of the present invention can be transported to the target of blood vessel or tube chamber by foley's tube
Site, medication coat covers on the outer surface of foley's tube, containing active medicine and medicine built agent, medicine in medication coat
Built agent accelerates active medicine rate of release from sacculus, and medicine discharged within the shortest period and rapid osmotic enters
Tissue at disease sites, thus improve medicine absorbance in the illing tissue of vascular system or other body lumens, can
Lose and medicine quickly turning to target lesion position after balloon expandable with solution medication amount in Clinical practice course of conveying
Carry.
Additionally it can be seen that compound medicine of the present invention can effectively solve lipophilic medicine crystal form, size and
The agglomeration problems that medicine crystal reunion causes.Obtaining the effect of good suppression lesion vessels restenosis simultaneously, greatly reducing
Blood vessel embolism odds.
Claims (10)
1. the compound medicine for arteries pathological changes expansion medicine carrying sacculus, it is characterised in that include raw material: be used for treating
The lipophilic active medicine of arteries pathological changes, medicine built agent, solvent, wherein active medicine with medicine built agent mass ratio is
1.2-4.8；The gross mass of active medicine and medicine built agent and the mass volume ratio of solvent are 8-20 (g/l)；Described medicine is multiple
Ingredients is hydrophilic surfactant active；Described solvent is non-polar solven miscible with water or non-polar solven and water
Mixed solution.
Compound medicine for arteries pathological changes expansion medicine carrying sacculus the most according to claim 1, it is characterised in that institute
Stating active medicine with medicine built agent mass ratio is 1.5-4.8.
Compound medicine for arteries pathological changes expansion medicine carrying sacculus the most according to claim 1, it is characterised in that institute
The mass volume ratio of the gross mass and solvent of stating active medicine and medicine built agent is 10-15 (g/l).
4. according to the compound medicine for arteries pathological changes expansion medicine carrying sacculus described in claim 1-3 any one, its
Being characterised by, described active medicine is paclitaxel, rapamycin or taxol.
5. according to the compound medicine for arteries pathological changes expansion medicine carrying sacculus described in claim 1-3 any one, its
Being characterised by, described medicine built agent is one or more in Fructus Vitis viniferae amine substance, acetamide, sorbitol, PEG100 etc..
Compound medicine for arteries pathological changes expansion medicine carrying sacculus the most according to claim 5, it is characterised in that institute
Stating Fructus Vitis viniferae amine substance is N-methyl-D-glucose methylamine, N-methyl-D-glucose ethamine or caprylyl-N-methyl glucoside
Amine.
7. according to the compound medicine for arteries pathological changes expansion medicine carrying sacculus described in claim 1-3 any one, its
Being characterised by, described solvent is at least one in methanol, ethanol, acetone, ethyl acetate, DMSO, DMF；Or described solvent
For at least one in methanol, ethanol, acetone, ethyl acetate, DMSO, DMF and the mixed mixed solution of water.
Compound medicine for arteries pathological changes expansion medicine carrying sacculus the most according to claim 7, it is characterised in that institute
Stating solvent is at least one in methanol, ethanol, DMSO, or described solvent be in methanol, ethanol, DMSO at least one with
The mixed mixed solution of water.
9. a medicine carrying sacculus, it is characterised in that include the sacculus rolling over valve structure, be attached with medication coat, medicine in balloon surface
Thing coating includes active medicine and medicine built agent；Described active medicine is the lipophilic active for treating arteries pathological changes
Medicine；Described medicine built agent is hydrophilic surfactant active.
Medicine carrying sacculus the most according to claim 9, it is characterised in that in described medication coat, medicine built agent parcel or
Interval active drug particles.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610612700.5A CN106237330A (en) | 2016-07-27 | 2016-07-27 | Compound medicine and medicine carrying sacculus for arteries pathological changes expansion medicine carrying sacculus |
| PCT/CN2017/089228 WO2018019055A1 (en) | 2016-07-27 | 2017-06-20 | Compound drug for drug-loaded balloon for diseased artery vasodilatation and drug-loaded balloon |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610612700.5A CN106237330A (en) | 2016-07-27 | 2016-07-27 | Compound medicine and medicine carrying sacculus for arteries pathological changes expansion medicine carrying sacculus |
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| WO (1) | WO2018019055A1 (en) |
Cited By (3)
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| CN107088259A (en) * | 2017-06-09 | 2017-08-25 | 上海心至医疗科技有限公司 | A kind of medicinal balloon and preparation method thereof |
| WO2018019055A1 (en) * | 2016-07-27 | 2018-02-01 | 杭州唯强医疗科技有限公司 | Compound drug for drug-loaded balloon for diseased artery vasodilatation and drug-loaded balloon |
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| WO2018019055A1 (en) | 2018-02-01 |
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