CN109381737A - Load the medicament slow release suppository and its preparation method and application of Finasteride - Google Patents
Load the medicament slow release suppository and its preparation method and application of Finasteride Download PDFInfo
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- CN109381737A CN109381737A CN201811144772.7A CN201811144772A CN109381737A CN 109381737 A CN109381737 A CN 109381737A CN 201811144772 A CN201811144772 A CN 201811144772A CN 109381737 A CN109381737 A CN 109381737A
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- finasteride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
- A61L2300/222—Steroids, e.g. corticosteroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
- A61L2300/434—Inhibitors, antagonists of enzymes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Abstract
The invention discloses the medicament slow release suppositories and its preparation method and application of load Finasteride, medicine polyvinyl alcohol (PVA) nanofiber is carried by the way that electrostatic spinning technique preparation is blended, Finasteride is carried in nanofiber, composition drug sustained release system is used for the intervention embolization of benign prostatic hyperplasis (BPH).By the intervention embolization method for changing oral Pharmaceutical dosage forms, dosing way by pharmaceutical carrier, Finasteride is efficiently controlled in the release of diseased region, reach make while intervention embolization purpose treat BPH drug Finasteride directly prostate local patholoic change area quickly, sustained release.The system biocompatibility is good, and the medicament slow release time is long, significant in efficacy.The present invention is introduced into medicine PVA nanofiber is carried in the intervention embolization of BPH, it will help the research and application of clinical treatment BPH.
Description
Technical field
The invention belongs to intervene field of medical materials, it is related to a kind of preparation method of intervention vascular suppository material and answers
With in particular to a kind of medicament slow release suppository and its preparation method and application for loading Finasteride.
Background technique
Benign prostatic hyperplasis (Benign Prostatic Hyperplasia, BPH) is to seriously affect middle-aging male
The common disease in the urological system of health.The reason of causing BPH is broadly divided into two aspects: first is that the testosterone that male testical generates exists
Is changed into protona under α 1- reduction enzyme effect, acts on prostate and cause hyperplasia of prostate, the prostate gland of increase is to two
Prominent in side and bladder, urethra simultaneously causes bladder outlet obstruction；It on the other hand is that prostate gland, coating and smooth muscle contain
There is α receptor abundant, caused tension to increase by after the stimulation of mechanical obstruction, the diseases such as frequent micturition, the urgent urination even urinary incontinence occurs
Shape.For the factor for causing BPH and thus bring symptom is the important evidence of remedy measures selection.Common treatment BPH's
Mode is mainly drug therapy, surgical intervention, and in addition there are the treatment means such as microwave radio, laser ablation.Surgical intervention is main
For open operation and transurethral prostatectomy, the two overall efficiency can reach 80% or more, be invasive treatment, and
Many patients are reluctant to receive this invasive surgery, and for worn with age and also should not be into other systems disease
Row operative treatment.Drug therapy is broadly divided into alpha 1-receptor retarding agent (Terazosin, Doxazosin etc.) and 5α-reductase inhibits
Agent (dutasteride, Finasteride etc.), but due to after clinically there is drug oral utilization rate it is lower, need frequent drug administration to tie up
Numerous disadvantages such as drug effect, curative effect be unstable and costly are held, Development of Novel treatment means are badly in need of.And microwave radio, laser ablation
Equal minimally-invasive treatments mode need to pass through urethra, rectum, make the atrophy of prostata tissue part, can be used as a kind of hand of adjuvant treatment
Section, long-term curative effect needs further look at.
With the development of clinically medical instrument and interventional medicine technology, prostatic artery Embolization (Prostatic
Arterial Embolization, PAE) gradually develop, main process is to insert the catheter into prostate feeding artery, injection
Embolism materials block prostate blood supply and nutrition, keep its hypoxic-ischemic downright bad, melt coelosis, and prostate volume reduces, lower urethra
Symptom resolution.The Embosphere that Sun etc. is 300-500 μm with diameter occurs brighter beasle dog row PAE for embolism 1 month
The phenomenon that aobvious blister cavities necrosis and prostate volume reduce, and complication is not occurred, it was demonstrated that its safety and validity are good
Good (Vascular and Interventional Radiology, 2011,197:495-501).Wang et al. is to 64 forefront
Body of gland product is greater than 80cm3BPH patients row PAE, and from international contest, quality of life, Qmax, forefront
Gland specific antigen and prostate volume etc. have carried out overall merit and data statistics, patient's various aspects to patient's recovery situation
Improve it is good, it is same to confirm that PAE is safe and effective, and for therapeutic treatment failure or not can be carried out operation patient it is equally applicable
(International Journal of Urology,2015,22:766-772).Ideal suppository is row PAE treatment
Key factor.Suppository currently used for BPH treatment has a single function, and only serves the function of physics embolism, and there is no load medicines, if
Physics embolism and drug therapy are organically combined, it will accelerate the therapeutic effect of embolism.In recent years, electrostatic spinning technique preparation is received
The research of rice fiber medicine-carried system is widely paid close attention to.Polyvinyl alcohol (Polyvinyl Alcohol, PVA) has preferable
Chemical stability and excellent biocompatibility are a kind of pole that can be used for fermented food industry, medical industry and chemical industry
Potential biological carrier materials have passed through U.S. Food and Drug Administration (FDA) certification.Patent CN
102936795 A disclose a kind of medicament-carrying nano-fiber membrane and preparation method thereof, are prepared for PVA/ by electrostatic spinning process
The medicament-carrying nano-fiber film of plain compound system, which has excellent drug slow release function, and passes through adjusting
The ratio controllable adjustment drug release rate of PVA and fibroin.Based on PVA Electrospun nano-fibers specific surface area with higher
The high feature with porosity researchs and develops one kind using PVA Electrospun nano-fibers as carrier, loads Finasteride drug,
It is required that time in certain mode appointed part discharge to achieve the purpose that treat BPH, have on clinical medicine
Important realistic meaning.
Up to now, domestic and foreign literature or patent search result show still not non-with electrostatic spinning technique preparation load
The PVA nanofiber medicine-carried system of that male amine and its application study.
Summary of the invention
In view of this, the present invention provides a kind of medicament slow release suppository for loading Finasteride and preparation method thereof and answering
With the nanofiber medicament slow release suppository can be realized the controlled release of drug, have physics embolism and drug therapy dual
Effect will have important application in the treatment of BPH.
First aspect present invention provides a kind of medicament slow release suppository for loading Finasteride, the medicament slow release embolism
Agent is the polyvinyl alcohol nano micron particles for loading Finasteride, and the Finasteride physics is coated on polyvinyl alcohol nano
In fiber, the carrying drug ratio of the polyvinyl alcohol nano is 5-8%, and polyvinyl alcohol nano diameter is 150-250nm.
Preferably, the partial size of the micron particles is 100-300 μm.Partial size too great Yi obstruction conduit, partial size too little Yi into
Enter at arteriovenous anastomosis and enters the arteries of other organs and cause accidentally bolt.
Second aspect of the present invention provides the preparation method of the medicament slow release suppository of above-mentioned load Finasteride, step packet
It includes:
S1, polyvinyl alcohol is dissolved by heating to Yu Shuizhong, Finasteride powder is added, sonic oscillation obtains electrostatic spinning solution；
S2, the polyethylene that electrostatic spinning solution described in step S1 is prepared to load Finasteride using method of electrostatic spinning
Alcohol nano-fiber film；
S3, polyvinyl alcohol nano film described in step S2 is heat-treated, then Freezing smashing must load it is non-that
The polyvinyl alcohol nano particle of male amine；
S4, it will sieve, obtain after the polyvinyl alcohol nano particle drying of load Finasteride obtained by step S3
Load the medicament slow release suppository of Finasteride.
Preferably, heating temperature described in step S1 is 80-95 DEG C, and the mass ratio of the Finasteride and polyvinyl alcohol is 1:
6-1:3。
More preferred, polyvinyl alcohol described in step S1, which dissolves by heating Yu Shuizhong, makes the mass concentration 6- of polyvinyl alcohol
10%, one of model PVA0588, PVA1788, PVA1799, PVA124 of the polyvinyl alcohol.Specific model PVA
Guarantee appropriate viscosity with mass concentration, conducive to the formation of silk thread linear in subsequent step, the syringe needle of spinning machine is avoided to block.
Preferably, the process conditions of method of electrostatic spinning described in step S2 are as follows: spinning flow velocity is 0.015-0.2mL/min,
Spinning temperature is 20-40 DEG C, and it is 10-20cm, voltage 10-20KV that positive and negative anodes, which receive distance,.Using be blended electrostatic spinning technique,
It adjusts spinning flow velocity and receives distance, electrostatic spinning solution is generated into table under electrostatic field under certain spinning temperature and voltage
The nano-fiber film of smooth, even thickness the load Finasteride in face.
Preferably, the mode of heat treatment described in step S3 is vacuum and heating drying, and heat treatment temperature is
150-180 DEG C, heat treatment time 10-120min.Specific heat treatment temperature and time has nanofiber
Excellent water stability, and treated carry medicine PVA nanofiber pattern it is still smooth, complete, the diameter of fiber will not occur
Apparent variation.And heat treatment can increase the crystallinity of PVA, delay the release of drug.
More preferred, Freezing smashing described in step S3 is liquid nitrogen grinding pulverization process 10-20min.Liquid nitrogen grinding is formed
Load medicine PVA nanofiber embolic particles be irregular rod shape, flakey and still maintain fine Nanofiber Network knot
Structure.
Preferably, drying mode described in step S4 is vacuum drying, and the screening is using 48 mesh and 150 the polished standard screens
It is sieved, obtains the partial size of particle between 100-300 μm.
Third aspect present invention provides the medicament slow release suppository of above-mentioned load Finasteride in benign prostatic hyperplasis
Treat the application in suppository.
Beneficial effects of the present invention: the nanometer fiber slow-releasing suppository of load Finasteride prepared by the present invention, by borrowing
It helps pharmaceutical carrier to change the intervention embolization method of oral Pharmaceutical dosage forms, dosing way, efficiently controls Finasteride in disease
The release for becoming position, reach makes the drug Finasteride for treating BPH directly in prostate while intervention embolization purpose
Local patholoic change area quickly, sustained release.In addition, nanofiber has the topological structure similar with extracellular matrix, convenient in blood
Deposition, embolism, are not easy reflux and drift in pipe.The nanofiber suppository it is nontoxic it is non-stimulated, biocompatibility is good, meet people
The safety standard that body uses, can permanent embolism it is intravascular in human body target.The method that the present invention prepares medicament-carrying nano-fiber suppository
It is simplicity, green non-pollution, at low cost, to equipment without particular/special requirement, it is conducive in large-scale production, high financial profit.
Detailed description of the invention
Fig. 1 is load medicine PVA nanofiber FESEM figure (a) and distribution of fiber diameters histogram prepared by the embodiment of the present invention 1
(b)；
Fig. 2 is the FESEM figure (a) of drug Finasteride loaded by the embodiment of the present invention 1, the PVA nanofiber of comparative example 2
TEM schemes (b) and embodiment 1 carries medicine PVA nanofiber TEM figure (c)；
Fig. 3 is the load medicine PVA nanofiber FESEM figure (a) and nanofiber particle that the embodiment of the present invention 1 is heat-treated
FESEM schemes (b)；
Fig. 4 is embodiment 1 and comparative example 1, and the heat treatment of comparative example 2 is not heat-treated, carries medicine and non-medicament-carrying nano-fiber
FTIR schemes (a) and XRD diagram (b)；
Fig. 5 is the nonheat-treated load medicine of the load medicine PVA nanofiber (a) that the embodiment of the present invention 1 is heat-treated and comparative example 1
The water stability of PVA nanofiber (b) tests digital photograph；The load medicine PVA nanofiber (a) and comparative example 1 of heat treatment be not warm
Microcosmic FESEM after the load medicine PVA nanofiber (c) of processing is handled for 24 hours in water schemes (d)；
Fig. 6 is the drug accumulation release profiles for the load medicine PVA nanofiber that the embodiment of the present invention 1 is heat-treated；
Fig. 7 is that the FESEM for the load medicine PVA nanofiber that the embodiment of the present invention 1 is heat-treated schemes (a) and after drug release 31 days
Surface microscopic topographic observes FESEM figure (b)；
Fig. 8 is the load medicine PVA nano-fiber film and human smooth muscle cell that the embodiment of the present invention 1 is heat-treated
(HVSMCs) the cell proliferation experiment result of measurement in 1,3,5 day is co-cultured；
Fig. 9 is that HVSMCs is trained on the load medicine PVA nano-fiber film (a), (b) and cell climbing sheet (c), (d) of heat treatment
FESEM figure after supporting 1 day；
Figure 10 is that HVSMCs is trained on the load medicine PVA nano-fiber film (a), (b) and cell climbing sheet (c), (d) of heat treatment
FESEM figure after supporting 3 days；
Figure 11 is the hemolysis rate test result of the load medicine PVA nano-fiber film of heat treatment；
Figure 12 is the external circulation assessment result of load medicine PVA nanofiber suppository of heat treatment；
Figure 13 is digital subtraction angiography (DSA) figure before and after beasle dog prostate embolization of tumors via feeders.(a) before on the right side of
DSA schemes before column gland embolization of tumors via feeders；(b) DSA schemes after prostate embolization of tumors via feeders on the right side of；(c) prostate blood supply on the left of
DSA schemes before arterial embolism；(d) DSA schemes after prostate embolization of tumors via feeders on the left of；
Figure 14 is (a) and bolt before the load medicine PVA nanofiber suppository embolism beasle dog prostate feeding artery being heat-treated
Fill in 1 month (b), 3 month (c) and 6 months (d) prostate Coronal T2WI MRI images；
Figure 15 is embolization of tumors via feeders 6 months solid tissues (a) of beasle dog prostate, carries medicine PVA nanofiber embolism
Agent is filled in the HE stained slice (b) of blood vessel, and prostata tissue necrosis forms the HE stained slice (c) of blister cavities；Remaining prostate
The HE stained slice of tissue shows the deposition (d) of iron xanthematin；The Masson stained slice (e) of prostate residual body of gland；
Figure 16 is kidney (a), vas deferens (b), bladder (c) and rectum (d) after beasle dog prostatic artery embolism 6 months
HE stained slice picture；
Figure 17 is CD34 (a), HIF-1 α (b) and VEGF in prostata tissue after beasle dog prostatic artery embolism 6 months
(c) immunohistochemistry slice.
Specific embodiment
To facilitate the understanding of the present invention, present invention work more comprehensively, is meticulously described below in conjunction with embodiment, but this hair
Bright protection scope is not limited to embodiment in detail below.
Unless otherwise defined, all technical terms used hereinafter and the normally understood meaning of those skilled in the art
It is identical.Technical term used herein is intended merely to the purpose of description specific embodiment, is not intended to the limitation present invention
Protection scope.
Unless otherwise specified, various raw material, reagent, the instrument and equipment etc. used in the present invention, can pass through
Market is commercially available or can be prepared by existing method.
Embodiment 1
A kind of nanofiber medicament slow release suppository for loading Finasteride is present embodiments provided, is included the following steps:
(1) PVA1799 for weighing 0.8g is dissolved in the deionized water of 9.2mL, and 90 DEG C of oil bath heatings are thick to clarifying, cooling
Defoaming is stand-by, then 0.2g Finasteride powder is added into PVA spinning solution, and sonic oscillation 30min or so is obtained to being uniformly mixed
The PVA spinning solution of carrying medicament.
(2) above-mentioned gained spinning solution is subjected to spinning, spinning parameter setting are as follows: selection 9 is not on electrostatic spinning apparatus
Become rusty steel needle head, and environment temperature is 25 DEG C, and spinning flow velocity is 0.015mL/min, and positive and negative pole tension is 18.0KV, stainless steel syringe needle
Be 15cm at a distance from aluminium foil, after the completion of electro-spinning process, remove the nano-fiber film with aluminium foil, be dried in vacuo under room temperature
24h。
(3) it is taken off with tweezers and carries medicine PVA nano-fiber film, be heated to 165 DEG C of processing 10min in a vacuum drying oven,
The preferable nano-fiber film of water resistance is made.
(4) with liquid nitrogen grinding pulverization process 15min after film obtained by step (3) being shredded, after vacuum drying with 48 mesh with
The screening of 150 the polished standard screens obtains 100-300 μm of nanofiber medicament slow release suppository.
Further, comparative example 1 and comparative example 2 are provided as control:
Comparative example 1
(1) PVA1799 for weighing 0.8g is dissolved in the deionized water of 9.2mL, and 90 DEG C of oil bath heatings are thick to clarifying, cooling
Defoaming is stand-by, then 0.2g Finasteride powder is added into PVA spinning solution, and sonic oscillation 30min or so is obtained to being uniformly mixed
The PVA spinning solution of carrying medicament.
(2) above-mentioned gained spinning solution is subjected to spinning, spinning parameter setting are as follows: selection 9 is not on electrostatic spinning apparatus
Become rusty steel needle head, and environment temperature is 25 DEG C, and spinning flow velocity is 0.015mL/min, and positive and negative pole tension is 18.0KV, stainless steel syringe needle
Be 15cm at a distance from aluminium foil, after the completion of electro-spinning process, remove the nano-fiber film with aluminium foil, be dried in vacuo under room temperature
For 24 hours up to load medicine PVA nano-fiber film.
Comparative example 2
(1) PVA1799 for weighing 0.8g is dissolved in the deionized water of 9.2mL, and 90 DEG C of oil bath heatings are thick to clarifying, cooling
Defoaming is stand-by, obtains PVA spinning solution.
(2) above-mentioned gained spinning solution is subjected to spinning, spinning parameter setting are as follows: selection 9 is not on electrostatic spinning apparatus
Become rusty steel needle head, and environment temperature is 25 DEG C, and spinning flow velocity is 0.015mL/min, and positive and negative pole tension is 18.0KV, stainless steel syringe needle
Be 15cm at a distance from aluminium foil, after the completion of electro-spinning process, remove the nano-fiber film with aluminium foil, be dried in vacuo under room temperature
24h。
(3) PVA nano-fiber film is taken off with tweezers, be heated to 165 DEG C of processing 10min in a vacuum drying oven, be made
The preferable nano-fiber film of water resistance.
FESEM observation the results show that carry medicine PVA nano-fiber film (before heat treatment) surface it is regular, morphological rules, diameter
Uniform, average diameter is 197.3nm (see attached drawing 1).Attached drawing 2 (a) show Finasteride solid powder FESEM figure, from figure
In it can be seen that random spherical, rod shape and flakey is mainly presented in Finasteride.PVA nanometers of the load medicine of comparative example 1
The TEM of fiber and the PVA nanofiber of comparative example 2 figure carries visible Finasteride drug particle in medicine PVA nanofiber and uniformly divides
It is distributed in nanofiber, illustrates that this hydrophobic drug is successfully loaded into PVA nanofiber (see attached drawing in the form of solid particle
2(b),2(c)).By attached drawing 3 (a) it is found that heat treatment after, carry medicine PVA nanofiber pattern it is still smooth, complete, fiber it is straight
Also there is no significantly changing for diameter.The load medicine PVA nanofiber embolic particles that cryogrinding is formed are irregular rod shape, squama
Sheet and fine Nanofiber Network structure is still maintained, the partial size of particle is between 100-300 μm (see attached drawing 3 (b)).By
The FTIR map of Fig. 4 (a) is it is found that carry medicine PVA nanofiber in 1666cm-1And 1598cm-1There is the bending vibration of two amino
Absorption peak is moved, distinctive amino absorption peak in that male amine molecule structure of this right and wrong illustrates that Finasteride is loaded into PVA nanofiber
In.The FTIR map for comparing heat treatment and untreated PVA nanofiber is found, is heat-treated PVA nanofiber in 1141cm-1Out
- OH bending vibration the absorption peak now reinforced increases PVA this is because heat treatment promotes the physical crosslinking of intramolecule-OH
The crystallinity of nanofiber.In addition, can be seen that pure Finasteride by the XRD diagram spectrum analysis of attached drawing 4 (b) is a kind of knot
The higher drug of crystalline substance carries medicine PVA nanofiber and the characteristic peak of Finasteride occurs, illustrates what Finasteride was coated with physics
There are in nanofiber for form.Meanwhile comparing heat treatment and the discovery of untreated PVA nanofiber in the appearance of 2 θ=19.8 °
New peak crystallization, this is because increasing the crystallinity of PVA nanofiber after heat treatment.
Embodiment 2
By the nonheat-treated load medicine PVA Nanowire for carrying medicine PVA nano-fiber film and being heat-treated with embodiment 1 of comparative example 1
Dimension film immerses in deionized water simultaneously, and the pattern situation of change of two kinds of nano-fiber films is observed after several minutes, continues 37
DEG C impregnation is taken out afterwards for 24 hours, after freeze-drying from it is microcosmic it is upper from nanofibrous structures variation.Two kinds from macroscopically
The result of the variation of nano-fiber film morphosis is as shown in figure 5, the nano-fiber film through Overheating Treatment impregnates in water
Afterwards, fiber is undissolved, and swelling only has occurred (see attached drawing 5 (a))；Not thermally treated load medicine PVA nano-fiber film is put into
Shrinkage crimping quickly after in water becomes hydrogel sample (see attached drawing 5 (b)).It is further looked at by FESEM and is received after water process
The variation of rice fiber membrane microstructure, from Fig. 5 (c) it is found that the load medicine PVA nano-fiber film after heat treatment can still be kept
Its fine nanofibrous structures, and untreated load medicine PVA nano-fiber film loses its nanofibrous structures completely
(see attached drawing 5 (d))), nanofiber has good water stability after illustrating heat treatment.
Embodiment 3
The measurement of vitro drug release and carrying drug ratio and encapsulation rate
PBS (pH=7.4) buffer solution for containing 0.1wt%Tween80 is prepared as drug release medium, is accurately weighed
Prepared by 20mg embodiment 1 carries in the centrifuge tube of medicine PVA nano-fiber film merging splendid attire 40mLPBS buffer, parallel testing
Five groups.Centrifuge tube is placed in constant-temperature table, set temperature is 37 DEG C, shaking speed 150rpm, at the time point of setting
2mL drug release liquid is taken, and adds 2mL PBS buffer solution and maintains constant volume.Using HPLC Finasteride absorption maximum
Medicament slow release liquid is measured at wavelength X=210nm and absorbs peak area, and drug concentration and burst size are measured according to standard curve, passed through
Calculation formula 1 calculates drug accumulation release percentage and draws cumulative release curve.After the dissolution of medicine PVA nanofiber will be carried, mistake
It filters off and removes polymer, the content for carrying Finasteride in medicine PVA nanofiber is measured by HPLC method.Divided according to formula 2 and formula 3
The carrying drug ratio and encapsulation rate for carrying medicine PVA nanofiber are not calculated.
It is learnt according to data analysis result, the carrying drug ratio for carrying medicine PVA nanofiber is 6.7%, encapsulation rate 53.52%.
By attached drug accumulation release profiles shown in fig. 6 it is found that carrying the drug Finasteride in medicine PVA nano fibrous membrane has certain dash forward
Effect is released, release is close to 30% in initial 48h, this is because what the drug release of blended drug-loading fibre early stage followed is medicine
Object surface parses and duct diffusion mechanism, and the drug near nanofiber surface, burst effect is bigger, and rate of release is also accordingly got over
Fastly.It releases the drug after 120h, release profiles start to become relatively gentle, this is because nearby drug release has connect nanofiber surface
Close fiber becomes loose completely, generates some hydrophilic holes, and drug molecule wraps up internal slow release from fiber, at this moment
The rate of release of drug is determined by nanofiber internal drug duct diffusion rate.With the extension of time, cumulative release
Amount variation is smaller, shows good stability, has achieved the effect that sustained release.
Formula 1:
Q: the cumulative release amount of drug, %；Cn: the sample concentration that n-th of time point is taken, μ g/mL；
V: dissolution medium volume；Vi: the sample volume at i-th of time point；Ci: i-th of time point samples taken concentration (V0
And C0It is zero) μ g/mL；mdrug: carry the quality of drug in medicine PVA nanofiber；N: the number of dissolution medium is replaced.
Formula 2:
DL (%)=MPacket/MAlways×100
Wherein, DL is the carrying drug ratio for carrying medicine PVA nanofiber, MPacketIt is the drug quality embedded in PVA nanofiber, M is total
It is the gross mass for carrying medicine PVA nanofiber.
Formula 3:
EE (%)=MPacket/MMedicine×100
Wherein, EE is the encapsulation rate for carrying medicine PVA nanofiber, MPacketIt is the drug quality embedded in PVA nanofiber, MMedicineIt is
The drug gross mass of investment.
In addition, nanofiber (attached drawing 7 (b)) pattern occurs after discharging drug by comparison attached drawing 7 (a) and 7 (b) discoveries
Very big variation, nanofiber surface just it is coarse and there are many holes, and the average diameter of nanofiber becomes larger, moisture
After son enters nanofiber, PVA nanofiber is caused to be swollen, promotes the formation of nanofiber surface hole, be conducive to drug and release
It releases.
Embodiment 4
Carry the Cyto-compatibility in vitro evaluation of medicine PVA nano-fiber film
A. cell proliferation experiment
Round cell creep plate, the round medicine PVA nano-fiber film that carries are put into 24 porocyte culture plates respectively, cell is climbed
Piece is as control sample.After 75% ethyl alcohol sterilization treatment 2h is added in the sample, rinsing 3 is impregnated with sterile phosphate buffer
It is secondary, each 15min or so.Then the DMEM high glucose medium material previously treated 30min for using serum-free, is put into 37 DEG C of incubator
In dry overnight, in case repopulating cell.Human smooth muscle cell (HVSMCs) is with 2 × 104The inoculum density in a/hole is planted in
On sample, the DMEM high glucose medium containing fetal calf serum is sequentially added in each hole, is put into 37 DEG C, 5%CO2It is incubated in incubator
It educates.The proliferation activity of cell is detected after culture 1,3,5 day with CCK-8, as a result as shown in Figure 8.HVSMCs and load medicine PVA Nanowire
After tieing up film co-cultivation 1,3,5 day, CCK-8 testing result shows compared with cell climbing sheet, and carrying medicine PVA nanofiber can more promote
Into the fast breeding of HVSMCs, this is because nano fibrous membrane has the structure feature similar with extracellular matrix, and three wieners
Rice network of fibers is cell growing space, is conducive to the exchange of the nutritional ingredient and waste in cell metabolism.
B. cell adhesion morphologic observation
In order to further look at HVSMCs and carry the interaction of medicine PVA nano-fiber film, sample is by same pre-
After processing, HVSMCs is with 2.5 × 104The inoculum density in a/hole is planted on sample, after culture in 1,3 day, with 2.5%
Glutaraldehyde solution is in 4 DEG C of fixed 1h, the remaining glutaraldehyde of sterile phosphate buffer cleaning removal, respectively with 30%, 50%,
70%, 90%, 95% and 100% Gradient elution using ethanol, each 10min, finally with 100% the tert-butyl alcohol replace 2 times, every time
10min.Sample is subjected to freeze-drying process after displacement, with observing cell under FESEM under the acceleration voltage of 15KV after metal spraying
Pattern, result are as shown in Figure 9 and Figure 10.It can be seen from the figure that HVSMCs can be preferable on carrying medicine PVA nanofiber
Proliferation diffusion, and only sprawled on cell climbing sheet, do not stretch out a large amount of pseudopodium；Cell on nanofiber presents polygon
Shape, and it is adhered to one another between cell, and the cell cultivated on cell climbing sheet is more dispersed, less connection between cell.Cell
It is better than cell climbing sheet in the situation of sticking for carrying medicine PVA nanofiber, it is huge that this should be attributed to the fact that Electrospun nano-fibers have
Big specific surface area, three-dimensional porous nano network of fibers provides for cell more sticks contact point, and nanofiber is thinner
Born of the same parents' creep plate surfaces versus rough is more advantageous to the absorption of albumen and sticking and being proliferated for cell.
Embodiment 5
Carry the hemolysis rate test of medicine PVA nano-fiber film
It is spare that fresh anticoagulant rabbit blood and physiological saline according to volume ratio 4:5 are hybridly prepared into diluted rabbit blood.Take 0.5cm
The load medicine PVA nano-fiber film of × 0.5cm is cleaned with physiological saline, is added in 10mL physiological saline and is impregnated for 24 hours, inhales and abandon physiology
Salt water rejoins after 5mL physiological saline is incubated for 30min in 37 DEG C of incubators, the diluted rabbit blood of 0.1mL is added, gently shakes
It is even, it is placed in 37 DEG C of incubators and continues to be incubated for 1h, supernatant liquor is drawn after 1000rpm centrifugation 5min, with UV-vis spectroscopy light
Degree meter measures absorbance in 545nm wavelength.Positive control is ultrapure water, and negative control is physiological saline, sample parallel testing 5 times
It is averaged, calculates hemolysis rate according to following formula.
Hemolysis rate=(X1-X2)/(X2-X3) × 100%
Wherein, X1For the absorbance value of sample, X2For the absorbance value of positive control, X3For the absorbance value of negative control.
Test result is as shown in Fig. 11, and the hemolysis rate for carrying medicine PVA nano-fiber film is 1.44%, is far below state's domestic discipline and family rules
Fixed standard (standard regulation, be safe when hemolysis rate is less than 5%), illustrates that carrying medicine PVA nanofiber has preferable blood
Compatibility can be used as interventional embolization material and be applied in vivo.
Embodiment 6
Carry the external circulation assessment of medicine PVA nanofiber suppository
The load medicine PVA nanofiber embolic particles for taking suitable embodiment 1 to prepare are mixed with physiological saline, are injected with 5mL
Device is drawn the load medicine PVA nanofiber suppository for being suspended in physiological saline and is connect with 5Fr microtubular, slow bolus syringe,
Observe suspended state of the embolic particles in syringe and the current intelligence in microtubular.As shown in attached drawing 12 (a), embolic particles
Suspension is good in syringe, pushes and has no that embolic particles block microtubular phenomenon during syringe, almost used to receive
Rice fiber embolic particles can pass through microtubular (see attached drawing 12 (b)), illustrate that the external circulation of embolic particles is good, can use
In interior animal experiment row arterial embolism.
Embodiment 7
Internal animal embolism experiment
Zoopery is carried out according to " Hubei Province's management of laboratory animal regulations ", and passes through Tongji University, Central China University of Science and Technology medicine
Attached Hospital Ethical Committee, Tongji University, institute passes.
It chooses 5 male beagle dogs that average weight is 13.2kg and beasle dog benign prostate is established by hormone induction method
Hyperplasia (BPH) model measures prostate volume size, according to formula (1) by MRI scan beasle dog prostate after modeling 3 months
Calculate prostate volume.
After modeling 3 months, the successful beasle dog anaesthetic treatment of modeling is placed on operating table, using Seldnger technology
Insertion 5F catheter sheath is punctured through right common femoral artery, uses seal wire and conduit super under the monitoring of digital subtraction angiography instrument (DSA)
Selection enters prostate feeding artery, after radiography confirms, will carry medicine PVA nanofiber suppository and physiological saline and Iohexol are molten
Liquid is slowly injected by conduit after mixing, with 5mL syringe, and prostate feeding artery blood flow can be observed at this time and gradually delay
Slow and close stagnation, until prostate vasculature bed does not develop.Left side radiography finishes, and radiography confirms that prostate feeding artery is hindered
It is disconnected, after inserting the catheter into right side internal iliac artery " at button loop method ", with seal wire and conduit insertion right side prostate feeding artery, bolt
The same left side of blocking method, radiography confirmation right side prostate feeding artery is complete by embolism after embolism, withdraws from all conduits, pulls out
Catheter sheath out, after pressing site of puncture 15min, intramuscular injection penicillin is to prevent infection.Attached drawing 13DSA is as the result is shown: before embolism
Row Iohexol angiography, prostatic artery trunk and branch's development are good, and form is smooth naturally, glandular substance of prostate dyeing in forefront is equal
It is even.It carries medicine PVA nanofiber suppository and is smoothly injected into prostate feeding artery through RUC conduit, entire injection process has no poly-
Collection, obstruction conduit phenomenon.Radiography shows that prostate blood supply is interrupted at once after embolism, and the angiography before and after embolism shows to carry medicine
PVA nanofiber suppository has good embolization effect.T2WI MRI is carried out to beasle dog prostate after embolism 6 months to sweep
It retouches, and calculates the size of prostate volume by formula (1), carry medicine PVA nanofiber suppository embolism BPH beasle dog prostate volume
Variation is shown in Table 1.
Table 1 carries the variation of medicine PVA nanofiber suppository embolism BPH beasle dog prostate volume
Note: volume-diminished rate (%)=(A-B)/A × 100% is percentage in ()
As can be seen from the table, beasle dog prostate volume is obviously reduced after embolism, and prostate embolism is more preoperative after 6 months
Volume averagely reduces 84.223%.Attached drawing 14 is that the load medicine PVA nanofiber suppository embolism beasle dog prostate of heat treatment supplies
Before blood artery and 1 after embolism, 3,6 months prostate Coronal T2WI MRI images.Image result shows, prostate before embolism
Volume is larger, and prostate volume is gradually reduced and apparent ischemic necrosis region, prostate bilateral occurs after embolism 1,3,6 month
There is biggish sack cavity structure.
Embodiment 8
Pathology section examination
A. prostate section is observed
Beasle dog embolism in embodiment 7 takes out after 6 months and observes prostate solid tissue, from attached drawing 15 (a)
The necrosis of prostate center of inside leaf area is significant, obvious blister cavities occurs.The histotomy of taking-up by dehydration, paraffin embedding and
Serial section (5 μm thick) is prepared, HE dyeing and Masson dyeing is carried out, in microscopically observation and takes pictures.By Figure 15 (b) institute
Show, carries medicine PVA nanofiber suppository and be filled in blood vessel, at nanofiber embolism, it can be seen that nanofiber suppository
Embolism is more tight in the blood vessel, and visible cell sticks and migrates to nanofiber suppository around vascular embolization, and carries medicine PVA
Nanofiber suppository is around blood vessel without obvious inflammatory reaction.The blister cavities HE stained tissue formed from prostata tissue necrosis is cut
Piece can be seen that it is downright bad (see attached drawing 15 (c)) to occur diffusivity around blister cavities.Pass through the visible remaining of Figure 15 (d) HE stained slice
Occurs the deposition of more iron xanthematin in prostata tissue, due to the postoperative microvessel density of PAE and vascular endothelial growth factor
Increase, new born microvessels permeabilities is high, capilary is fragile and it is unstable be easy to cause micro- bleeding, generate the blood red egg of a large amount of deoxidation
Bletilla hemosiderin.The residual body of gland of prostate as the result is shown of Masson stained slice shown in Figure 15 (e) occurs a large amount of fine
Dimensionization, it was confirmed that embolization effect is good.
B. kidney, vas deferens, bladder and the observation of rectal tissue HE stained slice
Periprostatic bladder, kidney, vas deferens and rectal tissue are taken out after embolism 6 months, using 4% paraformaldehyde
Solution is fixed, then alcohol serial dehydration, paraffin embedding and serial section (5 μm thick), and slice carries out HE dyeing, under microscope
It observes and takes pictures.As shown in Figure 16, prostate perienchyma does not occur dystopy embolism, and no inflammation cellular infiltration after embolism, says
The bright suppository be it is a kind of safely, effectively, without anaphylactoid suppository.
Embodiment 9
Immunohistochemical method detects the expression of prostata tissue CD34, HIF-1 α and VEGF after embolism
After embolism 6 months, operation cuts prostate sample, is fixed using 4% paraformaldehyde, paraffin embedding, makes ultra-thin
Slice, every slice thickness is about 5 μm, is used for Immunohistochemistry.Specific steps are as follows: paraffin section is de- with dimethylbenzene
Wax, graded ethanol dehydration, 3% dioxygen above-water method endogenous peroxydase, sterile phosphate buffer oscillation washing, tissue
Antigen Microwave method；Primary antibody is added dropwise on slice, is incubated in 37 DEG C of incubators, biotin is added dropwise after flushing three times in phosphate buffer
The secondary antibody of label, is developed the color after cleaning with DAB, and haematoxylin is redyed, and dehydration, dimethylbenzene is transparent, resinene mounting, finally by sample
It is placed in fluorescence microscopy under the microscope and takes pictures.The table of CD34, HIF-1 α and VEGF shown in Figure 17 (a), 17 (b) and 17 (c)
Up to situation it is found that three kinds of albumen have significant expression and related to the formation of capilary in prostate, promote after showing embolism
The increase of prostate microvessel density.
Embodiment 10
A kind of nanofiber medicament slow release suppository for loading Finasteride is present embodiments provided, is included the following steps:
(1) PVA124 for weighing 0.6g is dissolved in the deionized water of 9.4mL, and 95 DEG C of oil bath heatings are thick to clarifying, cooling
Defoaming is stand-by, then 0.1g Finasteride powder is added into PVA spinning solution, and sonic oscillation 30min or so is obtained to being uniformly mixed
The PVA spinning solution of carrying medicament.
(2) above-mentioned gained spinning solution is subjected to spinning, spinning parameter setting are as follows: selection 9 is not on electrostatic spinning apparatus
Become rusty steel needle head, and environment temperature is 25 DEG C, and spinning flow velocity is 0.02mL/min, and positive and negative pole tension is 10.0KV, stainless steel syringe needle
Be 20cm at a distance from aluminium foil, after the completion of electro-spinning process, remove the nano-fiber film with aluminium foil, be dried in vacuo under room temperature
24h。
(3) it is taken off with tweezers and carries medicine PVA nano-fiber film, be heated to 150 DEG C of processing 120min in a vacuum drying oven,
The preferable nano-fiber film of water resistance is made.
(4) with liquid nitrogen grinding pulverization process 15min after film obtained by step (3) being shredded, after vacuum drying with 48 mesh with
The screening of 150 the polished standard screens obtains 100-300 μm of nanofiber medicament slow release suppository.
Embodiment 11
A kind of nanofiber medicament slow release suppository for loading Finasteride is present embodiments provided, is included the following steps:
(1) PVA0588 for weighing 1.0g is dissolved in the deionized water of 9.0mL, and 80 DEG C of oil bath heatings are thick to clarifying, cooling
Defoaming is stand-by, then 0.4g Finasteride powder is added into PVA spinning solution, and sonic oscillation 30min or so is obtained to being uniformly mixed
The PVA spinning solution of carrying medicament.
(2) above-mentioned gained spinning solution is subjected to spinning, spinning parameter setting are as follows: selection 9 is not on electrostatic spinning apparatus
Become rusty steel needle head, and environment temperature is 25 DEG C, and spinning flow velocity is 0.018mL/min, and positive and negative pole tension is 20.0KV, stainless steel syringe needle
Be 10cm at a distance from aluminium foil, after the completion of electro-spinning process, remove the nano-fiber film with aluminium foil, be dried in vacuo under room temperature
24h。
(3) it is taken off with tweezers and carries medicine PVA nano-fiber film, be heated to 180 DEG C of processing 50min in a vacuum drying oven,
The preferable nano-fiber film of water resistance is made.
(4) with liquid nitrogen grinding pulverization process 15min after film obtained by step (3) being shredded, after vacuum drying with 48 mesh with
The screening of 150 the polished standard screens obtains 100-300 μm of nanofiber medicament slow release suppository.
Claims (10)
1. a kind of medicament slow release suppository for loading Finasteride, it is characterised in that: the medicament slow release suppository is that load is non-
The polyvinyl alcohol nano micron particles of that male amine, the Finasteride physics are coated in polyvinyl alcohol nano, institute
The carrying drug ratio for stating polyvinyl alcohol nano is 5-8%, and polyvinyl alcohol nano diameter is 150-250nm.
2. the medicament slow release suppository of load Finasteride as described in claim 1, it is characterised in that: the micron particles
Partial size is 100-300 μm.
3. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 1 or 2, it is characterised in that: step
Include:
S1, polyvinyl alcohol is dissolved by heating to Yu Shuizhong, Finasteride powder is added, sonic oscillation obtains electrostatic spinning solution；
S2, electrostatic spinning solution described in step S1 is received using the polyvinyl alcohol that load Finasteride is prepared in method of electrostatic spinning
Rice fiber membrane；
S3, polyvinyl alcohol nano film described in step S2 is heat-treated, then Freezing smashing must load Finasteride
Polyvinyl alcohol nano particle；
S4, it will sieve, loaded after the polyvinyl alcohol nano particle drying of load Finasteride obtained by step S3
The medicament slow release suppository of Finasteride.
4. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 3, it is characterised in that: step
Heating temperature described in S1 is 80-95 DEG C, and the mass ratio of the Finasteride and polyvinyl alcohol is 1:6-1:3.
5. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 4, it is characterised in that: step
Polyvinyl alcohol described in S1, which dissolves by heating Yu Shuizhong, makes the mass concentration 6-10% of polyvinyl alcohol, the model of the polyvinyl alcohol
One of PVA0588, PVA1788, PVA1799, PVA124.
6. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 3, it is characterised in that: step
The process conditions of method of electrostatic spinning described in S2 are as follows: spinning flow velocity is 0.015-0.2mL/min, and spinning temperature is 20-40 DEG C, just
It is 10-20cm, voltage 10-20KV that cathode, which receives distance,.
7. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 3, it is characterised in that: step
The mode of heat treatment described in S3 is dry for heating under vacuum, and heat treatment temperature is 150-180 DEG C, heat treatment time 10-
120min。
8. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 7, it is characterised in that: step
Freezing smashing described in S3 is liquid nitrogen grinding pulverization process 10-20min.
9. the preparation method of the medicament slow release suppository of load Finasteride as claimed in claim 3, it is characterised in that: step
Drying mode described in S4 is vacuum drying, and the screening is to be sieved using 48 mesh and 150 the polished standard screens.
10. the medicament slow release suppository of load Finasteride as claimed in claim 1 or 2 is in treatment of benign prostate hyperplasia suppository
In application.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115120562A (en) * | 2021-03-24 | 2022-09-30 | 苏州博创同康生物工程有限公司 | Drug-loaded nanofiber scaffold particle and preparation method and application thereof |
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