CN106619537A - Ibuprofen-carried slow release nanoparticle, preparation method thereof and application - Google Patents
Ibuprofen-carried slow release nanoparticle, preparation method thereof and application Download PDFInfo
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- CN106619537A CN106619537A CN201710154251.9A CN201710154251A CN106619537A CN 106619537 A CN106619537 A CN 106619537A CN 201710154251 A CN201710154251 A CN 201710154251A CN 106619537 A CN106619537 A CN 106619537A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
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Abstract
The invention belongs to the technical field of medicine, and particularly relates to an ibuprofen-carried slow release nanoparticle, a preparation method thereof and an application. The ibuprofen-carried slow release nanoparticle provided by the invention comprises a carrier and ibuprofen loaded on the carrier; the carrier is polylactic acid-glycolic acid copolymer. The ibuprofen-carried slow release nanoparticle provided by the invention takes polylactic acid-glycolic acid copolymer as a carrier, and has good slow release effect. The invention further provides an ibuprofen-carried slow release preparation for treating visceralgia; the slow release preparation comprises a slow release nanoparticle and pharmaceutically acceptable auxiliary materials. The slow release preparation can treat visceralgia while stop pain for a long time. In the preferential technical scheme provided by the invention, the slow release preparation is sole injection; through the sole injection, the ibuprofen-carried slow release nanoparticle can treat visceralgia and avoid related side effects by orally taking ibuprofen preparation.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to it is a kind of carry ibuprofen slow-release Nano microsphere and preparation method thereof and
Using.
Background technology
Splanchnodynia is clinically common symptom, often caused by the stimulation such as mechanic stretch, spasm, ischemic and inflammation.It is interior
Dirty pain is mainly characterized in that positioning is inaccurate, and the patient that suffers from abdominal pain typically does not can say the particular location of pain generation, main cause is
Due to internal organ algesiroreceptor be distributed than body it is sparse much, while splanchnesthetic afferent pathway is also than relatively decentralized.
Splanchnodynia another feature is to be frequently accompanied by referred pain, i.e., the inflammatory pain of internal organs usually has some region of pain of body surface
Bitterly.Additionally, splanchnodynia often causes offending emotional activity, and change with Nausea and vomiting and respiratory activity etc..At present,
The concrete pathogenesis of splanchnodynia is still unclear, clinically also without effective treatment means.
At present, clinically commonly use the anodyne such as brufen, aspirin, phenylbutazone, rofecoxib, Sai-Mi-Xi-Bu to alleviate
Splanchnodynia, wherein, due to brufen analgesic effect is more than aspirin, phenylbutazone and to flutter heat breath strong, and extremely consumer is blue or green
Look at.But the half-life of brufen is shorter, and analgesic effect is not lasting.
The content of the invention
In view of this, it is an object of the invention to provide a kind of carry ibuprofen slow-release Nano microsphere and preparation method thereof and answer
With the load ibuprofen slow-release Nano microsphere that the present invention is provided has good slow release effect.
The invention provides a kind of carry ibuprofen slow-release Nano microsphere, including carrier and the brufen being supported on carrier；
The carrier is Poly(D,L-lactide-co-glycolide.
Preferably, the weight average molecular weight of the Poly(D,L-lactide-co-glycolide is 40000～75000.
Preferably, there is the repetitive of lactic acid structure in the poly lactic coglycolic acid and there is hydroxyacetic acid
The mol ratio of the repetitive of structure is (50～80)：(50～20).
Preferably, content of the brufen in slow released nano microsphere is 5～20wt%.
Preferably, the particle diameter of the slow released nano microsphere is 50～200nm.
The invention provides described in a kind of above-mentioned technical proposal carry ibuprofen slow-release Nano microsphere preparation method, including with
Lower step：
A), brufen, carrier and organic solvent are mixed, mixed solution is obtained；
B), the mixed solution, emulsifying agent and water are mixed, emulsion is obtained；
C), the emulsion removes organic solvent, obtains carrying ibuprofen slow-release Nano microsphere.
Preferably, the organic solvent includes dichloromethane and/or chloroform；The emulsifying agent include polyvinyl alcohol and/or
Polyethylene glycol.
The invention provides a kind of load sustained release preparations of ibuprofen for treating splanchnodynia, including it is slow described in above-mentioned technical proposal
Release Nano microsphere and pharmaceutically acceptable auxiliary material.
Preferably, the sustained release preparation is subplantar injection agent.
Load ibuprofen slow-release Nano microsphere described in above-mentioned technical proposal is in subplantar injection treatment splanchnodynia medicine is prepared
Application.
Compared with prior art, the invention provides a kind of carry ibuprofen slow-release Nano microsphere and preparation method thereof and answer
With.What the present invention was provided carries ibuprofen slow-release Nano microsphere includes carrier and the brufen being supported on carrier；The carrier is
Poly(D,L-lactide-co-glycolide.The load ibuprofen slow-release Nano microsphere that the present invention is provided is with Poly(D,L-lactide-co-glycolide
As carrier, with good slow release effect.Present invention also offers a kind of load sustained release preparations of ibuprofen for treating splanchnodynia, institute
Sustained release preparation is stated including above-mentioned slow released nano microsphere and pharmaceutically acceptable auxiliary material.The sustained release preparation that the present invention is provided is in treatment
With lasting throe effect during splanchnodynia.In the optimal technical scheme that the present invention is provided, the sustained release preparation is vola note
Agent is penetrated, the present invention treats the related side effects that splanchnodynia can avoid oral ibuprofen formulations from bringing by subplantar injection.It is real
Test result to show, what the present invention was provided carries ibuprofen slow-release Nano microsphere can be relieved the splanchnodynia of rat, it is possible to hold
Continuous pain of alleviation reaches 3 hours.
Description of the drawings
In order to be illustrated more clearly that the embodiment of the present invention or technical scheme of the prior art, below will be to embodiment or existing
The accompanying drawing to be used needed for having technology description is briefly described, it should be apparent that, drawings in the following description are only this
Inventive embodiment, for those of ordinary skill in the art, on the premise of not paying creative work, can be with basis
The accompanying drawing of offer obtains other accompanying drawings.
Fig. 1 is the Nano microsphere grain size distribution that the embodiment of the present invention 1 is provided；
Fig. 2 is the Nano microsphere grain size distribution that the embodiment of the present invention 2 is provided；
Fig. 3 is the Nano microsphere grain size distribution that the embodiment of the present invention 3 is provided；
Fig. 4 is the In-vitro release curves figure of the load ibuprofen pharmaceutical Nano microsphere that the embodiment of the present invention 4 is provided；
Fig. 5 is the In-vitro release curves figure of the load ibuprofen pharmaceutical Nano microsphere that the embodiment of the present invention 5 is provided；
Fig. 6 is the In-vitro release curves figure of the load ibuprofen pharmaceutical Nano microsphere that the embodiment of the present invention 6 is provided；
Fig. 7 is the distribution map of fluorescence in the DRGs that the embodiment of the present invention 7 is provided；
Fig. 8 is the physiological saline of the load brufen Nano microsphere of the subplantar injection various dose that the embodiment of the present invention 8 is provided
Injection alleviates the design sketch of acute visceral pain in rats；
Fig. 9 is the physiological saline agent alleviation that the subplantar injection that the embodiment of the present invention 8 is provided carries brufen Nano microsphere
The time-histories design sketch of acute visceral pain in rats.
Specific embodiment
The technical scheme in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
Only a part of embodiment of the invention, rather than the embodiment of whole.Based on the embodiment in the present invention, the common skill in this area
The every other embodiment that art personnel are obtained under the premise of creative work is not made, belongs to the model of present invention protection
Enclose.
The invention provides a kind of carry ibuprofen slow-release Nano microsphere, including carrier and the brufen being supported on carrier；
The carrier is Poly(D,L-lactide-co-glycolide.
What the present invention was provided carries ibuprofen slow-release Nano microsphere includes carrier and the brufen being supported on carrier.Wherein,
The brufen is also called 2- (- 4- isobutyl phenenyls) propionic acid, and No. CAS is 15687-27-1.
In the present invention, the carrier is Poly(D,L-lactide-co-glycolide (abbreviation：PLGA), the copolymer is random
Copolymer, formed by lactic acid monomer and hydroxyacetic acid monomer copolymerization, copolymer include random arrangement with lactic acid structure
Repetitive and the repetitive with hydroxyacetic acid structure.In one embodiment that the present invention is provided, the polylactic acid-glycolic
The weight average molecular weight (Mw) of acetic acid copolymer is 40000～75000, concretely 45000,50000,55000,60000,
65000 or 70000.In one embodiment that the present invention is provided, there is lactic acid structure in the poly lactic coglycolic acid
Repetitive with have hydroxyacetic acid structure repetitive mol ratio be (50～80)：(50～20), preferably (65～
70)：(35～30).
In one embodiment that the present invention is provided, content of the brufen in ibuprofen slow-release Nano microsphere is carried is
5～20wt%, concretely 6wt%, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%,
15wt%, 16wt%, 17wt%, 18wt% or 19wt%.In one embodiment that the present invention is provided, the brufen is being carried
The particle diameter of ibuprofen slow-release Nano microsphere is 50～200nm, concretely 90～130nm.
The load ibuprofen slow-release Nano microsphere that the present invention is provided has using Poly(D,L-lactide-co-glycolide as carrier
Good slow release effect.Test result indicate that, the load ibuprofen slow-release Nano microsphere that the present invention is provided can be relieved rat
Splanchnodynia, it is possible to lasting remission pain reaches 3 hours.
The invention provides described in a kind of above-mentioned technical proposal carry ibuprofen slow-release Nano microsphere preparation method, including with
Lower step：
A), brufen, carrier and organic solvent are mixed, mixed solution is obtained；
B), the mixed solution, emulsifying agent and water are mixed, emulsion is obtained；
C), the emulsion removes organic solvent, obtains carrying ibuprofen slow-release Nano microsphere.
In the preparation method that the present invention is provided, brufen, carrier and organic solvent are mixed first.Wherein, it is described to have
Machine solvent includes but is not limited to dichloromethane and/or chloroform.In the present invention, the brufen is preferably with the mass ratio of carrier
1：(5～20), more preferably 1：(5～10), specifically may be selected to be 1：8；The mass volume ratio of the carrier and organic solvent is excellent
Elect (50～100) mg as：(1～10) mL.In the present invention, the temperature of the brufen, carrier and organic solvent mixing is preferred
For room temperature；The present invention is not particularly limited to the time for mixing, but brufen and carrier are completely dissolved in organic solvent i.e.
Can；The present invention equipment used to mixing is not particularly limited, preferably shaking table well known to those skilled in the art.Mixing is finished
Afterwards, mixed solution is obtained.
After obtaining mixed solution, by the mixing of the mixed solution, emulsifying agent and water.Wherein, the emulsifying agent include but not
It is limited to polyvinyl alcohol (referred to as：) and/or polyethylene glycol PVA.In the present invention the weight average molecular weight of the polyvinyl alcohol is preferably
9000～2000000, the weight average molecular weight of polyethylene glycol is preferably 5000～2000000.In the present invention, the emulsifying agent with
The mass ratio of carrier is preferably (500～1000) in the mixed solution:(50～100), specifically may be selected to be 600:100、
700:100、710:100、800:100 or 900:100；The water is preferably with the volume mass ratio of carrier in the mixed solution
(30～100) mL：(50～100) mg, specifically may be selected to be 40mL：100mg、50mL：100mg、53mL：100mg、60mL：
100mg、70mL：100mg、80mL：100mg or 90mL：100mg.In the present invention, the mixed solution, emulsifying agent and water
Mixing is preferably carried out under ultrasound condition；The power of the ultrasound is preferably 200～500W, concretely 300W or 400W；Institute
The time for stating ultrasound is preferably 1～10min, concretely 3min, 4min, 5min, 6min, 7min or 8min.
In one embodiment that the present invention is provided, the mixed solution, emulsifying agent and water preferably enter in such a way
Row mixing：First emulsifying agent and water are mixed, emulsion is obtained；The emulsion is mixed with the mixed solution again.Wherein, institute
State emulsion and preferably include the first emulsion and the second emulsion；The mass volume ratio of emulsifying agent and water in first emulsion
Preferably (0.1～0.5) g：(1～10) mL, concretely 0.21g：3mL；The matter of emulsifying agent and water in second emulsion
Amount volume ratio is preferably (0.1～1) g：(10～100) mL, concretely 0.5g：50mL.One in present invention offer includes
In the embodiment of the first emulsion and the second emulsion, first second emulsion and mixed solution are mixed under ultrasound condition
Close, afterwards again mix mixture under ultrasound condition with the first emulsion.Wherein, for the first time the time of mixing is preferably 0.5
～2min, specifically may be selected to be 1min；The time of second mixing is preferably 2～5min, specifically may be selected to be 3min.
After the mixing of the mixed solution, emulsifying agent and water is finished, emulsion is obtained.After obtaining emulsion, by the emulsus
Organic solvent in liquid is removed.In the present invention, the emulsion is stirred except the mode of organic solvent is preferably, so as to
The organic solvent in emulsion is set to volatilize.After organic solvent in emulsion is cleared, obtain carrying ibuprofen slow-release Nano microsphere.
In the present invention, the load ibuprofen slow-release Nano microsphere that preferred pair is obtained is washed, so as to improve the pure of slow released nano microsphere
Degree.
The method that the present invention is provided can be obtained the load ibuprofen slow-release Nano microsphere of uniform particle diameter, good dispersion, and this delays
Release Nano microsphere and there is good slow release effect.Test result indicate that, the load ibuprofen slow-release Nano microsphere that the present invention is provided can
To be relieved the splanchnodynia of rat, it is possible to which lasting remission pain reaches 3 hours.
The invention provides a kind of load sustained release preparations of ibuprofen for treating splanchnodynia, including it is slow described in above-mentioned technical proposal
Release Nano microsphere and pharmaceutically acceptable auxiliary material.
The sustained release preparation that the present invention is provided includes the slow released nano microsphere and pharmaceutically acceptable auxiliary material.In the present invention
In one embodiment of offer, the sustained release preparation is subplantar injection agent, and the subplantar injection agent includes that the slow release nanometer is micro-
Ball and solvent.In the subplantar injection agent that the present invention is provided, the solvent includes but is not limited to physiological saline or can be used for biology
The buffer solution of body injection, the buffer solution may be selected phosphate buffer；The slow released nano microsphere is in subplantar injection agent
Concentration is preferably 1～100mg/mL, specifically may be selected to be 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL, 6mg/mL,
7mg/mL、8mg/mL、9mg/mL、10mg/mL、11mg/mL、12mg/mL、13mg/mL、14mg/mL、15mg/mL、20mg/mL、
25mg/mL、30mg/mL、35mg/mL、40mg/mL、45mg/mL、50mg/mL、55mg/mL、60mg/mL、65mg/mL、70mg/
ML, 75mg/mL, 80mg/mL, 85mg/mL, 90mg/mL or 95mg/mL.
The sustained release preparation that the present invention is provided is when splanchnodynia is treated with lasting throe effect.In the excellent of present invention offer
In selecting technology scheme, the sustained release preparation is subplantar injection agent, and the present invention treats splanchnodynia by subplantar injection can be avoided
The related side effects that oral ibuprofen formulations bring.Test result indicate that, the load sustained release preparations of ibuprofen that the present invention is provided can be with
It is relieved the splanchnodynia of rat, it is possible to which lasting remission pain reaches 3 hours.
The above-mentioned technical proposal that the present invention is provided has one of following advantage：
1), using PLGA to prepare nanoparticulate carriers, PLGA is that a kind of degradable functional polymer is organic to the present invention
Compound, the nontoxic, performance with good biocompatibility, good encystation and film forming is widely used in pharmacy, medical
Engineering material and modernization industry field.In the U.S., PLGA is by FDA certifications, is formally included into U.S.'s medicine as pharmaceutic adjuvant
Allusion quotation.
2), the present invention carries ibuprofen pharmaceutical Nano microsphere using PLGA as carrier, can be by medicine ibuprofen being sustained
Mode discharges.PLGA can effectively extend the half-life of medicine ibuprofen as carrier.Our research shows and carries brufen medicine
Thing Nano microsphere can be relieved the splanchnodynia of rat, it is possible to which lasting remission pain reaches 3 hours；
3), the present invention carries ibuprofen pharmaceutical Nano microsphere and can avoid the high dose of medicine ibuprofen itself, caused by toxicity
Side effect；
4), present invention load ibuprofen pharmaceutical Nano microsphere has good biocompatibility, non-toxic, biochemical property
It is stable；
5), nano particle diameter obtained in preparation method of the present invention is more uniform, good dispersion.
6), the unique method of administration-subplantar injection medicine of the present invention, its method is simple, easy to operate；
7), the present invention treats splanchnodynia by carrying ibuprofen pharmaceutical Nano microsphere as analgesic medicine injection vola,
The side effects such as the renal failure that Long-term Oral brufen can be avoided to bring, indigestion.
For the sake of becoming apparent from, it is described in detail below by following examples.
Embodiment 1
Carry the preparation of ibuprofen slow-release Nano microsphere
Step 1)
Weigh 100mg PLGA (lactide:Glycolide=65:35(n:N), Mw=40000～75000) and 15mg
Brufen, in being then respectively adding the dichloromethane of 1mL, room temperature dissolves mixing on shaking table, obtains containing PLGA and brufen
Mixed solution；0.5g is weighed, 0.21gPVA (Mw=9000～2000000) is added separately in the distilled water of 50mL and 3mL, made
The PVA aqueous solution of standby 1g/100mL and 7g/100mL.
Step 2)
By step 1) PLGA that produces and the mixed solution of brufen mix and use ultrasound with the PVA aqueous solution of 7g/100mL
Broken instrument ultrasound 1 minute (power 300W) produces emulsion, then emulsion is added into step 1) PVA of 1g/100mL that produces
Continue 3 minutes (power 300W) of ultrasound in the aqueous solution, then persistently stir on agitator 24 hours and fully remove dichloromethane,
Finally (13000rpm centrifugations) is washed twice with distilled water, in being finally resuspended to 2mL distilled waters, obtain loading the nanometer of brufen
Microballoon.
The particle diameter distribution of above-mentioned Nano microsphere is determined by dynamic light scattering, as a result as shown in figure 1, Fig. 1 is of the invention real
The Nano microsphere grain size distribution of the offer of example 1 is applied, as seen in Figure 1, the particle diameter distribution of Nano microsphere is in 92～185nm.
It is as a result 11wt% by the drugloading rate of the above-mentioned Nano microsphere of high-performance liquid chromatogram determination.
Embodiment 2
Carry the preparation of ibuprofen slow-release Nano microsphere
Step 1)
Weigh 100mg PLGA (lactide:Glycolide=65:35(n:N), Mw=40000～75000) and 10mg
Brufen, in being then respectively adding the dichloromethane of 1mL, room temperature dissolves mixing on shaking table, obtains containing PLGA and brufen
Mixed solution；0.5g is weighed, 0.21g PVA (Mw=9000～2000000) are added separately in the distilled water of 50mL and 3mL,
Prepare the PVA aqueous solution of 1g/100mL and 7g/100mL.
Step 2)
By step 1) PLGA that produces and the mixed solution of brufen mix and use ultrasound with the PVA aqueous solution of 7g/100mL
Broken instrument ultrasound 1 minute (power 300W) produces emulsion, then emulsion is added into step 1) PVA of 1g/100mL that produces
Continue 3 minutes (power 300W) of ultrasound in the aqueous solution, then persistently stir on agitator 24 hours and fully remove dichloromethane,
Finally (13000rpm centrifugations) is washed twice with distilled water, in being finally resuspended to 2mL distilled waters, obtain loading the nanometer of brufen
Microballoon.
The particle diameter distribution of above-mentioned Nano microsphere is determined by dynamic light scattering, as a result as shown in Fig. 2 Fig. 2 is of the invention real
The Nano microsphere grain size distribution of the offer of example 2 is applied, as seen in Figure 2, the particle diameter distribution of Nano microsphere is in 85～180nm.
It is as a result 8wt% by the drugloading rate of the above-mentioned Nano microsphere of high-performance liquid chromatogram determination.
Embodiment 3
Carry the preparation of ibuprofen slow-release Nano microsphere
Step 1)
Weigh 100mg PLGA (lactide:Glycolide=65:35(n:N), Mw=40000～75000) and 20mg
Brufen, in being then respectively adding the dichloromethane of 1mL, room temperature dissolves mixing on shaking table, obtains containing PLGA and brufen
Mixed solution；0.5g is weighed, 0.21gPVA (Mw=9000～2000000) is added separately in the distilled water of 50mL and 3mL, made
The PVA aqueous solution of standby 1g/100mL and 7g/100mL.
Step 2)
By step 1) PLGA that produces and the mixed solution of brufen mix and use ultrasound with the PVA aqueous solution of 7g/100mL
Broken instrument ultrasound 1 minute (power 300W) produces emulsion, then emulsion is added into step 1) PVA of 1g/100mL that produces
Continue 3 minutes (power 300W) of ultrasound in the aqueous solution, then persistently stir on agitator 24 hours and fully remove dichloromethane,
Finally (13000rpm centrifugations) is washed twice with distilled water, in being finally resuspended to 2mL distilled waters, obtain loading the nanometer of brufen
Microballoon.
The particle diameter distribution of above-mentioned Nano microsphere is determined by dynamic light scattering, as a result as shown in figure 3, Fig. 3 is of the invention real
The Nano microsphere grain size distribution of the offer of example 3 is applied, as seen in Figure 3, the particle diameter distribution of Nano microsphere is in 90～185nm.
It is as a result 13wt% by the drugloading rate of the above-mentioned Nano microsphere of high-performance liquid chromatogram determination.
Embodiment 4
The detection test of the In-vitro release curves of slow released nano microsphere
At 37 DEG C, the load ibuprofen slow-release Nano microsphere for respectively preparing 100mg embodiments 1 and 10mg brufens are added
(0.01M, PH=7.4) dialysis, was sampled, using high performance liquid chromatography every 2 hours in the phosphate buffer of 10mL
(HPLC, C-18 post, mobile phase is methyl alcohol：Acetonitrile：Sodium dihydrogen phosphate (0.02mol/L)=50：25：25, mobile phase phosphorus
To 3.0 ± 0.05, Detection wavelength is 263nm to acid for adjusting pH value, and flow velocity is 1.0mL/min) concentration of brufen is determined, and draw
Brufen release profiles, as shown in figure 4, Fig. 4 is releasing in vitro for the load ibuprofen pharmaceutical Nano microsphere of the offer of the embodiment of the present invention 4
Put curve map.As seen in Figure 4, compared to brufen, the load brufen Nano microsphere that embodiment 1 is provided has good
Slow release effect.
Embodiment 5
The detection test of the In-vitro release curves of slow released nano microsphere
At 37 DEG C, the load ibuprofen slow-release Nano microsphere for respectively preparing 100mg embodiments 2 and 10mg brufens are added
(0.01M, PH=7.4) dialysis, was sampled, using high performance liquid chromatography every 2 hours in the phosphate buffer of 10mL
(HPLC, C-18 post, mobile phase is methyl alcohol：Acetonitrile：Sodium dihydrogen phosphate (0.02mol/L)=50：25：25, mobile phase phosphorus
To 3.0 ± 0.05, Detection wavelength is 263nm to acid for adjusting pH value, and flow velocity is 1.0mL/min) concentration of brufen is determined, and draw
Brufen release profiles, as shown in figure 5, Fig. 5 is releasing in vitro for the load ibuprofen pharmaceutical Nano microsphere of the offer of the embodiment of the present invention 5
Put curve map.As seen in Figure 5, compared to brufen, the load brufen Nano microsphere that embodiment 2 is provided has good
Slow release effect.
Embodiment 6
The detection test of the In-vitro release curves of slow released nano microsphere
At 37 DEG C, the load ibuprofen slow-release Nano microsphere for respectively preparing 100mg embodiments 3 and 10mg brufens are added
(0.01M, PH=7.4) dialysis, was sampled, using high performance liquid chromatography every 2 hours in the phosphate buffer of 10mL
(HPLC, C-18 post, mobile phase is methyl alcohol：Acetonitrile：Sodium dihydrogen phosphate (0.02mol/L)=50：25：25, mobile phase phosphorus
To 3.0 ± 0.05, Detection wavelength is 263nm to acid for adjusting pH value, and flow velocity is 1.0mL/min) concentration of brufen is determined, and draw
Brufen release profiles, as shown in fig. 6, Fig. 6 is releasing in vitro for the load ibuprofen pharmaceutical Nano microsphere of the offer of the embodiment of the present invention 6
Put curve map.As seen in Figure 6, compared to brufen, the load brufen Nano microsphere that embodiment 3 is provided has good
Slow release effect.
Embodiment 7
Double fluorescent tracer mark specificity domination volas and DRGs (DRG) neuron of colon
Using normal male rat (body weight 180g or so) as experimental subjects, first will with chloraldurate (360mg/kg)
Rat anesthesia, then aseptically by 10 μ L fluorescent tracer DiI (1,19-dioleyl-3,3,39,3-
tetramethylindocarbocyanine methanesulfonate；Invitrogen, Carlsbad, CA) point 5 point notes
(2 μ L of each point) are mapped in colon intestinal wall, while (each puts 2 by 5 point injection rat hindleg bottoms of the fluorogold (FG) of 10 μ L point
μ L), injection finish treat rat revive under normal condition (24 DEG C of room temperature, humidity 50-60%, well-ventilated, manually round the clock
(12h/12h), freely ingest water) feed one week, then anesthetized rat, perfusion takes DRGs, the Dorsal root god due to arranging vola
Warp knuckle is mainly distributed on waist section L2-6, and the DRGs for arranging colon is mainly distributed on chest section T13, waist section L1 and L2, institute
With the T13-L6DRGs that mainly take that draws materials.Then, distribution situation of the row frozen section observation fluorescence in DRGs.Observation knot
Fruit as shown in fig. 7, Fig. 7 be the embodiment of the present invention 7 provide DRGs in fluorescence distribution map, in Fig. 7, T13, L1, L2,
L6 represents the numbering of different DRGs, and left column is the distribution situation of FG fluorescence, and middle column is the distribution situation of DiI fluorescence,
Right column is the stacking chart of FG fluorescence and DiI fluorescence.As shown in Figure 7, there is Two Colour Fluorescence mark in T13, L1, L2, L6
Neuron, illustrates that arranging vola and the neuron of colon simultaneously is mainly distributed in the DRGs of T13, L1, L2, L6.
That is, the nerve fibre of the nerve fibre and domination vola of arranging internal organ can be sent out by same neuron in DRGs
Go out, i.e., some neurons can simultaneously arrange internal organ and vola in DRGs.So, can be by by drug injection foot
Bottom reaches the purpose for the treatment of splanchnodynia reducing while arrange the neuronal excitability in internal organ and vola.
Embodiment 8
Intrathecal injection carries the physiological saline agent of ibuprofen slow-release Nano microsphere and alleviates acute visceral pain in rats test
Give the 10th day SD In The Rat Sole of birth and inject complete Freund's adjuvant CFA, the AWR (abdomens of adult rat can be induced
Wall withdrawal reflex) scoring significantly rising, that is, visceral hyperalgesia is shown as, and this effect can be from the 6th week to the 12nd
Week.
Selection Model success rat, the physiological saline of the load ibuprofen slow-release Nano microsphere of rear solid end subplantar injection various dose
Injection, detects that it alleviates the quick effect of splanchnodynia.Detection adult rat internal organ pain reaction mainly passes through stomach wall withdrawal reflex
(Abdominalwithdrawalreflex, AWR) scores to measure the threshold of pain.Rat is moderately anaesthetized with ether first, rapidly will
The latex expanded balloon for scribbling paraffin oil carefully inserts the Colon and rectum of rat, intubating length about 8cm.With adhesive tape rat tail
It is fixed on plank, fixes relief rat and regain consciousness and adapt to 30 minutes, with to be tested.Give difference respectively with mercury manometer
Pressure inflatable.Colon and rectum expansion (CRD) can cause the contraction of rat abdomen muscle, and this is referred to as internal organ contractile response (Visceral
Motor Responses,VMR).Expanding Colon and rectum by CRD carries out belly withdrawal reflex AWR methods of marking detection visceral pain
Reactivity, CRD：With desk model sphygmomanometer by balloon Quick-pressing to constant pressure：20th, 40,60,80mmHg, 2min once, once stop
Stay 20s.
With the AWR methods of marking detection rat colon threshold of pain：0, without perceptible Novel presentation；1, head it is slight stiff and
Body is without substantially abnormal；2, flank portion shrinks；3, lower stomach wall is lifted away from desktop；4, lower abdomen arches upward.According to rat in different pressures
Reaction under power dilatation gives corresponding fraction, and the higher explanation rat of score value is more sensitive to pain under uniform pressure.
Load ibuprofen slow-release Nano microsphere prepared by the embodiment 1 of different meterings is added in physiological saline, is obtained respectively
Obtain the life of the load ibuprofen slow-release Nano microsphere that determination of ibuprofen is 0.14mg/0.1mL, 0.4mg/0.1mL, 1.2mg/0.1mL
Reason saline injections.Subplantar injection 1.2mg brufens, and the physiology of the above-mentioned load ibuprofen slow-release Nano microspheres of 0.1mL respectively
Saline injections, carry out after injection Colon and rectum expansion (20,40,60,80mmHg) stimulate, observe rat with AWR methods of marking
Splanchnodynia reactions change and time-effect.As a result as shown in Figure 8 and Figure 9, Fig. 8 is the subplantar injection that the embodiment of the present invention 8 is provided
The design sketch of acute visceral pain in rats is alleviated in the physiological saline agent of the load brufen Nano microsphere of various dose, and Fig. 9 is the present invention
The subplantar injection that embodiment 8 is provided carries the time-histories effect that acute visceral pain in rats is alleviated in the physiological saline agent of brufen Nano microsphere
Figure.It can be seen that, inject the physiological saline agent of the load ibuprofen slow-release Nano microsphere of 0.1mL determination of ibuprofen 1.2mg/0.1mL
The splanchnodynia of rat can substantially be overturn, it is possible to which lasting remission pain reaches 3 hours.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. it is a kind of to carry ibuprofen slow-release Nano microsphere, including carrier and the brufen being supported on carrier；
The carrier is Poly(D,L-lactide-co-glycolide.
2. slow released nano microsphere according to claim 1, it is characterised in that the Poly(D,L-lactide-co-glycolide
Weight average molecular weight is 40000～75000.
3. slow released nano microsphere according to claim 1, it is characterised in that have in the poly lactic coglycolic acid
There is the repetitive of lactic acid structure to be (50～80) with the mol ratio of the repetitive with hydroxyacetic acid structure：(50～20).
4. slow released nano microsphere according to claim 1, it is characterised in that the brufen is in slow released nano microsphere
Content is 5～20wt%.
5. the slow released nano microsphere according to any one of Claims 1 to 4, it is characterised in that the slow released nano microsphere
Particle diameter is 50～200nm.
6. the preparation method of ibuprofen slow-release Nano microsphere is carried described in a kind of claim 1, is comprised the following steps：
A), brufen, carrier and organic solvent are mixed, mixed solution is obtained；
B), the mixed solution, emulsifying agent and water are mixed, emulsion is obtained；
C), the emulsion removes organic solvent, obtains carrying ibuprofen slow-release Nano microsphere.
7. preparation method according to claim 6, it is characterised in that the organic solvent includes dichloromethane and/or chlorine
It is imitative；
The emulsifying agent includes polyvinyl alcohol and/or polyethylene glycol.
8. a kind of load sustained release preparations of ibuprofen for treating splanchnodynia, including the slow release nanometer described in any one of Claims 1 to 5 is micro-
Ball and pharmaceutically acceptable auxiliary material.
9. sustained release preparation according to claim 8, it is characterised in that the sustained release preparation is subplantar injection agent.
10. the load ibuprofen slow-release Nano microsphere described in any one of Claims 1 to 5 is preparing subplantar injection treatment splanchnodynia medicine
Application in thing.
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| CN110124091A (en) * | 2019-05-27 | 2019-08-16 | 南通大学附属医院 | Suture and preparation method thereof |
| CN110170068A (en) * | 2019-05-27 | 2019-08-27 | 南通大学附属医院 | The medical suture and preparation method thereof of more effects |
| CN111544648A (en) * | 2020-05-14 | 2020-08-18 | 南通大学 | Protein-modified PLGA microspheres and tissue-engineered nerves constructed by same |
| CN113750078A (en) * | 2021-09-10 | 2021-12-07 | 华中药业股份有限公司 | Ibuprofen quick-release and slow-release nanoparticles and preparation method thereof |
| US11788058B2 (en) | 2020-05-14 | 2023-10-17 | Nantong University | Protein-modified PLGA microsphere and tissue-engineered nerve constructed therewith |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110124091A (en) * | 2019-05-27 | 2019-08-16 | 南通大学附属医院 | Suture and preparation method thereof |
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| CN111544648A (en) * | 2020-05-14 | 2020-08-18 | 南通大学 | Protein-modified PLGA microspheres and tissue-engineered nerves constructed by same |
| US11788058B2 (en) | 2020-05-14 | 2023-10-17 | Nantong University | Protein-modified PLGA microsphere and tissue-engineered nerve constructed therewith |
| CN113750078A (en) * | 2021-09-10 | 2021-12-07 | 华中药业股份有限公司 | Ibuprofen quick-release and slow-release nanoparticles and preparation method thereof |
| CN113750078B (en) * | 2021-09-10 | 2023-10-10 | 华中药业股份有限公司 | Ibuprofen quick-release slow-release nanoparticle and preparation method thereof |
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