CN106474071A - A kind of blank polymer microsphere and preparation method thereof - Google Patents
A kind of blank polymer microsphere and preparation method thereof Download PDFInfo
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- CN106474071A CN106474071A CN201510551345.0A CN201510551345A CN106474071A CN 106474071 A CN106474071 A CN 106474071A CN 201510551345 A CN201510551345 A CN 201510551345A CN 106474071 A CN106474071 A CN 106474071A
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Abstract
The invention provides a kind of blank polymer microsphere, prepared by spray drying method.The present invention is using the wink-dry ability being spray-dried, and the superior solubility ability of dichloromethane etc., and macromolecular material is prepared into microsphere.By observing and particle size determination to the sign of this microsphere, learn the diameter of this slow-released carrier timbering material, surface sign, this macromolecule blank microsphere diameter meets and can be injected size.Compared with other method for preparing microsphere, spray drying method method is simple, and repetitive rate is high, and micro-sphere structure is clear and definite.Learnt by pharmacokineticss in animal body and delivery evaluation in vivo, be that different medicines serve as good slow-released carrier in this microsphere supported field in medicine sustained and controlled release.
Description
Technical field
The invention belongs to sustained-release drug carrier framework material, it is related to slow-release material and is spray-dried transformation method, more particularly, to a kind of
Polymer microsphere and preparation method.
Background technology
Biodegradable long-acting slow-release microsphere is the newtype drug Transmission system growing up in recent decades, and microball preparation is
Become the focus of sustained-release preparation research.The bad smell of medicine after microball preparation made by medicine, can be covered, improve patient
The compliance of medication.The microsphere being loaded with medicine also has the characteristics that slow mechanism dissolved release and orientation implantation, can be passively or actively
Be concentrated on target organs, long-term and stably discharge medicine, to maintain the concentration of topical remedy, greatly reduce dosage,
Extend drug treating time, reduce administration number of times, effectively reduce the generation of untoward reaction simultaneously, have very important
Clinical meaning.Medicine is made microsphere dosage forms, has both played the effect of targeting, reach the purpose of slow release again.
As the carrier material of medicine sustained and controlled release preparation, natural macromolecular material has a wide range of applications.Natural macromolecular material
Including collagen, fibrin, cellulose, shitosan etc., its biocompatibility is excellent and spy that have easily biological-degradable
Property, have simultaneously and delay drug release, stablize and protect the effect such as active constituents of medicine.
(poly (lactic-co-glycolic acid PLGA), is that one kind can drop for polylactic acid (PLA) and Poly(D,L-lactide-co-glycolide
The functional polymer organic compound of solution, has the performance of good biocompatibility, nontoxic, good encystation and film forming,
Originate fully, production process is pollution-free, is widely used in pharmacy, medical engineering material and modernization industry field simultaneously.
Pass through Food and Drug Admistraton (FDA) certification in U.S. PLGA, formally included into American Pharmacopeia as pharmaceutic adjuvant.
The PLGA microspheres product of listing has injection naltrexone long acting formulations (Vivitrol) at present, (injection octreotide acetate is micro- for SANDOSTATIN LAR
Ball) (Sandostatin) LAR, Risperdal Consta (Risperidone for Depot Suspension) (Risperdal Consta) and leuprorelin acetate injectable
Slow releasing preparation (Lupron Depot) etc..These preparations only need to be to patient's drug administration by injection 1 time, achievable sustained drug release 2
Week～4 months.
Method for preparing microsphere can be divided into physical-chemical process, chemical method and physicomechanical processes three class according to technological principle.Physical mechanical
Method is to prepare microsphere using the method for physics and theory of mechanics, have simple, easy to spread, be conducive to large-scale continuous production
The advantages of, it is frequently utilized that this method to prepare microsphere in commercial field particularly medicine, food industry, especially to be spray-dried
Method application is in the majority.Spray drying method is the method with spraying, makes liquid material be dispersed in steam with droplet state by nebulizer
In stream, in the presence of hot blast, material is fully contacted with hot gas, carries out heat exchange, completes heat transfer and mass transfer in moment
Process, make the solvent of misty liquid droplets be evaporated to gas rapidly, finally obtain powdery or granular product.Spraying droplets are done
Dry method can conveniently large-scale production, mild condition, the requirement for medicine and macromolecule dissolution is not very high.
The preparation method working condition of above-mentioned microsphere is excessively complicated, needs to control temperature, pH value, adds electrolyte etc. factor,
To prepare satisfactory microsphere or microcapsule.Chemical method and physico-chemical process typically can be carried out by reactor, though
Application is more, but is difficult to produce greatly.
Content of the invention
It is an object of the invention to provide a kind of blank polymer microsphere preparation method, the method can operate continuously, mild condition,
With low cost, the microspherulite diameter of preparation is little and controlled, easily separated, adhesion, can be used as medicine sustained and controlled release carrier material.
Described blank polymer microsphere is prepared by spray drying method, realizes especially by following steps：Carrier material is taken to be dissolved in
In a certain amount of solvent, carrier material concentration is made to be 0.5-30% (W/V), by mixed solution spray injection drying instrument, inlet temperature
40-200 DEG C, charging rate 100-1000ml/h, atomizing pressure 0.1-0.4KPa, carry out under power 15-40Hz Parameter Conditions
It is spray-dried, obtain microsphere powder.
Described solvent is dichloromethane, acetone, chloroform, ethyl acetate, dehydrated alcohol, methanol, purified water, dilute hydrochloric acid
One of or combination.Further, with dichloromethane, ethyl acetate, water, ethanol be preferred.
Described microspherical carrier material be fibroin albumen, chitin, shitosan, hyaluronic acid, collagen, gelatin, albumin,
Casein, o-phthalaldehyde(OPA) acid cellulose, polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), poly- (lactic acid
- aminoacid) copolymer, one of PLGA-PEG-PLGA (PEG-PLA) or combination.Further, described
Microspherical carrier material is polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), poly- (lactic acid-amino acid) copolymerization
One of thing, PLGA-PEG-PLGA (PEG-PLA) or combination.
Described carrier material solution concentration is preferably 15%-20% for 0.5-20% concentration.
Described method for preparing microsphere is spray drying method.
Described spray-dried instrument is with inlet temperature 40-200 DEG C, charging rate 100-1000ml/h, atomizing pressure
It is spray-dried under 0.1-0.4MPa, power 15-40Hz Parameter Conditions.
Further, described spray drying preferred parameter be inlet temperature 70-180 DEG C, charging rate 700-1000ml/h,
Atomizing pressure 0.1-0.2MPa, power 20Hz.
It is a further object to provide application in medicine sustained and controlled release carrier for the described microsphere.
The inventive method is based on following principle design：(1) in order to obtain being injected and biological tissue's compatibility is well to body
Nontoxic pharmaceutical carrier stent model；(2) realize carrier bracket slowly to degrade in organism, the purpose of slow release.
The invention has the beneficial effects as follows：
The present invention is using the wink-dry ability being spray-dried, and the superior solubility ability of solvent, by polymer carrier
It is prepared into microsphere.By observing and particle size determination to the sign of this microsphere, learn the diameter of this slow-released carrier timbering material,
Surface sign, this macromolecule blank microsphere diameter meets and can be injected size.Compared with other method for preparing microsphere, spray dried
Dry method method is simple, and repetitive rate is high, and micro-sphere structure is clear and definite.Obtained by pharmacokineticss in animal body and delivery evaluation in vivo
Know, be that different medicines serve as good slow-released carrier in this microsphere supported field in medicine sustained and controlled release.
Brief description
Fig. 1 is blank polymer microsphere SEM photograph.
Fig. 2 is blank polymer microsphere grain-size graph
Fig. 3 is to carry medicine PEG-PLA/PLA microsphere In-vitro release curves
Fig. 4 is to carry Drug-time curve in blood in medicine PEG-PLA/PLA microsphere animal body
Specific embodiment
Below by drawings and Examples, the present invention is made and further illustrating, but the present invention is not limited to these enforcements
Example.
Embodiment 1 makes blank PEG-PLA microsphere with 300gPEG-PLA (molecular weight 150,000)
This blank PEG-PLA microsphere preparation process：PEG-PLA300g is taken to be dissolved in 1000ml dichloromethane, using spray dried
Dry instrument is spray-dried, 40 DEG C of inlet temperature, charging rate 100ml/h, atomizing pressure 0.1KPa, power 40Hz, system
Standby obtain blank PLGA microsphere.
Embodiment 2 makes blank PLA microsphere with 100gPLA (molecular weight 700,000).
This blank PLA microsphere preparation process：PLA (100g) is dissolved in 20L ethyl acetate, is sprayed using spray-dried instrument
It is dried, 70 DEG C of inlet temperature, charging rate 1000ml/h, atomizing pressure 0.4KPa, power 15Hz, prepare blank
PLA microsphere.(under SEM form referring to Fig. 1, grain-size graph is referring to Fig. 2)
Embodiment 3 makes blank fibroin albumen microsphere with 100g fibroin albumen.
This blank fibroin albumen microsphere preparation process：Fibroin albumen is dissolved in 100ml purified water, is sprayed using spray-dried instrument
Mist is dried, and 200 DEG C of inlet temperature, charging rate 700ml/h, atomizing pressure 0.3KPa, power 20Hz, prepares sky
White fibroin albumen microsphere.
Embodiment 4 makes blank o-phthalaldehyde(OPA) acid cellulose microsphere with 400g o-phthalaldehyde(OPA) acid cellulose
This blank o-phthalaldehyde(OPA) acid cellulose microsphere preparation process：O-phthalaldehyde(OPA) acid cellulose (400g) is dissolved in 2000ml
Dehydrated alcohol, is spray-dried using spray-dried instrument, 80 DEG C of inlet temperature, charging rate 1000ml/h, atomizing pressure
0.3KPa, power 30Hz, prepare blank o-phthalaldehyde(OPA) acid cellulose microsphere.
Embodiment 5 makes blank chitin microsphere with 300g chitin
This blank chitin microsphere preparation process：Chitin (300g) is dissolved in 2000ml dilute hydrochloric acid, using spray-dried instrument
It is spray-dried, 170 DEG C of inlet temperature, charging rate 800ml/h, atomizing pressure 0.3KPa, power 15Hz, preparation
Obtain blank chitin microsphere.
Embodiment 6 makes blank chitosan microball with 150g shitosan
This blank chitosan microball preparation process：Shitosan (150g) is dissolved in 1000ml purified water, using spray-dried instrument
It is spray-dried, 190 DEG C of inlet temperature, charging rate 100ml/h, atomizing pressure 0.3KPa, power 15Hz, preparation
Obtain blank chitosan microball.
Embodiment 7 makes blank chitosan microball with shitosan, chitin
Preparation process：Shitosan 150g, chitin 150g are dissolved in 1000ml dilute hydrochloric acid, are sprayed using spray-dried instrument
Mist is dried, and 200 DEG C of inlet temperature, charging rate 1000ml/h, atomizing pressure 0.4KPa, power 40Hz, prepares sky
White shitosan, chitin microsphere.
Embodiment 8 makes blank microsphere with poly- (lactic acid-amino acid) copolymer, PLGA-PEG-PLGA (PEG-PLA)
Preparation process：Take poly- (lactic acid-amino acid) copolymer 50g, PLGA-PEG-PLGA (PEG-PLA) 50g molten
In 1000ml acetone, it is spray-dried using spray-dried instrument, 50 DEG C of inlet temperature, charging rate 100ml/h, mist
Change pressure 0.2KPa, power 30Hz, prepare blank microsphere.
Embodiment 9 makes blank microsphere with polylactic acid (PLA)
Preparation process：Take polylactic acid (PLA) 100g to be dissolved in 900ml methanol, be spray-dried using spray-dried instrument,
60 DEG C of inlet temperature, charging rate 100ml/h, atomizing pressure 0.2KPa, power 30Hz, prepare blank microsphere.
Embodiment 10 makes blank microsphere with albumin, casein
Preparation process：Albumin 30g, casein 70g is taken to be dissolved in 1000ml ethanol solution (40%), using spray dried
Dry instrument is spray-dried, 140 DEG C of inlet temperature, charging rate 100ml/h, atomizing pressure 0.2KPa, power 30Hz,
Prepare blank microsphere.
Embodiment 11 makes blank microsphere with collagen, gelatin
Preparation process：Take collagen 40g, gelatin 60g to be dissolved in 1000ml purified water, carry out spray dried using spray-dried instrument
Dry, 200 DEG C of inlet temperature, charging rate 100ml/h, atomizing pressure 0.4KPa, power 40Hz, prepare blank micro-
Ball.
Embodiment 12, with doxycycline hydrochloride as model drug, is carried by medicine and compares 1:10 preparations PEG-PLA (molecular weight 200,000) make
PEG-PLA medicine carrying microballoonss.
This PEG-PLA medicine carrying microballoonss preparation process：PEG-PLA (1000g) is dissolved in 2000ml dichloromethane, separately takes salt
Sour doxycycline (100g), two kinds of solution is mixed, using spray-dried instrument through high shear dispersion in 2000ml dichloromethane
It is spray-dried, 45 DEG C of inlet temperature, charging rate 800ml/h, aspiration pressure 0.2KPa, power 20Hz, be prepared into
To doxycycline hydrochloride PEG-PLA microsphere.
Embodiment 13, with doxycycline hydrochloride as model drug, is carried by medicine and compares 1:10 preparations PLA (molecular weight 100,000) make PLA
Medicine carrying microballoonss.
This PLA medicine carrying microballoonss preparation process：PLA (1000g) is dissolved in 2000ml dichloromethane, separately takes doxycycline hydrochloride
(100g) through high shear dispersion in 2000ml dichloromethane, two kinds of solution are mixed, carries out spray dried using spray-dried instrument
Dry, 45 DEG C of inlet temperature, charging rate 800ml/h, aspiration pressure 0.15KPa, power 20Hz, to prepare hydrochloric acid many
Western ring element PLA microsphere.
Embodiment 14 extracorporeal releasing test
Embodiment of the present invention 5-6 is taken to prepare doxycycline hydrochloride PEG-PLA microsphere and doxycycline hydrochloride PLA microsphere, with MCT
The injection that oil becomes 20% for substrate preparation carries out extracorporeal releasing test, with 20% doxycycline hydrochloride injection for comparison.Release
Curve is shown in Fig. 3.
Release in vitro method：
Discharge outer liquid：Phosphate buffer (pH7.0) 500mL
Method for releasing：Slurry processes
Rotating speed：100rpm
Temperature：37℃
Release medication amount：1ml
Sampling time point：0、0.25、0.5、0.75、1、1.5、2、2.5、3、3.5、4、4.5、5、8、12、
24、48、72、96、120、168h
Embodiment 15 pharmacokinetic trial
Embodiment of the present invention 5-6 is taken to prepare doxycycline hydrochloride PEG-PLA microsphere and doxycycline hydrochloride PLA microsphere, with MCT
The injection that oil becomes 20% for substrate preparation carries out pharmacokinetic trial in animal body, with 20% doxycycline hydrochloride injection is
Comparison.Plasma concentration curve is shown in Fig. 4.
Pharmacokinetic method：
Animal：Every group 8 of rat 200g only totally 24
Packet：Doxycycline hydrochloride PEG-PLA microsphere injection liquid group, doxycycline hydrochloride PLA microsphere injection liquid group, hydrochloric acid
Doxycycline injection group
Route of administration：Intramuscular injection
Take blood time point：0、0.25、0.5、1、2、3、4、6、8、12、18、24、36、48、60、72、96、
120、240h
Blood sampling volume：0.5ml
With the above-mentioned desirable embodiment according to the present invention for enlightenment, by above-mentioned description, relevant staff completely may be used
, in the range of without departing from this invention technological thought, to carry out various change and modification.The technical model of this invention
Enclose the content being not limited in description it is necessary to determine its technical scope according to right.
Claims (8)
1. a kind of blank polymer microsphere, is prepared by spray drying method it is characterised in that realizing especially by following steps：Polymer carrier is taken to be dissolved in a certain amount of solvent, carrier concn is made to be 0.5-30%, by mixed solution spray injection drying instrument, it is spray-dried under inlet temperature 40-200 DEG C, charging rate 100-1000ml/h, atomizing pressure 0.1-0.4KPa, power 15-40Hz Parameter Conditions, obtained microsphere powder.
2. a kind of blank polymer microsphere according to claim 1 is it is characterised in that carrier material includes one of fibroin albumen, chitin, shitosan, hyaluronic acid, collagen, gelatin, albumin, casein, o-phthalaldehyde(OPA) acid cellulose, polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), poly- (lactic acid-amino acid) copolymer, PLGA-PEG-PLGA (PEG-PLA) or combination.
3. a kind of blank polymer microsphere according to claim 2 is it is characterised in that carrier material is one of polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), poly- (lactic acid-amino acid) copolymer, PLGA-PEG-PLGA (PEG-PLA) or combination.
4. as requested described in 4 a kind of blank polymer microsphere it is characterised in that carrier material solution concentration be 15-20%.
5. as requested described in 1 a kind of blank polymer microsphere it is characterised in that solvent be one of dichloromethane, acetone, chloroform, ethyl acetate, dehydrated alcohol, purified water, normal hexane, methanol, hexamethylene or combination.
6. a kind of blank polymer microsphere according to claim 5 is it is characterised in that solvent is one of dichloromethane, ethyl acetate, purified water or ethanol.
7. a kind of blank polymer microsphere according to claim 1 is it is characterised in that described spray drying instrument parameter is inlet temperature 70-180 DEG C, charging rate 700-1000ml/h, atomizing pressure 0.1-0.2MPa, power 20Hz.
8. as requested described in 1 a kind of blank polymer microsphere it is characterised in that described blank polymer microsphere apply in medicine sustained and controlled release carrier.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107467672A (en) * | 2017-06-27 | 2017-12-15 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of ferrous composite gel microsphere |
| CN108939136A (en) * | 2018-08-20 | 2018-12-07 | 重庆医科大学附属永川医院 | A kind of dressing and preparation method thereof for nose filling hemostasis |
| CN109265710A (en) * | 2018-08-08 | 2019-01-25 | 武汉水木弘新材料有限公司 | Cellulose microsphere of uniform size and preparation method thereof |
| CN113750076A (en) * | 2021-09-30 | 2021-12-07 | 大连理工大学 | Chitin-gelatin-based composite porous microspheres as drug carrier and preparation method and application thereof |
-
2015
- 2015-09-01 CN CN201510551345.0A patent/CN106474071A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107467672A (en) * | 2017-06-27 | 2017-12-15 | 福格森（武汉）生物科技股份有限公司 | A kind of preparation method of ferrous composite gel microsphere |
| CN107467672B (en) * | 2017-06-27 | 2020-11-13 | 福格森（武汉）生物科技股份有限公司 | Preparation method of ferrous composite gel microspheres |
| CN109265710A (en) * | 2018-08-08 | 2019-01-25 | 武汉水木弘新材料有限公司 | Cellulose microsphere of uniform size and preparation method thereof |
| CN108939136A (en) * | 2018-08-20 | 2018-12-07 | 重庆医科大学附属永川医院 | A kind of dressing and preparation method thereof for nose filling hemostasis |
| CN108939136B (en) * | 2018-08-20 | 2020-12-22 | 重庆医科大学附属永川医院 | Dressing for nasal filling hemostasis and preparation method thereof |
| CN113750076A (en) * | 2021-09-30 | 2021-12-07 | 大连理工大学 | Chitin-gelatin-based composite porous microspheres as drug carrier and preparation method and application thereof |
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Application publication date: 20170308 |