CN103735518B - The preparation method of timolol maleate sustained-release micro-spheres - Google Patents
The preparation method of timolol maleate sustained-release micro-spheres Download PDFInfo
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Abstract
The invention discloses the preparation method of timolol maleate sustained-release micro-spheres.The present invention adopts oily bag oil tech, with timolol maleate, modified montmorillonite used, the interior phase of acrylic resin, tween, plasticizer preparation, foreign minister is prepared with vegetable oil, span, by the oily bag fat liquor of acquisition after supersound process, again by phase in electromagnetic agitation evaporation, obtain timolol maleate sustained-release micro-spheres, its size tunable, within the scope of 10 μm, meets the requirement of ophthalmic preparation.Its entrapment efficiency is up to 80 ~ 99%, and the release in vitro time can extend to 10 ~ 12h.Timolol maleate sustained-release micro-spheres prepared by the method, as intraocular pressure lowering medicine, can reduce ophthalmic sense of discomfort, reduces times for spraying, realizes the object that single administration reaches long-time intraocular pressure lowering.
Description
Technical field
The invention belongs to medical art, particularly a kind of preparation method of water solublity intraocular pressure lowering medicament slow-release microsphere.
Background technology
Timolol maleate (timololmaleate) is selectivity beta-blockers, can reduce aqueous humor and generate, have the effect obviously reducing intraocular pressure, and on pupil size, light reflex and vision all without impact.Extensive use Timolol maleate eye drops treatment primary open angle glaucoma and aphakic glaucoma clinically.The curative effect of eye medicinal depends on medicine in the valid density of cornea and holdup time, tradition eye drop is 30s in the precorneal holdup time, 5% medicine is only had to be absorbed by cornea, need frequent drug administration, eye drop dosage is difficult to control, and major part enters blood circulation by conjunctiva or lacrimal ductule, lachrymal sac, nasolacrimal duct, nasal cavity, can cause side effect.But current this traditional administering mode accounts for 90% of whole market.How improving the ocular absorption of medicine, improve its therapeutic effect, reduce its untoward reaction, is the hot issue of current dosing eyes systematic study.
Medicine carrying microballoons (microspheres) is a kind of widely used Novel medicine feeding system, and it is with suitable macromolecular material for carrier, and make the spherical or class spherical particle of parcel or absorption medicine, particle diameter is generally at 1 ~ 250 μm.Microball preparation can prolong drug in the precorneal holdup time and slow releasing medicine, improve the bioavailability of medicine, reduce times for spraying, improve therapeutic index, reduce the toxic and side effects of medicine at eye or whole body.Therefore, the research and apply of sustained-release micro-spheres drug-supplying system will become the new trend of ophthalmic preparation development from now on.Microball preparation can targeting, slow releasing pharmaceutical, suspendible liquid condition can be used as eye drop or intraocular injection agent, reduce ophthalmic sense of discomfort.
Carrier material for the preparation of sustained-release micro-spheres has multiple, by sources can be divided into (1) natural macromolecular material, as cellulose, chitosan, protein; (2) synthesized polymer material, can be divided into again by biodegradation character: non-biodegradation type macromolecular material, as polyacrylic resin and derivant, polyvinyl alcohol; Biodegradable macromolecular material, as polyester, condensing model, poe, Merlon etc.
The method preparing microsphere can be divided into single breast (O/W type by emulsion type, w/o type, O/O type)-intra-liquid desiccation method and emulsion (W/O/W type and O/W/O type)-intra-liquid desiccation method two class: (1) single breast (O/W)-intra-liquid desiccation method is the conventional method of hydrophobic drug microsphereization, the method weak point is, obtained microsphere surface often inlays medicine crystal, the method is unsuitable for wrapping and carries the larger medicine of water solublity, because be easy to be dispensed to outer aqueous phase from oil-water interfaces cause entrapment efficiency obviously to decline in emulsifying and fluid drying process Chinese medicine in addition.(2) volatility process in emulsion (W/O/W)-liquid, the method is consuming time longer, wayward, yields poorly.Owing to introducing oil-water interfaces, particularly when colostrum is formed, system is very unstable.YilmazCapan etc. adopt the preparation of W/O/W-solvent evaporation method to be loaded with water-solubility protein---the polylactide microsphere of human growth hormone, the inadequate rounding of microsphere surface prepared by the method also has hole, mean diameter reaches 44.6 ± 2.47 μm, the relatively large and skewness of particle diameter.And, cause its drug loading relatively low because water soluble drug is easily diffused into outer aqueous phase from interior aqueous phase.(3) volatility process in single breast (O/O)-liquid, because inside and outside phase solvent is all lyophobic dust, can make water soluble drug envelop rate and drug loading greatly improve.Obtained microsphere outward appearance rounding, dashing forward, it is little to release, and major part can discharge whole medicine.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of timolol maleate sustained-release micro-spheres.
The technical solution used in the present invention is:
The preparation method of timolol maleate sustained-release micro-spheres, comprises the following steps:
1) timolol maleate, acrylic resin, tween, plasticizer, Montmorillonitum are scattered in organic solvent, make the concentration of acrylic resin be 30 ~ 100g/L, the concentration of tween is 20 ~ 60g/L, and the concentration of plasticizer is 5 ~ 20g/L, obtains interior phase;
2) span is dissolved in vegetable oil, the concentration making span is 10 ~ 40g/L, obtains foreign minister;
3) under stirring, instill foreign minister mutually by interior, form oily bag fat liquor;
4) emulsion is after supersound process 5 ~ 30min, phase in evaporation under electromagnetic agitation, and washing is dry, obtains sustained-release micro-spheres.
Preferably, inside mutually in, the concentration of timolol maleate is 5 ~ 20g/L.
Preferably, Montmorillonitum is modified montmorillonite used, and its method of modifying is as follows: strong acid Montmorillonitum being placed in 3 ~ 15v/v%, and after 50 ~ 90 DEG C of activation 2 ~ 9h, washing is to neutral, dry, obtains modified montmorillonite used.
Preferably, inside mutually in, the concentration of Montmorillonitum is 4 ~ 25g/L.
Preferably, acrylic resin is EudragitRSPO and EudragitRLPO, and its mass ratio is 2 ~ 6:1.
Preferably, plasticizer is at least one in Polyethylene Glycol, propylene glycol, glycerol, triethyl citrate.
Preferably, organic solvent is acetonitrile or dichloromethane.
Preferably, in step 3), interior is 0.03 ~ 0.1:1 with the mass ratio of foreign minister.
Preferably, in step 3), mixing speed is 500 ~ 2000rpm.
Preferably, in step 4), at-10 ~ 20 DEG C, carry out electromagnetic agitation.
The invention has the beneficial effects as follows:
The present invention adopts oily bag oil tech, with timolol maleate, modified montmorillonite used, the interior phase of acrylic resin, tween, plasticizer preparation, foreign minister is prepared with vegetable oil, span, by the oily bag fat liquor of acquisition after supersound process, again by phase in electromagnetic agitation evaporation, obtain timolol maleate sustained-release micro-spheres, its size tunable, within the scope of 10 μm, meets the requirement of ophthalmic preparation.Its entrapment efficiency is up to 80 ~ 99%, and the release in vitro time can extend to 10 ~ 12h.Timolol maleate sustained-release micro-spheres prepared by the method, as intraocular pressure lowering medicine, can reduce ophthalmic sense of discomfort, reduces times for spraying, realizes the object that single administration reaches long-time intraocular pressure lowering.
Accompanying drawing explanation
Fig. 1 is the Electronic Speculum figure of sustained-release micro-spheres.
Fig. 2 is external SR test result.
Detailed description of the invention
The preparation method of timolol maleate sustained-release micro-spheres, comprises the following steps:
5) timolol maleate, acrylic resin, tween, plasticizer, Montmorillonitum are scattered in organic solvent, make the concentration of acrylic resin be 30 ~ 100g/L, the concentration of tween is 20 ~ 60g/L, and the concentration of plasticizer is 5 ~ 20g/L, obtains interior phase;
6) span is dissolved in vegetable oil, the concentration making span is 10 ~ 40g/L, obtains foreign minister;
7) under stirring, instill foreign minister mutually by interior, form oily bag fat liquor;
8) emulsion is after supersound process 5 ~ 30min, phase in evaporation under electromagnetic agitation, and washing is dry, obtains sustained-release micro-spheres.
The stability of emulsifying agent to oily bag fat liquor is most important, and emulsifying agent of the present invention is preferably tween cheap and easy to get and span, obtains rational HLB value, makes Emulsion consistencies moderate, formed and stablize oily oil-in emulsion by the ratio of adjustment tween and span.
Acrylic resin is preferably EudragitRSPO and EudragitRLPO, and its mass ratio is 2 ~ 6:1.The object regulating timolol maleate rate of release is reached by regulating the ratio of EudragitRSPO and EudragitRLPO.
The film material transition temperature of propenoic acid resin series material is higher, fragility is comparatively large, causes ball fractured, therefore must add a certain proportion of plasticizer in film material when balling-up because of bad mechanical property, in order to increase the pliability during balling-up of film material, freely to control the size of microsphere.Plasticizer of a great variety, the present invention is preferably extensively easy to get and at least one in high triethyl citrate (TEC), Polyethylene Glycol (PEG), propylene glycol and the glycerol of safety.Preferred, plasticizer is TEC and glycerol.
Below in conjunction with specific embodiment, set forth content of the present invention further.
embodiment 1
1) precision takes timolol maleate 30mg, sodium montmorillonite 20mg, TEC50mg, glycerol 50mg, acrylic resin (RSPO:RLPO mass ratio=2:1) 400mg, Tween 80 124mg, adds in 5ml acetonitrile, and dispersed with stirring mixing obtains interior phase.
2) 248mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
3), under 600rpm mixing speed, dropwise add in 0.3g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
4) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 10min, then under ice bath electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
embodiment 2
1) 500mg sodium montmorillonite is placed in the sulphuric acid of 5v/v%, after activating 2h at 90 DEG C, washing is to neutral, dry, obtains modified montmorillonite used.
2) precision takes timolol maleate 30mg, modified montmorillonite used 20mg, TEC50mg, glycerol 50mg, acrylic resin (RSPO:RLPO mass ratio=2:1) 400mg, Tween 80 124mg altogether, add in 5ml acetonitrile, dispersed with stirring mixing obtains interior phase.
3) 248mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
4), under 600rpm mixing speed, dropwise add in 0.3g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
5) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 10min, then under ice bath electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
embodiment 3
1) 500mg sodium montmorillonite is placed in the sulphuric acid of 8v/v%, after activating 4h at 80 DEG C, washing is to neutral, dry, obtains modified montmorillonite used.
2) precision takes timolol maleate 50mg, modified montmorillonite used 35mg, PEG40mg, propylene glycol 50mg, acrylic resin (RSPO:RLPO mass ratio=4:1) 500mg, Tween 80 150mg altogether, add in 5ml acetonitrile, dispersed with stirring mixing obtains interior phase.
3) 300mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
4), under 1200rpm mixing speed, dropwise add in 0.4g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
5) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 8min, then under ice bath electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
embodiment 4
1) 500mg sodium montmorillonite is placed in the sulphuric acid of 10v/v%, after activating 7h at 65 DEG C, washing is to neutral, dry, obtains modified montmorillonite used.
2) precision takes timolol maleate 75mg, modified montmorillonite used 50mg, TEC50mg, glycerol 25mg, acrylic resin (RSPO:RLPO mass ratio=4:1) 325mg, Tween 80 200mg altogether, add in 5ml dichloromethane, dispersed with stirring mixing obtains interior phase.
3) 350mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
4), under 1000rpm mixing speed, dropwise add in 0.4g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
5) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 15min, then at 4 DEG C electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
embodiment 5
1) 500mg sodium montmorillonite is placed in the hydrochloric acid of 15v/v%, after activating 9h at 50 DEG C, washing is to neutral, dry, obtains modified montmorillonite used.
2) precision takes timolol maleate 100mg, modified montmorillonite used 75mg, TEC20mg, PEG20mg, acrylic resin (RSPO:RLPO mass ratio=4:1) 250mg, Tween 80 100mg altogether, add in 5ml acetonitrile, dispersed with stirring mixing obtains interior phase.
3) 400mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
4), under 2000rpm mixing speed, dropwise add in 0.5g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
5) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 5min, then at-10 DEG C electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
embodiment 6
1) 500mg sodium montmorillonite is placed in the phosphoric acid of 3v/v%, after activating 5h at 85 DEG C, washing is to neutral, dry, obtains modified montmorillonite used.
2) precision takes timolol maleate 25mg, modified montmorillonite used 125mg, TEC25mg, acrylic resin (RSPO:RLPO mass ratio=6:1) 150mg, Tween 80 300mg altogether, adds in 5ml dichloromethane, and dispersed with stirring mixing obtains interior phase.
3) 100mg sorbester p17 is dissolved in 10ml vegetable oil, obtains foreign minister.
4), under 500rpm mixing speed, dropwise add in 0.15g in 5g foreign minister mutually, be uniformly dispersed, obtain oily bag fat liquor.
5) first this emulsion is placed in ultrasonic cell disrupte instrument supersound process 30min, then at 20 DEG C electromagnetic agitation evaporation in phase, n-hexane, normal temperature drying.
test example
electron microscopic observation:
Fig. 1 is the electron microscopic observation figure of timolol maleate sustained-release micro-spheres prepared by embodiment 2, visible, and sustained-release micro-spheres smooth surface prepared by the inventive method is fine and close, imporosity crackle, particle size distribution, between 3 ~ 10 μm, meets the requirement of ophthalmic preparation, can reduce ophthalmic sense of discomfort.
the mensuration of microsphere drug loading and envelop rate:
Assay method: (1) carries out linear regression with absorbance A to corresponding timolol maleate reference substance concentration C (mg/L), obtains standard curve.
(2) precision takes sustained-release micro-spheres 0.03g, put in 30ml dehydrated alcohol, the accurate 0.3ml that draws is in 10ml measuring bottle again, with ethanol dilution to scale, place 15min, filtering with microporous membrane, measure absorbance A at 273nm place, substitute into standard curve calculated mass concentration C, then press drug loading in microsphere of formula (1), (2) calculating timolol maleate and envelop rate respectively.
（1）
（2）
The sustained-release micro-spheres of mensuration embodiment 1 ~ 5 preparation as stated above, calculates drug loading and envelop rate is as shown in table 1.
The drug loading of table 1 sustained-release micro-spheres and envelop rate
。
Visible, the timolol maleate sustained-release micro-spheres prepared by the inventive method, entrapment efficiency is up to more than 72.10%, and after carrying out activation modification to medicine carrying Montmorillonitum, entrapment efficiency is increased to more than 90% further, and drug loading is up to more than 11%.
external SR test:
Test method: (1) precision takes sustained-release micro-spheres 50mg prepared by embodiment 2, put in bag filter, and add 5ml artificial tears, bag filter is placed in the artificial tears of 35ml, 34 DEG C of water-baths are hatched, sample 5ml respectively at 15min, 30min, 45min, 60min, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h and 12h, and add into artificial tears 5ml.Spectrophotography method is adopted to measure timolol maleate content.
Analyze the release in vitro result of gained timolol maleate sustained-release micro-spheres as shown in Figure 2, with microsphere Accumulation dissolution for vertical coordinate, the time is abscissa, the prominent amount of the releasing R of microsphere
0.5hbe 9.55 ± 3.2%, Cumulative release amount can reach 95.76 ± 2.2%, and sustainable release reaches 12h, has good release in vitro performance.
Carry out external SR test analysis to sustained-release micro-spheres prepared by other embodiments, its result is similar to this result, and the release in vitro time of timolol maleate is 10 ~ 12h.
Claims (9)
1. the preparation method of timolol maleate sustained-release micro-spheres, comprises the following steps:
1) timolol maleate, acrylic resin, tween, plasticizer, Montmorillonitum are scattered in organic solvent, make the concentration of acrylic resin be 30 ~ 100g/L, the concentration of tween is 20 ~ 60g/L, and the concentration of plasticizer is 5 ~ 20g/L, obtains interior phase;
2) span is dissolved in vegetable oil, the concentration making span is 10 ~ 40g/L, obtains foreign minister;
3) under stirring, instill foreign minister mutually by interior, form oily bag fat liquor;
4) emulsion is after supersound process 5 ~ 30min, phase in evaporation under electromagnetic agitation, and washing is dry, obtains sustained-release micro-spheres;
It is characterized in that: described Montmorillonitum is modified montmorillonite used, and its method of modifying is as follows: strong acid Montmorillonitum being placed in 3 ~ 15v/v%, after 50 ~ 90 DEG C of activation 2 ~ 9h, washing is to neutral, dry, obtains modified montmorillonite used.
2. preparation method according to claim 1, is characterized in that: inside mutually in, the concentration of timolol maleate is 5 ~ 20g/L.
3. preparation method according to claim 1 and 2, is characterized in that: inside mutually in, the concentration of Montmorillonitum is 4 ~ 25g/L.
4. preparation method according to claim 1, is characterized in that: acrylic resin is EudragitRSPO and EudragitRLPO, and its mass ratio is 2 ~ 6:1.
5. preparation method according to claim 1, is characterized in that: plasticizer is at least one in Polyethylene Glycol, propylene glycol, glycerol, triethyl citrate.
6. preparation method according to claim 1, is characterized in that: organic solvent is acetonitrile or dichloromethane.
7. preparation method according to claim 1, is characterized in that: in step 3), and interior is 0.03 ~ 0.1:1 with the mass ratio of foreign minister.
8. preparation method according to claim 1, is characterized in that: in step 3), and mixing speed is 500 ~ 2000rpm.
9. preparation method according to claim 1, is characterized in that: in step 4), carries out electromagnetic agitation at-10 ~ 20 DEG C.
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| CN104491867B (en) * | 2014-11-27 | 2018-07-17 | 广东药科大学 | A kind of preparation method of the novel Drug Delivery Systems of chitosan package load medicine montmorillonite |
| CN109646422A (en) * | 2019-01-18 | 2019-04-19 | 广东药科大学 | A kind of preparation method of the ophthalmic administration system of polyacrylic resin package load medicine montmorillonite |
| CN112451478A (en) * | 2020-11-26 | 2021-03-09 | 江苏远恒药业有限公司 | Timolol maleate eye drops and preparation process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278162A (en) * | 1997-11-05 | 2000-12-27 | 千寿制药株式会社 | Sustained release eyedrops |
| WO2008157614A2 (en) * | 2007-06-21 | 2008-12-24 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
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2013
- 2013-12-17 CN CN201310697827.8A patent/CN103735518B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278162A (en) * | 1997-11-05 | 2000-12-27 | 千寿制药株式会社 | Sustained release eyedrops |
| WO2008157614A2 (en) * | 2007-06-21 | 2008-12-24 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
Non-Patent Citations (2)
| Title |
|---|
| Montmorillonite as a drug delivery system: Intercalation and in vitro release of timolol maleate;Ghanshyam V. Joshi等;《International Journal of Pharmaceutics》;20090319(第374期);第53-57页，第57页第4节 * |
| 镶嵌蒙脱石载体的离子交换微球给药系统的研制;侯永恒等;《西北药学杂志》;20121130;第27卷(第6期);第560-563页，第562页第3.1、3.2.4节 * |
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