CN101590015A - Cationic adhesion type mycophenolate mofetil nano eye drop - Google Patents
Cationic adhesion type mycophenolate mofetil nano eye drop Download PDFInfo
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- CN101590015A CN101590015A CNA2009100163440A CN200910016344A CN101590015A CN 101590015 A CN101590015 A CN 101590015A CN A2009100163440 A CNA2009100163440 A CN A2009100163440A CN 200910016344 A CN200910016344 A CN 200910016344A CN 101590015 A CN101590015 A CN 101590015A
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Abstract
The present invention relates to a kind of cationic adhesion type mycophenolate mofetil nano eye drop.The mycophenolate that comprises mass percent concentration 1%, an amount of osmotic pressure regulator and pH regulator agent, it is characterized in that also comprising chitosan, pluronic F-68, phospholipid, mass percent concentration 0.5%-4%, chitosan the mass percent concentration 0.5-4% in eye drop of mass percent concentration 0.2%-2%, the pluronic F-68 of phospholipid in eye drop in eye drop wherein, the chitosan molecule amount is 5000～300000, deacetylation＞85%, and the particle diameter of mycophenolate is in the 10-700nm scope.Characteristics of the present invention are dissolubility that the mycophenolate of nanometer particle size increases medicine, improve safety and effectiveness.Make mycophenolate medicine particle positively charged again, absorb, strengthen drug effect and prolong drug action time, strengthen the cornea adhesion greatly to help the cornea that improves medicine.
Description
The present invention relates to a kind of mycophenolate eye drop, specially refer to a kind of cationic adhesion type mycophenolate mofetil nano eye drop.
Background technology
In the diseases causing blindness of China, keratopathy is only second to cataract and occupies second.At present, corneal allograft rejection becomes the first cause that causes graft failure.At avascular plant bed, rejection episodes is 5～10%, and in high-risk corneal transplantation, rejection episodes can be up to more than 65%.How effectively to prevent and treat immunological rejection after the Penetrating Keratoplasty, improve the survival rate of planting sheet and become one of focus of ophthalmology scholar research.
Mycophenolate (MMF) is a kind of effective anti-immunologic rejection medicine, but has only oral formulations at present.Untoward reaction is serious after the oral whole body administration, and bibliographical information accepts to have among the patient of mycophenolate 18% to be forced to discontinue medication because of poisonous side effect of medicine; In addition, influenced by blood-ocular barrier etc., be difficult to behind the drug oral enter part tissue of eye and reach active drug concentration, these have all limited the further application of existing mycophenolate in ophthalmology.
Summary of the invention
The purpose of this invention is to provide a kind of cationic adhesion type mycophenolate mofetil nano eye drop, to strengthen drug particle cornea anelasticity, prolong drug action time, improve cornea to the absorption of medicine, reduce administration number of times, improve patient's compliance, remedy the deficiencies in the prior art.
Technical conceive of the present invention: mycophenolate is prepared into a topical novel form such as an eye drop, the serious adverse reaction that then can avoid existing mycophenolate oral formulations in application, to exist.But ordinary eye drops is because be subjected to the restriction of cornea malabsorption, and bioavailability is very low.Mycophenolate is an insoluble drug, is fit to exploitation eye drip suspensoid.Medicine for indissoluble in tear, if reduce the particle diameter of suspensoid Chinese medicine particle, (particle diameter is at 1-10 μ m) is prepared into nano suspension (particle diameter is at 10-1000nm) by common suspensoid, can increase the dissolubility of insoluble drug, the cornea that changes medicine absorbs feature, improves safety and effectiveness.In addition, consider that any polymer solution or suspension splash into eye, at first the mucin with cornea and conjunctival surface combines, and mucin is mainly acidoglycoprotein, and side chain terminal is sulphuric acid or sialic acids groups, is negative charge.Common suspensoid and nano suspension be negative charge (approximately-30～-50mV), exist electric charge to repel each other with the positive charge on the cornea, hinder drug absorption, therefore, make it positively charged if the drug particle of common nano suspension modified, just help positive and negative charge and inhale mutually, help to improve the absorption of cornea medicine, and prolong drug action time, strengthen drug effect greatly and reach.
The present invention innovates the dosage form of existing common mycophenolate, being about to medicament nano technology and particle modification technique combines, be specifically mycophenolate is prepared into have the effect of sticking, the eye drop of positively charged nano-grade medicine particle, and the particle diameter that makes mycophenolate is in the nanoscale scope of 100-700nm.
Technical scheme of the present invention: the mycophenolate that comprises mass percent concentration 1%, an amount of osmotic pressure regulator and pH regulator agent, it is characterized in that also comprising chitosan, pluronic F-68, phospholipid, mass percent concentration 0.5%-4%, chitosan the mass percent concentration 0.5-4% in eye drop of mass percent concentration 0.2%-2%, the pluronic F-68 of phospholipid in eye drop in eye drop wherein, and the chitosan molecule amount is 5000～300000, deacetylation＞85%, wherein the particle diameter of mycophenolate is in the 100-700nm scope.
Phospholipid among the present invention is other soybean lecithin of pharmaceutic adjuvant level or Ovum Gallus domesticus Flavus lecithin.
The pressure of the homogenizer in the particle diameter of the mycophenolate among the present invention and the preparation process is relevant with cycle-index, pressure increases, particle diameter reduces, and cycle-index increases, and particle diameter also reduces, but pressure be increased to a certain degree as 1500bar, cycle-index be increased to a certain degree as 15 times after, pressure or cycle-index increase again, and particle diameter does not significantly reduce, but tend towards stability, therefore, the technique for fixing of selecting for use 15 further refinements of homogenizer pressure 1500bar circulation to pulverize among the present invention.The particle diameter of mycophenolate is also relevant with pluronic F-68, phospholipid and chitosan concentration.Pluronic F-68, phospholipid and chitosan three's concentration combined effect affects the particle diameter of mycophenolate.
The electric charge size of the positive charge of the mycophenolate among the present invention is relevant with the mass percent concentration of chitosan in eye drop, and chitosan concentration is big more, and the electric charge of the positive charge of mycophenolate is big more.
The method of the present invention's preparation adds down:
At first, in mycophenolate and phospholipid dissolving and ether, rotary evaporation is fully removed ether, obtain the homodisperse thin film of medicine and phospholipid, add chitosan solution and pluronic F-68 solution then, (particle of chitosan and phospholipid parcel is in conjunction with making on its particle surface band+positive charge of 20mV-+50mV current potential fully to wash film, the adhesion that has chitosan simultaneously), after washing the film end, the film ultra-sonic dispersion is obtained emulsion after evenly, emulsion is crossed the high pressure homogenizer, pulverize for the first time for 5 times with pressure 500bar circulation earlier, 15 further refinements of reuse pressure 1500bar circulation are pulverized, and particle diameter is at 100-700nm, the emulsion that to spare matter is then regulated osmotic pressure and is oozed to waiting, regulate pH value to 5.5-8.0 promptly.Record the particle diameter of nano suspension at 100-700nm with laser particle size potentiometric analysis analyzer.Therefore, the present invention is a thin film dispersion-high pressure homogenization method basically.
Characteristics of the present invention are that mycophenolate is prepared into nano suspension (particle diameter is at 100-700nm), increase the dissolubility of medicine, and the cornea that changes medicine absorbs feature, improves safety and effectiveness.In addition, the mycophenolate drug particle of suspensoid is modified by phospholipid and chitosan, make it positively charged, helping positive and negative charge inhales mutually, the cornea that helps to improve medicine absorbs, and prolong drug action time and strengthen drug effect greatly, and chitosan wherein has the bio-adhesive effect, make mycophenolate drug particle cornea adhesion strengthen the time of prolong drug effect.Than the mycophenolate oral formulations, the present invention has ocular drug bioavailability height, does not have untoward reaction, has particularly avoided the untoward reaction of systemic administration, for mycophenolate provides assurance in the extensive use of ophthalmology.This novel form can strengthen drug particle cornea anelasticity, prolong drug action time, improve cornea to the absorption of medicine, reduce administration number of times, improve patient's compliance,
The specific embodiment
The present invention includes mycophenolate, an amount of osmotic pressure regulator and pH regulator agent, it is characterized in that also comprising chitosan, pluronic F-68, phospholipid, mass percent concentration 0.5%-4%, chitosan the mass percent concentration 0.5-4% in eye drop of mass percent concentration 0.2%-2%, the pluronic F-68 of phospholipid in eye drop in eye drop wherein, and the chitosan molecule amount is 5000～300000, deacetylation＞85%, wherein the particle diameter of mycophenolate is in the 100-700nm scope.
Phospholipid among the present invention is other soybean lecithin of pharmaceutic adjuvant level or Ovum Gallus domesticus Flavus lecithin, mainly plays the suspending agent and the electric charge dressing agent of nano suspension, also can play the effect of similar liposome, increases the dissolubility of mycophenolate.
Concentration 0.5%-4% pluronic F-68 among the present invention is as suspending agent and stabilizing agent, prolongs the holdup time of eye drop at cornea.Concentration is lower than 0.5%, Zhi Bei eye drop instability then, and flocculation easily, concentration is higher than 4%, and then Zhi Bei eye drop thickness too blurs vision.
Osmotic pressure regulator of the present invention is a kind of formation in existing glucose, dextran, sorbitol, mannitol and the sodium chloride, is adjusted to etc. to ooze.
PH regulator agent of the present invention is a kind of in existing hydrochloric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium hydrogen phosphate, the sodium dihydrogen phosphate, regulates pH to 5.5-8.0.
Embodiment 1
0.3g mycophenolate and 60mg phospholipid are dissolved in the 50ml ether, rotary evaporation is fully removed ether, obtain the homodisperse thin film of medicine and phospholipid, add 2% chitosan (molecular weight 5000 then, deacetylation 85%) solution 7.5ml and 2% F-68 solution 7.5ml, fully wash film, obtain emulsion after ultra-sonic dispersion is even, emulsion is crossed the high pressure homogenizer, pulverize for the first time for 5 times with pressure 500bar circulation earlier, carrying out further refinement for 15 times with pressure 1500bar circulation then pulverizes, the emulsion that to spare matter then is settled to 30ml with water for injection, regulating osmotic pressure with sodium chloride oozes to waiting, dilute hydrochloric acid pH value to 6.5 gets cationic adhesion type mycophenolate mofetil nano suspensoid eye drop.
The particle size range that laser particle size potentiometric analysis analyzer records nano suspension is 100～700nm, and mean diameter is 480nm, and mycophenolate mofetil nano particle surface current potential is+37.5mV.The nano suspension that obtains was preserved 6 months at 4 ℃ of black outs, and the particle diameter current potential does not have substantial variation.
Embodiment 2
0.3g mycophenolate and 0.6g phospholipid are dissolved in the 50ml ether, rotary evaporation is fully removed ether, obtain the homodisperse thin film of medicine and phospholipid, add molecular weight 130000 then, the chitosan 1.2g of deacetylation 91% and F-681.2g are dissolved in fully dissolving in the 25ml water for injection, lysate with chitosan and F-68 is fully washed film, obtain emulsion after ultra-sonic dispersion is even, emulsion is crossed the high pressure homogenizer, pulverize for the first time for 5 times with the circulation of 500bar pressure earlier, carrying out further refinement for 15 times with the circulation of 1500bar pressure then pulverizes, the emulsion that to spare matter then is settled to 30ml with water for injection, regulating osmotic pressure with sodium chloride oozes to waiting, dilute hydrochloric acid pH value to 6.5 gets cationic adhesion type mycophenolate mofetil nano suspensoid eye drop.The particle size range that laser particle size potentiometric analysis analyzer records nano suspension is 100～700nm, and mean diameter is 410nm, and the particle surface current potential is+43mV.The nano suspension that obtains was preserved 6 months at 4 ℃ of black outs, and the particle diameter current potential does not have substantial variation.
Embodiment 3
With the chitosan among the embodiment 1 use that molecular weight is 300000 instead, deacetylation is 85% chitosan, also can obtain the present invention.The particle size range that light granularity potentiometric analysis analyzer records nano suspension is 100～700nm, and mean diameter is 427nm, and the particle surface current potential is+49mV.The nano suspension that obtains was preserved 6 months at 4 ℃ of black outs, and the particle diameter current potential does not have substantial variation.
Embodiment 4
0.3g mycophenolate and 0.3g phospholipid are dissolved in the 50ml ether, rotary evaporation is fully removed ether, obtain the homodisperse thin film of medicine and phospholipid, add molecular weight 175000 then, the chitosan 0.6g of deacetylation 95% and F-680.6g are dissolved in fully dissolving in the 25ml water for injection, lysate with chitosan and F-68 is fully washed film, obtain emulsion after ultra-sonic dispersion is even, emulsion is crossed the high pressure homogenizer, pulverize for the first time for 5 times with the 500bar pressures cycle earlier, carrying out further refinement for 15 times with the 1500bar pressures cycle then pulverizes, the emulsion that to spare matter then is settled to 30ml with water for injection, regulating osmotic pressure with sodium chloride oozes to waiting, dilute hydrochloric acid pH value to 6.5 gets cationic adhesion type mycophenolate mofetil nano suspensoid eye drop.The particle size range that laser particle size potentiometric analysis analyzer records nano suspension is 100～700nm, and mean diameter is 466nm, and the particle surface current potential is+45mV.The nano suspension that obtains was preserved 6 months at 4 ℃ of black outs, and the particle diameter current potential does not have substantial variation.
Use the present invention to carry out one of control experiment for example down:
Get 56 of healthy new zealand white rabbits, be divided into 2 groups at random, one group is 1% mycophenolate suspension, and every rabbit 50 μ l eye drips extract aqueous humor in 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, and HPLC analyzes drug level.Another group is 1% cationic adhesion type mycophenolate mofetil nano eye drop liquid group.Every rabbit 50 μ l 5% cationic adhesion type mycophenolate mofetil nano eye drop eye drip extracts aqueous humor in 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, and HPLC analyzes drug level.Aqueous humor Chinese medicine concentration sees the following form.Drug level aqueous humor determination of drug concentration result is that 1% cationic adhesion type mycophenolate mofetil nano eye drop group aqueous humor drug level is significantly higher than 1% mycophenolate suspension group, and action time significant prolongation.
Mycophenolate concentration (n=8) in table 1 aqueous humor
Claims (3)
1, a kind of cationic adhesion type mycophenolate mofetil nano eye drop, it comprises the mycophenolate of mass percent concentration 1%, an amount of osmotic pressure regulator and pH regulator agent, it is characterized in that this eye drop also comprises chitosan, pluronic F-68, phospholipid, wherein the mass percent concentration of phospholipid in eye drop is in the 0.2%-2% scope, the mass percent concentration of pluronic F-68 in eye drop is in the 0.5%-4% scope, the mass percent concentration of chitosan in eye drop is in the 0.5-4% scope, the chitosan molecule amount is 5000～300000, deacetylation＞85%, wherein the particle diameter of mycophenolate is in the 100-700nm scope, and its particle surface has+positive charge of 20mV-+50mV current potential.
2, cationic adhesion type mycophenolate mofetil nano eye drop as claimed in claim 1 is characterized in that above-mentioned phospholipid is other soybean lecithin of pharmaceutic adjuvant level or Ovum Gallus domesticus Flavus lecithin.
3, the method for preparing cationic adhesion type mycophenolate mofetil nano eye drop is as follows: at first, mycophenolate and phospholipid are dissolved in the ether, rotary evaporation is fully removed ether, obtain the homodisperse thin film of mycophenolate and phospholipid at container inner wall, add chitosan solution and pluronic F-68 solution then, behind the above-mentioned thin film of eluting, and the mixed liquor that obtains after this thin-film ultrasonic pulverized is via the high pressure homogenization machine, further pulverize for 5 times with pressure 500bar circulation earlier, and then pulverize the mixed liquor that obtains even matter with 15 refinements of pressure 1500bar circulation, wherein the particle diameter of mycophenolate is in the 100-700nm scope, the mixed liquor that to spare matter is at last regulated osmotic pressure and is oozed to waiting, regulate again pH value to 5.5-8.0 promptly.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565738A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Rapidly-dispersed water-mixed suspension medicine used for eyes |
| CN103565741A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Glucocorticoid ophthalmic water suspension having redispersibility |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101332180A (en) * | 2008-08-01 | 2008-12-31 | 北大方正集团有限公司 | Melbex eye drops and preparation method thereof |
| CN101385703B (en) * | 2008-10-01 | 2010-06-09 | 山东省眼科研究所 | Cation adhesion type natamycin nano eye drops |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103565738A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Rapidly-dispersed water-mixed suspension medicine used for eyes |
| CN103565741A (en) * | 2012-07-25 | 2014-02-12 | 天津金耀集团有限公司 | Glucocorticoid ophthalmic water suspension having redispersibility |
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