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CN100352508C - Block polymer for eyes - Google Patents

Block polymer for eyes Download PDF

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CN100352508C
CN100352508C CNB2005100022092A CN200510002209A CN100352508C CN 100352508 C CN100352508 C CN 100352508C CN B2005100022092 A CNB2005100022092 A CN B2005100022092A CN 200510002209 A CN200510002209 A CN 200510002209A CN 100352508 C CN100352508 C CN 100352508C
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polymer
medicine
block polymer
eye
pla
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CN1644215A (en
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涂家生
吴建梅
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Abstract

The present invention relates to a block polymer for eyes, which can be used as a medicine carrier for eyes. The polymer is composed of segments of two polymers A, B, wherein the segments of the polymers A, B are respectively a hydrophilic polymer of methoxypolyethylene glycol (mPEG) and a hydrophobic polymer of polylactic acid (PLA) or polyglycolic acid (PGA) or a glycollide-lactide polymer (PLGA). The block polymer can be an AB type two-block polymer or multi-block polymer.

Description

A kind of block polymer for eyes
Technical field:
The present invention relates to eye usefulness with the block polymer of forming by two kinds of polymer (A, B) segment, wherein A, B segment are respectively hydrophilic polymer-methoxypolyethylene glycol (mPEG) and hydrophobic polymer-polylactic acid (PLA) or polyglycolic acid (PGA) or Acetic acid, hydroxy-, bimol. cyclic ester-lactide polymer (PLGA) in the polymer, and block polymer can be AB type diblock polymer or multi-block polymer.This eye drops that is suitable for.
Background technology:
Eye drops is the important administering mode of treatment ocular disease, and the eye drops preparation comprises eye drop, gel for eye etc.At present, ophthalmic preparation can be divided into by the therapeutic purposes difference: 1) should see through the preparation that cornea enters ophthalmic, the example hydrochloric acid pirenzepine is the M1 receptor blocking agent, can stop bathomorphic further developing, its site of action is necessary so pirenzepine enters ophthalmic through cornea within the eye; 2) should be at the preparation of eye such as eye conjunctiva, cornea surface action, as the ciclosporin A of treatment xerophthalmia etc., this type of preparation should not absorb guaranteeing to be detained within the eye or by the tear Rapid Cleaning.
The low bioavailability of ophthalmic preparation is a factor of puzzlement dosing eyes always.In general, to enter a conjunctiva be to cause the low reason of common eye drops ophthalmic bioavailability for the Rapid Cleaning of the cornea hypotonicity of medicine, tear and absorption.Improving the method for bioavailability in the pharmaceutical ocular can pass through: (1) improves the corneal permeability of medicine; (2) increase the preparation holdup time within the eye, as preparing gel for eye etc.; (3) preparation has the preparation that the position selectivity discharges; (4) add corneal osmosis promoter.
Polymer micelle is meant with the Amphipathilic block polymer to be the micelle that material is made, this polymer is assembled in water voluntarily becomes a kind of corolla shape structure, wherein the hydrophilic block accumulates in the micelle outer surface, forms the paliform structure, and hydrophobic part accumulates in micellar kernel.This corolla shape structure has stable physical property, medicine can be wrapped in corolla part or kernel portion according to the difference of its solubility property respectively, also can be wrapped in the interface of corolla and kernel, for example, hydrophilic medicament can be wrapped in the corolla part, hydrophobic drug is wrapped in kernel portion (Torchilin, V.P., Structure and design of polymeric surfactant-based drug delivery systems.J ControlRelease, 2001.73 (2-3): p.137-72).This block polymer is compared with conventional surfactants, has critical micelle concentration (Critical Micellar Concentration, CMC) low characteristics.This kind block polymer has been used for carrying hydrophobic drug and biopharmaceutical macromolecular drug as adjuvant, be used for the administration of injecting pathway etc., for example A, B segment are respectively the polymer of hydrophilic polymer-methoxypolyethylene glycol (mPEG) and hydrophobic polymer-polylactic acid (PLA) or polyglycolic acid (PGA) or Acetic acid, hydroxy-, bimol. cyclic ester-lactide polymer (PLGA) in the polymer, and block polymer can be AB type block polymer or multi-block polymer.
Amphipathilic block polymer can be many block types of AB type or AB.So far, the research of polymer micelle is mainly used in injecting pathway, be used for carrying hydrophobic drug or macromole bio-pharmaceutical, to reach effect (the Kazunori Kataoka of targeted therapy effect or prolongation macromole biological half-life, Atsushi Harada, Yukio Nagasaki, Block copolymer micelles for drug delivery:design, characterization and biologicalsignificance, Advanced Drug Delivery Reviews 47 (2001) 113-131).By changing the ratio of A/B in the polymer, can change molecular weight, critical micelle concentration (CMC), micelle degree of association, the micelle particle diameter of AB polymerization thing.For example, the mPEG-PLA diblock polymer is along with the chain growth of hydrophobic part PLA, the particle diameter of polymer micelle diminishes, and kernel diminishes, and it is big that corolla partly becomes, after the ratio of A/B is greater than 60/40, the volume of polymer micelle kernel increases gradually, and CMC improves, otherwise, after the ratio of A/B is less than 50/50, the kernel of polymer micelle diminishes, and the corolla partial volume increases, and micelle is more stable.By changing the block pattern, can change the minimum solution temperature (LCST) of polymer, the multi-block polymer of mPEG-PLA (Kang Moo Huh for example, YouHan Bae, Synthesis and characterization of poly (ethylene glycol)/poly (l-lactic acid) alternating multiblock copolymers, Polymer 40 (1999) 6147-6155), after regulating polymerization methods, its LCST can be adjusted to about 30 ℃.
The particle diameter of this polymer micelle is generally at the diameter tens nanometer, and this provides a kind of acquisition function nano particulate new way.Studies show that: polymer micelle has effect (Jeffrey A.Hubbell, Science, 2003 of good permeate through cell membranes, 25 April, 595-596), therefore, can promote medicine to see through cornea effectively as a kind of carrier that carries medicine and enter ophthalmic.
United States Patent (USP) 6,579,519 have applied for a kind of eye polymer micelle of carrying NSAID (non-steroidal anti-inflammatory drug), wherein its polymer is that three blocks are with organic polymer, general formula is (X+Y+Z-) m, m is the integer greater than 2, and X is generally vinyl compound for reducing the monomer with gelling characteristic of eye irritation, as the ethylene pyrrolinone, Y is generally the polymer with thermal sensitivity, and (its general formula is formula R1-R2N-(C=O)-CH=CH2, and R1=a proton orCnH2n+1, n are the number between 3-6, R2 is the alkyl of 3-6 for the carbochain number), as poly-N-isopropyl acrylamide, Z is the polymer with mucosa adhesion and pH sensitivity, as polyacrylic acid.This patent shows: polymer micelle can significantly improve the cornea transmitance of medicine and avirulence.
Summary of the invention:
The invention provides the application of the block polymer formed by two kinds of polymer fragments as the medicament for the eyes carrier, wherein two kinds of polymer segments are respectively A fragment and B segment, they are respectively hydrophilic polymer fragment and hydrophobic polymer fragment, the hydrophilic polymer fragment is the fragment of methoxypolyethylene glycol (mPEG), the fragment of hydrophobic polymer is the fragment of polylactic acid (PLA), the fragment of the fragment of polyglycolic acid (PGA) or Acetic acid, hydroxy-, bimol. cyclic ester-lactide polymer (PLGA), can be called respectively: the mPEG-PLA block polymer, the mPEG-PGA block polymer, mPEG-PLGA block polymer, block polymer can be AB type diblock polymer or multi-block polymer.The block polymer that this class has amphipathic part can form polymer micelle in water, medicine can be aggregated the carrying of thing micelle, wherein hydrophobic drug is wrapped in micelle core (Core), and hydrophilic medicament is present in micellar corolla part (Corolla), and this class drug-carrying polymer micelle also can be called the block polymer carrier micelle.
The preferred block polymer of the present invention is the mPEG-PLA polymer, and it can be AB type diblock polymer or multi-block polymer.Its carrier micelle also can be called mPEG-PLA diblock polymer carrier micelle and mPEG-PLA multi-block polymer carrier micelle.
The objective of the invention is block polymer is used for the carrier of the medicine of suitable dosing eyes.The present invention also provides the medical composite for eye that contains block polymer.
The present invention finds that unexpectedly the availability that block polymer can make medicine enter ophthalmic improves, and by regulating the kind and the ratio of many blocks thing, can change the minimum solution temperature (LCST) of polymer, makes medicine be distributed in the ophthalmic different tissues specifically.
The described block polymer of this patent is a known substance, preferred mPEG-PLA diblock polymer, be documented in document Kazunori Kataoka, Atsushi Harada, Yukio Nagasaki, Block copolymer micelles fordrug delivery:design, characterization and biological significance, among Advanced DrugDeliveryReviews 47 (2001) 113-131, its general formula is:
Figure C20051000220900061
Wherein: m is the degree of polymerization of polylactic acid, and its numerical value is 5-100; N is the degree of polymerization of Polyethylene Glycol, and its numerical value is 6-50.This polymer can obtain through ring-opening polymerisation by literature method, compares with surfactant, and the mPEG-PLA diblock polymer, (CMC) is low for critical micelle concentration, can carrying possess hydrophilic property and lipophilic medicine, promote the cornea permeability of medicine.
The preferred mPEG-PLA multi-block polymer of the present invention, be documented in document Kang Moo Huh, You Han Bae, Synthesis and characterization of poly (ethylene glycol)/poly (l-lactic acid) alternatingmultiblock copolymers, among Polymer 40 (1999) 6147-6155, its general formula is:
Figure C20051000220900062
Wherein: X, Y represent the degree of polymerization of polylactic acid blocks different in the polymerized unit respectively, and both numerical value are 5-100; M represents the degree of polymerization of Polyethylene Glycol in the polymerized unit, and its numerical value is 6-50; N represents the degree of polymerization of polymerized unit, and its numerical value is 2-50.The LCST of this polymer presses X, Y, and M is in the 25-40 ℃ of scope that do not coexist of N.As LCST during near 32 ℃, block polymer dissociates in ocular surface, makes drug release generation effect, can be used for the ocular surface treatment of diseases, as treatment of xerophthalmia, conjunctivitis, keratitis etc.
Block polymer of the present invention can be used for the carrier of the medicine of suitable dosing eyes, utilizes the easily saturating property of polymer micelle corneal, makes medicine arrive at focus, reaches the purpose of treatment ocular disease.
Block polymer of the present invention can be used for the ocular surface treatment of diseases, and prolong drug plays therapeutical effect in the holdup time of conjunctiva, cornea.
The medicine of the above dosing eyes is meant any medicine that can be used for dosing eyes, mainly is selected from: antibacterials, antiviral drugs, anti-inflammatory drug influences immune medicine, the treatment medicine for treating myopia, treatment xerophthalmia medicine, treatment glaucoma medicine, treatment cataract medicine etc.These medicines specifically can be:
Antibacterials are selected from: quadracycline, polymyxin B, amphotericin B, erythromycin, sulphacetamide, chlortetracycline, rifampicin, streptomycin sulfate, gentamycin sulfate, lincomycin hydrochloride, chloromycetin, ofloxacin, levofloxacin, ciprofloxacin, norfloxacin;
Antiviral drugs is selected from: ribavirin: ftibamzone, moroxydine hydrochloride, acyclovir, ganciclovir; Anti-inflammatory drug is selected from:: prednisolone acetate, hydrocortisone acetate, dexamethasone, aspirin, indometacin, flurbiprofen, diclofenac, piroxicam;
Influencing immune medicine is selected from: ciclosporin A, mycophenolate, azathioprine, nedocromil, lodoxamide; Mydriatic, cycloplegic, anti-medicine for treating myopia are selected from: neostigmine methylsulfate, atropine sulfate, homatropine hydrobromide, pirenzepine hydrochloride;
Treatment xerophthalmia medicine is selected from: ciclosporin A;
Anti-glaucoma medicine is selected from: pilocarpine nitrate, carbachol, physostigmine, epinephrine, dipivefrine, clonidine, brimonidine, timolol, acetazolamide, daranide, many azoles amine, latanoprost, guanidine sulfate pyridine;
The treatment cataract medicine is selected from: tiopronin, glutathione etc.;
The present invention preferably is used for block polymer the treatment of bathomorphic treatment and xerophthalmia, and wherein contained medicine is pirenzepine or its pharmaceutical salts and ciclosporin A preferably.
The present invention finds that block polymer has superiority as the carrier of ophthalmic administration medicine the time, can be confirmed that by the cornea transmitance of measuring contained medicine described cornea transmitance is meant that medicine sees through the degree of cornea.After medicine splashes into eyelid, obtain by measuring the concentration of medicine in aqueous humor.
Pharmaceutical composition of the present invention wherein contains the ophthalmic administration thing and the block polymer of medicine effective quantity.Compositions of the present invention in case of necessity also can add other medicine acceptable auxiliary that is fit to.The ratio of ophthalmic administration thing in compositions can be 1-99%, and the ratio of block polymer in compositions can be 1-99%, and when containing the other drug carrier, ratio can be adjusted, and described ratio is weight percentage.Pharmaceutical composition of the present invention can be the dosage form of any dosing eyes, as being following dosage form: common eye drops, Eye ointments, gel for eye (comprise bioadhesive gel, the gel of ascending the throne) etc.
Block polymer of the present invention can be made lyophilized powder or be pressed into tablet, with before being dissolved in the The suitable solvent, uses with medicament mixed again.
Common eye drops comprises ophthalmic solution, suspensoid.Eye ointments is meant with vaseline to be the eye semi-solid preparation that excipient is made.
The bioadhesive gel agent be meant with the polymer that contains a plurality of hydrophilic groups be material make have the gel of adhesion with cornea.This base polymer comprises glass acid, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyacrylic acid (PAA).This gellike agent is the rheological properties of non-Newtonian fluid usually, and promptly along with cutting the raising of answering speed, the viscosity of liquid increases, and this helps preparation stop within the eye, prevents that medicine from being rinsed out by tear, thereby improves the ratio that medicine sees through cornea.
The gel of ascending the throne be meant eye drop this as can free-pouring liquid, be subjected to pH, variations in temperature, preparation forms gel after splashing into eyelid, thereby increases preparation resident in eye, improves the cornea transmitance.The thixotropic gel of ascending the throne of pH mainly is made up of cellulose acetate phthalate ester (CAP), CBP etc., can become gel rapidly under the condition of preparation at pH7.4.The thixotropic gel of ascending the throne of temperature mainly is made up of the polymer that can be changed into gel at 32-36 ℃, and this base polymer comprises compositions such as gellan gum.
In above-mentioned block polymer ophthalmic preparation, can add an amount of other adjuvant, these adjuvants comprise: isoosmotic adjusting agent, other cornea absorption enhancer, antiseptic etc.
Isoosmotic adjusting agent is mainly used in the osmotic pressure of regulating preparation, makes it suitable with the osmotic pressure of tear, to reduce zest.Isoosmotic adjusting agent comprises sodium chloride, potassium chloride etc.
Cornea promoter comprises disodium edetate, cationic surface active agent (as benzalkonium chloride), Polysorbate (as polysorbate 20,80 etc.), cholate (as sodium cholate, NaTDC etc.).
Pharmaceutical composition of the present invention can prepare by the following method:
1, the preparation of block polymer carrier micelle: way commonly used is adopted in the preparation of block polymer micelle, as fusion method, dissolving-solvent evaporated method, emulsifying-solvent evaporated method etc.With dissolving-solvent evaporated method is example, takes by weighing medicine respectively and mPEG-PLA places flask, adds organic solvent (being generally acetonitrile or ethanol), heats, is stirred to dissolving.Heating slowly boils off acetonitrile (Rotary Evaporators) under vacuum, obtains jelly, and jelly 60 ℃ of dissolvings down,, is filled in the lyophilizing bottle lyophilizing with water for injection with 0.22mm microporous filter membrane Entkeimung.
2, a preparation with polymer drug-carried micellar preparation: polymer micelle can be prepared into eye drop, gel for eye, eye ointment etc.
A) diluent: isoosmotic adjusting agent, buffer salt and other material are dissolved in the water for injection, sterilize 30 minutes down as diluent for 121 ℃.
B) it is an amount of to get block polymer carrier micelle dried frozen aquatic products, adds in the diluent, gets final product.
Advantage of the present invention also shows: can according to treatment require to make medicine within the eye different parts discharge specifically, reach the targeted therapy effect.Improve the availability of medicine, improve curative effect, reduce side effect at target site.
The specific embodiment:
Be the embodiment of this patent below, but following embodiment does not limit the interest field of putting this patent.
Embodiment 1 present embodiment is the preparation of eye with pirenzepine polymer micelle gel
Materials and methods
D, the L-lactide: available from Sigma company, with preceding employing anhydrous ethyl acetate in 60 ℃ of recrystallization three times, under the room temperature at P 2O 5Middle vacuum drying 24 hours.Stannous octoate and methyl Polyethylene Glycol (molecular weight 2000) are all available from Sigma company.
1. methyl polyethylene glycol-lactic acid (mPEG-PLA) diblock polymer is synthetic:
Adopt ring-opening polymerization method, the preparation quality ratio is 75/25 methyl polyethylene glycol-lactic acid block polymer respectively.That is: take by weighing methyl Polyethylene Glycol 7.5g and lactide 2.5g, place airtight reactor, be warming up to 120-140 ℃ and make the solid fusing under stream of nitrogen gas, add stannous octoate 50mg, elevated temperature was to 150-180 ℃ of reaction 3-6 hour.Cooling gets the white solid crude product.Crude product under agitation adds in the 100ml ether after dissolving with dichloromethane 5ml, filters, and three times repeatedly, product vacuum drying 24 hours gets final product.
It is 8530 that block polymer adopts the gel chromatography molecular weight, nuclear magnetic resonance, NMR ( 1HNMR) mass ratio that proves methyl polyethylene glycol-lactic acid is 75: 25, and its CMC is 200 μ g/ml.
2. the preparation of pirenzepine free alkali:
Get the 100g pirenzepine hydrochloride and be dissolved in an amount of distilled water,, remove methanol, get the pirenzepine free alkali through the cation exchange resin exchange, with methanol-eluted fractions.
3. the preparation of pirenzepine polymer micelle
Take by weighing the 2g pirenzepine respectively and 2g methyl polyethylene glycol-lactic acid block polymer places flask, add acetonitrile 50ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle every bottle of 2ml, lyophilizing with 0.22mm microporous filter membrane Entkeimung.
4. the eye preparation of pirenzepine polymer micelle gel:
A) it is an amount of to get hydroxypropyl methylcellulose K100M, ratio in 2% makes and is dissolved in the water for injection, adds Benzalkonii Chloridum (ten thousand/), disodium edetate (4/10000ths), adds sodium chloride an amount of (about 1%), drip 1N HCl or NaOH and regulate pH7.0, sterilize 30 minutes down as diluent for 121 ℃.
B) it is an amount of to get pirenzepine polymer micelle dried frozen aquatic products, adds in the diluent, makes dissolving, the concentration of pirenzepine is 2%, get final product.
Embodiment 2 present embodiments are that eye uses the isolated cornea of pirenzepine polymer micelle gel to see through experiment
Get rabbit, anesthesia causes death.Extracing eyeball places.Crosscut is done, isolated cornea by sclera place along elongation film edge 2mm.Remove eyeball rear portion tissues such as crystalline lens, vitreous body, peel off iris, must have the cornea of 2mm sclerotic ring.The interior beginning of 20min cornea sees through experiment after putting to death animal.Adopt the infiltration disperser, comprise supply pool and accept the pond, keep the shape of isolated cornea to be fixed between two ponds, make epithelial layer towards supply pool.Add pirenzepine hydrochloride in the supply pool and be dissolved in gel 2mL or the eye pirenzepine polymer micelle gel that diluent obtains among the embodiment 1, accepting the pond is Ringer's solution, and whole device is put into (34 ± 0 5) ℃ water bath with thermostatic control and begun experiment.After on-test the 5th, 15,30,45,60,90,120min is from accepting pond sampling 1mL and replenishing isopyknic blank immediately and use 95% in advance: 5%O 2And CO 234 ℃ of Ringer's solutions that mist is saturated.Sample is got the concentration that subsequent filtrate is measured pirenzepine with the filtering with microporous membrane of 0.22 μ m, is calculated as follows the cornea transmission coefficient of various salt.
p app = ΔQ Δt · C 0 · A · 3600
The result shows: the cornea transmission coefficient of pirenzepine acylate significantly improves.
Table 1 is with pirenzepine polymer micelle gel cornea transmission coefficient determination data (n=6)
Hydrochlorate Eye polymer micelle gel
Cornea transmission coefficient * 10 5(ug/s·cm 2) 1.07±0.08 2.18±0.29
Pharmacokinetics in embodiment 3 pirenzepine polymer micelle gels, the eye drop rabbit aqueous humor
40 rabbits are divided into 8 groups at random by the sampling time, every group of 5 rabbits.Change the prescription administration every two weeks, totally 2 times (the flat gel for eye of pirenzepine hydrochloride gel for eye and piperazine logical sequence west polymer micelle respectively).In a glance conjunctival sac, drip 2 of the pirenzepine eye drop (100 μ L) that prepare, not medication of left eye during administration respectively.Behind eye drip 0.5,1,2,4,8,12,24, during 48h, totally 8 time points extract the aqueous humor 0.2ml of right eye respectively.Get aqueous humor 0.1mL, add 0.1mL methanol, whirlpool mixes, with protein precipitation and impurity.With the centrifugal 10min of 16000r/min speed, get supernatant, inject high performance liquid chromatograph, the record peak area calculates content with external standard method.Each time point is got 5 eyes, with its meansigma methods as the concentration of this time point pirenzepine in aqueous humor.
The result shows: eye obviously improves with polymer A UC, and it has certain slow releasing function, slowly discharges in the prompting pirenzepine autohemagglutination compound micelle.
Concentration in the table 2 pirenzepine rabbit ophthalmic aqueous humor is (ng/ml) over time
Time
0.5 1 2 4 8 12 24 48
The pirenzepine hydrochloride gel 21.61± 13.08 49.08± 21.23 60.37± 15.37 77.51± 12.14 80.23± 16.5 34.62± 10.76 25.59± 11.34 12.34± 9.26
Eye polymer micelle gel 17.91± 10.12 45.19± 12.82 62.33± 17.31 99.14± 23.11 100.2± 36.13 60.32± 21.35 28.37± 14.21 11.31± 10.24
Embodiment 4 present embodiments are the preparation materials and methods of eye with ciclosporin A polymer micelle gel
L-lactic acid, succinic acid: Shanghai chemical reagents corporation.N-dimethyl aminopyridine (DMAP), dicyclohexyl carbon imidodicarbonic diamide (DCC) are all available from Sigma company.
1. methyl polyethylene glycol-lactic acid multi-block polymer (PEO/PLA) is synthetic:
1.1 dicarboxyl PLA's is synthetic: get 100g L-lactic acid with the 5g succinic acid places two-neck bottle, charge into nitrogen, be heated to 190-200 ℃ in the oil bath, after 24 hours, stop inflated with nitrogen, maintenance is 3 days under vacuum.Product is dissolved in acetone, with the distilled water precipitation, filters, and white product is dried overnight under vacuum.
1.2 the condensation of methyl polyethylene glycol-lactic acid multi-block polymer (PEO/PLA): the dicarboxyl PLA that gets equimolar Macrogol 2000 (5mmol) and above-mentioned acquisition is dissolved in the 70ml anhydrous methylene chloride.Add 1.3mmolDMAP as catalyst, 13mmol DCC is as coupling agent, and the inflated with nitrogen stirring reaction is 12 hours under the room temperature, removes by filter by-product of dicyclohexylurea.Filtrate is stirred adding 100ml ice ether down through concentrating under reduced pressure, obtains a large amount of white precipitates.The leaching precipitation is with dichloromethane dissolving, ether sedimentation, three times repeatedly.
2. the eye preparation of ciclosporin A polymer micelle gel
Take by weighing the 50mg ciclosporin A respectively and the 200mgPEO/PLA polymer places flask, add acetonitrile 50ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, sample is adjusted volume to 100ml with normal saline.Product is filled in the lyophilizing bottle every bottle of 2ml, lyophilizing with 0.22mm microporous filter membrane Entkeimung.
It is an amount of to get hydroxypropyl methylcellulose K100M, and the ratio in 2% makes and is dissolved in the water for injection, adds Benzalkonii Chloridum (ten thousand/), drips 1N HCl or NaOH and regulates pH7.0, sterilizes 30 minutes down as diluent for 121 ℃.
It is an amount of to get ciclosporin A polymer micelle dried frozen aquatic products, adds in the diluent, makes dissolving, and the concentration that gets ciclosporin A is 0.05%, promptly gets eye ciclosporin A polymer micelle.
Embodiment 5 present embodiments are the irritation test of eye with ciclosporin A polymer micelle gel
Experimental animal: get healthy rabbits, body weight 2.1-2.4kg, 10, be divided into 2 groups at random, 5 every group, promptly eye is organized with ciclosporin A Oleum Arachidis hypogaeae semen (0.05%), eye ciclosporin A polymer micelle gel (0.05%) group.Adopt consubstantiality left and right sides self matching type, the left side administration, normal saline is given on the right side.
Medication: every eyes splash into 0.1ml and are tried thing, about 10 seconds of the eyelid of gently sleeping then, every day 3 times, continuous 7 days.
Eye is observed: the single-dose eye irritant test, after administration, eye was checked in 1,24,48 and 72 hour; The multiple dosing eye irritant test was checked eye after the preceding and last administration of administration every day in 1,24,48 and 72 hour.The result shows: eye is not almost seen zest with ciclosporin A polymer micelle gel, and eye has tangible zest with the ciclosporin peanut oil solution.
6 of embodiment distribute with ciclosporin A polymer micelle gel rabbit intraocular drug
Get 5 of healthy rabbits.Consubstantiality left and right sides self matching type, ciclosporin A Oleum Arachidis hypogaeae semen (0.05%) is given in the left side, and ciclosporin A polymer micelle (0.05%) is given on the right side.Every day three times, rabbit is put to death in anesthesia two days later, gets aqueous humor 0.1ml, separates eyeball, get conjunctiva, separate an eye edge tissues, cornea, precision is weighed, place-20 ℃ freezing 48 hours, tissue at room temperature mixed 5 minutes with 0.2mL methanol vortex after taking out, the centrifugal 10min of 16000r/min speed gets supernatant, carries out LC-MS analytical calculation content.
The result shows: eye is compared with oil solution with polymer micelle, and both are suitable at the medicine on eye surface.
Table 3 ciclosporin A rabbit ocular tissue's distribution situation (ng/g)
Conjunctiva Edge tissues Cornea Aqueous humor
The eye oil solution 0.13±0.08 0.45±0.32 35.23±12.25 43.25±22.18
Eye polymer micelle gel 3.35±1.15 1.00±0.23 32.14±10.38 21.33±13.24
Embodiment 7 present embodiments are the preparation of eye with chloromycetin polymer micelle eye drop
Take by weighing 2g chloromycetin respectively and 2g mPEG-PLA (50/50) places flask, add acetonitrile 50ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the chloromycetin polymer micelle.
Get sodium chloride (about 1%) in right amount, add Benzalkonii Chloridum (ten thousand/), disodium edetate (4/10000ths), drip 1N HCl or NaOH and regulate pH6.5, sterilize 30 minutes down as diluent for 121 ℃.
The extracting chloromycetin polymer micelle is an amount of, adds in the diluent, makes dissolving, and the concentration that gets chloromycetin is 2%, gets final product.
Embodiment 8 present embodiments are the preparation of eye with acyclovir polymer micelle eye drop
Take by weighing the 0.2g acyclovir respectively and 1g mPEG-PLA (60/40) places flask, add acetonitrile 30ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the acyclovir polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), drip 1N HCl or NaOH and regulate pH7.2, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the acyclovir polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets acyclovir is 0.2%, gets final product.
Embodiment 9 present embodiments are the preparation of eye with dexamethasone polymer micelle eye drop
Take by weighing the 0.1g dexamethasone respectively and 0.5g mPEG-PLA (60/40) places flask, add ethanol 20ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the dexamethasone polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), drip 1NHCl or NaOH and regulate pH7.0, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the dexamethasone polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets dexamethasone is 0.1%, gets final product.
Embodiment 10 present embodiments are the preparation of eye with flurbiprofen polymer micelle eye drop
Take by weighing the 0.3g flurbiprofen respectively and 1g mPEG-PLA (60/40) places flask, add ethanol 30ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the flurbiprofen polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), drip 1NHCl or NaOH and regulate pH7.4, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the flurbiprofen polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets flurbiprofen is 0.3%, gets final product.
Embodiment 11 present embodiments are the preparation of eye with pilocarpine polymer micelle eye drop
Take by weighing 0.1g pilocarpine (free alkali) respectively and 0.5g mPEG-PLA (75/25) places flask, add acetonitrile 30ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the pilocarpine polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), drip 1N HCl or NaOH and regulate pH6.0, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the pilocarpine polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets pilocarpine is 0.1%, gets final product.
Embodiment 12 present embodiments are the preparation of eye with timolol polymer micelle eye drop
Take by weighing 0.25g timolol (free alkali) respectively and 0.25g mPEG-PLA (80/20) places flask, add acetonitrile 30ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the timolol polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), drip 1N HCl or NaOH and regulate pH6.2, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the timolol polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets timolol is 0.25%, gets final product.
Embodiment 13 present embodiments are the preparation of eye with tiopronin polymer micelle eye drop
Take by weighing the 0.05g tiopronin respectively and 0.5g mPEG-PLA (80/20) places flask, add acetonitrile 10ml, heat, be stirred to dissolving.Slowly boil off acetonitrile (Rotary Evaporators) under 60 ℃, vacuum, samples with water is adjusted volume to 100ml.Product is filled in the lyophilizing bottle with 0.22mm microporous filter membrane Entkeimung, every bottle of 2ml, and lyophilizing gets the tiopronin polymer micelle.
Get sodium chloride (about 0.9%) in right amount, add Benzalkonii Chloridum (ten thousand/), disodium edetate (4/10000ths), drip 1N HCl or NaOH and regulate pH7.2, sterilize 30 minutes down as diluent for 121 ℃.
It is an amount of to get the tiopronin polymer micelle, adds in the diluent, makes dissolving, and the concentration that gets tiopronin is 0.05%, gets final product.

Claims (5)

1, the block polymer of being made up of two kinds of polymer fragments is as the application of eye medicinal carrier, and wherein said block polymer is the mPEG-PLA block polymer, and block polymer is diblock polymer or multi-block polymer.
2, a kind of pharmaceutical composition, contain the active constituents of medicine of effective dose and the block polymer of forming by two kinds of polymer fragments, wherein said active constituents of medicine is selected from, antibacterials, antiviral drugs, anti-inflammatory drug, influence immune medicine, the treatment medicine for treating myopia, treatment xerophthalmia medicine, treatment glaucoma medicine, treatment cataract medicine, the described block polymer of being made up of two kinds of polymer fragments is the mPEG-PLA block polymer, and described mPEG-PLA block polymer is mPEG-PLA diblock polymer or mPEG-PLA multi-block polymer.
3, the compositions of claim 2, described treatment medicine for treating myopia are that pirenzepine or its pharmaceutical salts, treatment xerophthalmia medicine are ciclosporin A, and block polymer is the mPEG-PLA block polymer.
4, the compositions of claim 2 wherein also contains the medicine acceptable auxiliary that other are fit to the preparation medicament for the eyes.
5, the compositions of claim 2 is dosage forms of any dosing eyes.
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Publication number Priority date Publication date Assignee Title
CN101390825B (en) * 2008-10-01 2010-12-29 山东省眼科研究所 Intra-ocular release system of voriconazole
EP3246048B1 (en) * 2009-02-18 2024-04-03 Calm Water Therapeutics LLC Bi-functional co-polymer use for ophthalmic applications
CN104761710B (en) * 2014-02-14 2016-06-29 苏州海特比奥生物技术有限公司 A kind of mPEG-PDLLA and preparation method thereof
CN105902486B (en) * 2016-04-15 2019-06-04 青岛大学 A kind of hydroxytyrosol eye drops effectively targeting to trigeminal ganglion and preparation method thereof
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CN113425830A (en) * 2020-03-05 2021-09-24 科贝园(北京)医药科技有限公司 Cyclosporine polymer micelle preparation and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511660B1 (en) * 1999-12-15 2003-01-28 Hong-Ru Lin Ophthalmic drug delivery formulations and method for preparing the same
US6579519B2 (en) * 2000-09-18 2003-06-17 Registrar, University Of Delhi Sustained release and long residing ophthalmic formulation and the process of preparing the same
JP2008058614A (en) * 2006-08-31 2008-03-13 Nidec Copal Corp Blade drive device for camera

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6511660B1 (en) * 1999-12-15 2003-01-28 Hong-Ru Lin Ophthalmic drug delivery formulations and method for preparing the same
US6579519B2 (en) * 2000-09-18 2003-06-17 Registrar, University Of Delhi Sustained release and long residing ophthalmic formulation and the process of preparing the same
JP2008058614A (en) * 2006-08-31 2008-03-13 Nidec Copal Corp Blade drive device for camera

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
纳米药物的研究进展 王子妤等.东南大学学报，第23卷第2期 2004 *
聚乙二醇甲醚-聚(D、L-乳酸)嵌段共聚物纳米胶束的制备 邓联东等.应用化学，第21卷第3期 2004 *
聚合物胶束作为药物载体的研究与应用 张宏娟等.药学进展，第26卷第6期 2002 *

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