CN1644215A - Block polymer for eyes - Google Patents

Abstract

A block copolymer used as the carrier of ocular medicine is composed of hydrophilic polyethylene glycol methyleter (mPEG) and hydrophobic polylactic acid (PLA) or polyglycollin acid (PGA) or glycollide-lactide polymer (PLGA).

Description

A block polymer for ophthalmology

Technical field:

The present invention relates to the ophthalmic use of a block polymer composed of two polymers (A, B) fragments, wherein the A and B fragments in the polymer are respectively hydrophilic polymer-polyethylene glycol methyl ether (mPEG) and hydrophobic polymers - polylactic acid (PLA) or polyglycolic acid (PGA) or glycolide-lactide polymer (PLGA), block polymers can be AB type diblock polymers or multi-block polymers thing. This is suitable for intraocular administration.

Background technique:

Intraocular administration is an important administration method for the treatment of eye diseases, and intraocular preparations include eye drops, ophthalmic gels, etc. At present, ophthalmic preparations can be divided into: 1) preparations that should enter the eye through the cornea, such as pirenzepine hydrochloride as an M1 receptor blocker, which can prevent the further development of myopia. In the eye, it is necessary for pirenzepine to enter the eye through the cornea; 2) For preparations that should act on the ocular surfaces such as the conjunctiva and cornea, such as cyclosporine A for the treatment of dry eye, such preparations should be guaranteed Remains in the eye without absorption or is quickly washed away by tears.

The low bioavailability of ophthalmic formulations has been a factor that plagues ocular drug delivery. In general, the low corneal permeability of the drug, the rapid washing of tears, and the absorption into the conjunctiva are the reasons for the low intraocular bioavailability of common eye drops. The method for improving the bioavailability of the drug in the eye can be by: (1) improving the corneal permeability of the drug; (2) increasing the residence time of the preparation in the eye, such as preparing ophthalmic gels, etc.; (3) preparing a drug with site selection (4) adding corneal penetration enhancer.

Polymer micelles refer to micelles made of amphiphilic block polymers, which self-assemble into a corolla structure in water, in which hydrophilic blocks gather on the outer surface of the micelles to form Palisade-like structure, the hydrophobic part gathers in the inner core of the micelles. This corolla structure has stable physical properties. Drugs can be wrapped in the corolla or inner core according to their solubility properties, and can also be wrapped in the interface between the corolla and the inner core. For example, hydrophilic drugs can be wrapped in the corolla, hydrophobic Sexual drugs are wrapped in the core part (Torchilin, V.P., Structure and design of polymeric surfactant-based drug delivery systems. J Control Release, 2001.73 (2-3): p.137-72). Compared with ordinary surfactants, this block polymer has the characteristics of low critical micelle concentration (Critical Micellar Concentration, CMC). This type of block polymer has been used as an excipient to carry hydrophobic drugs and biomacromolecular drugs, for administration by injection, etc. For example, the A and B segments in the polymer are respectively hydrophilic polymers-polyethylene glycol Polymer of methyl ether (mPEG) and hydrophobic polymer - polylactic acid (PLA) or polyglycolic acid (PGA) or glycolide-lactide polymer (PLGA), block polymer can be AB type block polymers or multi-block polymers.

The amphiphilic block polymer may be of the AB type or a multi-block type of AB. So far, research on polymer micelles has been mainly used in the injection route for carrying hydrophobic drugs or macromolecular biopharmaceuticals to achieve targeted therapeutic effects or prolong the biological half-life of macromolecules (Kazunori Kataoka, Atsushi Harada, Yukio Nagasaki , Block copolymer micelles for drug delivery: design, characterization and biological significance, Advanced Drug Delivery Reviews 47(2001) 113-131). By changing the ratio of A/B in the polymer, the molecular weight, critical micelle concentration (CMC), degree of micelle association, and micelle particle size of the AB-type polymer can be changed. For example, mPEG-PLA diblock polymer, with the chain growth of the hydrophobic part of the PLA, the particle size of the polymer micelles becomes smaller, the inner core becomes smaller, and the corolla part becomes larger. When the ratio of A/B is greater than 60/40 , the volume of the inner core of the polymer micelles increases gradually, and the CMC increases. On the contrary, when the ratio of A/B is less than 50/50, the inner core of the polymer micelles becomes smaller, the volume of the corolla part increases, and the micelles are more stable. By changing the block mode, the minimum solution temperature (LCST) of the polymer can be changed, such as the multi-block polymer of mPEG-PLA (Kang Moo Huh, YouHan Bae, Synthesis and characterization of poly(ethylene glycol)/poly(l- lactic acid) alternating multiblock copolymers, Polymer 40 (1999) 6147-6155), when the polymerization method is adjusted, its LCST can be adjusted to about 30 °C.

The particle size of this polymer micelle is generally tens of nanometers in diameter, which provides a new way to obtain functional nanoparticles. Studies have shown that: polymer micelles have a good effect of permeating cell membranes (Jeffrey A. Hubbell, Science, 2003, 25 April, 595-596), therefore, as a carrier for carrying drugs, they can effectively promote drug penetration. The cornea enters the eye.

U.S. Patent 6,579,519 applied for an ophthalmic polymer micelle carrying non-steroidal anti-inflammatory drugs, wherein the polymer is a three-block random polymer, the general formula is (X+Y+Z-)m, and m is greater than An integer of 2, X is a monomer with gelling properties that can reduce eye irritation, usually a vinyl compound, such as vinylpyrrolidone, and Y is usually a heat-sensitive polymer (its general formula is formula R1-R2N- (C=O)-CH=CH2, R1=a proton orCnH2n+1, n is a number between 3-6, R2 is an alkyl group with a carbon chain number of 3-6), such as poly N-isopropylacrylamide , Z is a polymer with mucoadhesion and pH sensitivity, such as polyacrylic acid. The patent shows that polymer micelles can significantly improve the corneal permeability of drugs without toxicity.

Invention content:

The present invention provides the application of a block polymer composed of two polymer segments as ophthalmic drug carrier, wherein the two polymer segments are respectively A segment and B segment, which are respectively hydrophilic polymer segments and hydrophobic polymer segments Fragments, the hydrophilic polymer fragments are polyethylene glycol methyl ether (mPEG) fragments, and the hydrophobic polymer fragments are polylactic acid (PLA) fragments, polyglycolic acid (PGA) fragments or glycolide-lactide The fragments of lactide polymer (PLGA) can be called respectively: mPEG-PLA block polymer, mPEG-PGA block polymer, mPEG-PLGA block polymer, and the block polymer can be AB type diblock polymers or multi-block polymers. Such block polymers with amphiphilic moieties can form polymer micelles in water, and drugs can be carried by polymer micelles, in which hydrophobic drugs are wrapped in the micelle core (Core), while hydrophilic drugs exist in The corolla part of the micelles (Corolla), this type of drug-loaded polymer micelles can also be called block polymer drug-loaded micelles.

The preferred block polymers of the present invention are mPEG-PLA polymers, which may be diblock polymers or multiblock polymers of type AB. The drug-loaded micelles can also be called mPEG-PLA diblock polymer drug-loaded micelles and mPEG-PLA multi-block polymer drug-loaded micelles.

The object of the present invention is the use of block polymers as carriers for pharmaceuticals suitable for ophthalmic administration. The present invention also provides ophthalmic pharmaceutical compositions comprising block polymers.

The present invention unexpectedly finds that block polymers can improve the availability of drugs entering the eye, and by adjusting the type and ratio of multi-blocks, the minimum solution temperature (LCST) of the polymer can be changed to make the drugs specifically distributed different tissues in the eye.

The block polymers described in this patent are known substances, preferably mPEG-PLA diblock polymers, described in the literature Kazunori Kataoka, Atsushi Harada, Yukio Nagasaki, Block copolymer micelles fordrug delivery: design, characterization and biological significance, In Advanced Drug Delivery Reviews 47(2001) 113-131, its general formula is:

Wherein: m is the polymerization degree of polylactic acid, and its value is 5-100; n is the polymerization degree of polyethylene glycol, and its value is 6-50. The polymer can be obtained by ring-opening polymerization according to the method in the literature. Compared with surfactants, the mPEG-PLA diblock polymer has a low critical micelle concentration (CMC), and can carry drugs with hydrophilic and lipophilic properties. Corneal permeability of drugs.

The preferred mPEG-PLA multi-block polymer of the present invention is described in the document Kang Moo Huh, You Han Bae, Synthesis and characterization of poly(ethylene glycol)/poly(1-lactic acid) alternating multiblock copolymers, Polymer 40 (1999) 6147 In -6155, its general formula is:

Among them: X and Y respectively represent the polymerization degree of different polylactic acid blocks in the polymerization unit, and the values of both are 5-100; m represents the polymerization degree of polyethylene glycol in the polymerization unit, and its value is 6-50; n represents The degree of polymerization of the polymerized unit has a value of 2-50. The LCST of the polymer is in the range of 25-40°C depending on X, Y, M, N. When the LCST is close to 32°C, the block polymer dissociates on the surface of the eye to release the drug, which can be used for the treatment of eye surface diseases, such as dry eye disease, conjunctivitis, keratitis, etc.

The block polymer of the present invention can be used as a drug carrier suitable for eye administration, and utilizes the easy permeability of the polymer micelle to the cornea to allow the drug to reach the lesion and achieve the purpose of treating eye diseases.

The block polymer of the invention can be used for the treatment of eye surface diseases, prolongs the residence time of drugs in conjunctiva and cornea, and plays a therapeutic role.

The drugs for ocular administration mentioned above refer to any drugs that can be used for ocular administration, mainly selected from: antibacterial drugs, antiviral drugs, anti-inflammatory drugs, drugs that affect the immune system, drugs for treating myopia, treating Dry eye medicines, glaucoma medicines, cataract medicines, etc. Specifically, these drugs can be:

Antibacterial drugs selected from: tetracycline hydrochloride, polymyxin B, amphotericin B, erythromycin, sulfacetamide sodium, aureomycin, rifampicin, streptomycin sulfate, gentamicin sulfate, lincomycin hydrochloride Mycin, chloramphenicol, ofloxacin, levofloxacin, ciprofloxacin, norfloxacin;

The antiviral drugs are selected from: ribavirin, phthalide, morpholinidine hydrochloride, acyclovir, ganciclovir; the anti-inflammatory drugs are selected from: prednisone acetate, hydrocortisone acetate, Dexamethasone, Aspirin, Indomethacin, Flurbiprofen, Diclofenac, Pyroximate;

Drugs affecting the immune system are selected from: cyclosporin A, mycophenolate mofetil, azathioprine, nedocromil, lodoxamide; mydriatics, cycloplegics, and antimyopia drugs are selected from: methyl Neostigmine sulfate, atropine sulfate, homatropine hydrobromide, pirenzepine hydrochloride;

The medicine for treating dry eye is selected from: cyclosporine A;

Antiglaucoma drug selected from: pilocarpine nitrate, carbachol, physostigmine, epinephrine, dipifolin, clonidine, brimonidine, timolol, acetazolamide, dichlorosulfonamide, doxazole amines, latanoprost, guanidine sulfate;

Cataract treatment drugs are selected from: tiopronin, glutathione, etc.;

In the present invention, the block polymer is preferably used for the treatment of myopia and dry eye, and the drugs contained therein are preferably pirenzepine or its pharmaceutically acceptable salt and cyclosporine A.

The present invention finds that the block polymer has superiority as a carrier of ophthalmic drugs, which can be confirmed by measuring the corneal transmittance of the loaded drugs, and the corneal transmittance refers to the degree of drug penetration through the cornea. After the drug is instilled into the eyelid, it is obtained by measuring the concentration of the drug in the aqueous humor.

The pharmaceutical composition of the present invention contains pharmaceutically effective doses of ophthalmic drugs and block polymers. The composition of the present invention can also be added with other suitable pharmaceutically acceptable adjuvants when necessary. The ratio of ophthalmic medicine in the composition can be 1-99%, the ratio of block polymer in the composition can be 1-99%, when other drug carriers are contained, the ratio can be adjusted, and the ratio is by weight percentage. The pharmaceutical composition of the present invention can be any dosage form for ophthalmic administration, such as the following dosage forms: common eye drops, ophthalmic ointment, ophthalmic gel (comprising bioadhesive gel, immediate gel) )wait.

The block polymer of the present invention can be made into freeze-dried powder or compressed into tablets, dissolved in a suitable solvent before use, and then mixed with drugs for use.

Ordinary eye drops include ophthalmic solutions and suspensions. Eye ointment refers to ophthalmic semi-solid preparations made with vaseline as an excipient.

Bioadhesive gel refers to a gel that is made of a polymer containing multiple hydrophilic groups and has adhesion to the cornea. Such polymers include hyaluronic acid, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), sodium carboxymethylcellulose (CMC-Na), polyacrylic acid (PAA). Such gels usually exhibit the rheological properties of non-Newtonian fluids, that is, as the shear rate increases, the viscosity of the liquid increases, which is conducive to the retention of the preparation in the eye and prevents the drug from being washed out by tears, thereby improving the drug delivery rate. Permeation through the cornea.

Immediate gel refers to that the eye drop itself is a free-flowing liquid, subject to pH and temperature changes, the preparation forms a gel after being dropped into the eyelid, thereby increasing the residence of the preparation in the eye and improving the corneal transmittance. The pH-thixotropic in-situ gel is mainly composed of cellulose acetate phthalate (CAP), carbomer, etc., and can quickly become a gel when the preparation is at a pH of 7.4. The temperature-thixotropic in-situ gel is mainly composed of polymers that can become gels at 32-36°C, such polymers include gellan gum and the like.

In the above block polymer ophthalmic preparations, appropriate amount of other adjuvants may be added, and these adjuvants include: isotonic regulators, other corneal absorption accelerators, preservatives and the like.

Isotonic regulators are mainly used to adjust the osmotic pressure of the preparation to be equivalent to that of tear fluid to reduce irritation. Isotonicity adjusting agents include sodium chloride, potassium chloride and the like.

Corneal promoting agents include edetate disodium, cationic surfactants (such as benzalkonium chloride), polysorbates (such as polysorbate 20, 80, etc.), cholates (such as sodium cholate, sodium deoxycholate wait).

The pharmaceutical composition of the present invention can be prepared by the following methods:

1. Preparation of block polymer drug-loaded micelles: The preparation of block polymer micelles adopts common methods, such as melting method, dissolution-solvent evaporation method, emulsification-solvent evaporation method, etc. Taking the dissolution-solvent evaporation method as an example, the drug and mPEG-PLA were weighed and placed in a flask, and an organic solvent (usually acetonitrile or ethanol) was added, heated and stirred until dissolved. Heating under vacuum and slowly evaporating acetonitrile (rotary evaporator) to obtain a jelly, which was dissolved in water for injection at 60°C, sterilized by filtration with a 0.22mm microporous membrane, and filled into a freeze-dried vial , freeze-dried.

2. Preparation of ophthalmic polymer drug-loaded micelles: polymer micelles can be prepared into eye drops, ophthalmic gels, ophthalmic ointments, etc.

A) Diluent: Dissolve isotonic regulator, buffer salt and other materials in water for injection, and sterilize at 121° C. for 30 minutes as diluent.

B) Take an appropriate amount of the freeze-dried product of the drug-loaded micelles of the block polymer, and add it to the diluent.

The advantages of the present invention are also manifested in that the drug can be specifically released in different parts of the eye according to the treatment requirements, so as to achieve the targeted therapeutic effect. Improve the availability of drugs at the target site, improve curative effect, and reduce side effects.

Detailed ways:

The following are examples of this patent, but the following examples do not limit the scope of rights of this patent.

Embodiment 1 This embodiment is the preparation of ophthalmic pirenzepine polymer micelle gel

Materials and Methods

D, L-lactide: purchased from Sigma, recrystallized three times with anhydrous ethyl acetate at 60°C before use, and vacuum dried in P ₂ O ₅ at room temperature for 24 hours. Both stannous octoate and methyl polyethylene glycol (molecular weight 2000) were purchased from Sigma Company.

1. Synthesis of methyl polyethylene glycol-polylactic acid (mPEG-PLA) diblock polymer:

The ring-opening polymerization method was used to prepare methyl polyethylene glycol-polylactic acid block polymers with a mass ratio of 75/25. That is: Weigh 7.5g of methyl polyethylene glycol and 2.5g of lactide, place them in a closed reactor, raise the temperature to 120-140°C under nitrogen flow to melt the solid, add 50mg of stannous octoate, and raise the temperature Reaction at 150-180°C for 3-6 hours. After cooling, a white solid crude product was obtained. After the crude product was dissolved in 5ml of dichloromethane, it was added into 100ml of ether under stirring, filtered, and repeated three times, and the product was vacuum-dried for 24 hours.

The molecular weight of the block polymer was determined to be 8530 by gel chromatography, nuclear magnetic resonance ( ¹ HNMR) proved that the mass ratio of methyl polyethylene glycol-polylactic acid was 75:25, and its CMC was 200 μg/ml.

2. The preparation of pirenzepine free base:

Dissolve 100 g of pirenzepine hydrochloride in an appropriate amount of distilled water, exchange with a cation exchange resin, and elute with methanol to remove methanol to obtain pirenzepine free base.

3. Preparation of Pirenzepine Polymeric Micelles

Weigh 2g of pirenzepine and 2g of methylpolyethylene glycol-polylactic acid block polymer respectively into a flask, add 50ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22mm microporous membrane, filled into lyophilized vials, 2ml per vial, and lyophilized.

4. Preparation of Ophthalmic Pirenzepine Polymer Micellar Gel:

A) Take an appropriate amount of hydroxypropylmethylcellulose K100M, dissolve it in water for injection at a ratio of 2%, add benzalkonium chloride (1/10,000), edetate disodium (4/10,000), add chlorine An appropriate amount of sodium chloride (about 1%) was added dropwise with 1N HCl or NaOH to adjust the pH to 7.0, and sterilized at 121°C for 30 minutes as a diluent.

B) Take an appropriate amount of pirenzepine polymer micelle freeze-dried product, add it to the diluent, and dissolve it to obtain a concentration of pirenzepine of 2%.

Embodiment 2 This embodiment is the isolated corneal penetration experiment of ophthalmic pirenzepine polymer micelle gel

Rabbits were taken and anesthetized to death. The eyeballs were enucleated and placed in the center. Make a transverse cut along the sclera 2 mm from the corneal edge to separate the cornea. The lens, vitreous body and other tissues at the back of the eyeball were removed, and the iris was peeled off to obtain a cornea with a 2mm scleral ring. Corneal permeation experiments were started within 20 min after the animals were sacrificed. Adopt osmotic diffusion device, including supply pool and accept pool, maintain the shape of the isolated cornea and fix it between the two pools, so that the epithelial layer faces the supply pool. Add pirenzepine hydrochloride to be dissolved in the gel 2mL that diluent obtains in embodiment 1 in the supply pool or ophthalmic pirenzepine polymer micelle gel, accept the pool to be Ringer's solution, and whole device is put into (34 ± 0 5) Start the experiment in a constant temperature water bath. At the 5th, 15th, 30th, 45th, 60th, 90th, and 120th minute after the start of the test, 1mL samples were taken from the receiving pool, and an equal volume of blank was added immediately to a 34°C forest saturated with 95%: 5% _O2 and _CO2 mixed gas. Lattice solution. The samples were filtered with a 0.22 μm microporous membrane, and the filtrate was taken to measure the concentration of pirenzepine, and the corneal permeability coefficients of various salts were calculated according to the following formula.

${\mathrm{<span\; class="notranslate">\; P</span>}}_{\mathrm{<span\; class="notranslate">\; app</span>}}<span\; class="notranslate">\; =</span>\frac{\mathrm{<span\; class="notranslate">\; \&Delta;Q</span>}}{\mathrm{<span\; class="notranslate">\; \&Delta;t</span>}<span\; class="notranslate">\; \&Center\; Dot;</span>{\mathrm{<span\; class="notranslate">\; C</span>}}_{\mathrm{<span\; class="notranslate">\; 0</span>}}<span\; class="notranslate">\; \&Center\; Dot;</span>\mathrm{<span\; class="notranslate">\; A</span>}<span\; class="notranslate">\; \&Center\; Dot;</span>\mathrm{<span\; class="notranslate">\; 3600</span>}}$

The results showed that the corneal permeability coefficient of pirenzepine organic acid salt was significantly improved.

Table 1 Ophthalmic Pirenzepine Polymer Micellar Gel Corneal Transmission Coefficient Determination Data (n=6)

Polymer beam gel agent for polymer hydrochloride eye

Corneal transmission coefficient 1.07±0.08 2.18±0.29

×10 ⁵ (ug/s·cm ² )

The pharmacokinetics of embodiment 3 pirenzepine polymer micelle gel, eye drops rabbit aqueous humor

The 40 rabbits were randomly divided into 8 groups according to the sampling time, with 5 rabbits in each group. The prescription was changed every two weeks for a total of 2 times (pirenzepine hydrochloride ophthalmic gel and pirenzepine polymer micelles ophthalmic gel, respectively). During the administration, 2 drops (100 μL) of the prepared pirenzepine eye drops were dripped in the conjunctival sac of one eye respectively, and no medicine was used in the left eye. At 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after eye drops, 0.2ml of aqueous humor was drawn from the right eye at 8 time points in total. Take 0.1 mL of aqueous humor, add 0.1 mL of methanol, and vortex to mix to precipitate proteins and impurities. Centrifuge at a speed of 16000r/min for 10min, take the supernatant, inject it into a high-performance liquid chromatograph, record the peak area, and calculate the content by the external standard method. Five eyes were taken at each time point, and the average value was used as the concentration of pirenzepine in the aqueous humor at this time point.

The results showed that the AUC of the ophthalmic polymer was significantly increased, and it had a certain sustained-release effect, suggesting that pirenzepine was slowly released from the polymer micelles.

Table 2 Changes (ng/ml) of the concentration in aqueous humor in rabbit eyes of pirenzepine over time

time

0.5 1 2 2 4 4 8 12 24 48

Pirencil hydrochloride 21.61± 49.08± 60.37± 77.51± 80.23± 34.62± 25.59± 12.34±

Flat Gel 13.08 21.23 15.37 12.14 16.5 10.76 11.34 9.26

ophthalmic polymers

                                                                                                       

Micellar gel 10.12 12.82 17.31 23.11 36.13 21.35 14.21 10.24

Embodiment 4 This embodiment is the preparation of ophthalmic cyclosporin A polymer micelle gel

Materials and Methods

L-lactic acid, succinic acid: Shanghai Chemical Reagent Company. N-dimethylaminopyridine (DMAP) and dicyclohexylcarbodiimide (DCC) were purchased from Sigma.

1. Synthesis of methyl polyethylene glycol-polylactic acid multi-block polymer (PEO/PLA):

1.1 Synthesis of dicarboxy PLA: Take 100g of L-lactic acid and 5g of succinic acid in a double-neck flask, fill it with nitrogen, heat it to 190-200°C in an oil bath, stop nitrogen filling after 24 hours, and keep it under vacuum for 3 sky. The product was dissolved in acetone, precipitated with distilled water, filtered and the white product was dried under vacuum overnight.

1.2 Condensation of methylpolyethylene glycol-polylactic acid multi-block polymer (PEO/PLA): get equimolar polyethylene glycol 2000 (5mmol) and dicarboxy PLA obtained above and dissolve in 70ml of anhydrous methylene chloride . Add 1.3mmol DMAP as a catalyst, 13mmol DCC as a coupling agent, stir and react with nitrogen at room temperature for 12 hours, and filter to remove by-product dicyclohexyl urea. The filtrate was concentrated under reduced pressure, and 100 ml of glacial ether was added with stirring to obtain a large amount of white precipitate. The precipitate was collected by filtration, dissolved with dichloromethane, and precipitated with ether, and repeated three times.

2. Preparation of Ophthalmic Cyclosporine A Polymer Micellar Gel

Weigh 50mg of cyclosporin A and 200mg of PEO/PLA polymer respectively into a flask, add 50ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with physiological saline. The product is sterilized by filtration with a 0.22mm microporous membrane, filled into lyophilized vials, 2ml per vial, and lyophilized.

Take an appropriate amount of hydroxypropylmethylcellulose K100M, dissolve it in water for injection at a ratio of 2%, add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 7.0, and sterilize at 121°C 30 minutes as a thinner.

Take an appropriate amount of cyclosporine A polymer micelle freeze-dried product, add it to a diluent, and dissolve it to obtain a concentration of ciclosporin A of 0.05%, and obtain ophthalmic cyclosporine A polymer micelle.

Embodiment 5 This embodiment is the irritation test of ophthalmic cyclosporine A polymer micelle gel

Experimental animals: take healthy rabbits, weighing 2.1-2.4kg, 10, and randomly divide them into 2 groups, 5 in each group, that is, the cyclosporine A peanut oil (0.05%) group for ophthalmology, and the cyclosporine A polymer for ophthalmology group. Micellar gel (0.05%) group. The method of self-comparison of the left and right sides of the same body was adopted, the left side was given medicine, and the right side was given normal saline.

Administration method: drop 0.1ml of the test substance into each eye, then lightly close the eyelids for about 10 seconds, 3 times a day for 7 consecutive days.

Eye observation: single-dose eye irritation test, check the eyes at 1, 24, 48 and 72 hours after administration; multiple-dose eye irritation test, before dosing every day and after the last dosing 1, Eye examinations were performed at 24, 48 and 72 hours. The results showed that cyclosporin A polymer micelle gel for ophthalmic use had almost no irritation, but cyclosporin peanut oil solution for ophthalmic use had obvious irritation.

Example 6 Cyclosporine A polymer micelle gel for ophthalmic drug distribution in rabbit eyes

Take 5 healthy rabbits. In the method of self-comparison of the left and right sides of the same body, cyclosporine A peanut oil (0.05%) was given to the left side, and cyclosporine A polymer micelles (0.05%) were given to the right side. Three times a day, two days later, the rabbits were anesthetized and killed, and 0.1ml of the aqueous humor was taken, and the eyeball was separated, and the conjunctiva was taken, and the peripheral tissue and cornea were separated, weighed accurately, and placed in a freezer at -20°C for 48 hours. Vortex and mix with 0.2mL methanol for 5 minutes, centrifuge at 16000r/min for 10min, take the supernatant, and perform liquid chromatography-mass spectrometry analysis to calculate the content.

The results showed that compared with ophthalmic polymer micelles and oil solution, the drug on the ocular surface was equivalent.

Table 3 Cyclosporine A rabbit eye tissue distribution (ng/g)

Conjunctiva Limbic tissue Cornea Aqueous humor

Ophthalmic oil solution 0.13±0.08 0.45±0.32 35.23±12.25 43.25±22.18

ophthalmic polymer micelles

                          3.35 ± 1.15 1.00 ± 0.23 32.14 ± 10.38 21.33 ± 13.24

gel

Embodiment 7 This embodiment is the preparation of ophthalmic chloramphenicol polymer micelle eye drop

Weigh 2g of chloramphenicol and 2g of mPEG-PLA (50/50) into a flask, add 50ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22mm microporous membrane, filled into lyophilized vials, 2ml per vial, and lyophilized to obtain chloramphenicol polymer micelles.

Take an appropriate amount of sodium chloride (about 1%), add benzalkonium chloride (1/10,000), edetate disodium (4/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 6.5, and extinguish at 121°C. bacteria for 30 minutes as a diluent.

Take an appropriate amount of chloramphenicol polymer micelles, add it into the diluent, and dissolve it to obtain a concentration of chloramphenicol of 2%.

Example 8 This example is the preparation of ophthalmic acyclovir polymer micelle eye drops

Weigh 0.2g of acyclovir and 1g of mPEG-PLA (60/40) into a flask, add 30ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22 mm microporous membrane, filled into lyophilized vials, 2 ml per vial, and lyophilized to obtain acyclovir polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 7.2, and sterilize at 121°C for 30 minutes as a diluent.

Take an appropriate amount of acyclovir polymer micelle, add it to a diluent, and dissolve it to obtain a concentration of acyclovir of 0.2%.

Embodiment 9 This embodiment is the preparation of ophthalmic dexamethasone polymer micelle eye drops

Weigh 0.1g of dexamethasone and 0.5g of mPEG-PLA (60/40) into a flask, add 20ml of ethanol, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22mm microporous membrane, filled into freeze-dried bottles, 2ml per bottle, and freeze-dried to obtain dexamethasone polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 7.0, and sterilize at 121°C for 30 minutes as a diluent.

Take an appropriate amount of dexamethasone polymer micelles, add it into the diluent, and dissolve it, so that the concentration of dexamethasone is 0.1%.

Example 10 This example is the preparation of ophthalmic flubiphenyl propionic acid polymer micelles eye drops

Weigh 0.3g of flurbiprofen and 1g of mPEG-PLA (60/40) respectively into a flask, add 30ml of ethanol, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22 mm microporous membrane, filled into lyophilized vials, 2 ml per vial, and lyophilized to obtain flurbiprofen polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 7.4, and sterilize at 121°C for 30 minutes as a diluent.

Take an appropriate amount of flurbiphenyl propionic acid polymer micelles, add it into the diluent, and dissolve it, so that the concentration of flurbiphenyl propionic acid is 0.3%.

Example 11 This example is the preparation of ophthalmic pilocarpine polymer micellar eye drops

Weigh 0.1g of pilocarpine (free base) and 0.5g of mPEG-PLA (75/25) into a flask, add 30ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22mm microporous membrane, filled into freeze-dried bottles, 2ml per bottle, and freeze-dried to obtain pilocarpine polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 6.0, and sterilize at 121°C for 30 minutes as a diluent.

An appropriate amount of pilocarpine polymer micelles is taken, and added into a diluent to dissolve to obtain a concentration of pilocarpine of 0.1%.

Example 12 This example is the preparation of ophthalmic timolol polymer micelle eye drops

Weigh 0.25g timolol (free base) and 0.25g mPEG-PLA (80/20) respectively and place in a flask, add 30ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile (rotary evaporator) at 60° C. under vacuum, and adjust the volume of the sample to 100 ml with water. The product is sterilized by filtration with a 0.22 mm microporous membrane, filled into lyophilized vials, 2 ml per vial, and lyophilized to obtain timolol polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 6.2, and sterilize at 121°C for 30 minutes as a diluent.

An appropriate amount of timolol polymer micelles is taken, added into a diluent, and dissolved to obtain a timolol concentration of 0.25%.

Example 13 This example is the preparation of ophthalmic tiopronin polymer micelle eye drops

Weigh 0.05g tiopronin and 0.5g mPEG-PLA (80/20) respectively and place in a flask, add 10ml of acetonitrile, heat and stir until dissolved. Slowly distill off acetonitrile under vacuum at 60°C (rotary evaporator), and adjust the volume of the sample to 100ml with water. The product is sterilized by filtration with a 0.22 mm microporous membrane, filled into lyophilized vials, 2 ml per vial, and lyophilized to obtain tiopronin polymer micelles.

Take an appropriate amount of sodium chloride (about 0.9%), add benzalkonium chloride (1/10,000), edetate disodium (4/10,000), add dropwise 1N HCl or NaOH to adjust the pH to 7.2, and extinguish at 121°C. bacteria for 30 minutes as a diluent.

Take an appropriate amount of the tiopronin polymer micelle, add it into the diluent, and dissolve it, so that the concentration of the tiopronin is 0.05%.

Claims (10)

1, the block polymer of being made up of two kinds of polymer fragments is as the application of eye medicinal carrier.

2, the application of claim 1, described block polymer is selected from the mPEG-PLA block polymer, and mPEG-PGA block polymer, mPEG-PLGA block polymer, block polymer are diblock polymer or multi-block polymer.

3, the application of claim 2, wherein said mPEG-PLA block polymer are mPEG-PLA diblock polymer or mPEG-PLA multi-block polymer.

4, the application of claim 1, described application as pharmaceutical carrier are the application as the pharmaceutical carrier that is fit to dosing eyes.

5, a kind of pharmaceutical composition contains the active constituents of medicine of effective dose and the block polymer of being made up of two kinds of polymer fragments.

6, the compositions of claim 5, described active constituents of medicine is selected from, antibacterials, antiviral drugs, anti-inflammatory drug influences immune medicine, the treatment medicine for treating myopia, treatment xerophthalmia medicine, the treatment glaucoma medicine, the treatment cataract medicine, the described block polymer of being made up of two kinds of polymer fragments is the mPEG-PLA block polymer, the mPEG-PGA block polymer, the mPEG-PLGA block polymer.

7, the compositions of claim 5, 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.

8, the compositions of claim 7, described mPEG-PLA block polymer are mPEG-PLA diblock polymer or mPEG-PLA multi-block polymer.

9, the compositions of claim 5 wherein also contains the medicine acceptable auxiliary that other are fit to the preparation medicament for the eyes.

10, the compositions of claim 5 is dosage forms of any dosing eyes.