WO2022156371A1 - 一种眼用制剂的载体或辅料及其制备方法和应用 - Google Patents

一种眼用制剂的载体或辅料及其制备方法和应用 Download PDF

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WO2022156371A1
WO2022156371A1 PCT/CN2021/134149 CN2021134149W WO2022156371A1 WO 2022156371 A1 WO2022156371 A1 WO 2022156371A1 CN 2021134149 W CN2021134149 W CN 2021134149W WO 2022156371 A1 WO2022156371 A1 WO 2022156371A1
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eye
ophthalmic
carrier
povidone
ophthalmic preparation
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PCT/CN2021/134149
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English (en)
French (fr)
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董庆
张舒
成旋
薛陆兵
唐欣
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成都瑞沐生物医药科技有限公司
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Priority to JP2023544444A priority Critical patent/JP2024507327A/ja
Priority to EP21920747.9A priority patent/EP4282432A1/en
Publication of WO2022156371A1 publication Critical patent/WO2022156371A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

Definitions

  • the invention belongs to the field of ophthalmic drug delivery, and in particular relates to a carrier or auxiliary material of an ophthalmic preparation and a preparation method and application thereof.
  • DME diabetic macular edema
  • Drug therapy is the main treatment method and research trend for fundus diseases.
  • Finding an effective and safe drug or method for treating fundus diseases is the goal that researchers in this field have been striving for.
  • Conjunctival sac drug delivery After the drug enters the anterior aqueous humor through the cornea, it can be diffused and distributed to the iris and ciliary body, but the barrier effect of the lens and vitreous membrane makes it difficult for the drug. Enter the lens and vitreous body; (2) ocular injection: including subconjunctival injection, anterior chamber injection, vitreous injection, retrobulbar injection and orbital injection.
  • systemic Administration includes oral administration and intravenous administration: drugs generally accumulate in the liver, kidneys or lungs in the body, and are hindered by the blood-retinal barrier (BRB), the concentration reaching the eye tissue is low, and the systemic It is the main organ that suffers unnecessary toxic side effects.
  • BRB blood-retinal barrier
  • intraocular vitreous injection or vitreous implantation are usually used to deliver drugs to the vitreous of patients for the treatment of diseases of the posterior segment of the eye.
  • Science China Light Industry Press, 2010, P3; Wang et.al., Mediators of Inflammation, Vol.2013, Article ID 780634; Luaces-Rodr ⁇ guez et al., Pharmaceutics, 2018, 10, 66).
  • Drug intravitreal injection or vitreous implantation is a traumatic administration, which requires a specially trained ophthalmologist to operate in a sterile environment such as an operating room; Infectious endophthalmitis, vitreous hemorrhage, retinal damage, etc.; high operating conditions and operating environment, must be performed in qualified hospitals; high production and use costs of biological ophthalmic injections; The situation of delayed treatment due to medical conditions occurs, and the flexibility to adjust the dosing regimen is poor (M.HATA et al., RETINA, 37:1320–1328, 2017).
  • the cornea has a multi-layer structure, which is roughly divided into: liposome-rich epithelial layer, aqueous component-rich stromal layer and liposome-rich endothelial layer from outside to inside.
  • liposome-rich epithelial layer aqueous component-rich stromal layer
  • liposome-rich endothelial layer from outside to inside.
  • eye drops often have a high concentration in the tissues of the anterior segment of the eye, making it difficult to enter the posterior segment of the eye and achieve an effective therapeutic concentration . Therefore, although the conjunctival sac administration method is safe, the drug delivery is poor, and it is difficult to achieve the purpose of effectively treating fundus diseases.
  • the method of eye drop administration has significant advantages in safety and convenience.
  • the invention of ophthalmic ophthalmic preparations that can deliver drugs to the posterior segment of the eye is an urgent technical problem to be solved in clinical practice, and it is very useful for clinical treatment. value and social significance.
  • due to the particularity of the eyeball structure to enter the posterior segment of the eye, it must be able to pass through the multiple barriers of the water-soluble layer and the fat-soluble layer for many times.
  • Nanotechnology enables drugs to be dispersed to the nanometer level, giving them special physicochemical properties and different drug distribution and absorption characteristics, increasing tissue and cell penetration, and potentially enabling drugs to produce new therapeutic effects
  • T.L.CHANG et al. Nanocrystal technology for drug formulation and delivery, Front.Chem.Sci.Eng.2015, 9(1):1–14
  • S.Jiang et al. Nanotechnology in retinal drug delivery, Int.J.Ophthalmol., 2018, 11(6)1038 -1044
  • M.Kabiri et al. Astimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery, Drug Delivery and Translational Research, 2018, 8:484–495
  • Jia Chengzheng et al Penetration of Nanomaterials Advances in Tissue and Cell Research, Novel Industrialization, 2019, 9(9):99–118).
  • nanotechnology is used in the preparation of ophthalmic drugs for increased bioavailability and controlled-release drug delivery.
  • Hydrocortisone nanosuspension (particle size: 0.539-4.87 ⁇ m) prepared by Kassem et al. can increase intraocular pressure in rabbits (M.A.Kassem et al., Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs, International J.Pharmaceutics , 340(2007):126-133).
  • Non-ionic surfactant vesicles are composed of non-ionic surfactants/non-ionic amphiphilic compounds (such as Spans, Poloxamers, Tween, etc.) and cholesterol to encapsulate drugs to form vesicles with submicron diameters. , NSVs, also known as niosomes) as novel drug delivery vehicles.
  • Bioadhesive materials can enhance the residence time of the vesicles in the eye, maintain the slow release of the drug, reduce the clearance of the drug in the eye, etc., and can enhance the penetration into the cornea.
  • the bioavailability of vesicles prepared with cyclopentanolamine ester (mydriatic drug), timolol maleate (glaucoma drug) and acetazolamide (glaucoma drug) was improved in animal experiments (Zhao Xiaoyu et al., Advances in the Application of Novel Drug Carrier Non-Ionic Surfactant Vesicles, Chinese Journal of Hospital Pharmacy, 2008, 28(1): 833-5; X.Ge et al., Advances of Non-Ionic Surfactant Vesicles(Niosomes) and Their Application in Drug Delivery, Pharmaceuticals, 2019, 11, 55).
  • Nano-Emulsion also known as micro-emulsion, is composed of oil phase, water phase, surfactant and co-surfactant in appropriate proportions.
  • the oil phase of nanoemulsion often needs to use vegetable oil, and the decomposition of oil ester may lead to poor stability of the preparation; moreover, the amount of surfactant used is large (25-30%), which may cause toxic side effects and allergic reactions ; Cosurfactants such as ethanol will increase the osmotic pressure, are not suitable for eye drops, and are unstable (Jin Yiguang, editor-in-chief, "Application of Nanotechnology in Drug Delivery", P322, Chemical Industry Press, 2015; Pan Weisan, editor-in-chief , “Pharmaceutics", P404, Chemical Industry Press, 2017).
  • the present invention provides an eye drop drug delivery carrier for efficiently transporting drugs to the posterior segment of the eye and its application.
  • the eye drop drug delivery carrier of the present invention can efficiently transport the drug to the posterior segment of the eye, which solves the problem in the field of ophthalmic drug delivery.
  • the invention provides a carrier or auxiliary material for an ophthalmic preparation, which contains the following components: a surfactant, an ionic polymer, and a solvent.
  • the mass ratio of the surfactant and the ionic polymer is: (1 ⁇ 100):(0.1 ⁇ 50); the ratio of the surfactant to the solvent is: every 100mL of the solvent contains 5 ⁇ 3000mg of surfactant ;
  • the mass ratio of the surfactant to the ionic polymer is (2.5 ⁇ 31):(1 ⁇ 7.5); the ratio of the surfactant to the solvent is: every 100mL of the solvent contains 50 ⁇ 3000mg of the surfactant .
  • the above-mentioned surfactant is a nonionic surfactant.
  • nonionic surfactants are spans, polysorbates, poloxamers, alkyl glucosides, vitamin E polyethylene succinate, sucrose stearate or azone.
  • ionic macromolecule is selected from carboxymethyl cellulose and its salt, sodium starch glycolate, hyaluronic acid and its salt, xanthan gum, alginic acid and its salt, diacetate polyethylene glycol PEG-( COOH) 2 at least one.
  • the invention also provides a carrier or auxiliary material for an ophthalmic preparation, which contains the following components: povidone with low polymerization degree and povidone with medium polymerization degree, and also contains a solvent.
  • the mass ratio of above-mentioned low polymerization degree povidone, middle polymerization degree povidone is:
  • the mass ratio of the low polymerization degree povidone and the medium polymerization degree povidone is: (0.24 ⁇ 1):1, and the ratio of the low polymerization degree povidone to the solvent is: every 100 mL of the solvent contains 400 ⁇ 840 mg low degree of polymerization povidone.
  • the above-mentioned low degree of polymerization povidone is povidone with a weight average molecular weight of 2000-5000 Dalton, preferably povidone PVP K12 with a weight average molecular weight of 3500 Dalton.
  • the above-mentioned middle degree of polymerization povidone is povidone with a weight-average molecular weight of 20,000 to 60,000 Daltons, preferably povidone PVP K30 with a weight-average molecular weight of 35,000 to 50,000 Daltons.
  • the solvent in the carrier or adjuvant of the above-mentioned ophthalmic preparation is a polar solvent.
  • the above-mentioned polar solvent is water.
  • the carrier or adjuvant of the above-mentioned ophthalmic preparation also contains the following components: a tackifier and/or a cosolvent.
  • the tackifier is polyethylene glycol, carbomer, poloxamer, povidone, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, xanthogen At least one of glue, polyoxyethylene fatty alcohols, hyaluronic acid and its salt or hydroxypropyl methylcellulose, and the cosolvent is propylene glycol, glycerol, liquid polyethylene glycol, hydrogenated castor oil or Castor oil; tackifier and surfactant, or the mass ratio of tackifier and povidone with low polymerization degree is 1:(0.1-100), cosolvent and surfactant, or cosolvent and povidone with low polymerization degree The mass ratio of ketone is (1 ⁇ 10):1;
  • the mass ratio of the tackifier and the surfactant, or the tackifier and the low degree of polymerization povidone is 1:(0.1-30).
  • the carrier or adjuvant of the above-mentioned ophthalmic preparation contains nanobodies, the nanobodies are spherical and the particle size is 1-100 nm; the nanobodies are self-assembled by the components of the carrier or adjuvant of the ophthalmic preparation form.
  • the particle size of the nano-body is 5-30 nm.
  • the carrier or auxiliary material of the above-mentioned ophthalmic preparation also contains nano-spheres, and the nano-spheres are spherical and have a particle size of 10-2000 nm.
  • the nano-spheres are formed by self-assembly of nano-bodies.
  • the particle size of the above-mentioned nano-spheres is 100-2000 nm.
  • the present invention also provides a method for preparing the carrier or adjuvant of the above-mentioned ophthalmic preparation, which comprises uniformly mixing the components and the solvent into a solution, and then grinding or homogeneously dispersing the solution.
  • the present invention also provides the use of the carrier or adjuvant of the above-mentioned ophthalmic preparation in preparing an eye drop administration carrier for delivering a drug to the posterior segment of the eye.
  • the present invention also provides an ophthalmic preparation for ophthalmic administration, which is a preparation composed of the carrier or adjuvant of the above-mentioned ophthalmic preparation and an active ingredient for treating eye diseases.
  • the mass ratio of the surfactant in the carrier or adjuvant of the above-mentioned ophthalmic preparation to the active ingredient for treating eye diseases is (1-30): (1-2);
  • the mass ratio of povidone with low degree of polymerization in the carrier or auxiliary material of the ophthalmic preparation and the active ingredient for treating eye disease is (6-40):1.
  • the carrier or adjuvant of the above-mentioned ophthalmic preparation contains nanobodies, and the active ingredient for treating eye diseases is encapsulated in the nanobodies.
  • the above-mentioned nano-body is spherical, and its particle size is 1-100 nm, preferably, its particle size is 5-30 nm.
  • active ingredients for treating eye diseases include small-molecule compound drugs, or their free acids, or their free bases, or their pharmaceutically acceptable salts;
  • the small molecule compound drugs include nucleoside antiviral drugs, ocular hypotensive drugs, antibiotic drugs, antioxidant drugs, anti-inflammatory drugs, muscarinic receptor blocker drugs, immunosuppressive drugs Drugs, glucocorticoids;
  • the nucleoside antiviral drugs include ganciclovir, acyclovir, penciclovir, cidofovir, fomivirsen, lobcavir;
  • the ocular hypotensive drugs include carbonic anhydrase inhibitors, more preferably, brinzolamide, acetazolamide, and methazolamide;
  • the antibiotic drugs include amikacin, ceftriaxone, cefazolin, oxacillin, levofloxacin, ciprofloxacin, moxifloxacin, vancomycin;
  • the anti-inflammatory drugs include: oxytetracycline;
  • the antioxidants include taurine, anthocyanin, and lignin;
  • the muscarinic receptor blocker drugs include atropine, scopolamine, and anisodamine;
  • the immunosuppressive drugs include: cyclosporin, tacrolimus, sirolimus, everolimus, mycophenolate mofetil , methotrexate, azathioprine and cyclophosphamide;
  • the glucocorticoid drugs include cortisone, prednisone, prednisolone, methylprednisolone, fludroprednisolone, and triamcinolone acetonide.
  • the present invention also provides a method for preparing the above-mentioned ophthalmic preparation, comprising the following steps:
  • step (1) dispersing the active ingredient and/or cosolvent for the treatment of eye disease in the solution obtained in step (1), then adding ionic polymer or its solution, and dispersing and mixing to obtain an initial suspension;
  • step (b) dispersing the active ingredient and/or the cosolvent for the treatment of eye disease in the solution obtained in step (a), then adding a medium degree of polymerization povidone or its solution, and dispersing and mixing to obtain an initial suspension;
  • step (c) grinding or homogeneously dispersing the mixed solution obtained in step (b) to obtain.
  • step (2) or step (b) is selected from at least one of mechanical stirring dispersion, magnetic stirring dispersion, vortex shaking dispersion, shear dispersion, homogeneous dispersion, grinding dispersion, and ultrasonic dispersion. .
  • the present invention also provides the use of the above-mentioned ophthalmic preparation in preparing a medicament for treating ocular diseases.
  • the above-mentioned ophthalmic preparation is for the treatment of fundus diseases, and/or the treatment of viral infectious diseases in the posterior segment of the eye, and/or the treatment of chronic inflammation in the posterior segment of the eye, and/or the lowering of intraocular pressure, and/or eye pain, and/or Or ophthalmic preparations against intraocular bacterial or fungal infections, and/or ophthalmic preparations for the prevention and treatment of juvenile myopia and pseudomyopia, and/or ophthalmic preparations for treating autoimmune diseases, and/or treating anterior eye diseases ophthalmic preparations, and/or ophthalmic preparations that inhibit tumor growth.
  • ophthalmic preparations for treating fundus diseases include ophthalmic preparations for treating macular edema, inflammatory edema and inflammatory pain caused by fundus vascular diseases; more preferably, for the treatment of central retinal vein occlusion macular edema, Branch retinal vein occlusion macular edema, diabetic retinopathy, diabetic macular edema, pathological myopic macular edema, macular edema due to wet age-related macular degeneration, dry macular degeneration, geographic atrophy, non-infectious endophthalmitis , Ophthalmic preparations for acute retinal necrosis, postoperative inflammatory pain, and uveitis;
  • the ophthalmic preparations for treating viral infectious diseases in the posterior segment of the eye include ophthalmic preparations for treating cytomegalovirus uveitis, viral optic neuritis, and viral acute retinal necrosis;
  • the ocular preparations for lowering intraocular pressure include ophthalmic preparations for treating acute and chronic glaucoma and its complications;
  • the ophthalmic preparation for treating autoimmune diseases is an ophthalmic preparation for treating ocular immune diseases or ocular diseases caused by systemic autoimmune diseases, preferably, including the treatment of Graves ophthalmopathy, Behoet's syndrome, and shotgun pellets.
  • the ophthalmic preparations for treating anterior diseases of the eye include the treatment of high-risk keratoplasty sequelae or complications, spring catarrhal keratoconjunctivitis, eroding corneal ulcer or refractory corneal ulcer, herpes simplex keratitis, corneal neoplasia Ophthalmic preparations for angiogenesis and corneal pterygium.
  • the active ingredient of the above-mentioned ophthalmic preparation against intraocular bacterial or fungal infection is an antibiotic
  • the active ingredient of the ophthalmic preparation for prevention and treatment of juvenile myopia and pseudo-myopia is a muscarinic receptor blocker
  • the active ingredient of the ophthalmic preparation for treating autoimmune diseases is an immunosuppressant.
  • the present invention also provides a method for treating ocular diseases, that is, using the above-mentioned ophthalmic preparation to a patient.
  • the above-mentioned ocular diseases are fundus diseases, and/or viral infectious diseases in the posterior segment of the eye, and/or chronic inflammation in the posterior segment of the eye, and/or ocular hypertension, and/or ocular pain, and/or ocular Internal bacterial or fungal infection, and/or juvenile myopia, pseudomyopia, and/or autoimmune disease, and/or anterior eye disease, and/or ocular tumor.
  • the above-mentioned fundus diseases include macular edema, inflammatory edema, and inflammatory pain caused by fundus vascular diseases; preferably central retinal vein occlusion macular edema, branch retinal vein occlusion macular edema, diabetic retinopathy, diabetes mellitus.
  • macular edema pathological myopic macular edema, macular edema caused by wet age-related macular degeneration, dry macular degeneration, geographic atrophy, endophthalmitis, acute retinal necrosis, postoperative inflammatory pain, uveitis;
  • the viral infectious diseases of the posterior segment of the eye include cytomegalovirus uveitis, viral optic neuritis, and viral acute retinal necrosis;
  • the ocular hypertension disease includes acute and chronic glaucoma and its complications
  • the autoimmune disease is an ocular disease caused by an ocular immune disease or a systemic autoimmune disease, preferably, including Graves ophthalmopathy, Behoet's syndrome, shotgun-shot retinoid choroidopathy, Sjögren's syndrome, sympathetic eye inflammatory or granulomatous eye disease;
  • the anterior diseases include high-risk corneal transplant sequelae or complications, spring catarrhal keratoconjunctivitis, eroding corneal ulcer or refractory corneal ulcer, herpes simplex keratitis, corneal neovascularization or corneal pterygium Meat.
  • the above-mentioned mode of use is administration by eye drops.
  • the nanobodies referred to in the present invention are nano-scale spherical aggregates formed by self-assembly of components of ophthalmic preparation carriers or excipients in a solvent.
  • the nanospheres referred to in the present invention are spherical self-assembled structures formed by self-assembly of nanobodies in a solvent.
  • the solvent referred to in the present invention is a liquid that can dissolve the components of the ophthalmic preparation carrier or auxiliary material.
  • the surfactant referred to in the present invention refers to a substance that can significantly reduce the surface tension of a liquid; the nonionic surfactant referred to in the present invention refers to a surfactant that does not dissociate in water.
  • the ionic polymers referred to in the present invention are high molecular polymers with cations or anions.
  • the low degree of polymerization povidone referred to in the present invention refers to povidone with a molecular weight below 10,000 Dalton
  • the medium degree of polymerization povidone refers to a povidone with a molecular weight above 10,000 Dalton and below 100,000 Dalton.
  • active ingredients for treating eye diseases are: active substances that can be used to treat eye diseases, that is, active substances that have been used as ophthalmic medicines at present, and the mechanism of action and the target of action show that it can treat eye diseases.
  • active substance for use as an ophthalmic drug No active substance for use as an ophthalmic drug.
  • the eye drop administration of the present invention is an administration method of dropping medicine into the eye, which belongs to the corneal administration route.
  • the administration methods in the prior art cannot take into account both safe administration and effective administration.
  • There is a safety problem in the effective administration manner and the safe administration manner cannot effectively administer the administration.
  • intravitreal injection can be effectively administered, but there are serious complications such as intraocular hemorrhage and pain.
  • the safest eye drop administration is very safe, but because it cannot pass through the anterior segment of the eye, it is difficult for the drug to reach the posterior segment of the eye, and the effective concentration is not enough. , unable to achieve the purpose of effective treatment.
  • the inventors of the present application have invented the eye drop administration carrier of the present invention, and it has been verified by experiments that the eye drop administration carrier can carry the drug, deliver the drug to the vitreous body for action, and is stable, which solves the problem of ophthalmic drug administration.
  • the field of medicine has always been an urgent but unresolved technical problem.
  • the eye drop administration carrier of the present invention can deliver a variety of drugs, and can reach effective (expected) concentrations in the fundus without affecting the properties and effects of the active ingredients carried (wrapped) for treating eye diseases. It can be foreseen that the eye drop administration carrier of the present invention can be used to deliver the existing small molecule drugs that are administered by intravitreal injection, intravitreal injection, oral administration and systemic injection, thereby overcoming the existing vitreous injection, vitreous injection and administration.
  • the problems of injecting implants, oral administration and systemic injection administration can solve serious complications such as intraocular hemorrhage and pain, greatly reduce the suffering of patients with fundus diseases, increase medical compliance, and improve the lives of patients and their families quality, or avoid systemic side effects caused by systemic administration.
  • the present invention can avoid complications caused by local injection or implantation of the eye.
  • the preparation developed by the invention has small dosage and small toxic and side effects, and can not only be used as a therapeutic drug, but also can be used as a prevention and control of ophthalmic diseases.
  • the preparation of the present invention can meet the needs of clinical long-term administration.
  • the active ingredient can be a small molecule drug that has been used clinically and has a clear mechanism of action, the quality is controllable, the product is easy to use, and the patient's compliance is good. The patient's condition can be adjusted flexibly.
  • FIG. 1 is (A) a transmission electron microscope image of the sample prepared in Example 1 (the scale is 200 nm); (B) the transmission electron microscope image after staining with a dye (the scale is 1 ⁇ m).
  • FIG. 2 is a transmission electron microscope image of the sample prepared in Example 3 (the scale is 0.5 ⁇ m).
  • FIG. 3 is a transmission electron microscope image of the dyed sample prepared in Example 6 (the scale is 500 nm).
  • FIG. 4 is a transmission electron microscope image of the sample prepared in Example 13 after dyeing (the scale is 200 nm).
  • FIG. 5 is (A) a transmission electron microscope image of the sample prepared in Example 36 (the scale is 0.5 ⁇ m); (B) the transmission electron microscope image after adding a dye (the scale is 0.5 ⁇ m).
  • the reagents or instruments used in the present invention can be purchased from the market. If no specific conditions are indicated, the conventional conditions or the conditions suggested by the manufacturer are used.
  • API 4000 triple quadrupole mass spectrometer (Applied Biosystems, USA);
  • the property testing method of the preparation of the present invention is as follows
  • the freezing point drop of a solution is measured to determine its osmolarity.
  • Clean the probe of the STY-1A osmometer Take three 100 ⁇ L distilled water into three sample tubes, after the instrument is preheated, screw the sample tube containing 100 ⁇ L distilled water onto the probe of the instrument, choose to clean 3 times, click " Clean", repeated three times.
  • Detection After filling in the sample information in the instrument information table, click "Test”; use a pipette to transfer 100 ⁇ L of sample into the sample tube, gently screw on the instrument, and click "Start” to detect. The test was repeated three times, and the average of the three test results was taken as the test result.
  • the FE20 acidity meter is calibrated with pH buffer solution (pH are 4.00, 6.86 and 9.18 respectively), after the electrode is rinsed with pure water, the excess water is absorbed with non-fiber paper, immersed in the liquid sample to be tested, and the measurement is started by pressing the read button. The data obtained after the reading has stabilized is the sample pH value.
  • pH adjusters are NaOH and HCl, phosphoric acid and phosphate (such as sodium dihydrogen phosphate, disodium hydrogen phosphate). ), citric acid and citrate (such as sodium citrate), boric acid and borax; if the osmotic pressure of the obtained liquid does not reach isotonicity, add an appropriate amount of sodium chloride to make it at or near isotonic.
  • the method for verifying the effect of delivering the drug to the posterior segment of the eye is as follows:
  • Test equipment high performance liquid chromatograph, model: LC-20AD (Shimadzu, Japan); mass spectrometer: model: API4000 triple quadrupole mass spectrometer (Applied Biosystems, USA); chromatographic column: Fortis Pace C18 5 ⁇ M, 2.1X30mm (Fortis, UK).
  • Rats select healthy adult Sprague Dawley (SD) rats, be divided into a test group and a control group, each group has 6 eyes, the test group is dripped with the ophthalmic preparation prepared by the embodiment of the present invention, and the control group is dripped with 2 mg of medicine /5mL suspension of normal saline (vortexed before use), 20 ⁇ L per eye.
  • the animals were euthanized 0.5 hours or 1 hour after administration, and the vitreous body was quickly collected.
  • the vitreous body samples were homogenized and stored at -80°C.
  • New Zealand rabbits Healthy 3- to 4-month-old male New Zealand rabbits weighing 2.0-2.5 kg were selected and divided into two groups with 4 eyes in each group. Grab New Zealand rabbits on the operating table. After the animals were quiet, 30 ⁇ l of normal saline was dropped into the eyes of the animals in one group (blank control); 30 ⁇ l of the test substance was dropped into the eyes of the other group of animals. The animals were euthanized 1 hour later and collected quickly. The aqueous humor and vitreous body of both eyes were stored at -80°C.
  • Example 1 Preparation of the ophthalmic formulation of the present invention
  • CMC-Na sodium carboxymethyl cellulose, ionic polymer
  • Table 1 Weigh 0.24g of CMC-Na (sodium carboxymethyl cellulose, ionic polymer) according to Table 1 and add it to a glass conical flask containing 40mL of pure water, turn on magnetic stirring for 2 hours to obtain solution 1; weigh 1.0g respectively Polysorbate 80 (surfactant) and 0.24g HPMC (hydroxypropyl methylcellulose, tackifier) were added to a glass conical flask containing 60mL of purified water, turned on magnetic stirring, heated in a water bath at 40°C for about 1.5 hours, Get solution 2; Weigh 40mg dexamethasone and 4.0mL PEG400 (that is, 4.3 times (w/w) of surfactant consumption) and put into solution 2, continue to heat and stir for 30 minutes, add solution 1, stir for 30 minutes, get mixed Disperse the mixed solution with a dispersing machine at 9500 rpm for 5 minutes, stop and wait for the foam
  • HPLC detection detection instrument: Agilent 1100 high performance liquid chromatograph; operating software: OpenLab CDS c.01.10 (201) Chemstation Edition;
  • Particle size was 20.6 nm (85.6%), PdI: 0.266. Stored in the dark at room temperature for 1 month, the appearance and content of the sample did not change.
  • the vitreous dexamethasone concentration of animals was 53.4 (ng/g) at 0.5 hours after eye instillation, RSD: 36.6%.
  • the control group was dripped with a suspension of 2mg dexamethasone/5mL normal saline (vortexed before use), 20 ⁇ L per eye, and no dexamethasone was detected in the vitreous of animals in the control group 0.5 hours after eye instillation (lower than Detection limit, ⁇ 1ng/g).
  • the preparation method is with reference to Example 1, and the raw materials and dosage are shown in Table 1. A colorless and clear solution was obtained after removal of impurities.
  • pH Adjustment Adjust to pH 6.5 with 0.2N NaOH or/and 0.1N HCl.
  • HPLC detection method is the same as Example 1, HPLC content detection results: 95.1%, particle size 12.9nm (92.1%), PdI: 0.509; good stability, no obvious change in appearance and content after being placed in the dark at room temperature for 1 month; 2 A small amount of precipitation appeared after a month.
  • the concentration of API in rat vitreous body was 13.9ng/g 1 hour after eye instillation, RSD: 17.2%.
  • the preparation method refers to Example 1, and the raw materials and consumption are shown in Table 1. After obtaining the slightly yellow clear solution after removing impurities, sodium chloride is added to adjust the osmotic pressure to: 273mOsmol/kg.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: ACN. Temp.: 35°C, detection wavelength: 296nm, Flowrate: 0.8ml/min; gradient elution program: 0-2': 95%A-5%B, 15': 55%A-45%B, 18-21 ': 35%A-65%B, 23': 95%A-5%B. Test result: 98.2%.
  • the particle size is 13.2nm (81.2%) and 57.7nm (13.1%), PdI: 0.431; good stability, placed in the dark at 40°C for 20 days, there is no obvious change in appearance and content;
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was: 315ng/g, RSD: 29.4%.
  • the vitreous API concentration of New Zealand rabbits was 142ng/g, RSD: 34.3% 0.5 hours after eye instillation.
  • Example 3 For the preparation method, refer to Example 3 to obtain a slightly yellow clear solution after impurity removal.
  • the raw materials and dosage are shown in Table 1.
  • HPLC detection method is the same as that in Example 3, and the detection result is 97.5%; the stability is good, and the appearance and content have no obvious change after being placed in the dark at 40° C. for 20 days.
  • the preparation method is with reference to Example 1, and the raw materials and consumption are shown in Table 1. After obtaining the colorless and clear solution after removal of impurities, adjust the pH to 6.5 with 0.1N NaOH.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 40mM ammonium acetate aqueous solution (pH5.0), mobile phase B: MeOH, Temp.: 35°C, detection wavelength: 233nm, Flowrate: 0.8ml /min; gradient elution program: 0-2': 100% A, 20-22': 60% A-40% B, 23': 100% A. Test result: 97.4%;
  • the preparation method is with reference to Example 5, and the raw materials and consumption are shown in Table 1. After obtaining the colorless and clear solution after removing impurities, adjust the pH to 6.5 with 1N sodium citrate solution, and add sodium chloride to adjust the osmotic pressure to: 297mOsmol/ kg.
  • HPLC detection Column: ZORBAX 300SB-CN, 2.1x150mm, 5 ⁇ m; mobile phase: 40mM KH 2 PO 4 (pH4.5): methanol (75:25) isocratic elution, Temp.: 35°C, detection wavelength: 233nm , Flowrate: 0.8ml/min; detection result: 99.1%.
  • the particle size is 21.6 nm (94.4%), PdI: 0.206; it was placed in the dark at room temperature for 2 months, and the appearance and content did not change significantly.
  • the vitreous API concentration of animals was 39.8 ⁇ 16.6ng/g 0.5 hours after eye instillation.
  • the preparation method refers to Example 5, the raw materials and dosage are shown in Table 1, and a colorless and clear solution after impurity removal is obtained.
  • the pH test result is 6.9, and no adjustment is required.
  • HPLC detection method refers to Example 5, the detection result: 98.6%; particle size 16.6nm (98%), PdI: 0.227, placed in the dark at room temperature for 2 months, the appearance and content have no obvious change.
  • the preparation method refers to Example 5, the raw materials and the dosage are shown in Table 1, and the colorless and clear solution after impurity removal is obtained.
  • the pH test result is 6.5, and no adjustment is required.
  • Example 5 for the HPLC detection method, and the detection result: 97.8%.
  • the particle size is 17.1 nm (55.5%), 513 (36.3%), PdI: 0.795; placed in the dark at room temperature for 1 month, there is no obvious change in appearance and content.
  • Preparation method Weigh 60mg CMC-Na into a glass conical flask containing 15mL pure water, turn on magnetic stirring for 2 hours to obtain solution 1; respectively weigh 0.24g polysorbate 80 and 0.12g HPMC (viscosifier) and add In another glass conical flask containing 15mL of pure water, turn on magnetic stirring and heat in a water bath at about 40°C for 3 hours to obtain solution 2; weigh 15mg of lipoic acid and 1mL of glycerol (equivalent to 5.25 times the amount of surfactant ( w/w)) put it into solution 2, continue heating and stirring for 30 minutes, add solution 1, stir for 30 minutes to obtain a mixed solution; disperse the mixed solution with a disperser at 11,000 rpm for 3 minutes, and wait for the solution foam to disappear after shutdown Transfer to a high pressure homogenizer for homogenization treatment (refer to Example 1 for conditions) to obtain a colorless and clear solution, then sterilize under reduced pressure and remove mechanical impurities to obtain solution
  • pH and osmotic pressure adjustment method adjust the pH to 6.3 with 0.1N sodium citrate solution, add sodium chloride to adjust the osmotic pressure to: 294mOsmol/kg;
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6 ⁇ 100 mm 3.5 ⁇ m; mobile phase A: 0.1% phosphoric acid (pH 3.0), B: methanol-acetonitrile (1:1). Temp.: 35°C, detection wavelength: 215nm, Flowrate: 0.8ml/min; gradient elution program: 0-5': 60%A-40%B, 28-30': 40%A-60%B; detection Results: 97.4%. Particle size test results: 17.8nm (98.6%), PdI: 0.222; no change in appearance and content after being placed in the dark at 3-8°C for 1 month.
  • the concentration of API in rat vitreous body was 52.6 ⁇ 17.9ng/g 0.5 hours after eye instillation.
  • the control group was dripped with a suspension of 2mg lipoic acid/5mL physiological saline (vortexed before use), 20 ⁇ L per eye, and no lipoic acid was detected in the vitreous of animals in the control group 0.5 hours after eye instillation (below the detection limit). , ⁇ 1ng/g).
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 5, the raw materials and dosage are shown in Table 1, and the colorless and clear solution after impurity removal is obtained.
  • the HPLC detection method is the same as that of Example 5, and the HPLC detection result: 98.4%
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 9, the raw material and dosage are shown in Table 1, wherein the dosage of cosolvent propylene glycol is 6.2 times (w/w) of surfactant.
  • HPLC detection wavelength 233nm other detection methods are the same as in Example 9, detection results: 98.1%; particle size 25.8nm (87.4%), PdI: 0.317, 3 ⁇ 8 °C protected from light for 1 month, no change in appearance and content.
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 9, the raw material and the dosage are shown in Table 1, wherein the dosage of the cosolvent propylene glycol is 8.9 times (w/w) of the surfactant.
  • HPLC detection method is the same as that of Example 9, and the detection results are: 95.2%; particle size: 31.5 nm (82.9%); PdI: 0.347. Placed in the dark at 3-8°C for 1 month, the appearance and content have no change.
  • the preparation method refers to Example 1, the raw materials and the dosage are shown in Table 1, and the slightly yellow clear solution after impurity removal is obtained.
  • pH and osmotic pressure adjustment adjust to pH 6.3 with 0.1N NaOH, add sodium chloride to adjust the osmotic pressure to: 297mOsmol/kg;
  • HPLC detection wavelength 280nm other detection methods are the same as in Example 1, detection results: 97.3%; particle size 16.7nm (98.1%), PdI: 0.225; placed in the dark at room temperature for 1 month, no change in appearance and content.
  • the concentration of API in rat vitreous body was 66.5 ⁇ 18.1ng/g 0.5 hours after eye instillation.
  • control group was dripped with a suspension of 2 mg doxycycline/5 mL of normal saline (vortexed before use), 20 ⁇ L per eye, and no doxycycline was detected in the vitreous of animals in the control group 0.5 hours after eye instillation ( Below the detection limit, ⁇ 1ng/g).
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 13, the raw materials and dosage are shown in Table 1, and the slightly yellow clear solution after impurity removal is obtained.
  • HPLC detection method is the same as that of Example 13, and the HPLC detection result is: 98.2%; particle size is 17.2 nm (97.9%), PdI: 0.208; placed in the dark at room temperature for 1 month, there is no change in appearance and content.
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 13, and the addition of the cosolvent is: take 1.5mL of propylene glycol (equivalent to 10 times (w/w) of the surfactant) and add it to the medium water with the surfactant. Stir, heat and dissolve in a water bath to obtain solution 2, and obtain a slightly yellow clear solution after impurity removal.
  • the raw materials and dosage are shown in Table 1.
  • HPLC detection method is the same as that of Example 13, and the detection results are: 95.2%; particle size: 29.7 nm (89.3%); PdI: 0.382;
  • Example 9 The preparation method and pH, osmotic pressure adjustment method refer to Example 9, and the raw materials and dosage are shown in Table 1.
  • the HPLC detection method refers to Example 9, and the detection results are: 0.486 mg/mL (metformin), 0.481 mg/mL (lipoic acid); particle size 18.9 nm+302.1 nm, PdI: 0.529; 3 ⁇ 8°C protected from light for 1 month , the appearance and content are unchanged.
  • vitreous API concentrations of animals 0.5 hours after eye instillation were: 86.5ng/g lipoic acid, 69.5ng/g metformin.
  • Example 9 The preparation method and pH, osmotic pressure adjustment method refer to Example 9, and the raw materials and dosage are shown in Table 1.
  • the HPLC detection method refers to Example 9, and the detection results are: 0.487mg/mL (doxycycline), 0.478mg/mL (lipoic acid); particle size 20.2nm+251.6nm, PdI: 0.701, 3 ⁇ 8 °C protected from light 1 month, no change in appearance and content.
  • vitreous API concentrations of rats were 57.3ng/g lipoic acid and 68.4ng/g metformin 0.5 hours after eye instillation.
  • the preparation method refers to Example 1, the raw materials and dosage are shown in Table 1, after obtaining the colorless and clear solution after removing impurities, add sodium chloride to adjust the osmotic pressure to: 301mOsmol/kg; pH test result: 6.6 without adjustment.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 0.1% phosphoric acid, mobile phase B: acetonitrile, Temp.: 35°C, detection wavelength: 260nm, Flowrate: 0.8ml/min; gradient elution Procedure: 0-2': 95%A-5%B, 20-25': 65%A-35%B, 28': 95%A-5%B; test result: 98.2%.
  • the particle size is 20.3 nm (83.6%), PdI: 0.249; after being placed at room temperature for 1 month, there is no change in appearance and content.
  • the vitreous API concentration of New Zealand rabbits was 138ng/g 1 hour after eye instillation, and the concentration in aqueous humor was 681ng/g.
  • the preparation method and pH, osmotic pressure adjustment method refer to Example 1, the raw materials and the dosage are shown in Table 1, and the slightly yellow clear solution after impurity removal is obtained.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 0.1% phosphoric acid, mobile phase B: methanol (80:20) isocratic elution, Temp.: 35°C, detection wavelength: 280nm, Flowrate : 0.8ml/min; test result: 98.4%.
  • the particle size is 39.7 nm (95.5%), PdI: 0.318; it was placed in the dark at room temperature for 1 month, and the appearance and content did not change.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 78.3ng/g.
  • Example 19 The preparation method and pH and osmotic pressure adjustment refer to Example 19, and the raw materials and dosages are shown in Table 1. A slightly yellow clear solution was obtained after impurity removal.
  • HPLC detection method is the same as that of Example 19, and the detection result: 97.8%; particle size: 46.2 nm (95.5%), PdI: 0.343; the appearance and content are obviously unchanged after being placed in the dark at room temperature for 1 month.
  • the preparation method refers to Example 1, the raw materials and dosage are shown in Table 1, and the colorless and clear solution after impurity removal is obtained, and sodium chloride is added to adjust the osmotic pressure to 271mOsmol/kg; pH test result: 6.6, no need to adjust.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase: 0.1% H 3 PO 4 -acetonitrile (85:15) isocratic elution, Temp.: 35°C, detection wavelength: 217nm, Flowrate: 0.7ml/min; test result: 99.6%.
  • the particle size is 15.2 nm (93.4%), PdI: 0.227; it was placed in the dark at room temperature for 1 month, and the appearance and content were obviously unchanged.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 79.4 (ng/g).
  • the preparation method refers to Example 21, the raw materials and dosage are shown in Table 1, the colorless and clear solution after impurity removal is obtained, and sodium chloride is added to adjust the osmotic pressure to 265mOsmol/kg; pH test result: 6.5, no need to adjust.
  • HPLC detection method is the same as that of Example 21, and the detection results are: 98.3%; particle size 11.9 (91.9%) nm, PdI: 0.206; no obvious change in appearance and content after being placed in the dark at room temperature for 1 month.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 46.2 (ng/g).
  • the preparation method refers to Example 9; the raw materials and the dosage are shown in Table 1, wherein the dosage of the cosolvent propylene glycol is 4.5 times (w/w) of the surfactant, and the pH is 6.5, which is close to isotonic and does not need to be adjusted.
  • HPLC detection method Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 0.1% phosphoric acid, B: acetonitrile (80:20), isocratic elution; Temp.: 35°C, detection wavelength: 306nm, Flowrate : 0.8ml/min; test result: 95.7%;
  • the particle size is 27.5nm (77.9%), PdI: 0.328; placed in the dark at 3-8°C for 1 month, there is no obvious change in appearance and content.
  • the concentration of API in rat vitreous body was 20.3 ⁇ 9.3ng/g 0.5 hours after eye instillation.
  • the preparation method refers to Example 23, the raw materials and the consumption are shown in Table 1, and the consumption of the cosolvent propylene glycol is 4.5 times (w/w) of the surfactant to obtain a colorless and clear solution after the removal of impurities.
  • pH is 6.6, no need to adjust pH; osmotic pressure adjustment: add sodium chloride to adjust osmotic pressure to: 293mOsmol/kg;
  • the particle size is 24.5nm (85.5%), PdI: 0.253; placed in the dark at 3-8°C for 1 month, there is no obvious change in appearance and content.
  • the preparation method refers to Example 23, the raw materials and the consumption are shown in Table 1, and the consumption of the co-solvent glycerol is 4.5 times (w/w) of the surfactant to obtain a colorless and clear solution after removing impurities.
  • pH is 6.4, no need to adjust pH; osmotic pressure adjustment: add sodium chloride to adjust the osmotic pressure to 305mOsmol/kg;
  • the particle size is 26.2nm (75.2%), PdI: 0.325; placed in the dark at 3-8°C for 1 month, there is no obvious change in appearance and content.
  • the preparation method refers to Example 23, the raw materials and the consumption are shown in Table 1, and the consumption of the cosolvent propylene glycol is 4.5 times (w/w) of the surfactant to obtain a colorless and clear solution after the removal of impurities.
  • pH, osmotic pressure adjustment adjust to pH 6.2 with 0.2N NaOH, add sodium chloride to adjust the osmotic pressure to: 305mOsmol/kg;
  • the particle size is 22.7nm (83.4%), PdI: 0.372; placed in the dark at 3-8°C for 1 month, there is no obvious change in appearance and content.
  • the preparation method is with reference to Example 1, the raw materials and consumption are as shown in Table 1, the colorless and clear solution after the impurity removal is obtained, adjusted to pH6.2 with 1M aqueous sodium citrate solution, and the osmotic pressure is adjusted to: 307mOsmol/kg by adding sodium chloride ;
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: water: mobile phase B: methanol, Flowrate: 0.8ml/min; gradient elution program: 0-10': 100% A-0% B, 15': 55%A-45%B, 18-21': 35%A-65%B; Temp.: 30°C, detection wavelength: 255nm; purity test result: 99.2%; particle size 19.6nm (75.9 %), PdI: 0.424; placed in the dark at room temperature for 1 month, there was no obvious change in appearance and content.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 580ng/g.
  • the preparation method refers to Example 9, the raw materials and the consumption are shown in Table 1, wherein the consumption of the cosolvent propylene glycol is 5 times (w/w) of the surfactant, to obtain a colorless and clear solution after removing impurities.
  • pH and osmotic pressure adjustment adjust to pH 6.3 with 0.1N NaOH, add sodium chloride to adjust the osmotic pressure to: 290mOsmol/kg;
  • the particle size is 23.7 nm (84.2%), and PdI: 0.323; after being placed in the dark at room temperature for 1 month, there is no obvious change in appearance and content.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 62.5ng/g.
  • the preparation method refers to Example 1, the raw materials and the consumption are shown in Table 1, and the consumption of the cosolvent PEG400 is 5 times (w/w) of the surfactant to obtain a colorless and clear solution after removing impurities.
  • pH and osmotic pressure adjustment adjust to pH 6.2 with 1M Na 2 HPO 4 solution, add sodium chloride to adjust osmotic pressure to: 295mOsmol/kg;
  • HPLC detection method is the same as that of Example 1, and the detection results are: 97.3%; particle size 22.4 nm (91.4%), PdI: 0.293; placed in the dark at room temperature for 1 month, the appearance and content have no obvious change.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 42.7ng/g.
  • the preparation method is with reference to Example 9, the raw materials and the consumption are shown in Table 1, and the consumption of the cosolvent propylene glycol is 4.2 times (w/w) of the surfactant to obtain a colorless and clear solution after the removal of impurities.
  • pH and osmotic pressure adjustment adjust to pH 6.3 with 0.1N NaOH, add sodium chloride to adjust the osmotic pressure to: 288mOsmol/kg;
  • the HPLC detection method refers to Example 9, the detection result: 95.6%; particle size 24.1 nm (81.5%), PdI: 0.357; placed in the dark at room temperature for 1 month, the appearance and content have no obvious change.
  • the preparation method refers to Example 5, the raw materials and the consumption are shown in Table 1, and the consumption of the cosolvent propylene glycol is 5.2 times (w/w) of the surfactant to obtain a colorless and clear solution after removing impurities.
  • pH and osmotic pressure adjustment adjust to pH 6.3 with 0.2N NaOH, add sodium chloride to adjust osmotic pressure to: 310mOsmol/kg;
  • the HPLC detection method refers to Example 5, the detection result: 97.2%; particle size 27.5nm (79.6%), PdI: 0.364; placed in the dark at room temperature for 1 month, there are visible particles.
  • the preparation method is with reference to Example 1, and the raw materials and dosage are shown in Table 1.
  • HPLC detection Column: ZORBAX Eclipse Plus C18, 4.6x100mm 3.5 ⁇ m; mobile phase A: 0.1% phosphoric acid aqueous solution, mobile phase B: methanol. Temp.: 35°C, detection wavelength: 280nm, Flowrate: 0.8ml/min; gradient elution program: 0-2': 85%A-15%B, 15-20': 35%A-65%B, 22 -25': 15%A-85%B; test result: 95.3%; particle size 17.6nm (93.9%), PdI: 0.229; placed in the dark at room temperature for 1 month, no obvious change in appearance and content.
  • the concentration of API in rat vitreous body was 185.3ng/g 0.5 hours after eye drop.
  • the preparation method is with reference to Example 9, and the raw materials and consumption are shown in Table 1, wherein the consumption of the cosolvent castor oil is 3 times that of the surfactant.
  • HPLC detection wavelength 280nm other conditions are the same as Example 9, detection result: 94.7%, particle diameter 19.7nm (86.4%), PdI: 0.331; pH 6.8;
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 37.6 (ng/g).
  • the preparation method refers to Example 1, the raw materials and the dosage are shown in Table 1, and a colorless and clear solution after impurity removal is obtained. pH6.5 without adjustment;
  • HPLC detection wavelength 245nm other detection conditions are the same as Example 1, detection results: 98.1%; particle size 18.6nm (96.9%), PdI: 0.257; placed in the dark at room temperature for 1 month, no obvious change in appearance and content.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 43.8ng/g.
  • the raw materials and dosage are shown in Table 1, and the preparation method refers to Example 1. A colorless and clear solution was obtained after removal of impurities.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 5.1ng/g.
  • the raw materials and dosage are shown in Table 1, and the preparation method refers to Example 1.
  • the mass of the co-solvent PEG400 added is equal to that of the surfactant (1:1 (w/w)) to obtain a colorless and clear solution after impurity removal.
  • the preparation method and detection method refer to Example 1, and the raw materials and dosage are shown in Table 1.
  • Test results particle size 10.0 nm (98.8%), PdI: 0.363, stability: precipitation after being placed in a cool place for 1 month.
  • the preparation method and detection method refer to Example 1, and the raw materials and dosage are shown in Table 1.
  • the preparation method refers to Example 1, and the raw materials and dosage are shown in Table 2, wherein the dosage of cosolvent PEG400 is 5 times (w/w) of povidone with a low degree of polymerization.
  • the colorless and clear solution after impurity removal is obtained, and pH 6.5 does not need to be adjusted;
  • HPLC detection method is the same as that of Example 1, and the detection result: 98.1%;
  • the particle size is 15.1 nm (87.1%) and 3.1 nm (11.0%), PdI: 0.288; placed in the dark at room temperature for 1 month, there is no obvious change in appearance and content.
  • the concentration of API in rat vitreous body at 0.5 hours after eye instillation was 5.1ng/g.
  • HPLC detection result 99.3%; particle size 11.5nm (62.9%) and 77.8nm (23.6%), PdI: 0.362; appearance and content did not change after being placed in the dark at room temperature for 1 month.
  • the raw materials and dosage are shown in Table 2, and the preparation method refers to Example 1. A colorless and clear solution was obtained after removal of impurities.
  • the HPLC detection method refers to Example 1, the detection result: 98.5%; particle size 125.6nm (63.5%), 13.6nm (33.1%), PdI: 0.255; after being placed in a dark place at room temperature for 1 month, a light emulsion is formed, with white precipitation.
  • the raw materials and the dosage are shown in Table 2, and the preparation method refers to Example 1, and the medium degree of polymerization povidone is replaced with the ionic polymer CMC-Na to obtain a pale white emulsion.
  • the measurement results of the concentration of API in the rat vitreous after eye drop administration show that the ophthalmic medicine of the present invention can carry the active ingredient for treating eye diseases through the barrier of the eyeball structure, and administer it through the conjunctival sac (eye drop administration)
  • An effective dose of the drug can be delivered to the vitreous body, avoiding invasive administration methods such as vitreous injection, and also greatly reducing the total amount of the drug, reducing the absorption of the drug in the body, and avoiding toxic side effects.
  • the carrier or adjuvant prepared by the present invention can successfully encapsulate various types of ophthalmic drugs to prepare ophthalmic preparations, and the preparation has small particle size, high drug content detected by HPLC, and stable form and content after long-term placement. It shows that the carrier or adjuvant prepared by the present invention has high encapsulation rate for ophthalmic drugs and good stability. However, the preparation prepared by using a comparative example different from the auxiliary material of the present invention has poor stability, and precipitation or deterioration will occur in a short time.
  • the in vitro anti-human cytomegalovirus test was performed on the ganciclovir eye drop drug delivery system prepared in the example.
  • Human embryonic lung fibroblasts (MRC-5) were infected with human cytomegalovirus strain HCMV-AD169, and the antiviral activity of the ganciclovir test product was investigated with the half effective dose (EC50).
  • the test is divided into 4 groups, the test group of the eye drop drug delivery system prepared in this example, the test group of the original ganciclovir drug, the negative control group (MRC-5 cells), and the positive control group (MRC-5 cells infected with HCMV) -AD169).
  • CPE cytopathic effect
  • the experimental process is as follows: MRC-5 cells were adjusted to about 1.5 ⁇ 105/mL, added to a 96-well plate, 100 ⁇ L of culture medium was added to each well, and cultured in a 37°C, 5% CO 2 cell incubator until the cells adhered into a monolayer After the supernatant was discarded, except for the control group, each test group added 100 ⁇ L to each well at a concentration of 100 times the half of the virus-infected cells (TC50) obtained in the pre-test for 2 hours, discarded the supernatant, and added 100 ⁇ L of a series of The test samples were continuously cultured, and the CPE of each well was observed. When the CPE of the positive control group lesions reached more than 90%, the CPE of each well was recorded, and the half effective dose (EC50) was calculated according to the Reed-Muench method.
  • TC50 half of the virus-infected cells
  • the ganciclovir eye drop drug delivery system prepared in Example 27 has no difference in the in vitro inhibitory effect of the ganciclovir original drug.
  • the in vitro antibacterial test was performed on the moxifloxacin eye drop drug delivery system prepared in the example, the moxifloxacin crude drug was taken as the reference substance, and the moxifloxacin eye drop drug delivery system prepared in Example 6 was used as the test
  • the drug is prepared into a drug susceptibility plate, so that the drug susceptibility plate contains 7 to 8 times the dilution concentration of the moxifloxacin raw material drug (reference substance) and the receiving reagent.
  • the strains (25 strains) after incubation for 18h to 24h were picked from the inoculation loop and prepared into a bacterial suspension equivalent to 0.5 McFarland turbidity in sterile saline; added to the liquid drug susceptibility test medium, bacterial liquid and liquid The ratio of medium is 1:200, mix well, add 100 ⁇ L of diluted bacterial solution to each well; incubate at 35°C ⁇ 2°C for 16h-20h; judge the growth of bacteria in each well by turbidity, from low concentration Observed at high concentrations, the lowest drug concentration that can inhibit bacterial growth is the MIC of the drug.
  • the present invention provides a carrier or adjuvant for an ophthalmic preparation and its application.
  • the carrier or adjuvant of the ophthalmic preparation of the present invention as an eye drop administration carrier, will not affect the properties and effects of the active ingredient for treating eye diseases carried (wrapped), and can encapsulate the drug to pass through the anterior segment of the eye and efficiently deliver the drug to the posterior segment of the eye. It plays a therapeutic role, achieves the goal of treating ocular fundus diseases through eye drop administration, and solves the technical problem that has been urgently solved but not solved in the field of ophthalmic preparation administration.

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Abstract

一种眼用制剂的载体或辅料及其制备方法和应用，属于眼用药递送领域。所述眼用制剂的载体或辅料含有如下成分：表面活性剂和离子型高分子等，还含有溶剂；或者所述眼用制剂的载体或辅料含有如下成分：低聚合度聚维酮和中聚合度聚维酮，还含有溶剂。所述眼用制剂的载体或辅料中含有所述成分在溶剂中形成的纳米小体，纳米小体为球形，粒径为1～100nm，可自组装形成粒径为10～2000nm的球形的纳米小球。所述给药载体能够包裹药物穿过眼前段，将药物高效输送到眼后段发挥治疗作用，实现了通过滴眼给药治疗眼底疾病的目标，解决了眼科药品给药领域一直努力解决但未解决的技术问题，具有极为优良的临床使用前景和非常积极的社会意义。

Description

一种眼用制剂的载体或辅料及其制备方法和应用 技术领域
本发明属于眼用药递送领域，具体涉及一种眼用制剂的载体或辅料及其制备方法和应用。
背景技术
眼底疾病患者众多，仅中国患者数量已逾数千万，随着社会日益老龄化，电子产品的普及，发病率将会逐年上升；常见的眼底疾病有糖尿病性黄斑水肿、糖尿病性视网膜病变、年龄相关性黄斑病变、视网膜静脉阻塞、病理性近视、地图样萎缩、眼部肿瘤、眼内炎等，可能导致视力下降甚至失明，严重影响人们生活质量。例如，约有6.8％的糖尿病人患有糖尿病性黄斑水肿(DME)，该疾病是导致糖尿病人失明的主要原因(Urias et al.,Vision Research,V139:221-227,2017；Mandal et al.,Ocular delivery of proteins and peptides:Challenges and novel formulation approaches,Advanced Drug Delivery Reviews,126:67–95,2018)。
药物治疗是眼底疾病的主要治疗方法和研究趋势。但是，由于眼内存在复杂的生理结构和屏障，导致药物很难进入眼球，特别是眼后段，难以达到有效剂量，因而难以实现有效治疗。寻找一种有效且安全的治疗眼底疾病的药品或方法是本领域研究人员一直孜孜以求的奋斗目标。
临床眼科给药通常有3种途径：⑴结膜囊给药(滴眼)：药物通过角膜进入前房水后可以扩散分布到虹膜、睫状体，但晶状体和玻璃体膜的屏障作用，使药物难以进入晶状体和玻璃体；⑵眼部注射给药：包括结膜下注射、眼前房注射、玻璃体注射、眼球后注射和眼眶注射，注射给药可以使药物直接抵达治疗部位，但注射是创伤性的，存在潜在危险，如前房注射产生疼痛，畏光，流泪，前房浑浊，出血，角膜内皮细胞损害，外伤性白内障等；玻璃体注射会出现晶状体浑浊，玻璃体机化，视网膜/视神经损害等；⑶全身给药包括口服给药，静脉给药：药物在体内一般大多聚集在肝脏，肾脏或肺脏，受到血-视网膜屏障(blood retinal barrier，BRB)的阻碍，抵达眼球组织的浓度较低，同时全身尤其是主要脏器承受了不必要的毒副作用。
目前，临床上为了使药物穿过眼屏障，通常采用眼球玻璃体注射、或玻璃体植入(眼内插入)等技术手段，把药物输送到患者玻璃体，治疗眼后段疾病(凌沛学主编《眼科药物与制剂学》，中国轻工业出版社，2010，P3；Wang et.al.,Mediators of Inflammation,Vol.2013,Article ID 780634；Luaces-Rodríguez et al.,Pharmaceutics，2018,10,66)。药物玻璃体注射或玻璃体植入操作是创伤性给药，需要经过专门培训的眼科医师在手术室等无菌环境下操作；因为操作有创伤性可能会出现并发症，如高眼压、白内障、医源性感染性眼内炎、玻璃体出血、视网膜损伤等；操作条件及操作环境要求 高，必须在有条件的医院进行；生物药眼用注射剂生产成本和使用成本高；同时亦存在治疗时机上因为医疗条件限制而延误治疗的情况发生，调整给药方案灵活性差(M.HATA et al.,RETINA，37:1320–1328,2017)。
结膜囊给药是最方便、最安全的眼部给药方式。但是眼角膜有多层结构，从外至内大致分为：富含脂质体的上皮层、富含水性成分的基质层和富含脂质体的内皮层，滴眼液在滴眼后首先接触眼表泪水层，继而需要跨过上皮层、基质层和内皮层才可能到达眼后段。在此过程中，由于泪液的稀释、角膜、结膜的眼表屏障和晶状体、玻璃体的解剖位置，滴眼液往往在眼前段的组织中浓度高，很难进入眼后段并达到有效的治疗浓度。因此，结膜囊给药的方式虽然安全，但是药物输送性差，难以达到有效治疗眼底疾病的目的。
综上，现有治疗眼底疾病主要给药方法均难以兼顾安全和有效。
滴眼给药的方式相比于静脉注射、玻璃体注射具有安全、方便的显著优势，发明能将药物输送到眼后段的眼科眼用制剂是临床实践中亟待解决的技术问题，非常具有临床治疗价值和社会意义。然而，由于眼球结构的特殊性，要进入眼后段必须能多次通过水溶层和脂溶层多重屏障，目前研究人员进行了多种尝试，但均未达到理想的效果。
纳米技术使药物分散至纳米级使其有了特殊的理化性质和不同的药物分布吸收特性，增加组织和细胞渗透，有可能使药物产生新的治疗作用(T.L.CHANG et al.,Nanocrystal technology for drug formulation and delivery,Front.Chem.Sci.Eng.2015,9(1):1–14；S.Jiang et al.,Nanotechnology in retinal drug delivery,Int.J.Ophthalmol.，2018,11(6)1038-1044；M.Kabiri et al.,A stimulus-responsive,in situ-forming,nanoparticle-laden hydrogel for ocular drug delivery,Drug Delivery and Translational Research,2018,8:484–495；贾承政等，纳米材料穿透组织与细胞的研究进展，新型工业化，2019,9(9):99–118)。比如，将纳米技术用于制备眼药以增加生物利用度和控释给药。Kassem等制备氢化可的松纳米混悬剂(粒径：0.539～4.87μm)等滴眼可增加兔眼压(M.A.Kassem et al.,Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs,International J.Pharmaceutics,340(2007):126-133)。有研究报道环孢菌素A的纳米囊可进入试验动物角膜表层，但是却未能进入到角膜全层；又如，有研究报道PEG化聚已内酯纳米粒滴入兔眼后，纳米粒能够渗透进入角膜上皮；还有研究发现，将纳米药物经结膜下注射和玻璃体注射，可控制和延缓药物释放(金义光主编，《纳米技术在药物递送中的应用》，P319，化学工业出版社，2015年)。由非离子表面活性剂/非离子型双亲化合物(如司盘类、泊洛沙姆、吐温类等)、配上胆固醇来包裹药物组成直径多为亚微米的囊泡(non-ionic surfactant vesicles，NSVs，又称niosomes)作为新型药物输送载体。生物黏附性材料可增强囊泡在眼部的停留时间，维持药物的 缓慢释放，减少药物在眼部的清除等，可以增强对角膜的渗透。分别用环戊醇胺酯(扩瞳药)、马来酸噻吗心安(青光眼药)和乙酰唑胺(青光眼药)制备的囊泡在动物试验中药物的生物利用度的提高(赵晓宇等，新型药物载体非离子表面活性剂囊泡的应用研究进展，中国医院药学杂志，2008，28(1)：833-5；X.Ge et al.,Advances of Non-Ionic Surfactant Vesicles(Niosomes)and Their Application in Drug Delivery，Pharmaceutics，2019,11,55)。Puras等将制备的阳离子囊泡注射到大鼠视网膜和视网膜下作为基因输送手段(G.Puras et al.,A novel cationic niosome formulation for gene delivery to the retina，J.Control.Release，2014,174,27–36)。尽管利用纳米技术制备眼科用药具备一定的优势，但以上研究仍然没有实现通过无创伤的滴眼给药的方式使药物进入到眼后段，并保证有效药物浓度的目标。
纳米乳(Nano-Emulsion)又称微乳液，是由油相、水相、表面活性剂和助表面活性剂按适当比例组成的，能够兼具亲水、亲油的特性，具有制备滴眼给药输送药物到眼后段的给药系统的潜在可能。通常的纳米乳难以同时兼具有良好的亲水性和亲脂性，使其能逐次通过眼表泪液层、角膜上皮细胞层、实质层和内皮细胞层而后将有效药物输送进入到眼后段。纳米乳的油相往往需采用植物油脂，而油酯分解，可能导致制剂稳定性变差；而且，使用的表面活性剂用量较大(用量为25～30％)，可能产生毒副作用和过敏反应；助表面活性剂如乙醇，则会增加渗透压，不适合滴眼剂，且不稳定(金义光主编，《纳米技术在药物递送中的应用》，P322，化学工业出版社，2015年；潘卫三主编，《药剂学》，P404，化学工业出版社，2017年)。
因此，研究一种有效输送药物至眼后段的滴眼给药载体仍然是本领域亟待解决而又未解决的技术问题。
发明内容
针对上述问题，本发明提供了一种高效输送药物至眼后段的滴眼给药载体及其应用，本发明滴眼给药载体能够将药物高效运送至眼后段，解决了眼科用药递送领域人们一直渴望解决但始终未能获得成功的技术难题。
本发明提供了一种眼用制剂的载体或辅料，它含有如下成分：表面活性剂和离子型高分子，还含有溶剂。
进一步地，上述表面活性剂、离子型高分子的质量比为：(1～100):(0.1～50)；所述表面活性剂与溶剂的比例为：每100mL溶剂含5～3000mg表面活性剂；
优选地，所述表面活性剂、离子型高分子的质量比为(2.5～31):(1～7.5)；所述表面活性剂与溶剂的比例为：每100mL溶剂含50～3000mg表面活性剂。
进一步地，上述表面活性剂为非离子型表面活性剂。
进一步地，上述非离子型表面活性剂为司盘类、聚山梨酯、泊洛沙姆、烷基葡萄糖苷、维生素E聚琥珀酸乙二醇酯、蔗糖硬脂酸酯或氮酮。
进一步地，上述离子型高分子选自羧甲基纤维素及其盐、羟基乙酸淀粉钠、透明质酸及其盐、黄原胶、海藻酸及其盐、二乙酸聚乙二醇PEG-(COOH) 2中的至少一种。
本发明还提供了一种眼用制剂的载体或辅料，它含有如下成分：低聚合度聚维酮和中聚合度聚维酮，还含有溶剂。
进一步地，上述低聚合度聚维酮、中聚合度聚维酮的质量比为：
(0.1～10):1，所述低聚合度聚维酮与溶剂的比例为：每100mL溶剂含5～3000mg低聚合度聚维酮；
优选地，所述低聚合度聚维酮、中聚合度聚维酮的质量比为：(0.24～1):1，所述低聚合度聚维酮与溶剂的比例为：每100mL溶剂含400～840mg低聚合度聚维酮。
更进一步地，上述低聚合度聚维酮为重均分子量为2000～5000Dalton的聚维酮，优选为重均分子量为3500Dalton的聚维酮PVP K12。
更进一步地，上述中聚合度聚维酮为重均分子量为20000～60000Dalton的聚维酮，优选为重均分子量为35000～50000Dalton的聚维酮PVP K30。
进一步地，上述的眼用制剂的载体或辅料中所述溶剂为极性溶剂。
更进一步地，上述极性溶剂为水。
进一步地，上述的眼用制剂的载体或辅料还含有如下成分：增粘剂和/或助溶剂。
优选的，所述增粘剂为聚乙二醇、卡波姆、泊洛沙姆、聚维酮、羟丙基纤维素、甲基纤维素、羟乙基纤维素、聚乙烯醇、黄原胶、聚氧乙烯脂肪醇类、透明质酸及其盐或羟丙基甲基纤维素中的至少一种，所述助溶剂为丙二醇、丙三醇、液态聚乙二醇、氢化蓖麻油或蓖麻油；增粘剂和表面活性剂，或增粘剂和低聚合度聚维酮的质量比为1:(0.1～100)，助溶剂和表面活性剂，或助溶剂和低聚合度聚维酮的质量比为(1～10):1；
更优选地，所述增粘剂和表面活性剂，或增粘剂和低聚合度聚维酮的质量比为1:(0.1～30)。
进一步地，上述的眼用制剂的载体或辅料含有纳米小体，所述纳米小体为球形，其粒径为1～100nm；所述纳米小体由眼用制剂的载体或辅料的成分自组装形成。
进一步地，上述纳米小体粒径为5～30nm。
更进一步地，上述的眼用制剂的载体或辅料还含有纳米小球，所述纳米小球为球形，其粒径为10～2000nm。所述纳米小球是纳米小体自组装形成的。
更进一步地，上述纳米小球粒径为100～2000nm。
本发明还提供了一种上述的眼用制剂的载体或辅料的制备方法，它是将所述成分和溶剂均匀混合成溶液，然后将溶液进行研磨或均质分散。
本发明还提供了上述的眼用制剂的载体或辅料在制备输送药物至眼后段的滴眼给药载体中的用途。
本发明还提供了一种滴眼给药的眼用制剂，它是由上述眼用制剂的载体或辅料和治疗眼病的活性成分组成的制剂。
进一步地，上述眼用制剂的载体或辅料中的表面活性剂和治疗眼病的活性成分的质量比为(1～30):(1～2)；
或，所述眼用制剂的载体或辅料中的低聚合度聚维酮和治疗眼病的活性成分的质量比为(6～40):1。
进一步地，上述眼用制剂的载体或辅料含有纳米小体，所述治疗眼病的活性成分包裹于纳米小体中。
更进一步地，上述纳米小体为球形，其粒径为1～100nm，优选的，其粒径为5～30nm。
进一步地，上述治疗眼病的活性成分包括小分子化合物类药物、或其游离酸、或其游离碱、或其药学上可接受的盐；
优选地，所述小分子化合物类药物包括核苷类抗病毒药物、降眼压药物、抗生素类药物、抗氧化类药物、抗炎症类药物、毒蕈碱型受体阻断剂药物、免疫抑制剂类药物、糖皮质激素类药物；
更优选地，所述核苷类抗病毒药物包括更昔洛韦、阿昔洛韦、喷昔洛韦、西多呋韦、福米韦生、洛布卡韦；
所述降眼压药物包括碳酸酐酶抑制剂，更优选地，为布林佐胺、乙酰唑胺、醋甲唑胺；
所述抗生素类药包括阿米卡星、头孢曲松、头孢唑林、苯唑西林、左氧氟沙星、环丙沙星、莫西沙星、万古霉素；
所述抗炎症类药物包括：土霉素；
所述抗氧化类包括牛磺酸，花青素，木质素；
所述毒蕈碱型受体阻断剂药物包括阿托品、东莨菪碱、山莨菪碱；
所述免疫抑制剂类药物包括：环孢素(cyclosporin)、他克莫司(tacrolimus)、西罗莫司(sirolimus)、依维莫司(everolimus)、吗替麦考酚酯(mycophenolate mofetil)、氨甲喋呤、硫唑嘌呤及环磷酰胺；
所述糖皮质激素类药物包括可的松、强的松、强的松龙、甲基强的松龙、氟羟强的松龙、曲安奈德。
本发明还提供了一种制备上述的眼用制剂的方法，包括以下步骤：
(1)将表面活性剂、和/或增粘剂加入溶剂中配制成溶液；
(2)将治疗眼病的活性成分和/或助溶剂分散在步骤(1)得到的溶液中，再加入离子型高分子或其溶液，分散混合得到初悬液；
(3)将步骤(2)得到的初悬液搅拌分散或均质分散，即得；
或包括以下步骤：
(a)将低聚合度聚维酮、和/或增粘剂加入溶剂中配制成溶液；
(b)将治疗眼病的活性成分和/或助溶剂分散在步骤(a)得到的溶液中，再加入中聚合度聚维酮或其溶液，分散混合得到初悬液；
(c)将步骤(b)得到的混合液研磨或均质分散，即得。
进一步地，步骤(2)或步骤(b)中所述分散选自机械搅拌分散、磁力搅拌分散、涡旋振摇分散、剪切分散、均质分散、研磨分散、超声分散中的至少一种。
本发明还提供了上述眼用制剂在制备治疗眼部疾病的药物中的用途。
进一步地，上述眼用制剂是治疗眼底疾病，和/或治疗眼后段病毒感染性疾病，和/或治疗眼后段慢性炎症，和/或降眼压，和/或眼部疼痛，和/或抗眼内细菌或真菌感染的眼用制剂，和/或用于青少年近视、假近视的防治的眼用制剂，和/或治疗自身免疫性疾病的眼用制剂，和/或治疗眼前部疾病的眼用制剂，和/或抑制肿瘤生长的眼用制剂。
更进一步地，上述治疗眼底疾病的眼用制剂包括治疗眼底血管性疾病所致的黄斑水肿、炎性水肿、炎性疼痛的眼用制剂；更优选地，为治疗视网膜中央静脉阻塞性黄斑水肿、视网膜分支静脉阻塞性黄斑水肿、糖尿病性视网膜病变、糖尿病性黄斑水肿、病理性近视黄斑水肿、湿性年龄相关性黄斑变性所致黄斑水肿、干性黄斑病变、地图样萎缩、非感染性眼内炎、急性视网膜坏死、术后炎性疼痛、葡萄膜炎的眼用制剂；
所述治疗眼后段病毒感染性疾病的眼用制剂包括治疗巨细胞病毒性葡萄膜炎，病毒性视神经炎，病毒性急性视网膜坏死的眼用制剂；
所述降眼压的眼用制剂包括治疗急慢性青光眼及其并发症的眼用制剂；
所述治疗自身免疫性疾病的眼用制剂为治疗眼部免疫性疾病或全身自身免疫性疾病引起的眼部疾病的眼用制剂，优选地，包括治疗Graves眼病，Behoet氏综合征，鸟枪弹丸性视网膜脉络膜病变，干燥综合征，交感性眼炎或肉芽肿性眼病的眼用制剂；
所述治疗眼前部疾病的眼用制剂包括治疗高危角膜移植术后后遗症或并发症、春季卡他性角结膜炎，蚕蚀性角膜溃疡或顽固性角膜溃疡，单纯疱疹病毒性角膜炎，角膜新生血管形成及角膜翼状胬肉的眼用制剂。
更进一步地，上述抗眼内细菌或真菌感染的眼用制剂的活性成分是抗生素；
所述用于青少年近视、假近视防治的眼用制剂的活性成分是毒蕈碱型受体阻断剂；
所述治疗自身免疫性疾病的眼用制剂的活性成分是免疫抑制剂。
本发明还提供了一种治疗眼部疾病的方法，即对患者使用上述的眼用制剂。
进一步地，上述眼部疾病是眼底疾病，和/或眼后段病毒感染性疾病，和/或眼后段慢性炎症，和/或高眼压疾病，和/或眼部疼痛，和/或眼内细菌或真菌感染，和/或青少年近视、假近视，和/或自身免疫性疾病，和/或眼前部疾病，和/或眼肿瘤。
更进一步地，上述眼底疾病包括眼底血管性疾病所致的黄斑水肿、炎性水肿、炎性疼痛；优选为视网膜中央静脉阻塞性黄斑水肿、视网膜分支静脉阻塞性黄斑水肿、糖尿病性视网膜病变、糖尿病性黄斑水肿、病理性近视黄斑水肿、湿性年龄相关性黄斑变性所致黄斑水肿、干性黄斑病变、地图样萎缩、眼内炎、急性视网膜坏死、术后炎性疼痛、葡萄膜炎；
所述眼后段病毒感染性疾病包括巨细胞病毒性葡萄膜炎，病毒性视神经炎，病毒性急性视网膜坏死；
所述高眼压疾病包括急慢性青光眼及其并发症；
所述自身免疫性疾病为眼部免疫性疾病或全身自身免疫性疾病引起的眼部疾病，优选地，包括Graves眼病、Behoet氏综合征、鸟枪弹丸性视网膜脉络膜病变、干燥综合征、交感性眼炎或肉芽肿性眼病；
所述眼前部疾病包括高危角膜移植术后后遗症或并发症、春季卡他性角结膜炎，蚕蚀性角膜溃疡或顽固性角膜溃疡，单纯疱疹病毒性角膜炎，角膜新生血管形成或角膜翼状胬肉。
更进一步地，上述使用的方式是滴眼给予。
本发明所指的纳米小体是：眼用制剂载体或辅料的成分在溶剂中自组装形成的纳米级的球形聚集体。
本发明所指的纳米小球是：纳米小体在溶剂中自组装形成的球形自组装结构。
本发明所指的溶剂是：能溶解眼用制剂载体或辅料的成分的液体。
本发明所指表面活性剂是：能够显著降低液体表面张力的物质；本发明所指非离子型表面活性剂是指在水中不解离的表面活性剂。
本发明所指离子型高分子是：带有阳离子或阴离子的高分子聚合物。
本发明所指低聚合度聚维酮是：分子量在10000Dalton以下的聚维酮， 中聚合度聚维酮是指分子量在10000Dalton以上，100000Dalton以下的聚维酮。
本发明所指的“治疗眼病的活性成分”是：可以用于治疗眼病的活性物质，即目前已经作为眼科用药使用的活性物质，以及作用机理、作用靶点表明其能够治疗眼病，但目前暂没有作为眼科用药使用的活性物质。
本发明所述滴眼给药是：将药液滴入眼内的一种给药方法，属于角膜给药途径。
由于眼球结构的特殊性，现有技术中的给药方式均无法兼顾安全给药和有效给药，能够有效给药的方式存在安全问题，能够安全给药的方式无法有效给药。比如，玻璃体注射能够有效给药，但是存在眼内出血、疼痛等严重的并发症，目前最为安全的滴眼给药非常安全，但是由于无法透过眼前段，导致药物难以到达眼后段，有效浓度不够，无法达到有效治疗的目的。
本申请发明人经过多年的积累，发明了本发明滴眼给药载体，经过试验验证，该滴眼给药载体能够携载药物，将药物运送至玻璃体发挥作用，并且稳定，解决了眼科药品给药领域一直期限亟待解决但未解决的技术问题。
通过实验可知，采用本发明滴眼给药载体可运送多种药物，可以在眼底达到有效(预期)浓度，且不会影响其携载(包裹)的治疗眼病的活性成分的性质与效果。可以预见，本发明滴眼给药载体可用于运送现有采用玻璃体注射给药、玻璃液植入给药、口服给药和全身注射给药的小分子药物，进而能够克服现有玻璃体注射、玻璃体注射植入剂，口服给药和全身注射给药存在的问题，解决眼内出血、疼痛等严重的并发症问题，极大降低眼底疾病患者的痛苦，增加医从性、改善患者及其家庭的生活质量，或避免全身给药带来的全身毒副作用。
本发明可以避免眼局部注射或植入带来的并发症。
本发明开发的制剂给药量小，毒副作用小，不仅可以作为治疗药物，还可以作为眼科疾病防控。
本发明的制剂可以满足临床上长期给药的需求。
本发明的滴眼给药治疗系统，有效成分(Active Pharmaceutical Ingredient,API)可以采用已在临床使用且作用机理明确的小分子药物，质量可控，产品使用方便，病人顺应性好，医师可根据患者病情灵活调整给药方案。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为实施例1制得的样品的(A)透射电镜图(标尺为200nm)；(B)加染色剂染色后的透射电镜图(标尺为1μm)。
图2为实施例3制得的样品的透射电镜图(标尺为0.5μm)。
图3为实施例6制得的样品染色后的透射电镜图(标尺为500nm)。
图4为实施例13制得的样品染色后的透射电镜图(标尺为200nm)。
图5为实施例36制得的样品的(A)透射电镜图(标尺为0.5μm)；(B)加染色剂后的透射电镜图(标尺为0.5μm)。
具体实施方式
本发明所用试剂或仪器可以通过市售购买获得，未注明具体条件的，按照常规条件或制造商建议的条件使用。
部分仪器设备如下：
ES225SM-DR(E)电子分析天平，Precisa公司(瑞士)；
DF-101S集热式恒温加热磁力搅拌器，巩义市英峪高科仪器厂(河南，中国)；
WH-2微型涡旋混合仪，上海沪西分析仪器厂有限公司(上海，中国)；
分散机：T25easy clean digital，IKA公司(德国)；
KQ-500型超声清洗仪，昆山市超声波仪器有限公司(昆山，中国)；
JP-010T型超声清洗仪，深圳市洁盟清洗设备有限公司；
AH-NANO Plus高压均质机，安拓思纳米技术(苏州)有限公司(中国)；
PM-DK2行星式球磨机，卓的仪器设备(上海)有限公司(上海，中国)；
Mettler Toledo FE20pH meter，梅特勒-托利多公司(瑞士)；
NS-90纳米粒度分析仪，珠海欧美克仪器有限公司(珠海，中国)；
安捷伦1100HPLC高效液相色谱仪，安捷伦科技有限公司(美国)；
API 4000三重四极杆质谱仪(美国Applied Biosystems公司)；
STY-1A渗透压测定仪，天津市天大天发科技有限公司(天津，中国)。
本发明制剂的性质检测方法如下
粒径检测方法：
将1mL实施例或对比例制备得到的样品转移至样品池中，检测温度设置为40℃，将样品池放入NS-90纳米粒度分析仪，开始检测。每个样品重复检测3次，取3次检测结果的平均值为该样品检测结果为粒度(以光强分布，及占比％)和多分散指数(PdI，Polydispersity Index)表示。
渗透压检测方法：
测量溶液的冰点下降来测定其渗透压摩尔浓度。操作：清洗STY-1A渗透压测定仪探头：取三份100μL蒸馏水至3只样品管中，待仪器预热后，将装有100μL蒸馏水的样品管旋上仪器探头，选择清洗3次，点击“清洗”，重复三次。检测：在仪器信息表中填入样品信息后，点击“测试”；用移液 枪移取100μL样品至样品管中，轻轻旋上仪器，点击“启动”检测。重复检测三次，取3次检测结果的平均值为检测结果。
pH值检测方法：
FE20型酸度计分别用pH缓冲溶液(pH分别为4.00、6.86和9.18)校准，电极用纯净水冲洗后，用无纤维纸吸去多余水份，浸入待检测液体样品中按读数键开始测量，在读数稳定后所得数据，即为样品pH值。
检测得到的溶液若pH<5，或>9，则需要用酸或碱调节至pH6～8，常用的pH调节剂为NaOH和HCl，磷酸和磷酸盐(如磷酸二氢钠、磷酸氢二钠)，柠檬酸和柠檬酸盐(如柠檬酸钠)，硼酸和硼砂；检测所得液体的渗透压如未达到等渗，则添加适量氯化钠，使其达到或接近等渗。
除另有说明外，递送药物到达眼后段的效果验证方法如下：
试验仪器设备：高效液相色谱仪，型号：LC-20AD(日本岛津)；质谱仪：型号：API4000三重四极杆质谱仪(美国Applied Biosystems公司)；色谱柱：Fortis Pace C18 5μM,2.1X30mm(英国Fortis公司)。
大鼠：选用健康成年Sprague Dawley(SD)大鼠，分为受试剂组和对照组，每组6只眼，受试剂组滴加本发明实施例制备的眼用制剂，对照组滴加2mg药物/5mL生理盐水的混悬液(使用前涡旋振摇均匀)，每只眼睛20μL。给药后于0.5小时或1小时后安乐死处理动物，迅速采集玻璃体，玻璃体样品匀浆处理后，于-80℃保存。取10μL玻璃体匀浆，加入90μL 95％乙醇，超声2分钟，涡旋混合1分钟，得玻璃体匀浆液；取50μL匀浆液，加入175μL甲醇，涡旋混合3min，4℃ 12000rpm离心10min，取上清液用0.45μm的针头式过滤器过滤，滤液用于LC/MS/MS(正离子模式，MRM SCAN)分析。
新西兰兔：选用健康3～4月龄雄性新西兰兔，体重2.0～2.5k g，分为两组，每组4只眼睛。抓取新西兰兔至操作台上，待动物安静后，1组动物眼(空白对照)滴生理盐水各30μl；另一组动物眼各滴受试物30μl，于1小时后安乐处死动物，迅速采集双眼房水及玻璃体，保存于-80℃。
取新西兰兔房水样品50μl，加入50μl 75％乙腈-水，内标(咪达唑仑20ng/ml乙腈溶液)150μL，涡旋混合10min，4℃10000rpm离心5min，取上清液用于LC-MS/MS分析。取新西兰兔玻璃体样品匀浆后，取100μl，加入100μl 75％乙腈-水，内标(50ng/ml乙腈溶液)50μL，涡旋混合10min，4℃10000rpm离心5min，取上清液用于LC-MS/MS(正离子模式，MRM SCAN)分析。
实施例1：本发明眼用制剂的制备
按照表1称取0.24g CMC-Na(羧甲基纤维素钠，离子型高分子)加到含有40mL纯净水的玻璃三角瓶中，开启磁力搅拌2小时，得溶液1；分别称取1.0g聚山梨酯80(表面活性剂)和0.24g HPMC(羟丙基甲基纤维素，增黏剂)加到含有60mL纯净水的玻璃三角瓶中，开启磁力搅拌、水浴加热40℃ 左右1.5小时，得溶液2；称取40mg地塞米松和4.0mL PEG400(即表面活性剂用量的4.3倍(w/w))投入到溶液2，继续加热搅拌30分钟，加入溶液1，搅拌30分钟，得混合液；将混合液用分散机在转速9500转分散5分钟，停机待泡沫消失后，用布氏漏斗减压过滤，得分散液；将分散液转移至高压均质机，控制温度15±5℃，在压力400Bar左右均质3分钟，然后提高压力至>800Bar均质25分钟，减压至300Bar均质2分钟后排出，得到无色澄明溶液，进一步减压过滤除菌并除去机械杂质得到除杂后的无色澄明溶液。
pH和渗透压调节：加700mg NaH 2PO 4和400mg Na 2HPO 4调节pH至pH＝6.3；加氯化钠调节渗透压至282mOsmol/kg。
HPLC检测：检测仪器：安捷伦1100高效液相色谱仪；操纵软件：OpenLab CDS c.01.10(201)Chemstation Edition；
色谱条件：色谱柱为Waters XBridge C18 5μm,4.6x250mm；柱温35℃，流速1.0mL/min，检测波长240nm，流动相：0.1％磷酸水溶液(72.0％)-乙腈(28.0％)等度洗脱。样品用流动相5倍稀释后取10μL注入液相色谱仪。检测结果：96.2％。
粒度为20.6nm(85.6％)，PdI：0.266。室温避光保存1月，该样品外观和含量无变化。
滴眼后0.5小时动物玻璃体地塞米松浓度为：53.4(ng/g)，RSD：36.6％。对照组滴加2mg地塞米松/5mL生理盐水的混悬液(使用前涡旋振摇均匀)，每只眼睛20μL，对照组滴眼后0.5小时动物玻璃体中未检测到地塞米松(低于检测限，<1ng/g)。
实施例2：
制备方法参照实施例1，原料及用量如表1所示。得到除杂后的无色澄明溶液。
pH调节：用0.2N NaOH或/和0.1N HCl调节至pH6.5。
HPLC检测方法同实施例1，HPLC含量检测结果：95.1％,粒径12.9nm(92.1％)，PdI：0.509；稳定性较好，室温避光放置1个月外观和含量无明显变化；2个月后出现少量沉淀。
滴眼后1小时大鼠玻璃体API浓度为：13.9ng/g，RSD：17.2％。
实施例3：
制备方法参照实施例1，原料及用量如表1所示得到除杂后的微黄色澄明溶液后，加氯化钠调节渗透压至：273mOsmol/kg。
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％甲酸水溶液,流动相B:ACN。Temp.：35℃,检测波长：296nm，Flowrate:0.8ml/min；梯度洗脱程序：0-2’:95％A-5％B,15’:55％A-45％B,18-21’:35％A-65％B,23’:95％A-5％B。检测结果：98.2％。
粒径13.2nm(81.2％)和57.7nm(13.1％)，PdI：0.431；稳定性好，在 40℃避光放置20天，外观及含量无明显变化；
滴眼后0.5小时大鼠玻璃体API浓度为：315ng/g，RSD：29.4％。
滴眼后0.5小时新西兰兔玻璃体API浓度为：142ng/g，RSD：34.3％。
实施例4：
制备方法参照实施例3，得到除杂后的微黄色澄明溶液，原料及用量如表1所示。
检测结果：16.6nm(96.2％)，PdI：0.229。
HPLC检测方法同实施例3，检测结果：97.5％；稳定性好，在40℃避光放置20天，外观及含量无明显变化。
实施例5：
制备方法参照实施例1，原料及用量如表1所示，得到除杂后的无色澄明溶液后，用0.1N NaOH调节pH6.5。
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:40mM醋酸铵水溶液(pH5.0)，流动相B：MeOH，Temp.：35℃,检测波长：233nm，Flowrate:0.8ml/min；梯度洗脱程序：0-2’:100％A,20-22’:60％A-40％B,23’:100％A。检测结果：97.4％；
粒径11.8nm(71.6％)，PdI：0.519。室温避光放置1个月，外观及含量无明显变化。
实施例6：
制备方法参照实施例5，原料及用量如表1所示，得到除杂后的无色澄明溶液后，用1N柠檬酸钠溶液调节至pH6.5，加氯化钠调节渗透压至：297mOsmol/kg。
HPLC检测：Column:ZORBAX 300SB-CN,2.1x150mm，5μm；流动相:40mM KH 2PO 4(pH4.5)：甲醇(75:25)等度洗脱，Temp.：35℃,检测波长：233nm，Flowrate:0.8ml/min；检测结果：99.1％。
粒径21.6nm(94.4％)，PdI：0.206；室温避光放置2个月，外观及含量无明显变化。
滴眼后0.5小时动物玻璃体API浓度为：39.8±16.6ng/g。
实施例7：
制备方法参照实施例5，原料及用量如表1所示，得到除杂后的无色澄明溶液，pH检测结果：6.9，无需调节。
HPLC检测方法参照实施例5，检测结果：98.6％；粒径16.6nm(98％)，PdI：0.227，室温避光放置2个月，外观及含量无明显变化。
实施例8：
制备方法参照实施例5，原料及用量如表1所示，得到除杂后的无色澄明溶液，pH检测结果：6.5，无需调节。
HPLC检测方法参照实施例5，检测结果：97.8％。粒径17.1nm(55.5％)，513(36.3％)，PdI：0.795；室温避光放置1个月，外观及含量无明显变化。
实施例9：
制备方法：称取60mg CMC-Na加到含有15mL纯水的玻璃三角瓶中，开启磁力搅拌2小时，得溶液1；分别称取0.24g聚山梨酯80和0.12g HPMC(增黏剂)加入到含有15mL纯水的另一个玻璃三角瓶中，开启磁力搅拌、水浴加热40℃左右3小时，得溶液2；称取15mg硫辛酸和1mL丙三醇(相当于表面活性剂用量的5.25倍(w/w))投入到溶液2，继续加热搅拌30分钟后，加入溶液1，搅拌30分钟，得混合液；将混合液用分散机在转速11,000转分散3分钟，停机后待溶液泡沫消失后转入高压均质机均质处理(条件参照实施例1)得到无色澄明溶液，然后减压过滤除菌并除去机械杂质，得到除杂后的无色澄明溶液；
pH和渗透压调节方法：用0.1N柠檬酸钠溶液调节至pH6.3，加氯化钠调节渗透压至：294mOsmol/kg；
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％磷酸(pH3.0),B:甲醇-乙腈(1:1)。Temp.：35℃,检测波长：215nm，Flowrate:0.8ml/min；梯度洗脱程序：0-5’:60％A-40％B,28-30’:40％A-60％B；检测结果：97.4％。粒度检测结果：17.8nm(98.6％)，PdI：0.222；3～8℃避光放置1个月外观和含量无变化。
滴眼后0.5小时大鼠玻璃体API浓度为：52.6±17.9ng/g。
对照组滴加2mg硫辛酸/5mL生理盐水的混悬液(使用前涡旋振摇均匀)，每只眼睛20μL，对照组滴眼后0.5小时动物玻璃体中未检测到硫辛酸(低于检测限，<1ng/g)。
实施例10：
制备方法及pH、渗透压调节方法参照实施例5，原料及用量如表1所示，得到除杂后的无色澄明溶液。
HPLC检测方法同实施例5，HPLC检测结果：98.4％
检测结果：粒径348nm(85％)，PdI：0.422。
室温避光放置1个月外观和含量无变化，1个月无明显变化，2个月后出现少量沉淀。
实施例11：
制备方法和pH、渗透压调节方法参照实施例9，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的6.2倍(w/w)。
HPLC检测波长233nm，其余检测方法同实施例9，检测结果：98.1％； 粒径25.8nm(87.4％)，PdI：0.317，3～8℃避光放置1个月，外观和含量无变化。
实施例12：
制备方法和pH、渗透压调节方法参照实施例9，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的8.9倍(w/w)。
HPLC检测方法同实施例9，检测结果：95.2％；粒径31.5nm(82.9％)，PdI：0.347。3～8℃避光放置1个月，外观和含量无变化。
实施例13：
制备方法参照实施例1，原料及用量如表1所示，得到除杂后的微黄色澄明溶液。
pH、渗透压调节：用0.1N NaOH调节至pH6.3，加氯化钠调节渗透压至：297mOsmol/kg；
HPLC检测波长280nm，其余检测方法同实施例1，检测结果：97.3％；粒径16.7nm(98.1％)，PdI：0.225；室温避光放置1个月，外观和含量无变化。
滴眼后0.5小时大鼠玻璃体API浓度为：66.5±18.1ng/g。
对照组滴加2mg多西环素/5mL生理盐水的混悬液(使用前涡旋振摇均匀)，每只眼睛20μL，对照组滴眼后0.5小时动物玻璃体中未检测到多西环素(低于检测限，<1ng/g)。
实施例14：
制备方法和pH、渗透压调节方法参照实施例13，原料及用量如表1所示，得到除杂后的微黄色澄明溶液。
HPLC检测方法同实施例13，HPLC含检测结果：98.2％；粒径17.2nm(97.9％)，PdI：0.208；室温避光放置1个月，外观和含量无变化。
实施例15：
制备方法和pH、渗透压调节方法参照实施例13，助溶剂的加入是：称取1.5mL丙二醇(相当于表面活性剂的10倍(w/w))与表面活性剂一起加入介质水中，磁力搅拌，水浴加热溶解得到溶液2，得到除杂后的微黄色澄明溶液，原料及用量如表1所示。
HPLC检测方法同实施例13，检测结果：95.2％；粒径29.7nm(89.3％)，PdI：0.382；3～8℃避光放置1个月，有絮状物出现。
实施例16：
制备方法和pH、渗透压调节方法参照实施例9，原料及用量如表1所示。
HPLC检测方法参照实施例9，检测结果：0.486mg/mL(二甲双胍)、 0.481mg/mL(硫辛酸)；粒径18.9nm+302.1nm，PdI：0.529；3～8℃避光放置1个月，外观和含量无变化。
滴眼后0.5小时动物玻璃体API浓度为：86.5ng/g硫辛酸，69.5ng/g二甲双胍。
实施例17：
制备方法和pH、渗透压调节方法参照实施例9，原料及用量如表1所示。
HPLC检测方法参照实施例9，检测结果：0.487mg/mL(多西环素)、0.478mg/mL(硫辛酸)；粒径20.2nm+251.6nm，PdI：0.701，3～8℃避光放置1个月，外观和含量无变化。
滴眼后0.5小时大鼠玻璃体API浓度为：57.3ng/g硫辛酸，68.4ng/g二甲双胍。
实施例18：
制备方法参照实施例1，原料及用量如表1所示，得除杂后的无色澄明溶液后，加氯化钠调节渗透压至：301mOsmol/kg；pH检测结果：6.6无需调节。
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％磷酸,流动相B:乙腈，Temp.：35℃,检测波长：260nm，Flowrate:0.8ml/min；梯度洗脱程序：0-2’:95％A-5％B,20-25’:65％A-35％B,28’:95％A-5％B；检测结果：98.2％。粒径20.3nm(83.6％)，PdI：0.249；室温放置1个月，外观和含量无变化。
滴眼后1小时新西兰兔玻璃体API浓度为：138ng/g，房水中浓度为681ng/g。
实施例19：
制备方法和pH、渗透压调节方法参照实施例1，原料及用量如表1所示，得到除杂后的微黄色澄明溶液。
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％磷酸,流动相B:甲醇(80：20)等度洗脱，Temp.：35℃,检测波长：280nm，Flowrate:0.8ml/min；检测结果：98.4％。粒径39.7nm(95.5％)，PdI：0.318；室温避光放置1个月，外观和含量无变化。
滴眼后0.5小时大鼠玻璃体API浓度为：78.3ng/g。
实施例20：
制备方法和pH、渗透压调节参照实施例19，原料及用量如表1所示。得到除杂后的微黄色澄明溶液。
HPLC检测方法同实施例19，检测结果：97.8％；粒径：46.2nm(95.5％)，PdI：0.343；在室温避光放置1个月外观和含量明显无变化。
实施例21：
制备方法参照实施例1，原料及用量如表1所示，得到除杂后的无色澄明溶液，加氯化钠调节渗透压至271mOsmol/kg；pH检测结果：6.6，无需调节。
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相:0.1％H 3PO 4-乙睛(85:15)等度洗脱，Temp.：35℃,检测波长：217nm，Flowrate:0.7ml/min；检测结果：99.6％。粒径15.2nm(93.4％)，PdI：0.227；在室温避光放置1个月，外观和含量明显无变化。
滴眼后0.5小时大鼠玻璃体API浓度为：79.4(ng/g)。
实施例22：
制备方法参照实施例21，原料及用量如表1所示，得到除杂后的无色澄明溶液，加氯化钠调节渗透压至265mOsmol/kg；pH检测结果：6.5，无需调节。
HPLC检测方法同实施例21，检测结果：98.3％；粒径11.9(91.9％)nm，PdI：0.206；在室温避光放置1一个月外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：46.2(ng/g)。
实施例23：
制备方法参照实施例9；原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的4.5倍(w/w)，pH为6.5，接近等渗，无需调节。
HPLC检测方法：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％磷酸,B:乙腈(80:20)，等度洗脱；Temp.：35℃,检测波长：306nm，Flowrate:0.8ml/min；检测结果：95.7％；
粒径27.5nm(77.9％)，PdI：0.328；3～8℃避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：20.3±9.3ng/g。
实施例24：
制备方法参照实施例23，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的4.5倍(w/w)，得到除杂后的无色澄明溶液。
pH为6.6，无需调节pH；渗透压调节：加氯化钠调节渗透压至：293mOsmol/kg；
HPLC检测方法参照实施例14，检测结果：96.1％；
粒径24.5nm(85.5％)，PdI：0.253；3～8℃避光放置1个月，外观和含量无明显变化。
实施例25：
制备方法参照实施例23，原料及用量如表1所示，其中助溶剂丙三醇的用量为表面活性剂的4.5倍(w/w)，得到除杂后的无色澄明溶液。
pH为6.4，无需调节pH；渗透压调节：加氯化钠调节渗透压至305mOsmol/kg；
HPLC检测方法参照实施例14，检测结果：94.7％；
粒径26.2nm(75.2％)，PdI：0.325；3～8℃避光放置1个月，外观和含量无明显变化。
实施例26：
制备方法参照实施例23，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的4.5倍(w/w)，得到除杂后的无色澄明溶液。
pH、渗透压调节：用0.2N NaOH调节至pH6.2，加氯化钠调节渗透压至：305mOsmol/kg；
HPLC检测方法参照实施例14，检测结果：95.3％；
粒径22.7nm(83.4％)，PdI：0.372；3～8℃避光放置1个月，外观和含量无明显变化。
实施例27：
制备方法参照实施例1，原料及用量如表1所示，得到除杂后的无色澄明溶液，用1M柠檬酸钠水溶液调节至pH6.2，加氯化钠调节渗透压至：307mOsmol/kg；
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:水：流动相B:甲醇，Flowrate:0.8ml/min；梯度洗脱程序：0-10’:100％A-0％B,15’:55％A-45％B,18-21’:35％A-65％B；Temp.：30℃,检测波长：255nm；纯度检测结果：99.2％；粒径19.6nm(75.9％)，PdI：0.424；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：580ng/g。
实施例28：
制备方法参照实施例9，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的5倍(w/w)，得到除杂后的无色澄明溶液。
pH、渗透压调节：用0.1N NaOH调节至pH6.3，加氯化钠调节渗透压至：290mOsmol/kg；
HPLC检测方法参照实施例9，检测结果：96.1％；
粒径23.7nm(84.2％)，PdI：0.323；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：62.5ng/g。
实施例29：
制备方法参照实施例1，原料及用量如表1所示，其中助溶剂PEG400的用量为表面活性剂的5倍(w/w)，得到除杂后的无色澄明溶液。
pH和渗透压调节：用1M Na 2HPO 4溶液调节至pH6.2，加氯化钠调节渗透压至：295mOsmol/kg；
HPLC检测方法同实施例1，检测结果：97.3％；粒径22.4nm(91.4％)，PdI：0.293；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：42.7ng/g。
实施例30：
制备方法参照实施例9，原料及用量如表1所示,其中助溶剂丙二醇的用量为表面活性剂的4.2倍(w/w)，得到除杂后的无色澄明溶液。
pH、渗透压调节：用0.1N NaOH调节至pH6.3，加氯化钠调节渗透压至：288mOsmol/kg；
HPLC检测方法参照实施例9，检测结果：95.6％；粒径24.1nm(81.5％)，PdI：0.357；室温避光放置1个月，外观和含量无明显变化。
实施例31：
制备方法参照实施例5，原料及用量如表1所示，其中助溶剂丙二醇的用量为表面活性剂的5.2倍(w/w)，得到除杂后的无色澄明溶液。
pH、渗透压调节：用0.2N NaOH调节至pH6.3，加氯化钠调节渗透压至：310mOsmol/kg；
HPLC检测方法参照实施例5，检测结果：97.2％；粒径27.5nm(79.6％)，PdI：0.364；室温避光放置1个月，有可见微粒。
实施例32：
制备方法参照实施例1，原料及用量如表1所示。得到除杂后的无色澄明溶液，用1M柠檬酸钠溶液调节至pH6.2，加氯化钠调节渗透压至308mOsmol/kg；
HPLC检测：Column:ZORBAX Eclipse Plus C18,4.6x100mm 3.5μm；流动相A:0.1％磷酸水溶液,流动相B:甲醇。Temp.：35℃,检测波长：280nm，Flowrate:0.8ml/min；梯度洗脱程序：0-2’:85％A-15％B,15-20’:35％A-65％B,22-25’:15％A-85％B；检测结果：95.3％；粒径17.6nm(93.9％)，PdI：0.229；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：185.3ng/g。
实施例33：
制备方法参照实施例9，原料及用量如表1所示，其中助溶剂蓖麻油的用量为表面活性剂的3倍。
HPLC检测波长280nm，其余条件同实施例9，检测结果：94.7％，粒径 19.7nm(86.4％)，PdI：0.331；pH 6.8；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：37.6(ng/g)。
实施例34
制备方法参照实施例1，原料及用量如表1所示，得到除杂后的无色澄明溶液。pH6.5无需调节；
HPLC检测波长245nm，其余检测条件同实施例1，检测结果：98.1％；粒径18.6nm(96.9％)，PdI：0.257；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：43.8ng/g。
实施例35：
原料及用量如表1所示，制备方法参考实施例1。得到除杂后的无色澄明溶液。
检测结果：粒径18.6nm(96.5％)，PdI：0.218；
HPLC含量检测结果：97.2％；
室温避光放置1个月后，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：5.1ng/g。
实施例36：
原料及用量如表1所示，制备方法参考实施例1。助溶剂PEG400加入的质量与表面活性剂相等(1:1(w/w))，得到除杂后的无色澄明溶液。
检测结果：粒径19.6nm(97.0％)，PdI：0.289；pH6.33，渗透压：275mOsmol/kg；HPLC含量检测结果：N/A.
室温避光放置1个月后，外观和含量无明显变化。
对比例1
制备方法和检测方法参照实施例1，原料及用量如表1所示。
检测结果：粒径10.0nm(98.8％)，PdI：0.363，稳定性：阴凉处放置1个月后有沉淀。
对比例2
制备方法和检测方法参照实施例1，原料及用量如表1所示。
检测结果：粒径196nm(61.6％)，PdI：0.828，稳定性：阴凉处放置1个月，有絮状沉淀产生。取其上清液检测粒径结果：530nm(53.9％)和225nm(46.1％)，PDI：1.00，
实施例37：
按照表2称取0.25g聚维酮(PVP)K30加到含有15mL纯净水的玻璃三角瓶中，磁力搅拌2小时，得溶液1；分别称取60mg HPMC和60mg聚维酮(PVP)K12加入到含有15mL纯净水的另一玻璃三角瓶中，开启磁力搅拌、水浴40℃加热2小时，得溶液2；称取36mg盐酸莫西沙星投到溶液2，继续加热搅拌30分钟，加入溶液1，搅拌30分钟，得混合液；用实施例3相同的分散、高压均质和膜过滤操作除去细菌和机械杂质，得到除杂后的微黄色澄明溶液，加氯化钠调节渗透压至：285mOsmol/kg；
检测结果：粒径14.0nm(54.2％)，222nm(31.9％)和10.1nm(13.1％)，PdI：0.564；HPLC含量检测结果：96.4％
稳定性：在40℃放置20天，外观和含量无明显变化。粒径增大，检测结果：242nm(77.9％)和18.1nm(12.4％)。
实施例38：
制备方法参照实施例1，原料及用量如表2所示，其中助溶剂PEG400的用量为低聚合度聚维酮的5倍(w/w)。得到除杂后的无色澄明溶液，pH6.5无需调节；
HPLC检测方法同实施例1，检测结果：98.1％；
粒径15.1nm(87.1％)和3.1nm(11.0％)，PdI：0.288；室温避光放置1个月，外观和含量无明显变化。
滴眼后0.5小时大鼠玻璃体API浓度为：5.1ng/g。
实施例39：
原料及用量如表2所示，制备方法和HPLC检测方法参考实施例21。pH检测结果：6.68，无需调节。
HPLC检测结果：99.3％；粒径11.5nm(62.9％)和77.8nm(23.6％)，PdI：0.362；室温避光放置1个月后外观、含量无变化。
实施例40：
原料及用量如表2所示，制备方法参考实施例1。得到除杂后的无色澄明溶液。
HPLC检测方法参照实施例1，检测结果：98.5％；粒径125.6nm(63.5％)、13.6nm(33.1％)，PdI：0.255；室温避光处放置1个月后，形成淡乳液，有白色沉淀。
对比例3
原料及用量如表2所示，制备方法参照实施例1，将中聚合度聚维酮替换为离子型高分子CMC-Na，得到淡白色乳液。
检测结果：粒径1299nm，PdI：0.175，放置过夜，有白色沉淀产生。
通过滴眼给药后大鼠玻璃体内API浓度的测定结果，说明本发明眼用药品可以携载治疗眼病的活性成分穿过眼球结构的屏障，通过结膜囊给药(滴眼给药)的方式即可把有效剂量的药物递送到玻璃体，避免玻璃体注射等侵入性给药方式，还大幅度减少总的药物量，减少药物在全身的吸收，避免产生毒副作用。
表1
Figure PCTCN2021134149-appb-000001
Figure PCTCN2021134149-appb-000002
Figure PCTCN2021134149-appb-000003
表2
Figure PCTCN2021134149-appb-000004
以下通过实验例证明本发明眼用制剂载体或辅料的有益效果。
实验例1、本发明载体的透射电镜观察结果
透射电子显微镜(JEM-2100Plus，日本JEOL公司)
吸取1滴实施例3-1制备的液体样品于铜质样品网，静置5分钟后吸去多余的液体样品后，自然放干，放置于电镜样品室作检测；样品染色：吸取1滴液体样品于铜质样品网，在除去样品网上多余的样品后，加1滴2％磷钼酸，静置5分钟后吸去多余的液体，自然放干，样品网放置于电镜作检测。结果见图1可以看出，本发明制备的载药载体在溶剂中形成了粒径为1～100nm的球形结构(纳米小体，图1A)，纳米小体又能进一步自组装成粒径为10～2000nm的球体(纳米小球，图1B)。
实验例2、粒径、含量及稳定性检测
1、实验方法
将1mL实施例和对比例制备得到的样品转移至样品池中，检测温度设置为40℃，将样品池放入NS-90钠米粒度分析仪，开始检测。每个样品重复检测3次，取3次检测结果的平均值为该样品检测结果为粒度(以光强分布，及占比％)和多分散指数(PdI，Polydispersity Index)表示。检测后避光保存，观察外观变化并再次检测粒径。
采用安捷伦1100高效液相色谱仪检测本发明制得的眼用制剂样品的HPLC含量。
2、实验结果
见表4、表5：
表4：
Figure PCTCN2021134149-appb-000005
Figure PCTCN2021134149-appb-000006
Figure PCTCN2021134149-appb-000007
Figure PCTCN2021134149-appb-000008
表5：
Figure PCTCN2021134149-appb-000009
上述结果可以看出，本发明制备的载体或辅料可以成功包载多种类型的眼用药物制备成眼用制剂，并且制剂粒径小，HPLC检测药物含量高，长时间放置形态和含量均稳定；说明本发明制备的载体或辅料对眼用药物包封率高，稳定性好。而使用与本发明的辅料原料不同的对比例制得的制剂，稳定性很差，短时间就会出现沉淀或变质现象。
实验例3、本发明载体或辅料制备的眼用制剂的抗病毒实验
1、实验对象：实施例3-27制备的更昔洛韦滴眼给药系统
2、实验方法：
对实施例制备的更昔洛韦滴眼给药系统进行体外抗人巨细胞病毒测试。
选用人巨细胞病毒株HCMV-AD169感染人胚肺成纤维细胞(MRC-5)，以半数有效量(EC50)考察更昔洛韦受试品的抗病毒活性。试验分为4组， 本实施例制备的滴眼给药系统受试组，更昔洛韦原药受试组，阴性对照组(MRC-5细胞)，阳性对照组(MRC-5细胞感染HCMV-AD169)。二个受试组样品用培养液稀释成6个稀释浓度：500、250、125、62.5、31.25、15.63μg/mL，每个稀释度设4个复孔，以细胞病变效应(cytopathic effect,CPE)为指标：0为无细胞病变，1为≤25％细胞病变，2为25-50％细胞病变，3为50-75％细胞病变，4为75-100％细胞病变。用Reed-Muench方法计算半数有效量(EC50)：EC50＝10n；n＝[(有效率大于50％稀释度的对数)+(有效率大于50％的百分数-50％)/(有效率大于50％的百分数-有效率小于50％的百分数)×稀释系数的对数]。
试验过程如下，将MRC-5细胞调整大约为1.5×105/mL，加入96孔板，每孔加100μL培养液，置37℃、5％CO 2细胞培养箱培养，待细胞贴壁成单层后弃上清液，除对照组外，各受试组按预试获得的半数病毒感染细胞量(TC50)的100倍浓度，每孔加入100μL培养2小时，弃上清液，加入100μL一系列受试样品继续培养，观察各孔的CPE，待阳性对照组病变的CPE达到90％以上时，记录各孔CPE，按Reed-Muench方法计算半数有效量(EC50)。
3、实验结果：如表6所示
表6试样品对HCMV-AD169病毒的抑制试验结果
Figure PCTCN2021134149-appb-000010
结论：实施例27制备的更昔洛韦滴眼给药系统与更昔洛韦原药的体外抑制病毒作用没有差别。
以上结果说明将更表明本发明的眼用制剂的载体或辅料作为滴眼给药的药物载体，不会影响其携载(包裹)的治疗眼病的活性成分的药效。
实验例4、本发明载体或辅料制备的眼用制剂的体外抑菌实验
1、实验对象：实施例3-3制备的莫西沙星滴眼给药系统。
1.1实验方法：
对实施例制备的莫西沙星滴眼液给药系统进行体外抑菌试验(MIC)，取莫西沙星原料药作为对照品，实施例6制得的莫西沙星滴眼给药系统作为受试品，制作成药敏板，使药敏板上含7～8个倍比稀释浓度的莫西沙星原料药(对照品)和受试剂。接种环挑取经18h～24h孵育后的菌株(25株)，于无菌生理盐水中，调制成相当于0.5麦氏浊度的菌悬液；加入到液体药敏试验培养基，菌液和液体培养基的比例为1:200，充分混匀，每孔加入100μL稀释后的菌液；在35℃±2℃环境孵育16h～20h；通过浊度判断各孔内细菌的生长情况，由低浓度向高浓度观察，能抑制细菌生长的最低药物浓度即为该药的MIC。
1.2实验结果：如表7所示
表7莫西沙星滴眼液给药系统药敏试剂(微量肉汤稀释法)试验结果
Figure PCTCN2021134149-appb-000011
Figure PCTCN2021134149-appb-000012
结论：实施例3制备的制得的莫西沙星滴眼给药系统与对照相比其抑菌作用无显著性差异。
以上结果说明，本发明的眼用制剂的载体或辅料作为滴眼给药载体，不会影响其携载(包裹)的治疗眼病的活性成分的性质与效果。
综上，本发明提供了一种眼用制剂的载体或辅料及其应用。本发明眼用制剂的载体或辅料作为滴眼给药载体不会影响其携载(包裹)的治疗眼病的活性成分的性质与效果，能够包裹药物穿过眼前段，将药物高效输送到眼后段发挥治疗作用，实现了通过滴眼给药治疗眼底疾病的目标，解决了眼用制剂给药领域一直期限亟待解决但未解决的技术问题，具有极为优良的临床使用价值和非常积极的社会意义。

Claims (33)

  1. 一种眼用制剂的载体或辅料，其特征在于，它含有如下成分：表面活性剂和离子型高分子，还含有溶剂。
  2. 根据权利要求1所述的眼用制剂的载体或辅料，其特征在于，所述表面活性剂、离子型高分子的质量比为：(1～100):(0.1～50)；所述表面活性剂与溶剂的比例为：每100mL溶剂含5～3000mg表面活性剂；
    优选地，所述表面活性剂、离子型高分子的质量比为(1～31):(1～7.5)；所述表面活性剂与溶剂的比例为：每100mL溶剂含50～3000mg表面活性剂。
  3. 根据权利要求1或2所述的眼用制剂的载体或辅料，其特征在于：所述表面活性剂为非离子型表面活性剂。
  4. 根据权利要求3所述的眼用制剂的载体或辅料，其特征在于：所述非离子型表面活性剂为司盘类、聚山梨酯、泊洛沙姆、烷基葡萄糖苷、维生素E聚琥珀酸乙二醇酯、蔗糖硬脂酸酯或氮酮。
  5. 根据权利要求1或2所述的眼用制剂的载体或辅料，其特征在于：所述离子型高分子选自羧甲基纤维素及其盐、羟基乙酸淀粉钠、透明质酸及其盐、黄原胶、海藻酸及其盐、二乙酸聚乙二醇PEG-(COOH) 2中的至少一种。
  6. 一种眼用制剂的载体或辅料，其特征在于，它含有如下成分：低聚合度聚维酮和中聚合度聚维酮，还含有溶剂。
  7. 根据权利要求6所述的眼用制剂的载体或辅料，其特征在于，所述低聚合度聚维酮、中聚合度聚维酮的质量比为：(0.1～10):1，所述低聚合度聚维酮与溶剂的比例为：每100mL溶剂含5～3000mg低聚合度聚维酮；
    优选地，所述低聚合度聚维酮、中聚合度聚维酮的质量比为：(0.24～1):1，所述低聚合度聚维酮与溶剂的比例为：每100mL溶剂含400～840mg低聚合度聚维酮。
  8. 如权利要求6或7所述的眼用制剂的载体或辅料，其特征在于，所述低聚合度聚维酮为重均分子量为2000～5000Dalton的聚维酮，所述中聚合度聚维酮为重均分子量为20000～60000Dalton的聚维酮。
  9. 如权利要求6或7所述的眼用制剂的载体或辅料，其特征在于，所述低聚合度聚维酮是重均分子量为3500Dalton的聚维酮PVP K12，所述中聚合度聚维酮是重均分子量为35000～50000Dalton的聚维酮PVP K30。
  10. 根据权利要求1～9任一项所述的眼用制剂的载体或辅料，其特征在于：所述溶剂为极性溶剂。
  11. 根据权利要求10所述的眼用制剂的载体或辅料，其特征在于：所述极性溶剂为水。
  12. 根据权利要求1～11任意一项所述的眼用制剂的载体或辅料，其特征在于：它还含有如下成分：增粘剂和/或助溶剂；
    优选的，所述增粘剂为聚乙二醇、卡波姆、泊洛沙姆、聚维酮、羟丙基纤维素、羟乙基纤维素、甲基纤维素、聚乙烯醇、黄原胶、聚氧乙烯脂肪醇类、透明质酸及其盐或羟丙基甲基纤维素中的至少一种，所述助溶剂为丙二醇、丙三醇、液态聚乙二醇、氢化蓖麻油或蓖麻油；所述增粘剂和表面活性剂的质量比为1:(0.1～100)，助溶剂和表面活性剂的质量比为(1～10):1；所述增粘剂和低聚合度聚维酮的质量比为1:(0.1～100)，助溶剂和低聚合度聚维酮的质量比为(1～10):1；
    更优选地，所述增粘剂和表面活性剂的质量比为1:(0.1～30)；所述增粘剂和低聚合度聚维酮的质量比为1:(0.1～30)。
  13. 根据权利要求1～12任一项所述的眼用制剂的载体或辅料，其特征在于，它含有纳米小体，所述纳米小体为球形，其粒径为1～100nm；所述纳米小体由眼用制剂的载体或辅料的成分自组装形成。
  14. 根据权利要求13所述的眼用制剂的载体或辅料，其特征在于：所述纳米小体粒径为5～30nm。
  15. 根据权利要求13或14所述的眼用制剂的载体或辅料，其特征在于：它含有纳米小球，所述纳米小球为球形，其粒径为10～2000nm；所述纳米小球是纳米小体自组装形成的。
  16. 根据权利要求15所述的眼用制剂的载体或辅料，其特征在于：所述纳米小球粒径为100～2000nm。
  17. 一种权利要求1～16任意一项所述的眼用制剂的载体或辅料的制备方法，其特征在于：它是将所述成分和溶剂均匀混合成溶液，然后将溶液进行研磨或均质分散。
  18. 权利要求1～16任意一项所述的眼用制剂的载体或辅料在制备输送药物至眼后段的滴眼给药载体中的用途。
  19. 一种滴眼给药的眼用制剂，其特征在于：它是由权利要求1～16任一项所述眼用制剂的载体或辅料和治疗眼病的活性成分组成的制剂。
  20. 根据权利要求19所述的眼用制剂，其特征在于，所述眼用制剂的载体或辅料中的表面活性剂和治疗眼病的活性成分的质量比为(1～30):(1～2)；
    或，所述眼用制剂的载体或辅料中的低聚合度聚维酮和治疗眼病的活性成分的质量比为(6～40):1。
  21. 根据权利要求19所述的眼用制剂，其特征在于：所述眼用制剂的载体或辅料含有纳米小体，所述治疗眼病的活性成分包裹于纳米小体中。
  22. 根据权利要求21所述的眼用制剂，其特征在于：所述纳米小体为球形，其粒径为1～100nm，优选的，其粒径为5～30nm。
  23. 根据权利要求19～22所述的眼用制剂，其特征在于：所述治疗眼病的活性成分包括小分子化合物类药物、或其游离酸、或其游离碱、或其药学上可接受的盐；
    优选地，所述小分子化合物类药物包括核苷类抗病毒药物、降眼压药物、抗生素类药物、抗氧化类药物、抗炎症类药物、毒蕈碱型受体阻断剂药物、免疫抑制剂类药物、糖皮质激素类药物；
    更优选地，所述核苷类抗病毒药物包括更昔洛韦、阿昔洛韦、喷昔洛韦、西多呋韦、福米韦生、洛布卡韦；
    所述降眼压药物包括碳酸酐酶抑制剂，更优选地，为布林佐胺、乙酰唑胺、醋甲唑胺；
    所述抗生素类药包括阿米卡星、头孢曲松、头孢唑林、苯唑西林、左氧氟沙星、环丙沙星、莫西沙星、万古霉素；
    所述抗炎症类药物包括：土霉素；
    所述抗氧化类包括牛磺酸，花青素，木质素；
    所述毒蕈碱型受体阻断剂药物包括阿托品、东莨菪碱、山莨菪碱；
    所述免疫抑制剂类药物包括：环孢素(cyclosporin)、他克莫司(tacrolimus)、西罗莫司(sirolimus)、依维莫司(everolimus)、吗替麦考酚酯(mycophenolate mofetil)、氨甲喋呤、硫唑嘌呤及环磷酰胺；
    所述糖皮质激素类药物包括可的松、强的松、强的松龙、甲基强的松龙、氟羟强的松龙、曲安奈德。
  24. 一种制备19～23任意一项所述的眼用制剂的方法，其特征在于：包括以下步骤：
    (1)将表面活性剂、和/或增粘剂加入溶剂中配制成溶液；
    (2)将治疗眼病的活性成分和/或助溶剂分散在步骤(1)得到的溶液中，再加入离子型高分子或其溶液，分散混合得到初悬液；
    (3)将步骤(2)得到的初悬液搅拌分散或均质分散，即得；
    或包括以下步骤：
    (a)将低聚合度聚维酮、和/或增粘剂加入溶剂中配制成溶液；
    (b)将治疗眼病的活性成分和/或助溶剂分散在步骤(a)得到的溶液中，再加入中聚合度聚维酮或其溶液，分散混合得到初悬液；
    (c)将步骤(b)得到的混合液研磨或均质分散，即得。
  25. 如权利要求24所述的制备方法，其特征在于，步骤(2)或步骤(b)中所述分散选自机械搅拌分散、磁力搅拌分散、涡旋振摇分散、剪切分散、均质分散、研磨分散、超声分散中的至少一种。
  26. 权利要求19～23任意一项所述的眼用制剂在制备治疗眼部疾病的药物中的用途。
  27. 根据权利要求26所述的用途，其特征在于：所述眼用制剂是治疗眼底疾病，和/或治疗眼后段病毒感染性疾病，和/或治疗眼后段慢性炎症，和/或降眼压，和/或眼部疼痛，和/或抗眼内细菌或真菌感染的眼用制剂，和/或用于青少年近视、假近视的防治的眼用制剂，和/或治疗自身免疫性疾病的眼用制剂，和/或治疗眼前部疾病的眼用制剂，和/或抑制肿瘤生长的眼用制剂。
  28. 根据权利要求27所述的用途，其特征在于：
    所述治疗眼底疾病的眼用制剂包括治疗眼底血管性疾病所致的黄斑水肿、炎性水肿、炎性疼痛的眼用制剂；更优选地，为治疗视网膜中央静脉阻塞性黄斑水肿、视网膜分支静脉阻塞性黄斑水肿、糖尿病性视网膜病变、糖尿病性黄斑水肿、病理性近视黄斑水肿、湿性年龄相关性黄斑变性所致黄斑水肿、干性黄斑病变、地图样萎缩、眼内炎、急性视网膜坏死、术后炎性疼痛、葡萄膜炎的眼用制剂；
    所述治疗眼后段病毒感染性疾病的眼用制剂包括治疗巨细胞病毒性葡萄膜炎，病毒性视神经炎，病毒性急性视网膜坏死的眼用制剂；
    所述降眼压的眼用制剂包括治疗急慢性青光眼及其并发症的眼用制剂；
    所述治疗自身免疫性疾病的眼用制剂为治疗眼部免疫性疾病或全身自身免疫性疾病引起的眼部疾病的眼用制剂，优选地，包括治疗Graves眼病，Behoet氏综合征，鸟枪弹丸性视网膜脉络膜病变，干燥综合征，交感性眼炎或肉芽肿性眼病的眼用制剂；
    所述治疗眼前部疾病的眼用制剂包括治疗高危角膜移植术后后遗症或并发症、春季卡他性角结膜炎，蚕蚀性角膜溃疡或顽固性角膜溃疡，单纯疱疹病毒性角膜炎，角膜新生血管形成或角膜翼状胬肉的眼用制剂。
  29. 根据权利要求27所述的用途，其特征在于，所述抗眼内细菌或真菌感染的眼用制剂的活性成分是抗生素；
    所述用于青少年近视、假近视防治的眼用制剂的活性成分是毒蕈碱型受体阻断剂；
    所述治疗自身免疫性疾病的眼用制剂的活性成分是免疫抑制剂。
  30. 一种治疗眼部疾病的方法，其特征在于，对患者使用权利要求19～23任一项所述的眼用制剂。
  31. 根据权利要求30所述的方法，其特征在于，所述眼部疾病是眼底疾病，和/或眼后段病毒感染性疾病，和/或眼后段慢性炎症，和/或高眼压疾病，和/或眼部疼痛，和/或眼内细菌或真菌感染，和/或青少年近视、假近视，和/或自身免疫性疾病，和/或眼前部疾病，和/或眼肿瘤。
  32. 根据权利要求31所述的方法，其特征在于，所述眼底疾病包括眼底血管性疾病所致的黄斑水肿、炎性水肿、炎性疼痛；优选为视网膜中央静脉阻塞性黄斑水肿、视网膜分支静脉阻塞性黄斑水肿、糖尿病性视网膜病变、糖尿病性黄斑水肿、病理性近视黄斑水肿、湿性年龄相关性黄斑变性所致黄斑水肿、干性黄斑病变、地图样萎缩、眼内炎、急性视网膜坏死、术后炎性疼痛、葡萄膜炎；
    所述眼后段病毒感染性疾病包括巨细胞病毒性葡萄膜炎，病毒性视神经炎，病毒性急性视网膜坏死；
    所述高眼压疾病包括急慢性青光眼及其并发症；
    所述自身免疫性疾病为眼部免疫性疾病或全身自身免疫性疾病引起的眼部疾病，优选地，包括Graves眼病、Behoet氏综合征、鸟枪弹丸性视网膜脉络膜病变、干燥综合征、交感性眼炎或肉芽肿性眼病；
    所述眼前部疾病包括高危角膜移植术后后遗症或并发症、春季卡他性角结膜炎，蚕蚀性角膜溃疡或顽固性角膜溃疡，单纯疱疹病毒性角膜炎，角膜新生血管形成或角膜翼状胬肉。
  33. 根据权利要求30所述的方法，其特征在于，所述使用的方式是滴眼给予。
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