Ophthalmic medicine composition, preparation method thereof, ophthalmic medicine box containing ophthalmic medicine composition and application of ophthalmic medicine box

Abstract

The invention relates to an ophthalmic pharmaceutical composition which comprises or consists of the following components in parts by weight: 1 part of an active pharmaceutical ingredient, 0.95-1.25 parts of a liquid matrix and 0.35-0.45 part of a solid matrix, and the particle size D90 of the active pharmaceutical ingredient is less than or equal to 50 microns. The invention also relates to a preparation method of the ophthalmic medicine composition, an ophthalmic medicine box containing the ophthalmic medicine composition, and application of the ophthalmic medicine composition or the ophthalmic medicine box in preparation of medicines for preventing and / or treating eye diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to an ophthalmic pharmaceutical composition, a preparation method thereof, an ophthalmic medicine kit containing the ophthalmic pharmaceutical composition, and use of the ophthalmic pharmaceutical composition or the ophthalmic medicine kit in preparing drugs for preventing and / or treating eye diseases. Background Art

[0002] Anatomically, the eyeball consists of two parts: the anterior segment and the posterior segment. The anterior segment accounts for about 1 / 3 and is composed of the cornea, pupil, iris, aqueous humor, ciliary body and lens, while the posterior segment accounts for about 2 / 3 and is composed of the vitreous body, retina, macula, optic nerve, choroid and sclera. Abnormalities in any part of the eyeball may cause eye diseases, among which retinal phlebitis, diabetic retinopathy, proliferative vitreoretinopathy, choroidal neovascularization, age-related macular degeneration, cystoid macular edema, vitreomacular adhesion, macular holes and other eye diseases are the main causes of vision impairment.

[0003] At present, ocular surface administration and systemic administration are still the main drug delivery methods for the treatment of posterior segment diseases of the eye. However, due to the existence of tear barrier, corneal barrier and conjunctival barrier, it is difficult for ocular surface administration to reach the posterior segment of the eye. Moreover, affected by the blood-aqueous humor and blood-retinal barriers, systemic administration requires large doses and multiple administrations to ensure that the amount of drug reaching the posterior segment of the eye meets the treatment needs.

[0004] Based on this situation, in order to increase the amount of drugs reaching the posterior segment of the eye, periocular injections and intravitreal injections have gradually been adopted. However, the half-life of most drugs in the vitreous is short, and multiple injections are required to maintain the amount of drugs in the vitreous to meet the treatment requirements. This causes pain to patients, reduces patient compliance, and increases the risk of intraocular infection.

[0005] In order to solve the problems caused by multiple injections, sustained-release implants have been used clinically to treat posterior segment diseases of the eye. Sustained-release implants are divided into non-biodegradable and biodegradable types according to the materials. For example, Vitrasert, a ganciclovir implant developed by Australian pSivida for the treatment of cytomegalovirus retinitis, which was approved by the FDA in 1996, uses non-biodegradable materials polyvinyl alcohol and ethylene-vinyl acetate copolymer as controlled-release materials. In 2005, Retisert, a fluocinolone acetonide implant developed by the company mainly for the treatment of non-infectious uveitis, was approved by the FDA for marketing. Retisert uses non-biodegradable materials polyvinyl alcohol and silicone oil as controlled-release materials. Since non-biodegradable sustained-release implants cannot be degraded, they need to be removed through a secondary operation. To solve this problem, biodegradable implants came into being. Commonly used biodegradable sustained-release materials include hypromellose, polylactic acid, polyglycolic acid and polylactic acid-glycolic acid copolymer. Representative products on the market are Allergan's Surodex and Ozurdex. The former is a dexamethasone implant prepared with polylactic acid-glycolic acid copolymer and hypromellose. The preparation can continuously release dexamethasone for 7-10 days and is used for anti-inflammatory treatment after cataract surgery. The latter is a dexamethasone implant prepared with polylactic acid-glycolic acid copolymer and is used for the treatment of macular edema and uveitis.

[0006] However, both non-biodegradable implants and biodegradable implants currently need to be implanted into the eye through surgery or a special drug delivery device (such as Ozurdex equipped with a dedicated injection device). The operation is relatively complicated and also causes certain pain to the patient.

[0007] Furthermore, the use of a dedicated injection device causes inconvenience in operation and increases treatment costs, placing a heavy burden on patients.

[0008] Therefore, there is a need for an ophthalmic drug with a simple administration method and a sustained release effect, which does not require a complex administration device and can be administered by a common simple injection method, and is easy, simple and convenient to inject. The drug is simply and conveniently injected into the lesion site in liquid form, and achieves a slow release effect. Summary of the invention

[0009] The present invention provides an ophthalmic pharmaceutical composition, which can be injected into the eye by a common simple injection method, is convenient for drug administration, and can slowly release active pharmaceutical ingredients in the eye for a long time and can be degraded in the eye. In addition, the ophthalmic pharmaceutical composition has excellent storage stability, and the drug solution is evenly dispersed without stratification, aggregation, or agglomeration.

[0010] In the present invention, a simple injection means that the ophthalmic pharmaceutical composition can be injected into the eye by injection through a syringe prefilled with the ophthalmic pharmaceutical composition, and a small force that meets the requirements of ergonomics can be used to push the drug for injection. Referring to the standard YBB00112004-2015 on prefilled syringe assemblies (with needles), it is specified that the starting force for piston sliding performance should not exceed 25N. Referring to this standard, in the present invention, the starting force for pushing the prefilled syringe (e.g., 1ml syringe barrel) should preferably not exceed 25N.

[0011] The ophthalmic pharmaceutical composition of the present invention comprises the following components, or is composed of the following components:

[0012] 1 part by weight of active pharmaceutical ingredient,

[0013] 0.95-1.25 parts by weight of liquid matrix,

[0014] 0.35-0.45 parts by weight of solid matrix,

[0015] Wherein, the particle size of the active pharmaceutical ingredient satisfies: D 90 ≤50μm.

[0016] The present invention also provides a method for preparing the ophthalmic pharmaceutical composition.

[0017] The present invention also provides an ophthalmic kit comprising the ophthalmic pharmaceutical composition.

[0018] The present invention also provides the use of the ophthalmic pharmaceutical composition or ophthalmic pharmaceutical kit in preparing drugs for preventing and / or treating eye diseases.

[0019] In particular, the present invention is achieved by:

[0020] 1. An ophthalmic pharmaceutical composition comprising the following components:

[0021] 1 part by weight of active pharmaceutical ingredient,

[0022] 0.95-1.25 parts by weight of liquid matrix,

[0023] 0.35-0.45 parts by weight of solid matrix,

[0024] Wherein, the particle size of the active pharmaceutical ingredient satisfies: D 90 ≤50μm.

[0025] 2. The ophthalmic pharmaceutical composition as described in claim 1, wherein the particle size of the active pharmaceutical ingredient satisfies: 1 μm ≤ D 90 ≤50μm.

[0026] 3. The ophthalmic pharmaceutical composition according to any one of statements 1 to 2, which consists of the active pharmaceutical ingredient, the liquid matrix and the solid matrix.

[0027] 4. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein:

[0028] The active drug ingredient is one or a mixture of two or more selected from anti-tumor drugs, anti-inflammatory drugs, immunosuppressants, neovascularization inhibitors and glaucoma treatment drugs.

[0029] 5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, wherein:

[0030] The active pharmaceutical ingredient is selected from chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topotecan, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate, halobetasol propionate Ester, cortisone, hydrocortisone, cyclosporine, rapamycin, tacrolimus, mycophenolic acid, tacrolimus, mizoribine, sulfasalazine, azathioprine, methotrexate, bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, brinzolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole, dasatinib and a mixture of one or more of their pharmaceutically acceptable salts.

[0031] 6. The ophthalmic pharmaceutical composition according to any one of claims 1 to 5, wherein:

[0032] The active pharmaceutical ingredient is selected from one or a mixture of two or more of dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine, and pharmaceutically acceptable salts thereof.

[0033] 7. The ophthalmic pharmaceutical composition according to any one of claims 1 to 6, wherein:

[0034] The liquid matrix is ​​a biodegradable liquid matrix.

[0035] 8. The ophthalmic pharmaceutical composition according to any one of claims 1 to 7, wherein:

[0036] The liquid matrix is ​​one or a mixture of two or more of diethyl succinate, diethyl tartaric acid, dimethyl glutarate, triacetin, polyethylene glycol, glycerol, and propylene glycol.

[0037] 9. The ophthalmic pharmaceutical composition according to claim 8, wherein:

[0038] The polyethylene glycol of the liquid matrix is ​​one or a mixture of two or more polyethylene glycols having a number average molecular weight of 70-750.

[0039] 10. The ophthalmic pharmaceutical composition according to any one of claims 8 to 9, wherein:

[0040] The polyethylene glycol of the liquid matrix is ​​one or a mixture of two or more of PEG-200, PEG-300, PEG-400 and PEG-600.

[0041] 11. The ophthalmic pharmaceutical composition according to any one of claims 1 to 10, wherein:

[0042] The liquid matrix is ​​polyethylene glycol.

[0043] 12. The ophthalmic pharmaceutical composition according to any one of claims 1 to 11, wherein:

[0044] The liquid matrix is ​​polyethylene glycol PEG-400.

[0045] 13. The ophthalmic pharmaceutical composition according to any one of claims 1 to 12, wherein:

[0046] The solid matrix is ​​a biodegradable solid matrix.

[0047] 14. The ophthalmic pharmaceutical composition according to any one of claims 1 to 13, wherein:

[0048] The solid matrix is ​​polyethylene glycol, hydroxycarboxylate polymer, or a mixture of two or more thereof.

[0049] 15. The ophthalmic pharmaceutical composition according to any one of claims 1 to 14, wherein:

[0050] The solid matrix is ​​one or a mixture of two or more of polyethylene glycol, polylactic acid, polyglycolic acid, and polylactic acid-glycolic acid copolymer.

[0051] 16. The ophthalmic pharmaceutical composition according to any one of statements 14-15, wherein:

[0052] The polyethylene glycol of the solid matrix is ​​one or a mixture of two or more polyethylene glycols having a number average molecular weight of 800-20000.

[0053] 17. The ophthalmic pharmaceutical composition according to any one of statements 14 to 16, wherein:

[0054] The polyethylene glycol of the solid matrix is ​​one or a mixture of two or more of PEG-800, PEG-1000, PEG-1500, PEG-2000, PEG-4000, PEG-6000, PEG-8000, PEG-10000 and PEG-20000.

[0055] 18. The ophthalmic pharmaceutical composition according to any one of claims 1 to 17, wherein:

[0056] The solid matrix is ​​polylactic acid-glycolic acid copolymer.

[0057] 19. The ophthalmic pharmaceutical composition according to claim 18, wherein:

[0058] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100.

[0059] 20. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0060] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.02-50.

[0061] 21. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0062] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.05-20.

[0063] 22. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0064] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.1-10.

[0065] 23. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0066] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.2-5.

[0067] 24. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0068] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.5-4.

[0069] 25. The ophthalmic pharmaceutical composition of claim 18, wherein:

[0070] The mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:1-3.

[0071] 26. The ophthalmic pharmaceutical composition of claim 15, wherein:

[0072] The weight average molecular weight of the hydroxycarboxylic acid polymer of the solid matrix is ​​1,000-600,000.

[0073] 27. The ophthalmic pharmaceutical composition of claim 15, wherein:

[0074] The weight average molecular weight of the hydroxycarboxylic acid polymer of the solid matrix is ​​5,000-200,000.

[0075] 28. The ophthalmic pharmaceutical composition of claim 15, wherein:

[0076] The weight average molecular weight of the hydroxycarboxylic acid polymer of the solid matrix is ​​10,000-20,000.

[0077] 29. The ophthalmic pharmaceutical composition according to any one of claims 1 to 28, wherein:

[0078] The molecular weight distribution Mw / Mn of the solid matrix is ​​1.0-10.0.

[0079] 30. The ophthalmic pharmaceutical composition of any one of statements 1 to 29, wherein:

[0080] The molecular weight distribution Mw / Mn of the solid matrix is ​​1.5-5.0.

[0081] 31. The ophthalmic pharmaceutical composition according to any one of items 1 to 30, wherein:

[0082] The active pharmaceutical ingredient is triamcinolone acetonide,

[0083] The liquid matrix is ​​polyethylene glycol PEG-400;

[0084] The solid matrix is ​​polylactic acid-glycolic acid copolymer.

[0085] 32. The ophthalmic pharmaceutical composition of any one of statements 1 to 31, wherein:

[0086] The ophthalmic pharmaceutical composition is an ophthalmic pharmaceutical preparation.

[0087] 33. The ophthalmic pharmaceutical composition of any one of statements 1 to 32, wherein:

[0088] The ophthalmic pharmaceutical composition is an ophthalmic pharmaceutical injection preparation, or a sustained-release insert or implant.

[0089] 34. The ophthalmic pharmaceutical composition of claim 33, wherein:

[0090] The ophthalmic drug injection preparation is an intraocular injection preparation.

[0091] 35. The ophthalmic pharmaceutical composition of claim 33, wherein:

[0092] The ophthalmic drug injection preparation is a subconjunctival injection preparation, an intravitreal injection preparation, a periocular injection preparation, a retrobulbar injection preparation or an intracameral injection preparation;

[0093] 36. The ophthalmic pharmaceutical composition of claim 32, wherein:

[0094] The ophthalmic pharmaceutical preparation is a sustained-release preparation.

[0095] 37. The ophthalmic pharmaceutical composition of any one of statements 1 to 36, wherein:

[0096] The ophthalmic pharmaceutical composition is filled in a prefilled syringe.

[0097] 38. The ophthalmic pharmaceutical composition of claim 37, wherein:

[0098] The filling volume of the ophthalmic pharmaceutical composition is 0.01 ml-10 ml.

[0099] 39. The ophthalmic pharmaceutical composition of claim 37, wherein:

[0100] The filling volume of the ophthalmic pharmaceutical composition is 0.1 ml-2 ml.

[0101] 40. The ophthalmic pharmaceutical composition of any one of statements 1 to 39, wherein:

[0102] The dosage of the ophthalmic pharmaceutical composition is 1 μl-100 μl.

[0103] 41. The ophthalmic pharmaceutical composition of any one of statements 1 to 39, wherein:

[0104] The dosage of the ophthalmic pharmaceutical composition is 2-20 μl.

[0105] 42. The ophthalmic pharmaceutical composition of any one of statements 1 to 41, wherein:

[0106] The sustained release time limit of the ophthalmic pharmaceutical composition is 30 days to 730 days.

[0107] 43. The ophthalmic pharmaceutical composition of any one of statements 1 to 42, wherein:

[0108] The sustained release time limit of the ophthalmic pharmaceutical composition is 60-120 days.

[0109] 44. The ophthalmic pharmaceutical composition of any one of statements 1 to 43, wherein:

[0110] The administration frequency of the ophthalmic pharmaceutical composition is once every 30 days to 730 days.

[0111] 45. The ophthalmic pharmaceutical composition of any one of statements 1 to 43, wherein:

[0112] The ophthalmic pharmaceutical composition is administered once every 60-120 days.

[0113] 46. ​​The ophthalmic pharmaceutical composition of any one of statements 1 to 45, wherein:

[0114] The ophthalmic pharmaceutical composition is in liquid form at normal temperature.

[0115] 47. A method for preparing a pharmaceutical ophthalmic composition according to any one of statements 1 to 46, comprising:

[0116] (1) Providing an active pharmaceutical ingredient that satisfies the particle size relationship defined in any one of claims 1 to 2;

[0117] (2) mixing a solid matrix with a liquid matrix to obtain a mixed matrix; and

[0118] (3) dispersing the active pharmaceutical ingredient provided in step (1) in the mixed matrix obtained in step (2).

[0119] 48. The method of claim 47, wherein:

[0120] In step (2), a mixed matrix is ​​obtained by dissolving a solid matrix in a liquid matrix.

[0121] 49. The method of any one of statements 47-48, wherein:

[0122] The method further comprises the step of pulverizing the active pharmaceutical ingredient before step (1).

[0123] 50. An ophthalmic kit comprising the ophthalmic pharmaceutical composition of any one of statements 1-46.

[0124] 51. The ophthalmic kit of claim 50, wherein:

[0125] The ophthalmic kit comprises a prefilled syringe, wherein the ophthalmic pharmaceutical composition is filled in the prefilled syringe.

[0126] 52. The ophthalmic kit of statement 51, wherein:

[0127] The filling volume of the ophthalmic pharmaceutical composition is 0.01 ml-10 ml.

[0128] 53. The ophthalmic kit of statement 51, wherein:

[0129] The filling volume of the ophthalmic pharmaceutical composition is 0.1 ml-2 ml.

[0130] 54. Use of the ophthalmic pharmaceutical composition according to any one of statements 1 to 46 or the ophthalmic pharmaceutical kit according to any one of statements 50 to 53 in the preparation of a medicament for preventing and / or treating eye diseases.

[0131] When the amount of the liquid matrix in the ophthalmic pharmaceutical composition of the present invention is 0.95-1.25 parts by weight and the amount of the solid matrix is ​​0.35-0.45 parts by weight relative to 1 part by weight of the active pharmaceutical ingredient, and at the same time the active pharmaceutical ingredient satisfies the particle size range: D 90 When the diameter of the ophthalmic composition is ≤50 μm, the ophthalmic composition of the present invention meets the requirements of the starting force required for injection, can be injected into the eye, is convenient for injection operation, and can slowly release the active pharmaceutical ingredient in the eye for a long time and can be slowly degraded in the eye. In addition, the ophthalmic composition of the present invention has good storage stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] The drawings described herein are used to provide a further understanding of the present invention and constitute a part of this application. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0133] Figure 1 This is a schematic diagram of the in vitro drug release of ophthalmic preparation Example 1B;

[0134] Figure 2 This is a schematic diagram of the in vitro drug release of ophthalmic preparation Example 2B;

[0135] Figure 3 This is a schematic diagram of the in vitro drug release of the ophthalmic preparation comparative example 1. DETAILED DESCRIPTION

[0136] In the present invention, unless otherwise specified, the term "matrix" refers to a substance that does not react with the active pharmaceutical ingredient and helps the active pharmaceutical ingredient to exert its effect, such as a substance that affects the administration, release, penetration, and absorption of the active pharmaceutical ingredient, a substance that can give shape to the active pharmaceutical ingredient, etc.

[0137] In the present invention, unless otherwise specified, the term "liquid matrix" refers to a matrix that is liquid at room temperature (10-30° C.).

[0138] In the present invention, unless otherwise specified, the term "solid matrix" refers to a matrix that is solid at room temperature (10-30° C.).

[0139] In the present invention, unless otherwise specified, even if the term “about” is not used to modify a numerical value, the numerical value should be understood to be modified by “about”; the term “about” includes a deviation of ±5% of the stated numerical value, that is, for a numerical value a, whether or not it is modified by “about”, it should be understood to represent a range of a±5%a, that is, 0.95a to 1.05a.

[0140] Ophthalmic pharmaceutical composition

[0141] The first aspect of the present invention provides an ophthalmic pharmaceutical composition, which comprises or consists of the following components:

[0142] 1 part by weight of active pharmaceutical ingredient,

[0143] 0.95-1.25 parts by weight of liquid matrix,

[0144] 0.35-0.45 parts by weight of solid matrix,

[0145] Wherein, the particle size of the active pharmaceutical ingredient satisfies: D 90 ≤50μm.

[0146] In the present invention, when the term "particle size of an active pharmaceutical ingredient" is used, it means that the active pharmaceutical ingredient is in the form of particles.

[0147] In some embodiments of the first aspect of the present invention, the particle size of the active pharmaceutical ingredient satisfies: 1 μm ≤ D 90 ≤50μm.

[0148] In some embodiments of the first aspect of the present invention, the active pharmaceutical ingredient is one or a mixture of two or more selected from anti-tumor drugs, anti-inflammatory drugs, immunosuppressants, neovascularization inhibitors and glaucoma treatment drugs.

[0149] In some embodiments of the first aspect of the present invention, the active pharmaceutical ingredient is selected from chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topotecan, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate Ester, halobetasol propionate, cortisone, hydrocortisone, cyclosporine, rapamycin, tacrolimus, mycophenolate mofetil, tacrolimus, mizoribine, sulfasalazine, azathioprine, methotrexate, bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, brinzolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole, dasatinib and a mixture of one or more of their pharmaceutically acceptable salts.

[0150] In some embodiments of the first aspect of the present invention, the active pharmaceutical ingredient is selected from one or a mixture of two or more of dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine, and pharmaceutically acceptable salts thereof.

[0151] In the present invention, anti-tumor drugs include but are not limited to chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topotecan, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, and sunitinib.

[0152] In the present invention, anti-inflammatory drugs include but are not limited to dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate, halobetasol propionate, cortisone, and hydrocortisone.

[0153] In the present invention, immunosuppressants include but are not limited to cyclosporine, rapamycin, tacrolimus, mycophenolic acid, tacrolimus, mizoribine, sulfasalazine, azathioprine, and methotrexate.

[0154] In the present invention, the angiogenesis inhibitors include but are not limited to bevacizumab, ranibizumab, pegaptanib sodium, and aflibercept.

[0155] In the present invention, the glaucoma treatment drugs include but are not limited to latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, brinzolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, and dapprazole.

[0156] In the ophthalmic pharmaceutical composition of the present invention, the particle size of the active pharmaceutical ingredient satisfies: 90 ≤50μm, preferably 1μm≤D 90 ≤50μm. For example, the particle size of active pharmaceutical ingredients D 90 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 30, 31, 32, 33, 34, 35, 36, 37,

[0159] 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 μm, or a range defined by any two thereof.

[0160] In the present invention, if not otherwise specified, the particle size D 90 It is measured by light (laser) scattering method. 90 It refers to a particle size in which, in a cumulative volume distribution curve of the particles, 90% by volume of the particles have a particle size lower than this particle size and 10% by volume of the particles have a particle size higher than this particle size.

[0161] In some embodiments of the first aspect of the present invention, the liquid matrix is ​​a biodegradable liquid matrix.

[0162] In some embodiments of the first aspect of the present invention, the liquid matrix is ​​one or a mixture of two or more of diethyl succinate, diethyl tartaric acid, dimethyl glutarate, triacetin, polyethylene glycol, glycerol, and propylene glycol.

[0163] In some embodiments of the first aspect of the present invention, the liquid matrix is ​​polyethylene glycol, or a mixture of polyethylene glycol and at least one selected from diethyl succinate, diethyl tartaric acid, dimethyl glutarate, triacetin, glycerol, and propylene glycol.

[0164] In some embodiments of the first aspect of the present invention, the liquid matrix is ​​polyethylene glycol.

[0165] In some embodiments of the first aspect of the present invention, the liquid matrix is ​​a mixture of polyethylene glycol and at least one selected from diethyl succinate, diethyl tartaric acid, dimethyl glutarate, triacetin, glycerol, and propylene glycol.

[0166] In some embodiments of the first aspect of the present invention, the polyethylene glycol of the liquid matrix is ​​one or a mixture of two or more polyethylene glycols having a number average molecular weight of 70-750 (e.g., 190-210, 300, 380-420, 570-630, 100, 200, 400, 500, 600, 700); for example, one or a mixture of two or more of PEG-200, PEG-300, PEG-400 and PEG-600.

[0167] In some embodiments of the first aspect of the present invention, the polyethylene glycol of the liquid matrix is ​​PEG-400.

[0168] In some embodiments of the first aspect of the present invention, the amount of the liquid matrix can be 0.95-1.25 parts by weight relative to 1 part by weight of the active pharmaceutical ingredient. For example, the amount of the liquid matrix can be 0.950, 0.955, 0.960, 0.965, 0.970, 0.975, 0.980, 0.985, 0.990, 0.995, 1.000, 1.005, 1.010, 1.015, 1.020, 1.025, 1.030, 1.035, 1.040, 1.045, 1.050, 1.055, 1.060, 1.065, 1.070, 1.075, 1 1.220, 1.225, 1.230, 1.235, 1.240, 1.245, 1.250 parts by weight, or a range defined by any two of them.

[0169] In some embodiments of the first aspect of the present invention, when the liquid matrix is ​​a mixture of polyethylene glycol and at least one selected from diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, glycerol, and propylene glycol, the mass ratio of polyethylene glycol to at least one selected from diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, glycerol, and propylene glycol can be 1:0.01-100, preferably 1:0.1-10, for example, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.10, 1:0.11, 1:0.12, 1:0.13, 1:0.14, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.20, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25 .12, 1:0.15, 1:0.20, 1:0.25, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.2, 1:1.5, 1:1.8, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, 1:4.5, 1:5.0, 1:6.0, 1:7.0, 1:8.0, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, or a range defined by any two of them.

[0170] In some embodiments of the first aspect of the present invention, the solid matrix is ​​a biodegradable solid matrix.

[0171] In some embodiments of the first aspect of the present invention, the solid matrix is ​​polyethylene glycol, hydroxycarboxylate polymer, or a mixture of two or more thereof.

[0172] In some embodiments of the first aspect of the present invention, the hydroxycarboxylate polymer is a homopolymer, a copolymer, or a mixture thereof of hydroxycarboxylic acid.

[0173] In some embodiments of the first aspect of the present invention, the hydroxycarboxylic acid may be lactic acid, glycolic acid, or a mixture thereof.

[0174] In some embodiments of the first aspect of the present invention, the hydroxycarboxylate polymer is one or a mixture of two or more of polylactic acid (or polylactide), polyglycolic acid (or polyglycolide), and polylactic acid-glycolic acid copolymer.

[0175] In some embodiments of the first aspect of the present invention, the solid matrix is ​​polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, or a mixture of two or more thereof.

[0176] In some embodiments of the first aspect of the present invention, the solid matrix is ​​polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, or a mixture of two or more thereof.

[0177] In some embodiments of the first aspect of the present invention, the solid matrix is ​​polylactic acid-glycolic acid copolymer, or a mixture of polylactic acid-glycolic acid copolymer and at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid.

[0178] In some embodiments of the first aspect of the present invention, the solid matrix is ​​poly(lactic acid-co-glycolic acid).

[0179] In some embodiments of the first aspect of the present invention, the solid matrix is ​​a mixture of polylactic acid-glycolic acid copolymer and at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid.

[0180] In some embodiments of the first aspect of the present invention, the polylactic acid-glycolic acid copolymer is a random copolymer, a block copolymer, an alternating copolymer, a statistical copolymer, a gradient copolymer, or a mixture of two or more thereof.

[0181] In some embodiments of the first aspect of the present invention, the mass ratio of the unit derived from glycolic acid to the unit derived from lactic acid in the polylactic acid-glycolic acid copolymer can be 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3, for example, it can be 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.10, 1:0.12, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.20, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0 1:8.0, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, or a range defined by any two of them.

[0182] In some embodiments of the first aspect of the present invention, the polyethylene glycol of the solid matrix has a number average molecular weight of 800-20000 (e.g., 800, 900, 1000, 1200, 1400, 1600, 2000, 2800, 3000, 4000, 5000, 6000, 7000, 8000, 9500, 9000, 10000, 11000, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, or a range defined by any two of them), for example, a mixture of one or more of PEG-800, PEG-1000, PEG-1500, PEG-2000, PEG-4000, PEG-6000, PEG-8000, PEG-10000 and PEG-20000.

[0183] In some embodiments of the first aspect of the present invention, the weight average molecular weight of the hydroxycarboxylic acid polymer of the solid matrix is ​​1000-600000, preferably 5000-200000, for example 10000-20000, for example 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, 20000 0000, 25000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 150000, 200000, 250000, 300000, 400000, 450000, 500000, 550000, 600000, or a range limited by any two of them.

[0184] In some embodiments of the first aspect of the invention, the weight average molecular weight of the polylactic acid is 1000-600000, preferably 5000-200000, for example 10000-20000, for example 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, 20000, 25000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 150000, 200000, 250000, 300000, 400000, 450000, 500000, 550000, 600000, or a range limited by any two of them.

[0185] In some embodiments of the first aspect of the invention, the weight average molecular weight of the polyglycolic acid is 1000-600000, preferably 5000-200000, for example 10000-20000, for example 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, 20000, 25000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 150000, 200000, 250000, 300000, 400000, 450000, 500000, 550000, 600000, or a range limited by any two thereof.

[0186] In some embodiments of the first aspect of the present invention, the weight average molecular weight of the polylactic acid-co-glycolic acid is 1000-600000, preferably 5000-200000, for example 10000-20000, for example 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, 200 00, 25000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 150000, 200000, 250000, 300000, 400000, 450000, 500000, 550000, 600000, or a range limited by any two of them.

[0187] The number average molecular weight (Mn) can be measured by conventional methods, such as end group analysis, boiling point elevation, freezing point depression, vapor pressure osmosis, thin film osmosis, gel permeation chromatography, etc. In the present application, unless otherwise specified, the number average molecular weight is measured by size exclusion chromatography.

[0188] The weight average molecular weight (Mw) can be measured by conventional methods, such as light scattering, gel chromatography, ultracentrifugal sedimentation velocity method, small angle X-ray diffraction, gel permeation chromatography, etc. In the present application, unless otherwise specified, the weight average molecular weight is measured by molecular exclusion chromatography.

[0189] In some embodiments of the first aspect of the present invention, the molecular weight distribution (Mw / Mn) of the solid matrix, such as polyethylene glycol, or hydroxycarboxylate polymer (such as polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer) is not particularly limited, and can be, for example, 1.0-10.0, such as 1.5-5.0, such as 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, or a range defined by any two of them. In the present application, unless otherwise specified, the molecular weight distribution is determined by size exclusion chromatography.

[0190] In some embodiments of the first aspect of the present invention, the amount of the solid matrix relative to 1 part by weight of the active pharmaceutical ingredient can be 0.35-0.45 part by weight, for example, 0.350, 0.355, 0.360, 0.365, 0.370, 0.375, 0.380, 0.385, 0.390, 0.395, 0.400, 0.405, 0.410, 0.415, 0.420, 0.425, 0.430, 0.435, 0.440, 0.445, 0.450 part by weight, or a range limited by any two of them.

[0191] In some embodiments of the first aspect of the present invention, when the solid matrix is ​​a mixture of polylactic acid-co-glycolic acid and at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid, the mass ratio of polylactic acid-co-glycolic acid to the at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid can be 1:0.01-100, preferably 1:0.1-10, for example, 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.10, 1:0.12, 1:0.15, 1:0.16, 1:0.17, 1:0.18, 1:0.19, 1:0.20, 1:0.21, 1:0.22, 1:0.23, 1:0.24, 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0 1:8.0, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100, or a range defined by any two of them.

[0192] In a preferred embodiment of the first aspect of the present invention, the ophthalmic pharmaceutical composition comprises or consists of the following components:

[0193] Active pharmaceutical ingredient; preferably, the active pharmaceutical ingredient is one or a mixture of two or more selected from anti-tumor drugs, anti-inflammatory drugs, immunosuppressants, neovascularization inhibitors and glaucoma treatment drugs; preferably, the active pharmaceutical ingredient is selected from chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topoisomerase inhibitors, sirolimus ... Vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate, halobetasol propionate, cortisone, hydrocortisone, cyclocortisone spores, rapamycin, tacrolimus, mycophenolate mofetil, tacrolimus, mizoribine, sulfasalazine, azathioprine, methotrexate, bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, bulin Zolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole, dasatinib and a mixture of one or more of their pharmaceutically acceptable salts; preferably, the active pharmaceutical ingredient is selected from dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine and a mixture of one or more of their pharmaceutically acceptable salts; preferably, the active pharmaceutical ingredient is triamcinolone acetonide;

[0194] A liquid matrix, wherein the liquid matrix is ​​polyethylene glycol, or a mixture of polyethylene glycol and at least one selected from diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, glycerol, and propylene glycol; preferably, when the liquid matrix is ​​a mixture of polyethylene glycol and at least one selected from diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, glycerol, and propylene glycol, the mass ratio of polyethylene glycol to the at least one selected from diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, glycerol, and propylene glycol is 1:0.01-100, preferably 1:0.1-10; preferably, the liquid matrix is ​​polyethylene glycol; preferably, the polyethylene glycol is one or a mixture of two or more polyethylene glycols having a number average molecular weight of 70-750 (e.g., 190-210, 300, 380-420, 570-630, 100, 200, 400, 500, 600, 700, or a range defined by any two thereof); for example, one or a mixture of two or more of PEG-200, PEG-300, PEG-400 and PEG-600; preferably, the polyethylene glycol is PEG-400;

[0195] A solid matrix, wherein the solid matrix is ​​a polylactic acid-glycolic acid copolymer, or a mixture of a polylactic acid-glycolic acid copolymer and at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid; preferably, when the solid matrix is ​​a mixture of a polylactic acid-glycolic acid copolymer and at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid, the mass ratio of the polylactic acid-glycolic acid copolymer to the at least one selected from polyethylene glycol, polylactic acid, and polyglycolic acid may be 1:0.01-100, preferably 1:0.1-10; preferably, the mass ratio of the unit derived from glycolic acid to the unit derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3; preferably, the solid matrix is ​​a polylactic acid-glycolic acid copolymer;

[0196] in,

[0197] The amount of the liquid matrix is ​​0.95-1.25 parts by weight, preferably 1.0-1.125 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0198] The amount of the solid matrix is ​​0.35-0.45 parts by weight, preferably 0.375-0.40 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0199] The particle size of the active pharmaceutical ingredient meets: D 90 ≤50μm, preferably 1μm≤D90 ≤50μm.

[0200] In a further preferred embodiment of the first aspect of the present invention, the ophthalmic pharmaceutical composition comprises or consists of the following components:

[0201] Active pharmaceutical ingredient; preferably, the active pharmaceutical ingredient is one or a mixture of two or more selected from anti-tumor drugs, anti-inflammatory drugs, immunosuppressants, neovascularization inhibitors and glaucoma treatment drugs; preferably, the active pharmaceutical ingredient is selected from chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topoisomerase inhibitors, sirolimus ... Vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate, halobetasol propionate, cortisone, hydrocortisone, cyclocortisone spores, rapamycin, tacrolimus, mycophenolate mofetil, tacrolimus, mizoribine, sulfasalazine, azathioprine, methotrexate, bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, bulin Zolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole, dasatinib and a mixture of one or more of their pharmaceutically acceptable salts; preferably, the active pharmaceutical ingredient is selected from dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine and a mixture of one or more of their pharmaceutically acceptable salts; preferably, the active pharmaceutical ingredient is triamcinolone acetonide;

[0202] A liquid matrix, wherein the liquid matrix is ​​polyethylene glycol; preferably, the polyethylene glycol is one or a mixture of two or more polyethylene glycols having a number average molecular weight of 70-750 (e.g., 190-210, 300, 380-420, 570-630, 100, 200, 400, 500, 600, 700, or a range defined by any two thereof); for example, one or a mixture of two or more of PEG-200, PEG-300, PEG-400 and PEG-600; preferably, the polyethylene glycol is PEG-400; and

[0203] A solid matrix, wherein the solid matrix is ​​a polylactic acid-glycolic acid copolymer; preferably, the mass ratio of the unit derived from glycolic acid to the unit derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3;

[0204] in,

[0205] The amount of the liquid matrix is ​​0.95-1.25 parts by weight, preferably 1.0-1.125 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0206] The amount of the solid matrix is ​​0.35-0.45 parts by weight, preferably 0.375-0.40 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0207] The particle size of the active pharmaceutical ingredient meets: D 90 ≤50μm, preferably 1μm <D 90 ≤50μm.

[0208] In a further preferred embodiment of the first aspect of the present invention, the ophthalmic pharmaceutical composition comprises or consists of the following components:

[0209] An active pharmaceutical ingredient, which is one or a mixture of two or more of dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine, and pharmaceutically acceptable salts thereof, preferably triamcinolone acetonide;

[0210] A liquid matrix, wherein the liquid matrix is ​​polyethylene glycol; preferably, the polyethylene glycol is one or a mixture of two or more polyethylene glycols having a number average molecular weight of 70-750 (e.g., 190-210, 300, 380-420, 570-630, 100, 200, 400, 500, 600, 700, or a range defined by any two thereof); for example, one or a mixture of two or more of PEG-200, PEG-300, PEG-400 and PEG-600; preferably, the polyethylene glycol is PEG-400; and

[0211] A solid matrix, wherein the solid matrix is ​​a polylactic acid-glycolic acid copolymer, preferably, the mass ratio of the unit derived from glycolic acid to the unit derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3;

[0212] in,

[0213] The amount of the liquid matrix is ​​0.95-1.25 parts by weight, preferably 1.0-1.125 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0214] The amount of the solid matrix is ​​0.35-0.45 parts by weight, preferably 0.375-0.40 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0215] The particle size of the active pharmaceutical ingredient meets: D 90 ≤50μm, preferably 1μm <D 90 ≤50μm.

[0216] In an even further preferred embodiment of the first aspect of the present invention, the ophthalmic pharmaceutical composition comprises or consists of the following components:

[0217] An active pharmaceutical ingredient, which is one or a mixture of two or more of dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine, and pharmaceutically acceptable salts thereof, preferably triamcinolone acetonide;

[0218] A liquid matrix, wherein the liquid matrix is ​​polyethylene glycol PEG-400; and

[0219] A solid matrix, wherein the solid matrix is ​​a polylactic acid-glycolic acid copolymer, preferably, the mass ratio of the unit derived from glycolic acid to the unit derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3;

[0220] in,

[0221] The amount of the liquid matrix is ​​0.95-1.25 parts by weight, preferably 1.0-1.125 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0222] The amount of the solid matrix is ​​0.35-0.45 parts by weight, preferably 0.375-0.40 parts by weight, relative to 1 part by weight of the active pharmaceutical ingredient.

[0223] The particle size of active pharmaceutical ingredients meets the following requirements: 1μm≤D 90 ≤50μm.

[0224] In some embodiments of the first aspect of the present invention, the ophthalmic pharmaceutical composition is an ophthalmic pharmaceutical preparation, preferably an ophthalmic pharmaceutical injection preparation, or a sustained-release (sustained-release) insert or implant, and the ophthalmic pharmaceutical injection preparation is preferably an intraocular injection preparation, preferably a subconjunctival injection preparation, an intravitreal injection preparation, a periocular injection preparation, a retrobulbar injection preparation or an intracameral injection preparation.

[0225] In some embodiments of the first aspect of the present invention, the ophthalmic pharmaceutical composition is in liquid form at room temperature (10-30° C.).

[0226] In some embodiments of the first aspect of the present invention, the ophthalmic pharmaceutical composition can be filled in a prefilled syringe. Preferably, the syringe barrel of the syringe can be made of glass (e.g., low borosilicate glass, medium borosilicate glass, high borosilicate glass, soda-lime glass, etc.), cyclic olefin copolymer (COC), and / or cyclic olefin polymer (COP). Preferably, the syringe barrel may or may not contain silicone oil.

[0227] In some embodiments of the first aspect of the present invention, when filled in a prefilled syringe, the ophthalmic pharmaceutical composition has a filling volume of 0.01 ml-10 ml. Most preferably, the filling volume ranges from 0.1 ml to 2 ml. For example, the filling volume range can be 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5. 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7, 12.8, 12.9,

[0228] In some embodiments of the first aspect of the present invention, the dosage of the ophthalmic pharmaceutical composition is 1 μl-100 μl. Most preferably, 2-20 μl. For example, the dosage can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55 , 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 μl, or a range limited by any two of them.

[0229] In some embodiments of the first aspect of the present invention, the ophthalmic pharmaceutical composition is a sustained release preparation. Its sustained release period is 30 days to 730 days. Most preferably, its sustained release period is 60 to 120 days. For example, the sustained release period can be 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210 , 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390 ,395,400,405,410,415,420,425,430,435,440,445,450,455,460,465,470,475,480,485,490,495,500,505,510,515,520,525,530,535,540,545,550,555,560,565,570 , 575, 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, or a range limited by any two of them.

[0230] In some embodiments of the first aspect of the present invention, the ophthalmic pharmaceutical composition is administered once every 30 days to 730 days. Most preferably, it is administered once every 60 to 120 days. For example, the administration frequency can be 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 3 95, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500, 505, 510, 515, 520, 525, 530, 535, 540, 545, 550, 555, 560, 565, 570, 575 5. 580, 585, 590, 595, 600, 605, 610, 615, 620, 625, 630, 635, 640, 645, 650, 655, 660, 665, 670, 675, 680, 685, 690, 695, 700, 705, 710, 715, 720, 725, 730, or the range limited by any two of them, or once a day.

[0231] When the amount of the liquid matrix in the ophthalmic pharmaceutical composition of the present invention is 0.95-1.25 parts by weight and the amount of the solid matrix is ​​0.35-0.45 parts by weight relative to 1 part by weight of the active pharmaceutical ingredient, and at the same time the active pharmaceutical ingredient satisfies the particle size range: D 90 When the diameter of the ophthalmic composition is ≤50 μm, the ophthalmic composition of the present invention meets the requirements of the starting force required for injection, can be injected into the eye, is convenient for injection operation, and can slowly release the active pharmaceutical ingredient in the eye for a long time and can be slowly degraded in the eye. In addition, the ophthalmic composition of the present invention has good storage stability.

[0232] Preparation method of ophthalmic pharmaceutical composition

[0233] The second aspect of the present invention relates to a method for preparing the ophthalmic pharmaceutical composition of the first aspect of the present invention, comprising the following steps:

[0234] (1) providing an active pharmaceutical ingredient satisfying the particle size relationship defined in the first aspect of the present invention;

[0235] (2) mixing a solid matrix with a liquid matrix, preferably dissolving the solid matrix in the liquid matrix, to obtain a mixed matrix; and

[0236] (3) dispersing the active pharmaceutical ingredient provided in step (1) in the mixed matrix obtained in step (2).

[0237] In some embodiments of the second aspect of the present invention, the method further comprises the step of pulverizing the active pharmaceutical ingredient to provide the active pharmaceutical ingredient having the particle size before step (1).

[0238] The pulverizing step can be performed by any method known to those skilled in the art that can effectively pulverize the active pharmaceutical ingredient without adversely destroying or denaturing the active pharmaceutical ingredient. For example, the pulverizing can be performed by grinding, jet milling, and other pulverizing methods.

[0239] In some embodiments of the second aspect of the invention, the mixing in step (2) is performed under conditions effective to promote dispersion, preferably dissolution, of the solid matrix in the liquid matrix without causing decomposition or denaturation.

[0240] For example, in some embodiments of the second aspect of the invention, the mixing in step (2) can be carried out at a temperature of 20°C-100°C, for example, 20°C, 25°C, 30°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C.

[0241] For example, in some embodiments of the second aspect of the present invention, the mixing in step (2) can be optionally carried out in the presence of a solvent to promote the dispersion, preferably dissolution, of the solid matrix. The solvent can be appropriately selected according to the polymer used, and can be, for example, ethyl acetate, ethanol, supercritical carbon dioxide, etc. After the solid matrix has been uniformly dispersed, preferably dissolved, the solvent can be removed, for example, by any method known in the art, such as heating evaporation, decompression, etc.

[0242] In some embodiments of the second aspect of the present invention, step (3) is carried out under conditions that effectively disperse the active pharmaceutical ingredient in the mixed matrix without destroying or denaturing the active pharmaceutical ingredient. For example, depending on the decomposition or denaturation temperature of the active pharmaceutical ingredient, the dispersion in step (3) can be carried out at a temperature of 30-80°C, such as 40-60°C, such as 30°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, or a temperature within a range defined by any two thereof.

[0243] Eye medicine box

[0244] The third aspect of the present invention relates to an ophthalmic kit comprising the ophthalmic pharmaceutical composition of the first aspect of the present invention.

[0245] In some embodiments of the third aspect of the present invention, the ophthalmic kit comprises one or more of the following i to ii:

[0246] i. The ophthalmic kit further comprises a syringe (eg, a medical syringe);

[0247] ii. The ophthalmic kit is an ophthalmic injection kit.

[0248] Preferably, the ophthalmic drug kit comprises a prefilled syringe, wherein the ophthalmic pharmaceutical composition is filled in the prefilled syringe. Preferably, the syringe barrel of the syringe may be made of glass (e.g., low borosilicate glass, medium borosilicate glass, high borosilicate glass, soda-lime glass, etc.), cyclic olefin copolymer (COC), and / or cyclic olefin polymer (COP). Preferably, the syringe barrel may or may not contain silicone oil.

[0249] In some embodiments of the third aspect of the present invention, when filled in a prefilled syringe, the ophthalmic pharmaceutical composition has a filling volume of 0.01 ml-10 ml. Most preferably, the filling volume range is 0.1 ml-2 ml. For example, the filling volume range can be 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 ml, or a range limited by any two thereof.

[0250] In some embodiments of the third aspect of the present invention, when pushing the syringe, the starting force does not exceed 25N with reference to the standard YBB00112004-2015 for prefilled syringe assemblies.

[0251] application

[0252] The fourth aspect of the present invention relates to the use of the ophthalmic pharmaceutical composition of the first aspect of the present invention and the ophthalmic pharmaceutical kit of the third aspect of the present invention in the preparation of drugs for preventing and / or treating eye diseases.

[0253] In some embodiments of the fourth aspect of the present invention, the eye disease is a posterior segment disease.

[0254] In some embodiments of the fourth aspect of the present invention, the eye disease is selected from one or a mixture of two or more of postoperative inflammation of cataract surgery, glaucoma, uveitis, retinal vein occlusion, retinal artery occlusion, diabetic retinopathy, retinal phlebitis, proliferative vitreoretinopathy, choroidal neovascularization, cystoid macular edema, age-related macular degeneration, vitreomacular adhesion, macular hole, optic neuritis, optic disc edema, optic nerve meningioma, optic nerve glioma, retinoblastoma and choroidoblastoma.

[0255] Example

[0256] The embodiments of the present invention will be described in detail below in conjunction with examples and drawings, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0257] The materials used in the embodiments and comparative examples are as follows:

[0258] PEG 400: provided by Nanjing Well Pharmaceutical Co., Ltd., with a number average molecular weight of 380-420.

[0259] Glycerin: provided by Tyco Brown Chemical (Zhangjiagang) Co., Ltd., injection grade.

[0260] Propylene glycol: provided by Hunan Erkang Pharmaceutical Co., Ltd.

[0261] Glycerol triacetate, diethyl succinate, and diethyl tartrate: provided by Sigma-Aldrich (Shanghai) Trading Co. Ltd.

[0262] Polylactic acid-glycolic acid copolymer: provided by Evonik Specialty Chemicals (Shanghai) Co., Ltd. (material name: 7525DLG2CA, PS5210C), with an intrinsic viscosity of 0.17 dL / g (30°C) and 0.18 dL / g (25°C), a weight average molecular weight Mw of 16,000, a number average molecular weight of 9,000, and a molecular weight distribution (Mw / Mn, also known as polydispersity) of 1.9 when measured in CHCl3, and a weight average molecular weight Mw of 14,000, a number average molecular weight of 8,000, and a molecular weight distribution of 1.7 when measured in THF, wherein the mass ratio of glycolic acid unit:lactic acid unit is 1:3.

[0263] PEG1000: provided by Sigma-Aldrich (Shanghai) Trading Co. Ltd., number average molecular weight: 950-1050.

[0264] PEG20000: provided by Shanghai Aladdin Biochemical Technology Co., Ltd., with an average number average molecular weight of 20000 (average number average molecular weight range is 18500-22000).

[0265] Polyglycolic acid: provided by Shanghai Aladdin Biochemical Technology Co., Ltd., intrinsic viscosity 1.4 dl / g (HFIP, 25°C, 0.1 g / dl, 1.3-1.6 dl / g).

[0266] Polylactic acid: provided by Shanghai Aladdin Biochemical Technology Co., Ltd., Mw ~ 60000 (molecular weight range is 50000-70000).

[0267] Triamcinolone acetonide and dexamethasone: provided by Tianjin Tianyao Pharmaceutical Co., Ltd. Pilocarpine and brimonidine: provided by Guangzhou Anxin Pharmaceutical Co., Ltd. Methotrexate: provided by Hunan Zhanwang Pharmaceutical Co., Ltd. Cyclosporine: provided by Zhejiang Ruibang Pharmaceutical Co., Ltd. Each raw material (i.e., active drug) was crushed by a jet mill to prepare a corresponding particle size D 90 The raw material particles are 1, 10, 20, 30, 50, and 70 μm, wherein the particle size is measured by a laser particle size analyzer using a laser scattering method.

[0268] Examples 1A-5C

[0269] According to the formulations in Table 1, ophthalmic preparations of Examples 1A-5C were prepared.

[0270] Table 1

[0271]

[0272] Each ophthalmic preparation was prepared specifically as follows.

[0273] Example 1A, 1B, 1C Preparation of Ophthalmic Preparations

[0274] Weigh 11.25 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 33.75 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparations of Examples 1A, 1B, and 1C.

[0275] Preparation of ophthalmic preparations in Examples 2A, 2B, and 2C

[0276] Weigh 10.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 28.5 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparations of Examples 2A, 2B, and 2C.

[0277] Preparation of ophthalmic preparations in Examples 3A, 3B, and 3C

[0278] Weigh 13.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 28.5 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparations of Examples 3A, 3B, and 3C.

[0279] Example 4A, 4B, 4C Preparation of Ophthalmic Preparations

[0280] Weigh 13.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 37.5 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparations of Examples 4A, 4B, and 4C.

[0281] Preparation of ophthalmic preparations in Examples 5A, 5B, and 5C

[0282] Weigh 10.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 37.5 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparations of Examples 5A, 5B, and 5C.

[0283] Comparative Examples 1-35

[0284] Comparative Examples 1-35 ophthalmic preparations were prepared according to the formulations in Table 2.

[0285] Table 2

[0286]

[0287]

[0288] Each ophthalmic preparation was prepared specifically as follows.

[0289] Comparative Examples 1-3 Preparation of Ophthalmic Preparations

[0290] Weigh 9 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 33.75 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 1-3.

[0291] Comparative Examples 4-6 Preparation of Ophthalmic Preparations

[0292] Weigh 15 g of poly(lactic acid-co-glycolic acid) copolymer into a beaker, add 33.75 g of PEG400, stir at 60 °C until the poly(lactic acid-co-glycolic acid) copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 4-6.

[0293] Comparative Examples 7-9 Preparation of Ophthalmic Preparations

[0294] Weigh 11.25 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 27 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 7-9.

[0295] Comparative Examples 10-12 Preparation of Ophthalmic Preparations

[0296] Weigh 11.25 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 39 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, and the filling volume of each syringe was 0.2 ml. The syringe was sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 10-12.

[0297] Comparative Examples 13-15 Preparation of Ophthalmic Preparations

[0298] Weigh 9 g of polylactic acid-co-glycolic acid copolymer and place it in a beaker, add 27 g of PEG400, stir at 60°C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, and the filling volume of each syringe was 0.2 ml. The syringe was sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 13-15.

[0299] Comparative Examples 16-18 Preparation of Ophthalmic Preparations

[0300] Weigh 15 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 39 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 16-18.

[0301] Comparative Examples 19-21 Preparation of Ophthalmic Preparations

[0302] Weigh 3 g of polylactic acid-co-glycolic acid copolymer and place it in a beaker, add 3 g of PEG400, stir at 60°C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121 ° C for 15 min to obtain Comparative Examples 19-21.

[0303] Comparative Examples 22-24 Preparation of Ophthalmic Preparations

[0304] Weigh 60 g of polylactic acid-co-glycolic acid copolymer and place it in a beaker, add 150 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Examples 22-24.

[0305] Comparative Examples 25-27 Preparation of Ophthalmic Preparations

[0306] Weigh 3 g of poly(lactic acid-co-glycolic acid) copolymer into a beaker, add 90 g of PEG400, stir at 60 °C until the poly(lactic acid-co-glycolic acid) copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain comparative examples 25-27.

[0307] Comparative Examples 28-30 Preparation of Ophthalmic Preparations

[0308] Weigh 30 g of poly(lactic acid-co-glycolic acid) copolymer into a beaker, add 9 g of PEG400, stir at 60 °C until the poly(lactic acid-co-glycolic acid) copolymer is completely dissolved, and add the drug particles D 90 30 g of 1 μm, 30 μm, and 50 μm triamcinolone acetonide were added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into a 1 ml prefilled syringe, and the filling volume of each syringe was 0.2 ml. The syringe was sterilized by wet heat at 121 ° C for 15 min to obtain comparative examples 28-30.

[0309] Comparative Example 31 Preparation of ophthalmic preparation

[0310] Weigh 10.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 28.5 g of PEG400, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D 90 30 g of 70 μm triamcinolone acetonide was added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into 1 ml prefilled syringes, with a filling volume of 0.2 ml per syringe, and sterilized by wet heat at 121° C. for 15 min to obtain Comparative Example 31.

[0311] Comparative Example 32 Preparation of ophthalmic preparation

[0312] Weigh 11.25 grams of polylactic acid-glycolic acid copolymer and place it in a beaker, add 33.75 grams of PEG400 thereto, stir at 60°C until the polylactic acid-glycolic acid copolymer is completely dissolved, add 30 grams of triamcinolone acetonide with a drug particle size D90 of 70 μm under stirring, continue stirring until the mixture is uniform, fill the mixture into a 1 ml prefilled syringe, each filling volume is 0.2 ml, and sterilize by wet heat at 121°C for 15 min to obtain Comparative Example 32.

[0313] Comparative Example 33 Preparation of ophthalmic preparation

[0314] Weigh 13.5 grams of polylactic acid-glycolic acid copolymer and place it in a beaker, add 28.5 grams of PEG400 thereto, stir at 60°C until the polylactic acid-glycolic acid copolymer is completely dissolved, add 30 grams of triamcinolone acetonide with a drug particle size D90 of 70 μm under stirring, continue stirring until the mixture is uniform, fill the mixture into a 1 ml prefilled syringe, each filling volume is 0.2 ml, and sterilize by wet heat at 121°C for 15 min to obtain Comparative Example 33.

[0315] Comparative Example 34 Preparation of ophthalmic preparation

[0316] Weigh 13.5 grams of polylactic acid-glycolic acid copolymer and place it in a beaker, add 37.5 grams of PEG400 thereto, stir at 60°C until the polylactic acid-glycolic acid copolymer is completely dissolved, add 30 grams of triamcinolone acetonide with a drug particle size D90 of 70 μm under stirring, continue stirring until the mixture is uniform, fill the mixture into a 1 ml prefilled syringe, each filling volume is 0.2 ml, and sterilize by wet heat at 121°C for 15 min to obtain Comparative Example 34.

[0317] Comparative Example 35 Preparation of ophthalmic preparation

[0318] Weigh 10.5 grams of polylactic acid-glycolic acid copolymer and place it in a beaker, add 37.5 grams of PEG400 thereto, stir at 60°C until the polylactic acid-glycolic acid copolymer is completely dissolved, add 30 grams of triamcinolone acetonide with a drug particle size D90 of 70 μm under stirring, continue stirring until the mixture is uniform, fill the mixture into a 1 ml prefilled syringe, each filling volume is 0.2 ml, and sterilize by wet heat at 121°C for 15 min to obtain Comparative Example 35.

[0319] Evaluation Example 1: Investigation of in vitro release and initial release of ophthalmic preparations

[0320] Take 5 μL of each of ophthalmic preparation examples 1A, 1B, 1C-5A, 5B, 5C, and comparative examples 1-35, and inject them into beakers containing 100 mL of release medium (0.9% sodium chloride solution, pH=7.4, osmotic pressure=290 mOsmol / kg), place the beaker in a water bath oscillator, control the temperature to 37±0.5°C, draw 95 mL of release medium at different times, and add an equal amount of release medium. The above release medium is filtered through a 0.22 μm microporous membrane, and the content of triamcinolone acetonide in the release medium is determined by high performance liquid chromatography (HPLC).

[0321] Liquid chromatography conditions: Ultimate, XB-C18 column (4.6×250 mm, 5 μm); mobile phase: methanol-water (52.5:47.5, v / v); detection wavelength: 240 nm; column temperature: 30°C; flow rate: 1.0 mL min- 1 ; Injection volume: 20μL.

[0322] The cumulative release amount Rn% of the drug was calculated according to the following formula.

[0323]

[0324] Wherein, V0 is the volume of release medium, Cn is the concentration at the nth sampling, V is the sampling volume, and Mt is the total drug concentration.

[0325] Take one of each of the pre-filled finished products of ophthalmic preparation examples 1A, 1B, 1C-5A, 5B, 5C, and comparative examples 1-35, put them into the jacket, adjust the upper and lower limit devices, clamp the test sample, input various test parameters in the test interface, and perform the measurement.

[0326] Verification parameter determination settings:

[0327] Instrument type: Discovery HR-1TFL-IS electronic tensile testing machine

[0328] Control mode: Constant speed

[0329] Direction (compression): 2mm / min

[0330] Each sample was tested 5 times, the test results were recorded, and the average value was calculated.

[0331] The in vitro sustained release time and onset force of ophthalmic preparation preparation examples 1A, 1B, 1C-5A, 5B, 5C and comparative examples 1-35 are shown in Table 3.

[0332] The schematic diagram of in vitro release of ophthalmic preparation examples 1B, 2B and comparative example 1 is shown in Figure 1-3 .

[0333] Table 3

[0334]

[0335]

[0336] In addition to considering the release time of the drug, when judging whether the sustained release effect can be achieved, factors such as whether the starting force meets the requirements of ergonomics and the sealing requirements of the syringe itself should also be considered. According to the provisions of the starting force of "sliding performance" (≤25N) in the quality standard of prefilled syringe assemblies and the provisions of "applying a pressure of 30N, there must be no leakage at the contact point between the piston and the syringe" in "body tightness", the starting force of the preparation is set to ≤25N. Under this standard, the drug is easy to push and the body is well sealed. Referring to this principle, all examples in Table 3 meet the starting force of ≤25N. In addition, the starting forces of Comparative Examples 1-3, Comparative Examples 10-12, and Comparative Examples 25-27 do not exceed 25N, but the release time of Comparative Examples 1-3, Comparative Examples 10-12, and Comparative Examples 25-27 is too fast and cannot achieve a sustained release effect.

[0337] From the results in Table 3, it can be seen that only when the weight ratio of active drug: liquid matrix: solid matrix is ​​1: 0.95-1.25: 0.35-0.45, and the particle size range of active drug is D 90 ≤50μm, especially 1μm≤D 90 When the particle size is ≤50μm, the ophthalmic pharmaceutical composition can meet the requirements of the initial force and achieve the effect of sustained release. It can be easy to push and convenient for drug administration while meeting the effect of long-term sustained release of the preparation in the eye.

[0338] Evaluation Example 2: Investigation of in vitro release and initial release of ophthalmic preparations with different prescriptions

[0339] Embodiment 6-10

[0340] Referring to the preparation method of the ophthalmic preparations of Examples 1A-5C, the ophthalmic preparations of Examples 6-10 were prepared according to the formulations in Table 4.

[0341] Table 4

[0342]

[0343] Each ophthalmic preparation was prepared specifically as follows.

[0344] Example 6 Preparation of ophthalmic preparations

[0345] Weigh 12 g of PEG20000 into a beaker, add 30 g of triacetin, stir at 60°C until PEG20000 is completely dissolved, and add the drug particle size D 90The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparation of Example 6.

[0346] Example 7 Preparation of ophthalmic preparations

[0347] Weigh 10.5 g of polyglycolic acid into a beaker, add 37.5 g of propylene glycol, stir at 60 °C until the polyglycolic acid is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparation of Example 7.

[0348] Example 8 Preparation of ophthalmic preparations

[0349] Weigh 12 g of polylactic acid into a beaker, add 33 g of glycerol, stir at 60 °C until the polylactic acid is completely dissolved, and add the drug particles D 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparation of Example 8.

[0350] Example 9 Preparation of ophthalmic preparations

[0351] Weigh 13.5 g of PEG1000 into a beaker, add 28.5 g of diethyl succinate, stir at 60 °C until PEG1000 is completely dissolved, and add the drug particle size D 90 30 g of 10 μm cyclosporine was added, and stirring was continued until the mixture was uniformly mixed. The mixture was filled into 1 ml prefilled syringes, with each syringe having a filling volume of 0.2 ml. The mixture was sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparation of Example 9.

[0352] Example 10 Preparation of ophthalmic preparations

[0353] Weigh 10.5 g of polylactic acid-co-glycolic acid copolymer into a beaker, add 28.5 g of diethyl tartaric acid, stir at 60 °C until the polylactic acid-co-glycolic acid copolymer is completely dissolved, and add the drug particles D under stirring. 90 The mixture was filled into 1 ml prefilled syringes with a filling volume of 0.2 ml each, and sterilized by wet heat at 121° C. for 15 min to obtain the ophthalmic preparation of Example 10.

[0354] The in vitro release and initial release of the ophthalmic preparation were investigated according to the method in Evaluation Example 1. The results are shown in Table 5.

[0355] Table 5

[0356] Ophthalmic preparations Release time (days) Starting force (Fmax, N) Example 6 95 22 Example 7 85 17 Example 8 88 20 Example 9 100 18 Example 10 104 23

[0357] As can be seen from the above table, the sustained release time of Examples 6-10 is within the range of 85-104 days and the starting force is within the range of 17-23N, which is equivalent to that of Examples 1A-5C, indicating that when different active ingredients, liquid matrices or solid matrices are used, when the weight ratio of the three satisfies that the active pharmaceutical ingredient is 1 part by weight, the liquid matrix is ​​0.95-1.25 parts by weight, and the solid matrix is ​​0.35-0.45 parts by weight, and the particle size of the active ingredient satisfies D 90 ≤50μm, especially when 1μm≤D90≤50μm, the optimal slow release and convenient injection effect can be achieved.

[0358] Evaluation Example 3: Investigation of the Dispersion Uniformity of Ophthalmic Preparations

[0359] The ophthalmic preparation examples 1A, 1B, 1C-5A, 5B, 5C, and comparative examples 1-35 were taken and the dispersion uniformity of each formulation was examined after stability testing.

[0360] Dispersion uniformity test: Place the samples at 60℃ and illumination of (4500±500)Lx for 10 days, and take samples on the 5th and 10th days. Low temperature cycle test: Place the samples at 2-8℃ for 2 days and then at 40℃ for 2 days for each cycle, and take samples for testing. This is recorded as one cycle, and three cycles are performed continuously. Evaluation index of prescription: Appearance inspection: Check whether the state of the liquid medicine changes before and after each dispersion uniformity test, and whether stratification, aggregation, and agglomeration occur.

[0361] The dispersion uniformity results of ophthalmic preparation preparation examples 1A, 1B, 1C-5A, 5B, 5C, and comparative examples 1-35 are shown in Table 6.

[0362] Table 6

[0363]

[0364]

[0365]

[0366] Note: Even dispersion of drug solution means that the active ingredients of the drug are evenly dispersed in the matrix without stratification, precipitation, agglomeration, etc. Stratification of drug solution means that the drug is unevenly dispersed and clear liquid appears on the upper layer of the drug solution. Agglomeration of drug solution means that the drug is unevenly dispersed and the drug aggregates and agglomerates.

[0367] From the results in Table 6, it can be seen that the weight ratio of the active ingredient, the liquid matrix or the solid matrix satisfies that the active drug is 1 part by weight, the liquid matrix is ​​0.95-1.25 parts by weight, and the solid matrix is ​​0.35-0.45 parts by weight. At the same time, the particle size range of the active drug is D 90 When the particle size D is less than 50 μm, the drug solution has good dispersion uniformity, and there is no stratification, precipitation, or agglomeration. It can meet the effect of long-term sustained release of the preparation in the eye, and it is easy to push and convenient for drug administration, and has good dispersion uniformity. 90 When the particle size D of the active ingredient is 70 μm (e.g., Comparative Examples 31-35), the prepared liquid medicine exhibits stratification. 90 When the particle size is ≤50 μm, if the amount of both the liquid matrix and the solid matrix is ​​too small (for example, Comparative Examples 19-21), the prepared liquid medicine will agglomerate; if the amount of the liquid matrix is ​​too large and the amount of the solid matrix is ​​too small (for example, Comparative Examples 25-27), the prepared liquid medicine will be stratified.

[0368] The above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. An ophthalmic pharmaceutical composition comprising or consisting of the following components: 1 part by weight of active pharmaceutical ingredient, 0.95-1.25 parts by weight of liquid matrix, 0.35-0.45 parts by weight of solid matrix, in, The particle size of the active pharmaceutical ingredient meets: D 90 ≤50μm.

2. The ophthalmic pharmaceutical composition according to claim 1, wherein: The particle size of active pharmaceutical ingredients meets the following requirements: 1μm≤D 90 ≤50μm.

3. The ophthalmic pharmaceutical composition according to any one of claims 1 to 2, wherein: The active pharmaceutical ingredient is one or a mixture of two or more selected from anti-tumor drugs, anti-inflammatory drugs, immunosuppressants, neovascularization inhibitors and glaucoma treatment drugs; Preferably, the active pharmaceutical ingredient is selected from chlorambucil, phenylalanine mustard, cyclophosphamide, ifosfamide, carmustine, lomustine, semustine, chlorozotocin, cisplatin, carboplatin, oxaliplatin, fluorouracil, mitoxantrone, irinotecan, topotecan, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, paclitaxel, docetaxel, bleomycin, methotrexate, gemcitabine, capecitabine, hydroxyurea, mitomycin, gefitinib, sunitinib, dexamethasone, dexamethasone acetate, prednisone, prednisone acetate, fluocinolone acetonide, fluocinolone acetate, triamcinolone acetonide, methylprednisolone, methylprednisolone ethylpropionate, halobetasol Propionate, cortisone, hydrocortisone, cyclosporine, rapamycin, tacrolimus, mycophenolate mofetil, tacrolimus, mizoribine, sulfasalazine, azathioprine, methotrexate, bevacizumab, ranibizumab, pegaptanib sodium, aflibercept, latanoprost, travoprost, bimatoprost, tafluprost, pilocarpine, atropine, scopolamine, betaxolol, metoprolol, bunolol, metipranolol, propranolol, timolol, benfuranolol, acetazolamide, dorzolamide, brinzolamide, alaclonidine, brimonidine, dipivefrin, guanethidine, dapprazole, dasatinib and a mixture of one or more of their pharmaceutically acceptable salts; Preferably, the active pharmaceutical ingredient is selected from the group consisting of dexamethasone, latanoprost, dasatinib, triamcinolone acetonide, pilocarpine, methotrexate, cyclosporine, brimonidine, and pharmaceutically acceptable salts thereof, or a mixture of two or more thereof.

4. The ophthalmic pharmaceutical composition according to any one of claims 1 to 3, wherein: The liquid matrix is ​​a biodegradable liquid matrix, preferably the liquid matrix is ​​a mixture of one or more of diethyl succinate, diethyl tartrate, dimethyl glutarate, triacetin, polyethylene glycol, glycerol, and propylene glycol, preferably the polyethylene glycol of the liquid matrix is ​​a mixture of one or more of polyethylene glycols having a number average molecular weight of 70-750, for example, a mixture of one or more of PEG-200, PEG-300, PEG-400, and PEG-600; Preferably, the liquid matrix is ​​polyethylene glycol, preferably polyethylene glycol PEG-400.

5. The ophthalmic pharmaceutical composition according to any one of claims 1 to 4, wherein: The solid matrix is ​​a biodegradable solid matrix, preferably the solid matrix is ​​a mixture of one or more of polyethylene glycol and hydroxycarboxylate polymers, preferably the solid matrix is ​​a mixture of one or more of polyethylene glycol, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, preferably the polyethylene glycol of the solid matrix is ​​a mixture of one or more of polyethylene glycols having a number average molecular weight of 800-20000, for example, a mixture of one or more of PEG-800, PEG-1000, PEG-1500, PEG-2000, PEG-4000, PEG-6000, PEG-8000, PEG-10000 and PEG-20000; Preferably, the solid matrix is ​​poly(lactic acid-co-glycolic acid); Preferably, the mass ratio of the units derived from glycolic acid to the units derived from lactic acid in the polylactic acid-glycolic acid copolymer is 1:0.01-100, preferably 1:0.02-50, preferably 1:0.05-20, preferably 1:0.1-10, preferably 1:0.2-5, preferably 1:0.5-4, preferably 1:1-3; Preferably, the weight average molecular weight of the hydroxycarboxylic acid polymer of the solid matrix is ​​1000-600000, preferably 5000-200000, for example 10000-20000; preferably, the molecular weight distribution Mw / Mn of the solid matrix is ​​1.0-10.0, for example 1.5-5.

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6. The ophthalmic pharmaceutical composition according to any one of claims 1 to 5, wherein: The active pharmaceutical ingredient is triamcinolone acetonide, The liquid matrix is ​​polyethylene glycol PEG-400; The solid matrix is ​​polylactic acid-glycolic acid copolymer.

7. The ophthalmic pharmaceutical composition according to any one of claims 1 to 6, wherein: The ophthalmic pharmaceutical composition is an ophthalmic pharmaceutical preparation, preferably an ophthalmic pharmaceutical injection preparation, or a sustained-release insert or implant, and the ophthalmic pharmaceutical injection preparation is preferably an intraocular injection preparation, preferably a subconjunctival injection preparation, an intravitreal injection preparation, a periocular injection preparation, a retrobulbar injection preparation or an intracameral injection preparation; Preferably, the ophthalmic pharmaceutical preparation is a sustained-release preparation; Preferably, the ophthalmic pharmaceutical composition is filled in a prefilled syringe, and preferably the filling volume of the ophthalmic pharmaceutical composition is 0.01 ml-10 ml, preferably 0.1 ml-2 ml; Preferably, the dosage of the ophthalmic pharmaceutical composition is 1 μl-100 μl, preferably 2-20 μl; Preferably, the sustained release time limit of the ophthalmic pharmaceutical composition is 30 days to 730 days, preferably 60 to 120 days; Preferably, the ophthalmic pharmaceutical composition is administered once every 30 to 730 days, preferably once every 60 to 120 days; Preferably, the ophthalmic pharmaceutical composition is in liquid form at room temperature.

8. A method for preparing a pharmaceutical ophthalmic composition according to any one of claims 1 to 7, comprising: (1) Providing an active pharmaceutical ingredient that satisfies the particle size relationship defined in any one of claims 1 to 2; (2) mixing a solid matrix with a liquid matrix, preferably dissolving the solid matrix in the liquid matrix, to obtain a mixed matrix; and (3) dispersing the active pharmaceutical ingredient provided in step (1) in the mixed matrix obtained in step (2); Optionally, the method further comprises a step of pulverizing the active pharmaceutical ingredient before step (1).

9. An ophthalmic kit comprising the ophthalmic pharmaceutical composition according to any one of claims 1 to 7, preferably, the ophthalmic kit comprises a prefilled syringe, wherein the ophthalmic pharmaceutical composition is filled in the prefilled syringe, preferably, the filling volume of the ophthalmic pharmaceutical composition is 0.01 ml-10 ml, preferably 0.1 ml-2 ml.

10. Use of the ophthalmic pharmaceutical composition according to any one of claims 1 to 7 or the ophthalmic pharmaceutical kit according to claim 9 in the preparation of drugs for preventing and / or treating eye diseases.

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