Ophthalmic composition containing ciclosporin

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to an ophthalmic composition containing cyclosporine. The ophthalmic composition comprises a first component and a second component, wherein the first component is ciclosporin or a pharmaceutically acceptable salt or a pharmaceutically acceptable derivative thereof; and a second component, wherein the second component is selected from at least one of alkyl glycoside and polyethylene glycol-15-hydroxystearate. The cyclosporine composition disclosed by the invention is good in stability, and repeated administration results show that the composition is free from eye irritation, so that the safety and the patient compliance are greatly improved. Meanwhile, the preparation process of the cyclosporine composition is simple, batch production can be realized through a conventional ophthalmic preparation production line, and the cyclosporine composition is beneficial to popularization and application in actual production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly, to an ophthalmic composition containing cyclosporine. Background Art

[0002] Dry eye disease is a disorder caused by multiple factors and complex reasons, mainly manifested as abnormal quality or quantity of tears, or abnormal tear fluid dynamics, resulting in decreased tear film stability, accompanied by eye discomfort and / or ocular surface tissue lesions. Artificial tears, as the first-line treatment for dry eye disease, are mainly used to replace or supplement tears. However, ester-containing eye drops are considered to be closer to natural tears because they better mimic the structure of the aqueous and lipid layers of the tear film.

[0003] Cyclosporine is a highly effective immunosuppressant with no bone marrow toxicity and selective inhibitory effects, and is also the first-choice drug for the local administration of eye inflammation in the eye. However, due to the high molecular weight and hydrophobicity of cyclosporine, combined with the natural barrier function of the eye to foreign substances, it is challenging to achieve therapeutic levels of cyclosporine in eye tissues. Given that cyclosporine is highly soluble in various oils, there are currently ester-containing (emulsion type) cyclosporine eye drops approved for marketing in the United States, China, and South Korea. Its mechanism of action is that the lipid layer of the tear film is composed of outer lipids, and a small part of the oil droplets encapsulating cyclosporine fuse with the lipid layer of the tear film, thereby forming a drug reservoir that enables the sustained release of cyclosporine.

[0004] Currently, there are several products of cyclosporine eye drops on the market for the treatment of dry eye disease. For example, Restasis TM (0.05%, O / W type emulsion, single dose) marketed in the United States has been considered by the Committee for Medicinal Products for Human Use (CHMP) in Europe to have poor efficacy, and 17% of patients experienced ocular burning after use. Cequa TM (0.09%, nano micelle aqueous solution, single dose) of Sun Pharmaceutical Industries needs to be administered twice a day with an interval of more than 12 hours, and its common adverse reactions include pain at the infusion site (22%) and conjunctival congestion (6%). Ikervis TM (0.1%, cationic nanoemulsion, single dose) marketed in France by Santen Pharmaceutical Co., Ltd. only needs to be administered once a day. Due to the addition of cetalkonium chloride as a cationic surfactant in the formulation, the most common adverse reactions are eye pain (19%), eye irritation (17.8%), and eye congestion.

[0005] Due to the hydrophobicity of cyclosporine itself and the natural barrier mechanism of the eye, the prior art mainly solves its solubility problem by using oils or organic solvents such as castor oil, polyoxyethylene hydrogenated castor oil, medium-chain triglycerides (such as perfluorobutyl pentane). In the related patent, CN114246935A discloses a composition containing cyclosporine and its application in the preparation of drugs for treating dry eye. In this patent application, medium-chain fatty acid triglycerides are used as a carrier to form an oil solution with cyclosporine, aiming to promote the penetration of cyclosporine into the cornea and connective tissue and extend its retention time, but the use of unconventional solvents may affect patient compliance. In addition, CN117598993A discloses a cyclosporine eye drop and its preparation method. In this patent application, vegetable oil is used as a carrier, and the solution is prepared by a water-oil two-phase shear mixing, high-pressure homogenization, and moist heat sterilization process to reduce adverse reactions such as pain at the instillation site, conjunctival congestion, blepharitis, and eye irritation. However, the cyclosporine eye drop provided therein is an emulsion, and this dosage form is prone to problems such as demulsification and particle size coarsening during long-term storage, and is not suitable for sterile filtration. Moreover, the 121-degree sterilization method mentioned in this patent application may cause deformation of the LDPE material, making its leachables enter the medicinal liquid, posing a safety hazard.

[0006] However, the prior art still faces some problems that need to be solved urgently. For example, excipients added for solubilization or emulsification may cause eye irritation, quality stability problems of emulsions (such as stratification, flocculation, inversion, demulsification, etc.), and relatively high manufacturing costs due to the complex emulsion process. These problems need to be further optimized and solved in subsequent research and development. Summary of the Invention

[0007] The present invention provides an ophthalmic composition, which comprises: a first component, wherein the first component is cyclosporine or a pharmaceutically acceptable salt or derivative thereof; and a second component, wherein the second component is selected from at least one of alkyl glycoside and polyethylene glycol-15-hydroxystearate.

[0008] The cyclosporine composition of the present invention has good stability, and the results of multiple administrations show that the composition has no eye irritation, greatly improving safety and patient compliance. At the same time, the preparation process of the cyclosporine composition is simple, and batch production can be achieved through a conventional ophthalmic preparation production line, which is conducive to popularization and application in actual production. Detailed Embodiments

[0009] The following provides a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not used to limit the present invention. Those skilled in the art can make various modifications and changes to the present invention without departing from the scope or spirit of the present invention. For example, features described or illustrated as part of one embodiment can be used in another embodiment to produce a further embodiment.

[0010] Unless otherwise specified, the meanings of all terms (including technical and scientific terms) used to disclose the present invention are the same as those commonly understood by those of ordinary skill in the art to which the present invention pertains. Through further guidance, the following definitions are used to better understand the teachings of the present invention. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention.

[0011] As used herein, the terms "and / or", "or / and", and "and / or" include any one of two or more related listed items, as well as any and all combinations of the related listed items. The said any and all combinations include combinations of any two related listed items, any more than two related listed items, or all related listed items. It should be noted that when at least two conjunctions selected from "and / or", "or / and", and "and / or" are used to connect at least three items, it should be understood that in this application, this technical solution undoubtedly includes the technical solution connected by "logical AND", and also undoubtedly includes the technical solution connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A + B. Another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, it includes combinations of any two or any three of A, B, C, and D, and also includes the combination of the four items A, B, C, and D (that is, the technical solution connected by "logical AND").

[0012] The terms "comprising", "containing", and "including" used in the present invention are synonyms, which are inclusive or open-ended and do not exclude additional, unrecited members, elements, or method steps.

[0013] In the present invention, the numerical ranges represented by endpoints include all the numerical values and fractions included in the range, as well as the recited endpoints.

[0014] Regarding the concentration values involved in the present invention, their meanings include fluctuations within a certain range. For example, it can fluctuate within the corresponding accuracy range. For example, for 2%, a fluctuation within the range of ±0.1% is allowed. For larger numerical values or those that do not require overly precise control, a greater fluctuation is also allowed for their meanings. For example, for 100 mM, fluctuations within the ranges of ±1%, ±2%, ±5%, etc. are allowed. Regarding the molecular weight, a fluctuation of ±10% is allowed for its meaning.

[0015] In the present invention, regarding descriptions such as "a plurality of" and "a variety of", unless otherwise specified, it means greater than or equal to 2 in quantity.

[0016] In the present invention, among the technically characterized features described in an open-ended manner, it includes both a closed technical solution composed of the listed features and an open technical solution containing the listed features.

[0017] In the present invention, "preferably", "better", "more preferably", and "appropriately" are only used to describe the embodiments or examples with better effects, and it should be understood that they do not constitute a limitation on the protection scope of the present invention.

[0018] In the present invention, "optionally", "optional", "option", "optionally", "optional", "option", mean that it can be either present or absent, that is, it refers to any one of the two parallel options of "present" or "absent". If there are multiple "optionally" or "optional" in a technical solution, without special instructions and without contradictions or mutual constraints, each "optionally" or "optional" is independent.

[0019] In the present invention, the term "Cyclosporine" is an immunosuppressant, a cyclic polypeptide composed of 11 amino acids, with a strong immunomodulatory effect. It reduces the inflammatory response by inhibiting the activation of T cells and the release of cytokines. Currently, it is mainly used to treat ocular inflammatory diseases such as dry eye and corneal transplant rejection. In "Cyclosporine or its pharmaceutically acceptable salts or pharmaceutically acceptable derivatives", "pharmaceutically acceptable salts" refer to pharmaceutically acceptable salts formed by Cyclosporine and acids or bases, and their purpose is generally to improve the solubility, stability, or bioavailability of Cyclosporine, etc.; "pharmaceutically acceptable derivatives" are compounds obtained by chemically modifying the molecular structure of Cyclosporine, generally aiming to improve its pharmaceutical properties (such as solubility, stability, absorbability, etc.).

[0020] In the present invention, "% w / v" represents the weight / volume percentage concentration, specifically referring to the weight (grams, g) of the solute contained in every 100 milliliters (mL) of the solution. The calculation formula is: % w / v = (solute weight (g) / solution volume (mL)) × 100.

[0021] In the present invention, a "clear and transparent liquid" refers to a liquid that has no turbidity, no suspended matter, no precipitation in appearance, and through which light can pass smoothly.

[0022] The present invention provides an ophthalmic composition, which comprises: a first component, and the first component is Cyclosporine or its pharmaceutically acceptable salts or pharmaceutically acceptable derivatives; and a second component, and the second component is selected from at least one of alkyl glycoside and polyethylene glycol-15-hydroxystearate (HS15). The present invention discovers that using alkyl glycoside and / or HS15 as solubilizers can significantly improve the dissolution effect of the first component, and there is no eye irritation, which can greatly improve patient compliance while ensuring the drug efficacy.

[0023] In order to further improve the solubilization effect on the active ingredient (i.e., the first component), the present invention further optimizes the selection of alkyl glycosides and obtains the following preferred embodiments.

[0024] In some embodiments, in the alkyl glycoside, the alkyl part is composed of 8 to 14 carbon atoms, and the average number of sugar units bonded to each alkyl is 1.1 to 3.0. The present invention further discovers that the alkyl glycoside meeting the above limitations has a better solubilization effect on cyclosporine.

[0025] In some specific embodiments, the alkyl glycoside includes at least one of octyl glycoside (C8), decyl glycoside (C10), dodecyl glycoside (C12), and tetradecyl glycoside (C14).

[0026] In some embodiments, the alkyl glycoside includes at least one of dodecyl maltoside, decyl glucopyranoside, tetradecyl maltoside, dodecyl glucoside, coconut alkyl glucoside, and octyl glucoside. The above alkyl glycosides have a better solubilization effect on the active ingredient of the present invention.

[0027] In the present invention, the selection of alkyl glycosides is not limited to a specific configuration. In specific implementations, those skilled in the art can select commercially available products with a specific configuration in combination with common knowledge. As an example, in some specific embodiments, the dodecyl maltoside is dodecyl-β-D-maltoside. In some specific embodiments, the decyl glucopyranoside is decyl-β-D-glucopyranoside. In some specific embodiments, the tetradecyl maltoside is tetradecyl-β-D-maltoside.

[0028] In some embodiments, based on the total volume of the ophthalmic composition, the concentration of the first component is 0.01 to 0.50% w / v.

[0029] As an example, in some specific embodiments, based on the total volume of the ophthalmic composition, the concentration of the first component is 0.01% w / v, 0.05% w / v, 0.08% w / v, 0.1% w / v, 0.12% w / v, 0.15% w / v, 0.20% w / v, 0.25% w / v, 0.30% w / v, 0.35% w / v, 0.40% w / v, 0.45% w / v, 0.50% w / v, or any value within the range of 0.01 to 0.50% w / v.

[0030] In some embodiments, when the second component is alkyl polyglycoside, the mass ratio of the second component to the first component is greater than or equal to 5; when the second component is polyethylene glycol-15-hydroxystearate, the mass ratio of the second component to the first component is greater than or equal to 10. When the above limitations are met, complete dissolution of the active ingredient can be achieved, and as the amount of the second component increases, the solubilization effect is better and the dissolution is faster.

[0031] Taking into account the drug cost, eye irritation and comprehensive drug performance, in some embodiments, based on the total volume of the ophthalmic composition, the concentration of the second component is 0.05-10% w / v, more preferably 0.05-7.5% w / v.

[0032] As an example, in some specific embodiments, based on the total volume of the ophthalmic composition, the concentration of the second component is 0.05% w / v, 0.10% w / v, 0.25% w / v, 0.30% w / v, 0.40% w / v, 0.50% w / v, 0.60% w / v, 0.70% w / v, 0.80% w / v, 0.90% w / v, 1.0% w / v, 1.5% w / v, 2.0% w / v, 2.5% w / v, 3.0% w / v, 3.5% w / v, 4.0% w / v, 4.5% w / v, 5.0% w / v, 5.5% w / v, 6.0% w / v, 6.5% w / v, 7.0% w / v, 7.5% w / v, 8.0% w / v, 9.0% w / v, 10.0% w / v or any value within the range of 0.05-10% w / v.

[0033] In some specific embodiments, the second component is alkyl polyglycoside, and based on the total volume of the ophthalmic composition, the concentration of the alkyl polyglycoside is 0.05-5% w / v.

[0034] As an example, in some specific embodiments, based on the total volume of the ophthalmic composition, the concentration of the alkyl polyglycoside is 0.05% w / v, 0.10% w / v, 0.25% w / v, 0.30% w / v, 0.40% w / v, 0.50% w / v, 0.60% w / v, 0.70% w / v, 0.80% w / v, 0.90% w / v, 1.0% w / v, 1.5% w / v, 2.0% w / v, 2.5% w / v, 3.0% w / v, 3.5% w / v, 4.0% w / v, 4.5% w / v, 5.0% w / v or any value within the range of 0.05-5% w / v.

[0035] In some specific embodiments, the second component is polyethylene glycol-15-hydroxystearate, and based on the total volume of the ophthalmic composition, the concentration of the polyethylene glycol-15-hydroxystearate is 0.1-10% w / v.

[0036] As an example, in some specific embodiments, based on the total volume of the ophthalmic composition, the concentration of polyethylene glycol-15-hydroxystearate is any value within the range of 0.10% w / v, 0.25% w / v, 0.30% w / v, 0.40% w / v, 0.50% w / v, 0.60% w / v, 0.70% w / v, 0.80% w / v, 0.90% w / v, 1.0% w / v, 1.5% w / v, 2.0% w / v, 2.5% w / v, 3.0% w / v, 3.5% w / v, 4.0% w / v, 4.5% w / v, 5.0% w / v, 5.5% w / v, 6.0% w / v, 6.5% w / v, 7.0% w / v, 7.5% w / v, 8.0% w / v, 9.0% w / v, 10.0% w / v, or 0.1-10% w / v.

[0037] In some embodiments, the osmolality of the ophthalmic composition is 200-400 mOsm / L, preferably 300±10 mOsm / L. Those skilled in the art can adjust and determine the specific dosage of the osmotic pressure regulator in combination with this parameter range.

[0038] As an example, in some specific embodiments, the osmolality of the ophthalmic composition is 200 mOsm / L, 250 mOsm / L, 280 mOsm / L, 290 mOsm / L, 300 mOsm / L, 310 mOsm / L, 320 mOsm / L, 350 mOsm / L, 400 mOsm / L, or any value within the range of 200-400 mOsm / L.

[0039] In some embodiments, the viscosity of the ophthalmic composition is 1-50 mPa·s, preferably 5-30 mPa·s. Those skilled in the art can adjust and determine the specific dosage of the thickening agent in combination with this parameter range.

[0040] As an example, in some specific embodiments, the viscosity of the ophthalmic composition is 1 mPa·s, 3 mPa·s, 5 mPa·s, 10 mPa·s, 15 mPa·s, 20 mPa·s, 25 mPa·s, 30 mPa·s, 40 mPa·s, 50 mPa·s, or any value within the range of 1-50 mPa·s.

[0041] In some embodiments, the viscosity of the ophthalmic composition has a pH value of 5.0-8.0. Those skilled in the art can adjust and determine the specific dosage of the pH regulator and / or pH buffer in combination with this parameter range. Within this range, the pH value has little effect on the physicochemical properties and drug efficacy of the composition of the present invention.

[0042] As an example, in some specific embodiments, the pH value of the ophthalmic composition is 5.0, 5.5, 6.0, 6.5, 6.8, 6.9, 6.95, 7.0, 7.05, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 8.0, or any value within the range of 6.5 to 8.0.

[0043] In some embodiments, the ophthalmic composition further comprises at least one selected from the group consisting of an osmotic pressure regulator, a thickening agent, a pH regulator, and a pH buffer.

[0044] It has been verified that when the active component and the solubilizing component of the present invention are applied in various types of ophthalmic preparations, they all have excellent solubilizing effects and do not cause eye irritation. In specific implementation, those skilled in the art can further add at least one of an osmotic pressure regulator, a thickening agent, a pH regulator, and a pH buffer in this system in combination with common knowledge, and determine the specific dosage of each component in combination with the foregoing parameter range description.

[0045] In some embodiments, the osmotic pressure regulator includes at least one of sodium chloride, potassium chloride, phosphate buffer solution, glucose, mannitol, sucrose, glycerol, propylene glycol, sorbitol, glycine, alanine, boric acid, and polyethylene glycol.

[0046] In some embodiments, the thickening agent includes at least one of sodium hyaluronate, hypromellose, polyvinylpyrrolidone, poloxamer 407, poloxamer 188, carbomer, methylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, polyvinyl alcohol, polyethylene glycol, chitosan, hyaluronic acid, polyacrylic acid, agar, polyacrylamide, hydroxyethyl cellulose, sodium polyacrylate, and polyethylene oxide.

[0047] The present invention does not make a special limitation on the specific selection of the pH regulator. In some specific embodiments, the pH regulator includes at least one of hydrochloric acid, acetic acid, citric acid, sodium hydroxide, sodium bicarbonate, ammonia water, triethanolamine, and sodium carbonate. In specific implementation, those skilled in the art can also select other pH regulators in combination with common knowledge, which will not have a substantial impact on the technical effects of the ophthalmic composition of the present invention.

[0048] In some specific embodiments, the pH buffer includes at least one of phosphate buffer solution, borate buffer solution, acetate buffer solution, and citrate buffer solution. In specific implementation, those skilled in the art can also select other pH buffers in combination with common knowledge.

[0049] In some embodiments, the solvent of the ophthalmic composition is water.

[0050] In some specific embodiments, the water used in the present invention is sterile water, water for injection, etc.

[0051] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 0.5 - 1.5% w / v of sodium chloride, and 0.1 - 0.5% w / v of sodium hyaluronate, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0052] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 0.5 - 1.5% w / v of sodium chloride, and 0.2 - 0.3% w / v of hypromellose, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0053] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, and 0.5 - 1.5% w / v of sodium chloride, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0054] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 4 - 6% w / v of mannitol, and 0.1 - 0.5% w / v of sodium hyaluronate, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0055] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 0.5 - 1.5% w / v of sodium chloride, and 4 - 5% w / v of povidone, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0056] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 1.5 - 3.0% w / v of glycerol, and 0.2 - 0.3% w / v of hypromellose, and the pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0057] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 0.5 - 1.5% w / v of sodium chloride, 15 - 25% w / v of poloxamer 407, and 3 - 5% w / v of poloxamer 188. The pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0058] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, and 1.5 - 3.0% w / v of glycerol. The pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0059] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 4.0 - 6.0% w / v of sorbitol, and 0.2 - 0.3% w / v of hypromellose. The pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0060] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 1.5 - 3.0% w / v of glycerol, and at least one selected from 0.05 - 0.15% w / v of sodium dihydrogen phosphate and 0.15 - 0.20% w / v of disodium hydrogen phosphate. The pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0061] In some specific embodiments, based on the total volume of the ophthalmic composition, the ophthalmic composition comprises the following components: 0.01 - 0.50% w / v of the first component, 0.05 - 10% w / v of the second component, 1.5 - 3.0% w / v of glycerol, and 0.1 - 0.5% w / v of sodium hyaluronate. The pH value is adjusted to 5.0 - 8.0 with an appropriate amount of hydrochloric acid and / or sodium hydroxide, and the balance is water.

[0062] In some embodiments, the ophthalmic composition is a clear and transparent liquid at 5°C to room temperature.

[0063] In some embodiments, the ophthalmic composition does not contain an oil solvent.

[0064] In some embodiments, the ophthalmic composition does not contain other solubilizers (surfactants) except those defined in the present invention.

[0065] In some specific embodiments, the ophthalmic composition is any one of eye drops (ophthalmic solutions), ophthalmic irrigation solutions, ophthalmic gels, ophthalmic injections, and ophthalmic sprays.

[0066] In some specific embodiments, the ophthalmic composition is not an eye oil solvent or an eye emulsion.

[0067] In specific preparation, conventional mixing methods can be used to mix the components mentioned in the present invention to obtain the ophthalmic composition, and the present invention does not particularly limit its preparation method.

[0068] In some specific embodiments, the preparation method includes: mixing the components, then subjecting the mixed ophthalmic composition to sterile filtration (such as sterile filtration using a 0.22 μm filter), and then filling.

[0069] The embodiments of the present invention will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the guidance given in the present invention is preferably referred to, and it can also be carried out according to the experimental manuals or conventional conditions in the art, or other experimental methods known in the art, or according to the conditions recommended by the manufacturer.

[0070] In the following specific examples, for the measurement parameters of the raw material components, if not otherwise specified, there may be slight deviations within the weighing accuracy range. For the temperature and time parameters, acceptable deviations caused by the instrument test accuracy or operation accuracy are allowed.

[0071] In the following examples, when “%” is involved, it is all “% w / v”.

[0072] Example 1 Dissolution of Cyclosporine in Different Solubilizers

[0073] Solution-type preparations have a simple production process, stable quality, convenient use, and high patient compliance, making them the preferred dosage form for ophthalmic preparations. Solubilizers are often used to increase the solubility of drugs in water to prepare solution-type preparations. Commonly used solubilizers include cationic surfactants, anionic surfactants, and non-ionic surfactants. The solubilization effects of different surfactants on cyclosporine were studied. Aqueous solutions with different concentrations and different solubilizers were prepared, 0.1% cyclosporine was added, and its dissolution was confirmed at 5°C and room temperature respectively. The results showed (see Table 1 for details) that cyclosporine could not be dissolved in polysorbate 80 with a concentration less than 1%, and could be completely dissolved in sodium dodecyl sulfate with a concentration less than 0.7%, but the solubility decreased and precipitation occurred at low temperatures. Cyclosporine could be completely dissolved in alkyl glycosides (dodecyl-β-D-maltoside, decyl-β-D-glucopyranoside, tetradecyl-β-D-maltoside) with a concentration of 0.5% - 1%, and remained clear and transparent from 5°C to room temperature, showing good solubilization effects.

[0074] Alkyl glycosides with different carbon chains have similar properties and no obvious difference in solubilization effects.

[0075] Table 1

[0076]

[0077] Example 2 Solubilization Effects of Different Concentrations of Alkyl Glycosides

[0078] As shown in Table 2, different amounts of DDM were dissolved in 500 mL of water for injection respectively, the same concentration of cyclosporine was added, and magnetic stirring was carried out at the same rotation speed until completely dissolved to confirm the solubilization effects of different concentrations of alkyl glycosides. The results showed (see Table 2 for details) that with the increase of the concentration of alkyl glycosides, the solubilization effect on the same concentration of cyclosporine was better and the dissolution rate was faster.

[0079] Table 2

[0080] serial number Group 1 Group 2 Group 3 Group 4 Cyclosporine 0.1％ 0.1％ 0.1％ 0.1％ DDM 0.5％ 0.7％ 1.0％ 2.0％ Complete dissolution time About 24h 3h 1h 0.5h

[0081] Example 3 Different Formulations

[0082] Prepare the liquid medicine according to the different formulations (different concentrations, different alkyl glycosides, different osmotic pressure regulators, different thickeners) designed in Table 3 below. Take water for injection at room temperature, add each auxiliary material in turn to dissolve, add cyclosporine, adjust the pH value to the target value, weigh, and the liquid medicine is sterilized and filtered through a 0.22 μm filter respectively. After filtration, the liquid medicine is filled into the packaging material.

[0083] Table 3

[0084]

[0085]

[0086] Example 4 Physicochemical Properties

[0087] Upon observation and measurement, the different formulated cyclosporine solutions prepared in Example 3 were all clear and transparent liquids, and their indicators such as pH value, viscosity, and osmolarity met the requirements for ophthalmic preparations (see Table 4 below). Among them, Formulation 7 was an in-situ gelling eye drop of cyclosporine using poloxamer 407 and poloxamer 188 as carriers. This carrier has the property of being a solution at low temperatures and forming a gel when the temperature rises. At the formulated ratio, the gelation temperature was 33.8 °C, and it could form a gel in-situ after instillation, significantly increasing the residence time of cyclosporine on the ocular surface and thus better exerting its drug effect.

[0088] Table 4

[0089]

[0090] Example 5 Stability

[0091] Through stability research tests, it was found that alkyl glycosides with different carbon chains within the scope of the present invention had no obvious effect on the stability of the composition. In this example, specific data were provided taking different formulations containing DDM as examples.

[0092] Specifically, samples of Formulation 1, Formulation 4, and Formulation 5 prepared in Example 3 were subjected to stability research. The test conditions included high temperature at 40 °C, high temperature at 60 °C, light (4500 lx ± 500 lx), and freeze-thaw (-20 °C for 2 days, then placed at 40 °C for 2 days, cycled 3 times). Then, their related substances were detected, and the results are shown in Table 5, indicating that they had good stability under light, high temperature, and low temperature conditions.

[0093] Table 5

[0094]

[0095]

[0096] Example 6 Single-dose Ocular Irritation Test

[0097] Through the ocular irritation research test for drug administration, it was found that alkyl glycosides with different carbon chains within the scope of the present invention had no obvious effect on the ocular irritation of the composition. In this example, specific data were provided taking different formulations containing DDM as examples. The specific experiment is as follows:

[0098] Samples to be tested: Formulation 1, Formulation 4, Formulation 5, Comparative Example 1.

[0099] The formulation of Comparative Example 1 is shown in Table 6 below, and the preparation method is the same as that in Example 3.

[0100] Table 6

[0101]

[0102] Test animals: Dutch rabbits, both male and female, 4 animals per group of the preparation.

[0103] Test method: Examine the eyes of each animal within 24 hours before the test to ensure that there are no irritating symptoms in the rabbit eyes and no corneal and conjunctival injuries. During the test, instill the preparations of each group (30 μL) into the conjunctival sac of the left eye of the rabbit, and instill the same amount of normal saline into the right eye as a control. Gently close the eyelids for about 10 seconds after administration, and then instill 2.0% sodium fluorescein and observe with a slit lamp. Observe the local reactions of the eyes at 1, 2, 4, 24, 48, and 72 hours after administration, and observe the recovery at 4 and 7 days. Conduct single-dose eye irritation tests on Prescription 1, Prescription 4, Prescription 5, and Comparative Example 1 respectively according to the above method, and evaluate the eye irritation intensity. The evaluation criteria are shown in Tables 7 - 8.

[0104] Table 7 Scoring criteria for eye irritation response

[0105] Eye irritation reaction Points cornea No turbidity 0 Scattered or diffuse opacity, iris clearly visible 1 The translucent area is easy to distinguish, and the iris is blurred 2 A grayish-white translucent area appears, the details of the iris are unclear, and the size of the pupil is barely visible 3 Cornea is opaque and iris is unrecognizable 4 Iris normal 0 The wrinkles are obviously deepened, congested, and swollen, the cornea is slightly congested, and the pupil still reacts to light 1 Bleeding / visible necrosis / no reaction to light 2 conjunctiva Hyperemia (in the palpebral and bulbar conjunctiva, not the cornea and iris) Normal blood vessels 0 Blood vessels are bright red 1 The blood vessels are dark red due to congestion and it is difficult to distinguish the blood vessels. 2 Diffuse congestion purple 3 Edema No edema 0 Slight edema (including eyelids) 1 Marked edema with partial ectropion 2 Edema to the point where the eyelids are nearly half closed 3 Swelling to the point where the eyelid is more than half closed 4 Secretions No secretion 0 A small amount of secretion (excluding a small amount of normal secretion at the inner canthus) 1 Discharge that makes the eyelids and eyelashes wet or sticky 2 Discharge that makes the entire eye area wet or sticky 3 Maximum total points 16

[0106] Table 8 Evaluation and scoring criteria for eye irritation response

[0107]

[0108]

[0109] Statistically analyze the eye irritation data of each animal according to the scoring standard values. The test results are shown in Table 9. The 0.1% cyclosporine prescriptions containing different concentrations of alkyl glycosides have no eye irritation, and the 0.1% cyclosporine prescriptions containing 1% sodium dodecyl sulfate all have mild eye irritation.

[0110] Table 9 Results of single-dose eye irritation test

[0111]

[0112] Example 7 Multiple-dose eye irritation test

[0113] Through the single-dose eye irritation study test, it was found that the 0.1% cyclosporine prescriptions containing different concentrations of alkyl glycosides have no eye irritation. In this example, Prescription 1 is used as an example to provide a multiple-dose eye irritation test. The specific experiment is as follows:

[0114] Test sample: Prescription 1.

[0115] Test animals: Dutch rabbits, both male and female, 4 animals per group of the preparation.

[0116] Test method: Examine the eyes of each animal within 24 hours before the test to ensure that there are no irritating symptoms in the rabbit eyes and no corneal and conjunctival injuries. During the test, instill the test preparation (30 μL) into the conjunctival sac of the left eye of the rabbit, and instill the same amount of normal saline into the right eye as a control. Gently close the eyelids for about 10 seconds after administration, and then instill 2.0% sodium fluorescein and observe with a slit lamp. Administer the drug 2 times a day for 14 consecutive days. Conduct slit lamp examinations before each drug administration and at 1, 2, 4, 24, 48, and 72 hours after the last drug administration. Observe the cornea, iris, conjunctival congestion, conjunctival edema, and conjunctival secretions with a slit lamp, and score according to the eye irritation response score standard (Table 7).

[0117] Statistically analyze the eye irritation data of each animal according to the scoring standard value (Table 8), and the test results are shown in Table 10. There is no irritation after continuous administration of the preparation of Prescription 1 for 14 days.

[0118] Table 10 Results of multiple eye irritation tests

[0119]

[0120] Based on the results of Example 6 and Example 7, it can be seen that the cyclosporine composition using alkyl glycoside as a solubilizer avoids the irritation and eye toxicity caused by other solubilizers such as surfactants like sodium dodecyl sulfate. Compared with the marketed cyclosporine products, it is expected to reduce adverse reactions such as eye pain, conjunctival congestion, and eye irritation, and greatly improve safety and patient compliance.

[0121] Solubilization effect of different concentrations of HS15 in Example 8

[0122] HS15 (polyethylene glycol-15-hydroxystearate) is a new type of non-ionic solubilizer with good solubilization ability, safety, and stability. In addition, it also has functions such as promoting drug absorption and improving bioavailability. Dissolve different amounts of HS15 in 10 mL of water for injection respectively, then add the same concentration of cyclosporine, and stir magnetically at the same rotation speed until completely dissolved, and then dilute with water to 100 mL to confirm the solubilization effect of different concentrations of HS15. The results show (see Table 11) that 0.1% cyclosporine can be completely dissolved in HS15 solutions with a concentration of not less than 1.0%, and with the increase of the HS15 concentration, the solubilization effect is better and the dissolution is faster.

[0123] Table 11

[0124] serial number Group 1 Group 2 Group 3 Group 4 Group 5 Cyclosporine 0.1％ 0.1％ 0.1％ 0.1％ 0.1％ HS15 0.5％ 1.0％ 1.5％ 2.0％ 3.0％ Complete dissolution time Cannot be completely dissolved within 24 hours 18h 2h 1h 0.5h

[0125] Prescription research of HS15 in Example 9

[0126] Use HS15 as a solubilizer and design different prescriptions (different concentrations, different osmotic pressure regulators, different viscosity enhancers) according to Table 12 below to prepare the liquid. Take 10% of the final amount of room temperature injection water and add the prescribed amount of HS15, stir until completely dissolved, then add cyclosporine and stir until completely dissolved. Add the remaining excipients and stir until completely dissolved, adjust the pH value to the target value, weigh it, and sterilize and filter the liquid through a 0.22μm filter. After filtration, fill the liquid into the packaging material to obtain a clear and transparent liquid.

[0127] Table 12

[0128]

[0129]

[0130] Example 10 Stability

[0131] Through the stability study test, it was found that there was no obvious difference in the stability of different formulations containing HS15 within the scope of the present invention. In this embodiment, specific data are provided by taking formulation I, formulation IV and formulation V as examples.

[0132] The samples of Formulation I, Formulation IV and Formulation V prepared in Example 3 were subjected to a stability study. The test conditions included high temperature of 40°C, high temperature of 60°C, light (4500lx±500lx) and freeze-thaw (placed at -20°C for 2 days, taken out and placed in a 40°C environment for 2 days, and cycled 3 times). Then, the relevant substances were detected. The results are shown in Table 13, which shows that they have good stability under light, high temperature and low temperature conditions.

[0133] Table 13

[0134]

[0135] Note: “√” indicates clear and transparent liquid.

[0136] Example 11 HS15 ocular toxicity study (Dutch black belt rabbit)

[0137] The test article HS15 (1%, 3% and 10% concentration) was topically administered to the conjunctiva of both eyes of Dutch black-belted rabbits twice a day (BID; 4 hours apart), 30 μL / eye each time, for 28 days. The animals were monitored for another 2 weeks (recovery period) after the 28-day dosing period to study late or delayed toxicity and the time to recovery from potential toxicity by evaluating the following parameters: survival, clinical signs, ocular observations, body weight, food intake, ophthalmological examination, electroretinogram, hematology, coagulation, clinical biochemistry, toxicokinetics, gross observations, microscopic examinations, and organ weights.

[0138] The research design is shown in Table 14:

[0139] Table 14

[0140]

[0141] Note: "M" represents male, and "F" represents female.

[0142] The results showed that no drug administration-related effects were recorded during the eye examinations. No test article-related effects were observed in terms of clinical signs, body weight, food intake, hematology, coagulation, biochemical parameters, organ weights, or gross and microscopic examinations. This indicates that all animals tolerated well after 4 weeks of topical administration of HS15 to the eyes of Dutch black-belt rabbits at 1%, 3%, and 10% BID (ophthalmic doses of 0.6, 1.8, and 6 mg / eye / day respectively, and total daily doses of 1.2, 3.6, and 12 mg / day respectively).

[0143] Example 12 HS15 Ocular Toxicity Study (Beagle Dogs)

[0144] The purpose of this study was to evaluate the cumulative toxicity of HS15 upon topical administration to the canine conjunctiva. The study animals received either a control HS15 vehicle solution (containing sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium chloride, and water for injection) or the test article Kolliphor HS15, via topical administration to the conjunctiva twice a day for 28 days (at 4-hour intervals, both eyes). The recovery animals received similar administration for 28 days, followed by a 2-week drug withdrawal period. During the test period, pharmacokinetics, clinical observations, body weight, food intake, ophthalmic examinations, electroretinogram, electrocardiogram, hematology (peripheral blood), blood biochemistry, urine analysis, organ weights, gross pathology, and histopathology examinations were conducted.

[0145] The design of this study is as follows in Table 15:

[0146] Table 15

[0147]

[0148] The results showed that there were no test article-related effects on clinical observations, body weight, food intake, ophthalmic examinations, electroretinogram, electrocardiogram, hematology, coagulation, biochemistry, urine analysis parameters, or organ weights, nor on gross or histopathology examination results. This indicates that Beagle dogs tolerated well the topical administration of HS15 to the bilateral conjunctiva twice a day for 28 days at a concentration ≤10%, with no ocular or systemic test article-related effects observed.

[0149] The toxicity study test results of HS15 in Example 11 and Example 12 showed that animals had good tolerance to this component, indicating no toxicity. In addition, other excipients selected for the composition of the present invention are all ophthalmic excipients that have been verified to be non-toxic, and there is no need to separately investigate toxicity. Based on this, it can be confirmed that the composition of the present invention has good safety.

[0150] Ocular Tissue Distribution Test of Cyclosporine Eye Drops in Example 13

[0151] The purpose of this test was to study the ocular tissue distribution of the novel cyclosporine eye drops provided by the present invention and the reference product in Chinchilla rabbits, and to evaluate their ocular tissue similarity. The test articles were 0.1% concentration colorless and clear cyclosporine eye drops (Self-made Group 1 and Self-made Group 2, whose formulations are shown in Table 16) prepared according to the method of the present invention, and commercially available 0.1% concentration white and homogeneous milky cyclosporine eye drops (Original Research Group). The research animals were 48 Chinchilla rabbits, half male and half female. They were weighed 1 day before dosing and randomly grouped by stratification according to their body weights. The specific grouping and dosing information are shown in Table 17. The dosing frequency was single-dose administration, and the dosing method was bilateral eye administration: 50 μL of the test article preparation was accurately pipetted, the lower eyelid of the rabbit eye was gently pulled open, and the test article preparation was completely dropped into the conjunctival sac of the rabbit, and the upper and lower eyelids were closed for about 30 seconds to prevent the test substance from flowing out. All groups were sacrificed at the corresponding time points (0.5 h, 2 h, 6 h, 24 h, etc.) and ocular tissues (conjunctiva, cornea, aqueous humor, lens, iris, ciliary body, retina + choroid, and sclera) were collected. Finally, the collected samples were processed and the concentration of cyclosporine in the whole blood samples of each group of rabbits was quantitatively detected by the validated LC-MS / MS method.

[0152] Table 16

[0153]

[0154] Table 17

[0155]

[0156]

[0157] The results showed that in the collected ocular tissues (conjunctiva, cornea, aqueous humor, lens, iris, ciliary body, retina + choroid, and sclera), the concentrations of cyclosporine eye drops in Self-made Group 1 and Self-made Group 2 were not inferior to or were superior to those in the Original Research Group, and the distribution of cyclosporine eye drops in the ocular tissues of the self-made groups was good.

[0158] The above-described embodiments merely represent several implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation on the protection scope of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. An ophthalmic composition, comprising: a first component, which is cyclosporine or a pharmaceutically acceptable salt or derivative thereof; and a second component, which is selected from at least one of alkyl glycosides and polyethylene glycol-15-hydroxystearate.

2. The ophthalmic composition according to claim 1, wherein In the alkyl glycoside, the alkyl part consists of 8 to 14 carbon atoms, and the average number of sugar units bonded to each alkyl is 1.1 to 3.

0.

3. The ophthalmic composition according to claim 2, wherein, The alkyl glycoside includes at least one of dodecyl maltoside, decyl glucopyranoside, tetradecyl maltoside, dodecyl glucoside, coconut alkyl glucoside, and octyl glucoside.

4. The ophthalmic composition according to claim 1, wherein Based on the total volume of the ophthalmic composition, the concentration of the first component is 0.01 to 0.50% w / v.

5. The ophthalmic composition according to any one of requirements 1 to 4, wherein When the second component is an alkyl glycoside, the mass ratio of the second component to the first component is greater than or equal to 5; when the second component is polyethylene glycol-15-hydroxystearate, the mass ratio of the second component to the first component is greater than or equal to 10.

6. The ophthalmic composition according to any one of claims 1 to 5, wherein, Based on the total volume of the ophthalmic composition, the concentration of the second component is 0.05 to 10% w / v.

7. The ophthalmic composition according to any one of claims 1 to 6, wherein, The osmolarity of the ophthalmic composition is 200 to 400 mOsm / L, preferably 300 ± 10 mOsm / L.

8. The ophthalmic composition according to any one of claims 1 to 7, wherein, The viscosity of the ophthalmic composition is 1 to 50 mPa·s, preferably 5 to 30 mPa·s.

9. The ophthalmic composition according to any one of claims 1 to 7, wherein The pH value of the ophthalmic composition is 5.0 to 8.

0.

10. The ophthalmic composition according to any one of claims 1 to 9, further comprising at least one selected from osmotic pressure regulators, thickeners, pH regulators, and pH buffers; Optionally, the osmotic pressure regulator includes at least one of sodium chloride, potassium chloride, phosphate buffer, glucose, mannitol, sucrose, glycerol, propylene glycol, sorbitol, glycine, alanine, boric acid, and polyethylene glycol; Optionally, the thickener includes at least one of sodium hyaluronate, hypromellose, povidone, poloxamer 407, poloxamer 188, carbomer, methylcellulose, sodium carboxymethylcellulose, xanthan gum, sodium alginate, polyvinyl alcohol, polyethylene glycol, chitosan, hyaluronic acid, polyacrylic acid, agar, polyacrylamide, hydroxyethyl cellulose, sodium polyacrylate, and polyethylene oxide.

11. The ophthalmic composition according to any one of claims 1 to 10, wherein, The solvent of the ophthalmic composition is water.

12. The ophthalmic composition according to any one of claims 1 to 11, wherein, The ophthalmic composition is a clear and transparent liquid at 5°C to room temperature.

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