Ophthalmic composition

Abstract

The present invention provides a stable, dorzolamide-containing ophthalmic composition. Disclosed is an ophthalmic composition comprising dorzolamide or a pharmaceutically acceptable salt thereof and having a pH of 6.5-8.5, said ophthalmic composition containing sulfobutyl-β-cyclodextrin or a pharmaceutically acceptable salt thereof and polyoxyethylene hydrogenated castor oil. Thus, it is possible to suppress the occurrence of dorzolamide analogs, maintain long-term stability, and extend an expiration date.

Description

Ophthalmic composition

[0001] The present disclosure relates to an ophthalmic composition containing dorzolamide. This application claims priority to Japanese Patent Application No. 2023-108175, filed on June 30, 2023, the entire contents of which are incorporated herein by reference.

[0002] Ophthalmic compositions (e.g., eye drops) for the treatment of glaucoma are known to slow the progression of glaucoma by lowering the intraocular pressure in the patient's eye. There are various types of eye drops that have an intraocular pressure-lowering effect. One example of such eye drops is dorzolamide hydrochloride eye drops, which have a carbonic anhydrase inhibitory effect.

[0003] Generally, commercially available dorzolamide hydrochloride ophthalmic solutions are designed to have a pH of 5.5 to 5.9, which is on the acidic side. This is because dissolving dorzolamide hydrochloride in isotonic purified water results in a pH in the weakly acidic range. In contrast, Patent Document 1 discloses dorzolamide hydrochloride ophthalmic solutions adjusted to a pH of 6.5 to 8.5. Patent Document 1 describes that eye irritation can be reduced by adjusting the pH to a neutral range.

[0004] Furthermore, Patent Document 2 discloses an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof, cyclodextrin, and latanoprost, and having a pH adjusted to 5.8 to 6.5. Patent Document 2 describes that the stability of a composition containing dorzolamide can be improved by using hydroxypropyl-β-cyclodextrin.

[0005] JP 2009-242368 A JP 2011-516537 A

[0006] It is extremely important for pharmaceuticals such as ophthalmic compositions to maintain their efficacy and safety and ensure long-term quality stability, thereby achieving a long shelf life. Typically, commercially available pharmaceuticals require at least several months (e.g., approximately three months) from production to distribution on the market due to quality assurance testing, transportation, and other factors. Pharmaceuticals that have passed their expiration date must be promptly disposed of. Therefore, there is a need to allow ample time for the expiration date when the product is actually displayed in stores or prescribed to patients. For this reason, there is a demand for technology to extend the shelf life of ophthalmic compositions containing dorzolamide.

[0007] Therefore, an object of the present disclosure is to extend the shelf life of ophthalmic compositions containing dorzolamide.

[0008] The ophthalmic composition disclosed herein contains dorzolamide and / or a pharmacologically acceptable salt of dorzolamide as an active ingredient, sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin, and polyoxyethylene hydrogenated castor oil, and has a pH of 6.5 to 8.5.

[0009] As a result of extensive investigations, the inventors have surprisingly discovered that a combination of sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil significantly extends the shelf life of ophthalmic compositions containing dorzolamide. This effect is expected to be due to the suppression of the generation of dorzolamide analogues while maintaining the pH in the neutral range. In other words, an ophthalmic composition having the above-described configuration can extend the shelf life of ophthalmic compositions containing dorzolamide.

[0010] In one embodiment of the ophthalmic composition disclosed herein, the pharmacologically acceptable salt of dorzolamide is dorzolamide hydrochloride, which is easy to handle and is preferably used as an active ingredient in the ophthalmic composition.

[0011] The ophthalmic composition of one embodiment disclosed herein contains 0.5 g to 20.0 g of the sulfobutyl ether-β-cyclodextrin when the total volume of the ophthalmic composition is 100 mL, thereby more effectively suppressing the generation of dorzolamide analogues.

[0012] In one embodiment of the ophthalmic composition disclosed herein, the polymerization number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is from 20 to 100. This makes it possible to more reliably suppress the generation of dorzolamide analogues.

[0013] The ophthalmic composition of one embodiment disclosed herein contains, when the total volume of the ophthalmic composition is 100 mL, 0.1 g to 10.0 g of the polyoxyethylene hydrogenated castor oil 60. This more reliably maintains long-term stability and extends the expiration date of the composition.

[0014] The ophthalmic composition of one embodiment disclosed herein is used as an eye drop, and can thus be suitably used for the prevention or treatment of glaucoma or ocular hypertension.

[0015] The ophthalmic solution contains 0.1 g to 5.0 g of dorzolamide and / or a pharmacologically acceptable salt of dorzolamide per 100 g of total weight, making it more suitable for use in the prevention or treatment of glaucoma or ocular hypertension.

[0016] One embodiment of the method disclosed herein for suppressing the generation of dorzolamide analogues in an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof comprises adding sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil to the ophthalmic composition, which has a pH of 6.5 to 8.5. This suppresses the generation of dorzolamide analogues in the ophthalmic composition and extends its shelf life.

[0017] Exemplary embodiments of the present disclosure will be described in detail below. Matters necessary for implementation other than those specifically mentioned in this specification can be understood as design matters for those skilled in the art based on prior art in the relevant field. The present disclosure can be implemented based on the contents disclosed in this specification and common general technical knowledge in the relevant field.

[0018] <1. Definition of Terms> In this specification, when a numerical range is described as "A to B (where A and B are any numerical values)," this means "A or more and B or less," and also encompasses the meanings of "greater than A and less than B," "greater than A and B or less," and "greater than A and less than B."

[0019] As used herein, the term "ophthalmic composition" refers to a composition administered to the eye for the prevention or treatment of eye diseases, and is applied to ocular tissues such as the conjunctival sac. The dosage form of the ophthalmic composition is not particularly limited, and includes liquid (including concentrated solutions diluted before use), semi-solid, and solid preparations that are dissolved or suspended before use. Specifically, ophthalmic compositions include eye drops (synonymous with eye drops or eye drops), artificial tears, eyewashes, eye drops for contact lenses, eye ointments, etc., and also include forms administered by local ocular injection. Of these, the ophthalmic composition of the present disclosure is preferably an aqueous composition, and is preferably, for example, an eye drop.

[0020] As used herein, the term "expiration date" refers to the final expiration date during which the efficacy and safety of the ophthalmic composition are maintained and long-term stability of quality is guaranteed.

[0021] 2. Components and pH of the Ophthalmic Composition The ophthalmic composition of the present disclosure is an ophthalmic composition containing dorzolamide and / or a pharmacologically acceptable salt of dorzolamide as an active ingredient. This ophthalmic composition also contains sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin, and polyoxyethylene hydrogenated castor oil. The ophthalmic composition of the present disclosure has a pH of 6.5 to 8.5. Each component is described in detail below.

[0022] <Dorzolamide> In this specification, dorzolamide is (4S,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide ((4S,6S)-4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide7,7-deiooxide), a compound represented by the following chemical formula (I). Dorzolamide can be synthesized by known methods or is available as a commercially available product.

[0023] In the ophthalmic composition of the present disclosure, dorzolamide may be in the form of a salt. Such dorzolamide salts are not particularly limited as long as they are pharmacologically acceptable. Examples of dorzolamide salts include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts. For example, salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, etc. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, etc. Examples of salts with alkali metals include salts with lithium, sodium, potassium, etc. Examples of salts with alkaline earth metals include salts with calcium, magnesium, etc. Examples of metal salts include salts with iron, zinc, etc. Other examples include quaternary ammonium salts, salts with halogen ions, salts with organic amines, etc. Among these, the dorzolamide salt is particularly preferably the monohydrochloride salt (dorzolamide hydrochloride).

[0024] Dorzolamide and salts of dorzolamide may also be in the form of a hydrate or solvate.

[0025] The content of dorzolamide or a dorzolamide salt is not particularly limited as long as it is a pharmacologically acceptable amount. From the viewpoint of effective concentration, the lower limit is preferably 0.1 w / v% or more, more preferably 0.2 w / v% or more, and most preferably 0.5 w / v% or more. The upper limit is preferably 5.0 w / v% or less, more preferably 3.0 w / v% or less, and most preferably 2.0 w / v% or less. In this specification, unless otherwise specified, "w / v%" means "g / 100 mL", i.e., the mass (g) of the target ingredient contained in 100 mL of the composition.

[0026] <Sulfobutylether-β-cyclodextrin> The ophthalmic composition of the present disclosure contains sulfobutylether-β-cyclodextrin (SBE-β-CD) as a stabilizer. SBE-β-CD can be synthesized by known methods or is commercially available. SBE-β-CD is an anionic cyclodextrin derivative. Because SBE-β-CD has an anionic functional group, it can improve the binding affinity of cyclodextrin to cationic guests (e.g., dorzolamide, which contains a nitrogen atom).

[0027] In the ophthalmic composition of the present disclosure, the SBE-β-CD contained may be in the form of a salt. There are no particular limitations on the salt of SBE-β-CD, so long as it is a pharmacologically acceptable salt. Examples of salts of SBE-β-CD include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts. For example, salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, etc. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, etc. Examples of salts with alkali metals include salts with lithium, sodium, potassium, etc. Examples of salts with alkaline earth metals include salts with calcium, magnesium, etc. Examples of metal salts include salts with iron, zinc, etc. Other examples include quaternary ammonium salts, salts with halogen ions, and salts with organic amines. Of these, the monosodium salt (sodium SBE-β-CD) is particularly preferred as the salt of SBE-β-CD.

[0028] In this specification, the content of SBE-β-CD or an SBE-β-CD salt is not particularly limited as long as it is an amount that is bioacceptable. From the viewpoint of stabilizing dorzolamide, the lower limit may be 0.5 w / v% or more, preferably 1.0 w / v% or more, more preferably 5.5 w / v% or more, even more preferably 6.0 w / v% or more, and most preferably 8.0 w / v% or more. The upper limit may be 20.0 w / v% or less, 15.0 w / v% or less, or 11.0 w / v% or less.

[0029] <Polyoxyethylene hydrogenated castor oil> The ophthalmic composition of the present disclosure contains polyoxyethylene hydrogenated castor oil, a nonionic surfactant, as a solubilizing agent. Various polyoxyethylene hydrogenated castor oils with different polymerization numbers of ethylene oxide can be used as the polyoxyethylene hydrogenated castor oil. The polymerization number of ethylene oxide is not particularly limited. From the viewpoint of stabilizing dorzolamide, the lower limit of the polymerization number is preferably 20 or more, more preferably 30 or more, and most preferably 40 or more. The upper limit is preferably 100 or less, more preferably 80 or less, and most preferably 60 or less. Specific examples of polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 80. From the viewpoint of more significantly enhancing the effects of the present disclosure, polyoxyethylene hydrogenated castor oil 60 is most preferred. The content of polyoxyethylene hydrogenated castor oil is not particularly limited, as long as it is an amount acceptable to the body. From the viewpoint of stabilizing dorzolamide, the lower limit is preferably 0.1 w / v% or more, more preferably 0.5 w / v% or more, and most preferably 1.0 w / v% or more, and the upper limit may be 10.0 w / v% or less, 5.0 w / v% or less, or 3.0 w / v% or less.

[0030] <pH of Ophthalmic Composition> The ophthalmic composition of the present disclosure has a pH of 6.5 to 8.5 (neutral range). When dorzolamide or a dorzolamide salt is dissolved in isotonic purified water, the pH of the aqueous solution falls into the acidic range (e.g., pH 5.5 to 5.9), so a pH adjuster is added to adjust the pH to 6.5 to 8.5. Ophthalmic compositions containing dorzolamide as an active ingredient are highly irritating to the eye. However, by adjusting the pH to a neutral range, eye irritation can be reduced, making it easier for patients to continue treatment while adhering to the dosage instructions.

[0031] Examples of pH adjusters include sodium hydroxide or calcium hydroxide, alkaline aqueous solutions such as potassium hydroxide, and acidic aqueous solutions such as hydrochloric acid and citric acid. In the present disclosure, when dorzolamide or a salt of dorzolamide is dissolved in isotonic purified water, the pH of the resulting aqueous solution falls into the acidic range, so it is preferable to use sodium hydroxide to adjust the pH to the neutral range. From the above-mentioned viewpoints, the lower limit of the pH of the ophthalmic composition of the present disclosure is preferably 6.5 or more, more preferably 6.7 or more. The upper limit is preferably 8.5 or less, more preferably 8.2 or less, and even more preferably 7.8 or less.

[0032] 2. Effects of the Ophthalmic Composition of the Present Disclosure The ophthalmic composition as described above suppresses the generation of dorzolamide analogues and can extend the expiration date of ophthalmic compositions containing dorzolamide up to three years. Because the efficacy and toxicity of these dorzolamide analogues to the human body are unknown when the standard values ​​are exceeded, safety cannot be maintained and the expiration date is shortened.

[0033] Specifically, it has been found that when an ophthalmic composition containing dorzolamide and / or a dorzolamide salt and having a neutral pH is stored for an extended period of time, dorzolamide analogues are generated, resulting in a shelf life of only 1.5 years. In this specification, one form of dorzolamide analogue is (4R,6S)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide ((4R,6S)-4-Ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-deoxide). This compound is represented by the following chemical formula (II): Also included is (4S,6R)-4-ethylamino-6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide, which is an enantiomer of the compound of formula (II). This compound is represented by the following chemical formula (III):

[0034] Furthermore, experiments have confirmed that in order to achieve a long shelf life, it is necessary to add SBE-β-CD, a cyclodextrin, and polyoxyethylene hydrogenated castor oil, a surfactant, to an ophthalmic composition containing dorzolamide and / or a salt of dorzolamide. This is presumably due to the promotion of inclusion of dorzolamide by SBE-β-CD.

[0035] 3. Other Components The ophthalmic composition of the present disclosure may contain other components that can be used as additives in pharmaceuticals, as long as the effects of the technology of the present disclosure are not significantly impaired. Such components may include active ingredients expected to have medicinal effects used in known ophthalmic compositions, additives required for formulation design, and the like. Specifically, known buffers, pH adjusters, thickeners, isotonicity agents, chelating agents, humectants, fragrances or fresheners, medicines, antibacterial agents, preservatives / bactericides, and the like may be blended singly or in combination.

[0036] In addition to dorzolamide, the ophthalmic composition of the present disclosure may further contain other ingredients usable as active pharmaceutical ingredients. These other active ingredients are preferably those that exhibit an intraocular pressure-reducing effect and are useful for treating glaucoma or ocular hypertension. Examples of other active ingredients include α2 receptor agonists such as brimonidine, β-receptor blockers such as befunolol, carteolol, nipradilol, betaxolol, levobunolol, and metipranolol, and prostaglandin F derivatives such as latanoprost, travoprost, and bimatoprost. Timolol is preferred because it is advantageously useful for treating intraocular hypertension.

[0037] Like dorzolamide, timolol is (2S)-1-[(1,1-dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)propan-2-ol, and is represented by the following chemical formula (IV). Timolol can be synthesized by known methods or is available as a commercially available product.

[0038] In the ophthalmic composition of the present disclosure, the timolol or the like contained therein may be a salt. There are no particular limitations on the salt of timolol or the like, so long as it is a pharmacologically acceptable salt. Examples of the salt of timolol or the like include salts with inorganic acids, salts with organic acids, salts with alkali metals, salts with alkaline earth metals, and metal salts. For example, salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, thiocyanic acid, etc. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, mesylic acid, lactic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, stearic acid, tannic acid, besylic acid, salicylic acid, benzoic acid, etc. Examples of salts with alkali metals include salts with lithium, sodium, potassium, etc. Examples of salts with alkaline earth metals include salts with calcium, magnesium, etc. Examples of metal salts include salts with iron, zinc, etc. Other examples include quaternary ammonium salts, salts with halogen ions, salts with organic amines, etc. Timolol monomaleate (timolol maleate) is particularly preferred as a salt of timolol.

[0039] In the ophthalmic composition of the present disclosure, the timolol and salts of timolol contained therein may be in the form of a hydrate or solvate.

[0040] The ophthalmic composition of the present disclosure may contain timolol or a pharmacologically acceptable salt thereof. This allows for the prevention or treatment of glaucoma or ocular hypertension through a mechanism different from that of dorzolamide, thereby enhancing the effectiveness. The content of timolol or a salt thereof is not particularly limited as long as it is a pharmacologically acceptable amount. From the viewpoint of effective concentration, the lower limit is preferably 0.1 w / v% or more, more preferably 0.2 w / v% or more, and most preferably 0.3 w / v% or more. The upper limit is preferably 3.0 w / v% or less, more preferably 2.0 w / v% or less, and most preferably 1.0 w / v% or less.

[0041] Examples of buffering agents include phosphoric acid, citric acid, acetic acid, tartaric acid, carbonic acid, boric acid and their salts, trometamol, etc. Among these, boric acid or its salts are preferred because of their bacteriostatic effect. Furthermore, when phosphoric acid is used, it has the advantage of having buffering ability in the neutral pH range, which further enhances the stability of the composition of the present disclosure.

[0042] Examples of the thickening agent include hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and salts thereof, polyvinylpyrrolidone, macrogol, and the like.

[0043] Examples of the isotonic agent include sugars such as sorbitol, glucose, mannitol, etc.; polyhydric alcohols such as glycerin, polyethylene glycol, propylene glycol, etc.; salts such as sodium chloride, potassium chloride, etc.; and the like.

[0044] Examples of preservatives and disinfectants include polyhexanide hydrochloride, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, parahydroxybenzoic acid esters (parabens), benzyl alcohol, etc. Glaucoma and ocular hypertension require long-term treatment, and it is preferable that the ophthalmic composition contains a preservative and disinfectant to prevent contamination. From the viewpoints of safety and preservative efficacy, benzalkonium chloride is preferred.

[0045] 4. Method of Use, etc. The ophthalmic composition of the present disclosure can be contained in a unit-dose container or a multi-dose container, and from the perspective of long-term treatment, it is preferable to contain it in a multi-dose container. A unit-dose container is a container intended for single use, i.e., for single use. On the other hand, a multi-dose container is a container intended for multiple uses and can be freely opened and closed with a cap or the like. The ophthalmic composition of the present disclosure may also be contained in a special container that exhibits antiseptic effects through a backflow prevention function, a filter, or the like. The material of the container is not particularly limited, and for example, polyethylene, polypropylene, polystyrene, polyethylene terephthalate, etc. can be used for the container.

[0046] The dosage form of the ophthalmic composition of the present disclosure is not particularly limited as long as it can be used as a pharmaceutical, but eye drops are particularly preferred, and can be produced according to conventional methods in the art.

[0047] The ophthalmic composition of the present disclosure is useful as a preventive and / or therapeutic agent for ophthalmology, particularly as a preventive and / or therapeutic agent for glaucoma or ocular hypertension.

[0048] When administering the ophthalmic composition of the present disclosure, from the viewpoint of effective prevention and / or treatment of eye diseases and ocular disorders, the dosage is preferably one drop per time, twice a day, but the dosage is not necessarily limited thereto and can be changed as appropriate.

[0049] 5. Method for Suppressing the Generation of Dorzolamide Analogues In another aspect of the technology disclosed herein, as described above, the ophthalmic composition has a neutral pH of 6.5 or higher and contains dorzolamide or a pharmacologically acceptable salt thereof, sulfobutylether-β-cyclodextrin or a pharmacologically acceptable salt thereof, and polyoxyethylene hydrogenated castor oil, thereby significantly suppressing the generation of dorzolamide analogues, maintaining long-term stability, and extending the shelf life. Therefore, this embodiment provides a method for suppressing the generation of dorzolamide analogues by adding sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil to an ophthalmic composition having a pH of 6.5 to 8.5 and containing dorzolamide or a pharmacologically acceptable salt thereof as an active ingredient.

[0050] The ophthalmic composition of the present disclosure will be specifically described below with reference to examples and comparative examples. Here, an eye drop will be used as an example of the ophthalmic composition of the present disclosure, but the present disclosure is not limited to the following examples.

[0051] <Preparation of Examples 1 and 2 and Comparative Examples 1 to 6> The basic formulation is as follows: Dorzolamide hydrochloride: 1.113 w / v % Timolol maleate: 0.683 w / v % 1 mol / L sodium hydroxide solution (aqueous sodium hydroxide solution): appropriate amount Purified water: appropriate amount Osmotic pressure ratio: approximately 1.0

[0052] First, 0.22 g of dorzolamide hydrochloride and 0.136 g of timolol maleate were added to 16 mL of purified water and dissolved. Furthermore, other compounds were dissolved according to the compositions shown in Table 1. The pH of each mixed solution was adjusted by adding 1 mol / L sodium hydroxide solution dropwise, and then the total volume was adjusted to 20 mL with purified water. The pH of each prepared solution was then measured using a pH meter (S210: Mettler Toledo K.K.). The prepared solution was filled into a plastic container, and a plastic inner stopper and plastic cap were attached to obtain the ophthalmic solutions of Examples 1 and 2 and Comparative Examples 1 to 6.

[0053]

[0054] <Test Example: Accelerated Test> The ophthalmic solutions of Examples 1 and 2 and Comparative Examples 1 to 6 were stored at 40°C, and the dorzolamide analogues contained in each ophthalmic solution were measured 2, 4, and 6 months after the start of storage. The accelerated test performed under the above-mentioned 40°C condition can predict chemical changes that occur when a pharmaceutical product is stored for a long period of time, and can also evaluate the effects of short-term deviations from the above-mentioned storage method that may occur during distribution. According to the Arrhenius equation, storage for 2, 4, and 6 months at 40°C corresponds to 1, 2, and 3 years at room temperature (25°C).

[0055] <Measurement of dorzolamide related substances> Dorzolamide related substances were measured using the method described in the Purity Test for Dorzolamide Hydrochloride / Timolol Maleate Ophthalmic Solution (Related Substance 1) stipulated in the 18th Edition of the Japanese Pharmacopoeia, Supplement 1 (Ministry of Health, Labour and Welfare Notification No. 355, December 12, 2022). Specifically, the peak areas in the ophthalmic solution were measured using high-performance liquid chromatography with an automatic integration method, and the peak area ratio of the related substance with a relative retention time of 1.2 to the peak area of ​​dorzolamide was calculated. Note that, according to the standards of the Japanese Pharmacopoeia, if the peak area ratio exceeds 0.024 during storage, the formulation cannot be certified as such.

[0056] The specific equipment and conditions used in the high-performance liquid chromatography are shown below. Liquid chromatograph: Prominence-i (Shimadzu Corporation) Liquid chromatograph data processing device: LabSolutions (Shimadzu Corporation) Detector: Ultraviolet absorption photometer (measurement wavelength: 253 nm) Mobile phase: Diluted phosphoric acid (1 → 500) / acetonitrile mixture (19:1) Column: XBridge C18 inner diameter 4.6 mm, length 250 mm, particle size 5 μm (Waters) Column temperature: 25°C Flow rate: 1.2 mL / min Injection volume: 20 μL

[0057] The results of the above test are shown in Table 2. In the column "Japanese Pharmacopoeia Standard (0.024 or less)" in Table 2, the expiration date was evaluated as extended (○) when the peak area ratio (dorzolamide analogue / dorzolamide) was 0.024 or less at all of the 2-month, 4-month, and 6-month storage periods. The expiration date was evaluated as not extended (×) when the peak area ratio (dorzolamide analogue / dorzolamide) was 0.024 or more at any one of the 2-month, 4-month, or 6-month storage periods. A regression equation was calculated using the peak area ratio (dorzolamide analogue / dorzolamide) at each measurement time point as the y-axis and the storage period at 40°C as the x-axis. From the regression equation, the expiration date at 25°C was calculated based on the storage period at 40°C at which the y-axis reached 0.024.

[0058]

[0059] The above test results show that the dorzolamide analogues exceeded the standard value during storage, making it impossible to extend the expiration date, in Comparative Examples 1-5, 4-6, and 6, which did not contain sulfobutylether-β-cyclodextrin, and in Comparative Examples 3 and 6, which did not contain polyoxyethylene hydrogenated castor oil 60. In contrast, it was found that in Examples 1 and 2, the inclusion of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil 60 significantly suppressed the generation of dorzolamide analogues, enabling the expiration date to be extended to three years.

[0060] The present disclosure has been described above using preferred embodiments, but these descriptions are not limiting, and various modifications such as the numerical values ​​of the compounding amounts and additives are of course possible.

[0061] In the technology disclosed herein, each component and each process mentioned herein may be omitted or combined as appropriate, unless a particular problem arises. This specification also includes the disclosures described in the following sections.

[0062] Item 1: An ophthalmic composition containing dorzolamide and / or a pharmacologically acceptable salt of dorzolamide as an active ingredient, the ophthalmic composition containing sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil, and having a pH of 6.5 to 8.5.

[0063] Item 2: The ophthalmic composition according to Item 1, wherein the pharmacologically acceptable salt of dorzolamide is dorzolamide hydrochloride.

[0064] Item 3: The ophthalmic composition according to Item 1 or 2, wherein the ophthalmic composition contains 0.5 g to 20.0 g of the sulfobutyl ether-β-cyclodextrin when the total volume of the ophthalmic composition is 100 mL.

[0065] Item 4: The ophthalmic composition according to any one of Items 1 to 3, wherein the polyoxyethylene hydrogenated castor oil has a polymerization number of ethylene oxide of 20 or more and 100 or less.

[0066] Item 5: The ophthalmic composition according to Item 4, wherein the ophthalmic composition contains 0.1 g to 10.0 g of the polyoxyethylene hydrogenated castor oil 60 when the total volume of the ophthalmic composition is 100 mL.

[0067] Item 6: The ophthalmic composition according to any one of Items 1 to 5, which is used as an eye drop.

[0068] Item 7: The ophthalmic composition according to Item 6, wherein the dorzolamide and / or pharmacologically acceptable dorzolamide is contained in an amount of 0.1 g to 5.0 g when the total volume of the eye drops is 100 mL.

[0069] Item 8: A method for suppressing the generation of dorzolamide-related substances in an ophthalmic composition, comprising adding sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil to the ophthalmic composition, which contains dorzolamide or a pharmacologically acceptable salt thereof and has a pH of 6.5 to 8.5.

Claims

1. An ophthalmic composition containing dorzolamide and / or a pharmacologically acceptable salt of dorzolamide as an active ingredient, comprising: sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin; and polyoxyethylene hydrogenated castor oil; and having a pH of 6.5 to 8.

5.

2. The ophthalmic composition of claim 1, wherein the pharmacologically acceptable salt of dorzolamide is dorzolamide hydrochloride.

3. The ophthalmic composition according to claim 2, which contains 0.5 g to 20.0 g of the sulfobutyl ether-β-cyclodextrin when the total volume of the ophthalmic composition is 100 mL.

4. The ophthalmic composition according to claim 1, wherein the polymerization number of ethylene oxide in the polyoxyethylene hydrogenated castor oil is 20 or more and 100 or less.

5. The ophthalmic composition according to claim 4, containing 0.1 g to 10.0 g of the polyoxyethylene hydrogenated castor oil 60 when the total volume of the ophthalmic composition is 100 mL.

6. An ophthalmic composition according to any one of claims 1 to 5, which is used as an eye drop.

7. The ophthalmic composition according to claim 6, which contains 0.1 g to 5.0 g of the dorzolamide and / or pharmacologically acceptable dorzolamide when the total volume of the eye drops is 100 mL.

8. A method for suppressing the generation of dorzolamide-related substances in an ophthalmic composition by adding sulfobutylether-β-cyclodextrin and / or a pharmacologically acceptable salt of sulfobutylether-β-cyclodextrin and polyoxyethylene hydrogenated castor oil to an ophthalmic composition containing dorzolamide or a pharmacologically acceptable salt thereof and having a pH of 6.5 to 8.5.