Ophthalmic pharmaceutical products

Abstract

The object of the present invention is to provide an ophthalmic pharmaceutical product in which brimonidine and / or a salt thereof and brinzolamide and / or a salt thereof are contained in an ophthalmic solution in which brimonidine and / or a salt thereof is photostable, and the ophthalmic solution is contained in a container that allows the contents to be visually inspected. [Solution] By housing eye drops containing brimonidine and / or its salt and brinzolamide and / or its salt in a transparent container having a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm, internal visibility can be ensured while suppressing degradation of brimonidine and / or its salt due to light exposure, thereby ensuring formulation stability.

Description

Technical Field

[0001] The present invention relates to an ophthalmic pharmaceutical product in which an eye drop containing brimonidine and / or its salt and brinzolamide and / or its salt is contained in a container that can visually recognize the contents while having the photo stability of brimonidine and / or its salt. Furthermore, the present invention relates to a method for photostabilizing brimonidine and / or its salt in an eye drop containing brimonidine and / or its salt and brinzolamide and / or its salt.

Background Art

[0002] Brimonidine and its salts are known as adrenergic α2 receptor agonists, and have the effect of lowering intraocular pressure by suppressing the production of aqueous humor and promoting the outflow of aqueous humor through the uveoscleral outflow pathway. Conventionally, they have been used for the treatment of glaucoma and ocular hypertension.

[0003] Also, brinzolamide and / or its salts are known as carbonic anhydrase inhibitors, and have the effect of lowering intraocular pressure by suppressing the production of aqueous humor, and are used for the treatment of glaucoma.

[0004] In recent years, in order to enhance the therapeutic effect of glaucoma and ocular hypertension, formulations combining brimonidine and / or its salt and brinzolamide and / or its salt have been proposed. For example, Patent Document 1 reports that eye diseases such as glaucoma can be effectively treated by administering brimonidine and brinzolamide simultaneously or separately. Also, Patent Document 2 discloses a multi-dose ophthalmic composition containing brimonidine tartrate and brinzolamide.

[0005] On the other hand, in order to commercialize eye drops, it is necessary to have excellent formulation stability and be able to stably maintain the active ingredients. However, Patent Documents 1 and 2 do not discuss formulation stability at all. Therefore, in order to commercialize an eye drop containing brimonidine and / or its salt and brinzolamide and / or its salt, it is necessary to examine the stability of each active ingredient and verify the formulation stability. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 6316441 [Patent Document 2] International Publication No. 2010 / 148190 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] The present inventors, in an effort to commercialize an eye drop solution containing brimonidine and / or its salt and brinzolamide and / or its salt, investigated its formulation stability and encountered a new problem: brimonidine and / or its salt in the eye drop solution is easily degraded by light exposure.

[0008] Generally, to ensure the stability of formulations containing light-unstable components, methods are employed to house them in light-shielding containers that can almost completely block light, such as metal containers or opaque containers. However, in Japan, for the storage of eye drops, it is necessary to use transparent, airtight containers that do not interfere with the insoluble foreign body detection test for eye drops (see Commentary on the 16th Revised Japanese Pharmacopoeia A-108, Tokyo Hirokawa Shoten). For this reason, there are restrictions on using light-shielding containers that may affect the insoluble foreign body detection test when storing eye drops containing brimonidine and / or its salts and brinzolamide and / or its salts. Furthermore, for multi-dose eye drops, it is desirable to use transparent containers that are transparent enough to allow the user to see the remaining amount of liquid, but if eye drops containing brimonidine and / or its salts and brinzolamide and / or its salts are stored in transparent containers, there is a concern that brimonidine and / or its salts may decompose due to light exposure.

[0009] Therefore, the objective is to provide an ophthalmic pharmaceutical product in which brimonidine and / or its salt and brinzolamide and / or its salt are contained in an eye drop solution in which brimonidine and / or its salt are photostabilized, and the eye drop solution is contained in a container that allows the contents to be visually inspected. [Means for solving the problem]

[0010] The inventors faced the aforementioned problem, which was previously unknown, and after diligently studying to solve it, they surprisingly discovered that by encapsulating an eye drop solution containing brimonidine and / or its salt and brinzolamide and / or its salt in a transparent container having a maximum transmittance of 67% or less for light at wavelengths of 360-460 nm and a maximum transmittance of 78% or less for light at wavelengths of 600-680 nm, it is possible to suppress the degradation of brimonidine and / or its salt due to light exposure while enabling insoluble foreign matter testing and visualization of the remaining solution volume, thereby ensuring formulation stability. The present invention was completed by further studies based on this finding.

[0011] In other words, the present invention provides inventions in the following embodiments. Item 1. Ophthalmic solutions containing brimonidine and / or its salts, and brinzolamide and / or its salts, It is housed in a transparent container that has a maximum transmittance of 67% or less for light with a wavelength of 360-460nm, and a maximum transmittance of 78% or less for light with a wavelength of 600-680nm. An ophthalmic pharmaceutical product characterized by the following features. Item 2. The ophthalmic pharmaceutical product according to Item 1, wherein the transparent container is an eye drop container. Item 3. The ophthalmic pharmaceutical product according to item 1 or 2, wherein the eye drops do not contain mannitol. Item 4. A method for photostabilizing brimonidine and / or its salts in eye drops containing brimonidine and / or its salts, A stabilization method characterized by containing the eye drops in a transparent container having a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm. Item 5. The stabilization method according to item 4, wherein the eye drops do not contain mannitol. [Effects of the Invention]

[0012] According to the present invention, in an eye drop solution containing brimonidine and / or a salt thereof and brinzolamide and / or a salt thereof, the brimonidine and / or salt thereof is photostabilized, thereby providing excellent formulation stability. Furthermore, according to the present invention, since the eye drop solution is contained in a transparent package that allows the contents to be seen, an insoluble foreign matter test can be easily performed, simplifying quality control, and the remaining amount of eye drop solution can be seen from outside the container, thus improving convenience for the user. [Brief explanation of the drawing]

[0013] [Figure 1] This figure shows the results of measuring the light transmittance at each wavelength for each coating and polyethylene terephthalate container used as a component of the containment in Test Example 1. [Figure 2] This figure shows the results of measuring the light transmittance at each wavelength of each cellophane used as a component of the containment in Test Example 2. [Modes for carrying out the invention]

[0014] In this specification, "ophthalmic drug" refers to a product in which eye drops are contained in a transparent container. Furthermore, "transparent container" refers to a container that contains eye drops and has a transparent area, at least in part, for visualizing the interior necessary for performing insoluble foreign body tests, etc. Additionally, "photostabilization of brimonidine and / or its salts" refers to inhibiting the degradation of brimonidine and / or its salts due to light exposure.

[0015] 1. Ophthalmic pharmaceutical products The ophthalmic pharmaceutical product of the present invention is characterized in that an eye drop containing brimonidine and / or its salt, and brinzolamide and / or its salt is housed in a transparent container having a maximum transmittance of light with a wavelength of 360 to 460 nm of 67% or less and a maximum transmittance of light with a wavelength of 600 to 680 nm of 78% or less. Hereinafter, the ophthalmic pharmaceutical product of the present invention will be described in detail.

[0016] eye drops (Brimonidine and / or its salt) The eye drop used in the present invention contains brimonidine and / or its salt. In an eye drop containing brimonidine and / or its salt and brinzolamide and / or its salt, brimonidine and / or its salt is liable to be decomposed by light exposure. However, according to the present invention, by housing it in a specific container described later, the photo-stabilization of brimonidine and / or its salt can be achieved.

[0017] Brimonidine is a compound known as an adrenergic α2 receptor agonist. The salt of brimomidine is not particularly limited as long as it is pharmaceutically acceptable, and specific examples include tartrate, hydrochloride, and acetate.

[0018] In the present invention, either brimonidine or its salt may be used alone, or they may be used in combination. Among brimonidine and its salts, preferably brimonidine tartrate is mentioned.

[0019] In the eye drop used in the present invention, the content of brimonidine and / or its salt is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be applied, the dosage per application, etc. For example, 0.01 to 1 w / v%, preferably 0.05 to 0.3 w / v%, more preferably 0.1 to 0.2 w / v% can be mentioned.

[0020] (Brinzolamide) The eye drops used in this invention contain brinzolamide and / or a salt thereof. Brinzolamide is a compound known as a carbonic anhydrase inhibitor. The salt of brinzolamide is not particularly limited to the extent that it is pharmaceutically acceptable, but specific examples include hydrochloride and acetate salts.

[0021] In the eye drops used in the present invention, the content of brinzolamide and / or its salt is not particularly limited and can be appropriately set according to the severity of the symptoms of the patient to whom it is applied, the amount applied per dose, etc., but for example, 0.1 to 3 w / v%, preferably 0.5 to 2 w / v%, and more preferably 1 w / v%.

[0022] (Other ingredients) In addition to the components described above, the eye drops used in the present invention may also contain dihydric or trihydric alcohols for purposes such as adjusting osmotic pressure and assisting in the dissolution of the components.

[0023] The dihydric or trihydric alcohol is not particularly limited as long as it is permissible to incorporate it into eye drops, but examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol, etc. These dihydric or trihydric alcohols may be used individually or in combination of two or more. Among these dihydric or trihydric alcohols, glycerin is preferred.

[0024] When a divalent or trivalent alcohol is incorporated into the eye drops used in the present invention, its content can be appropriately set to achieve the desired osmotic pressure, for example, 0.1 to 5 w / v%, preferably 0.5 to 3 w / v%, and more preferably 1 to 2 w / v%.

[0025] Furthermore, the eye drops used in the present invention may contain surfactants as needed to enhance the solubility of brimonidine and / or its salts, as well as brinzolamide and / or its salts.

[0026] The surfactant is not particularly limited as long as it is permissible to incorporate it into eye drops, but examples include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually or in combination of two or more. Among these surfactants, nonionic surfactants are preferred, and tyroxapol is more preferred.

[0027] When a surfactant is incorporated into the eye drops used in the present invention, there are no particular limitations on its content, but for example, it may be 0.005 to 0.1 w / v%, preferably 0.01 to 0.05 w / v%, and more preferably 0.02 to 0.03 w / v%.

[0028] Furthermore, the eye drops used in the present invention may contain a viscous agent as needed to provide the desired viscosity.

[0029] The viscosity agent is not particularly limited as long as it is permissible to incorporate it into eye drops, but examples include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer (cross-linked polyacrylic acid polymer, etc.), xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hypromellose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These viscosity agents may be used individually or in combination of two or more. Among these viscosity agents, carboxyvinyl polymer is preferred. These are some examples.

[0030] When a viscosity-enhancing agent is incorporated into the eye drops used in the present invention, its content can be appropriately set according to the viscosity to be imparted, for example, 0.1 to 1 w / v%, preferably 0.1 to 0.5 w / v%, and more preferably 0.3 to 0.5 w / v%.

[0031] Furthermore, the eye drops used in the present invention may contain alkali metal chlorides such as sodium chloride and potassium chloride, as needed, for purposes such as adjusting osmotic pressure. These alkali metal chlorides may be used individually or in combination of two or more. Among these alkali metal chlorides, sodium chloride is preferred.

[0032] When alkali metal chlorides are incorporated into the eye drops used in the present invention, their content can be appropriately set according to the osmotic pressure to be imparted, taking into account the content of other components. For example, 0.01 to 1 w / v%, preferably 0.05 to 0.5 w / v%, and more preferably 0.1 to 0.3 w / v% are given.

[0033] Furthermore, the eye drops used in the present invention may contain a buffering agent as needed to provide a buffering effect, regulate osmotic pressure, and so on.

[0034] The buffering agent is not particularly limited as long as it is permissible to include it in eye drops, but examples include phosphate buffers, borate buffers, citrate buffers, tartaric acid buffers, acetate buffers, Tris buffers, and amino acids. These buffering agents may be used individually or in combination of two or more. Among these buffering agents, borate buffers are preferred.

[0035] When a buffering agent is incorporated into the eye drops used in the present invention, the amount of the buffering agent can be appropriately set according to the type of buffering agent used, etc. For example, if boric acid is used, the amount of boric acid can be, for example, 0.01 to 5 w / v%, preferably 0.05 to 1 w / v%, and more preferably 0.1 to 0.5 w / v%.

[0036] Furthermore, the eye drops used in the present invention may contain, as necessary, additives such as chelating agents, cooling agents, and preservatives, in addition to the above-mentioned components.

[0037] Examples of chelating agents include EDTA salts, citric acid, or their salts. These chelating agents may be used individually or in combination of two or more.

[0038] Examples of cooling agents include l-menthol, borneol, camphor, and eucalyptus oil. These cooling agents may be used individually or in combination of two or more.

[0039] Examples of preservatives include sorbic acid or its salts, benzoic acid or its salts, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate, boric acid or its salts, dehydroacetic acid or its salts, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, and dibutylhydroxytoluene. These preservatives may be used individually or in combination of two or more.

[0040] Examples of stabilizers include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, EDTA, taurine, tocopherol, and dibutylhydroxytoluene. These stabilizers may be used individually or in combination of two or more.

[0041] Furthermore, in conventional technology, it is known that by incorporating mannitol, a radical scavenger, into formulations containing components that are easily degraded by light exposure, photostability can be imparted to those components (International Journal of Pharmaceutics (1994), 107(3), 199-203: Effect of sweetening agents on the light stability of aqueous solutions of L-ascorbic acid; Yoshihiko Oyanagi, "SOD and reactive oxygen species regulators - their pharmacological effects and clinical applications," pp. 225-229, Nippon Igakukan). On the other hand, in the present invention, photostability can be imparted to brimonidine and / or its salt by using a specific containment described later, even without incorporating mannitol. In view of these effects of the present invention, one preferred embodiment of the eye drop solution used in the present invention is one that does not contain mannitol.

[0042] Furthermore, in addition to brimonidine and / or its salts, and brinzolamide and / or its salts, the eye drops used in the present invention may also contain, as necessary, pharmacological components that exhibit therapeutic effects against glaucoma and ocular hypertension, to the extent that they do not interfere with the effects of the present invention.

[0043] Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathetic stimulants such as pilocarpine hydrochloride; anticholinesterases such as distigmine bromide; sympathetic stimulants such as dipivefrin hydrochloride; beta-blockers such as timolol maleate; beta-blockers such as betaxolol hydrochloride; alpha-1 and beta-blockers such as nipradilol and levovunol hydrochloride; and alpha-1 blockers such as bunazosin hydrochloride. These pharmacological components may be used individually or in combination of two or more.

[0044] (pH) The pH of the eye drops used in the present invention is not particularly limited, as long as it is applicable to the ocular mucosa, but examples include 4 to 8, preferably 5 to 8, and more preferably 6 to 7.

[0045] (Application) The eye drops used in this invention have the effect of lowering intraocular pressure by suppressing aqueous humor production and promoting aqueous humor outflow via the uveoscleral outflow pathway through the action of brimonidine and / or its salt and brinzolamide and / or its salt, and are suitable for use in the treatment of glaucoma and ocular hypertension.

[0046] containment In the ophthalmic pharmaceutical product of the present invention, the eye drops are provided in a transparent container having a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm.

[0047] The transparent container used in the present invention may have an eye drop container for containing the eye drop solution. The transparent container used in the present invention may consist of the eye drop container itself, or it may be a state in which part or all of the eye drop container is covered with a covering member.

[0048] The structure of the eye drop container is not particularly limited and can be the same as that of conventional eye drop containers. Specifically, it should have a main body for containing the eye drops, a dispensing section with a spout for dispensing the eye drops, and a lid that can be detachably closed over the spout. Furthermore, if part or all of the eye drop container is covered with a covering material, the covering material can be used to tightly adhere to the entire or a part of the eye drop container (sides, or sides and bottom) using a shrink label, tack label, or the eye drop container can be packaged or contained using a pillow packaging film, zipper bag, or other covering material.

[0049] The transparent container used in this invention has a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm, and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm. Light with wavelengths of 360 to 460 nm and 600 to 680 nm is a factor in the decomposition of brimonidine and / or its salt in the eye drops, and by using a transparent container with reduced transmittance of light at these wavelengths, it is possible to provide photostability to brimonidine and / or its salt in the eye drops. In the case of an eye drop container in which a covering member is tightly attached to the entire or partial transparent container, the maximum transmittance of light is the value measured while the eye drop container is in the state in which the covering member is tightly attached.

[0050] From the viewpoint of further improving the photostability of brimonidine and / or its salt in the eye drops, the transparent container is preferably one in which the maximum transmittance of light with a wavelength of 360 to 460 nm is 63% or less and the maximum transmittance of light with a wavelength of 600 to 680 nm is 74% or less; more preferably one in which the maximum transmittance of light with a wavelength of 360 to 460 nm is 30% or less and the maximum transmittance of light with a wavelength of 600 to 680 nm is 48% or less; even more preferably one in which the maximum transmittance of light with a wavelength of 360 to 460 nm is 26% or less and the maximum transmittance of light with a wavelength of 600 to 680 nm is 44% or less; even more preferably one in which the maximum transmittance of light with a wavelength of 360 to 460 nm is 5% or less and the maximum transmittance of light with a wavelength of 600 to 680 nm is 12% or less; particularly preferably one in which the maximum transmittance of light with a wavelength of 360 to 460 nm is 1% or less and the maximum transmittance of light with a wavelength of 600 to 680 nm is 8% or less.

[0051] In this invention, the maximum transmittance of light with wavelengths of 360 to 460 nm is obtained by measuring the transmittance of light at wavelength intervals of 5 nm from 360 nm to 460 nm using an ultraviolet-visible spectrophotometer, and then determining the maximum value among the measured transmittance values. The same method is used to obtain the maximum transmittance of light with wavelengths of 600 to 680 nm.

[0052] Furthermore, the transparent container used in the present invention may have an opaque area in part for the purpose of displaying the product name, ingredient name, expiration date, warnings, etc., but at least a portion of it must have a transparent area for visualizing the inside, such as for conducting an insoluble foreign matter test. The transparent container used in the present invention must have a maximum transmittance of light with wavelengths of 360-460 nm and 600-680 nm across its entire surface in order to provide photostability to brimonidine and / or its salt in the eye drops, and the maximum transmittance of light with wavelengths of 360-460 nm and 600-680 nm must also be within the aforementioned range in the transparent area.

[0053] For example, in the case of eye drop containers where the transparent container is attached to the eye drop container itself, or to the whole or a part thereof, it is desirable that the transparent area occupies 5% or more, preferably 7% or more, more preferably 10% or more, and even more preferably 15% or more of the side surface of the eye drop container (the outer surface of the main body excluding the area covered by the lid).

[0054] The transparent region of the transparent container only needs to have transparency sufficient to allow the interior to be seen, and the transmittance of visible light in wavelength ranges other than 360-460 nm and 600-680 nm should be high enough to allow the interior to be seen. From the viewpoint of facilitating insoluble foreign matter testing and confirmation of the amount of remaining liquid, the transparent region of the transparent container used in the present invention has an average transmittance of light in the wavelength range of 480-580 nm and 700-780 nm, for example, 10% or more, preferably 20% or more, more preferably 30% or more, and particularly preferably 30-80%. Here, the average transmittance of light in the wavelength range of 480-580 nm and 700-780 nm is a value obtained by measuring the transmittance of light in the range from 480 nm to 580 nm and the range from 700 nm to 780 nm at wavelength intervals of 5 nm using an ultraviolet-visible spectrophotometer, and calculating the average value of each measured transmittance.

[0055] The material used to construct the transparent container is not particularly limited, as long as it possesses the characteristics described above, and can be appropriately chosen according to the form of the transparent container, etc. It may be made of plastic, glass, pulp, or any other material. In the case of an eye drop container, plastic is preferred as the material used, from the viewpoint of squeezeability and durability.

[0056] When the transparent container is made of plastic, there are no particular restrictions on the type of resin component, but thermoplastic resins are preferred. Specifically, thermoplastic resins include olefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate and polybutylene terephthalate; polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, rigid polyvinyl chloride resins, styrene resins, and the like. These thermoplastic resins may be used individually or in combination of two or more. Among these thermoplastic resins, polyethylene is particularly suitable as a constituent material for the transparent container used in the present invention because it is easy to impart the aforementioned light transmittance properties to it.

[0057] The method for manufacturing the transparent container used in the present invention is not particularly limited, as long as it possesses the characteristics described above. Conventional known methods for controlling light transmittance can be used, taking into account the characteristics of the constituent materials used to form the transparent container and the thickness of the transparent container. Specifically, methods for manufacturing a transparent container having the above-mentioned characteristics include: forming an eye drop container using a constituent material that incorporates a substance capable of absorbing light with wavelengths of 360-460 nm and a substance capable of absorbing light with wavelengths of 600-680 nm; applying a coating solution containing a substance capable of absorbing light with wavelengths of 360-460 nm and a substance capable of absorbing light with wavelengths of 600-680 nm to the outer surface of the eye drop container; covering the outer surface of the eye drop container with a film (such as a heat-shrinkable film) incorporating a substance capable of absorbing light with wavelengths of 360-460 nm and a substance capable of absorbing light with wavelengths of 600-680 nm; pillow-packaging the eye drop container with a film incorporating a substance capable of absorbing light with wavelengths of 360-460 nm and a substance capable of absorbing light with wavelengths of 600-680 nm; and storing the eye drop container in a resealable bag incorporating a substance capable of absorbing light with wavelengths of 360-460 nm and a substance capable of absorbing light with wavelengths of 600-680 nm. For materials that can absorb light with wavelengths of 360-460 nm and materials that can absorb light with wavelengths of 600-680 nm, pigments, light absorbers, etc., can be appropriately selected.

[0058] 2. Light-stabilizing method for brimonidine and / or its salts The present invention relates to a photostabilization method for brimonidine and / or its salts in an eye drop solution containing brimonidine and / or its salts, and brinzolamide and / or its salts, characterized in that the eye drop solution is contained in a transparent container having a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm.

[0059] The composition of the eye drops used in the photostabilization method of the present invention, the type and characteristics of the transparent container, etc., are as described in the "1. Ophthalmic Pharmaceutical Products" section above. [Examples]

[0060] The present invention will be specifically described below with reference to examples, but the present invention is not limited in any way by these examples.

[0061] Test Example 1 1. Manufacturing of ophthalmic pharmaceutical products 1-1. Preparation of eye drops The eye drops (aqueous suspension) of Formulation 1 shown in Table 1 were prepared by the following procedure. First, Carbopol was dissolved in purified water to prepare a 0.8 w / v% Carbopol solution. Next, according to the composition shown in Table 1, brimonidine tartrate, tyroxapol, boric acid, sodium chloride, propylene glycol, benzalkonium chloride, and the 0.8 w / v% Carbopol solution were added to purified water and dissolved. After adjusting the pH to 6.5 with sodium hydroxide, brinzolamide was added and mixed to obtain the eye drops (aqueous suspension).

[0062] [Table 1]

[0063] 1-2. Containment in a containment vessel Five ml of the eye drops of Formulation 1 obtained above were placed in containers as shown in Table 2 to produce various specimens (ophthalmic pharmaceutical products). Specifically, in Examples 1-3 and Comparative Examples 1-4, glass containers (container bodies) (manufactured by Maruemu Co., Ltd.) filled with eye drops were placed in various polyethylene zipper bags (manufactured by Seisan Nipponsha Co., Ltd., Unipack Color Semi-Transparent C-4 Blue, Red, Yellow, Colorless, Green) to create specimens. In Examples 2 and 3, the glass containers (container bodies) filled with eye drops were placed in a layered state using the types and predetermined number of zipper bags shown in Table 2. In Comparative Example 5, no container covering was used for the PET container body (container body used in New Mytear CL (registered trademark) (Senju Pharmaceutical Co., Ltd.)). In Comparative Example 6, the glass containers (container bodies) filled with eye drops were covered with a film made of laminated polyethylene and polyethylene terephthalate (manufactured by Mitsubishi Plastics, Inc., Tech Barrier AX) to create the specimen.

[0064] Furthermore, to confirm the light transmittance of the containers used in the test, each coating or polyethylene terephthalate container used was cut to 1.0 cm × 3.0 cm, and the transmittance (%) of light at each wavelength was measured using a UV-Vis spectrophotometer ("UV-2450" model, manufactured by Shimadzu Corporation). Figure 1 shows the light transmittance of each coating and polyethylene terephthalate container at each wavelength, and Table 2 shows the maximum light transmittance at wavelengths of 360-460 nm, the maximum light transmittance at 600-680 nm, and the average light transmittance in the wavelength regions of 480-580 nm and 700-780 nm. The average light transmittance in the wavelength regions of 480-580 nm and 700-780 nm was determined by measuring the light transmittance at 5 nm intervals in the 480-580 nm and 700-780 nm regions and calculating the average value. Furthermore, in the wavelength ranges of 360-460 nm and 600-680 nm, the light transmittance of glass containers coated with each coating was up to 4% lower than the transmittance of the coating alone.

[0065] 2. Evaluation of the photostability of brimonidine tartrate Each of the samples obtained above was subjected to a photostability test using a photostability tester ("LT-120A-WCD" model, manufactured by Nagano Science Co., Ltd.) at a temperature of 25°C, irradiated with 0.7 million lx of light from a white fluorescent lamp for 28.6 hours, and then tested with a chemical lamp at 5 W·h / m². 2 The sample was continuously irradiated with light for 8 hours, and 200,000 lx·h and 40 W·h / m² of light were applied to the sample. 2 It exposed the light of [something].

[0066] The concentration of brimonidine tartrate in the eye drops of each sample before and after light exposure was measured using an ultra-high-performance liquid chromatography system (UPLC, Waters), and the degradation rate (%) of brimonidine tartrate was calculated according to the following formula.

[0067]

number

[0068] 3. Evaluation of Transparency Each of the samples obtained as described above was visually observed and evaluated for transparency according to the following criteria. (Judgment criteria) ○: The container has sufficient transparency to allow for testing of insoluble foreign matter. ×: The container is opaque, making it impossible to perform insoluble foreign matter testing.

[0069] 4. Evaluation Results The results obtained are shown in Table 2. As is clear from Table 2, when a containment was used in which the maximum light transmittance at wavelengths of 360-460 nm was greater than 67% and the maximum light transmittance at wavelengths of 600-680 nm was greater than 78%, the degradation rate of brimonidine tartrate exceeded 1%, indicating that brimonidine tartrate could not be stably retained (Comparative Examples 1, 2, 4-7). Furthermore, even when the maximum light transmittance at wavelengths of 360-460 nm was 67% or less, the containment in which the maximum light transmittance at wavelengths of 600-680 nm was greater than 78% could not stably retain brimonidine tartrate (Comparative Example 3). In contrast, when a containment was used in which the maximum light transmittance at wavelengths of 360-460 nm was 67% or less and the maximum light transmittance at wavelengths of 600-680 nm was 78% or less, the degradation rate of brimonidine tartrate was low, and brimonidine tartrate was given photostability (Examples 1-3). In particular, in the case of a containment that satisfies the maximum light transmittance of 27% or less at wavelengths of 360-460 nm and the maximum light transmittance of 44% or less at wavelengths of 600-680 nm, the photostability of brimonidine tartrate was significantly improved (Examples 2 and 3).

[0070] From these results, it became clear that by using a containment that can reduce the transmittance of light at wavelengths of 360-460 nm and 600-680 nm, the photostability of brimonidine tartrate can be improved in eye drops containing brimonidine tartrate and brinzolamide.

[0071] [Table 2]

[0072] Test Example 2 In the aforementioned Test Example 1, it was confirmed that in eye drops containing brimonidine tartrate and brinzolamide, reducing the light transmittance at wavelengths of 360-460 nm and 600-680 nm would improve the photostability of brimonidine tartrate. In this Test Example 2, the following tests were conducted to examine in more detail the wavelength ranges that affect the photostability of brimonidine tartrate.

[0073] 1. Manufacturing of eye drops containing a encapsulated substance Using the same method as in Test Example 1, eye drops (aqueous suspension) of Formulation 1 shown in Table 1 were prepared. These eye drops were placed in containers and coverings as shown in Table 3, and various specimens (ophthalmic pharmaceutical products), Examples 4-7 and Comparative Example 8, were manufactured. Specifically, glass containers filled with 5 ml of eye drops were covered with various cellophane (Okina Co., Ltd., product numbers CCM5 (colorless and transparent), CCM1 (red), CCM2 (green), CCM4 (yellow), CCM3 (blue)) to create specimens.

[0074] Furthermore, to confirm the light transmittance of the containers used in the test, the light transmittance (%) at each wavelength of each cellophane used was measured using the same method as in Test Example 1. The light transmittance of each cellophane at each wavelength is shown in Figure 2, and Table 3 shows the maximum light transmittance at wavelengths of 360-460 nm, the maximum light transmittance at 600-680 nm, the wavelength range where the light transmittance is 10% or less, and the average light transmittance in the wavelength regions of 480-580 nm and 700-780 nm.

[0075] 2. Evaluation of the photostability of brimonidine tartrate Each of the samples obtained above was subjected to a photostability test using a photostability tester ("LT-120A-WCD" model, manufactured by Nagano Science Co., Ltd.) at a temperature of 25°C, irradiated with 0.7 million lx of light from a white fluorescent lamp for 28.6 hours, and then tested with a chemical lamp at 20 W·h / m². 2 The sample was continuously irradiated with light for 20 hours, and 200,000 lx·h and 400 W·h / m² were applied to the sample. 2The samples were exposed to light. In this example 2, the light exposure conditions were set to be more severe than in example 1 in order to more thoroughly investigate the wavelength range that affects the photostability of brimonidine tartrate.

[0076] The concentration of brimonidine tartrate in the eye drops of each sample before and after light exposure was measured using an ultra-high-performance liquid chromatography system (UPLC, Waters), and the degradation rate (%) of brimonidine tartrate was calculated using the same method as in Test Example 1.

[0077] 3. Evaluation of Transparency The transparency of each sample obtained above was evaluated using the same method as in Test Example 1.

[0078] 4. Evaluation Results The results obtained are shown in Table 3. As is clear from Table 3, a tendency was observed for the degradation rate of brimonidine tartrate to decrease as the maximum light transmittance at wavelengths of 360-460 nm and 600-680 nm decreased. In particular, the containment used in Example 5, which showed the lowest degradation rate of brimonidine tartrate, had low light transmittance at wavelengths of 360-460 nm and 600-680 nm, but high light transmittance in the visible light region at wavelengths of 480-580 nm and 700-780 nm. In other words, the results of Example 5 showed that in eye drops containing brimonidine tartrate and brinzolamide, the visible light region with wavelengths of 480-580 nm and 700-780 nm did not adversely affect the photostability of brimonidine tartrate, while visible light with wavelengths of 360-460 nm and 600-680 nm did. Therefore, it became clear that to ensure the photostability of brimonidine tartrate while maintaining internal visibility, it is effective to lower the light transmittance in both the 360-460 nm and 600-680 nm wavelength regions.

[0079] [Table 3]

[0080] Test Example 3 In the aforementioned Test Examples 1 and 2, the evaluation was conducted for the case where the brimonidine tartrate content in the eye drops was 0.1 w / v%. Therefore, in Test Example 3, the brimonidine tartrate content was changed to 0.2 w / v% and the photostability of brimonidine tartrate was evaluated.

[0081] 1. Manufacturing of eye drops containing a encapsulated substance Using the same method as in Test Example 1, the eye drop solution (aqueous suspension) of Formulation 2 shown in Table 4 was prepared. This eye drop solution was placed in the containers and coverings shown in Table 5, and Examples 8 and Comparative Example 9, which are various specimens (ophthalmic pharmaceutical products), were manufactured. The containers and coverings used in Examples 8 and Comparative Example 9 are the same as those used in Examples 5 and Comparative Example 8 in Test Example 2, respectively.

[0082] [Table 4]

[0083] 2. Evaluation of the photostability and transparency of brimonidine tartrate. For each sample obtained as described above, the photostability of brimonidine tartrate was evaluated using the same method as in Test Example 2. Furthermore, the transparency of each sample obtained was evaluated using the same method as in Test Example 1.

[0084] 3. Evaluation Results The results obtained are shown in Table 5. From these results, it was confirmed that in eye drops containing brimonidine tartrate and brinzolamide, even with a brimonidine tartrate content of 0.2 gw / v%, the photostability of brimonidine tartrate can be ensured while maintaining internal visibility by lowering the light transmittance in both the 360-460 nm and 600-680 nm wavelength ranges.

[0085] [Table 5]

[0086] Reference example In this reference example, the relationship between the wavelengths that affect the photostability of brimonidine tartrate and the absorption wavelength of brimonidine tartrate was investigated in eye drops containing brimonidine tartrate and brinzolamide.

[0087] First, the UV spectrum of brimonidine tartrate was measured using a UV-Vis spectrophotometer ("UV-2450" model, manufactured by Shimadzu Corporation). As a result, absorption wavelengths of brimonidine tartrate were observed in the region below 370 nm, and the maximum absorption wavelengths of brimonidine tartrate were 246 nm and 319 nm. On the other hand, for the packaging used in Test Example 1 (Examples 1-3 and Comparative Examples 6 and 7), the transmittance of light at wavelengths of 246 nm and 319 nm, and the average transmittance of light in the region below 370 nm were calculated and are shown in Table 6. In other words, it was confirmed that the wavelengths that affect the photostability of brimonidine tartrate in eye drops containing brimonidine tartrate (i.e., 360-460 nm and 600-680 nm) are not related to the absorption wavelengths of brimonidine tartrate.

[0088] [Table 6]

[0089] Manufacturing example Example 9 A transparent container is manufactured by triple-layering polyethylene / polyethylene terephthalate film on the outer surface of a PET container (the container used in New Mytear CL (registered trademark) (Senju Pharmaceutical Co., Ltd.)). This transparent container (maximum light transmittance of 30% for light with wavelengths of 360-460 nm, and 40% for light with wavelengths of 600-680 nm) is filled with eye drops of formulation 3 in Table 7 to obtain the ophthalmic pharmaceutical product of the present invention.

[0090] Example 10 The eye drops of Formulation 4 in Table 7 are filled into a PET container (the container used for New Mytear CL (registered trademark) (Senju Pharmaceutical Co., Ltd.)). The filled container is double-packaged in a green polyethylene zipper bag (maximum light transmittance of light with wavelengths of 360-460 nm: 26%, maximum light transmittance of light with wavelengths of 600-680 nm: 45%) to obtain the ophthalmic pharmaceutical product of the present invention.

[0091] [Table 7]

Claims

[Claim 1] Ophthalmic solutions containing brimonidine and / or its salts, and brinzolamide and / or its salts, It is housed in a transparent container that has a maximum transmittance of 67% or less for light with a wavelength of 360 to 460 nm, and a maximum transmittance of 78% or less for light with a wavelength of 600 to 680 nm. An ophthalmic pharmaceutical product characterized by the following features.

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