WO2021131092A1 - Pharmaceutical product - Google Patents

Abstract

A purpose of the present invention is to provide a technology pertaining to an ophthalmological pharmaceutical product wherein an aqueous liquid agent that includes brimonidine and/or a salt thereof is housed in a colorless, transparent container.　This pharmaceutical product is obtained by housing, in a colorless, transparent polyethylene container, an aqueous liquid agent that includes brimonidine and/or a salt thereof as well as a metal chloride.

Description

Pharmaceutical products

The present invention relates to a pharmaceutical product in which an aqueous solution containing brimonidine and / or a salt thereof is contained in a colorless transparent container and can suppress the formation of decomposition products of brimonidine and / or a salt thereof due to light exposure.

Brimonidine and its salts are known as adrenaline α2 receptor agonists and have the effect of reducing intraocular pressure by suppressing the production of aqueous humor and promoting the outflow of aqueous humor through the uveoscleral outflow tract. It has been used in the treatment of glaucoma and ocular hypertension.

Conventionally, for a formulation in which brimonidine and / or a salt thereof and timolol and / or a salt thereof are used in combination, a formulation technique focusing on the formulation stability has also been studied. For example, in Patent Document 1, a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5 can suppress the production of decomposition products. It is disclosed that the stability is improved. Further, Patent Document 2 describes an eye drop containing brimonidine and / or a salt thereof, and brinzolamide and / or a salt thereof, having a maximum transmittance of light having a wavelength of 360 to 460 nm of 67% or less and a wavelength of 600 to 680 nm. It is disclosed that the decomposition of brimonidine and / or a salt thereof due to light exposure can be suppressed and the stability of the preparation can be ensured by accommodating the brimonidine and / or a salt thereof in a transparent container having a maximum light transmittance of 78% or less.

Special Table 2009-533462 International Publication No. 2017/099207

An object of the present invention is to provide a technique for an ophthalmic pharmaceutical product in which an aqueous liquid containing brimonidine and / or a salt thereof is contained in a colorless transparent container.

When an aqueous solution containing brimonidine and / or a salt thereof and a metal chloride is contained in a colorless and transparent polyethylene container, the present inventor produces a decomposition product of brimonidine and / or a salt thereof even by light exposure. We found that it could be suppressed.

Further, the present inventor puts brimonidine and / or a salt thereof and an aqueous solution containing boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container, and the brimonidine is also exposed to light. And / or found that the formation of decomposition products of the salt thereof can be suppressed.

Furthermore, the present inventor holds an aqueous solution containing brimonidine and / or a salt thereof, boric acid and / or a salt thereof, and tromethamole and / or a salt thereof in a colorless and transparent polyethylene container, and even by light exposure. It has been found that the formation of decomposition products of brimonidine and / or a salt thereof can be suppressed.

The present invention has been completed by further studies based on these findings.

That is, the present invention provides the following invention as an embodiment.
Item 1-1. A pharmaceutical product in which an aqueous liquid containing brimonidine and / or a salt thereof, and a metal chloride is contained in a colorless and transparent polyethylene container.
Item 1-2. Item 2. The pharmaceutical product according to Item 1-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate.
Item 1-3. Item 2. The pharmaceutical product according to Item 1-1 or 1-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 1-4. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-3, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 1-5. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-4, which contains at least sodium chloride as the metal chloride.
Item 1-6. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-5, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 1-7. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-6, wherein the total concentration of the metal chloride is 0.01 to 2 w / v%.
Item 1-8. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 2. The pharmaceutical product according to Item 1-6, which has a concentration of 0.001 to 0.2 w / v%.
Item 1-9. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-8, wherein the aqueous solution contains boric acid and / or a salt thereof.
Item 1-10. Item 2. The pharmaceutical product according to Item 1-9, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 1-11. Item 2. The pharmaceutical product according to Item 1-9 or 1-10, wherein the concentration of boric acid and / or a salt thereof is 10 to 1000 mM in terms of boron concentration.
Item 1-12. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-11, wherein the aqueous solution contains tromethamole and / or a salt thereof.
Item 1-13. Item 2. The pharmaceutical product according to Item 1-12, wherein the tromethamole and / or a salt thereof is tromethamole.
Item 1-14. Item 2. The pharmaceutical product according to Item 1-12 or 1-13, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 1-15. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-14, wherein the aqueous solution is an eye drop.
Item 1-16. Item 2. The item according to any one of Items 1-1 to 1-15, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a wavelength region of 400 to 800 nm. Pharmaceutical products.
Item 1-17. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-16, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 1-18. Item 2. The pharmaceutical product according to any one of Items 1-1 to 1-17, wherein the polyethylene container is a multi-dose type container.
Item 1-19. The pharmaceutical product according to any one of Items 1-1 to 1-18, which is used for the treatment of glaucoma.
Item 1-20. A pharmaceutical product in which an aqueous solution containing brimonidine tartrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and boric acid and / or borax is contained in a colorless and transparent polyethylene container.
The concentration of the brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
The concentration of sodium chloride is 0.5 to 0.6 w / v%, the concentration of potassium chloride is 0.1 to 0.2 w / v%, and the concentration of magnesium chloride is 0.01 to 0.02 w / v%. And the concentration of the calcium chloride is 0.01 to 0.02 w / v%.
The concentration of boric acid and / or borax is 30 to 60 mM in terms of boron concentration.
The aqueous solution is an eye drop and
The main decomposition product in the aqueous solution detected under the measurement conditions described in the specification after irradiating the pharmaceutical product with light of 30,000 lux with a white fluorescent lamp for 200 hours under a temperature condition of 25 ° C. (RRT = 1.5) The amount is 1.0% or less,
The polyethylene container is a multi-dose type container.
The polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 40% or more in a wavelength region of 400 to 800 nm.
Pharmaceutical products.
Item 1-21. Item 2. The pharmaceutical product according to Item 1-20, wherein the aqueous solution contains tromethamole and the concentration of tromethamole is 0.01 to 3 w / v%.
Item 1-22. A method for producing a pharmaceutical product, wherein an aqueous liquid containing brimonidine and / or a salt thereof, and a metal chloride is contained in a colorless and transparent polyethylene container.
A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, and a metal chloride, and
A step of preparing a pharmaceutical product by accommodating the aqueous solution in a colorless and transparent polyethylene container, and
Before shipping the pharmaceutical product, a step of confirming the properties (color tone) of the aqueous solution contained in the container, and
Manufacturing method including.

As another embodiment, the present invention provides the inventions listed below.
Item 2-1. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, and a metal chloride in a colorless and transparent polyethylene container.
Item 2-2. Item 2. The method according to Item 2-1. The method according to Item 2-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 2-3. Item 2. The method according to Item 2-1 or 2-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 2-4. Item 6. The method according to any one of Items 2-1 to 2-3, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 2-5. Item 2. The method according to any one of Items 2-1 to 2-4, wherein the metal chloride contains at least sodium chloride.
Item 2-6. Item 2. The method according to any one of Items 2-1 to 2-5, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 2-7. Item 2. The method according to any one of Items 2-1 to 2-6, wherein the concentration of the total amount of the metal chloride is 0.01 to 2 w / v%.
Item 2-8. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 2. The method according to Item 2-6, wherein the concentration is 0.001 to 0.2 w / v%.
Item 2-9. Item 8. The method according to any one of Items 2-1 to 2-8, wherein the aqueous solution contains boric acid and / or a salt thereof.
Item 2-10. Item 2. The method according to Item 2-9, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 2-11. Item 2. The method according to Item 2-9 or 2-10, wherein the concentration of boric acid and / or a salt thereof is 10 to 1000 mM in terms of boron concentration.
Item 2-12. Item 8. The method according to any one of Items 2-1 to 2-11, wherein the aqueous solution contains tromethamole and / or a salt thereof.
Item 2-13. Item 2. The method according to Item 2-12, wherein the trometamole and / or a salt thereof is tromethamole.
Item 2-14. Item 2. The method according to Item 2-12 or 2-13, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 2-15. Item 2. The method according to any one of Items 2-1 to 2-14, wherein the aqueous solution is an eye drop.
Item 2-16. Item 2. The item according to any one of Items 2-1 to 2-15, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a wavelength region of 400 to 800 nm. the method of.
Item 2-17. Item 2. The method according to any one of Items 2-1 to 2-16, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 2-18. Item 2. The method according to any one of Items 2-1 to 2-17, wherein the polyethylene container is a multi-dose type container.
Item 2-19. Item 8. The method according to any one of Items 2-1 to 2-18, wherein the aqueous solution is used for the treatment of glaucoma.

As another embodiment, the present invention provides the inventions listed below.
Item 3-1. A pharmaceutical product containing brimonidine and / or a salt thereof, and an aqueous solution containing boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container.
Item 3-2. Item 3. The pharmaceutical product according to Item 3-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 3-3. Item 3. The pharmaceutical product according to Item 3-1 or 3-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 3-4. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-3, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 3-5. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-4, wherein the aqueous solution contains a metal chloride.
Item 3-6. Item 3. The pharmaceutical product according to Item 3-5, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 3-7. Item 3. The pharmaceutical product according to Item 3-5 or 3-6, which comprises at least sodium chloride as the metal chloride.
Item 3-8. Item 4. The pharmaceutical product according to any one of Items 3-5 to 3-7, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 3-9. Item 4. The pharmaceutical product according to any one of Items 3-5 to 3-8, wherein the total concentration of the metal chloride is 0.01 to 2 w / v%.
Item 3-10. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 3. The pharmaceutical product according to Item 3-8, which has a concentration of 0.001 to 0.2 w / v%.
Item 3-11. Item 2. The pharmaceutical product according to any one of Items 3-1 to 3-10, wherein the aqueous solution contains tromethamole and / or a salt thereof.
Item 3-12. Item 3. The pharmaceutical product according to Item 3-11, wherein the tromethamole and / or a salt thereof is tromethamole.
Item 3-13. Item 3. The pharmaceutical product according to Item 3-11 or 3-12, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 3-14. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-13, wherein the aqueous solution is an eye drop.
Item 3-15. Item 2. The item according to any one of Items 3-1 to 3-14, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a wavelength region of 400 to 800 nm. Pharmaceutical products.
Item 3-16. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-15, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 3-17. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-16, wherein the polyethylene container is a multi-dose type container.
Item 3-18. Item 4. The pharmaceutical product according to any one of Items 3-1 to 3-17, wherein the aqueous solution is used for the treatment of glaucoma.
Item 3-19. A pharmaceutical product in which an aqueous solution containing brimonidine tartrate, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, and boric acid and / or borax is contained in a colorless and transparent polyethylene container.
The concentration of the brimonidine and / or a salt thereof is 0.05 to 0.2 w / v%.
The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the chloride. The concentration of calcium is 0.001 to 0.2 w / v%,
The concentration of boric acid and / or borax is 70 mM or more in terms of boron concentration.
The aqueous solution is an eye drop and
The main decomposition product in the aqueous solution detected under the measurement conditions described in the specification after irradiating the pharmaceutical product with light of 30,000 lux with a white fluorescent lamp for 200 hours under a temperature condition of 25 ° C. (RRT = 1.5) The amount is 1.0% or less,
A pharmaceutical product in which the polyethylene container is a multi-dose type container.
Item 3-20. Item 3. The pharmaceutical product according to Item 3-19, wherein the aqueous solution contains tromethamole and the concentration of tromethamole is 0.01 to 3 w / v%.
Item 3-21. A method for producing a pharmaceutical product, wherein an aqueous solution containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more is contained in a colorless and transparent polyethylene container.
A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more.
A step of preparing a pharmaceutical product by accommodating the aqueous solution in a colorless and transparent polyethylene container, and
Before shipping the pharmaceutical product, a step of confirming the properties (color tone) of the aqueous solution contained in the container, and
Manufacturing method including.

As another embodiment, the present invention provides the inventions listed below.
Item 4-1. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container.
Item 4-2. Item 4. The method according to Item 4-1. The method according to Item 4-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 4-3. Item 4. The method according to Item 4-1 or 4-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 4-4. Item 8. The method according to any one of Items 4-1 to 4-3, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 4-5. Item 8. The method according to any one of Items 4-1 to 4-4, wherein the aqueous solution contains a metal chloride.
Item 4-6. Item 4. The method according to Item 4-5, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 4-7. Item 4. The method according to Item 4-5 or 4-6, wherein the metal chloride contains at least sodium chloride.
Item 4-8. Item 4. The method according to any one of Items 4-5 to 4-7, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 4-9. Item 6. The method according to any one of Items 4-5 to 4-8, wherein the concentration of the total amount of the metal chloride is 0.01 to 2 w / v%.
Item 4-10. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 4. The method according to Item 4-8, wherein the concentration is 0.001 to 0.2 w / v%.
Item 4-11. Item 8. The method according to any one of Items 4-1 to 4-10, wherein the aqueous solution contains tromethamole and / or a salt thereof.
Item 4-12. Item 4. The method according to Item 4-11, wherein the trometamole and / or a salt thereof is tromethamole.
Item 4-13. Item 4. The method according to Item 4-11 or 4-12, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 4-14. Item 8. The method according to any one of Items 4-1 to 4-13, wherein the aqueous solution is an eye drop.
Item 4-15. Item 4. The item according to any one of Items 4-1 to 4-14, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a region having a wavelength of 400 to 800 nm. Method.
Item 4-16. Item 2. The method according to any one of Items 4-1 to 4-15, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 4-17. Item 4. The method according to any one of Items 4-1 to 4-16, wherein the polyethylene container is a multi-dose type container.
Item 4-18. Item 8. The method according to any one of Items 4-1 to 4-17, wherein the aqueous solution is used for the treatment of glaucoma.

As another embodiment, the present invention provides the inventions listed below.
Item 5-1. A pharmaceutical product in which an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof are contained in a colorless and transparent polyethylene container.
Item 5-2. Item 2. The pharmaceutical product according to Item 5-1. The brimonidine and / or a salt thereof is brimonidine tartrate.
Item 5-3. Item 2. The pharmaceutical product according to Item 5-1 or 5-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 5-4. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-3, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 5-5. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-4, wherein the concentration of boric acid and / or a salt thereof is 10 to 1000 mM in terms of boron concentration.
Item 5-6. Item 2. The pharmaceutical product according to any one of Items 5-1 to 5-5, wherein the tromethamole and / or a salt thereof is tromethamole.
Item 5-7. Item 2. The pharmaceutical product according to any one of Items 5-1 to 5-6, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 5-8. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-7, wherein the aqueous solution contains a metal chloride.
Item 5-9. Item 5. The pharmaceutical product according to Item 5-8, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 5-10. Item 5. The pharmaceutical product according to Item 5-8 or 5-9, which comprises at least sodium chloride as the metal chloride.
Item 5-11. Item 4. The pharmaceutical product according to any one of Items 5-8 to 5-10, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 5-12. Item 4. The pharmaceutical product according to any one of Items 5-8 to 5-11, wherein the total concentration of the metal chloride is 0.01 to 2 w / v%.
Item 5-13. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 5. The pharmaceutical product according to Item 5-11, which has a concentration of 0.001 to 0.2 w / v%.
Item 5-14. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-13, wherein the aqueous solution is an eye drop.
Item 5-15. Item 2. The item according to any one of Items 5-1 to 5-14, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a region having a wavelength of 400 to 800 nm. Pharmaceutical products.
Item 5-16. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-15, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 5-17. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-16, wherein the polyethylene container is a multi-dose type container.
Item 5-18. Item 4. The pharmaceutical product according to any one of Items 5-1 to 5-17, wherein the aqueous solution is used for the treatment of glaucoma.
Item 5-19. A pharmaceutical product in which an aqueous solution containing brimonidine tartrate, borate and / or borax, and tromethamole is contained in a colorless and transparent polyethylene container.
The concentration of the brimonidine tartrate is 0.05 to 0.2 w / v%.
The concentration of boric acid and / or borax is 10 to 1000 mM in terms of boron concentration.
The concentration of the trometamole is 0.01 to 3 w / v%.
The aqueous solution is an eye drop and
The main decomposition product in the aqueous solution detected under the measurement conditions described in the specification after irradiating the pharmaceutical product with light of 30,000 lux with a white fluorescent lamp for 200 hours under a temperature condition of 25 ° C. (RRT = 1.5) The amount is 1.0% or less,
The polyethylene container is a multi-dose type container.
The polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 40% or more in a wavelength region of 400 to 800 nm.
Pharmaceutical products.
Item 5-20. The aqueous solution contains sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
The sodium chloride concentration is 0.01 to 2 w / v%, the potassium chloride concentration is 0.01 to 2 w / v%, the magnesium chloride concentration is 0.001 to 0.2 w / v%, and the chloride. Item 5. The pharmaceutical product according to Item 5-19, wherein the calcium concentration is 0.001 to 0.2 w / v%.
Item 5-21. A method for producing a pharmaceutical product, wherein an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof is contained in a colorless and transparent polyethylene container. And
A step of preparing an aqueous solution containing brimonidine and / or a salt thereof, boric acid and / or a salt thereof, and tromethamole and / or a salt thereof, and
A step of preparing a pharmaceutical product by accommodating the aqueous solution in a colorless and transparent polyethylene container, and
Before shipping the pharmaceutical product, a step of confirming the properties (color tone) of the aqueous solution contained in the container, and
Manufacturing method including.

As another embodiment, the present invention provides the inventions listed below.
Item 6-1. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof in a colorless and transparent polyethylene container.
Item 6-2. Item 6. The method according to Item 6-1, wherein the brimonidine and / or a salt thereof is brimonidine tartrate.
Item 6-3. Item 6. The method according to Item 6-1 or 6-2, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.5 w / v%.
Item 6-4. Item 6. The method according to any one of Items 6-1 to 6-3, wherein the boric acid and / or a salt thereof is boric acid and / or borax.
Item 6-5. Item 8. The method according to any one of Items 6-1 to 6-4, wherein the concentration of boric acid and / or a salt thereof is 10 to 1000 mM in terms of boron concentration.
Item 6-6. Item 8. The method according to any one of Items 6-1 to 6-5, wherein the trometamole and / or a salt thereof is tromethamole.
Item 6-7. Item 8. The method according to any one of Items 6-1 to 6-6, wherein the concentration of the tromethamole and / or a salt thereof is 0.01 to 3 w / v%.
Item 6-8. Item 8. The method according to any one of Items 6-1 to 6-7, wherein the aqueous solution contains a metal chloride.
Item 6-9. Item 6. The method according to Item 6-8, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 6-10. Item 6. The method according to Item 6-8 or 6-9, wherein the metal chloride contains at least sodium chloride.
Item 6-11. Item 6. The method according to any one of Items 6-8 to 6-10, wherein the metal chloride is sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
Item 6-12. Item 6. The method according to any one of Items 6-8 to 6-11, wherein the concentration of the total amount of the metal chloride is 0.01 to 2 w / v%.
Item 6-13. The concentration of the sodium chloride is 0.01 to 2 w / v%, the concentration of the potassium chloride is 0.01 to 2 w / v%, the concentration of the magnesium chloride is 0.001 to 0.2 w / v%, and the concentration of the calcium chloride is Item 6. The method according to Item 6-11, wherein the concentration is 0.001 to 0.2 w / v%.
Item 6-14. Item 6. The method according to any one of Items 6-1 to 6-13, wherein the aqueous solution is an eye drop.
Item 6-15. Item 2. The item according to any one of Items 6-1 to 6-14, wherein the polyethylene container has a brightness of 70 or more, a saturation of 20 or less, and a maximum light transmittance of 10% or more in a region having a wavelength of 400 to 800 nm. Method.
Item 6-16. Item 6. The method according to any one of Items 6-1 to 6-15, wherein the polyethylene container has a light transmittance of 10% or more at a wavelength of 400 nm.
Item 6-17. Item 6. The method according to any one of Items 6-1 to 6-16, wherein the polyethylene container is a multi-dose type container.
Item 6-18. Item 8. The method according to any one of Items 6-1 to 6-17, wherein the aqueous solution is used for the treatment of glaucoma.

According to the present invention, even if an aqueous solution containing brimonidine and / or a salt thereof is contained in a colorless and transparent container, the formation of a decomposition product of brimonidine and / or a salt thereof can be suppressed by light exposure, and brimonidine and / or a salt thereof can be suppressed. Alternatively, the content of the salt thereof can be stably maintained. Further, according to the present invention, since the aqueous solution is housed in a colorless and transparent container having high internal visibility, an insoluble foreign matter test can be easily performed, quality control is facilitated, and the aqueous solution remains. The amount can be easily visually recognized from the outside of the container, and the convenience of the user can be improved.

It is a figure which shows the result of having measured the light transmittance at each wavelength of the container used in Test Examples 1 to 4.

1. 1. Definitions It should be understood that the terms used herein are used in the meaning commonly used in the art unless otherwise noted. Thus, unless otherwise defined, all terminology and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, this specification (including definitions) takes precedence.

In the present specification, the "aqueous liquid agent" is a preparation containing water as a base and exhibiting a liquid state.

As used herein, "brimonidine" is a compound known as an adrenergic α2 receptor agonist, and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to. Further, in the present specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

In the present specification, "boric acid" is an oxo acid of boron.

In the present specification, "metal chloride" refers to a compound in which metal ions and chloride ions are ionically bonded.

In the present specification, "tromethamole" is trishydroxymethylaminomethane, which is a compound sometimes abbreviated as Tris.

In the present specification, "osmotic pressure of aqueous solution" is measured according to the method specified in "30. Osmotic pressure measurement method (osmolality measurement method)" of "General test method" of the 17th revised Japanese Pharmacopoeia. Is the value to be.

In the present specification, the "osmotic pressure ratio of the aqueous solution" refers to the ratio of the osmotic pressure of the aqueous solution to the osmotic pressure of physiological saline (0.9 w / v% sodium chloride aqueous solution).

In the present specification, "colorless and transparent" means that the inside is transparent to the extent that it is not colored and does not interfere with the test of the insoluble foreign matter inspection method.

In the present specification, the "polyethylene container" is a container that houses an aqueous liquid agent, and at least the inner wall that comes into contact with the contained aqueous liquid agent is made of polyethylene. In the "polyethylene container", other members may be made of a material other than polyethylene, as long as the inner wall in contact with the contained aqueous liquid agent is made of polyethylene.

In the present specification, the "multi-dose type container" refers to a container filled with an aqueous solution for a plurality of times and used repeatedly.

In the present specification, the "unit dose type container" refers to a container filled with a single dose of an aqueous liquid agent and used after one instillation.

In the present specification, the "pharmaceutical product" refers to a product in which an aqueous solution is contained in a container.

In the present specification, the notation such as "suppression of decomposition products of brimonidine and / or a salt thereof caused by light exposure" refers to an aqueous solution containing brimonidine and / or a salt thereof of brimonidine and / or a salt thereof by light exposure. It refers to suppressing the formation of decomposition products and maintaining a stable content of brimonidine and / or a salt thereof. The degree of suppression of the formation of decomposition products of brimonidine and / or its salt by light exposure was determined by a white fluorescent lamp under a temperature condition of 25 ° C. for a container containing an aqueous solution containing brimonidine and / or its salt. After irradiating with light of 30,000 lux for 200 hours and exposing with light of 600,000 lux · h, the aqueous solution after light exposure was subjected to HPLC under the following conditions, and was observed at a retention time of 1.5 minutes. It can be confirmed from the amount of the main decomposition product (RRT = 1.5) corresponding to the peak.
<HPLC conditions>
-Preparation of sample solution Weigh accurately 2.5 mL of the aqueous solution, add purified water to make exactly 50 mL, and use this as the sample solution.
-Preparation of standard solution Weigh exactly 50 mg of brimonidine tartrate standard and add purified water to make exactly 50 mL. Weigh exactly 5 mL of the solution and add purified water to make exactly 100 mL to make a standard solution.
-Measurement by liquid chromatography 25 μL of the sample solution and standard solution were measured by liquid chromatography (High Performance Liquid Chromatograph manufactured by Shimadzu Corporation) under the following conditions, and the peak area of decomposition products in each sample solution and the peak area of the decomposition products in each sample solution. The peak area of brimonidine tartrate in the standard solution is determined by automatic integration.
<Measurement conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength: 264 nm)
Column: Symmetry C18, 4.6 mm I. D. × 75 mm, 3.5 μm, Waters column temperature: 25 ° C
Mobile phase: 2.3 g of potassium dihydrogen phosphate and 47.5 mg of sodium 1-heptane sulfonate are dissolved in 830 mL of water, and the pH is adjusted to 3.0 using phosphoric acid. 84 mL of acetonitrile and 84 mL of methanol were mixed with this solution, and water was added to make 1 L to prepare a mobile phase.
Cleaning liquid: Acetonitrile / water (volume ratio: 1/1) mixed liquid flow rate: 1.0 mL / min
Area measurement range: 20 minutes <Calculation formula>
The amount of main decomposition product (RRT = 1.5) (% of display ratio) is calculated according to the following formula.

In the present specification, "a method for suppressing the decomposition product of brimonidine and / or a salt thereof caused by light exposure" means that an aqueous solution containing brimonidine and / or a salt thereof decomposes and produces brimonidine and / or a salt thereof by light exposure. Refers to a method performed to suppress the formation of substances and maintain a stable content of brimonidine and / or a salt thereof.

As used herein, "glaucoma" is characterized by functional and structural abnormalities of the eye that have characteristic changes in the optic nerve and visual field and can usually improve or suppress optic nerve damage by sufficiently lowering intraocular pressure. Means the disease. In addition, "treatment" means alleviation, alleviation, or decrease in progression rate of a disease or symptom.

2. Description of Preferred Embodiments Although the description of preferred embodiments will be described below, it should be understood that this embodiment is an example of the present invention and the scope of the present invention is not limited to such preferred embodiments. .. It should be understood that those skilled in the art can also easily make modifications, changes, etc. within the scope of the present invention with reference to the following preferred embodiments. For these embodiments, those skilled in the art may optionally combine any embodiments.

3. 3. Pharmaceutical products (1)
Generally, in order to ensure the stability of a preparation containing a component that is unstable to light, a method of accommodating the preparation in a container such as a metal container or an opaque container that can substantially block light is adopted. However, in Japan, it is necessary to use a transparent airtight container that does not interfere with the test of the insoluble foreign substance test method for eye drops for the storage of eye drops (16th revised Japanese Pharmacy Manual A). See -108, Tokyo Hirokawa Book Store). Therefore, there is a limitation in using a light-shielding container that affects the inspection of insoluble foreign substances as a container for containing eye drops containing brimonidine and / or a salt thereof. In addition, when a colored transparent container such as brown is used, it is possible to block light to some extent, but the internal visibility is lowered and the insoluble foreign matter is detected and detected by the color of the foreign matter itself. May be difficult. Further, since the aqueous solution containing brimonidine and / or a salt thereof is a yellowish aqueous solution, if any abnormality in quality (for example, decrease in content) occurs, it can be detected by changing the color. This confirmation can be difficult with colored containers. Further, since foreign substances in the contents are more conspicuous in the case of the aqueous solution than in the case of the suspendable aqueous solution or emulsion, the visibility inside the container becomes more important in quality control. For eye drops contained in a multi-dose container, it is most preferable to use a colorless transparent container so that the user can easily visually recognize the amount of liquid remaining, but an eye drop containing brimonidine and / or a salt thereof is used. When placed in a colorless and transparent multi-dose container, brimonidine and / or a salt thereof is decomposed by light exposure.

Such a decrease in the content of brimonidine and / or its salt would diminish the efficacy of brimonidine and / or its salt. Therefore, even if an eye drop containing brimonidine and / or a salt thereof is contained in a colorless transparent container, it is possible to suppress a decrease in the content of brimonidine and / or its salt due to light exposure, and the content of brimonidine and / or its salt is stabilized. Development of technology to maintain is required.

Patent Document 2 describes brimonidine and / or a salt thereof, and an eye drop containing brinzolamide and / or a salt thereof in a transparent container having a maximum transmittance of light at wavelengths of 360 to 460 nm and 600 to 680 nm in a predetermined range. It is disclosed that by accommodating, the decomposition of brimonidine and / or a salt thereof due to light exposure can be suppressed. In addition, eye drops containing brimonidine tartrate are marketed as pharmaceuticals, and colored (green) polyethylene containers are used. However, conventionally, the effect of the combination of the composition of the aqueous liquid containing brimonidine and / or its salt and the material of the colorless transparent container on the photostability of brimonidine and / or its salt has not been reported.

Since eye drops are administered directly to the ocular mucosa, it is necessary to ensure high safety, and it is necessary to suppress the production of decomposition products due to storage. In particular, in the development of medical drugs, when the concentration of the decomposition product produced by storage under predetermined conditions exceeds a certain amount, it is obligatory to identify the structure of the decomposition product and report on its safety. (Pharmaceutical Tribunal No. 0624001 "Revision of guidelines for pharmaceutical impurities among new active ingredient-containing drugs"), and in the development of eye drops, the concentration of decomposition products usually exceeds 1.0%. This obligation arises in some cases. For this reason, in the formulation of eye drops, it is necessary to sufficiently suppress the production of decomposition products generated by storage.

Therefore, in one embodiment of the present invention, in a pharmaceutical product containing brimonidine and / or an aqueous solution containing a salt thereof in a transparent container, a technique for suppressing the formation of a decomposition product of brimonidine and / or a salt thereof due to light exposure is provided. The purpose is to provide.

The present inventor puts an aqueous solution containing brimonidine and / or a salt thereof and a metal chloride in a colorless and transparent polyethylene container to produce a decomposition product of brimonidine and / or a salt thereof by light exposure. It was found that it can be suppressed and the content of brimonidine and / or its salt can be stably maintained. That is, as one embodiment, the present invention provides a pharmaceutical product in which an aqueous solution containing brimonidine and / or a salt thereof and a metal chloride is contained in a colorless and transparent polyethylene container. Hereinafter, the pharmaceutical product of the embodiment will be referred to as the first embodiment. The pharmaceutical product of the first embodiment will be described in detail below.

[Aqueous solution]
Brimonidine and / or a salt thereof The aqueous solution used in the first embodiment contains brimonidine and / or a salt thereof. The salt of brimonidine used in the first embodiment is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts and inorganic acid salts. Examples of the organic acid salt include tartrate salt and acetate. Examples of the inorganic acid salt include hydrochloride and the like. Further, brimonidine or a salt thereof may be in the form of a solvate such as a hydrate. Among brimonidine or salts thereof, brimonidine tartrate is preferably used because it has been marketed as a pharmaceutical product and its safety has been established.

In the aqueous solution used in the first embodiment, either brimonidine or a salt thereof may be used alone, or these may be used in combination.

The concentration of brimonidine and / or a salt thereof in the aqueous solution used in the first embodiment is, for example, 0.05 to 0.5 w / v%, preferably 0.1 to 0.2 w / v%, more preferably 0.1 to 0.2 w / v%. 0.1 w / v% can be mentioned. In the present specification, the concentration of brimonidine and / or a salt thereof is the concentration converted to brimonidine tartrate unless otherwise specified.

-Metal Chloride The aqueous solution used in the first embodiment contains metal chloride. The metal chloride contributes to the suppression of the production of the decomposition products of brimonidine and / or its salt by light exposure in a state of being contained in a colorless and transparent polyethylene container.

The metal chloride used in the first embodiment is not particularly limited as long as it is pharmaceutically acceptable, but for example, alkali metal chlorides such as sodium chloride and potassium chloride; magnesium chloride, calcium chloride and the like. Chloride of alkaline earth metal; zinc chloride, iron chloride and the like. These metal chlorides may be in the form of hydrates. Among these metal chlorides, sodium chloride, potassium chloride, magnesium chloride, and calcium chloride are preferable from the viewpoint of further improving the effect of suppressing the decomposition products of brimonidine and / or salts thereof generated by light exposure. Be done.

These metal chlorides may be used alone or in combination of two or more.

A preferred embodiment of the aqueous solution used in the first embodiment is that it contains at least sodium chloride as the metal chloride.

In addition, as another preferred embodiment of the aqueous liquid agent used in the first embodiment, as the metal chloride, a combination of an alkali metal chloride and an alkaline earth metal chloride can be mentioned. A more preferred embodiment includes the combined use of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.

The concentration of metal chloride in the aqueous solution used in the first embodiment is, for example, 0.01 to 2 w / v%, preferably 0.05 to 1 w / v%, more preferably the total amount of metal chloride. 0.1 to 0.9 w / v% can be mentioned.

More specifically, in the aqueous solution used in the first embodiment, when sodium chloride, potassium chloride, magnesium chloride, and calcium chloride are used in combination as the metal chloride, for example, sodium chloride is used. 0.01-2w / v%, preferably 0.05-1w / v%, more preferably 0.1-0.6w / v%, particularly preferably 0.5-0.6w / v%; potassium chloride Is 0.01 to 2 w / v%, preferably 0.05 to 1 w / v%, more preferably 0.1 to 0.5 w / v%, particularly preferably 0.1 to 0.2 w / v%; chloride. Magnesium is 0.001 to 0.2 w / v%, preferably 0.005 to 0.051 w / v%, more preferably 0.01 to 0.02 w / v%; and calcium chloride is 0.001 to 0. 2 w / v%, preferably 0.005 to 0.05 w / v%, more preferably 0.01 to 0.02 w / v%.

-Boric acid and / or a salt thereof In one aspect of the aqueous solution used in the first embodiment, boric acid and / or a salt thereof is contained. By further containing boric acid and / or a salt thereof in addition to the metal chloride, the effect of suppressing the decomposition products of brimonidine and / or a salt thereof generated by light exposure can be further improved.

The boric acid used in the first embodiment is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include orthoboric acid, metaboric acid, and tetraboric acid. Among these boric acids, orthoboric acid and tetraboric acid are preferable. These boric acids may be used alone or in combination of two or more.

The salt of boric acid used in the first embodiment is not particularly limited as long as it is pharmaceutically acceptable, but is an alkali metal salt such as borax, sodium salt, potassium salt; calcium salt, magnesium salt, etc. Alkaline earth metal salts such as; aluminum salts; organic amine salts such as triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine and the like. The salt of boric acid may be in the form of a hydrate, such as borax. These boric acid salts may be used alone or in combination of two or more.

One of boric acid and its salt may be selected and used alone, or two or more of these may be used in combination. Among boric acid and salts thereof, at least one of boric acid and borax is preferable, and more preferably ortho-borax, from the viewpoint of further improving the effect of suppressing the decomposition products of brimonidine and / or its salt generated by light exposure. At least one of acid and borax can be mentioned.

Further, as a preferable aspect of boric acid and / or a salt thereof used in the first embodiment, a combination of boric acid and borax can be mentioned. By using boric acid and borax in combination in this way, it is possible to provide an appropriate buffering action while improving the effect of suppressing the decomposition products of brimonidine and / or a salt thereof generated by light exposure. .. The ratio of boric acid to borax is not particularly limited, but for example, borax is 10 to 300 parts by mass, preferably 10 to 250 parts by mass, more preferably 30 to 100 parts by mass, and particularly, per 100 parts by mass of boric acid. Preferably, it is 40 to 60 parts by mass.

The concentration of boric acid and / or a salt thereof in the aqueous solution used in the first embodiment is not particularly limited, but for example, brimonidin and / or a salt thereof produced by light exposure such as 10 to 1000 mM in terms of boron concentration. From the viewpoint of further improving the inhibitory effect on the decomposition products of boric acid, the concentration of boric acid and / or a salt thereof is preferably 20 to 400 mM, more preferably 30 to 120 mM, particularly preferably 40 to 40 in terms of boron concentration. 100 mM, more preferably 30 to 60 mM. In the present specification, the "concentration converted to boric acid" is a value obtained by converting the concentration of boric acid and / or its salt into the concentration of boron atoms derived from boric acid and / or its salt, for example. 1 w / v% boric acid corresponds to 162 mM in terms of boron concentration, and 1 w / v% boric acid corresponds to 105 mM in terms of boron concentration.

-Trometamol and / or a salt thereof In one aspect of the aqueous solution used in the first embodiment, it contains trometamol and / or a salt thereof. When the aqueous solution used in the first embodiment contains tromethamole and / or a salt thereof together with boric acid and / or a salt thereof, the effect of suppressing the decomposition products of brimonidine and / or the salt caused by light exposure. It can be further improved.

The salt of tromethamole is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as acetate; and inorganic acid salts such as hydrochloride and sulfonate.

One of Trometamol and its salt may be selected and used alone, or two or more of these may be used in combination. Among the trometamole and its salt, tromethamole is preferably mentioned.

The concentration of tromethamole and / or a salt thereof in the aqueous solution used in the present invention is not particularly limited, but is, for example, 0.01 to 3 w / v%, preferably 0.05 to 2 w / v%, and more preferably 0. .1 to 1 w / v% can be mentioned. In the present specification, "concentration of tromethamole and / or a salt thereof" is a value converted to tromethamole in the case of a salt of tromethamole.

-Other Additives In one embodiment, the aqueous liquid agent used in the first embodiment is, if necessary, an isotonic agent (other than metal chloride), a polyhydric alcohol, a surfactant, a viscous agent, and the like. Additives such as chelating agents, buffers (other than boric acid, tromethamole, and salts thereof), preservatives or preservatives, cooling agents, stabilizers, pH regulators and the like may be contained.

The tonicity agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, polyethylene glycol; sodium acetate, potassium acetate, sodium hydrogen sulfite, etc. Examples thereof include metal salts such as sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These isotonic agents may be used alone or in combination of two or more.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used alone or in combination of two or more.

The surfactant is not particularly limited as long as it is pharmaceutically acceptable, and for example, tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy. Nonionic surfactants such as Noll; Amphoteric surfactants such as alkyldiaminoethylglycine, betaine lauryldimethylaminoacetate; alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl Anionic surfactants such as ether sulfate; cationic surfactants such as alkylpyridinium salt and alkylamine salt can be mentioned. These surfactants may be used alone or in combination of two or more.

The thickener is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate. Polymers: Cellulose such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and the like can be mentioned. These thickeners may be used alone or in combination of two or more.

The chelating agent is not particularly limited as long as it is pharmaceutically acceptable, and for example, edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1, Examples thereof include 1-diphosphonic acid, polyphosphoric acid, metaphosphate, hexametaphosphate, and salts thereof. The form of the salt is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. These chelating agents may be used alone or in combination of two or more.

The buffer (other than boric acid, tromethamole, and salts thereof) is not particularly limited as long as it is pharmaceutically acceptable, and for example, a phosphate buffer, a citrate buffer, a tartrate buffer, and an acetate buffer are used. Agents, amino acid buffers and the like. These buffers may be used alone or in combination of two or more.

The preservative or preservative is not particularly limited as long as it is pharmaceutically acceptable, and for example, sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid. Propyl, chlorobutanol, benzalkonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, dehydroacetic acid or salts thereof, benzethonium chloride, benzyl alcohol, zinc chloride, parachloromethoxylenol, chlorcresol, phenethyl alcohol, chloride Examples thereof include polydronium, timerosal and dibutylhydroxytoluene. These preservatives or preservatives may be used alone or in combination of two or more.

The refreshing agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.

The stabilizer is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfites, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. Can be mentioned. These stabilizers may be used alone or in combination of two or more.

The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable, and is, for example, an acid such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide. , Hosand, triethanolamine, monoethanolamine, sodium hydrogen carbonate, sodium carbonate and other alkalis. These pH adjusters may be used alone or in combination of two or more.

The concentration of these additives may be appropriately set according to the type of additive used, the characteristics to be imparted to the aqueous solution, and the like.

-Other pharmacological components In one embodiment, the aqueous solution used in the first embodiment may contain a pharmacological component other than brimonidine and / or a salt thereof, if necessary. Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropylunoprostone; parasympathomimetic agents such as pilocarpine hydrochloride; anticholineresterase agents such as distigmine bromide; and sympathetic nerves such as dipivefrine hydrochloride. _{Stimulants; β 1} blockers such as betaxolol hydrochloride; β blockers such as timolol maleate; α _{1 / β blockers such as nipradirol and levobnorol hydrochloride; α 1} blockers such as bunazosin hydrochloride. .. These pharmacological components may be used alone or in combination of two or more. The concentration of these pharmacological components may be appropriately set according to the type of the pharmacological component to be used, the medicinal effect to be imparted, and the like.

In another aspect, the aqueous solution used in the first embodiment contains brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and substantially does not contain other active ingredients. ..

・ PH
The pH of the aqueous solution used in the first embodiment is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include pH 5.0 to 9.0. If the aqueous solution used in the first embodiment is an ophthalmic composition such as an eye drop or an eyewash, the pH is set from the viewpoint of further alleviating irritation to the eye that can be applied to the ocular mucosa. , Preferably 5.0 to 9.0, more preferably 6.0 to 8.0, and even more preferably 6.5 to 7.5.

-Osmotic pressure / osmotic pressure ratio The osmotic pressure of the aqueous liquid agent used in the first embodiment is not particularly limited as long as it can be applied to the intended use. When the aqueous solution used in the present invention is an ophthalmic composition such as an eye drop or an eyewash, the osmotic pressure is 250 to 350 mOsm / kg.

Further, the osmotic pressure ratio of the aqueous liquid agent used in the first embodiment is not particularly limited as long as it can be applied to the intended use. For example, when the aqueous solution used in the first embodiment is an ophthalmic composition such as an eye drop or an eyewash, the osmotic pressure ratio may be 0.85 to 1.15. From the viewpoint of alleviating eye irritation, 0.9 to 1.1 is preferable, and 1.0 is more preferable.

-Formation form The formulation form of the aqueous liquid agent used in the first embodiment is not particularly limited and may be in the form of an aqueous solution, a suspension, an emulsion, or the like, but an aqueous solution is preferable. ..

The aqueous solution used in the first embodiment is prepared into a pharmaceutical composition for various purposes such as for ophthalmology, dentistry, otolaryngology, and dermatology, and is used as a topically administered preparation. As one aspect of the aqueous solution used in the first embodiment, a composition for ophthalmology, dentistry, otolaryngology, or dermatology can be mentioned, and an aqueous solution for ophthalmology is preferable.

Specific examples of the aqueous solution for ophthalmology include eye drops, eyewashes, contact lens agents, injections and the like. Among these, eye drops are preferably mentioned.

-Use / Dosage / Usage Brimonidine and / or a salt thereof contained in the aqueous solution used in the first embodiment can suppress the production of aqueous humor and have an effect of lowering intraocular pressure. In one aspect of the aqueous solution used in the embodiment, it is provided as an eye drop and can be suitably used for the treatment of glaucoma.

When the aqueous solution used in the first embodiment is used as an eye drop, one drop may be instilled once or multiple times a day. Further, in one aspect of the aqueous liquid preparation used in the first embodiment, one drop is instilled twice a day.

-Manufacturing method The aqueous liquid agent used in the first embodiment may be produced according to a known preparation method according to its use. For example, the method described in the 17th revised Japanese Pharmacopoeia general rules for preparation may be used. Can be manufactured.

Specifically, in one embodiment, the method for producing an aqueous solution used in the first embodiment comprises pharmaceutically acceptable aqueous solution of brimonidine and / or a salt thereof, a metal chloride, and other components. Includes a step of blending into the medium. "Pharmaceutically acceptable aqueous medium" means a pharmaceutically acceptable aqueous medium, and examples thereof include purified water. Further, in the compounding step, the compounding order of each component is not particularly limited, and may be sequentially compounded in any order, or may be compounded at the same time. Further, after the compounding step, a sterilization treatment step such as filter sterilization, filtration sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization may be performed, if necessary.

[Colorless and transparent polyethylene container]
In the pharmaceutical product of the first embodiment, the aqueous solution is contained in a colorless and transparent polyethylene container. The colorless and transparent container has excellent internal visibility and facilitates the insoluble foreign matter inspection method and confirmation of the amount of remaining liquid, but on the other hand, it is easy to generate decomposition products of brimonidine and / or its salt by light exposure. In the first embodiment, by accommodating the aqueous liquid agent having the above-mentioned composition in a colorless and transparent polyethylene container, excellent internal visibility and an effect of suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure are obtained. It is possible to achieve both.

The polyethylene container used in the first embodiment should be transparent enough to be visible without interfering with the test of the insoluble foreign matter inspection method without being colored. Specifically, the brightness is 70 or more and / or the saturation is 25 or less, and the maximum transmittance of light in the wavelength region of 400 to 800 nm is 10% or more. Here, "brightness" is the L ^* value in the CIELAB display system, and "saturation" is the formula: ((a ^* value) ² + (b ^* value)) ^{from the a *} value and b ^{* value in the CIELAB display system. 2} ) It is a value obtained according to ^1/2. The maximum transmittance of light in the wavelength region of 400 to 800 nm is such that the transmittance of light is measured with an ultraviolet-visible spectrophotometer at intervals of a wavelength width of 5 nm from a wavelength of 400 nm to a wavelength of 800 nm, and each measured transmittance is measured. It is a value obtained by finding the maximum value among the values of. If both the lightness and the saturation do not meet the above range, the polyethylene container becomes colored and sufficient internal visibility cannot be ensured. In particular, the color of the insoluble foreign matter itself detects or finds the insoluble foreign matter. Can be difficult (especially foreign matter of the same color as the container can be difficult to detect).

From the viewpoint of further improving the internal visibility, the polyethylene container used in the first embodiment 1) preferably has a brightness of 70 or more and a saturation of 25 or less, more preferably a brightness of 70 or more, and The saturation is 20 or less, and 2) the maximum transmittance of light in the region of wavelength 400 to 800 nm is 10% or more, preferably 20% or more, particularly preferably 30% or more, and further preferably 40% or more. Be done. The upper limit of the brightness is, for example, 100 or less, preferably 95 or less, more preferably 90 or less, particularly preferably 85 or less, still more preferably 80% or less; and the lower limit of the saturation is, for example, 0 or more. The upper limit of the maximum transmittance of light in the wavelength region of 400 to 800 nm is, for example, 80% or less, preferably 70% or less, more preferably 60% or less. Particularly preferably, 50% or less is mentioned. Even in a polyethylene container having such high internal visibility, the decomposition products of brimonidine and / or a salt thereof caused by light exposure can be suppressed by adopting the aqueous liquid agent having the above-mentioned composition.

A preferred embodiment of the polyethylene container used in the first embodiment has a transmittance of light having a wavelength of 400 nm of 5% or more, preferably 10% or more, and more preferably 12% or more. Examples of the upper limit of the transmittance of light having a wavelength of 400 nm include 40% or less, preferably 35% or less, more preferably 30% or less, particularly preferably 25% or less, and further preferably 20% or less. By using a polyethylene container in which the transmittance of light having a wavelength of 400 nm satisfies the above range, the effect of suppressing the decomposition products of brimonidine and / or its salt generated by light exposure and the internal visibility can be further improved. it can.

In the polyethylene container used in the first embodiment, the colorless and transparent region may be provided in the entire container, but it is necessary to ensure the internal visibility necessary for the insoluble foreign matter test, the confirmation of the residual liquid amount, and the like. As a limit, it may be provided on at least a part of the container. For example, the polyethylene container used in the first embodiment may be provided with a non-colorless and transparent region for the purpose of displaying a trade name, an ingredient name, an expiration date, a cautionary note, or the like. As one aspect of the polyethylene container used in the first embodiment, the colorless and transparent region is 5% or more, preferably 7% or more, more than the side surface of the container (the outer peripheral surface of the main body excluding the region covered by the lid). It is desirable to occupy a region of preferably 10% or more, more preferably 15% or more.

In the polyethylene container used in the first embodiment, the inner wall that comes into contact with the contained aqueous liquid agent may be made of polyethylene, and other members such as the nozzle and the lid are made of a material other than polyethylene. May be good. Further, in the polyethylene container used in the first embodiment, the container body is made of a laminated body in which a layer of another material is laminated on a polyethylene layer, provided that the inner wall is made of polyethylene and is colorless and transparent. It may be formed. Further, the polyethylene container used in the first embodiment may be covered with a covering member such as a shrink label or a tack label as long as a colorless and transparent region can be secured.

The polyethylene container used in the first embodiment may be either a multi-dose type container or a unit-dose type container. Since the multi-dose type container is used repeatedly and it is necessary to check the residual liquid amount each time it is used, high internal visibility is required. Therefore, the polyethylene container used in the first embodiment is required. Is suitable as.

The type of polyethylene constituting the polyethylene container used in the first embodiment is not particularly limited, and is, for example, low density polyethylene (LDPE), linear low density polyethylene (LLDPE), high density polyethylene (HDPE). Etc., but low density polyethylene (LDPE) is preferable.

The polyethylene container used in the first embodiment may be in the form of an eye drop container, an eye wash container, or the like, depending on the use of the aqueous liquid agent to be contained.

[Degree of suppression of the formation of decomposition products of brimonidine and / or its salts by light exposure]
In the pharmaceutical product of the first embodiment, the formation of decomposition products of brimonidine and / or a salt thereof due to light exposure can be suppressed. In one aspect of the pharmaceutical product of the first embodiment, the pharmaceutical product is irradiated with light of 30,000 lux with a white fluorescent lamp under a temperature condition of 25 ° C. for 200 hours, and then the aqueous solution contained in the pharmaceutical product is contained. The amount of the main decomposition product (RRT = 1.5) in the liquid preparation is 1.0% or less, preferably 0.9% or less, more preferably 0.8% or less, still more preferably 0.7% or less, and particularly 0. It can be mentioned that it is 6% or less.

[Manufacturing method of pharmaceutical products]
The pharmaceutical product of the first embodiment is produced through a step of preparing the aqueous solution and a step of storing the aqueous solution in a colorless and transparent polyethylene container to prepare a pharmaceutical product. Further, it is desirable that the obtained pharmaceutical product undergoes a step (inspection step) of confirming the properties (color tone) of the aqueous liquid agent contained in the container before shipping.

The pharmaceutical product of the first embodiment is manufactured under manufacturing control and quality control in accordance with the GMP Ministerial Ordinance and each guideline based on the Pharmaceutical Affairs Law. Further, since a container having high internal visibility is used for the pharmaceutical product of the first embodiment, insoluble foreign matter inspection can be facilitated and automation of the inspection process can be simplified from the aspect of quality control. In addition, by adopting a colorless and transparent polyethylene container, the color tone (hue / shade) and the like can be maintained even when an aqueous solution containing brimonidine and / or a salt thereof is contained in the container during such an inspection process. It is possible to inspect and confirm the properties including. That is, according to the method for producing a pharmaceutical product of the first embodiment, brimonidine and / or a salt thereof, and an aqueous liquid containing metal chloride are contained in a colorless and transparent polyethylene container, whereby brimonidine and / or by light exposure. It is possible to provide a pharmaceutical product capable of suppressing the formation of decomposition products of the salt, maintaining the content of brimonidine and / or the salt thereof stably for a predetermined period of time, and water-based the pharmaceutical product in a container before shipment. Since the properties (color tone) of the liquid agent can be easily confirmed from the outside of the container, it is possible to provide a pharmaceutical product having extremely high safety in terms of quality control.

Further, from another aspect, the method for inspecting the pharmaceutical product of the first embodiment is provided, which includes a step of confirming the properties (color tone) of the aqueous liquid agent in the container of the pharmaceutical product of the first embodiment.

4. Method for suppressing the formation of decomposition products of brimonidine and / or a salt thereof (1)
One embodiment of the present invention is a method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure in an aqueous solution containing brimonidine and / or a salt thereof, wherein brimonidine and / or a salt thereof, and metal chloride are used. Provided is a method comprising the step of accommodating an aqueous solution containing a substance in a colorless and transparent polyethylene container. Hereinafter, the method of the embodiment will be referred to as a first embodiment. The method of the first embodiment will be described in detail below.

According to the method of the first embodiment, the production of the decomposition product of brimonidine and / or its salt due to light exposure can be suppressed even though the aqueous solution containing brimonidine and / or its salt is contained in a colorless and transparent container. , Brimonidine and / or its salt can be kept stable.

In one aspect of the method of the first embodiment, the aqueous solution may contain boric acid and / or a salt thereof. Further, in one aspect of the method of the first embodiment, the aqueous solution may further contain tromethamole and / or a salt thereof.

In the method of the first embodiment, the type and concentration of brimonidine and / or a salt thereof, and the type and concentration of metal chloride are as described in the column of "3. Pharmaceutical product (1)". Further, in the method of the first embodiment, the type and concentration of boric acid and / or a salt thereof used as necessary, the type and concentration of tromethamole and / or a salt thereof used as necessary, and an aqueous solution. The types of other additives and pharmacological components to be blended, the pH of the aqueous solution, the osmotic pressure, the formulation form, the application, etc. are also as described in the column of "3. Pharmaceutical product (1)". Further, the colorless and transparent polyethylene container used in the method of the first embodiment is also as described in the column of "3. Pharmaceutical product (1)". Further, the degree of suppression of the production of the decomposition products of brimonidine and / or its salt by light exposure, which is realized by the method of the first embodiment, is also as described in the column of "3. Pharmaceutical product (1)". Is.

5. Pharmaceutical product (2)
The present inventor further contains an aqueous solution containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container by light exposure. It has been found that the resulting decomposition products of brimonidine and / or a salt thereof can be suppressed. That is, as one embodiment, in the present invention, an aqueous liquid containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more is contained in a colorless and transparent polyethylene container. Providing pharmaceutical products. Hereinafter, the embodiment will be referred to as a second embodiment. The pharmaceutical product of the second embodiment will be described in detail below.

[Aqueous solution]
Brimonidine and / or a salt thereof The aqueous solution used in the second embodiment contains brimonidine and / or a salt thereof. The type and concentration of brimonidine and / or a salt thereof used in the second embodiment are the same as in the case of the first embodiment.

-Boric acid and / or a salt thereof The aqueous solution used in the second embodiment contains boric acid and / or a salt thereof having a boron concentration of 70 mM or more. In the second embodiment, by containing boric acid and / or a salt thereof in terms of boron concentration of 70 mM or more, a decomposition product of brimonidine and / or a salt thereof generated by light exposure when stored in a colorless and transparent polyethylene container. Suppression becomes possible.

The type of boric acid and / or a salt thereof used in the second embodiment is the same as in the case of the first embodiment.

The aqueous liquid agent used in the second embodiment may be used alone by selecting one from boric acid and a salt thereof, or may be used in combination of two or more of these. .. Among boric acid and salts thereof, at least one of boric acid and borax is preferable, and more preferably ortho-borax, from the viewpoint of further improving the effect of suppressing the decomposition products of brimonidine and / or its salt generated by light exposure. At least one of acid and borax can be mentioned.

A preferred embodiment of boric acid and / or a salt thereof used in the second embodiment is a combination of boric acid and borax. By using boric acid and borax in combination in this way, it is possible to provide an appropriate buffering action while improving the effect of suppressing the decomposition products of brimonidine and / or a salt thereof generated by light exposure. .. The ratio of boric acid to borax is not particularly limited, but for example, borax is 10 to 100 parts by mass, preferably 10 to 70 parts by mass, more preferably 20 to 50 parts by mass, and particularly, per 100 parts by mass of boric acid. 20 to 30 parts by mass is preferable.

The concentration of boric acid and / or its salt in the aqueous solution used in the second embodiment may be 70 mM or more in terms of boron concentration, but suppression of the decomposition products of brimonidine and / or its salt caused by light exposure. From the viewpoint of further improving the effect, in terms of boron concentration, it is preferably 85 mM or more, more preferably 100 to 200 mM, and particularly preferably 110 to 150 mM.

-Metal Chloride In one aspect of the aqueous solution used in the second embodiment, the metal chloride is contained. By containing the metal chloride, the effect of suppressing the decomposition products of brimonidine and / or a salt thereof generated by light exposure can be further improved. The type and concentration of the metal chloride used in the second embodiment are the same as in the case of the first embodiment.

-Trometamol and / or a salt thereof In one aspect of the aqueous solution used in the second embodiment, it contains trometamol and / or a salt thereof. When tromethamole and / or a salt thereof is contained, the effect of suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure can be further improved. The type and concentration of tromethamole and / or a salt thereof used in the second embodiment are the same as in the case of the first embodiment.

-Other Additives In one embodiment, the aqueous liquid agent used in the second embodiment is, if necessary, an isotonic agent (other than metal chloride), a polyhydric alcohol, a surfactant, a viscous agent, and the like. Additives such as chelating agents, buffers (other than boric acid, tromethamole, and salts thereof), preservatives or preservatives, cooling agents, stabilizers, pH regulators and the like may be contained. Specific examples of these additives are the same as in the case of the first embodiment. Further, the concentration of these additives may be appropriately set according to the type of the additive to be used, the characteristics to be imparted to the aqueous solution, and the like.

-Other pharmacological components In one embodiment, the aqueous solution used in the second embodiment may contain a pharmacological component other than brimonidine and / or a salt thereof, if necessary. Specific examples are the same as in the case of the first embodiment.
In another aspect, the aqueous solution used in the second embodiment contains brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and substantially does not contain other active ingredients. ..

-PH / osmotic pressure / osmotic pressure ratio / formulation form / use / dose / usage Regarding the pH, osmotic pressure, osmotic pressure ratio, formulation form, use, dose, usage, etc. of the aqueous liquid used in the second embodiment, This is the same as in the case of the aqueous liquid agent used in one embodiment.

-Manufacturing method The aqueous liquid agent used in the second embodiment may be produced according to a known preparation method according to its use. For example, the method described in the 17th revised Japanese Pharmacopoeia general rules for preparation may be used. Can be manufactured.

Specifically, in one embodiment, the method for producing the aqueous solution used in the second embodiment includes brimonidine and / or a salt thereof, boric acid having a boron concentration of 70 mM or more and / or a salt thereof, and the like. Including the step of blending the components of the above into a pharmaceutically acceptable aqueous medium. The “pharmaceutically acceptable aqueous medium” is the same as in the case of the aqueous solution used in the first embodiment. Further, in the compounding step, the compounding order of each component is not particularly limited, and may be sequentially compounded in any order, or may be compounded at the same time. Further, after the compounding step, a sterilization treatment step such as filter sterilization, filtration sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization may be performed, if necessary.

[Colorless and transparent polyethylene container]
In the pharmaceutical product of the second embodiment, the aqueous solution is contained in a colorless and transparent polyethylene container. In the second embodiment, by accommodating the aqueous liquid agent having the above-mentioned composition in a colorless and transparent polyethylene container, it is possible to achieve both excellent internal visibility and improved photostability of brimonidine and / or a salt thereof. It is possible.

The polyethylene container used in the second embodiment is the same as that used in the first embodiment.

[Degree of suppression of the formation of decomposition products of brimonidine and / or its salts by light exposure]
The degree of suppression of the production of the decomposition products of brimonidine and / or a salt thereof by light exposure, which the pharmaceutical product of the second embodiment can provide, is the same as that of the aqueous liquid preparation used in the first embodiment.

[Manufacturing method of pharmaceutical products]
The pharmaceutical product of the second embodiment is produced through a step of preparing the aqueous solution and a step of storing the aqueous solution in a colorless and transparent polyethylene container to prepare a pharmaceutical product. Further, it is desirable that the obtained pharmaceutical product undergoes a step (inspection step) of confirming the properties (color tone) of the aqueous liquid agent contained in the container before shipping.

In the method for producing a pharmaceutical product of the second embodiment, as in the case of the first embodiment, it is possible to provide a pharmaceutical product capable of stably maintaining the content of brimonidine and / or a salt thereof for a predetermined period of time, and the pharmaceutical product is shipped. Since the properties (color tone) of the aqueous liquid agent can be easily confirmed from the outside of the container in the state of being previously contained in the container, it is possible to provide a pharmaceutical product having extremely high safety in terms of quality control.

Further, from another aspect, the method for inspecting the pharmaceutical product of the second embodiment is provided, which includes a step of confirming the properties (color tone) of the aqueous liquid agent in the container of the pharmaceutical product of the second embodiment.

6. Method for suppressing the formation of decomposition products of brimonidine and / or a salt thereof (2)
One embodiment of the present invention is a method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure in an aqueous solution containing brimonidine and / or a salt thereof, wherein the brimonidine and / or a salt thereof and a boron concentration thereof. Provided is a method comprising a step of accommodating an aqueous solution containing 70 mM or more of boric acid and / or a salt thereof in a colorless and transparent polyethylene container. Hereinafter, the method of the embodiment will be referred to as a second embodiment. The method of the second embodiment will be described in detail below.

According to the method of the second embodiment, the production of the decomposition product of brimonidine and / or its salt due to light exposure can be suppressed even though the aqueous solution containing brimonidine and / or its salt is contained in a colorless and transparent container. , Brimonidine and / or its salt can be kept stable.

In one aspect of the method of the second embodiment, the aqueous solution may contain a metal chloride. Further, in one aspect of the method of the second embodiment, the aqueous solution may further contain tromethamole and / or a salt thereof.

In the method of the second embodiment, the type and concentration of brimonidine and / or its salt, and the type and concentration of boric acid and / or its salt are as described in the column of "5. Pharmaceutical product (2)". In addition, in the method of the second embodiment, the type and concentration of the metal chloride used as needed, the type and concentration of tromethamole and / or a salt thereof used as needed, and the addition to the aqueous solution. The types of additives and pharmacological components, pH, osmotic pressure, formulation form, use, etc. of the aqueous solution are also as described in the column of "5. Pharmaceutical product (2)". Further, the colorless and transparent polyethylene container used in the method of the second embodiment is also as described in the column of "5. Pharmaceutical product (2)". Further, the degree of suppression of the production of the decomposition products of brimonidine and / or its salt by light exposure, which is realized by the method of the second embodiment, is also as described in the column of "3. Pharmaceutical product (2)". Is.

7. Pharmaceutical products (3)
The present inventor further contains an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof in a colorless and transparent polyethylene container by light exposure. It has been found that the resulting decomposition products of brimonidine and / or salts thereof can be suppressed. That is, in one embodiment, in the present invention, an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof are contained in a colorless and transparent polyethylene container. Providing pharmaceutical products. Hereinafter, the embodiment will be referred to as a third embodiment. The pharmaceutical product of the third embodiment will be described in detail below.

[Aqueous solution]
Brimonidine and / or a salt thereof The aqueous solution used in the third embodiment contains brimonidine and / or a salt thereof. The type and concentration of brimonidine and / or a salt thereof used in the third embodiment are the same as in the case of the first embodiment.

-Boric acid and / or a salt thereof The aqueous solution used in the third embodiment contains boric acid and / or a salt thereof. The type and concentration of boric acid and / or a salt thereof used in the second embodiment are the same as in the case of the first embodiment.

-Trometamol and / or a salt thereof The aqueous solution used in the third embodiment contains tromethamole and / or a salt thereof. In the second embodiment, the decomposition and production of brimonidine and / or a salt thereof caused by light exposure when contained in a colorless and transparent polyethylene container by containing boric acid and / or a salt thereof and tromethamole and / or a salt thereof. It becomes possible to suppress things. The type and concentration of tromethamole and / or a salt thereof used in the third embodiment are the same as in the case of the first embodiment.

-Metal Chloride In one aspect of the aqueous solution used in the third embodiment, the metal chloride is contained. By containing the metal chloride, the effect of suppressing the decomposition products of brimonidine and / or a salt thereof generated by light exposure can be further improved. The type and concentration of the metal chloride used in the third embodiment are the same as in the case of the first embodiment.

-Other Additives In one embodiment, the aqueous liquid agent used in the third embodiment is, if necessary, an isotonic agent (other than metal chloride), a polyhydric alcohol, a surfactant, a viscous agent, and the like. Additives such as chelating agents, buffers (other than boric acid, tromethamole, and salts thereof), preservatives or preservatives, cooling agents, stabilizers, pH regulators and the like may be contained. Specific examples of these additives are the same as in the case of the first embodiment. Further, the concentration of these additives may be appropriately set according to the type of the additive to be used, the characteristics to be imparted to the aqueous solution, and the like.

-Other pharmacological components In one embodiment, the aqueous solution used in the third embodiment may contain a pharmacological component other than brimonidine and / or a salt thereof, if necessary. Specific examples are the same as in the case of the first embodiment.

In another aspect, the aqueous solution used in the third embodiment contains brimonidine and / or a salt thereof as a direct active ingredient for glaucoma, and substantially does not contain other active ingredients. ..

-PH / osmotic pressure / osmotic pressure ratio / formulation form / use / dose / usage Regarding the pH, osmotic pressure, osmotic pressure ratio, formulation form, use, dose, usage, etc. of the aqueous liquid used in the third embodiment, This is the same as in the case of the aqueous liquid agent used in one embodiment.

-Manufacturing method The aqueous solution used in the third embodiment may be manufactured according to a known preparation method according to its use. For example, the method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulation may be used. Can be manufactured.

Specifically, in one embodiment, the method for producing the aqueous solution used in the third embodiment comprises brimonidine and / or a salt thereof, boric acid and / or a salt thereof, tromethamole and / or a salt thereof, and the like. It comprises the step of blending the other ingredients into a pharmaceutically acceptable aqueous medium. The “pharmaceutically acceptable aqueous medium” is the same as in the case of the aqueous solution used in the first embodiment. Further, in the compounding step, the compounding order of each component is not particularly limited, and may be sequentially compounded in any order, or may be compounded at the same time. Further, after the compounding step, a sterilization treatment step such as filter sterilization, filtration sterilization, dry heat sterilization, electron beam sterilization, gamma ray sterilization may be performed, if necessary.

[Colorless and transparent polyethylene container]
In the pharmaceutical product of the third embodiment, the aqueous solution is contained in a colorless and transparent polyethylene container. In the second embodiment, by accommodating the aqueous liquid agent having the above-mentioned composition in a colorless and transparent polyethylene container, it is possible to achieve both excellent internal visibility and improved photostability of brimonidine and / or a salt thereof. It is possible.

The polyethylene container used in the third embodiment is the same as that used in the first embodiment.

[Degree of suppression of the formation of decomposition products of brimonidine and / or its salts by light exposure]
The degree of suppression of the production of the decomposition product of brimonidine and / or a salt thereof by light exposure, which the pharmaceutical product of the third embodiment can provide, is the same as that of the aqueous liquid preparation used in the first embodiment.

[Manufacturing method of pharmaceutical products]
The pharmaceutical product of the third embodiment is produced through a step of preparing the aqueous solution and a step of storing the aqueous solution in a colorless and transparent polyethylene container to prepare a pharmaceutical product. Further, it is desirable that the obtained pharmaceutical product undergoes a step (inspection step) of confirming the properties (color tone) of the aqueous liquid agent contained in the container before shipping.

Also in the method for producing a pharmaceutical product of the third embodiment, as in the case of the first embodiment, it is possible to provide a pharmaceutical product capable of stably maintaining the content of brimonidine and / or a salt thereof for a predetermined period of time, and the pharmaceutical product is shipped. Since the properties (color tone) of the aqueous liquid agent can be easily confirmed from the outside of the container in the state of being previously contained in the container, it is possible to provide a pharmaceutical product having extremely high safety in terms of quality control.

Further, from another aspect, the method for inspecting the pharmaceutical product of the third embodiment is provided, which includes a step of confirming the properties (color tone) of the aqueous liquid agent in the container of the pharmaceutical product of the third embodiment.

8. Method for suppressing the formation of decomposition products of brimonidine and / or a salt thereof (3)
One embodiment of the present invention is a method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure in an aqueous solution containing brimonidine and / or a salt thereof, wherein brimonidine and / or a salt thereof, borate and the like. Provided is a method comprising the step of accommodating / or a salt thereof, and an aqueous solution containing tromethamole and / or a salt thereof in a colorless and transparent polyethylene container. Hereinafter, the method of the embodiment will be referred to as a third embodiment. The method of the third embodiment will be described in detail below.

According to the method of the third embodiment, the production of the decomposition product of brimonidine and / or its salt due to light exposure can be suppressed even though the aqueous solution containing brimonidine and / or its salt is contained in a colorless and transparent container. , Brimonidine and / or its salt can be kept stable.

In one aspect of the conversion method of the third embodiment, the aqueous solution may contain a metal chloride.

In the method of the third embodiment, the type and concentration of brimonidine and / or its salt, the type and concentration of boric acid and / or its salt, and the type and concentration of tromethamole and / or its salt are described as "7. Pharmaceutical products (3). ) ”, As described in the column. Further, in the method of the third embodiment, the type and concentration of the metal chloride used as needed, the types of other additives and pharmacological components to be blended in the aqueous solution, the pH, osmotic pressure, and the formulation of the aqueous solution. The form, use, etc. are also as described in the column of "7. Pharmaceutical product (3)". Further, the colorless and transparent polyethylene container used in the method of the third embodiment is also as described in the column of "7. Pharmaceutical product (3)". Further, the degree of suppression of the production of the decomposition products of brimonidine and / or its salt by light exposure, which is realized by the method of the third embodiment, is also as described in the column of "7. Pharmaceutical product (3)". Is.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. In the following test examples, orthoboric acid was used as the boric acid.

Test Example 1
1. 1. Manufacture of ophthalmic pharmaceutical products
1-1. Preparation of eye drops Eye drops were prepared by the following procedure. According to the composition shown in Table 1, brimonidine tartrate, boric acid, borosand, sodium chloride, potassium chloride, calcium chloride hydrate, and magnesium chloride are added and dissolved in purified water in a predetermined amount, and the pH is adjusted with sodium hydroxide or hydrochloric acid. The adjustment was made to 7.2, and an eye drop was obtained.

1-2. Containment in a container 5 ml of each of the eye drops obtained above is put into a colorless transparent polyethylene (colorless transparent PE) container (LDPE), a colorless transparent polypropylene (colorless transparent PP) container, and a brown transparent polyethylene (brown transparent PE). ) Each sample (medicinal product for ophthalmology) was prepared by containing it in a container (each containing 5 ml).

2. Evaluation method of photostability of brimonidine tartrate
2-1. Method for measuring the residual rate of brimonidine tartrate For each sample obtained above, a photostability test device (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.) was used under a temperature condition of 25 ° C. Underneath, a white fluorescent lamp was used to irradiate the sample with light of 3,000 lpx for 400 hours to expose the sample to light of 1.2 million lpxh.

The concentration of brimonidine tartrate contained in the eye drops of each sample before and after light exposure was measured by a high performance liquid chromatograph system (HPLC, manufactured by Shimadzu Corporation) under the conditions shown below. The survival rate (%) was calculated.

<High Performance Liquid Chromatograph Conditions>
Detector : Ultraviolet absorptiometer (measurement wavelength: 264 nm)
Column : A stainless steel tube having an inner diameter of 4.6 mm and a length of 7.5 cm was filled with 3.5 μm of ODS silica gel for high performance liquid chromatography (Symmetry C18 column, manufactured by Waters).
Column temperature : Constant temperature around 25 ° C
Mobile phase : 2.3 g of potassium dihydrogen phosphate and 47.5 mg of sodium 1-heptane sulfonate were dissolved in 830 mL of water, and the pH was adjusted to 3.0 using phosphoric acid. 84 mL of acetonitrile and 84 mL of methanol were mixed with this liquid, and water was added to make 1 L.
Flow velocity : Approximately 1 mL / min

<Residual rate of brimonidine tartrate>
The residual rate (%) of brimonidine tartrate was calculated according to the following formula.

2-2. Method for measuring the amount of main decomposition product of brimonidine tartrate The eye drops of each sample before and after light exposure were subjected to HPLC under the following conditions, and the amount of main decomposition product (RRT = 1.5) was analyzed according to the following formula.
<HPLC conditions>
-Preparation of sample solution 2.5 mL of each eye drop was accurately weighed, and purified water was added to make exactly 50 mL, which was used as a sample solution.

-Preparation of standard solution Weigh exactly 50 mg of brimonidine tartrate standard, add purified water, and make exactly 50 mL. The solution was accurately weighed 5 mL, and purified water was added to make exactly 100 mL, which was used as a standard solution.

-Measurement by liquid chromatography 30 μL of the sample solution and standard solution were measured by liquid chromatography (High Performance Liquid Chromatograph manufactured by Shimadzu Corporation) under the following conditions, and the peak area of the main decomposition product in each sample solution was determined. And the peak area of brimonidine tartrate in the standard solution was determined by automatic integration.

<Measurement conditions>
Detector: Ultraviolet absorptiometer (measurement wavelength: 264 nm)
Column: Symmetry C18, 4.6 mm I. D. × 75 mm, 3.5 μm, Waters column temperature: 25 ° C
Mobile phase: 2.3 g of potassium dihydrogen phosphate and 47.5 mg of sodium 1-heptane sulfonate were dissolved in 830 mL of water, and the pH was adjusted to 3.0 using phosphoric acid. 84 mL of acetonitrile and 84 mL of methanol were mixed with this solution, and water was added to make 1 L to prepare a mobile phase.
Cleaning liquid: Acetonitrile / water (volume ratio: 1/1) mixed liquid flow rate: 1.0 mL / min
Area measurement range: 20 minutes

<Calculation formula>
The amount of main decomposition product (RRT = 1.5) produced (% of display ratio) was calculated according to the following formula.

3. 3. Evaluation Results Table 2 shows the results of determining the residual rate of brimonidine tartrate for each eye drop after light irradiation. When filled in a colorless transparent PP container and a brown transparent PE container, the residual rate of brimonidine tartrate in the eye drops of Formulations 1 and 2 was about the same. On the other hand, when filled in a colorless and transparent PE container, the eye drops of Formulation 2 had an improved residual rate of brimonidine tartrate as compared with the eye drops of Formulation 1. That is, it was clarified that when an eye drop containing brimonidine tartrate was filled in a colorless transparent PE container, the stability of brimonidine tartrate was improved by adding a metal chloride. Further, in the sample in which the eye drop of Formulation 2 was contained in a colorless transparent PE container, no foreign matter was generated and the color tone did not change.

Table 3 shows the results of the main decomposition products (RRT = 1.5) in each eye drop after light irradiation when using a colorless transparent PE container. Before light irradiation, the main decomposition product (RRT = 1.5) was not detected with any of the eye drops, but after light irradiation, the main decomposition product (RRT) correlates with the residual rate of brimonidine tartrate. = 1.5) was detected. That is, it was revealed that the main decomposition product produced by light exposure to brimonidine tartrate is the main decomposition product (RRT = 1.5). Therefore, in the following test examples, the photostability of brimonidine tartrate was evaluated by the amount of the main decomposition product (RRT = 1.5).

Test Example 2
1. 1. Production of Ophthalmic Pharmaceutical Products An eye drop having the composition shown in Table 4 was prepared in the same manner as in Test Example 1 above. 5 ml of this eye drop was placed in a colorless transparent PE container (manufactured by LDPE) and a colorless transparent PP container (both containing 5 ml) to prepare various samples (medicinal products for ophthalmology).

2. Evaluation method of photostability of brimonidine tartrate For each sample obtained above, a photostability test device (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.) was used at a temperature of 25 ° C. Under the conditions, a white fluorescent lamp was irradiated with light of 30,000 lpx for 200 hours, and the sample was exposed to light of 600,000 lux · h.

Under the same conditions as in Test Example 1, the amount of main decomposition product (RRT = 1.5) in the eye drops of each sample before and after light exposure was analyzed.

3. 3. Evaluation Results Table 5 shows the results obtained. Prior to light irradiation, no main decomposition product (RRT = 1.5) was detected with any of the eye drops. In the eye drops filled in a colorless transparent PE container, the amount of main decomposition product (RRT = 1.5) in the sample after light irradiation tends to decrease depending on the concentration of boric acid and borax, and boron is observed. When boric acid and borax of 70 mM or more are contained in terms of concentration, the amount of main decomposition product (RRT = 1.5) is reduced to less than 1.0% even if metal chloride is not contained. It was able to be reduced. On the other hand, in the eye drops filled in a colorless transparent PP container, the amount of the main decomposition product (RRT = 1.5) does not depend on the boric acid and borax concentrations, and the main in the eye drops after light irradiation. The amount of decomposition product (RRT = 1.5) did not fall below 1.0%. From this result, it was found that some interaction between the colorless transparent PE container and boric acid and borax affects the photostability of brimonidine.

Test Example 3
1. 1. Production of ophthalmic pharmaceutical products An eye drop having the composition shown in Table 6 was prepared in the same manner as in Test Example 1 above. 5 ml of this eye drop was placed in a 5 ml colorless transparent PE container (manufactured by LDPE) to prepare various samples (medicinal products for ophthalmology).

2. Evaluation method of photostability of brimonidine tartrate For each sample obtained above, a photostability test device (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.) was used at a temperature of 25 ° C. Under the conditions, a white fluorescent lamp was irradiated with light of 30,000 lpx for 200 hours, and the sample was exposed to light of 600,000 lux · h.

Under the same conditions as in Test Example 1, the amount of main decomposition product (RRT = 1.5) in the eye drops of each sample before and after light exposure was analyzed.

3. 3. Evaluation Results Table 7 shows the results obtained. Prior to light irradiation, no main decomposition product (RRT = 1.5) was detected with any of the eye drops. In the eye drops filled in the colorless transparent PE container, the amount of the main decomposition product (RRT = 1.5) after light irradiation decreased when the metal chloride was contained.

On the other hand, when sodium hydrogen phosphate and sodium dihydrogen phosphate are used in place of boric acid and borax in eye drops containing metal chloride, the amount of main decomposition product (RRT = 1.5) after light irradiation is increased. Although it increased, the amount of main decomposition product (RRT = 1.5) could be reduced as compared with the case where the metal chloride was not contained. Further, even if the eye drops contained brinzolamide together with the metal chloride, the amount of the main decomposition product (RRT = 1.5) could be reduced, but it could not be reduced to 1.0% or less.

Test Example 4
1. 1. Production of Ophthalmic Pharmaceutical Products An eye drop having the composition shown in Table 8 was prepared in the same manner as in Test Example 1 above. 5 ml of this eye drop was placed in a 5 ml colorless transparent PE container (manufactured by LDPE) to prepare various samples (medicinal products for ophthalmology).

2. Evaluation method of photostability of brimonidine tartrate For each sample obtained above, a photostability test device (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.) was used at a temperature of 25 ° C. Under the conditions, a white fluorescent lamp was irradiated with light of 30,000 lpx for 200 hours, and the sample was exposed to light of 600,000 lux · h.

Under the same conditions as in Test Example 1, the amount of main decomposition product (RRT = 1.5) in the eye drops of each sample before and after light exposure was analyzed.

3. 3. Evaluation Results Table 9 shows the results obtained. Prior to light irradiation, no main decomposition product (RRT = 1.5) was detected with any of the eye drops. When the eye drops filled in a colorless transparent PE container contain metal chloride and borax, the amount of main decomposition product (RRT = 1.5) after light irradiation is compared with the case where metal chloride is not contained. Was declining. In addition, when the eye drops filled in a colorless transparent PE container contain borax in addition to metal chloride and boric acid, the amount of main decomposition product (RRT = 1.5) after light irradiation is further reduced. It was.

Test Example 4
1. 1. Production of ophthalmic pharmaceutical products An eye drop having the composition shown in Table 10 was prepared in the same manner as in Test Example 1 above. 5 ml of this eye drop was placed in a 5 ml colorless transparent PE container (manufactured by LDPE) to prepare various samples (medicinal products for ophthalmology).

2. Evaluation method of photostability of brimonidine tartrate For each sample obtained above, a photostability test device (“LT-120A-WCD type”, manufactured by Nagano Science Co., Ltd.) was used at a temperature of 25 ° C. Under the conditions, a white fluorescent lamp was irradiated with light of 30,000 lpx for 200 hours, and the sample was exposed to light of 600,000 lux · h.

Under the same conditions as in Test Example 1, the amount of main decomposition product (RRT = 1.5) in the eye drops of each sample before and after light exposure was analyzed.

3. 3. Evaluation Results Table 11 shows the results obtained. Prior to light irradiation, no main decomposition product (RRT = 1.5) was detected with any of the eye drops. In the eye drops filled in a colorless transparent PE container, when boric acid and tromethamole are contained, the amount of main decomposition product (RRT = 1.5) after light irradiation is lower than that when tromethamole is not contained. It was. In addition, when the eye drops filled in the colorless transparent PE container contained metal chloride, boric acid and tromethamole, the amount of the main decomposition product (RRT = 1.5) after light irradiation was significantly reduced. ..

Reference test example 1
The color tone and transparency of each container used in Test Examples 1 to 4 were confirmed. Specifically, the body of each container is cut into 1.0 cm × 2.0 to 3.0 cm, and the brightness (L ^* value) is measured using a spectrophotometer (CM-5, manufactured by Konica Minolta Co., Ltd.). And the chromaticity (a ^* value, b ^* value) were measured. In addition, the saturation (c ^* value) was calculated according to the formula: ((a ^* value) ² + (b ^* value) ² ) ^1/2. In addition, the body of each container is cut into 1.0 cm x 2.0 to 3.0 cm, and an ultraviolet visible spectrophotometer (“UV-2450 type”, manufactured by Shimadzu Corporation) is used to cover a region of 200 to 800 nm. The light transmittance (%) of the light was measured.

The results are shown in Table 12. The results of measuring the light transmittance at each wavelength are shown in FIG. The colorless and transparent PE container had a brightness of 70 or more and a saturation of 20 or less, had a maximum light transmittance of 43% in the wavelength region of 400 to 800 nm, and was colorless and highly transparent.

The colorless and transparent PE container made it easy to clearly see the properties, foreign substances, color tone and liquid volume of the contained eye drops, had outstanding internal visibility, and was able to easily and accurately inspect insoluble foreign substances. On the other hand, in the brown transparent container, since it is brown, it is difficult to visually recognize the inside.

Claims (17)

1. A pharmaceutical product in which an aqueous liquid containing brimonidine and / or a salt thereof and a metal chloride is contained in a colorless and transparent polyethylene container.
2. The pharmaceutical product according to claim 1, wherein the aqueous solution contains boric acid and / or a salt thereof.
3. The pharmaceutical product according to claim 1 or 2, wherein the aqueous solution contains tromethamole and / or a salt thereof.
4. The pharmaceutical product according to any one of claims 1 to 3, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
5. The pharmaceutical product according to any one of claims 1 to 4, wherein the aqueous solution is an eye drop.
6. The pharmaceutical product according to any one of claims 1 to 5, which is used for the treatment of glaucoma.
7. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
   The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, and a metal chloride in a colorless and transparent polyethylene container.
8. A pharmaceutical product containing brimonidine and / or a salt thereof, and an aqueous solution containing boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container.
9. The pharmaceutical product according to claim 8, wherein the aqueous solution contains a metal chloride.
10. The pharmaceutical product according to claim 9, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
11. The pharmaceutical product according to any one of claims 8 to 10, wherein the aqueous solution contains tromethamole and / or a salt thereof.
12. The pharmaceutical product according to claim 11, wherein the metal chloride is at least one selected from the group consisting of sodium chloride, potassium chloride, magnesium chloride, and calcium chloride.
13. The pharmaceutical product according to any one of claims 8 to 12, wherein the aqueous solution is an eye drop.
14. The pharmaceutical product according to any one of claims 8 to 13, which is used for the treatment of glaucoma.
15. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
    The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, and boric acid and / or a salt thereof having a boron concentration of 70 mM or more in a colorless and transparent polyethylene container.
16. A pharmaceutical product in which an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof are contained in a colorless and transparent polyethylene container.
17. A method for suppressing the decomposition products of brimonidine and / or a salt thereof caused by light exposure to an aqueous solution containing brimonidine and / or a salt thereof.
    The method comprising the step of accommodating an aqueous solution containing brimonidine and / or a salt thereof, borate and / or a salt thereof, and tromethamole and / or a salt thereof in a colorless and transparent polyethylene container.

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