WO2021107033A1

WO2021107033A1 - Pharmaceutical composition

Info

Publication number: WO2021107033A1
Application number: PCT/JP2020/044068
Authority: WO
Inventors: 根本　夫規子
Original assignee: 千寿製薬株式会社
Priority date: 2019-11-29
Filing date: 2020-11-26
Publication date: 2021-06-03
Also published as: JP7217364B2; CN114761022B; CN114761022A; JPWO2021107033A1

Abstract

The purpose of the present invention is to provide a pharmaceutical composition having a high storage stability. This pharmaceutical composition comprises 0.0005-0.05 w/v% inclusive of glucose, a nonionic surfactant and an alkyldiaminoethylglycine hydrochloride.

Description

Pharmaceutical composition

The present invention relates to a pharmaceutical composition having excellent storage stability.

Various ophthalmic pharmaceutical compositions that assist tear fluid have been studied in order to reduce discomfort, dry eyes, eyestrain, blurred vision, etc. when wearing soft or hard contact lenses. There is.

Lacrimal gland is a mixture of lacrimal gland secretion secreted from the main lacrimal gland and substances secreted from four or more types of accessory lacrimal glands, and contains Na, K, Ca, Cl, etc. as inorganic components, and is an organic component. It contains glucose, ascorbic acid, citric acid, urea, ammonia, amino acids, proteins and the like.

Although there are individual differences, the concentration of glucose contained in tears is about 0.001 to 0.01 w / v%. Since glucose is blended as a nutritional component in ophthalmic pharmaceutical compositions, its concentration should be high, and when the ophthalmic pharmaceutical composition contains glucose, its general concentration is 0.1 w / v% or It is 0.2 w / v% (Patent Documents 1 to 8).

Japanese Unexamined Patent Publication No. 2005-336153 JP-A-2007-99643 JP-A-2009-46480 Japanese Unexamined Patent Publication No. 2011-93888 Japanese Unexamined Patent Publication No. 2011-213729 Japanese Unexamined Patent Publication No. 2014-5417 JP-A-2015-78248 JP-A-2017-178880

An object of the present invention is to provide a pharmaceutical composition having excellent storage stability.

The present inventor has conducted extensive research to solve the above problems. As a result, it was found that when a low concentration of glucose is added to the pharmaceutical composition, the residual rate of glucose tends to decrease with time, but the nonionic surfactant is very effective in stabilizing glucose. It was. However, although white turbidity during storage was observed in the pharmaceutical composition due to the addition of a nonionic surfactant, the present invention was completed by finding that such white turbidity was suppressed by the addition of alkyldiaminoethylglycine hydrochloride.
Hereinafter, one aspect of the present invention will be shown.

[1] A pharmaceutical composition containing 0.0005 w / v% or more and 0.05 w / v% or less of glucose, a nonionic surfactant, and an alkyldiaminoethylglycine hydrochloride.
[2] The pharmaceutical composition according to the above [1], which contains glucose of 0.0005 w / v% or more and 0.01 w / v% or less.
[3] The pharmaceutical composition according to the above [1] or [2], which contains glucose of 0.002 w / v% or more and 0.01 w / v% or less.
[4] The nonionic surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan mono-long-chain fatty acid ester, mono-long-chain fatty acid polyethylene glycol, and polyoxyethylene polyoxypropylene block copolymer. The pharmaceutical composition according to any one of the above [1] to [3], which is one or more nonionic surfactants.
[5] The pharmaceutical composition according to any one of the above [1] to [4], which contains a nonionic surfactant of 0.001 w / v% or more and 0.5 w / v% or less.
[6] The pharmaceutical composition according to any one of the above [1] to [4], which contains a nonionic surfactant of 0.005 w / v% or more and 0.3 w / v% or less.
[7] The pharmaceutical composition according to the above [4], wherein the polyoxyethylene hydrogenated castor oil is polyoxyethylene hydrogenated castor oil 60.
[8] The pharmaceutical composition according to any one of the above [1] to [7], which contains an alkyldiaminoethylglycine hydrochloride of 0.0005 w / v% or more and 0.05 w / v% or less.
[9] The pharmaceutical composition according to any one of the above [1] to [7], which contains an alkyldiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.01 w / v% or less.
[10] Glucose of 0.002 w / v% or more and 0.01 w / v% or less,
Nonionic surfactants of 0.005 w / v% or more and 0.3 w / v% or less, and
The pharmaceutical composition according to any one of the above [1] to [9], which contains an alkyldiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.01 w / v% or less.
[11] The pharmaceutical composition according to any one of the above [1] to [10], which further contains an inorganic salt.
[12] The pharmaceutical composition according to the above [11], wherein the inorganic salt is sodium chloride and / or potassium chloride.
[13] The pharmaceutical composition according to the above [11] or [12], which contains an inorganic salt of 0.05 w / v% or more and 5.0 w / v% or less.
[14] The pharmaceutical composition according to the above [11] or [12], which contains an inorganic salt of 0.1 w / v% or more and 2.0 w / v% or less.
[15] The pharmaceutical composition according to any one of the above [1] to [14], which further contains a buffer.
[16] One or more buffers selected from the group consisting of borate buffer, phosphate buffer, carbon dioxide buffer, citric acid buffer, acetate buffer, HEPES buffer, and MOPS buffer. The pharmaceutical composition according to the above [15].
[17] The pharmaceutical composition according to the above [15], wherein the buffer is boric acid and / or borax.
[18] The pharmaceutical composition according to any one of the above [15] to [17], which contains a buffer of 0.05 w / v% or more and 5.0 w / v% or less.
[19] The pharmaceutical composition according to any one of the above [15] to [17], which contains a buffer of 0.1 w / v% or more and 2.0 w / v% or less.
[20] The pharmaceutical composition according to any one of the above [1] to [19], which further contains a thickener.
[21] The pharmaceutical composition according to the above [20], wherein the thickener is hydroxypropylmethyl cellulose.
[22] The pharmaceutical composition according to the above [20] or [21], which contains a thickener of 0.01 w / v% or more and 3.0 w / v% or less.
[23] The pharmaceutical composition according to the above [20] or [21], which contains a thickener of 0.05 w / v% or more and 2.0 w / v% or less.
[24] The pharmaceutical composition according to any one of the above [1] to [23], which further contains an amino acid.
[25] One or more amino acids selected from the group consisting of taurine, glutamic acid, aspartic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, chondroitin sulfate ester, and salts thereof. The pharmaceutical composition according to the above [24], which is an amino acid.
[26] The pharmaceutical composition according to the above [24], wherein the amino acid is taurine.
[27] The pharmaceutical composition according to any one of the above [24] to [26], which contains amino acids of 0.01 w / v% or more and 1.0 w / v% or less.
[28] The pharmaceutical composition according to any one of the above [24] to [26], which contains an amino acid of 0.05 w / v% or more and 0.5 w / v% or less.
[29] Glucose of 0.002 w / v% or more and 0.01 w / v% or less,
Nonionic surfactants of 0.005 w / v% or more and 0.3 w / v% or less,
Alkylationdiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.01 w / v% or less,
Inorganic salts of 0.1 w / v% or more and 2.0 w / v% or less,
Buffering agent of 0.1 w / v% or more and 2.0 w / v% or less,
Thickeners of 0.05 w / v% or more and 2.0 w / v% or less, and
The pharmaceutical composition according to any one of the above [1] to [28], which contains an amino acid of 0.05 w / v% or more and 0.5 w / v% or less.
[30] The pharmaceutical composition according to any one of the above [1] to [29], which further contains a pH adjuster.
[31] The pharmaceutical composition according to any one of the above [1] to [30], which has a pH of 5.0 or more and 8.5 or less.
[32] The pharmaceutical composition according to any one of the above [1] to [30], which has a pH of 5.5 or more and 8.0 or less.
[33] The pharmaceutical composition according to any one of the above [1] to [32], which further contains a monoterpene.
[34] The pharmaceutical composition according to the above [33], wherein the monoterpene is one or more monoterpenes selected from the group consisting of menthol, camphor, and borneol.
[35] The pharmaceutical composition according to the above [33], wherein the monoterpene is l-menthol.
[36] The pharmaceutical composition according to any one of the above [33] to [35], which contains a monoterpene of 0.0005 w / v% or more and 0.1 w / v% or less.
[37] The pharmaceutical composition according to any one of the above [33] to [35], which contains a monoterpene of 0.001 w / v% or more and 0.05 w / v% or less.
[38] The pharmaceutical composition according to any one of the above [1] to [37], which further contains a chelating agent.
[39] The pharmaceutical composition according to the above [38], wherein the chelating agent is ethylenediaminetetraacetic acid or a salt thereof.
[40] The pharmaceutical composition according to the above [38] or [39], which contains a chelating agent of 0.001 w / v% or more and 0.15 w / v% or less.
[41] The pharmaceutical composition according to the above [38] or [39], which contains a chelating agent of 0.002 w / v% or more and 0.1 w / v% or less.
[42] Glucose of 0.002 w / v% or more and 0.01 w / v% or less,
Nonionic surfactants of 0.005 w / v% or more and 0.3 w / v% or less,
Alkylationdiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.01 w / v% or less,
Inorganic salts of 0.1 w / v% or more and 2.0 w / v% or less,
Buffering agent of 0.1 w / v% or more and 2.0 w / v% or less,
Viscous agent of 0.05 w / v% or more and 2.0 w / v% or less,
Amino acids of 0.05 w / v% or more and 0.5 w / v% or less,
Monoterpenes of 0.001 w / v% or more and 0.05 w / v% or less, and
The pharmaceutical composition according to any one of the above [1] to [41], which contains a chelating agent of 0.002 w / v% or more and 0.1 w / v% or less.
[43] Glucose of 0.002 w / v% or more and 0.01 w / v% or less,
Nonionic surfactants of 0.005 w / v% or more and 0.1 w / v% or less,
Alkylationdiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.005 w / v% or less,
Inorganic salts of 0.1 w / v% or more and 2.0 w / v% or less,
Buffering agent of 0.1 w / v% or more and 2.0 w / v% or less,
Viscous agent of 0.05 w / v% or more and 0.5 w / v% or less,
Amino acids of 0.05 w / v% or more and 0.5 w / v% or less,
Monoterpenes of 0.001 w / v% or more and 0.05 w / v% or less, and
Contains a chelating agent of 0.005 w / v% or more and 0.05 w / v% or less,
The pharmaceutical composition according to any one of the above [1] to [42], which has a pH of 6.5 or more and 8.0 or less.
[44] 0.005 w / v% glucose,
0.01w / v% nonionic surfactant and
A pharmaceutical composition containing 0.0025 w / v% alkyldiaminoethylglycine hydrochloride.
[45] The pharmaceutical composition according to any one of the above [1] to [44] for ophthalmology.
[46] The pharmaceutical composition according to any one of the above [1] to [45], which is an aqueous solution.
[47] The pharmaceutical composition according to any one of the above [1] to [46], which is an eye drop.
[48] Use of glucose, nonionic surfactant, and alkyldiaminoethylglycine hydrochloride of 0.0005 w / v% or more and 0.05 w / v% or less to improve the storage stability of the pharmaceutical composition.
[49] Of glucose, nonionic surfactant, and alkyldiaminoethylglycine hydrochloride of 0.0005 w / v% or more and 0.05 w / v% or less for producing a pharmaceutical composition having excellent storage stability. use.
[50] A method for improving the storage stability of a pharmaceutical composition containing glucose.
The pharmaceutical composition contains glucose of 0.0005 w / v% or more and 0.01 w / v% or less.
A method of blending a pharmaceutical composition with a nonionic surfactant and an alkyldiaminoethylglycine hydrochloride.
The above-mentioned provisions [1] to [47] can be applied to the above-mentioned uses and methods.

The pharmaceutical composition according to the present invention has excellent storage stability.

As described above, various ophthalmic pharmaceutical compositions for assisting tear fluid have been developed, and the glucose concentration of the ophthalmic pharmaceutical composition is generally adjusted to be higher than the actual tear fluid concentration. Is the target.

However, the present inventor has found that when the glucose concentration in the composition is adjusted to be as low as the concentration in tears, the glucose concentration cannot be maintained during storage. Therefore, when the components that stabilize glucose were examined, it was found that nonionic surfactants were effective. However, it was found that when a nonionic surfactant was added to a composition containing a low concentration of glucose, the composition became cloudy during storage. As a result of examining the components capable of suppressing such cloudiness, it was found that alkyldiaminoethylglycine hydrochloride is effective.

The pharmaceutical composition according to the present invention contains glucose of 0.0005 w / v% or more and 0.05 w / v% or less, a nonionic surfactant, and alkyldiaminoethylglycine hydrochloride.

"Pharmaceutical composition" means a composition for pharmaceutical use. The pharmaceutical composition can be prepared according to a conventional method. The pharmaceutical composition according to the present invention is particularly useful as a pharmaceutical composition for ophthalmology.

"Glucose" is _{one of the aldohexoses represented by the formula C 6} H ₁₂ O ₆ , and is also called glucose. D-glucose is naturally present, and in animals with a respiratory system, it couples with the electron transport chain to produce a large amount of ATP, and 0.001 w / v% or more and 0.01 w / v% or less in tears. There is a degree. Glucose is also blended as an isotonic agent and a thickening agent in pharmaceutical compositions.

The pharmaceutical composition according to the present invention contains glucose of 0.0005 w / v% or more and 0.05 w / v% or less. When the concentration is 0.0005 w / v% or more, the action and effect as a tear fluid component can be sufficiently exhibited. The lower limit is preferably 0.001 w / v% or more, 0.002 w / v% or more, more preferably 0.003 w / v% or more, and even more preferably 0.004 w / v% or more. Is. In addition, the lower the concentration of glucose, the lower the stability tends to be. When the concentration is 0.05 w / v% or less, cloudiness does not become remarkable in the pharmaceutical composition according to the present invention, and storage stability is sufficiently exhibited. The upper limit of the concentration is preferably 0.01 w / v% or less, more preferably 0.008 w / v% or less, and even more preferably 0.006 w / v% or less.

A "nonionic surfactant" is a surfactant that does not dissociate into ions even when dissolved in water. Generally, a polyoxyethylene chain or a hydroxyl group acts as a hydrophilic group, and a long-chain alkyl group is hydrophobic. Is the basis. Examples of the nonionic surfactant include nonionic surfactants such as polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan mono-long-chain fatty acid ester, mono-long-chain fatty acid polyethylene glycol, and polyoxyethylene polyoxypropylene block copolymer. Can be mentioned. Only one type of nonionic surfactant may be used, or two or more types may be used in combination.

Polyoxyethylene hydrogenated castor oil is a compound obtained by etherifying hardened castor oil with a polyoxyethylene chain. The number of moles of ethylene oxide added to the polyoxyethylene chain in the polyoxyethylene hydrogenated castor oil can be, for example, 5 or more and 100 or less. Regarding the lower limit of the number of added moles, 10 or more is preferable, 20 or more is more preferable, 30 or more is further preferable, and 40 or more is particularly preferable, from the viewpoint of improving solubility. The upper limit of the number of added moles is preferably 90 or less, more preferably 80 or less, and even more preferably 70 or less, from the viewpoint of lower toxicity. As the polyoxyethylene hydrogenated castor oil, for example, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 60 and the like can be used. As the polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, which is widely used in eye drops, is preferable.

Polyoxyethylene sorbitan monolong-chain fatty acid ester, also called polysorbate, is a sorbitan fatty acid obtained by condensing ethylene oxide with sorbitan long-chain fatty acid ester produced by heating and reacting sorbitol and long-chain fatty acid under an alkali catalyst. It is an ester polyoxyethylene ether. For example, usually, a total of 18 or more and 22 or less ethylene oxides are bound to each molecule. The carbon number of a long-chain fatty acid is generally 10 or more and 20 or less, and examples of the long-chain fatty acid include lauric acid, palmitic acid, stearic acid, and oleic acid. As the polyoxyethylene sorbitan monolong-chain fatty acid ester, for example, polysorbate 20, polysorbate 60, polysorbate 65, and polysorbate 80 can be used. As the polyoxyethylene sorbitan mono long-chain fatty acid ester, polysorbate 80, which is widely used in eye drops, is preferable.

Mono long-chain fatty acid polyethylene glycol is an ester of long-chain fatty acid and polyethylene glycol. Examples of long-chain fatty acid include stearic acid, and the degree of polymerization of polyethylene glycol is about 10 or more and 60 or less. Preferably, it is polyoxyl 40 stearate.

Polyoxyethylene polyoxypropylene block copolymer is a copolymer of propylene oxide and ethylene oxide. Examples of the polyoxyethylene polyoxypropylene block copolymer include polyoxyethylene (160) polyoxypropylene (30) glycol (poloxamer 188), polyoxyethylene (196) polyoxypropylene (67) glycol (poloxamer 407), and poloxamer. 235 and the like can be mentioned.

The present inventor has found that the concentration of low-concentration glucose in a pharmaceutical composition decreases during storage. In addition, the present inventor has found that such a decrease in glucose concentration can be suppressed by adding a nonionic surfactant. The concentration of the nonionic surfactant in the pharmaceutical composition can be adjusted as appropriate. The concentration can be, for example, 0.001 w / v% or more and 0.5 w / v% or less. When the concentration is 0.001 w / v% or more, the glucose concentration can be sufficiently maintained. The lower limit of the concentration is preferably 0.005 w / v% or more, more preferably 0.008 w / v% or more, and even more preferably 0.01 w / v% or more. When the concentration is 0.5 w / v% or less, the white turbidity of the pharmaceutical composition is not remarkable, and the storage stability is sufficiently exhibited. The upper limit of the concentration is preferably 0.3 w / v% or less, more preferably 0.1 w / v% or less, and even more preferably 0.05 w / v% or less.

The ratio of the nonionic surfactant to glucose may be adjusted as appropriate. For example, the amount of nonionic surfactant is 0.02 parts by mass or more and 1000 parts by mass or less with respect to 1 part by mass of glucose. When the mass part of the nonionic surfactant is 0.02 parts by mass or more, the glucose concentration can be maintained more effectively. The lower limit of the mass portion is preferably 0.5 parts by mass or more, more preferably 1.0 part by mass or more, and even more preferably 1.7 parts by mass or more. Further, when the mass part of the nonionic surfactant is 1000 parts by mass or less, the white turbidity of the pharmaceutical composition is not remarkable, and the storage stability is sufficiently exhibited. The upper limit of the parts by mass is more preferably 500 parts by mass or less or 150 parts by mass or less, still more preferably 33 parts by mass or less, and particularly preferably 13 parts by mass or less.

"Alkyldiaminoethylglycine hydrochloride" is a compound having the following chemical structure, and has been conventionally used mainly as a component having a bactericidal action.
_{_{R-NH- (CH 2) 2}} -NH- (CH 2) 2 -NH-CH 2 -CO 2 H · HCl
[In the formula, R represents an alkyl group _{of C 8} H ₁₇ to C ₁₆ H ₃₃ _{, mainly C 12} H ₂₅ and C ₁₄ H ₂₉ . ]

The present inventor has found that the white turbidity of a pharmaceutical composition caused by blending low-concentration glucose and a nonionic surfactant can be reduced by blending alkyldiaminoethylglycine hydrochloride. The concentration of alkyldiaminoethylglycine hydrochloride in the pharmaceutical composition may be adjusted as appropriate. For example, it can be 0.0005 w / v% or more and 0.05 w / v% or less. When the concentration is 0.0005 w / v% or more, the white turbidity of the pharmaceutical composition can be sufficiently suppressed. The lower limit of the concentration is preferably 0.001 w / v% or more, more preferably 0.0015 w / v% or more, and even more preferably 0.002 w / v% or more. When the concentration is 0.05 w / v% or less, the irritation generated when the pharmaceutical composition is administered to the eye can be sufficiently suppressed. The upper limit of the concentration is preferably 0.01 w / v% or less, more preferably 0.005 w / v% or less, and even more preferably 0.003 w / v% or less.

The ratio of alkyldiaminoethylglycine hydrochloride to glucose may be adjusted as appropriate. For example, the mass part of alkyldiaminoethylglycine hydrochloride with respect to 1 part by mass of glucose can be 0.01 part by mass or more and 100 parts by mass or less. When the mass portion of the alkyldiaminoethylglycine hydrochloride is 0.01 parts by mass or more, the white turbidity of the pharmaceutical composition can be sufficiently suppressed. The lower limit of the mass part is preferably 0.1 part by mass or more, more preferably 0.2 part by mass or more, and further preferably 0.33 part by mass or more. When the mass portion of the alkyldiaminoethylglycine hydrochloride is 100 parts by mass or less, the irritation generated when the pharmaceutical composition is administered to the eye can be sufficiently suppressed. The upper limit of the parts by mass is preferably 50 parts by mass or less, 5.0 parts by mass or less, more preferably 1.7 parts by mass or less, and even more preferably 0.8 parts by mass or less.

The ratio of alkyldiaminoethylglycine hydrochloride to nonionic surfactant may be adjusted as appropriate. For example, the mass part of alkyldiaminoethylglycine hydrochloride with respect to 1 part by mass of the nonionic surfactant can be 0.001 part by mass or more and 50 parts by mass or less. When the mass part of the alkyldiaminoethylglycine hydrochloride is 0.001 part by mass or more, the white turbidity of the pharmaceutical composition can be sufficiently suppressed. The lower limit of the parts by mass is preferably 0.003 parts by mass or more, more preferably 0.015 parts by mass or more, and even more preferably 0.04 parts by mass or more. When the mass portion of the alkyldiaminoethylglycine hydrochloride is 50 parts by mass or less, the irritation generated when the pharmaceutical composition is administered to the eye can be sufficiently suppressed. The upper limit of the parts by mass is preferably 2.0 parts by mass or less, more preferably 0.6 parts by mass or less, and even more preferably 0.3 parts by mass or less.

"Inorganic salt" refers to an inorganic compound in which the hydrogen atom of an inorganic acid is replaced with a metal, and is mainly blended as an isotonic agent. The inorganic salt is preferably one that is soluble in water, which is the solvent of the pharmaceutical composition. "Soluble in water" means when the test object is made into fine particles that pass through a No. 100 (opening: 150 μm) sieve, then 1 g is placed in water and shaken vigorously every 5 minutes for 30 seconds at 20 ° C. , It means that the amount of water required to dissolve within 30 minutes is less than 10 mL.

Examples of the inorganic salt include alkali metal chlorides such as sodium chloride and potassium chloride; Group 2 metal chlorides such as calcium chloride and magnesium chloride; alkali metal carbonates such as sodium carbonate; alkali metal carbonates such as sodium hydrogencarbonate. Hydrogen salts; Group 2 metal sulfates such as magnesium sulfate; Alkali metal sulfites such as sodium sulfite; Alkali metal sulfites such as sodium hydrogen sulfite; Alkali metal thiosulfates such as sodium thiosulfate; Disodium hydrogen phosphate Alkali metal hydrogen phosphates such as; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate, and the like, and sodium chloride and / or potassium chloride are preferably used. As the group 2 metal, an alkaline earth metal such as calcium is preferable. Only one kind of inorganic salt may be used, or two or more kinds may be used in combination.

The concentration of the inorganic salt in the pharmaceutical composition may be adjusted as appropriate. For example, from the viewpoint of the isotonic action of the inorganic salt, it can be 0.05 w / v% or more and 5.0 w / v% or less. The lower limit of the concentration is preferably 0.1 w / v% or more, more preferably 0.5 w / v% or more, and even more preferably 0.55 w / v% or more. The upper limit of the concentration is preferably 2.0 w / v% or less, more preferably 1.0 w / v% or less, and even more preferably 0.9 w / v% or less.

The "buffer" mainly refers to a component for softening a change in pH due to an external substance, for example, a borate buffer, a phosphate buffer, a carbonic acid buffer, a citric acid buffer, an acetate buffer, and a HEPES buffer. Agents, MOPS buffers and the like. Only one type of buffer may be used, or two or more types may be used in combination. As the buffer, a boric acid buffer is preferable, and boric acid and / or borax is more preferable. Boric acid and borax are also used as preservatives and also have a disinfecting effect on the conjunctival sac.

The concentration of the buffer in the pharmaceutical composition may be adjusted as appropriate. For example, from the viewpoint of the buffering action of the buffer, it can be 0.05 w / v% or more and 5.0 w / v% or less. The lower limit of the concentration is preferably 0.1 w / v% or more, more preferably 0.25 w / v% or more, and even more preferably 0.4 w / v% or more. The upper limit of the concentration is preferably 2.0 w / v% or less, more preferably 1.0 w / v% or less, and even more preferably 0.6 w / v% or less.

The "viscosity agent" is a component that increases the viscosity of the pharmaceutical composition and contributes to the suppression of rapid evaporation of the pharmaceutical composition, the improvement of liquid drainage, the suppression of variation in the dropping amount, and the improvement of usability. .. Glucose is also used as a thickener, but since glucose is essential in the pharmaceutical composition according to the present invention, glucose is excluded from the category of the thickener in the present invention for convenience.

The viscosity of the pharmaceutical composition according to the present invention may be adjusted as appropriate. For example, it can be 1 mPa · s or more and 100 mPa · s or less. Regarding the lower limit of the viscosity, 1.2 mPa · s or more is preferable, 1.5 mPa · s or more is more preferable, and 2.0 mPa · s or more is further more preferable, in order to sufficiently suppress the rapid evaporation of the pharmaceutical composition. preferable. The upper limit of the viscosity is preferably 30 mPa · s or less, more preferably 10 mPa · s or less, and even more preferably 5.0 mPa · s or less in order to sufficiently secure a feeling of use.

Examples of the thickener include hydroxypropyl methylcellulose, carboxyvinyl polymer, hydroxyethyl cellulose, methyl cellulose, alginic acid, polyvinyl alcohol, polyvinylpyrrolidone and the like, and hydroxypropyl methyl cellulose is preferable. Only one type of thickener may be used, or two or more types may be used in combination.

The concentration of the viscous agent in the pharmaceutical composition may be adjusted as appropriate. For example, from the viewpoint of the above-mentioned action by the thickener, it can be 0.01 w / v% or more and 3.0 w / v% or less. Regarding the lower limit of the concentration, 0.05 w / v% or more is preferable, 0.08 w / v% or more is more preferable, and 0.1 w / v% or more is preferable, in order to sufficiently suppress the rapid evaporation of the pharmaceutical composition. Is even more preferable. The upper limit of the concentration is preferably 2.0 w / v% or less, more preferably 0.5 w / v% or less, and even more preferably 0.2 w / v% or less in order to ensure a feeling of use.

"Amino acid" refers to a compound having an acidic group and an amino group such as a carboxy group or a sulfonic acid group (-SO ₃ H) in the molecule is not limited to the 20 so-called proteinogenic amino acids. Amino acids mainly serve as nutrients for the eyes and contribute to the reduction of eyestrain. Examples of amino acids include amino acids such as taurine, glutamic acid, aspartic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, chondroitin sulfate ester, and salts thereof. Examples of the amino acid salt include alkali metal salts such as sodium salt and potassium salt. Only one type of amino acid may be used, or two or more types may be used in combination. As the amino acid, taurine is preferable. In addition to being a nutritional component, taurine is also said to have a metabolic promoting effect.

The concentration of amino acids in the pharmaceutical composition may be adjusted as appropriate. For example, from the viewpoint of nutritional supplementation, it can be 0.01 w / v% or more and 1.0 w / v% or less. The lower limit of the concentration is preferably 0.03 w / v% or more, more preferably 0.05 w / v% or more. The upper limit of the concentration is preferably 0.5 w / v% or less, more preferably 0.2 w / v% or less.

The pH of the pharmaceutical composition according to the present invention is adjusted to a range applicable to living organisms, especially eyes. The pH can be, for example, 5.0 or more and 8.5 or less, and preferably 5.5 or more and 8.0 or less. The pH of the pharmaceutical composition may be adjusted with the buffering agent described above or with a pH adjuster. The lower limit of the pH is preferably 6.0 or more, more preferably 6.5 or more, and even more preferably 6.7 or more in order to sufficiently secure a feeling of use. The upper limit of the pH is preferably 7.7 or less, more preferably 7.5 or less, and even more preferably 7.2 or less in order to sufficiently maintain the glucose concentration.

The pH adjuster is not particularly limited as long as it is applicable to living organisms, especially to the eyes, but for example, inorganic acids such as hydrochloric acid and boric acid; organic acids such as acetic acid, glutamic acid and aspartic acid; sodium hydroxide and sodium carbonate. , Inorganic bases such as sodium hydrogen carbonate; organic bases such as triethanolamine and monoethanolamine. The type and amount of the pH adjuster may be determined according to the pH of the pharmaceutical composition to be adjusted.

The "monoterpene" is _{a compound composed of two isoprene units and having a molecular formula of C 10} H ₁₆ , and in the present invention, a monoterpene monoterpene that mainly exhibits a cooling action is used. Examples of monoterpenes include monoterpenes such as menthol, camphor, and borneol. As the menthol, either l-menthol or dl-menthol can be used, but l-menthol is preferable. As camphor and borneol, both d-form and dl-form can be used, but d-form is preferable. Only one type of monoterpene may be used, or two or more types may be used in combination.

The concentration of monoterpene in the pharmaceutical composition may be appropriately adjusted, but for example, it can be 0.0005 w / v% or more and 0.1 w / v% or less from the viewpoint of an appropriate refreshing sensation. The lower limit of the concentration is preferably 0.001 w / v% or more, more preferably 0.0015 w / v% or more, and even more preferably 0.002 w / v% or more. Regarding the upper limit of the concentration, 0.05 w / v% or less is preferable, 0.015 w / v% or less is more preferable, and 0.01 w / v% or less is even more preferable.

The "chelating agent" improves the storage stability of the composition by blocking metal ions such as calcium ions and suppressing the formation of insoluble metal salts thereof. The chelating agent is not particularly limited as long as it is applicable to the living body, particularly to the eyes, and has such an action, and examples thereof include ethylenediaminetetraacetic acid (edetic acid), ascorbic acid, citric acid, and salts thereof. Be done. Examples of the salt of ethylenediaminetetraacetic acid salt include ethylenediaminetetraacetic acid tetrasodium and ethylenediaminetetraacetic acid disodium. Only one type of chelating agent may be used, or two or more types may be used in combination.

The concentration of the chelating agent in the pharmaceutical composition may be appropriately adjusted, but for example, it should be 0.001 w / v% or more and 0.15 w / v% or less in order to sufficiently exert the stabilizing effect of the chelating agent. Can be done. When the concentration is within the above range, the stabilizing effect of the chelating agent can be sufficiently obtained. The lower limit of the concentration is preferably 0.002 w / v% or more, more preferably 0.005 w / v% or more, and even more preferably 0.007 w / v% or more. The upper limit of the concentration is preferably 0.1 w / v% or less, more preferably 0.05 w / v% or less, and even more preferably 0.03 w / v% or less.

The pharmaceutical composition according to the present invention is not particularly limited as long as the effects of the present invention are not impaired, but a preservative or preservative other than alkyldiaminoethylglycine hydrochloride may be added. Preservatives or preservatives include, for example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, chlorobutanol, benzyl alcohol, phenethyl alcohol, sorbic acid or the like. Salt, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, dehydroacetic acid or salts thereof, zinc chloride, polydronium chloride, thimerosal, dibutylhydroxytoluene, sodium chlorate, polyhexamethylene biguanide, boric acid, boric acid And so on. These preservatives or preservatives may be used alone or in combination of two or more.

The pharmaceutical composition according to the present invention can be produced by a conventional method. For example, each component may be dissolved in water as a solvent. As the solvent, water such as distilled water, purified water, sterilized water, etc., which has impurities, bacteria, viruses, fungi, etc. less than the detection limit or sufficiently less than the detection limit is used.

The container for accommodating the pharmaceutical composition of the present invention is not particularly limited as long as it is conventionally used as an eye drop container, and may be made of glass or plastic. When a plastic container is used as a container for accommodating the pharmaceutical composition of the present invention, the constituent material of the plastic container is not particularly limited, and for example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polybutylene terephthalate, polypropylene, polyethylene. , Any one of polyimides, or a mixture of two or more. From the viewpoint of more reliably ensuring the storage stability of the pharmaceutical composition, polyethylene terephthalate, polyethylene or polypropylene is preferable as the material of the container body, that is, the member forming the accommodating portion for accommodating the pharmaceutical composition, and polyethylene terephthalate. Is more preferable.

The "storage stability" of the pharmaceutical composition according to the present invention refers to the degree to which the glucose concentration is maintained and the white turbidity is suppressed even after the aqueous preparation is stored for a predetermined period of time. The phrase "maintaining the glucose concentration" of the pharmaceutical composition according to the present invention means that after the aqueous preparation has been stored for a predetermined period of time, the concentration of glucose in the aqueous preparation before storage is compared with that in the aqueous preparation after storage. It means that the glucose concentration is not maintained or significantly reduced. The degree to which the glucose concentration is maintained can be expressed by the glucose residual rate. For example, it means that the residual rate of glucose with respect to the initial concentration is 75% or more after the pharmaceutical composition according to the present invention is maintained at 80 ° C. for 2 weeks. The glucose residual rate is preferably 80% or more.

In addition, "white turbidity is suppressed" of the pharmaceutical composition according to the present invention means that white turbidity is not observed with the naked eye in the appearance properties of the pharmaceutical composition after the aqueous preparation is stored for a predetermined period of time. .. For example, it means that no cloudiness is observed with the naked eye after the pharmaceutical composition according to the present invention is maintained at 80 ° C. for 2 weeks.

The "improvement of storage stability" of the pharmaceutical composition according to the present invention means that the glucose concentration is maintained and the white turbidity is suppressed after the aqueous preparation is stored for a predetermined period of time. For example, one or more of glucose, nonionic surfactant, and alkyldiaminoethylglycine hydrochloride, which are essential components of the pharmaceutical composition according to the present invention, which are 0.0005 w / v% or more and 0.05 w / v% or less. The glucose residual rate in the pharmaceutical composition according to the present invention is equal to or higher than that of the pharmaceutical composition which does not contain the above-mentioned component or whose glucose concentration is out of the range, after being maintained at 80 ° C. for 2 weeks. , The degree of cloudiness is equal to or less than, and the residual rate of glucose is higher, and / or the degree of cloudiness is lower.

The pharmaceutical composition according to the present invention assists tears and reduces discomfort, dry eyes, tired eyes, blurred vision, etc. when wearing soft contact lenses or hard contact lenses. It is effective, and is particularly effective in reducing discomfort when wearing soft contact lenses.

The pharmaceutical composition of the present invention can be used in either an internal or external form depending on the purpose. It can be provided as a topical liquid preparation for various purposes such as internal medicine as a form of internal medicine and ophthalmology, dentistry, otolaryngology, and dermatology as a form of external use. Especially preferably for ophthalmology.

"Pharmaceutical composition for ophthalmology" means a pharmaceutical composition for ophthalmic use. Examples of the pharmaceutical composition include an aqueous liquid preparation containing water as a solvent. The "aqueous solution" means a liquid pharmaceutical composition containing water as a solvent. The aqueous liquid preparation can be prepared according to a conventional method, such as dissolving or dispersing each component in water as a solvent.

Examples of pharmaceutical compositions for ophthalmology include eye drops (including eye drops that can be used while wearing contact lenses, also referred to as eye drops and eye drops), and eyewashes (even while wearing contact lenses). Contains eye drops that can be used, and is also called eye wash or eye drop), eye ointment, contact lens wearing solution, contact lens care agent (cleaning solution, preservative solution, bactericidal solution, disinfectant solution {multipurpose (Including solutions), etc.), and the like, preferably an eye drop, a contact lens wearing solution, an eye wash, or a contact lens care agent, and particularly preferably an eye drop.

The pharmaceutical composition of the present invention contains eye drops that can be used while wearing contact lenses. Further, in the present specification, the contact lens includes all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses. The type of soft contact lens is not particularly limited, and can be used for any of disposable soft contact lenses, regular replacement soft contact lenses, conventional soft contact lenses, silicone hydrogel contact lenses, and color contact lenses. Silicone hydrogel contact lenses are contact lenses made of silicone hydrogel material.

The dosage and administration of the eye drops of the present invention varies depending on the patient's symptoms, age, etc., but usually, it is sufficient to instill 1 or more, 6 times or less per day, 1 or more and 3 or less drops per day. ..

The container used for the pharmaceutical composition of the present invention is sterilized according to a conventional method. The sterilization method is not particularly limited as long as it is a generally used method, and examples thereof include dry heat sterilization, electron beam sterilization, gamma ray sterilization, ethylene gas sterilization, and hydrogen peroxide sterilization. In one embodiment, the sterilization process is electron beam sterilization.

The present invention is a method for improving the storage stability of a pharmaceutical composition containing glucose, wherein the pharmaceutical composition contains glucose of 0.0005 w / v% or more and 0.05 w / v% or less, and the pharmaceutical composition contains glucose. It also relates to a method of blending a nonionic surfactant and an alkyldiaminoethylglycine hydrochloride.

In the method for improving the storage stability of the present invention, the pharmaceutical composition containing glucose is particularly effective in the present invention by setting the glucose concentration to 0.0005 w / v% or more and 0.05 w / v%. Demonstrate.

Regarding the type and concentration of glucose, nonionic surfactant, alkyldiaminoethylglycine hydrochloride, and other optional components used in the method for improving the storage stability of the pharmaceutical composition containing glucose, the pharmaceutical composition. The type and concentration of the substance may be adopted alone or in combination. The same applies to the pH and container of the pharmaceutical composition.

This application claims the benefit of priority based on Japanese Patent Application No. 2019-217421 filed on November 29, 2019. The entire contents of the specification of Japanese Patent Application No. 2019-217421 filed on November 29, 2019 are incorporated herein by reference.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited by the following examples as well as the present invention, and appropriate modifications are made to the extent that it can be adapted to the gist of the above and the following. Of course, it is possible to carry out, and all of them are included in the technical scope of the present invention.

Test Example 1: Storage stability test-Appearance evaluation Each component was dissolved in purified water according to the composition shown in Table 1. The unit of the numerical value in Table 1 is w / v%. Each prepared aqueous solution (5 mL) was filled in a glass ampoule and then stored at 80 ° C. for 2 weeks.
After storage, the appearance was evaluated according to the property test method of the 17th revised Japanese Pharmacopoeia. Specifically, a glass ampoule filled with each aqueous solution was placed in front of a black background, and it was observed whether it was colorless and had a clear name, or whether white insoluble components were precipitated and turbidity was generated. .. The evaluation results are shown in Table 1.

Test Example 2: Storage Stability Test-Measurement of Glucose Residual Rate 17th Revised Japanese Pharmacopoeia General Test Method Refer to the ultraviolet-visible absorbance measurement method, and refer to the glucose quantification kit ("Glucose CII Test Wako" manufactured by Fuji Film Wako Pure Chemical Industries, Ltd. ) Was used to determine the residual glucose rate after storage at 80 ° C. for 2 weeks. Specifically, among the aqueous solutions prepared in Test Example 1, the aqueous solution having a glucose concentration of 0.005 w / v% remains as it is, and the aqueous solution having a glucose concentration of 0.1 w / v% has a glucose concentration of 0.005 w. The color test solution (3 mL) was mixed with the solution diluted to / v% (2 mL), heated at 37 ° C. for 5 minutes, and the absorbance at 505 nm was measured using the same operation with water as a control. Separately, a glucose standard solution is prepared by dissolving glucose (50 mg) in water to make a total volume of 100 mL, and adding water to the solution (2 mL) to make a total volume of 20 mL, and the glucose concentration is clear in advance. The absorbance of the glucose standard solution was measured in the same manner. From the obtained measurement results, the glucose content (%) and the glucose residual rate (%) were calculated according to the following formulas. The results are shown in Table 1.
Glucose content (%) = [Standard product weighing amount (mg) x sample absorbance / standard solution absorbance] x 2
Glucose residual rate (%) = [Glucose content after storage / Glucose content before storage] x 100

* Products used Glucose: Brand name "Glucose" Sanei Saccharification Co., Ltd. Alkyldiaminoethylglycine hydrochloride: Brand name "Levon LAG-40" Sanyo Chemical Industries, Ltd. Polyoxyethylene hydrogenated castor oil 60: Brand name "HCO-60 (pharmaceutical) For) ”Made by Nikko Chemicals Co., Ltd.

As shown in the results shown in Table 1, in the glucose aqueous solution of 0.1 w / v%, the appearance and the residual glucose rate did not change so much even after storage, but the glucose concentration as low as 0.005 w / v% was observed. In aqueous solution, the residual rate of glucose was clearly reduced. It has not been clarified what kind of compound glucose is converted into, but it can be said that such a decrease in residual rate is a clear decrease in quality.
However, when the polyoxyethylene hydrogenated castor oil 60 was added, the decrease in the residual rate of low-concentration glucose was suppressed. However, instead, white turbidity occurred over time.
Therefore, by blending alkyldiaminoethylglycine hydrochloride in addition to polyoxyethylene hydrogenated castor oil 60, not only the decrease in the residual rate of low-concentration glucose is suppressed, but also the white turbidity is suppressed, and the storage stability is remarkable. It was clarified that an excellent aqueous solution can be obtained.

Test Example 3: Storage stability test-Appearance evaluation and glucose residual rate measurement According to the composition shown in Table 2, each component was dissolved in purified water to prepare an aqueous solution. The unit of the numerical value in Table 2 is w / v%.
Under the same conditions as in Test Example 1 and Test Example 2, the appearance of each aqueous solution of Example 2 after storage was evaluated, and the glucose residual rate was measured. The results are shown in Table 2.

* Products used Polysorbate 80: Brand name "Polysorbate 80 (SS)" manufactured by NOF Corporation Polyoxyl stearate 40: Brand name "MYS-40MV" manufactured by Nippon Surfrant Industry Co., Ltd.

As shown in the results shown in Table 2, the glucose residual rate was reduced by adding polysorbate 80 (polyoxyethylene sorbitan mono long-chain fatty acid ester), which is a nonionic surfactant, to a 0.005 w / v% glucose aqueous solution. Was suppressed, but cloudiness occurred depending on the storage conditions (Comparative Example 4). The same was true even if the nonionic surfactant was changed to polyoxyl 40 stearate, which is a monolong-chain fatty acid polyethylene glycol (Comparative Example 5).
On the other hand, by blending alkyldiaminoethylglycine hydrochloride in addition to the nonionic surfactant, not only the decrease in the residual rate of low-concentration glucose is suppressed, but also the white turbidity is suppressed, and the storage stability is remarkable. It was proved that an excellent aqueous solution was obtained (Examples 2 and 3).

Example of preparation As a specific embodiment of the aqueous liquid preparation according to the present invention, an example of preparation is given below. The unit of the numerical value in the table is w / v% other than pH. In the aqueous liquid preparation of the pharmaceutical example, by blending the nonionic surfactant and alkyldiaminoethylglycine hydrochloride, not only the decrease in the residual rate of low-concentration glucose is suppressed, but also the white turbidity is suppressed, which is remarkable. Excellent storage stability is recognized.

Test Example 4-Examination of Glucose Concentration An aqueous glucose solution having the concentration shown in Table 5 was prepared, and the glucose residual rate after storage at 80 ° C. for 2 weeks was determined in the same manner as in Test Example 1. The results are shown in Table 5.

As shown in the results shown in Table 5, it can be said that the stability of glucose in an aqueous glucose solution having a relatively high concentration of 0.1% by mass is relatively high, but the lower the glucose concentration, the lower the stability tends to be, and at least It was found that the stability of glucose was not sufficient in the range of 0.0005% by mass or more and 0.01% by mass or less.

Test Example 5-Examination of Nonionic Surfactant Concentration A glucose-nonionic surfactant aqueous solution having the concentration shown in Table 6 was prepared and stored at 80 ° C. for 2 weeks in the same manner as in Test Example 1. And evaluated the appearance. As the nonionic surfactant, polyethylene glycol monostearate (40EO) (“NIKKOL MYS-40” manufactured by Nikko Chemicals Co., Ltd.) was used. The results are shown in Table 6.

As shown in the results shown in Table 6, the stability of the low-concentration glucose is improved by blending 0.005% by mass or more and 0.05% by mass or less of the nonionic surfactant, but the mixed solution may become cloudy. Admitted.

Test Example 6-Examination of Alkyldiaminoethylglycine Hydrochloride Concentration A mixed solution having the composition shown in Table 7 was prepared, and the glucose residual rate after storage at 80 ° C. for 2 weeks was determined in the same manner as in Test Example 1 to obtain the appearance. evaluated. The results are shown in Table 7.

As shown in the results shown in Table 7, the white turbidity of the mixture in which the low-concentration glucose was stabilized by the addition of the nonionic surfactant was not improved by the addition of excess alkyldiaminoethylglycine hydrochloride, but 0. It was demonstrated that the elimination was achieved by blending 0.001% by mass or more and 0.005% by mass or less of alkyldiaminoethylglycine hydrochloride.

Claims

A pharmaceutical composition containing 0.0005 w / v% or more and 0.05 w / v% or less of glucose, a nonionic surfactant, and an alkyldiaminoethylglycine hydrochloride.
The pharmaceutical composition according to claim 1, which contains glucose of 0.0005 w / v% or more and 0.01 w / v% or less.
One or more nonionic surfactants selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolong fatty acid ester, monolong chain fatty acid polyethylene glycol, and polyoxyethylene polyoxypropylene block copolymers. The pharmaceutical composition according to claim 1 or 2, which is a nonionic surfactant.
The pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of the nonionic surfactant is 0.001 w / v% or more and 0.5 w / v% or less.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the concentration of alkyldiaminoethylglycine hydrochloride is 0.0005 w / v% or more and 0.05 w / v% or less.
Glucose of 0.002 w / v% or more and 0.01 w / v% or less,
Nonionic surfactants of 0.005 w / v% or more and 0.05 w / v% or less, and
The pharmaceutical composition according to any one of claims 1 to 5, which contains an alkyldiaminoethylglycine hydrochloride of 0.001 w / v% or more and 0.005 w / v% or less.
The pharmaceutical composition according to any one of claims 1 to 6, further containing an amino acid.
The pharmaceutical composition according to claim 7, wherein the amino acid is taurine.
The pharmaceutical composition according to claim 7 or 8, which contains amino acids of 0.01 w / v% or more and 1.0 w / v% or less.
The pharmaceutical composition according to any one of claims 1 to 9, wherein the pH is 5.0 or more and 8.5 or less.
0.005w / v% glucose,
0.01w / v% nonionic surfactant and
A pharmaceutical composition containing 0.0025 w / v% alkyldiaminoethylglycine hydrochloride.