JP2023009258A - Ophthalmological preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide multi-dose type ophthalmological preparations which contain an acidic saccharide and a cation preservative and are excellent in storage properties.

SOLUTION: An ophthalmological preparation containing (A) an acidic saccharide, (B) a cation preservative, and (C) eucalyptus oil is prepared. There are also provided: a preservative for a composition in which an acidic saccharide and a cation preservative coexist, the preservative containing eucalyptus oil; as well as a storage effect enhancement method for a composition by allowing eucalyptus oil to coexist with a composition containing an acidic sugar and a cationic preservative.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to ophthalmic formulations. More particularly, it relates to multi-dose ophthalmic formulations.

Ophthalmic preparations such as eye drops are usually used by being housed in unit-dose type containers or multi-dose type containers. Multi-dose ophthalmic preparations are supposed to be used many times over a certain period of time after being opened, but once opened, there is a concern that air containing germs will be mixed in with the ophthalmic preparations once opened. Microbial contamination can also be caused by contact with ocular tissue or skin during use.

Therefore, in multi-dose ophthalmic formulations, it is essential to prevent their putrefaction and ensure their preservative efficacy. (Patent Document 1).

On the other hand, until now, the influence of the ingredients blended in ophthalmic preparations on other ingredients has not been sufficiently studied.

Japanese Patent Laid-Open No. 9-235233

An object of the present invention is to provide an ophthalmic preparation with excellent stability.

The present invention is based on the point of view that it is important to verify the effects of the components of ophthalmic preparations on the preservative efficacy and to improve the preservative efficacy. The present inventors have found a new problem that a composition containing a cationic preservative and an acidic saccharide is inferior in preservability. The present inventors have found that a high preservative effect can be maintained by this method, and have completed the present invention.

That is, the present invention provides the following ophthalmic preparations.
Section 1.
(A) acidic sugars,
A multi-dose ophthalmic formulation containing (B) a cationic preservative and (C) eucalyptus oil.
Section 2.
Item 1. The multi-dose ophthalmic preparation according to Item 1, which has a pH of 6-8.
Item 3.
Item 3. The multi-dose ophthalmic preparation according to Item 1 or 2, wherein the component (A) is at least one selected from the group consisting of glycyrrhizic acid, chondroitin sulfate and salts thereof.
Section 4.
Item 4. The multi-dose ophthalmic preparation according to any one of items 1 to 3, wherein the total content of component (A) is 0.01 to 1 w/v%.
Item 5.
Any one of items 1 to 4, wherein the component (B) is at least one selected from the group consisting of a quaternary ammonium compound, a salt of a quaternary ammonium compound, a biguanide compound, and a salt of a biguanide compound. A multi-dose ophthalmic preparation according to the paragraph.
Item 6.
Item 6. The multi-dose ophthalmic preparation according to any one of items 1 to 5, wherein the content of component (C) is 0.001 to 0.1 w/v%.
Item 7.
7. The multi-dose ophthalmic preparation according to any one of items 1 to 6, wherein the content of component (C) is 0.0007 to 0.07 w/v% as cineol.
Item 8.
The multi-dose ophthalmic preparation according to any one of claims 1 to 8, wherein the ophthalmic preparation is an eye drop.

Furthermore, the present invention relates to preservatives shown below.
Item 9.
A preservative for a composition in which an acidic saccharide and a cationic preservative coexist, the preservative containing eucalyptus oil.

Furthermore, the present invention relates to a method for enhancing the preservative efficacy of the composition shown below.
Item 10.
A method for enhancing the preservative efficacy of a composition by allowing eucalyptus oil to coexist with a composition containing an acidic saccharide and a cationic preservative.

The present invention can provide ophthalmic preparations with excellent storage stability.

FIG. 1 is a graph showing the results of a storage test of an ophthalmic preparation of one embodiment of the present invention and an ophthalmic preparation of a comparative example.

In this specification, the content unit "w/v%" is synonymous with "g/100 mL".

The ophthalmic preparation of the present invention is a multi-dose ophthalmic preparation containing (A) an acidic saccharide, (B) a cationic preservative, and (C) eucalyptus oil.

The ophthalmic formulation herein contains water at 1 w/v% or more of the total ophthalmic formulation, preferably 5 w/v.
v% or more, more preferably 20 w/v% or more, more preferably 50 w/v% or more,
More preferably 70 w/v% or more, particularly preferably 90 w/v% or more, most preferably 95 w/v% or more. The water contained in the ophthalmic preparation of the present invention may be pharmaceutically, pharmacologically or physiologically acceptable. For example, distilled water, normal water, purified water, sterilized purified water, water for injection, distilled water for injection and the like can be used. These definitions are based on the 16th revision of the Japanese Pharmacopoeia.

[(A) Acidic saccharides]
The acidic saccharide used in the present invention is not particularly limited as long as it is a compound having a sugar skeleton and an acidic group such as a carboxyl group or a sulfo group in either structure. Examples of such acidic saccharides include glycyrrhizic acid, mucopolysaccharides such as heparin, heparan sulfate, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, and glycosaminoglycans.
Or salts thereof can be used, but not limited. For example, any compound having an acidic sugar skeleton with a molecular weight of 600 or more, preferably 700 or more, more preferably 800 or more can be used.

Here, a salt is a pharmaceutically acceptable salt. Examples include, but are not limited to, salts with organic bases (e.g., trimethylamine salts, triethylamine salts, monoethanolamine salts, triethanolamine salts, salts with tertiary amines such as pyridine salts, basic ammonium salts such as arginine, etc.). etc.), salts with inorganic bases (eg, alkali metal salts such as ammonium salts, sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts). Preferred salts are salts with inorganic bases, more preferred salts are alkali metal salts, and particularly preferred salts are sodium salts and potassium salts. Specific examples include dipotassium glycyrrhizinate, sodium chondroitin sulfate, sodium hyaluronate and the like.

In the present invention, acidic saccharides can be used singly or in combination of two or more. In the present invention, dipotassium glycyrrhizinate or mucopolysaccharide is particularly preferred, and dipotassium glycyrrhizinate or sodium chondroitin sulfate is more preferably used. In a particularly preferred embodiment, both dipotassium glycyrrhizinate and sodium chondroitin sulfate are used.

In the present specification, the acidic saccharide of component (A) may be synthesized by a known method or obtained as a commercial product.

In the ophthalmic preparation of the present invention, the total content of component (A) with respect to the total amount of the ophthalmic preparation is appropriately set according to the balance with other components. The total content of component (A) is preferably 0.001 w/v% or more, more preferably 0.005, relative to the total amount of the ophthalmic preparation.
w/v% or more, more preferably 0.01 w/v% or more, still more preferably 0.05
w/v % or more, particularly preferably 0.1 w/v % or more, more particularly preferably 0.25 w/v %
% or more, even more particularly preferably 0.5 w/v % or more, most preferably 0.7 w/v
% or more. When the ophthalmic formulation is an eye drop, it is preferably 0.01 w/v% or more, more preferably 0.05 w/v% or more, even more preferably 0.1 w/v% or more, and even more preferably 0 0.25 w/v % or more, particularly preferably 0.5 w/v % or more, most preferably 0.7 w/v % or more. When the ophthalmic formulation is an eyewash, preferably 0.5.
001 w/v% or more, more preferably 0.005 w/v% or more, still more preferably 0.01
w/v% or more, still more preferably 0.05 w/v% or more. The total content of component (A) is preferably 5 w/v% or less, more preferably
2 w/v % or less, more preferably 1 w/v % or less. When the ophthalmic formulation is an eye drop, it is preferably 5 w/v % or less, more preferably 2 w/v % or less, and more preferably 1 w/v % or less. When the ophthalmic preparation is an eyewash, the content is 0.5 w/v% or less, preferably 0.2 w/v% or less, and more preferably 0.1 w/v% or less. The total content of component (A) is preferably 0.001 w/v with respect to the total amount of the ophthalmic preparation
% to 5 w/v %, more preferably 0.005 w/v % to 2 w/v %, even more preferably 0.01 w/v % to 1 w/v %, even more preferably 0.1 w/v % ~1w/v%
is.

[(B) Cationic preservative]
Cationic preservatives for use in the present invention include, but are not limited to, quaternary ammonium compounds and salts thereof, and biguanide compounds and salts thereof. Such cationic preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, cetrimonium chloride, dophanium chloride, tetraethylammonium bromide, didecyldimethylammonium chloride, bromine Examples include quaternary ammonium compounds such as domiphene or salts thereof, biguanide compounds such as chlorhexidine hydrochloride, chlorhexidine gluconate, chlorhexidine acetate, polyhexanide hydrochloride, and alexidine, or salts thereof. Preferred are benzalkonium chloride, chlorhexidine gluconate and polyhexanide hydrochloride, more preferred are benzalkonium chloride and chlorhexidine gluconate, and still more preferred is benzalkonium chloride.

In the present invention, cationic preservatives can be used singly or in combination of two or more.

In this specification, the component (B) may be synthesized by a known method and available as a commercial product.

In the ophthalmic preparation of the present invention, the total content of component (B) with respect to the total amount of the ophthalmic preparation is appropriately set according to the balance with other components. The total content of component (B) is preferably 0.000001 w/v% or more, more preferably 0.000001 w/v% or more, based on the total amount of the ophthalmic preparation.
000005 w/v% or more, more preferably 0.00001 w/v% or more.
When component (B) is benzalkonium chloride, the total content of component (B) is preferably 0.0001 w/v% or more, more preferably 0.001 w/v% or more. , more preferably 0.005 w/v% or more, still more preferably 0.01 w/v% or more, and when component (B) is chlorhexidine and/or a salt thereof, component (B) The total content is preferably 0.0001 w/v% or more, more preferably 0.00
1 w/v% or more, more preferably 0.002 w/v% or more, still more preferably 0.005 w/v% or more, and when the component (B) is polyhexanide and its salt, The total content of component (B) is preferably 0.000001 w/v% or more, more preferably 0.000005 w/v% or more, still more preferably 0.00001 w/v%
v % or more, and more preferably 0.00005 w/v % or more. The total content of component (B) is preferably 0.1 w/v% or less, more preferably 0.05 w/v% or less, more preferably 0, based on the total amount of the ophthalmic preparation. .02 w/v% or less, more preferably 0.015 w/v% or less. When component (B) is benzalkonium chloride, it is preferably 0.1 w/v% or less, more preferably 0.05 w/v%.
below, more preferably 0.02 w/v% or less, still more preferably 0.015 w/v
%, and when the component (B) is chlorhexidine and/or a salt thereof, it is preferably 0.3 w/v % or less, more preferably 0.1 w/v % or less, still more preferably , 0.05 w/v% or less, particularly preferably 0.01 w/v% or less, particularly more preferably 0.005 w/v% or less, and when the component (B) is polyhexanide and its salt,
It is preferably 0.001 w/v% or less, more preferably 0.0005 w/v% or less, still more preferably 0.0001 w/v% or less. For the total amount of ophthalmic preparation,
The total content of component (B) is preferably 0.000001 w/v% to 0.1 w/v%, more preferably 0.000005 w/v% to 0.05 w/v%, still more preferably 0 .
00001 w/v % to 0.02 w/v %, most preferably 0.00005 w/v % to 0
. 015 w/v%.

In the ophthalmic preparation of the present invention, the ratio of the amount of component (B) to component (A) is (A
The total content of component (B) is preferably 0.000005 to 1 part by weight, more preferably 0.000025 to 0.5 part by weight, more preferably 0.00005 to 0 .
15 parts by weight is even more preferred.

[(C) Eucalyptus oil]
The eucalyptus oil used in the present invention is not limited, but eucalyptus oil that is commonly used as a drug or quasi-drug can be used. Here, in particular, eucalyptus oil listed in the Japanese Pharmacopoeia 16th Edition can be used. Here, the eucalyptus oil listed in the Japanese Pharmacopoeia 16th Edition is Eucalyptus Eucalyptus globulus Labillardi
An essential oil obtained by steam distillation of the leaves of ere or its related plants, containing 70.0% cineole
Contains more than

In the ophthalmic preparation of the present invention, the total content of component (C) with respect to the total amount of the ophthalmic preparation is appropriately set according to the balance with other components. The total content of component (C) is preferably 0.0001 w/v% or more, more preferably 0.00, relative to the total amount of the ophthalmic preparation.
05 w/v% or more, more preferably 0.001 w/v% or more, still more preferably
0.002 w/v% or more, particularly preferably 0.003 w/v% or more, more particularly preferably 0.004 w/v% or more, most preferably 0.005 w/v% or more. The total content of component (C) is preferably 0.1 w/v % or less, more preferably 0.05 w/v % or less, more preferably 0.05 w/v % or less, based on the total amount of the ophthalmic preparation. 01 w/v% or less. The total content of component (C) is preferably 0.0001 w based on the total amount of the ophthalmic preparation
/v % to 0.1 w/v %, more preferably 0.001 w/v % to 0.1 w/v %, even more preferably 0.002 w/v % to 0.05 w/v %, most preferably is 0.00
5 w/v% to 0.01 w/v%.

The presence of eucalyptus oil can also be converted into cineole content.
The content of cineol is preferably 0.5% with respect to the total amount of the ophthalmic preparation of the present invention.
00007 w/v% or more, more preferably 0.00035 w/v% or more, still more preferably 0.0007 w/v% or more, still more preferably 0.0014 w/v% or more, particularly preferably 0 .0021 w/v% or more, more preferably 0.0028 w
/v% or more, most preferably 0.0035w/v% or more. The content of cineol is preferably 0.07 w/v% or less, more preferably 0.035 w/v% or less, more preferably 0.007 w/v%, relative to the total amount of the ophthalmic preparation. It is below. The total content of the component (C) is preferably 0.0 as cineole with respect to the total amount of the ophthalmic preparation.
0007 w/v% to 0.07 w/v%, more preferably 0.0007 w/v% to 0.0
7 w/v %, even more preferably 0.0014 w/v % to 0.035 w/v %, most preferably 0.0035 w/v % to 0.007 w/v %.

In the ophthalmic preparation of the present invention, the ratio of the amount of component (C) to component (A) is (A
The total content of component (C) is preferably 0.0005 to 1 part by weight, more preferably 0.001 to 0.5 part by weight, more preferably 0.005 to 0 .1 part by weight is even more preferred.
For cineole, 0.0 cineole per 1 part by weight of the total content of component (A)
0035 to 0.7 parts by weight is preferred, 0.0007 to 0.35 parts by weight is more preferred, and 0
. 0035 to 0.07 parts by weight is even more preferred.

In the ophthalmic preparation of the present invention, due to the coexistence of components (A), (B), and (C), even immediately after production and when stored for a long period of time, preserved state is maintained. Here, the term "good storage condition" refers to, but is not limited to, having antibacterial activity immediately after production, and maintaining a certain degree of antibacterial activity even after storage for a certain period of time. Such antibacterial activity can be, for example, an antibacterial activity against Escherichia coli. Specifically, for example, according to the preservative efficacy test method specified in the Japanese Pharmacopoeia (16th revision),
Antiseptic properties (preservative efficacy) of ophthalmic formulations can be evaluated. By such a method, 1
After 4 days, the number of inoculated bacteria will be 0.1% or less, and after that, it can be kept to the extent that it does not grow until 28 days later. The present inventors have found that the coexistence of component (A) and component (B) tends to reduce the preservative efficacy of ophthalmic preparations containing component (B). ) component, it was found that the preservative efficacy was improved.

[Anti-allergic agent]
The ophthalmic preparation of the present invention may further contain an antiallergic agent in addition to components (A), (B) and (C). Antiallergic agents that can be incorporated into the ophthalmic preparation of the present invention include, but are not limited to, acitazanolast, amlexanox, ibudilast, tranilast, levocabastine hydrochloride, sodium cromoglycate, ketotifen fumarate,
pemirolast potassium, pemirolast, olopatadine hydrochloride and the like.

In the present invention, antiallergic agents can be used singly or in combination of two or more. In particular, at least one antiallergic agent selected from the group consisting of sodium cromoglycate, tranilast, acitazanolast, pemirolast potassium, olopatadine hydrochloride, and ketotifen fumarate is preferred, and tranilast, cromoglyc Sodium phosphate is more preferred, and sodium cromoglycate is particularly preferred.

In the present specification, the antiallergic agent can be synthesized by a known method or obtained as a commercial product.

In the ophthalmic preparation of the present invention, the total content of the antiallergic agent with respect to the total amount of the ophthalmic preparation is appropriately set according to the balance with other ingredients. The total content of the antiallergic agent is preferably 0.001 w/v% or more, more preferably 0, based on the total amount of the ophthalmic preparation.
. 01 w/v % or more, more preferably 0.1 w/v % or more. The total content of the antiallergic agent is preferably 5 w/v% or less, more preferably 2 w/v% or less, more preferably 1 w/v% or less, relative to the total amount of the ophthalmic preparation. . The total content of the antiallergic agent is preferably 0.001 w/v% to 5 w/v% with respect to the total amount of the ophthalmic preparation,
More preferably 0.01 w/v% to 2 w/v%, still more preferably 0.1 w/v% to
1 w/v %.

In the ophthalmic preparation of the present invention, the ratio of the amount of the antiallergic agent to the component (A) is
(A) The total content of the antiallergic agent is 0.005 to 10 per 1 part by weight of the total content of the component
0 parts by weight is preferred, 0.05 to 50 parts by weight is more preferred, and 0.1 to 10 parts by weight is even more preferred.

Even when an antiallergic agent is added, the preservative efficacy of the ophthalmic preparation of the present invention is maintained or improved with little decrease in preservative efficacy.

[Other ingredients]
The ophthalmic preparation of the present invention may further contain a buffering agent in addition to components (A), (B) and (C). The buffering agent that can be incorporated into the ophthalmic preparation of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. agents can be used. Examples of such buffers include borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, hydrochloric acid, sodium hydroxide and the like. These buffering agents may be used in combination. Borate buffers, phosphate buffers, carbonate buffers, citrate buffers, and acetate buffers are preferred as buffers.

Examples of the borate buffer include boric acid and borates such as alkali metal borates and alkaline earth metal borates. Phosphate buffers include phosphoric acid and phosphates such as alkali metal phosphates and alkaline earth metal phosphates. Carbonic acid buffering agents include carbonic acid,
Alternatively, carbonates such as alkali metal carbonates and alkaline earth metal carbonates can be used. Citric acid buffers include citric acid, alkali metal citrate salts, alkaline earth metal citrate salts, and the like. Hydrates of each salt may also be used as the buffering agent. More specific examples include boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.) as a borate buffer; Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or its salts (sodium hydrogen carbonate, sodium carbonate,
ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citric acid or its salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, citric acid buffer); Disodium acetate, etc.); acetic acid or salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) can be exemplified as acetate buffers. These buffering agents may be used singly or in any combination of two or more.

When a buffering agent is added to the ophthalmic preparation of the present invention, the blending ratio of the buffering agent is appropriately set according to the balance with other ingredients. The total content of the buffering agent is not limited to the total amount of the ophthalmic preparation, but is preferably 0.01 w/v% or more, more preferably 0.01 w/v% or more.
05 w/v% or more, more preferably 0.1 w/v% or more, preferably 10 w/v%
v % or less, more preferably 5 w/v % or less, and still more preferably 3 w/v % or less.

In the ophthalmic preparation of the present invention, the ratio of the buffering agent to component (A) is such that the total content of buffering agent is 0.01 to 100 parts by weight per 1 part by weight of component (A). parts are preferred, 0.05 to 10 parts by weight are more preferred, 0.05 to 5 parts by weight are even more preferred, and 0
. 1 to 2 parts by weight is particularly preferred.

The ophthalmic preparation of the present invention may contain a surfactant in addition to components (A), (B) and (C). Surfactants that can be incorporated into the ophthalmic preparation of the present invention are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable, nonionic surfactants, amphoteric surfactants, It may be either a surfactant or an anionic surfactant.

Specific examples of nonionic surfactants that can be incorporated in the ophthalmic preparation of the present invention include polyoxyethylene (hereinafter also referred to as POE) and polyoxypropylene (hereinafter also referred to as POP).
) glycols (e.g. Poloxamer 407, Poloxamer 235, Poloxamer 18
8, Poloxamers such as POP (200) POE (70) glycol); POE-POP block copolymer adducts of ethylene diamines such as poloxamine; monolauric acid P
OE (20) sorbitan (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), POE sorbitan monostearate (polysorbate 60)
, POE sorbitan fatty acid esters such as POE sorbitan tristearate (polysorbate 65); POE hydrogenated castor oil 5, POE hydrogenated castor oil 10, POE hydrogenated castor oil 20, POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60
, POE hydrogenated castor oil 100; POE castor oils such as POE castor oil 3, POE castor oil 10, POE castor oil 35; POE alkyl ethers such as POE (9) lauryl ether; POE ( 20) POP (4) POE POP alkyl ethers such as cetyl ether; POE (10) PO such as nonylphenyl ether
E alkylphenyl ethers; polyethylene glycol monostearate such as polyoxyl 40 stearate; The numbers in parentheses indicate the number of added moles.

Examples of amphoteric surfactants include glycine-type surfactants such as alkyldiaminoethylglycine, betaine-acetate-type surfactants such as betaine lauryldimethylaminoacetate, and imidazoline-type surfactants.

As an anionic surfactant, PO such as POE(10) sodium lauryl ether phosphate
E Alkyl ether phosphoric acid and its salts, N-acyl amino acid salts such as sodium lauroyl methyl alanine, alkyl ether carboxylates, N-acyl taurate salts such as sodium N-cocoyl methyl taurate, sulfonic acids such as sodium tetradecene sulfonate salts, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefin sulfonates, and the like.

These surfactants may be used singly or in combination of two or more in the ophthalmic formulation of the present invention.

Among these surfactants, nonionic surfactants are preferred. Suitable examples of nonionic surfactants include at least one selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, poloxamers, and polyethylene glycol monostearate. A nonionic surfactant, more preferably poloxamer 407, poloxamer 188, polyoxyethylene castor oil 10, polyoxyethylene castor oil 35, polysorbate 80, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated Castor oil 60 and polyoxyl stearate 40 are preferred, and polysorbate 80 and polyoxyethylene hydrogenated castor oil 60 are particularly preferred.

When a surfactant is blended in the ophthalmic preparation of the present invention, the blending ratio of the surfactant is as follows:
It can be appropriately set according to the type of surfactant, the type and amount of other components, the application of the ophthalmic preparation, and the like.
As an example of the blending ratio of surfactants, the total amount of surfactants is preferably 0.001 w/v% or more, more preferably 0.005 w/v% or more, and still more preferably 0 with respect to the total amount of the ophthalmic preparation. .01 w/v% or more, preferably 5 w/v% or less, more preferably 3 w
/v% or less, more preferably 1w/v% or less.

In the ophthalmic preparation of the present invention, the ratio of the amount of the surfactant to the component (A) is (A
) with respect to 1 part by weight of the total content of the components, the total content of the surfactant is preferably 0.001 to 100 parts by weight, more preferably 0.005 to 50 parts by weight, and 0.01 to 10 parts by weight More preferably, 0.05 to 1 part by weight is particularly preferred.

The pH of the ophthalmic preparation of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. .0~
9.5, preferably 5.0 to 9.0, more preferably 6.0 to 8.5, still more preferably 6.0 to 8.0, particularly preferably 6.5 to 8.0, even more particularly A range of 6.5 to 7.5 is preferred. In the present invention, even in the neutral region, the preservative efficacy is maintained, which is highly useful.

The ophthalmic formulation of the present invention can be further adjusted to have an osmotic pressure ratio within a range acceptable to the body, if necessary. The appropriate osmotic pressure ratio varies depending on the application site, dosage form, etc., but is usually 0.5 to 5
. 0, more preferably 0.6 to 3.0, more preferably 0.7 to 2.0. Osmotic pressure can be adjusted using inorganic salts, polyhydric alcohols, etc. by methods known in the art. The osmotic pressure ratio is 286 mOsm (0.9 w
/v% sodium chloride aqueous solution), and the osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the Japanese Pharmacopoeia. In addition, the standard solution for osmotic pressure ratio measurement (
0.9 w/v% sodium chloride aqueous solution) is 50% sodium chloride (Japanese Pharmacopoeia standard reagent).
After drying at 0-650°C for 40-50 minutes, allow to cool in a desiccator (silica gel). Accurately weigh 0.900 g and dissolve in purified water to make exactly 100 mL. A standard solution (0.9 w/v % sodium chloride aqueous solution) is used.

The viscosity of the ophthalmic preparation of the present invention is within a physiologically or pharmaceutically acceptable range, depending on the type and content of ingredients, the application, formulation form, method of use, etc. of the ophthalmic preparation. set. Rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor; 1 ° 34' × R24
) is preferably 0.01 to 10000 mPa s, more preferably 0.05 to 8000 mPa s, and 0.5 to 1000 mPa
· s, more preferably 1 to 500 mPa·s, particularly preferably 1 to 100 mPa·s, and most preferably 1 to 15 mPa·s.

The ophthalmic preparation of the present invention may contain, in addition to the above ingredients, various pharmacologically active ingredients and physiologically active ingredients in appropriate amounts in combination as long as the effects of the present invention are not impaired. Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various drugs described in the Standards for Approval of Manufacturing and Marketing of OTC Drugs 2012 Edition (supervised by the Japanese Society of Regulatory Science). Specifically, the following components are mentioned.

Decongestants: tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride and the like.
Antihistamines: diphenhydramine hydrochloride, chlorpheniramine maleate and the like.
Vitamins: flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate and the like.
Amino acids: potassium aspartate, magnesium aspartate, magnesium/potassium aspartate (equal mixture), aminoethylsulfonic acid, and the like.
Antiphlogistic agents: epsilon-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, lysozyme chloride, sodium azulene sulfonate, indomethacin, pranoprofen, ibuprofen, etc.
Astringents: zinc white, zinc lactate, zinc sulfate, etc. Others: sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, neostigmine methylsulfate and the like.

Furthermore, in the ophthalmic preparation of the present invention, carriers, thickeners, general sugar alcohols and sugars, general tonicity agents, pH adjusters, stabilizers, chelating agents, oils, and the like are added. Agents may be selected and at least one of them may be used in combination and contained in an appropriate amount. As those additives, for example,
Various additives described in Pharmaceutical Excipients Encyclopedia 2007 (edited by Japan Pharmaceutical Excipients Association) can be exemplified. Typical ingredients include the following additives.

Carrier: Aqueous carriers such as water and hydrous ethanol.
Thickener: Vinyl thickener such as polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, gellan gum, alginic acid and the like.
Sugar alcohols: xylitol, sorbitol, mannitol and the like. These are d-body, l
Either the isomer or the dl isomer may be used.
Sugars: such as glucose.
Tonicity agent: sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride and the like.
pH adjusters: hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, etc.
Stabilizers: dibutylhydroxytoluene, butylhydroxyanisole, sodium formaldehyde sulfoxylate (Rongalite), tocopherol, sodium pyrosulfite, aluminum monostearate, glyceryl monostearate, cyclodextrin and the like.
Chelating agents: ascorbic acid, tetrasodium edetate, sodium edetate, and the like.
Oils: vegetable oils such as sesame oil, castor oil, soybean oil and olive oil, animal oils such as squalane,
Mineral oils such as liquid paraffin and vaseline.

The ophthalmic formulation of the present invention can also contain a cellulose-based thickening agent. Cellulose-based thickeners include cellulose-based polymer compounds such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), carboxymethyl cellulose and its salts, carboxyethyl cellulose and its salts. are exemplified. On the other hand, as one aspect of the ophthalmic preparation of the present invention, the content of the cellulose-based thickener is 0.2 w/
It can also be an ophthalmic preparation with v% or less. Alternatively, in yet another aspect, the ophthalmic formulation may be free of cellulosic thickeners. When the content of the cellulose-based thickener is low, or when the cellulose-based thickener is not contained, the effects of the present invention can be remarkably exhibited, which is preferable.

The ophthalmic preparation of the present invention may further contain preservatives other than cationic preservatives. Preservatives other than cationic preservatives include sodium benzoate, ethanol, zinc chloride, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, and parahydroxybenzoic acid. Propyl, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol,
Benzyl alcohol and the like are exemplified. On the other hand, as one aspect of the ophthalmic preparation of the present invention, an ophthalmic preparation containing 0.004 w/v% or less of preservatives other than such cationic preservatives can also be used. Alternatively, in another aspect, the ophthalmic preparation may have a zinc chloride or potassium sorbate content of 0.0009 w/v% or less. In yet another aspect, the ophthalmic formulation may be free of zinc chloride or potassium sorbate. Such ophthalmic preparations are particularly less burdensome to the eyes and are therefore preferred.

It is also preferred to include a terpenoid in the ophthalmic formulation of the present invention. A terpenoid is a known compound that has a structure with an isoprene unit as a structural unit and is widely used as a cooling agent. Terpenoids are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specific examples of terpenoids include menthol, menthone, camphor, borneol, geraniol, citronellol, carvone, anethole,
Eugenol, limonene, linalool, linalyl acetate, thymol, camphene, isoborneol, fenchene, nerol, myrcene, myrcenol, linalool acetate, lavandulol, and at least one selected from the group consisting of derivatives thereof. The terpenoid content can usually be 0.0001 to 0.1 w/v%. On the other hand, as one aspect of the ophthalmic preparation of the present invention, the content of menthol is 0.004 w/v
% or less ophthalmic formulation. Alternatively, in yet another aspect, the ophthalmic formulation may be menthol-free. Menthol-free formulations are particularly preferred if specific irritation is to be avoided.

In the present specification, the "physiologically or pharmaceutically acceptable salt" in components other than component (A) includes, for example, alkali metal salts, alkaline earth metal salts, salts with organic bases, and the like. , sodium, potassium, calcium, magnesium, ammonium, or salts with diethanolamine, ethylenediamine, and the like. These salts can be obtained, for example, by converting the sulfate group or carboxyl group present in the substance into a salt by a known method. Furthermore, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-
amine salts such as methylglucamine and L-glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine and arginine. Also, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; Salts with organic acids such as malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid; or aspartic acid, glutamic acid Also included are salts with acidic amino acids such as

"Physiologically or pharmaceutically acceptable salts" as used in the present invention may include solvates or hydrates of salts.

The ophthalmic preparation of the present invention is prepared by adding desired amounts of the above components (A), (B), and (C) and, if necessary, other ingredients to achieve desired concentrations. be done.
The ophthalmic formulation of the present invention is preferably a liquid formulation. The ophthalmic preparation of the present invention can be used as a preparation for pharmaceuticals, quasi-drugs, and the like.

The ophthalmic preparations referred to in the present invention include, for example, eye drops (including eye drops that can be used while wearing contact lenses), or artificial tears (artificial tears that can be used while wearing contact lenses). liquid), eye washes (also referred to as eye washes or eye washes. Eye washes include eye washes that can be washed while wearing contact lenses.), contact lens compositions [contact lens wetting solutions, contact lenses care compositions (contact lens disinfectants, contact lens preservatives, contact lens cleaners, contact lens cleaning preservatives), etc.]. The term "contact lens" includes hard contact lenses and soft contact lenses (both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).

Among the above uses of ophthalmic preparations, multi-dose ophthalmic preparations may pose a significant problem in terms of whether or not the preservative efficacy of the composition as the content of the ophthalmic preparations changes, compared to other uses. Multi-dose ophthalmic formulations require frequent opening and closing of lids during use, and maintenance of preservative efficacy is especially desired. that is preferably a sterile formulation at least at the beginning of use,
More preferably, it is desired to maintain a sterile preparation or a near-sterile state even after use.

INDUSTRIAL APPLICABILITY The present invention allows for pharmaceutically very stable ophthalmic formulations particularly suitable for multi-dose ophthalmic formulations.
Since the ophthalmic preparation according to the present embodiment can exhibit the effects of the present invention more remarkably,
Eye drops (including eye drops that can be dropped while wearing contact lenses) or eye washes (eye drops that can be washed while wearing contact lenses) are preferred. When the ophthalmic preparation according to the present embodiment is an eye drop, its usage and dosage are not particularly limited as long as they are effective and cause few side effects. For children above, 1 to 2 drops at a time, 4 times a day, 1 to 2 drops at a time, 2 to 3 drops
Drops, or 1 to 3 drops, 5 to 6 times a day, can be exemplified.

The ophthalmic preparation of the present invention is preferably used as an anti-allergic ophthalmic preparation having a therapeutic or preventive effect on allergic diseases. Furthermore, the ophthalmic preparation of the present invention can be used to treat redness of the eyes, itchy eyes, blurred vision, watery eyes, etc. caused by pollen, house dust (indoor dust), etc.
It is effective in relieving allergic symptoms such as foreign body sensation.

[Production method]
The method for producing the ophthalmic preparation of the present invention is not particularly limited. For example, eucalyptus oil can be preliminarily stirred with a nonionic surfactant or the like, and then mixed with other components and purified water.

[Preservative containing eucalyptus oil]
The present invention also relates to a preservative for compositions in which acidic sugars and cationic preservatives coexist, the preservative containing eucalyptus oil. At this time, acidic sugars, types of cationic preservatives,
The concentration and the concentration of eucalyptus oil, as well as the respective component ratios, are the same as those described for the multi-dose ophthalmic formulation.

[Method for enhancing preservative efficacy]
The present invention also relates to a method for enhancing the preservative efficacy of a composition by allowing eucalyptus oil to coexist with a composition containing an acidic saccharide and a cationic preservative. At this time, the types and concentrations of acidic saccharides and cationic preservatives, the concentration of eucalyptus oil, and the ratio of each component are the same as those described for the multi-dose ophthalmic preparation.

The ophthalmic preparation of the present invention is provided in any container. The container for containing the ophthalmic preparation of the present invention is not particularly limited, and may be made of glass or resin, for example. The container containing the ophthalmic preparation of the present invention may be a resin container reinforced with a reinforcing agent such as glass fiber.

Specifically, in the ophthalmic preparation of the present invention, at least part of the container is made of polyethylene terephthalate (PET), polyethylene naphthalate (PEN), or polypropylene (PP).
made of polyarylate (PAR), polybutylene terephthalate (PBT), polycarbonate (PC), and polyethylene (PE). PET, PEN, PP, PAR, PBT, PC,
Made of PE, more preferably made of PET, PBT, PP, or PE, more preferably made of PET, PP, or PE, particularly preferably made of PET or PP, most preferably of the present invention It is made of PET from the viewpoint of remarkably exhibiting the effect of. That is, the use of a PET container is particularly preferable from the viewpoint of suppressing the adsorption of eucalyptus oil to the container and thus achieving the effects of the present invention.

As used herein, a container means a container (primary container) that directly contains an ophthalmic preparation. The container may also have a lid and a spout attached to the container body. The above material mainly means the material of the container main body.

When the container containing the ophthalmic preparation according to the present embodiment is made of resin, the container may be molded from only a single resin, or may be molded from a combination of multiple synthetic resins.

When the container containing the ophthalmic preparation according to this embodiment is a synthetic resin container, the total weight of PET, PEN, PP, PAR, PBT, PC and PE with respect to the weight of the entire constituent materials of the container is not particularly limited. Preferably, PET, PEN, P
P, PAR, PBT, PC and PE may be contained, and among them, the total weight is preferably 10 w/v% or more, more preferably 30 w/v% or more, and still more preferably 50 w/v% or more. , more preferably 65 w/v % or more, and particularly preferably 80 w/v % or more.

The container for containing the ophthalmic preparation of the present invention is not particularly limited as long as it is a usual container for multi-dose ophthalmic preparations. The container containing the ophthalmic preparation of the present invention may be a transparent container that allows the inside of the container to be visually recognized, or an opaque container that makes it difficult to visually confirm the inside of the container. A transparent container is preferred. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container.

In the present invention, the shape of the container and the capacity that can be accommodated therein are not particularly limited. The container of the present invention has an internal volume of preferably 1 mL or more and 100 mL or less, more preferably 2 mL or more and 50 mL or more.
It may be a container that can hold mL or less, more preferably 5 mL or more and 20 mL or less. In the multi-dose ophthalmic preparation of the present invention, the liquid volume in the container is 1 mL or more and 100 mL
It is preferably less than, more preferably 2 mL or more and 50 mL or less, and 5 mL
L or more and 20 mL or less is most preferable.

These capacities are
the most appropriate capacity.

EXAMPLES Next, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.
The unit of each component amount in the table is w/v%.

Test Example 1: Preservative efficacy test immediately after preparation An ophthalmic preparation having the composition shown in Table 1 was prepared according to a conventional method. After filtering this composition with a 0.2 μm membrane filter, it was filled in a sterilized eyedrop bottle to prepare each eyedrop (Reference Test Example 1, Comparative Examples 1 and 2, Example 1). The drug substance used was a product conforming to the Japanese Pharmacopoeia 16th Edition or a product conforming to the Japanese Pharmacopoeia Non-Pharmaceutical Standards. Here, the eucalyptus oil is a product conforming to the Japanese Pharmacopoeia 16th Edition. Immediately after preparation, the antiseptic properties (preservative efficacy) of the eye drops were evaluated according to the preservative efficacy test method specified in the Japanese Pharmacopoeia (16th revision).

Specifically, Escherichia coli (ATCC8739 strain) was inoculated onto the surface of a soybean-casein-digest agar medium and cultured at 33° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop, suspended in an appropriate amount of sterilized physiological saline, and
A bacterial suspension containing 10 ⁷ CFU/mL viable bacteria was prepared. This bacterial suspension was added to each eye drop shown in Table 1 so as to give about 1×10 ⁵ CFU/mL, and then allowed to stand at 25° C. for 7 days. After that, the bacteria are collected according to the membrane filter method, and the number of viable bacteria per 1 mL of the sample prepared after standing at 33 ° C. for 2 days on the surface of the soybean-casein-digest agar medium is measured. Based on this, the Log reduction was calculated.

Test Example 2: Preservative efficacy test of products stored at 60 ° C. An ophthalmic preparation was prepared according to the formulation shown in Table 1 below, filtered through a 0.2 μm membrane filter, and then sterilized plastic eye drop containers (container body: PET, Nozzle: PE, capacity 13 mL) of each ophthalmic preparation (Reference Test Example 1, Comparative Examples 1 and 2, Example 1), 60
It was stored in a thermostat at °C for 3 weeks. After that, according to the preservative efficacy test method specified in the Japanese Pharmacopoeia (16th revision), the above test example 1. The preservative efficacy was evaluated according to the same procedure as the preservative efficacy test immediately after preparation.

The evaluation results of Test Examples 1 and 2 are shown in Table 1 and FIG. Here, the reduction in the number of viable bacteria, that is, the greater the log reduction, the higher the preservation efficacy.

From these results, (b) the preservative efficacy of ophthalmic formulations containing benzalkonium chloride is
When (a) dipotassium glycyrrhizinate and sodium chondroitin sulfate are blended, it tends to decrease, but it can be seen that high preservative efficacy can be obtained by further blending (c) eucalyptus oil. Moreover, this tendency was more remarkably confirmed in the ophthalmic preparation after storage at 60°C for 3 weeks.

Here, the concentrated benzalkonium chloride solution 50 is a product compliant with the Japanese Pharmacopoeia 16th Edition, and in Reference Comparative Examples, Comparative Examples, and Examples, 0.01 to 0.011 w/v% in the formulation concentration range.

Test Example 3: Preservative efficacy test immediately after preparation An ophthalmic preparation (eye drops) having the composition shown in Table 2 was prepared according to a conventional method.
The eucalyptus oil used had a cineole content of 79.8%.
The viable cell count per 1 mL of the sample was measured in the same manner as in Test Example 1, and the log reduction was calculated. After that, from the calculated Log reduction of each formulation, the rate of improvement in preservation efficacy of Example 2 relative to Comparative Example 3 was calculated using the following formula.

(Formula 1)
Improvement rate (%) of preservation efficacy with respect to Comparative Example 3 = {(Log reduction of Example 2 - Comparative Example 3
of Log reduction) / Log reduction of Comparative Example 3} × 100

Table 2 shows the evaluation results of Test Example 3.
From these results, (b) the preservative efficacy of the ophthalmic preparation containing chlorhexidine gluconate instead of benzalkonium chloride was also confirmed by adding (a) dipotassium glycyrrhizinate and sodium chondroitin sulfate as in Test Example 1. Although it tended to decrease,
(c) It can be seen that by further blending eucalyptus oil, high preservative efficacy can be obtained.

[Formulation example]
Eye drops (Formulation Examples 1 to 16) were prepared according to the formulations shown in Tables 3 and 4 below, and contained in the multi-dose containers described below.
The unit of each component amount in Tables 3 and 4 below is w/v %.

The container containing Formulation Examples 1 to 16 is made of polyethylene terephthalate (PET) and is fitted with a nozzle made of polyethylene (PE).

Similarly, formulations having exactly the same composition as Formulation Examples 1 to 16 were placed in polyethylene terephthalate (PET) containers, and polybutylene terephthalate (PBT) nozzles were attached (Formulation Examples 1' to 16'). ).

Claims (1)

The invention described in the specification.

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