JP7320638B2 - A method for alleviating eye irritation caused by an ophthalmic composition, a method for sustaining the fragrance of menthol in an ophthalmic composition, and a method for inhibiting deterioration of a soft contact lens by an ophthalmic composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for reducing eye irritation caused by an ophthalmic composition, a method for maintaining the fragrance of menthol in the ophthalmic composition, and a method for inhibiting deterioration of soft contact lenses caused by the ophthalmic composition.

The cornea is a tissue that constitutes the outermost surface of the eyeball. Corneal perception is considered one of the most sensitive perceptions of pain in the human body. Therefore, the cornea sensitively perceives the effects of external factors such as dryness or bacterial infection, and internal factors such as changes in the composition of tears, whether consciously or unconsciously. In addition, ingredients contained in ophthalmic compositions used for treating or improving various eye symptoms may also irritate the eyes as one of the external factors. Therefore, an ophthalmic composition is required that not only improves each symptom but also does not give pain or burden to the user. An ophthalmic composition containing dextran, menthol and a surfactant has been found as a countermeasure against irritation caused by polysorbate 80 or cooling agents (Patent Document 1). However, no effect of specific properties of polysorbate 80 has been reported so far.

JP 2009-046480 A

It has been known that polysorbate 80 or cooling ingredients (such as cooling agents) may have various effects such as irritation on the eyes. In other words, controlling the effects on the surface of the eyeball is important from the viewpoint of removing indefinite complaints and improving the quality of life.
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an ophthalmic composition capable of alleviating eye irritation.

The present inventors have made intensive studies to solve the above problems, and found that when polysorbate 80, which has a relatively high polydispersity in the ophthalmic composition, coexists with a cooling agent, the adsorption speed to phospholipids is suppressed. It was newly confirmed that That is, an ophthalmic composition containing (A) polysorbate 80 (hereinafter sometimes referred to as "component (A)") and (B) a cooling agent (hereinafter sometimes referred to as "component (B)"). It has been found that an ophthalmic composition in which the component (A) in the ophthalmic composition has a polydispersity of 1.27 to 1.63 suppresses the rate of adsorption to phospholipids. The present inventors are the first to pay attention to the polydispersity of polysorbate 80 in an ophthalmic composition with regard to the effect on the rate of adsorption to phospholipids. As a result of further studies, the present inventors have found that the ophthalmic composition having the above-described configuration can maintain the fragrance in the ophthalmic composition and suppress deterioration of contact lenses. Based on these findings, the present inventors have completed the present invention.

That is, the present invention provides ophthalmic compositions of the following aspects. Although details such as the control mechanism of the adsorption rate to phospholipids by setting the polydispersity of polysorbate 80 to the following range have not been clarified, the micelle structure of polysorbate 80 and the cooling agent depends on the difference in polydispersity. may be slightly different, affecting affinity with phospholipids. The affinity of phospholipids influences the adsorptivity of components in the composition to cells, and may also be involved in stimulation.

That is, the present invention provides the following [1] to [10].
[1] Polysorbate 80;
a cooling agent;
An ophthalmic composition containing
An ophthalmic composition, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity (M _z /M _w ) of 1.27 to 1.63.
[2] The above [1], further comprising at least one selected from the group consisting of polyvinyl alcohol, glycerin, panthenol, sulfamethoxazole and its salts, calcium chloride, magnesium sulfate, sodium bicarbonate, and mannitol. ] The ophthalmic composition according to .
[3] The above [1] or [2], wherein the total content of the cooling agent is 0.0001 to 100 parts by mass with respect to 1 part by mass of the polysorbate 80 contained in the ophthalmic composition. ] The ophthalmic composition according to .
[4] The ophthalmic composition according to any one of [1] to [3] above, which has a pH of 4.0 to 9.5.
[5] An agent for suppressing the rate of adsorption to ocular cells, containing polysorbate 80 and a cooling agent,
An adsorption rate inhibitor to ocular cells, wherein the polysorbate 80 in the adsorption rate inhibitor has a polydispersity (M _z /M _w ) of 1.27 to 1.63.
[6] A fragrance persistence agent for an ophthalmic composition containing polysorbate 80 and a cooling agent, wherein the polydispersity (M _z /M _w ) of the polysorbate 80 in the fragrance persistence agent is 1.27-1.63, fragrant lasting agent.
[7] A soft contact lens deterioration inhibitor containing polysorbate 80 and a cooling agent, wherein the polydispersity of the polysorbate 80 in the soft contact lens deterioration inhibitor is from 1.27 to 1.27. 63, a deterioration inhibitor for soft contact lenses.
[8] A method for imparting a phospholipid adsorption rate inhibitory action to the ophthalmic composition, comprising blending polysorbate 80 and a cooling agent in the ophthalmic composition,
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity (M _z /M _w ) of 1.27 to 1.63.
[9] A method for imparting an effect of sustaining the fragrance of the cooling agent to the ophthalmic composition, comprising blending polysorbate 80 and a cooling agent in the ophthalmic composition,
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity (M _z /M _w ) of 1.27 to 1.63.
[10] A method for imparting an effect of suppressing deterioration of a soft contact lens to the ophthalmic composition, comprising blending polysorbate 80 and a cooling agent in the ophthalmic composition,
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity (M _z /M _w ) of 1.27 to 1.63.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide an ophthalmic composition capable of alleviating eye irritation.
Moreover, according to the present invention, it becomes possible to provide an ophthalmic composition capable of controlling the rate of adsorption to phospholipids. Specifically, it is possible to provide an ophthalmic composition that suppresses the rate of adsorption of polysorbate 80 or a cooling agent to phospholipids and alleviates irritation or toxicity to eye cells.

Preferred embodiments of the present invention are described in detail below. However, the present invention is not limited to the following embodiments. As used herein, the content unit "%" means "w/v %" and is synonymous with "g/100 mL".

As used herein, eye irritation includes not only eye disorders, but also subjective eye symptoms caused by dry eyes, use of contact lenses, or allergic conjunctivitis, as well as subconscious eye symptoms. Therefore, the present inventors focused on controlling the rate of adsorption to ocular cells and improving the subjective symptoms themselves in order to alleviate eye irritation or discomfort. In particular, suppressing the adsorption speed of component (A) or component (B) exhibits the effect of suppressing damage to ocular cells or discomfort.

The ophthalmic composition according to the present embodiment (hereinafter sometimes simply referred to as "ophthalmic composition") contains (A) polysorbate 80 and (B) a cooling agent, and The polydispersity of polysorbate 80 is between 1.27 and 1.63.

(ophthalmic composition)
(A) Component Polysorbate 80 according to the present embodiment (hereinafter sometimes simply referred to as "polysorbate 80") is not particularly limited as long as it has a polydispersity of 1.27 to 1.63. Polysorbate 80 can be obtained by measuring polysorbate 80 obtained as a commercial product by the measurement method described later and selecting polysorbate 80 having a polydispersity of 1.27 to 1.63.

Alternatively, polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained by further fractionating or purifying polysorbate 80 obtained as a commercial product by a known method. The method for fractionating or purifying polysorbate 80 is not particularly limited, but purification treatment using ion exchange resin, activated carbon or adsorbent, steam deodorization treatment, decolorization treatment, dehydration and solvent removal, filter filtration, cake filtration, centrifugation, sedimentation A method such as removal or a combination of two or more of these methods can be used. These fractionation or purification methods can be performed if necessary to eliminate adverse effects on polydispersity measurement errors and the like. Other methods for fractionating polysorbate 80 include, for example, a membrane filtration method, a method by distillation, an extraction method or washing method using an organic solvent, a reprecipitation method, a liquid/liquid separation method, or two or more of these methods. A combined method is included. Specific examples include the following membrane filtration method. The molecular weight and polydispersity of polysorbate 80 obtained as a commercial product are measured by the size exclusion chromatography (SEC) method described below, and an appropriate ultrafiltration membrane that achieves a rejection close to 90% and a permeation flux is selected. . A commercially available filter membrane can be used (for example, UF disk PLBC Ultracell RC 3K NMWL (molecular weight cutoff 3 KDa, cellulose membrane) (manufactured by Millipore)). A pressure of 0.5 to 200 Pa is applied according to the limit pressure of the filtration membrane. Polysorbate 80 is available with a polydispersity of 1.27 to 1.63 fractionated based on weight average molecular weight and Z average molecular weight.
Other purification methods for polysorbate 80 include, for example, crystallization, resin chromatography, a method of drying the reaction solution as it is with a spray dryer and pulverizing it, a method of removing by steam distillation, and a method of using an organic solvent and water. A liquid-liquid extraction method and the like can be mentioned. Specific examples of the purification method include the following methods. First, polysorbate 80 is dissolved in methanol and the molecular weight at the critical micelle concentration is measured by a light scattering method to determine the cutoff molecular weight of the ultrafiltration membrane. Next, membrane filtration is performed at a flow rate of 0.5-10 ml/min and a pressure of 0.1-20 bar.

Alternatively, the method for producing polysorbate 80 is not particularly limited, but polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained by the following method. It is produced by adding ethylene oxide to a mixture obtained by partially esterifying sorbitol and/or sorbitol anhydride with a fatty acid consisting mainly of oleic acid. The ester reaction can be carried out between sorbitan and a fatty acid in the presence of a basic catalyst under an inert gas stream under normal pressure or reduced pressure at a temperature of generally 150 to 280°C. After the reaction, neutralization is accomplished by adding a small amount of acid sufficient to deactivate the basic catalyst. Sorbitol as a raw material can be obtained by subjecting glucose to high-pressure hydrogen reduction, and commercially available products may be used (for example, Sorbitol D-70 (manufactured by Towa Kasei Kogyo Co., Ltd.), Sorbitol S (Japan manufactured by Ken Kagaku Co., Ltd.). Sorbitan can be obtained by cyclodehydration of sorbitol, and commercially available products may be used (for example, products manufactured by Toei Chemical Co., Ltd., etc.). Alternatively, commercially available sorbitan oleate can also be used. The step of adding ethylene oxide to the sorbitan fatty acid ester uses catalysts such as alkali metal catalysts and fatty acid soaps. The polysorbate 80 produced can be filtered. The basic catalyst in the ester reaction includes alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydrogen carbonates, alkali metals, Alkaline compounds such as alkaline earth metals, alkaline earth metal oxides, alkaline earth metal hydroxides, other metals, oxides thereof, and mixtures thereof, and phosphorous acid (salt) and/or hypochlorite Combination with phosphoric acid (salt). Also, the inert gas used can be, for example, nitrogen or argon. Examples of the metal catalyst for adding ethylene oxide to the product after esterification include potassium hydroxide, sodium hydroxide, sodium methylate, and the like. Polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained by further fractionating or purifying the polysorbate 80 thus obtained by a known method.

Furthermore, polysorbate 80 with a polydispersity of 1.27 to 1.63 can be prepared by mixing two or more polysorbates 80 with different polydispersities.

The ophthalmic composition according to the present embodiment includes polysorbate 80 obtained as a commercial product having a polydispersity of 1.27 to 1.63, and a polydispersity of 1.0 obtained by purifying the commercial product by the above purification method. Polysorbate 80 having a polydispersity of 27 to 1.63, or polysorbate 80 having a polydispersity of 1.27 to 1.63 produced by the above production method, and a cooling agent. good too. It may also be produced by a method comprising combining two or more types of polysorbate 80 obtained by different methods and a cooling agent. By producing by such a method, polysorbate 80 in the ophthalmic composition can have a polydispersity of 1.27 to 1.63.

The polydispersity of polysorbate 80 is 1.27-1.63, preferably 1.29-1.63, more preferably 1.34-1.63, 1.27-1. 0.50 is even more preferred, and 1.29 to 1.50 is even more preferred. By setting the polydispersity to such a range, the effects of the present invention, such as control of the adsorption speed to ocular cells or alleviation of eye discomfort, can be exhibited more remarkably.

Although the weight average molecular weight of polysorbate 80 is not particularly limited, it is preferably in the range of 1200-3200, more preferably in the range of 1300-3000. Although the Z-average molecular weight of polysorbate 80 is not particularly limited, it is preferably in the range of 1,300 to 3,500, more preferably in the range of 1,400 to 3,300.
By setting the weight-average molecular weight and Z-average molecular weight of polysorbate 80 within the ranges described above, the effects of the present invention, such as controlling the rate of adsorption to ocular cells and alleviating eye discomfort, can be exhibited more remarkably.
The weight average molecular weight, Z average molecular weight and polydispersity are measured and calculated as described below.

The polydispersity of polysorbate 80 is defined as _Mz / _Mw . _Mz indicates the Z-average molecular weight and _Mw indicates the weight-average molecular weight.

Various molecular weight measurement methods are known, such as liquid chromatography, ultracentrifugation, light scattering, and intrinsic viscosity. Depending on the measurement method, the type of average molecular weight obtained, such as weight average molecular weight and Z-average molecular weight, or the measurable molecular weight range differs. Weight-average molecular weight, Z-average molecular weight and polydispersity as defined in the present invention are determined by size exclusion chromatography (SEC) method. The SEC method can measure weight-average molecular weight, Z-average molecular weight and polydispersity, and is easy to operate.

The SEC method uses a column filled with a gel having pores, and has a mechanism of separating by different elution times caused by differences in migration distance in the column depending on the molecular size in the sample solution. Average molecular weights such as _Mz and _Mw are calculated based on a calibration curve prepared from standard substances with known molecular weights. Thus, the Z-average molecular weight, weight-average molecular weight and polydispersity obtained by the SEC method are relative values obtained by performing molecular weight calibration using a standard substance. can only be obtained. Therefore, the SEC method of the present invention is defined as using polyethylene oxide and polyethylene glycol as standard substances, as will be described later. In addition, since it is a relative value, it is also important to set the conditions for separating the test components and preparing the calibration curve. In view of these characteristics of the SEC method, the present inventors diligently studied the measurement conditions of the SEC method in order to improve the accuracy of calculating the Z-average molecular weight, weight-average molecular weight and polydispersity of polysorbate 80.

In this embodiment, the weight average molecular weight, Z average molecular weight and polydispersity of polysorbate 80 in the ophthalmic composition are measured as follows.
(Preparation of calibration curve solution)
1. Polyethylene oxide (Tosoh Corporation) and polyethylene glycol (Wako Pure Chemical Industries, Ltd.) having a molecular weight of several hundred thousand to several hundred are used as standard substances. Polyethylene oxide and polyethylene glycol used as standard substances are: It is preferable to use one kind of a certain thing. More preferably, polyethylene oxides with molecular weights of 580,000, 255,000, 146,000, 44,900 and 27,000 and polyethylene glycols with molecular weights of 8,000, 1,000, and 600 are used, and are divided into molecular weights of 580,000, 146,000, 27,000, and 1,000 and molecular weights of 255,000, 44,900, 8,000, and 600. , combined so that the elution positions do not overlap.
2. An aqueous solution having a standard substance concentration of 0.1 w/v% is prepared and used as a standard solution. Setting the concentration of the standard substance to 0.1 w/v % is very important for suppressing the relative standard deviation of the Z-average molecular weight, weight-average molecular weight and polydispersity.
3. Accurately take 1.0 mL of the standard solution, add exactly 4.0 mL of methanol, and use the solution as a calibration curve solution.
(Preparation of sample solution)
4. Accurately take 1.0 mL of the test solution and add exactly 4.0 mL of methanol to obtain a sample solution.
(Measurement by liquid chromatograph)
5. Each calibration curve solution and sample solution are measured with a high-performance liquid chromatograph (Agilent 1200 series, manufactured by Agilent Technologies).
6. The columns are manufactured by Tosoh Corporation, and TSK-Gelα-4000 (exclusion limit molecular weight of about 400,000) and TSK-Gelα-2500 (exclusion limit molecular weight of about 5000) filled with a hydrophilic vinyl polymer (both columns have an inner diameter of 7.8 mm , length 300 mm) are connected and installed one by one in this order. The column temperature is 40.0°C. Keeping the temperature constant at 40.0° C. is very important to suppress the relative standard deviation of the Z-average molecular weight, weight-average molecular weight and polydispersity.
7. As the eluent, a mixed solution in which the volume of methanol is 4.0 times the volume of 0.10 mol/L sodium chloride aqueous solution is prepared for each measurement and used. Including sodium chloride in the eluent to suppress interactions between sample molecules or between sample molecules and the packing material is very important for suppressing the relative standard deviation of Z-average molecular weight, weight-average molecular weight, and polydispersity. is.
8. The flow rate is 0.5 mL/min.
9. The injection volume is 50 μL. Filter through a 0.45 μm filter before injection.
10. The calibration curve solution and the sample solution are measured in order, and the analysis cycle is 60 minutes for the calibration curve solution and 90 minutes for the sample solution. Continuous measurement of the calibration curve solution and the sample solution without interrupting the measurement is very important for suppressing the relative standard deviation of the Z-average molecular weight, weight-average molecular weight and polydispersity.
11. The detector is a differential refractive index detector and the detector temperature is 35.0°C.
(Calculation of Z-average molecular weight, weight-average molecular weight and polydispersity)
12. The obtained chromatogram is analyzed by an SEC analyzer, and the Z-average molecular weight and weight average molecular weight are calculated for the range between the chromatogram curve and the baseline. The elution time and molecular weight of each peak are plotted from the calibration curve solution and approximated by a linear equation to obtain a calibration curve with a correlation coefficient of 0.99 or more. Furthermore, in order to reduce errors in chromatogram analysis processing, the obtained peak is divided vertically at intervals of 0.1 minute or more and less than 0.001 minute to calculate the average molecular weight.
13. Polydispersity is calculated from the formula _Mz / _Mw . 4 above. The sample solution in the step shown in is measured three times, and the average value of the Z-average molecular weight, weight-average molecular weight or polydispersity obtained in each is adopted as the Z-average molecular weight, weight-average molecular weight or polydispersity of the present application. do.

The relative standard deviation of the average molecular weight by the commonly known SEC method is calculated by the following formulas A and B, and is about 4 to 5%. Since the relative standard deviation of the polydispersity is less than 5% under the SEC measurement conditions described above, it can be said that the measurement conditions are reasonable. Polydispersity in this application shall be measured and calculated so that the relative standard deviation is less than 5%. If the reagents, columns, liquid chromatographs, etc. mentioned above are not available, equivalent substitutes can be used for the measurement. However, it should be measured so that the relative standard deviation of the polydispersity is less than 5%. When the relative standard deviation is 5% or more, it is necessary to suppress the relative standard deviation within the examination range of the measurement conditions that are normally carried out. In order to suppress the relative standard deviation in the study of the present inventors, it is important to satisfy the above conditions for the concentration of the standard substance, the column temperature, the composition of the eluent, and the analysis cycle of the calibration curve solution and the sample solution. rice field.

The content of component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type and content of component (B) used in combination. The content of component (A) is, for example, preferably 0.0001 to 8 w/v%, more preferably 0.0001 to 4 w/v%, based on the total amount of the ophthalmic composition. More preferably 0.0005 to 2 w/v%, particularly preferably 0.001 to 1 w/v%. The content of the above component (A) is suitable from the viewpoint of the effect of controlling the rate of adsorption to ocular cells or alleviating eye discomfort.

Component (B) Component (B) is a cooling agent. (B) component may be used individually by 1 type, or may be used in arbitrary combinations of 2 or more types.

The cooling agent used in the ophthalmic composition according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Cooling agents include, for example, terpenoids, terpenoid-containing essential oils (e.g., eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint, and peppermint oil). mentioned. Terpenoids include, for example, menthol, menthone, camphor (also referred to as "camphor" or "camphor"), borneol (also referred to as "ryunou" or "borne"), geraniol, nerol, cineol, citronellol, carvone, anethole, Eugenol, limonene, linalool and linalyl acetate. Terpenoids may be d-, l- or dl-forms, and examples include l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol and d-borneol. However, some terpenoids, such as geraniol, nerol and cineole, do not have optical isomers. From the viewpoint of controlling the rate of adsorption to eye cells or alleviating eye discomfort, the cooling agent preferably contains at least one selected from the group consisting of menthol, camphor, borneol and geraniol. It is particularly preferred to contain at least one selected from the group consisting of l-menthol, dl-camphor, d-camphor and d-borneol.

The content of the cooling agent in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of cooling agent, the type and content of component (A) used in combination, and the like. The content of cooling agents can be measured as terpenoids. For example, the total content of cooling agents (as terpenoids) is 0.00005 to 0.5 w/v based on the total amount of the ophthalmic composition. %, more preferably 0.0001 to 0.3 w/v%, even more preferably 0.0005 to 0.2 w/v%, 0.001 to 0.1 w/v% % is particularly preferred. The above content of the cooling agent is suitable from the viewpoint of the effect of controlling the rate of adsorption to ocular cells or alleviating eye discomfort.

The content ratio of the cooling agent to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the cooling agent. As the content ratio of the cooling agent to the component (A), for example, the total content of the cooling agent is 0.0001 to 100 with respect to 1 part by mass of the component (A) contained in the ophthalmic composition. It is preferably 0.001 to 80 parts by mass, even more preferably 0.005 to 60 parts by mass, and particularly preferably 0.01 to 50 parts by mass. The content ratio of the cooling agent to the above component (A) is suitable from the viewpoint of the effect of controlling the adsorption speed to eye cells or alleviating eye discomfort.

(C) Component The ophthalmic composition according to the present embodiment may further contain a component (C) described below. Component (C) is selected from the group consisting of polyvinyl alcohol (completely saponified or partially saponified), glycerin, panthenol, sulfamethoxazole and its salts, calcium chloride, magnesium sulfate, sodium bicarbonate, and mannitol. is at least one (C) Component may be used individually by 1 type, or may be used in arbitrary combinations of 2 or more types. By using the component (C) in combination, the effects of the present invention can be exhibited more remarkably. In particular, by using the component (C) in combination, the fragrance of the cooling agent contained in the ophthalmic composition can be further maintained. Although details such as the control mechanism of the adsorption rate to phospholipids by using the component (C) in combination have not been clarified, the micelle structure of polysorbate 80 and the cooling agent is formed by using the component (C) in combination. It is also possible that they are slightly different and affect their affinity for phospholipids.

The component (C) used in the ophthalmic composition according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

The content of the component (C) used in the ophthalmic composition according to the present embodiment is not particularly limited. is set as appropriate. The content of component (C) is, for example, preferably 0.00005 to 10 w/v%, more preferably 0.0001 to 8 w/v%, based on the total amount of the ophthalmic composition. is more preferable, 0.0005 to 6 w/v% is even more preferable, and 0.001 to 5 w/v% is particularly preferable. The content of the component (C) is suitable from the viewpoint of controlling the rate of adsorption to ocular cells or alleviating eye discomfort.

(D) Component The ophthalmic composition according to the present embodiment may further contain a component (D) described below. Component (D) is at least one selected from the group consisting of taurine, propylene glycol, benzalkonium chloride, sorbic acid and its salts, polyoxyethylene hydrogenated castor oil, trometamol, and epsilon-aminocaproic acid. Component (D) may be used alone or in any combination of two or more. By using the component (D) in combination, the effects of the present invention can be exhibited more remarkably. In particular, by using the component (D) in combination, deterioration of the contact lens can be further suppressed. Although details such as the control mechanism of the adsorption rate to phospholipids by using the component (D) in combination have not been clarified, the micelle structure of polysorbate 80 and the cooling agent is formed by using the component (D) in combination. It is also possible that they are slightly different and affect their affinity for phospholipids.

The component (D) used in the ophthalmic composition according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable.

The content of the component (D) used in the ophthalmic composition according to the present embodiment is not particularly limited. is set as appropriate. The content of component (D) is, for example, preferably 0.00005 to 10 w/v%, more preferably 0.0001 to 8 w/v%, based on the total amount of the ophthalmic composition. is more preferable, 0.0005 to 6 w/v% is even more preferable, and 0.001 to 5 w/v% is particularly preferable. The content of the component (D) is suitable from the viewpoint of the effect of controlling the rate of adsorption to ocular cells or alleviating eye discomfort.

The ophthalmic composition according to this embodiment preferably further contains a buffering agent. By this, the pH of the ophthalmic composition can be adjusted, and the effects of the present invention can be exhibited more remarkably.

The buffering agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of buffers include borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, Tris buffers, aspartic acid, aspartate, edetate and the like. These buffering agents may be used singly or in any combination of two or more. Boric acid buffers include boric acid or salts thereof (alkali metal borates, alkaline earth metal borates, etc.). Phosphate buffers include phosphoric acid and salts thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Carbonic acid buffers include carbonic acid or salts thereof (alkali metal carbonates, alkaline earth metal carbonates, etc.). Citric acid buffers include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). A borate or phosphate hydrate may be used as the borate buffer or phosphate buffer. 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, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); or salts thereof (sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); citric acid or salts thereof (sodium citrate, potassium citrate, calcium citrate, citric sodium dihydrogen acid, disodium citrate, etc.); acetic acid or salts thereof (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetate buffer; aspartic acid or salts thereof (sodium aspartate, magnesium aspartate, Potassium aspartate, etc.) can be exemplified. Among these buffers, borate buffers (for example, a combination of boric acid and borax) or phosphate buffers (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate) are preferred. , borate buffers are more preferred.

When a buffering agent is added to the ophthalmic composition according to the present embodiment, the content thereof includes the type of the buffering agent, the type and content of other ingredients, the application of the ophthalmic composition, the formulation form, the method of use, etc. is set as appropriate. As for the content of the buffering agent, for example, the total content of the buffering agent is preferably 0.001 to 15 w/v%, preferably 0.01 to 10 w/v%, based on the total amount of the ophthalmic composition. is more preferable, 0.05 to 7.5 w/v% is more preferable, and 0.1 to 5 w/v% is particularly preferable.

The ophthalmic composition according to this embodiment preferably further contains a chelating agent. As a result, the ophthalmic composition can be used stably for a long period of time, and the effects of the present invention can be exhibited more remarkably.

The chelating agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of chelating agents include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), and the like. can be exemplified. Among these chelating agents, ethylenediaminetetraacetic acid is preferred. These chelating agents may be used singly or in any combination of two or more.

When a chelating agent is added to the ophthalmic composition according to the present embodiment, the content of the chelating agent depends on the type of chelating agent, the type and content of other ingredients, the application, formulation form, method of use, etc. of the ophthalmic composition. It is set accordingly. The content of the chelating agent is, for example, preferably 0.0001 to 2 w/v%, preferably 0.0004 to 1.5 w/v, based on the total amount of the ophthalmic composition. %, more preferably 0.0008 to 1 w/v %, and particularly preferably 0.001 to 0.8 w/v %.

The pH of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. The pH of the ophthalmic composition ranges from 4.0 to 9.5, preferably from 4.5 to 9.0, more preferably from 5.0 to 8.5. When the pH is within the above range, there is less irritation to the eyes when the ophthalmic composition is used, the rate of adsorption to ocular cells can be further controlled, and discomfort in the eyes tends to be more alleviated.

The ophthalmic composition according to this embodiment preferably further contains a tonicity agent. By this, the osmotic pressure of the ophthalmic composition can be adjusted, and the effects of the present invention can be exhibited more remarkably. The tonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Examples of tonicity agents include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, carbonate sodium, sodium thiosulfate, polyethylene glycol, glucose, sorbitol and the like. Among these tonicity agents, polyethylene glycol, glucose, sodium chloride, potassium chloride, or magnesium chloride is preferred, sodium chloride, potassium chloride, or polyethylene glycol is more preferred, and sodium chloride is particularly preferred. These tonicity agents may be used singly or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains a tonicity agent, the content thereof is appropriately set according to the type of the tonicity agent, the type and content of other ingredients, and the like. The content of the tonicity agent is, for example, preferably 0.001 to 10w/v%, preferably 0.01 to 5w, based on the total amount of the ophthalmic composition. /v%, more preferably 0.05 to 3w/v%.

The osmotic pressure of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range acceptable to living organisms. The osmotic pressure ratio of the ophthalmic composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. It is preferably 0.8 to 1.6, and particularly preferably 0.8 to 1.6. Adjustment of osmotic pressure can be performed by methods known in the art using inorganic salts, polyhydric alcohols, sugar alcohols or sugars. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 16th revision of the Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (freezing point depression method). In addition, for the standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes, in a desiccator (silica gel) Allow to cool, accurately weigh 0.900 g, dissolve in purified water to prepare exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution). .

The ophthalmic composition according to this embodiment preferably further contains a thickening agent. By this, the viscosity of the ophthalmic composition can be adjusted, and the effects of the present invention can be exhibited more remarkably.

Examples of thickeners include polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivatives [methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose (2208, 2906, 2910, etc.), carboxy methylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof], polyethylene glycol (macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, etc.), sodium chondroitin sulfate, sodium hyaluronate, gum arabic, Examples include gellan gum, tragacanth, dextran (40, 70, etc.), glucose, sorbitol, etc., preferably polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, cellulose derivatives [methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose]. methylcellulose (2208, 2906, 2910), carboxymethylcellulose or salts thereof, etc.], polyethylene glycol (macrogol 300, macrogol 400, macrogol 4000, macrogol 6000, etc.) or dextran (70), more preferably polyvinyl pyrrolidone (K25, K30, K90), carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or its salts, polyethylene glycol (macrogol 300, macrogol 400, macrogol 4000, macrogol 6000) or dextran (70). Polyvinylpyrrolidone, hydroxyethylcellulose, or hydroxypropylmethylcellulose are more preferred, and hydroxypropylmethylcellulose is particularly preferred, from the viewpoint of controlling the rate of adsorption to ocular cells or alleviating eye discomfort. These thickeners may be used singly or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains a thickening agent, its content is appropriately set according to the type of thickening agent, the type and content of other ingredients, and the like. The content of the thickening agent is, for example, preferably 0.0001 to 8 w/v%, preferably 0.0005 to 5 w/v, based on the total amount of the ophthalmic composition. %, more preferably 0.001 to 4 w/v %, particularly preferably 0.01 to 3 w/v %.

The viscosity of the ophthalmic composition according to this embodiment is not particularly limited as long as it is within a range acceptable to living organisms. The viscosity at 25 ° C. measured with a rotational viscometer (RE550 type viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1 ° 34' x R24) is, for example, preferably 0.1 to 1000 mPa s, and 0.5 It is more preferably up to 100 mPa·s, still more preferably 1 to 50 mPa·s.

The ophthalmic composition according to this embodiment may contain, in addition to the above ingredients, various pharmacologically active ingredients or physiologically active ingredients in combination in appropriate amounts as long as the effects of the present invention are not impaired. Such ingredients are not particularly limited, and examples thereof include active ingredients in various drugs described in the 2012 version of the Approval Standards for Manufacturing and Marketing of OTC Drugs (supervised by the Japanese Society of Regulatory Science). Specifically, the components used in ophthalmic drugs include the following components.
Antiallergic agents: cromoglycate, amlexanox, ibudilast, suplatast, pemirolast potassium, tranilast, olopatadine hydrochloride, levocabastine hydrochloride, acitazanolast and the like.
Antihistamines: such as chlorpheniramine maleate, diphenhydramine hydrochloride and ketotifen fumarate.
Vasoconstrictors (decongestants): tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride and dl-methylephedrine hydrochloride.
Anti-inflammatory agents: pranoprofen, glycyrrhizic acid, allantoin, berberine sulfate, berberine chloride, azulene sulfonic acid, zinc sulfate, zinc lactate, lysozyme, salicylic acid, tranexamic acid, licorice and salts thereof, and the like.
Ocular muscle modulating agents: For example, cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methyl sulfate, tropicamide, helenien and atropine sulfate.
Bactericides: Acrinol, cetylpyridinium, benzethonium chloride, chlorhexidine, polyhexamethylenebiguanide and alkyldiaminoethylglycine hydrochloride.
Amino acids: glycine, alanine, γ-aminobutyric acid, aspartic acid, potassium L-aspartate, glutamic acid, arginine, lysine, chondroitin sulfate, sodium chondroitin sulfate, sodium hyaluronate and alginic acid.
Vitamins: vitamin _B1 , vitamin _B2 (flavin adenine dinucleotide sodium), niacin (nicotinic acid and nicotinamide), pantothenic acid, vitamin _B6 (pyridoxine, pyridoxal and pyridoxamine), biotin, folic acid, vitamin _B12 ( cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin), retinol acetate, retinyl palmitate and tocopherol acetate.

In the ophthalmic composition according to the present embodiment, various additives are appropriately selected in accordance with conventional methods according to the application or formulation form, as long as the effects of the present invention are not impaired, and one or more additives are added. may be used in combination to contain an appropriate amount. Examples of such additives include various additives described in the Encyclopedia of Pharmaceutical Excipients 2007 (edited by the Japan Pharmaceutical Excipients Association). Typical ingredients include the following additives.
Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin, and the like.
Sugar alcohols: For example, xylitol, sorbitol and the like. These may be d-, l- or dl-forms.
Non-ionic surfactants: POE (20) sorbitan monourarate (polysorbate 20), POE (20) sorbitan monopalmitate (polysorbate 40), POE (20) sorbitan monostearate (polysorbate 60) and POE tristearate (polysorbate 60). 20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 65); POE castor oils such as POE (10) castor oil (polyoxyethylene castor oil 10) and POE (35) castor oil (polyoxyethylene castor oil 35); POE (9) POE alkyl ethers such as lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE (54) POP (39) glycol, POE (120) POP (40) glycol, POE Polyoxyethylene-polyoxypropylene block copolymers such as (160) POP(30) glycol, POE(196) POP(67) glycol (poloxamer 407, Pluronic F127) and POE(200) POP(70) glycol; polyoxyl stearate polyethylene glycol monostearate such as 40; In the compounds exemplified above, the numbers in parentheses indicate the number of added moles.
Amphoteric surfactants: N-[2-[[2-(alkylamino)ethyl]amino]ethyl]glycine and salts thereof (also called alkyldiaminoethylglycine or alkylpolyaminoethylglycine), and the like.
Anionic surfactants: alkylbenzenesulfonates, alkylsulfates, polyoxyethylene alkylsulfates, α-sulfo fatty acid ester salts, α-olefinsulfonic acids and the like.
Cationic surfactants: benzethonium chloride and the like.
Preservatives, bactericides or antibacterial agents: for example zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, Propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, polyhexanide hydrochloride, etc.), Glokyl (trade name, manufactured by Rhodia), and the like.
Stabilizers: sodium formaldehyde sulfoxylate (Rongalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, sodium edetate and the like.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, paraffin, plastibase, lanolin and the like.

The ophthalmic composition according to the present embodiment is prepared by adding components (A) and (B) and, if necessary, other ingredients to a carrier so as to have desired contents. Specifically, for example, it can be prepared by dissolving or suspending the above components in purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

The water content in the ophthalmic composition according to the present embodiment is preferably 85 w/v% or more, more preferably 90 w/v% or more, and 92 w/v of the total amount of the ophthalmic composition. % or more, even more preferably 94 w/v % or more, and particularly preferably 96 w/v % or more. As the water used in the ophthalmic composition, pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable water may be used. Water, purified water, sterilized purified water, water for injection, distilled water for injection and the like are exemplified.

The ophthalmic composition according to this embodiment is provided in an arbitrary container. There are no particular restrictions on the container containing the ophthalmic composition, and for example, it may be made of glass or plastic. It is preferably made of plastic. Examples of plastics include polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polytetrafluoroethylene, polypropylene, polybutylene terephthalate, polyimide, polymethylpentene, copolymers of these monomers, and these A mixture of two or more kinds including materials can be mentioned. Preferred is polyethylene terephthalate. Moreover, the container containing the ophthalmic composition 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. For example, the ophthalmic composition may be stored in a colored and transparent plastic container or the like in a multi-dose form that can be used repeatedly, or may be used in a single-use form.

The ophthalmic composition according to this embodiment can be used as a pharmaceutical or quasi-drug formulation, and is a so-called eye drop [however, eye drops include eye drops that can be instilled while wearing contact lenses. ], artificial tears, eye washes [however, eye washes include eye washes that can be washed while wearing contact lenses. ], contact lens compositions [contact lens wetting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), etc.] . Preferred examples of the present invention include eye drops, artificial tears, eye washes, and contact lens-wearing solutions, and particularly preferred examples include eye drops and artificial tears. In addition, when the ophthalmic composition is used as a composition for contact lenses, it can be applied to all contact lenses including hard contact lenses and soft contact lenses, and can be applied while being worn on the contact lenses. It is possible. The ophthalmic composition according to the present embodiment is suitable for application to contact lenses also from the viewpoint of the effect of controlling the adsorption speed to eye cells or alleviating eye discomfort due to the burden on eye cells caused by wearing contact lenses. is.

The ophthalmic composition can be applied to any known contact lens. It is particularly preferably applied to soft contact lenses from the viewpoint that the diameter of the lens is large and the contact area with the eye is large. Soft contact lenses (SCL) are classified, for example, according to the methods described in ISO18369-1:2006 and ISO18369-1:AMENDMENT1.

The ophthalmic composition according to the present embodiment can not only improve the symptoms themselves but also control the rate of adsorption to mucosal cells in order to alleviate eye irritation or toxicity. Symptoms include, for example, not only subjective symptoms of rolling or prickling eyes (discomfort, irritation) but also unconscious symptoms, which can be triggered by dry eyes, use of contact lenses, or allergic conjunctivitis. be. The ophthalmic composition according to this embodiment can be applied for the purpose of preventing, improving or treating various symptoms. From the viewpoint of being able to control eye irritation or toxicity, it is suitable for discomfort caused by allergic conjunctivitis, contact lens wear, eye dryness, and the like. That is, the ophthalmic composition is suitably used as a discomfort alleviating agent. In other words, the discomfort-relieving agent comprises the ophthalmic composition.

From another point of view, the ophthalmic composition according to the present embodiment can also maintain the fragrance of the cooling agent contained in the ophthalmic composition, and thus is suitably used as an fragrance-sustaining agent for ophthalmic compositions. .

From another point of view, the ophthalmic composition according to the present embodiment can also suppress deterioration of contact lenses, and therefore is suitably used as a deterioration inhibitor for soft contact lenses.

(Method for imparting an effect of relieving discomfort)
In another embodiment of the present invention, the ophthalmic composition comprises adding (A) polysorbate 80 and (B) a cooling agent to the ophthalmic composition to impart an effect of alleviating eye discomfort. a method for
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63.
In yet another embodiment of the present invention, the ophthalmic composition comprises applying to the eye an ophthalmic composition containing (A) polysorbate 80 and (B) a cooling agent. 1. A method of alleviating the discomfort of
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63.

According to the ophthalmic composition according to the present embodiment, polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition is combined with a cooling agent to increase the adsorption rate to ocular cells. By controlling, it is possible to alleviate eye discomfort.

(Method for imparting an effect of sustaining fragrance)
In another embodiment of the present invention, the ophthalmic composition comprises blending (A) polysorbate 80 and (B) a cooling agent to maintain the fragrance of the cooling agent in the ophthalmic composition. A method for imparting the effect of
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63.
In another embodiment of the present invention, the fragrance of the cooling agent contained in the ophthalmic composition is obtained by blending (A) polysorbate 80 and (B) a cooling agent in the ophthalmic composition. A method of prolonging sexuality, comprising:
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63.

According to the ophthalmic composition according to the present embodiment, polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition and a cooling agent are combined to obtain a cooling agent contained in the ophthalmic composition. It is possible to maintain the fragrance of the agent.

(Method for imparting an effect of suppressing deterioration of soft contact lenses)
In another embodiment of the present invention, the action of suppressing deterioration of soft contact lenses in the ophthalmic composition, comprising blending (A) polysorbate 80 and (B) a cooling agent in the ophthalmic composition. A method of giving
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63.
In yet another embodiment of the present invention, the ophthalmic composition comprising (A) polysorbate 80 and (B) a cooling agent is contacted with a soft contact lens. A method for suppressing deterioration of a soft contact lens, comprising:
A method is provided wherein the polydispersity of said polysorbate 80 in said ophthalmic composition is from 1.27 to 1.63. Here, the "step of bringing the ophthalmic composition into contact with the soft contact lens" includes, for example, storing the soft contact lens in a storage solution, washing the soft contact lens with a washing solution, and instilling the soft contact lens while wearing the soft contact lens. and applying the agent to the eye.

According to the ophthalmic composition according to the present embodiment, polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition is combined with a cooling agent to suppress deterioration of soft contact lenses. It is possible to

(Production method)
In the production of the ophthalmic composition according to the present embodiment, polysorbate 80 having a polydispersity of 1.27 to 1.63 and a cooling agent are blended in the ophthalmic composition to reduce the adsorption rate to ocular cells. It is suggested that it can contribute to the provision of a formulation in which the control effect (control action) of the drug is maintained or improved.

EXAMPLES The present invention will be described in more detail below based on examples, but the present invention is not limited by these examples.

Test example 1. Measurement of adsorption rate to phospholipids (1) Test method Using polysorbate 80 having a different polydispersity, which is described in Table 1, test solution A (which is an ophthalmic composition described in Tables 2 and 3) ( Comparative Example 1-A, Comparative Example 2-A, Example 1-A, Example 2-A, Example 3-A) and Test Liquid B (Comparative Example 1-B, Comparative Example 2-B, Example 1 -B, Example 2-B, Example 3-B) were prepared, and the polydispersity of polysorbate 80 in each test solution was measured. Next, a QCM (Quartz Crystal Microbalance) device was used to measure in real time the frequency that fluctuated according to the adsorption amount of each test solution to the phospholipid immobilized on the quartz sensor. After that, using the adsorption rate constants of test liquid A and test liquid B with corresponding numbers, the inhibition rate of adsorption rate was calculated based on Equation 1 described later. Test liquid A and test liquid B with corresponding numbers are, for example, Comparative Example 1-A and Comparative Example 1-B.

An attached stirrer and 7 mL of PBS (Kohjin Bio Co., Ltd.) were placed in a glass cell attached to a biomolecular interaction quantitative QCM device AFFINIX Q (manufactured by Initium Co., Ltd.). The glass cell was set in a QCM device. The temperature was kept constant at 25° C. and the stirring speed at 1000 rpm. Phospholipids were then immobilized on the quartz sensor. Specifically, a cotton swab soaked with a 1% SDS aqueous solution was used to scrub the gold electrode portion of the crystal sensor without damaging it, and then rinsed with ultrapure water. After that, 5 μL of a piranha solution prepared by mixing concentrated sulfuric acid and 30% hydrogen peroxide solution at a ratio of 3:1 was added to the electrode portion and allowed to stand for 5 minutes. The Piranha solution was rinsed with ultrapure water, and the water remaining on the electrode surface was removed by blowing air. The quartz sensor was attached to the QCM device and allowed to stand until the average frequency stabilized within the range of 27,000,000±100,000 Hz, and both the average frequency change per minute and the amplitude of vibration were within 3 Hz. Next, remove the electrode from the QCM device, phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) (manufactured by Sigma) dissolved in chloroform to 1 mg / mL, 2 μL on the electrode Dropped in and air dried. After confirming that the electrodes were dry, they were bathed in hot water at 60° C. for 30 minutes. After that, excess phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) remaining unfixed on the electrodes of the crystal sensor was washed with ultrapure water, and the moisture around the electrodes was wiped off with paper. removed with a cloth. The quartz sensor on which the phospholipids were immobilized in this way was set in the QCM device and submerged in a glass cell containing PBS. We waited until the vibration frequency stabilized, and the vibration frequency at that time was taken as the initial value. Next, 7 μL of the test liquid was added to the glass cell, and the fluctuating frequency was monitored by the adsorption behavior of the test liquid to the phospholipids on the quartz sensor. Monitoring continued until the oscillation frequency stabilized.

Select the vibration frequency from the initial value to 1 minute after the addition of the test solution, perform fitting to an exponential function using analysis software AQUA (Initium Co., Ltd.), and calculate the apparent adsorption rate constant K _obs . Calculated. In addition, slope correction was performed when a constant drift (inclination) appeared in the frequency after immobilization on the phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) crystal sensor.

From the obtained K _obs , the inhibition rate of the adsorption rate was calculated based on the formula (1). Suppression rate is the rate of reduction.
Inhibition rate of adsorption rate (%) = [{(K _obs of test solution containing no cooling agent) - (K _obs of test solution containing cooling agent)} / (of test solution containing cooling agent) K _obs )]×100 (equation 1)

(2) Test results Table 4 shows the results. By combining various components (A) with different polydispersities and components (B), the effect of suppressing the adsorption rate is reduced for components (A) with a polydispersity of 1.21 or less in the test solution. (Comparative Examples 1 and 2), it was shown that the effect of suppressing the adsorption rate was improved in the component (A) having a polydispersity of 1.27 or more in the test solution (Examples 1 and 3).

Test example 2. Sensory test (1)
(1) Test method According to Tables 5 and 6 below, each test liquid as an ophthalmic composition was prepared according to a conventional method, and the polydispersity of polysorbate 80 in each test liquid was measured. 9 mL of each test solution was filled in a transparent glass vial (septum cap) having a capacity of 10 mL. A heat treatment was performed in a constant temperature bath at 60° C. for 24 hours. 30 μL of each test solution immediately after preparation and each test solution after heat treatment were dropped on the arm, spread in a circle with a diameter of about 2 cm with a finger, smelled, and evaluated by the VAS (Visual Analog Scale) method. That is, for "exhilarating and refreshing scent" and "good scent", at both ends of the 10 cm straight line, "do not feel at all" is 0 mm, and "very much" is 100 mm, corresponding to the size of the smell of each test solution. The subject was asked to point to a point on the straight line. A sensory score was obtained by measuring the distance (mm) from the 0 mm point. Five test subjects who were sensitive to odors were selected, and the average score was calculated.

(2) Test Results Table 5 shows the average fragrant score of each test solution immediately after preparation, and Table 6 shows the average fragrant score of each test solution after heat treatment. Test solution 2-2 containing (A) polysorbate 80 and (B) l-menthol, d-camphor or d-borneol, wherein the polydispersity of polysorbate 80 in the test solution is 1.27 to 1.34, 2-3, 2-5, 2-6, 2-8, and 2-10 are test liquids 2-1, 2-4, and 2- whose polydispersity of polysorbate 80 in the test liquid is less than 1.27 It was confirmed that, compared to 7 and 2-9, a significantly higher fragrance was exhibited immediately after preparation. Furthermore, the test solution after the heat treatment also contained (A) polysorbate 80 and (B) 1-menthol, d-camphor or d-borneol, and the polydispersity of polysorbate 80 in the test solution was 1.27 to 1.27. 63 of the test liquids 2-2, 2-3, 2-5, 2-6, 2-8, 2-10, 2-11, and 2-12 have a polydispersity of 1 for polysorbate 80 in the test liquid. Compared to test solutions 2-1, 2-4, 2-7, and 2-9, which are less than .27, it exhibits a significantly higher fragrance, so even during long-term use or storage of the ophthalmic composition, the fragrance persistence was confirmed.

Test example 3. Sensory test (2)
(1) Test method Evaluation of fragrance after heat treatment by the same method as in Test Example 2, except that each test liquid, which is an ophthalmic composition, was prepared according to the usual method according to Tables 7 and 8 below. did Five test subjects who were sensitive to odors were selected, and the average score was calculated.

(2) Test Results Tables 7, 8 and 9 show the average fragrant scores. (A) polysorbate 80, (B) a cooling agent (l-menthol), and compared to test solution 2-3 in which the polydispersity of polysorbate 80 in the test solution is 1.34, (A) polysorbate 80 , (B) a cooling agent (l-menthol) and (C) polyvinyl alcohol, glycerin, panthenol, sulfamethoxazole, calcium chloride, magnesium sulfate, sodium hydrogen carbonate or D-mannitol, in the test solution Test solutions 3-1 to 3-8 in which polysorbate 80 has a polydispersity of 1.34 show a significantly high fragrance after heat treatment, so that during long-term use or storage of the ophthalmic composition, the fragrance is confirmed to persist. In addition, test liquids 2-5 and 2 containing (A) polysorbate 80 and (B) a cooling agent (d-borneol), wherein the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.34 -6, it contains (A) polysorbate 80, (B) a cooling agent (d-borneol) and (C) polyvinyl alcohol or glycerin, and the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1. Test solutions 3-9 to 3-12, which are .34, exhibit remarkably high fragrance after heat treatment, confirming that the fragrance persists during long-term use or storage of the ophthalmic composition. Furthermore, test liquids 2-10 and 2 containing (A) polysorbate 80 and (B) a cooling agent (d-camphor), wherein the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.34 -11, it contains (A) polysorbate 80, (B) a cooling agent (d-camphor) and (C) glycerin, and the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.34. Certain test liquids 3-14 and 3-15 exhibit remarkably high fragrance after heat treatment, confirming that the fragrance persists during long-term use or storage of the ophthalmic composition. In addition, (A) polysorbate 80, (B) a cooling agent (d-borneol) is contained, and the polydispersity of polysorbate 80 in the test solution is 1.19. Test liquid 3-13, which contains polysorbate 80, (B) a cooling agent (d-borneol), and (C) polyvinyl alcohol, and in which the polydispersity of polysorbate 80 in the test liquid is 1.19, has no aroma after heat treatment. sexuality decreased.

Test example 4. Evaluation of contact lenses (1)
(1) Test method Each test solution was prepared according to the usual method according to Tables 10 and 11 below, and the polydispersity of polysorbate 80 in each test solution was measured.
Soak one soft contact lens (USAN name: EtafilconA; water content 58.0%, POWER-3.00, B.C.8.5, DIA14.2 mm) in 10 mL of physiological saline for 4 hours or more. Set aside at 25°C. 5 mL of each test solution was filled in a transparent glass vial (septum cap) having a capacity of 10 mL, and a soft contact lens treated with a physiological saline solution was immersed one by one. A heat treatment was performed in a constant temperature bath at 25° C. for 24 hours or at 60° C. for 24 hours. After the heat treatment, the glass vial was allowed to stand at room temperature for 1 hour, and the test solution and contact lens were brought to the same temperature as room temperature. The contact lens was removed from the glass vial, wiped dry, and gently placed on a graduated glass slide with its convex shape facing downward. At this time, care was taken so that the contact surface between the contact lens and the slide glass was circular without distortion. Five seconds after installation, the diameter of the tangent circle was measured with a microscope. Immediately thereafter, the contact lens was placed back into the test solution in the heat-treated glass vial. In order to avoid drying the contact lens, it was quickly taken out from the glass vial and measured. Three contact lenses were used for one test liquid, and one contact lens was measured three times to calculate the average value.

Under the same test conditions, the contact lens was immersed in physiological saline (sodium chloride 0.9 w/v%, pH 7.0), the diameter of the tangential circle between the contact lens and the slide glass was measured, and the average value was calculated. . The average value after treatment with physiological saline and the average value after immersion in each test solution after heat treatment at 25° C. or 60° C. were applied to the following formula 2 to calculate the deterioration rate of the soft contact lens. Degeneration of a soft contact lens means a change in the diameter of the tangential circle between the soft contact lens and the slide glass. That is, the closer the absolute value of the alteration rate to 0, the smaller the alteration. Alteration rate (%) = [{(Diameter of tangential circle after treatment with physiological saline)-(Diameter of tangential circle after treatment with test solution)}/Diameter of tangential circle after treatment with physiological saline] x 100 (Formula 2)

(2) Test results The results are shown in Tables 10 and 11. Test liquid 4-2 containing (A) polysorbate 80 and (B) l-menthol, d-camphor or d-borneol, wherein the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.63, 4-3, 4-4, 4-6, 4-7, 4-8, 4-10, 4-11 are test liquids 4-1, 4-5, 4- with a polydispersity of 1.19 It was confirmed that the absolute value of the alteration rate was smaller than that of No. 9. That is, it was found that the test liquids in which polysorbate 80 had a polydispersity of 1.27 to 1.63 suppressed deterioration of the contact lens at 25°C. In addition, test liquids 4-13, 4-14, 4- containing (A) polysorbate 80 and (B) d-camphor, wherein the polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.63 It was confirmed that Sample No. 15 had a smaller absolute value of alteration rate after treatment at 60° C. than Test Liquid 4-12, which had a polydispersity of 1.19. In other words, it was found that test liquids having a polydispersity of polysorbate 80 in the test liquid of 1.27 to 1.63 suppress deterioration of contact lenses even after heat treatment. Therefore, it was found that deterioration of the contact lens is suppressed even during long-term use or storage.

Test example 5. Evaluation of contact lenses (2)
(1) Test method Contact lenses were evaluated in the same manner as in Test Example 4, except that each test solution was prepared according to a conventional method according to Table 12 below.

(2) Test results The results are shown in Table 12. (A) polysorbate 80, (B) cooling agent (l-menthol) and (D) taurine, propylene glycol, benzalkonium chloride, potassium sorbate, polyoxyethylene hydrogenated castor oil, trometamol or epsilon-aminocaproic acid and the polydispersity of polysorbate 80 in the test solution is 1.34. , (B) Compared with test solution 4-3, which contains a cooling agent (l-menthol) and has a polydispersity of polysorbate 80 in the test solution of 1.34, the absolute change rate after treatment at 60 ° C. confirmed to be small. In other words, it was found that deterioration of contact lenses is suppressed even during long-term use or storage. Also, a test containing (A) polysorbate 80, (B) a cooling agent (l-menthol) and (D) trometamol or epsilon-aminocaproic acid, and the polydispersity of polysorbate 80 in the test solution is 1.63 Liquids 5-7 and 5-8 contain (A) polysorbate 80 and (B) a cooling agent (l-menthol), and the polydispersity of polysorbate 80 in the test liquid is 1.63. It was confirmed that the absolute value of the alteration rate after the 60° C. treatment was smaller than that of -4. In other words, it was found that deterioration of contact lenses is suppressed even during long-term use or storage.

Claims (7)

A method for alleviating eye irritation caused by polysorbate 80 in an ophthalmic composition containing polysorbate 80 and menthol, comprising:
comprising blending an ophthalmic composition with polysorbate 80 having a polydispersity (M _z /M _w ) of 1.27 to 1.63 and menthol;
Method. A method for suppressing deterioration of a soft contact lens due to polysorbate 80 in an ophthalmic composition containing polysorbate 80 and menthol, comprising:
comprising blending an ophthalmic composition with polysorbate 80 having a polydispersity (M _z /M _w ) of 1.27 to 1.63 and menthol;
Method. The method according to claim 1 or 2, wherein the polysorbate 80 contained in the ophthalmic composition has a weight average molecular weight of 1200-3200. The method of any one of claims 1-3, wherein the polysorbate 80 contained in the ophthalmic composition has a Z-average molecular weight of 1300-3500. The content of the polysorbate 80 contained in the ophthalmic composition is 0.0001 to 8 w/v%, and the content of the menthol contained in the ophthalmic composition is 0.00005 to 0.5 w/v%. , the method according to any one of claims 1 to 4 . The total content of the menthol is 0.0001 to 100 parts by mass with respect to 1 part by mass of the polysorbate 80 contained in the ophthalmic composition, according to any one of claims 1 to 5 . the method of. Polyvinyl alcohol, glycerin, panthenol, sulfamethoxazole and its salts, calcium chloride, magnesium sulfate, sodium bicarbonate, mannitol, taurine, propylene glycol, benzalkonium chloride, sorbic acid and its salts, polyoxyethylene hydrogenated castor Oil, trometamol, and at least one selected from the group consisting of epsilon-aminocaproic acid, the content of which is 0.00005 to 10 w/v%, according to any one of claims 1 to 6 described method.