JP2003183157A - Ophthalmologic composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an ophthalmologic composition which hardly irritates eyes, can give a good feel of refreshing, and is excellent in persistence of the feel of refreshing. <P>SOLUTION: This ophthalmologic composition contains a terpenoid, a water- soluble polymer compound, and a local anesthetic. The terpenoid is preferably at least one substance selected from among menthol, camphor, borneol, geraniol, cineole, linalol, eucalyptus oil, bergamot oil, fennel oil, and rose oil. The water- soluble polymer compound is preferably at least one polymer selected from among methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, a carboxyviyl polymer, sodium hyaluronate, and sodium chondroitin sulfate. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ophthalmic composition, and more specifically, by containing a terpenoid, a water-soluble polymer, and a local anesthetic, a good refreshing feeling can be imparted and a refreshing effect can be obtained. The present invention relates to an ophthalmic composition having a long-lasting feeling and low irritation, which is particularly suitable for eye drops, eye washes, and contact lens mounting solutions.

[0002]

2. Description of the Related Art Conventionally, a refreshing agent such as a fragrance is often used in an ophthalmic composition for the purpose of enhancing the usability of eye drops. By adding the cooling agent to an ophthalmic composition, it gives a refreshing feeling of use, relieves eye fatigue, and further removes or alleviates eye discomfort when pollinosis occurs. be able to. Examples of the cooling agent include terpenoids such as menthol, camphor, borneol, geraniol, cineol, linalool, eucalyptus oil, bergamot oil, fennel oil, and rose oil.

These refreshing agents are widely used as external medicines, but when used for the eyes, which are said to be the organs most sensitive to irritation, that is, they are blended in ophthalmic preparations such as eye drops. If it does, the irritation must be fully considered. If the amount of the refreshing agent is too large in order to enhance the refreshing feeling, there is a problem that problems such as feeling of heat and irritation occur. Further, when the eye drop is administered to the eye, it is diluted with tear fluid and rapidly disappears from the conjunctival sac, so that there is a problem that the refreshing feeling hardly lasts.

In Japanese Patent Application Laid-Open No. 9-132526,
Disclosed is an eye drop that has improved refreshing feeling and durability by combining menthols, camphors, and borneols in combination. In addition, JP-A-10-30602
Japanese Patent Publication No. 2 discloses an eye drop in which menthols are clathrated with cyclodextrins to enhance the refreshing feeling and durability. However, these methods have a problem that it is extremely difficult to enhance a sufficient refreshing feeling and sustainability without increasing irritation to eyes.

[0005]

SUMMARY OF THE INVENTION The present invention aims to solve the above-mentioned problems in the prior art and achieve the following objects, that is, the present invention has low eye irritation,
An object of the present invention is to provide an ophthalmic composition capable of imparting a good cooling sensation and having a high refreshing sensation.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that by combining a terpenoid, a water-soluble polymer, and a local anesthetic, It was found that an ophthalmic composition having low irritation to the skin, providing a good refreshing feeling, and having a high refreshing feeling can be provided, and thus completed the present invention. That is,
The means for solving the above problems are as follows.

<1> An ophthalmic composition comprising a terpenoid, a water-soluble polymer compound, and a local anesthetic. <2> Terpenoids include menthols, camphors, borneols, geraniol, cineol, linalool, eucalyptus oil, bergamot oil, fennel oil,
And the ophthalmic composition according to <1>, which is at least one kind selected from rose oil. <3> The <1> or <2>, wherein the water-soluble polymer compound is at least one kind of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium hyaluronate, and sodium chondroitin sulfate. The ophthalmic composition described in <4> The ophthalmic composition according to any one of <1> to <3>, wherein the local anesthetic is at least one of chlorobutanol, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and oxybuprocaine hydrochloride. Is. <5> The ophthalmic composition according to any one of <1> to <4>, which is used for at least one of eye drops, eye wash, and contact lens mounting liquid. <6> The water-soluble polymer compound is the ophthalmic composition according to any one of <1> to <5>, which is a refreshing feeling sustaining agent. <7> A method for sustaining a cooling sensation, which comprises blending a terpenoid, a water-soluble polymer compound, and a local anesthetic.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The ophthalmic composition of the present invention contains a terpenoid, a water-soluble polymer compound, and a local anesthetic, and optionally other components.

[Terpenoids] The terpenoids are not particularly limited, but monoterpenoid compounds are preferable because they can impart a strong cooling sensation and have high durability.
Specifically, menthol (l-menthol, dl-menthol), camphor (dl-camphor, d-camphor), borneol (d-borneol, ryuno), geraniol, cineol, and linalool are preferably used. To be done. As the terpenoids, an essential oil containing terpenoids may be used, and examples of the essential oil containing the terpenoids include eucalyptus oil, bergamot oil, fennel oil, rose oil, mint oil, peppermint oil. , Spearmint oil, essential oil of Dipterocarpaceae plant, rosmarinic oil, and lavender oil. These terpenoids (including essential oils containing terpenoids) may be used alone,
You may use 2 or more types together. As the terpenoids, specifically, the following commercially available products can be preferably used. For example, 1-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, geraniol, cineole, linalool, eucalyptus oil, bergamot oil, fennel oil, rose manufactured by Takasago International Corporation. Oil, peppermint oil, d-borneol made by Fujisawa Pharmaceutical Co., Ltd. or Koshiro Pharmaceutical Co., Ltd.,
Examples include commercially available products such as dl-borneol.

The content of the terpenoids in the ophthalmic composition is 0.0001 to 2 w / v%.
(This means “mass / volume%”. The same applies hereinafter.)
Is preferred, 0.0005 to 1 w / v% is more preferred, and 0.001 to 0.5 w / v% is still more preferred. If the content is less than 0.0001 w / v%, a sufficient refreshing feeling may not be obtained, while if it exceeds 2 w / v%, irritation to the eyes during use may be high.

[Water-Soluble Polymer Compound] The water-soluble polymer compound is particularly advantageous in that it can effectively prevent the eye drops and the like from disappearing from the conjunctival sac due to dilution with tear fluid or the like. preferable. The water-soluble polymer compound is not particularly limited, and specific examples thereof include methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium hyaluronate, and sodium chondroitin sulfate. To be These may be used alone or in combination of two or more.

As the water-soluble polymer, specifically,
The following commercial products can be preferably used. For example,
If it is methyl cellulose, Shin-Etsu Chemical Co., Ltd.'s Metro's SM (viscosity grade 15, 25, 100, 40
0, 1500, 4000, 8000) and hydroxypropyl methylcellulose, Metroze 60SH manufactured by Shin-Etsu Chemical Co., Ltd. (viscosity grade 15, 50, 10)
0, 400, 1500, 4000, 8000), 65S
H (viscosity grade 50, 400, 1500, 400
0), 90SH (viscosity grade 100, 400, 400
0) and hydroxyethyl cellulose, Fuji Chemie HEC (CF-G, CF-H, CF) manufactured by Sumitomo Seika
-V, CF-W, CF-X, CF-Y) and polyvinyl alcohol are Gohsenol (EG-05, EG-25, EG-30, EG-4) manufactured by Nippon Synthetic Chemical Industry Co., Ltd.
0) and polyvinylpyrrolidone, BASF's Kollidon (12PF, 17PF, 25, 30,
90F), if it is a carboxyvinyl polymer, Goo
Carbopole made by drich (981, 980, 97
4P, 974-NF, 941, 940, 934P, 91
0) and sodium hyaluronate, hyaluronic acid (HA-AM, HA-Q, manufactured by QP Corporation)
A), hyaluronic acid manufactured by Maruha Co., Ltd., sodium "Maruha" (for eye drops) (average degree of polymerization 1500-3000),
If it is sodium chondroitin sulfate, Maruha Co., Ltd.
Commercially available products such as sodium chondroitin sulfate externally manufactured by the company.

The content of the water-soluble polymer compound in the ophthalmic composition is such that the water-soluble polymer compound is methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, and sodium hyaluronate. ,
0.001-5w / v% is preferable, and 0.005-3w
/ V% is more preferable, and 0.01 to 2 w / v% is further preferable. When the water-soluble polymer compound is polyvinyl alcohol, polyvinylpyrrolidone, and sodium chondroitin sulfate, 0.01 to 20 w / v% is preferable, 0.05 to 10 w / v% is more preferable,
0.01 to 5 w / v% is more preferable. The content is
If it is less than each of the preferable numerical ranges, the refreshing feeling may not be maintained, while if it exceeds each of the preferable numerical ranges, the usability may be deteriorated.

[Local Anesthetic] As the local anesthetic,
Although not particularly limited, specific examples thereof include chlorobutanol, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and oxybuprocaine hydrochloride. These local anesthetics may be used alone or in combination of two or more.

The content of the local anesthetic in the ophthalmic composition is preferably 0.001 to 3 w / v% when the local anesthetic is chlorobutanol,
005-1.0 w / v% is more preferable, and 0.01-
0.5 w / v% is more preferable. When the local anesthetic is lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and oxybuprocaine hydrochloride, 0.001-1 w /
v% is preferable, 0.005-0.5 w / v% is more preferable, and 0.01-0.4 w / v% is further preferable. If the content is less than each of the numerical ranges described above, irritation by a cooling agent may occur, and the refreshing feeling may not be maintained, while if it exceeds each of the preferable numerical ranges, the feeling of use may be poor. It may get worse.

[Other Ingredients] In the present invention, in addition to the above-mentioned ingredients, known ingredients used for the preparation of various ophthalmic preparations such as eye drops, eye washes, contact lens mounting solutions, for example, buffers. Various additives such as a solubilizer, a tonicity agent, a stabilizer, a chelating agent, a pH adjuster, a preservative and the like, and other pharmaceutically active ingredients can be added in the amounts usually used.

Examples of the buffer include boric acid or salts thereof (borax etc.), citric acid or salts thereof (sodium citrate etc.), phosphoric acid or salts thereof (sodium monohydrogen phosphate etc.), tartaric acid or Its salt (sodium tartrate, etc.),
Gluconic acid or its salt (sodium gluconate etc.), acetic acid or its salt (sodium acetate etc.), carbonic acid or its salt (sodium hydrogen carbonate etc.), various amino acids (epsilon-aminocaproic acid, potassium aspartate, aminoethyl sulfonic acid) , Glutamic acid, sodium glutamate, etc.) and the like. These may be used alone or in combination of two or more.

Examples of the solubilizing agent include polyoxyethylene (p = 60) polyoxyethylene higher fatty acid ester such as hydrogenated castor oil and polyoxyethylene (p
= 20) Polyoxyethylene sorbitan higher fatty acid ester such as sorbitan monooleate. These may be used alone or in combination of two or more.

Examples of the isotonicity agent include sodium chloride, potassium chloride, glycerin and the like. These may be used alone or in combination of two or more.

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfite, citric acid or its salt, and dibutylhydroxytoluene. These may be used alone or in combination of two or more.

Examples of the chelating agent include sodium edetate and sodium citrate. These may be used alone or in combination of two or more.

Examples of the pH adjusting agent include sodium hydroxide, potassium hydroxide, hydrochloric acid and the like. These may be used alone or in combination of two or more.

Examples of the preservatives include paraoxybenzoic acid esters such as methylparaben, ethylparaben, propylparaben and butylparaben, alcohol derivatives such as phenylethyl alcohol and benzyl alcohol, sorbic acid and salts thereof (potassium sorbate, etc.). ),
Examples thereof include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, cetylpyridinium chloride, and alkylpolyaminoethylglycine. These may be used alone or in combination of two or more.

Examples of the pharmaceutically active ingredient include decongestants (naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine dl, tetrahydrozoline nitrate, naphazoline nitrate, etc.)
Anti-inflammatory / astringent (neostigmine methylsulfate, ε-aminocaproic acid, allantoin, berberine chloride, berberine sulfate, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, azulene Sodium sulfonate, sodium cromoglycate, etc., antihistamines (iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipendyl hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin), fat-soluble Vitamin (vitamin A (eg retinol acetate, retinol palmitate), vitamin E (tocopherol acetate (eg Acetic acid d-α-tocopherol)), amino acids (L-aspartate potassium, L-magnesium aspartate, aminoethyl sulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, fungicides (sulfamethoxazole, sulfamethoxa) Sol sodium, sulfisoxazole, sulfisomidine sodium, isopropylmethylphenol, hinokitiol, etc., etc.
They may be used alone or in combination of two or more.

<Various Physical Properties of Ophthalmic Composition> The liquid property (pH) of the ophthalmic composition of the present invention is preferably pH 4 to 9 and preferably 5 to 8.5 in terms of eye safety. A range is more preferable.

The osmotic pressure of the ophthalmic composition of the present invention is
From the viewpoint of eye safety, a pressure ratio of 0.1 to 5 is preferable,
A pressure ratio of 0.2 to 2 is more preferable.

The viscosity of the ophthalmic composition of the present invention at 20 ° C. is 1 to 1 from the viewpoint of enhancing the sustainability of the refreshing feeling.
000 mPa · s is preferable, 1 to 200 mPa · s is more preferable, and 1 to 100 mPa · s is further preferable.
When the viscosity is more than 1000 mPa · s, the feeling of use may be poor such as stickiness.

<Use of Ophthalmic Composition> The use of the ophthalmic composition of the present invention is not particularly limited, but it has a good refreshing feeling and a good sustainability of the cooling feeling, and a refreshing agent. It is particularly preferable to be blended as an eye drop, since it has low irritation to the eye. As the eye drops,
It may be a medical eye drop or a general eye drop, and can be applied even when a soft contact lens, a hard contact lens or the like is worn. Further, as an application of the ophthalmic composition of the present invention, an eye wash, a contact lens mounting liquid, etc. are also preferable.

<Preparation Method of Ophthalmic Composition> The preparation method of the ophthalmic composition of the present invention is not particularly limited, but, for example, in the case of application to eye drops, first, each compounding component (others such as drug etc.) Of the above components) is dissolved in sterilized purified water, and p
After adjusting H, a method of aseptically filling an eye drop container (15 mL) made of polyethylene terephthalate may be mentioned.

[0030]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

(Example 1 and Comparative Examples 1 to 3) Ophthalmic compositions (eye drops) having the formulations shown in Table 1 were prepared (blending amount: g /
100 mL), and after filling the container, a refreshing feeling immediately after instillation, persistence of the refreshing feeling, and eye irritation were evaluated. The results are shown in Table 1. The refreshing sensation immediately after instillation and the persistence of the refreshing sensation were evaluated by a sensory test by a professional panelist. The eye irritation was carried out in accordance with the short-term test method for mucous membrane irritation for preservatives for eye drops in the Ministry of Health and Welfare Scientific Research Report (1965). In each evaluation,
It evaluated according to the following evaluation criteria.

<Evaluation criteria> -Cool feeling immediately after instillation- 5: Feels very refreshing 4: Feel a refreshing feeling 3: Feeling cool 2: Almost no refreshing feeling 1: No refreshing feeling

-Persistence of refreshing feeling- ◎: A refreshing feeling can be felt for 10 minutes or more ◯: A refreshing feeling is continuously felt for 5 minutes or more and less than 10 minutes Δ: A refreshing feeling is felt continuously for 1 minute or more and less than 5 minutes ×: The refreshing feeling is not felt in less than 1 minute

-Eye irritation- A: Average score by Draize method is 0 or more and less than 2 points. O: Average score by Draize method is 2 or more and less than 4 points. Δ: Average score by Draize method is 4 points. The above is less than 6 points x: The average score by the Draize method is 6 points or more

[0035]

[Table 1]

In Table 1, hydroxypropyl methylcellulose is Metroose 60SH-4000 (manufactured by Shin-Etsu Chemical Co., Ltd.).

As is clear from the results shown in Table 1, in Example 1 in which a terpenoid (1-menthol), a water-soluble polymer (hydroxypropylmethylcellulose), and a local anesthetic (chlorobutanol) were mixed, immediately after instillation. The refreshing feeling, the refreshing feeling persistence, and the eye irritation were excellent. On the other hand, in Comparative Examples 1 to 3 which do not contain one of each of these three components, no refreshing feeling is felt (Comparative Example 1), the refreshing feeling is less persistent (Comparative Example 2), and eye irritation is high. There was a defect such as (Comparative Example 3).

From the above results, by simultaneously blending the three components of the terpenoids, the water-soluble polymer, and the local anesthetic agent, the eye irritation is low, and the refreshing feeling and the sustaining of the refreshing feeling are extremely high. It was confirmed that an ophthalmic composition could be prepared.

(Examples 2 to 22) With the formulations shown in Tables 2 to 4 (blending amount: g / 100 mL), the ophthalmic compositions (eye drops) of Examples 2 to 19 were prepared according to the conventional method. 20-21
The ophthalmic composition (eyewash) and the ophthalmic composition of Example 22 (contact lens mounting liquid) were prepared and evaluated in the same manner as in Example 1 and Comparative Examples 1 to 3. In each of the examples, it was confirmed that the eye irritation was low and the refreshing feeling and the refreshing feeling were extremely long lasting. The results are shown in Table 2.
To 4 respectively.

[0040]

[Table 2]

In Table 2, methyl cellulose is
Shin-Etsu Chemical Co., Ltd. make Metroze SM-4000 (Example 5), SM-400 (Example 7), and hydroxypropylmethylcellulose is the same 60SH-4000.
(Examples 2, 4, 8) and 60SH-50 (Example 3), and polyvinyl alcohol is manufactured by Nippon Synthetic Chemical Industry Co., Ltd.
Goshenol EG-05, polyvinylpyrrolidone is Kollidon manufactured by BASF, 30 carboxyvinyl polymer is Carbopol 971P-NF manufactured by Goodrich, and sodium hyaluronate is sodium hyaluronate manufactured by Maruha Co., Ltd. Maruha "
(For eye drops).

[0042]

[Table 3]

In Table 3, methyl cellulose is
Shin-Etsu Chemical Co., Ltd. manufactured by Metroses SM-100,
Hydroxypropyl methylcellulose is the same as 60SH-
50 (Examples 9 and 10), 60SH-4000 (Examples 11 and 12), 65SH-1500 (Example 14), 6
5SH-4000 (Example 15), and hydroxyethyl cellulose is Fuji Chemi HEC manufactured by Sumitomo Seika Chemicals Ltd.
CF-W, polyvinyl alcohol is Gohsenol EG-05 manufactured by Nippon Synthetic Chemical Industry Co., Ltd., and polyvinylpyrrolidone is Kollidon 2 manufactured by BASF.
5 and the carboxyvinyl polymer is Goodri
Carbopol 981 manufactured by CH, and sodium hyaluronate is Hyaluron Sun HA manufactured by QP Corporation.
-QA.

[0044]

[Table 4]

In Table 4, methylcellulose is
Shin-Etsu Chemical Co., Ltd. manufactured by Metroses SM-4000, hydroxypropyl methylcellulose is 60S
H-4000 (Examples 17, 19, 21), 60SH-
50 (Examples 18 and 22), polyvinyl alcohol is Gohsenol EG-05 manufactured by Nippon Synthetic Chemical Industry Co., Ltd., and polyvinylpyrrolidone is Kol manufactured by BASF.
lidon 90F, sodium hyaluronate is sodium hyaluronate "Maruha" manufactured by Maruha Co., Ltd.
(For eye drops).

[0046]

EFFECTS OF THE INVENTION According to the present invention, it is possible to provide an ophthalmic composition having low irritation to the eye, providing a good refreshing sensation, and having a high refreshing sensation.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/34 A61K 31/34 31/35 31/35 31/4704 31/4704 35/78 35/78 C H K N 47/32 47/32 47/36 47/36 47/38 47/38 A61P 27/02 A61P 27/02 F term (reference) 4C076 AA11 BB24 CC10 EE06M EE08M EE16M EE32M EE37M FF31 GG45 4C086 AA01 AA02 BC29 CA01 MA03 MA05 MA17 MA58 NA12 ZA33 4C088 AB40 AB51 AB57 AB62 BA18 MA05 MA17 MA58 NA12 ZA33 4C206 AA01 AA02 CA03 CA08 CA14 FA40 GA01 GA31 KA08 MA03 MA05 MA14 MA16 MA37 MA78 NA12 ZA33

Claims (7)

[Claims] 1. An ophthalmic composition containing a terpenoid, a water-soluble polymer compound, and a local anesthetic. 2. The terpenoids include menthols, camphors, borneols, geraniol, cineol,
The ophthalmic composition according to claim 1, which is at least one selected from linalool, eucalyptus oil, bergamot oil, fennel oil, and rose oil. 3. The water-soluble polymer compound is at least one of methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium hyaluronate, and sodium chondroitin sulfate. The ophthalmic composition according to. 4. The ophthalmic composition according to claim 1, wherein the local anesthetic is at least one of chlorobutanol, lidocaine, lidocaine hydrochloride, dibucaine hydrochloride, and oxybuprocaine hydrochloride. 5. The ophthalmic composition according to claim 1, which is used for at least one of eye drops, eye wash, and contact lens mounting liquid. 6. The ophthalmic composition according to any one of claims 1 to 5, wherein the water-soluble polymer compound is a refreshing feeling-maintaining agent. 7. A method for sustaining a cooling sensation, which comprises blending a terpenoid, a water-soluble polymer compound, and a local anesthetic.