JP2002332225A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition containing a hydrophobic oxidizable substance, in which the appearance of a preparation is clear and the stability of the compound itself is enhanced even when the amount of a surfactant is reduced. I do. An ophthalmic composition containing a hydrophobic easily oxidizable substance and prepared by high-energy emulsification. Examples of the hydrophobic easily oxidizable substances include vitamin A, vitamin D, vitamin E, vitamin K,
Examples include macrophene antibiotics such as diphenhydramine, indomethacin, tacrolimus (FK506) and rifampicin, and foscholine. Examples of high energy emulsification include high-pressure emulsification, ultrasonic emulsification, and high-speed concentrated shearing emulsification.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an ophthalmic composition containing a hydrophobic oxidizable substance, and more particularly to an oil-in-water ophthalmic composition which is stable even when the amount of a surfactant is reduced.

[0002]

2. Description of the Related Art Generally, when a hydrophobic easily oxidizable substance is prepared in an aqueous solution, a surfactant or a solubilizing agent is used.
It is necessary to emulsify or solubilize and furthermore to be easily oxidized by dissolved oxygen, so that the appearance of the preparation and the stability of the compound itself must be enhanced.

[0003] Therefore, when preparing a hydrophobic easily oxidizable substance into an aqueous solution, various antioxidants and stabilizers have been conventionally developed, an optimum surfactant is selected, and a micelle size is controlled. A variety of technologies for improving stability have been created and used, such as the suppression of oxidation from the packaging surface, such as replacing the head space inside the container and the interior of the package with nitrogen.
At present, a stable product has not yet been obtained.

When the amount of the surfactant used for emulsification and solubilization is large, it causes irritation to the eyes and skin, but when the amount of the surfactant is small, the hydrophobic oxidizing substance can be sufficiently removed. Since emulsification and solubilization are not possible, there is a problem that the stability of the appearance of the preparation cannot be maintained.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned conventional problems and the current situation, and is intended to solve the problem. Even if the amount of surfactant is reduced, the appearance of the preparation is clear,
An object of the present invention is to provide an ophthalmic composition containing a hydrophobic oxidizable substance and having enhanced stability of the compound itself.

[0006]

Means for Solving the Problems The present inventors have conducted intensive studies on the above-mentioned conventional problems and the like. As a result, by preparing a composition by high-energy emulsification, a stable emulsification with a small amount of surfactant was achieved. -It has been found that an ophthalmic composition that can be solubilized and that can significantly increase the stability of a hydrophobic easy oxide can be obtained, thereby completing the present invention. That is, the present invention resides in the following (1) to (4). (1) An ophthalmic composition containing a hydrophobic easily oxidizable substance and prepared by high-energy emulsification. (2) The content of the surfactant is 0.5 to the total amount of the composition.
g / 100 ml or less, the ophthalmic composition according to (1) above, (3) The ophthalmic composition according to the above (1) or (2), wherein the hydrophobic easily oxidizable substance is a fat-soluble vitamin. (4) The ophthalmic composition according to any one of the above (1) to (3), wherein the micelle size in the composition is 0.1 μm or less.

[0007]

Embodiments of the present invention will be described below in detail. The ophthalmic composition of the present invention contains a hydrophobic easily oxidizable substance and is prepared by high-energy emulsification.

[0008] The hydrophobic easily oxidizable substance in the present invention includes Japanese Pharmacopoeia, Japanese Pharmacopoeia Standards, Pharmaceutical Excipients Dictionary, Pharmaceutical Excipients Standard, Cosmetic Ingredients Standard, Cosmetic Variety Component Standards, and Food Additives Official Among the listed components, substances that are "slightly soluble" in water and "almost insoluble" can be used, and include all substances that undergo oxidative decomposition. Specific oxidizable substances include vitamin A, vitamin D, vitamin E, vitamin K, diphenhydramine, indomethacin, tacrolimus (FK506), macrolite antibiotics such as rifampicin, and foskolin.
It is not limited to these. Examples of the vitamin A include retinol, β-carotene, retinol palmitate, retinoic acid, and derivatives thereof. Examples of vitamin D include, for example, cholecalciferol, 1α, 25-dihydroxycholecalciferol and derivatives thereof. Examples of vitamin Es include α-tocopherol and d-α-acetic acid.
Examples include tocopherol and derivatives thereof, and examples of vitamin Ks include phytylmenadione and derivatives thereof. These hydrophobic oxidizable substances can be used alone or in combination of two or more. Preferred hydrophobic easily oxidizable substances are useful as ophthalmic substances, and therefore, retinol palmitate and d-acetate.
Macrolite antibiotics such as α-tocopherol, tacrolimus (FK506) and rifampicin, and fat-soluble vitamins such as forskolin are preferred.

The amount of the above-mentioned hydrophobic easily oxidizable substance is 0.0001 to 20 g / 100 ml, preferably 0.0005 to 10 g / 100 ml, based on the total amount of the composition. 0.0001 g / 1 of hydrophobic oxidizable substance
If the amount is less than 00 ml, the effectiveness is not exhibited.
If it exceeds 0 g / 100 ml, side effects may be caused.

In the present invention, various surfactants can be used, if necessary, and nonionic surfactants usually used for ophthalmology are preferred from the viewpoint of safety. Nonionic surfactants that can be used include:
For example, polyoxyethylene hydrogenated castor oil 60 [for example, HCO-60 (manufactured by Nippon Surfactant Industry Co., Ltd.)], polyoxyethylene (20) sorbitan monooleate [for example, TO-10 (Japan Surfactant Industry Co., Ltd.) Co., Ltd.)], polyoxyethylene polyoxypropylene block copolymer [for example, Poloxamer-407
(Manufactured by NOF CORPORATION)] and the like, but are not limited thereto. These various surfactants can be used alone or in combination of two or more.

The amount of the surfactant is 0.5 g / 100 ml or less based on the total amount of the composition in consideration of irritation to the eyes and sufficient emulsification and solubilization of the hydrophobic oxidizable substance. Is desirable, preferably 0.0001 to
0.5 g / 100 ml, more preferably 0.0005
０．３0.3 g / 100 ml. If the amount of the surfactant is more than 0.5 g / 100 ml, irritation to eyes is increased, which is not preferable.

Further, the ophthalmic composition of the present invention may further contain, in addition to the above-mentioned components, if necessary, various components usually used for preparing ophthalmic compositions such as eye drops in the usual amounts. be able to. For example, anti-inflammatory agents such as dipotassium glycyrrhizinate, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysozyme chloride, flavin adenine dinucleotide sodium (active vitamin B2), pyridoxine hydrochloride (Vitamin B6), cyanocobalamin (vitamin B12), vitamins such as vitamin E acetate, calcium pantothenate, sodium pantothenate, retinol acetate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, naphazoline hydrochloride, naphazoline nitrate,
Decongestant components such as phenylephrine hydrochloride and tetrahydrozoline hydrochloride; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; sulfa drugs such as sulfamethoxazole, sodium sulfamethoxazole, sulfisoxazole, and sodium sulfisomidine. , Cromoglycic acid, sodium cromoglycate, tranilast, anti-allergic agents such as potassium pemirolast,
Potassium L-aspartate, magnesium L-aspartate, potassium magnesium L-aspartate (mixture of equal amounts), aminoethylsulfonic acid (taurine), sodium chondroitin sulfate, epsilon aminocaproic acid, L-glutamic acid, sodium L-glutamate and the like. Active ingredients such as amino acids, neostigmine methyl sulfate, inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate, dried sodium carbonate, magnesium sulfate, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate (edetate) Sodium), an antioxidant such as dibutylhydroxytoluene (BHT) and ascorbic acid, a dissolution aid such as ethylene glycol and propylene glycol, menthol, Perfume (cooling agent) such as influ, borneol, geraniol, linalool, cineole, cool mint, peppermint water, peppermint oil, fennel oil, bergamot oil, eucalyptus oil, methylcellulose , Ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, hyaluronic acid Additives such as a thickener such as sodium and a local anesthetic such as chlorobutanol can be blended within a range that does not impair the effects of the present invention.

The ophthalmic composition of the present invention can be obtained by preparing an easily oxidizable substance containing each of the above components by high-energy emulsification. In the present invention, "high energy emulsification" refers to emulsification in which emulsification energy is intensively applied to a liquid during emulsification of oil and water, for example, as described in detail below
(1) High-pressure emulsification, (2) ultrasonic emulsification, and (3) high-speed concentrated shearing type emulsification.

(1) High-energy emulsification by high-pressure emulsification This high-pressure emulsification is preferably carried out at a processing pressure of about 200 to 3000 atm, more preferably 800 to 25 atm.
The number of passages through the high-pressure emulsification apparatus is set to about 1 to 5 times at a pressure of 00 atm. In the case of using this high-pressure emulsification, it is desirable to carry out a coarse emulsification in advance and further to carry out a treatment with a high-pressure emulsifier. Coarse emulsification is the usual emulsification method,
Preferably, the oil phase is added to the aqueous phase under high shear and emulsified. As an apparatus, an azihomomixer, a disper mixer, or the like can be used. As an apparatus used for the high-pressure emulsification, for example, Gorin (AP
V Runny Co., Ltd.), Microfluidizer (Microfluidics Co., Ltd.), Ultimizer (Sugino Machine Co., Ltd.), high-pressure jet emulsifier (Nippon BEE Co., Ltd.), wet jet mill (Genus Co., Ltd.), Soavi-Niro ( (Manufactured by Niro Co., Ltd.) or a nanomizer.

(2) High energy emulsification by ultrasonic emulsification This ultrasonic emulsification can be performed using an ultrasonic emulsifier. Examples of the ultrasonic emulsifier include an ultrasonic homogenizer (manufactured by Nippon Seiki Seisakusho) equipped with an ultrasonic generating unit and an ultrasonic homogenizer (manufactured by Ultrasonic Industry Co., Ltd.). As a processing method, the water phase and the oil phase are combined and continuously supplied to the apparatus, and then processed by passing through an ultrasonic unit. This ultrasonic emulsification is preferably carried out at a normal ultrasonic oscillation level of the apparatus for about 15 minutes.

(3) High-energy emulsification by high-speed concentrated shearing emulsification This high-speed concentrated shearing emulsification can be performed using a high-speed homogenizer (loop type, injection type) or the like. Examples of the high-speed homogenizer (loop type) include a milder (manufactured by Ebara Corporation). As a processing method of the loop type high-speed homogenizer, an oil phase can be fed to an aqueous phase circulation line connecting a tank and an emulsifier. In addition, examples of the high-speed homogenizer (injection type) include CLEARMIX (manufactured by M Technique) and Polytron. As a processing method of this injection type high-speed homogenizer, an oil phase is added to an aqueous phase under high shearing and emulsified. This high-speed concentrated shearing emulsification reduces the peripheral speed of the rotating blades to 15
It is preferable to rotate at a high speed of about 30 m / s, and more preferably to apply a shearing force of about 20 to 30 m / s.

The liquid temperature at the time of preparing each of the above-mentioned high-energy emulsifications is desirably about 30 to 80 ° C., preferably about 35 to 60 ° C. for all the apparatuses. Further, since the applied energy is large, a part of the liquid is converted into heat energy and may lead to a rise in the liquid temperature. Therefore, it is preferable to cool the liquid during and after emulsification.

In the ophthalmic composition of the present invention, the easily oxidizable substance containing each of the above components is prepared by high energy emulsification. Preferably, the micelle in the composition at a liquid temperature of 25 ° C. is used. The size is desirably 0.1 μm or less. The micelle size in the composition is 0.1 μm
If it exceeds the following, the appearance of the liquid tends to be impaired. By setting the micelle size in the composition to 0.1 μm or less,
Its appearance is more translucent to transparent (clear). That is, when the micelle size is 0.1 μm or less, the liquid becomes finer than the wavelength of visible light, and the liquid easily transmits light, so that the appearance of the liquid becomes more translucent to transparent by visual observation. In addition, the pH of the ophthalmic composition of the present invention is 5 to 8, in consideration of irritation to the eyes and safety, by a pH adjuster or the like.
Preferably, it is adjusted to around 7.

The ophthalmic composition of the present invention constituted as described above has a clear appearance even when the amount of surfactant is reduced.
Further, an ophthalmic composition containing a hydrophobic oxidizable substance and having improved stability of the compound itself can be obtained. The ophthalmic composition of the present invention can be used as eye drops, eyewashes and the like irrespective of medical or commercial use. Further, the ophthalmic composition of the present invention has a small amount of a surfactant and a small amount of irritation to the eyes, so that an ophthalmic solution for a dry eye patient or a hard contact lens having a small amount of tears, an oxygen-permeable type. -It is useful as a contact eye drop which can be instilled while wearing a contact lens, a soft contact lens, a frequently exchangeable soft contact lens, and a daily exchangeable soft contact lens. It is also useful as a single-use eye drop containing no preservative.

[0020]

Next, the present invention will be described in detail with reference to examples and comparative examples, but the present invention is not limited to the following examples.

Example 1 (Preparation of Ophthalmic Composition) In an appropriate amount of purified water, 10 g of boric acid, 2 g of borax, 0.1 g of sodium edetate, 5 g of sodium chloride, 0.5 g of pyridoxine hydrochloride, neostigmine methyl sulfate 0.05 g, epsilon-aminocaproic acid 10 g, chlorpheniramine maleate 0.3 g, tetrahydrozoline hydrochloride 0.1
g and stirred with a magnetic stirrer (about 30
0 rpm) to completely dissolve. Separately, 0.3 g of retinol palmitate (1.7 million international units / g), d-α acetate
0.5 g of tocopherol, 0.03 g of dibutylhydroxytoluene, polyoxyethylene hydrogenated castor oil 60
1 g was mixed and dissolved at 50 ° C., added to the aqueous solution heated to 70 ° C., and stirred and mixed with a magnetic stirrer (about 300 rpm, about 20 minutes). This was placed in a microfluidizer (M-
110EH, manufactured by Mizuho Kogyo Co., Ltd.) and emulsified with high energy (processing pressure: 1000 atm), and beforehand, 0.08 g of l-menthol was added to 5 g of propylene glycol, and dl-
A mixture of 0.05 g of camphor and 0.05 g of d-borneol and a benzalkonium chloride solution (10%)
0.3 g was added, and the mixture was dissolved by stirring with a magnetic stirrer (about 300 rpm), and purified water was added to make a total volume of 1000 ml. This is applied to a 0.2 μm filter
The solution was aseptically filtered and filled in a PET container to obtain an eye drop (ophthalmic composition).

[Examples 2 to 8 and Comparative Examples 1 and 2 (Preparation of Ophthalmic Composition)] Examples 2 to 8 and Comparative Examples 1 and 2 also have the composition shown in Table 1 below and the respective emulsions. According to the method, an eye drop (ophthalmic composition) was prepared in the same manner as in Example 1 above.

For each of the obtained ophthalmic compositions, the micelle size was measured, the appearance was observed, the stability of the hydrophobic oxidizable substance was evaluated, and the eye irritation test was carried out by the following methods, and evaluated. The results are shown in Tables 1 and 2 below.

[Method of Micelle Size Measurement] The volume average diameter at 25 ° C. was measured using a particle size analyzer (Microtrac UPA, manufactured by Nikkiso Co., Ltd.).

[Evaluation Method of Appearance] After the test solution was sealed in a glass ampoule (20 ml in content, the same applies hereinafter),
Weekly severe storage was performed. The appearance of the liquid before and after storage was visually observed under a brightness of 4000 Lux or more using a white or black background, and evaluated according to the following evaluation criteria. Evaluation Criteria: 極: Ultrafine milky light to clear colorless ○: Milky light to slightly milky light △: Milky light slightly opaque ×: Precipitation to cloudy

[Method for Evaluating Stability of Hydrophobic Oxidizable Substance] After the test solution was sealed in a glass ampule, it was subjected to severe storage at 70 ° C. for one week. For the liquid after storage, the mass of the hydrophobic easily oxide (retinol palmitate, d-α acetate) was determined by HPLC.
-Tocopherol), and the residual ratio of the hydrophobic oxidizable substance was determined by the following formula, and evaluated according to the following evaluation criteria. Residual rate of hydrophobic oxidizable substance (%) = (mass of hydrophobic oxidizable substance after storage / mass of hydrophobic oxidizable substance before storage) × 100 Evaluation criteria: ◎: residual rate is 90% or more ：: residual rate Is 80% or more and less than 90% Δ: Residual rate is 70% or more and less than 80% ×: Residual rate is less than 70%

[Eye irritation test method] Evaluation of eye irritation was carried out in accordance with the short-term test method for ocular mucosal irritation test of an ophthalmic preservative in the Ministry of Health and Welfare Scientific Research Report (1970). evaluated. Evaluation criteria: ：: Average score by the Draize method is 0 or more and less than 2 points Δ: 2 or more by the Draize method and less than 5 points ×: 5 or more points by the Draize method

[0028]

[Table 1]

[0029]

[Table 2]

As is evident from the results of Tables 1 and 2, Examples 1 to 8 which fall within the scope of the present invention reduce the surfactant compared with Comparative Examples 1 and 2 which fall outside the scope of the present invention. However, it was found that an excellent ophthalmic composition containing a hydrophobic oxidizable substance, which had a clear appearance of the preparation and enhanced the stability of the compound itself, was obtained. In the above Examples 1 to 8, high energy emulsification was performed using a microfluidizer, but high energy emulsification performed by emulsifying for 15 minutes using an ultrasonic emulsifier instead of the microfluidizer, or high-speed emulsification was performed. Even in high energy emulsification by emulsification at a blade peripheral speed of 25 m / s by a shearing type emulsifier,
As in Examples 1 to 8, an excellent ophthalmic composition containing a hydrophobic easily oxidizable substance was obtained, in which the appearance of the preparation was clear and the stability of the compound itself was enhanced.

[Example 9: (Preparation of ophthalmic composition)] In an appropriate amount of purified water, 15 g of boric acid, 0.5 g of borax, 0.1 g of sodium edetate, 0.1 g of pyridoxine hydrochloride, chlorpheni maleate Add 0.03 g of lamin and stir (about 300 rpm) with a magnetic stirrer to completely dissolve. Separately, retinol palmitate (170
10,000 international units / g) 0.03 g, d-α-tocopherol acetate 0.05 g, dibutylhydroxytoluene 0.03 g
g, polyoxyethylene hydrogenated castor oil 60 0.3 g was mixed and dissolved at 50 ° C., added to the aqueous solution heated to 70 ° C., and stirred with a magnetic stirrer (about 300 rpm, about 20 minutes). ), Mixed. This was placed in a microfluidizer (M-110) kept at about 40 ° C.
EH, manufactured by Mizuho Industry Co., Ltd.), repeated three times with high-energy emulsification (processing pressure: 1000 atm), beforehand adding 1.07 g of l-menthol to 5 g of propylene glycol, d
A mixture of 0.03 g of l-camphor and 0.3 g of benzalkonium chloride solution (10%) was added, and the mixture was dissolved by stirring (about 300 rpm) with a magnetic stirrer. To 1000 ml. This was aseptically filtered through a 0.2 μm filter to obtain PE.
It was filled in a container made of T and used as an eyewash (preparation of an ophthalmic composition). With respect to the obtained eyewash, the micelle size was measured, the appearance was observed, the stability of the hydrophobic oxidizable substance was evaluated, and the eye irritation test was performed by the above-described methods. Observation: ◎, 70 ° C immediately after production
・ The stability of the hydrophobic oxidizer after storage for one week is both ◎
And the eye irritation test was Δ.

[0032]

According to the present invention, there is provided an ophthalmic composition containing a hydrophobic oxidizable substance, which has a clear appearance of the preparation and enhances the stability of the compound itself even when the surfactant is reduced. Provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/18 A61K 47/18 47/22 47/22 47/34 47/34 A61P 27/02 A61P 27 / 02 // A61K 31/27 A61K 31/27 31/4174 31/4174 (72) Inventor Masahiko Matsubara 1-3-7 Honjo, Sumida-ku, Tokyo Inside Lion Corporation (72) Inventor Hiroaki Umezawa Tokyo 1-7-7 Honjo, Sumida-ku F-term in Lion Corporation (reference) 4C076 AA17 BB24 CC10 DD01 DD09 DD17 DD21 DD22 DD59 DD60 EE23 FF36 FF43 FF51 FF65 4C086 AA01 AA02 BC38 MA58 NA03 NA06 ZA33 4C206 AA01 NAA02 NA06 ZA33

Claims (4)

[Claims] 1. An ophthalmic composition containing a hydrophobic oxidizable substance and prepared by high-energy emulsification. 2. The ophthalmic composition according to claim 1, wherein the content of the surfactant is 0.5 g / 100 ml or less based on the total amount of the composition. 3. The ophthalmic composition according to claim 1, wherein the hydrophobic oxidizable substance is a fat-soluble vitamin. 4. The composition according to claim 1, wherein the micelle size is 0.1 μm.
The ophthalmic composition according to any one of claims 1 to 3, wherein: