WO2002076442A1

WO2002076442A1 - Stable aqueous liquid preparation

Info

Publication number: WO2002076442A1
Application number: PCT/JP2002/002877
Authority: WO
Inventors: Yutaka Morishita; Norihisa Hatano; Kenji Morishima
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2001-03-27
Filing date: 2002-03-26
Publication date: 2002-10-03

Abstract

An aqueous preparation which contains a solubilized vitamin A, has a transparent appearance, and is stable over long. The aqueous liquid preparation, which is stable over long, can be obtained by incorporating a vitamin A and polyoxyethylene castor oil. The stability of the aqueous liquid preparation is improved further by incorporating a vitamin E and ethylenediamine tetraacetate (or a salt thereof) besides the vitamin A and polyoxyethylene castor oil.

Description

Description Stable aqueous liquids Technical field

TECHNICAL FIELD The present invention relates to a stable aqueous solution characterized by blending a bimin A and a polyoxyethylene castor oil, and particularly to an aqueous solution which can be suitably used for ophthalmic pharmaceutical preparations such as eye drops. Background art

Vitamin A is a component that is essential for maintaining vital functions. In particular, deficiency of bimin A in the eyes causes various eye diseases such as night blindness and keratoconjunctivitis. Therefore, attempts have been made to supplement vitamin A with eye drops.

However, vitamin A has extremely low solubility in water, and even if it can be dissolved in water, it tends to become cloudy and precipitate over time. Vitamin A is an unstable substance, and if it is used as an aqueous preparation, it will be degraded in a short period of time, and it will be extremely difficult to stably store an aqueous preparation containing biminmin A over a long period.

Therefore, in order to commercialize an aqueous preparation containing vitamin A, for example, JP-A-3-38519 contains a nonionic surfactant such as polyoxyethylene hydrogenated castor oil and liquid paraffin. It has been proposed to stabilize the ophthalmic solution containing vitamin A by the following method. Japanese Patent Application Laid-Open No. 6-24783 discloses the use of polyoxyethylene hydrogenated castor oil, vitamin E and ethylenediaminetetraacetic acid. Thus, it has been proposed to solubilize vitamin A and stabilize eye drops over time. As mentioned above, the power that polyoxyethylene hydrogenated castor oil is effective in solubilizing and stabilizing the ophthalmic solution of vitamin A is already known The effect is still insufficient There is a need for the development of ophthalmic compositions having better stabilizing effects. Disclosure of the invention

Accordingly, the present inventors have conducted intensive studies to solubilize vitamins A to obtain an aqueous preparation which is stable for a long period of time, and found that by blending polyoxyethylene castor oil, a known polyoxyethylene cured product was obtained. It has been found that a stabilizing effect superior to the case where castor oil is blended is exhibited. In addition, they found that the stability of the aqueous solution was enhanced by adding vitamin Es and ethylenediaminetetraacetic acid to the aqueous solution. That is, the aqueous liquid preparation of the present invention contains at least vitamins A and polyoxyethylene castor oil as its compounding components.

In the present invention, the vitamin A includes, in addition to vitamin A itself, a mixture containing vitamin A such as vitamin A oil, a derivative having vitamin A activity such as retenal, retinoic acid, and a fatty acid ester of vitamin A. It is. Specifically, there are 1.7 million international units (I.U.) / G of retinol palmitate manufactured by Roche Co., Ltd. of Japan.

The amount of the vitamin A in the aqueous solution is not particularly limited, but is 0.001 to 2.0% by weight, and more preferably 0.003 to 1.0% by weight. The amount of vitamin A may be appropriately selected in consideration of the use of the aqueous liquid formulation and the like.For example, when used as eye drops, the amount of vitamin A is 0.05 to 0.5. It is desirable to make it 5% by weight.

Polyoxyethylene castor oil is obtained by addition polymerization of castor oil with ethylene oxide. Depending on the difference in the average number of moles of ethylene oxide (P), for example, polyoxyethylene (p = 20) castor oil, polyoxyethylene Ethylene (p = 35) castor oil, polyoxyethylene (p = 60) castor oil, and the like. Specific examples include Cremophor manufactured by B-85, Nikkor CO—20T manufactured by Nikko Chemicals Co., Ltd. X, CO-6 OTX, etc.

On the other hand, known polyoxyethylene hydrogenated castor oil is obtained by addition polymerization of hydrogenated castor oil with hydrogen added to the double bond of castor oil and acetic acid, and the difference in average number of moles of ethylene oxide (P) For example, polyoxyethylene (p = 5) hydrogenated castor oil, polyoxyethylene (p = 20) hydrogenated castor oil, polyoxyethylene (p = 40) hydrogenated castor oil, polyoxyethylene (p = 60) hydrogenated castor oil, etc. However, its chemical properties are completely different from polyoxetylene castor oil.

The amount of the polyoxyethylene castor oil in the aqueous liquid formulation is not particularly limited, but is 0.001 to 5.0% by weight, and more preferably 0.01 to 3.0% by weight. Since polyoxyethylene castor oil is blended to solubilize and stabilize vitamins A, it is desirable that the blending amount be as small as possible as long as the transparency and stability of the aqueous solution containing vitamins A is maintained.

The aqueous liquid preparation of the present invention may contain vitamin Es, ethylenediaminetetraacetic acid or a salt thereof. By mixing vitamin Es, the aqueous solution is more stabilized, and when ethylenediaminetetraacetic acid or a salt thereof is added, the aqueous solution is further stabilized.

In the present invention, vitamins E are used not only for the purpose of stabilizing the aqueous preparation but also as an effective drug by itself. That is, it is said that vitamins E have an antioxidant effect and are closely related to disorders of blood circulation, improvement of blood flow retention in capillaries, and suppression of oxidation of the lens of the eye. Examples of vitamin Es include tocopherol, tocopherol acetate, and tocopherol succinate. The amount of vitamin E is 0.001 to 1.0% by weight, more preferably 0.01 to 0.5% by weight. If the amount of vitamin E is less than 0.001% by weight, the stabilizing effect of vitamin E is reduced.

As the salt of ethylenediaminetetraacetic acid, tetrasodium salt and disodium salt (sodium edetate) can be preferably used. Ethylenediaminetetraacetic acid or its salt Is from 0.0001 to 0.5% by weight, more preferably from 0.005 to 0.3% by weight. If the amount of ethylenediaminetetraacetic acid or a salt thereof is less than 0.001% by weight, the stabilizing effect of ethylenediaminetetraacetic acid or a salt thereof is reduced.

The aqueous liquid preparation of the present invention has high safety for the human body and is particularly preferably used as eye drops. Further, since the aqueous liquid preparation of the present invention has little adsorption to contact lenses and plastic containers, it can be used as eye drops for contact lens wearers. It can also be used as an aqueous solution for food. In order to prepare these aqueous solutions, in addition to the above-mentioned components, additional components such as tonicity agents, buffers, pH regulators, preservatives, thickeners, drugs other than vitamins A and E, Examples of the tonicity agent to which a fragrance such as 1-menthol can be appropriately added include glycerin, propylene glycol, polyethylene glycol, sodium salt sodium, potassium salt sodium, sorbitol, mannitol and the like.

As the buffer, for example, citric acid, boric acid, sodium hydrogen phosphate, glacial acetic acid, tromethol, epsilon-amino diprotic acid and the like can be mentioned. Examples of the pH regulator include citric acid, phosphoric acid, acetic acid, 7K sodium oxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

Examples of preservatives include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, paraoxybenzoate, sodium benzoate, dibutylhydroxytoluene, chlorobutanol, and chlorhexidine dalconate. it can.

Examples of the thickener include cellulosic polymers such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, and hydroxyethylcellulose, and polyvinyl alcohol and polyvinylpyrrolidone. Can be.

When using the aqueous liquid preparation of the present invention as ophthalmic solution, bi evening optionally besides Min A acids and E group, such as various vitamins (vitamin B _2, vitamin B _6, vitamin 8 _{1 2,} Panthenol, etc.), decongestant, tetrahydrozoline, naphazoline, etc.), anti-inflammatory agents (dipotassium dalycyrrhizinate, epsilon-amino cabronate, allantoin, etc.), antihistamines (chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), anti-allergy Drugs (such as sodium cromoglycate), antibacterial agents (such as sulfamethoxazole), amino acids (such as potassium L-aspartate, aminoethylsulfonic acid, and sodium chondroitin sulfate), drugs such as sodium hyaluronate and neostigmine methyl sulfate Can be added.

If necessary, a nonionic surfactant such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 400, etc. is further added to the aqueous liquid preparation of the present invention. can do.

The pH of the aqueous »J of the present invention is preferably in the range of 4 to 8, more preferably 5 to 8. If the pH of the aqueous solution is outside the above range, the stability of vitamin A over time will decrease. When the aqueous liquid preparation of the present invention is used as an ophthalmic solution, the pH is preferably set to 6.5 to 7.5, and the osmotic pressure ratio is preferably set to around 1.0.

The storage container for the aqueous »j of the present invention is not particularly limited, and examples thereof include containers made of materials such as polypropylene, polyethylene terephthalate, and glass.

Hereinafter, the present invention will be described in detail with reference to examples, but this does not limit the scope of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

Test Example 1-: L 3

In order to examine the stability of the aqueous liquid preparation of the present invention, The study (one and two weeks) was performed.

Stability test 1

Aqueous liquids of Test Examples 1 to 5 containing retinol palmitate and polyoxyethylene (p = 35) castor oil (hereinafter referred to as “CO-35”), and hydrogenated castor with retinol palmitate and polyoxyethylene (p = 60) The aqueous liquid preparation of Comparative Example 1 containing oil (hereinafter referred to as “HCO-60”) was prepared by a conventional method. In addition, boric acid was added to each solution as a buffer, and pH was adjusted to 7.0 by adding sodium hydroxide as needed. Each aqueous solution was kept at 60, and the residual ratio of retinopalmitate (vitamin A) after one week was measured using a high performance liquid chromatograph. Table 1 shows the results.

Note) * 1: Retinol palmitate manufactured by Nippon Roche Co., Ltd. 1701. U.

* 2: BASF Cremophor EL [polyoxyethylene (p = 35) castor oil, tan oil]

* 3: Nikkor HC〇-60 manufactured by Nikko Chemicals Co., Ltd. [polyoxyethylene (p = 60) hard castor oil] '

10 Om 1

As is evident from the test results in Table 1 (stored at 60 ° C for 1 week), Test Examples 1 to 5 in which polyoxyethylene castor oil was blended used polyoxyethylene hydrogenated castor oil. Compared with Comparative Example 1, the residual ratio of vitamin A is improved.

Stability test 2

Aqueous liquid preparations having the components shown in Test Examples 6 to 8 and Comparative Example 2 in Table 2 were prepared by a conventional method. Further, boric acid was added as a buffer to each solution, and the pH was adjusted to 7.0 by adding sodium hydroxide as needed. Each aqueous solution was kept at 60 ° C, and after 2 weeks, the residual ratio of retinol palmitate was measured using a high-performance liquid chromatograph. Table 2 shows the results.

-Table 2

* 1, * 2 and * 3 are the same as in Table 1

* 4: Acetic acid d—one tocopherol

Total volume 1 0 0 m 1

In Table 2 (stored at 60 ° C for 2 weeks), the results of the tests containing vitamin E also showed that Test Examples 6 to 8 in which poloxyethylene castor oil was blended were compared with those in which polyoxyethylene hydrogenated castor oil was blended. Compared with Example 2, the residual rate of vitamin A is improved. Stability test 3

Aqueous liquid preparations having the components shown in Test Examples 9 to 13 and Comparative Example 3 in Table 3 were prepared by a conventional method. Further, boric acid was added as a buffer to each solution, and pH was adjusted to 7.0 by adding sodium hydroxide as needed. Keep each aqueous solution at 60 ° C, After one week, the residual ratio of retinol palmitate was measured using a high performance liquid chromatograph. Table 3 shows the results.

Table 3

* 1, * 2, * 3 and * 4 are the same as those in Table 1.

* 5: Sodium edetate

100 m 1

As is clear from the test results in Table 3 (6 O, stored for 2 weeks), Examples 9 to 13 in which polyoxyethylene castor oil, vitamin E and ethylenediaminetetraacetic acid were blended were compared with Test Examples 6 to 8 and Comparative Example 3. As a result, the residual ratio of Bimin A has improved.

Examples 1-4

Formulation examples when the aqueous preparation of the present invention is used as eye drops are shown below.

Example 1

Retinol palmitate 32,500 I.U.

Polyoxyethylene (p = 35) castor oil 0.2 g

D-acetic acid d-tocopherol 0.05 g Sodium edetate 0.05 g Propylene glycol 1.0 g Boric acid 0.5 g Benzalkonium chloride (10% aqueous solution) 0.05 g Dibutylhydroxytoluene 0.005 g

Sodium hydroxide

Sterilized purified water Total volume 100ml (pH 7.0) Example 2

Retinol palmitate 32, 50 0 I. U. Polyoxyethylene (p = 35) Castor oil 0.2 g Acetic acid d-a-tocopherol 0.05% Sodium edetate 0.055 g Pyridoxine hydrochloride 0.1 g aminoethyl sulfonic acid 1.0 g sodium chloride 0.43 g boric acid 0.5 g sodium chloride benzalkonium (10% aqueous solution) 0.05 g dibutylhydroxytoluene 0.005 g dilute hydrochloric acid

Sodium hydroxide

100 ml of sterilized purified water

(pH 7.0) Example 3 Retinol palmitate 32,500 IU Polyoxyethylene (p = 35) Castor oil 0.2 g d--tocopherol acetate 0.05 g g Sodium edetate 0.05 g ibcilon-aminocaproic acid 1.0 g propylene dalicol 1. 0 g Boric acid 0.5 g Shiosai benzalkonium (10% aqueous solution) 0.05 g Dibutylhydroxytoluene 0.005 g dilute concept

Sodium hydroxide

Sterile purified water 00m 1 (ρΗ7.0) Example 4

Retinol luminate 32,500 1. U. polyoxyethylene (p = 35) castor oil 0.2 g d-α-tocopherol acetate 0.05 g sodium edetate 0.05 g gepsilon-aminocaproic acid 1. O g Pyridoxine hydrochloride 0. 1 g Aminoethyl sulfonic acid 1.0 g Sodium hyaluronate 0.05 g g Sodium chloride 0.3 g Boric acid 0.5 g Benzalkonidium chloride (10% aqueous solution) 0.05 g

'' 0.005 g Dilute hydrochloric acid

Sodium hydroxide

100 ml of sterilized purified water

(pH 7.0) Stability test As is evident from the results of 1-3, when polyoxyethylene castor oil is blended, compared with the case of blending known polyoxetylene hardened castor oil, The residual rate of Class A is improved. Industrial applicability

The aqueous solution containing vitamin A and polyoxyethylene castor oil of the present invention has a transparent appearance and can be stably stored for a long period of time, so that night blindness and keratoconjunctiva caused by vitamin A deficiency are caused. It is useful as a prophylactic or therapeutic agent for symptoms such as sickness.

Claims

The scope of the claims

1. A stable aqueous liquid formulation that contains Biyumin A and polyoxyethylene castor oil.

2. A stable aqueous liquid containing vitamin A, polyoxyethylene castor oil and vitamin E.

3. The stable aqueous liquid preparation according to claim 2, further comprising ethylenediaminetetraacetic acid or a salt thereof.

4. Stable aqueous liquid formulation containing 0.001 to 2.0% by weight of vitamin A and 0.001 to 5.0% by weight of polyoxyethylene castor oil

5. Vitamin A 0.001 to 2.0% by weight, polyoxyethylene castor oil 0.001 to 5.0% by weight and vitamin E 0.001 to 1.0% by weight. A stable aqueous solution.

6. The stable aqueous liquid preparation according to claim 5, further comprising 0.0001 to 0.5% by weight of ethylenediaminetetraacetic acid or a salt thereof.

7. The aqueous liquid preparation according to claim 1, wherein the dosage form is an eye drop.