JPS61249918A - Eye drops - Google Patents

Abstract

PURPOSE:Eye drops having much more improved durability of absorption in eye tissue than well-known type eye drops and no toxicity except side effects of eye disease remedy of its own, comprising lipid microspheres containing eye disease remedy. CONSTITUTION:The titled dye drops comprising liquid microspheres which have about 0.1-1.0mu average particle diameter and contain eye disease remedy with extremely improved shelf stability, obtained by heating a mixture of (a) about 5-50w/v% oily component, preferably soybean oil, (b) about 1-50pts.wt. based on 100pts.wt. oily component of an emulsifying agent, preferably lecithin, (c) a proper amount of, preferably 0.01-1.2w/v% eye disease remedy, and, if necessary, an emulsification auxiliary, a stabilizer and an isotonic agent at 30-80 deg.C, making the mixture uniform by a homogenizer, adding a necessary amount of sterilized water to the mixture and homogenizing the mixture by the homogenizer.

Description

[Detailed description of the invention] [Industrial application field] The present invention relates to eye drops.

[Prior Art and Problems to be Solved by the Invention] Various eye drops have been known so far, but most of them are in the form of a solution or suspension of a drug for treating eye diseases. Various studies have been conducted to improve the absorption and action of eye drops into the eye tissue.For example, methylcellulose, polyvinyl alcohol,
Water-soluble polymers such as hydroxypropyl methylcellulose have been used, but they are not sufficient.

Additionally, adrenocortical hormone eye drops are used to treat eye lesions caused by Behcet's disease, of which the number of patients has been increasing recently. However, the transfer of these eye drops to the various intraocular tissues is not sufficient, and for lesions in the eye, it is necessary to use both whole-house administration and intraocular injection. Therefore, side effects of the adrenocortical hormone itself are likely to occur.

In addition, recently, a new therapy of oral administration of cyclosporine has been tested for corneal transplantation, but this also tends to cause side effects on the kidneys and the like.

The present inventors have discovered the present invention as a result of research into eye drops that have a long-lasting effect and absorption into the Kusaka tissues that cannot be achieved with conventional eye drops, and which have no side effects.

[Means for solving problems]

That is, the present invention relates to eye drops made of lipid microspheres (hereinafter referred to as LMS) containing a therapeutic agent for eye diseases.

The eye disease therapeutic agent used in the eye drops of the present invention may be any drug that is generally used for the treatment of eye diseases. For example, corticosteroids (e.g. cortisone acetate, hydrocortisone acetate, prednisolone acetate, dexamethacin, dexamethacin sodium metasulfobenzoate, dexamethacin sodium sulfate, dexamethacin sodium phosphate, betamethacin sodium phosphate,
cyclosporin; antibiotics (e.g. erythromycin, erythromycin lactobionate, kanamycin sulfate, bekanamycin sulfate, gentamicin sulfate, dibekacin sulfate, tobramycin, micronomycin sulfate); , tetracycline hydrochloride, oxytetracycline hydrochloride, chloramphenicol, etc.); non-steroidal anti-inflammatory agents (e.g. water-soluble azulene, flubiprofen, indomethacin, glycyl phosphate, etc. and their esters); cataract treatment agents (e.g. catalin, cineraria, 5.12-dihydroazabentacene disulponate sodium, glutathione, etc.); glaucoma therapeutic agents (eg, timolol, befunolol, etc.), and the like. These may be used alone or in combination. If necessary, a preservative or the like may be added to the eye drops of this other invention.

The eye drops of the present invention are produced by adding the above-mentioned eye disease therapeutic agent to the conventional production of LMB. For example, soybean oil, cottonseed oil, sesame oil, sunflower oil, tori and pea oil, squalene, stingray, etc. are preferably used as oil components, and nonionic surfactants and phospholipids (lecithin, hydrogenated lecithin) are used as emulsifiers. Preferably, lecithin is used, the oil component is about 5 to 50% (W/v), and the emulsifier is added to the oil component in an amount of about 5 to 50% (W/v).
About 1 to 50 parts by weight and an appropriate amount of a drug for treating eye diseases are used and mixed with 00 parts by weight. At this time, if necessary, emulsification aid (e.g. C6-22 within 0.31 b (w/v))
fatty acids), stabilizers (e.g. 0.5% (vr/v
) and tonicity agents (such as glycerin) may be added. The amount of eye disease treatment drugs used varies depending on the type, symptoms, etc., but the amount used is the amount that these drugs are approved for as eye drops, for example 0.005
~2 To (w/v), preferably 0.01-1.2
It is (vr/v). Next, the mixture is heated to 30 to 80° C., homogenized using a homogenizer, etc., and then the required amount of sterilized water is added and homogenized again using a homogenizer. The obtained LMS is
Its average particle diameter is about 0.1 to 10 μm, and its storage stability is extremely good.

The eye drops of the present invention are used by instilling the eye drops several times a day.

Furthermore, the eye drops of the present invention have no toxicity other than the side effects inherent to the eye disease therapeutic agent it contains.

Although the eye drops of the present invention have been described above as eye drops, LMS-containing eye ointments can also be produced according to conventional methods.

〔Example〕

Next, examples will be shown.

Example 1 Refined soybean oil 100f, refined egg yolk lecithin 25? , sodium oleate o, osr and hydrocortiscin, 1
7-putylate, 21-propionate 1? 65~7
The mixture was heated to 5°C and homogenized using a homomixer. Next, add 5% of glycerin and 870% of sterilized water, and use a Manton-Gallalin type homogenizer to make the first stage 120 kg.
/cat 2 and a total pressure of 500 ky/cm 2 for 10 passes to emulsify. The obtained product was a fine emulsion with a particle size of about 0.2μ.

Example 2 In order to increase the concentration of hydrocortiscin, 17-butyrate, and 21-propionate in a fat emulsion in Example 1, a fat emulsion was prepared by replacing soybean oil with eicosapentaenoic acid.

That is, 10 t of eicosapentaenoic acid, 1.2 F of purified egg yolk lecithin, sodium oleate α05, 500 g of hydrocortiscin, 17-butylate, 21-propionate, and 2.5 t of glycerin were added, and the total amount was diluted to 100 d with sterile distilled water. and emulsified using the same procedure as in Example 1. The obtained product had an average particle diameter of α1μ and had good storage stability.

Example 3 10 t of purified soybean oil, 1.2 F of purified egg yolk lecithin, and 200 mg of cyclosporin were heated and mixed at 65 to 75°C, 2.5 fP of glycerin was added, and the total amount was diluted to 10 t with sterile purified water.
0-, and emulsified in the same manner as in Example 1. The obtained product was a fine emulsion with a particle diameter of α1 to tOμ. Storage stability was good, and no change in particle size was observed.

Example 4 In the method of Example 2, Azone (*
A fat emulsion containing erythromycin was prepared using 1-dodecylhexahydro-2H-azepin-2-one (1-dodecylhexahydro-2H-azepin-2-one). That is, Azone 10t1, refined egg yolk lecithin t2t, erythromycin 500mg, and chrycerin 2.52% were mixed, and the total amount was diluted to 100% with sterile distilled water.
- Stitching and emulsification using the same procedure as in Example 1. The obtained product was a fine emulsion with an average particle size of 0.2 μm.

Storage stability was good.

〔effect〕

The effects of the eye drops of the present invention are shown below.

According to the method of Example 1, 5H-labeled hydrocortiscin, 17-butyrate, 21-propionate 14.6μ
An eye drop containing C1/1.4 q/- was produced (hereinafter referred to as eye drop A).

While 3H-labeled hydrocortiscin, 17-butyrate, 21-propionate, o, oss polysorbate 8
0 (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.) to make a suspension for eye drops, and the concentration was set to 66.5 μCi/a 27 Q/d (hereinafter referred to as
(referred to as eye drops B).

Measurement of drug concentration in intraocular tissue after instillation
Using 4 kg of New Sealant white rabbits, they were divided into two groups, ophthalmic solution A or B administration group, and 6 eyes in each group were compared. The amount of eye drops to be used was 20 μt/time. 1 hour and 3 hours after instillation, bentoparbitone sodium was injected into the ear vein, the eyeball was removed, each intraocular tissue was separated, and tulene ( Soluene 350) (manufactured by Barakat) K Soluene 35 by soaking for 4 days and decomposing
0 was added, and the contents of 3H-labeled hydrocortiscine, 17-butyrate, and 21-propionate in each intraocular tissue were determined using a liquid scintillation counter. Results first
Shown in the table. The numerical value is -the 3H content of each tissue relative to the 3H of the total amount of instilled fluid.

Table 1 As can be seen from Table 1, the data 3 hours after instillation revealed that eye drops A penetrated and accumulated the drug in each ocular tissue compared to eye drops B. This fact is
This shows that the eye drops of the present invention have far superior effects compared to eye drops of conventional dosage form.

Claims (1)

[Claims] Eye drops made of lipid microspheres containing a drug for treating eye diseases.