WO2005072744A1

WO2005072744A1 - Vitreous-visualizing agents

Info

Publication number: WO2005072744A1
Application number: PCT/JP2005/001737
Authority: WO
Inventors: Yuichi Kaji
Original assignee: Yuichi Kaji
Priority date: 2004-02-02
Filing date: 2005-02-01
Publication date: 2005-08-11

Abstract

Vitreous-visualizing agents containing suspensions of steroid derivatives satisfying the requirements: (1) they have steroid skeletons, (2) they do not have activity as glucocorticoid or mineralocorticoid, and (3) they dot not have ophthalomotoxicity or systemic toxicity can visualize the vitreous body without causing increased ocular tension, glaucoma, cataract, endophthalmitis, or other complications.

Description

Specification

Vitreous visualization agent

The present invention relates to a vitreous visualization agent, a method for producing the same, and a vitreous visualization method using the same. Background art

The vitreous is a colorless and transparent gel-like substance, and occupies about 80% in the eye. It is known that the vitreous body escapes out of the eye or into the anterior chamber due to cataract, vitreous surgery, perforated eye trauma, etc., causing various ocular complications. In addition, pulling the retina may cause the retina to tear or cause retinal detachment. In addition, the vitreous can proliferate on the surface of the retina and form wrinkles in the retina, leading to a decrease in visual acuity.

In order to prevent or treat these ocular complications caused by the vitreous, the vitreous is resected using a scissors or a dedicated device. In diseases where the vitreous is involved in the pathological condition, it is necessary to completely remove the vitreous. However, since the vitreous body is colorless and transparent, it is impossible to visually recognize and remove the vitreous body. Therefore, at present, surgery is often performed without knowing the position of the vitreous body in many cases, and the vitreous body that is the cause of eye disease is often not completely removed.

A method of visualizing the vitreous body by injecting a suspension of a triamcinsonacetonide preparation having affinity for the vitreous body into the eye and facilitating the vitrectomy is widely used. (See, for example, RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES, 2000, Vol. 20, No. 5.). However, when the triamcinolone acetonide preparation is injected into the eye to visualize the vitreous body, complications due to triamcinolone acetonide that remains in the eye after injection or after surgery, for example, increased intraocular pressure, glaucoma, cataract, Intraocular inflammation etc. may be caused.

Also, in the conventional method, the triamcinolone preparation used in preparing the suspension In addition to Tween 80, which is an emulsifying agent, and carboxymethyl cellulose, benzyl alcohol, which is a preservative, was also added. Because these emulsifiers and preservatives are ocular toxic, Tween 80 damages corneal endothelial cells, and carboxymethyl cellulose causes an increase in intraocular pressure. In addition, it has been suggested that benzyl alcohol has retinal toxicity. Disclosure of the invention

The present invention is an agent for visualizing the vitreous body without causing complications such as intraocular pressure increase, glaucoma, cataract, endophthalmitis, which is a drawback in the conventional method for visualizing the vitreous body by triamcinolone acetate. The present invention relates to a method of manufacturing the same and a method of visualizing a vitreous body using the method.

The present invention was achieved by finding a steroid derivative that does not cause complications such as intraocular pressure increase, glaucoma, cataract, endophthalmitis while visualizing the vitreous body, and using it as a suspension. It is a thing.

That is, the present invention is a suspension of a steroid derivative which has (1) a steroid skeleton, (2) no action as glucocorticoid or electrolyte corticoid, and (3) no ocular toxicity or systemic toxicity. It is a visualization agent of the vitreous including liquid.

Furthermore, the present invention provides a steroid derivative having (1) a steroid skeleton, (2) no action as glucocorticoid or electroglucocorticoid, and (3) no ocular or systemic toxicity. A method for producing a vitreous visualization agent, comprising suspending in a medium.

Furthermore, the present invention is a method of visualizing a vitreous, comprising using the above-mentioned visualizing agent as a vitreous visualizing agent.

According to the present invention, it is possible to visualize the vitreous body without causing complications such as elevated intraocular pressure, glaucoma, cataracts, endophthalmitis and the like, so that not only vitrectomy becomes easy, but the vitreous body is thoroughly It can be removed to minimize the amount of residual vitreous, and the therapeutic effect of ocular diseases in which the glass body is involved in pathogenesis and the surgical outcome of vitrectomy will be enhanced. Furthermore, according to the present invention, it is possible to eliminate ocular toxicity caused by additives such as emulsifiers and preservatives. Brief description of the drawings

Figure 1 is a photograph of a case in which the posterior capsule was damaged during cataract surgery.

FIG. 2 is a photograph immediately after injecting the visualization agent of the present invention into the anterior chamber.

Fig. 3 is a picture of perfusion of the anterior chamber and removal of the vitreous body.

Figure 4 is a photograph after vitrectomy.

FIG. 5 is a slit lamp photograph immediately after injection of the visualization agent of the present invention into the anterior chamber.

FIG. 6 is a slit lamp photograph 12 hours after injection of the visualization agent of the present invention into the anterior chamber. FIG. 7 is a slit lamp photograph one day after injection of the visualization agent of the present invention into the anterior chamber.

FIG. 8 shows the change in intraocular pressure before and after injecting the visualization agent of the present invention into the anterior chamber.

FIG. 9 shows the corneal endothelial cell density before and after injecting the visualization agent of the present invention into the anterior chamber. FIG. 10 is a photograph showing the fine morphology of corneal endothelial cells two days after injection of the visualization agent of the present invention into the anterior chamber.

FIG. 11 is a photograph showing the fine morphology of corneal endothelial cells 28 days after injection of the visualization agent of the present invention into the anterior chamber.

FIG. 12 is a photograph showing the fine morphology of corneal endothelial cells on the second day after injecting human studio water into the anterior chamber.

FIG. 13 is a photograph showing the fine morphology of corneal endothelial cells on day 28 after injecting human studio water into the anterior chamber.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to a steroid derivative having (1) a steroid skeleton, (2) no action as glucocorticoid or electrolytic colycoid, and (3) no ocular or systemic toxicity.

Here, the steroid skeleton means a hydrocarbon structure in which three six-membered rings and one five-membered ring are similar in molecular structure to cholesterol (33-hydroxy-15-cholestene).

The action as a glucocorticoid means that in the eye there is an immune depression, hypertension, cataract and endophthalmitis, and the action as an electrolyte corticoid means a diabetic retina. It means the hate of the disease.

The above-mentioned steroid derivative in the present invention can include a steroid hormone metabolite and the like, and examples thereof include cholesterol, 11-dihydroxycortisol, 17α-hydroxyprogesterone, progesterone, predanenolone, estrone, estradiol, Examples include estriol, testosterone, tetrahydro-S, 1 1 α 1 epichdroxycortisol, and cortexolone, but in terms of effect, highly water-soluble steroid derivatives are preferable, and 1 1 -deoxycortisol is particularly preferable.

In the present invention, the suspension of the steroid derivative is prepared by suspending the steroid derivative in an aqueous medium such as water, physiological saline, artificial aqueous humor, water-soluble solvent or a mixture thereof.

• Can be manufactured by The suspension can be manufactured under sterilization or sterilized after manufacture. After dissolving the steroid derivative in an organic solvent such as alcohol, as in the method described in the following example, the solution is filtered through a sterile filter such as Millipore filter and then recrystallized in an aqueous medium such as physiological saline. If a suspension is prepared by suspending the steroid derivative in an aqueous medium, there is no need to add an emulsifier or preservative.

The visualization agent of the present invention is injected into the eye of a human or non-human animal by an appropriate method, and then the eye is perfused with saline, buffer solution or the like, and aspiration is performed as necessary. Thus, the suspended particles of the steroid derivative not attached to the vitreous can be flowed out, and the suspended particles of the steroid derivative attached to the vitreous can visualize the structure of the vitreous.

The visualization agent of the present invention can also be applied to the vitreous body separated from animals such as humans to visualize it.

The visualizing agent of the present invention may be any disease associated with vitreous, such as proliferative vitreo-retonosis, proliferative diabetic retinopathy, macular hole, epiretinal membrane, traction retinal detachment, puditis, infectious disease Endophthalmitis, perforating eye trauma, blunt eye trauma, posterior capsular fracture associated with cataract surgery, intraocular lens secondary injection, iritis, age-related jaundice degeneration, intraocular foreign body, retinopathy of prematurity It can be applied to vitrectomy such as jaundice edema, central retinal vein occlusion, supraretinal vein branch occlusion, reticular choroidal atrophy, and myopic macular degeneration. 'Example

Example 1

Production of the visualization agent of the present invention

4 O mg of powder of 1-deoxycortisol was dissolved in 0.5 ml of ethanol. Sterilization was carried out by filtering this solution through a filter of diameter 0.22. A precipitate was formed by mixing the filtrate with saline after filtration. Only the precipitate was removed by centrifugation at 200 G, and the alcohol was evaporated to obtain sterilized 11 1-deoxycortisol. By mixing 4 O mg of this sterile 1-deoxycortisol with 1 ml of saline,

A suspension of 1-deoxycortisol was made.

Immediately before the operation, the supernatant saline was removed and replaced with a balanced salt solution. A suspension of 11-deoxycortisol using this artificial aqueous humor is used for surgery.

Example 2

Application example 1 of the visualization agent of the present invention

The patient was a human who developed posterior capsule fracture during cataract surgery and vitreous prolapsed in the anterior chamber (8 cases and 8 eyes). In FIG. 1, the posterior capsule is broken in the area surrounded by the arrow, but it is not possible to determine at all whether the vitreous body has escaped from the capsule rupture site into the anterior chamber.

The visualization agent prepared in Example 1 was injected into the patient's anterior chamber using a 27 gauge blunt needle (arrow in FIG. 2) to fill the anterior chamber with the agent. Even in this state, it was impossible to see the vitreous body that had escaped into the anterior chamber (Fig. 2).

The anterior chamber was perfused with saline using a vitreous cutter (arrow in FIG. 3), and the suspended particles of 11-deoxycortisol that did not adhere to the vitreous body in the anterior chamber were aspirated. Suspended particles of 1 1-deoxycortisol were attached to the surface of the vitreous body that had prolapsed into the anterior chamber, so the vitreous structure could be clearly grasped (circled by the white line in Figure 3). Range). Because the vitreous was visualized, the resection was easy. The vitreous body prolapsed in the anterior chamber can be completely resected along with the remaining lens (Figure 4). As a result, the frequency of postoperative eye complications could be significantly reduced.

Example 3

Application Example 2 of the Visualization Agent of the Present Invention

Visualization and ablation of the vitreous body were performed in the same manner as in Example 2 for the following cases.

• In the case of surgery for congenital cataract, the posterior crystalline lens was peeled in a circle, and the vitreous body prolapsed into the anterior chamber.

• Vitrectomy with proliferative vitreoretinopathy, proliferative diabetic retinopathy, retinal detachment or endophthalmitis 1 0 6 cases 1 0 6 eyes

Visualization of the vitreous was possible in all cases, facilitating surgery. As a result, intraoperative and postoperative complications were significantly reduced, and the surgical prognosis was improved.

Example 4

Evaluation of eye toxicity

experimental method

Experimental animal

Male New Zealand white rabbits weighing approximately 1.5 kg were used. Under general anesthesia, a suspension of 11-deoxycortisol was infused into the anterior chamber and evaluated for its ocular toxicity. As a control group, a group injected with an equal volume of human surgery water, which is an eye surgery buffer, was used.

Preparation of 1-deoxycortisol

A suspension was prepared by diluting 1 1 -deoxycortisol to 40 rag / ml using man made water as eye surgery buffer solution. This suspension was injected into the anterior chamber of 0.125 ml (5. O mg as 11-deoxycortisol).

Slit lamp inspection

Before and after injection of 1-deoxycortisol into the anterior chamber, 1 2 hours,

At 1, 2, 3, 7, 14 and 28 days, changes in the eyelid, cornea, conjunctiva, sclera, anterior chamber, lens, and anterior vitreous were observed using a slit lamp microscope.

Intraocular pressure measurement

After injection of 1-deoxycortisol 12 hours after injection 1, 2, 3, 7, 1 4, Intraocular pressure was measured on day 28. Intraocular pressure was measured using a pneumatic tonometer (MENTOR®, model 30 classic, Norwell, Mass.) Under general anesthesia.

Corneal endothelial cell density measurement

1 1 deoxycortisol was injected into the anterior chamber, and after 1, 2, 3, 7, 14 and 28 days, contact corneal endothelial cell counting device (Konan medical, type class I) was used The corneal endothelial cells were photographed. The number of corneal endothelial cells in the range of 0.5 × 0.5 mm (0.2 mm ² ) of the developed photograph was measured, and the value was multiplied by 5 to obtain the corneal endothelial cell density per square millimeter.

Examination of corneal endothelial cell ultrastructure

Before injecting 1-deoxycortisol into the anterior chamber and on the 28th day after injection, the eyeball was removed and the fine morphology of corneal endothelial cells was observed. The excised eyeballs were immediately cut into corneal pieces and immersed in a solution of 0.1 M phosphate buffer (pH 7.4) and 2.5% daltalaldehyde. After fixation with osmium, the fine morphology of corneal endothelial cells was observed using an electron microscope (model 1200 EX, JE0L, Tokyo, Japan).

Result

Slit lamp inspection

5 to 7 show slit lamp photographs after intravaginal injection of 11-deoxycortisol. Immediately after injection of 4 O mg of 1 1-deoxycortisol into the anterior chamber, the anterior chamber was filled with white particles (Fig. 5), and at 12 hours after injection into the anterior chamber, it was white. Most of the particles from the left chamber disappeared from the anterior chamber (Fig. 6). On the first day after injection into the anterior chamber, white particles were not observed in the anterior chamber (Fig. 7). During the follow-up of 28 days after injection into the anterior chamber, corneal edema, conjunctival congestion, hairy congestion, inflammation in the anterior chamber, inflammation of the cataract, vitreous inflammation, etc. were not observed at all. .

Thigh

Figure 8 shows the changes in intraocular pressure before and after intrathecal injection of 11-deoxycortisol or BSK (Manufacturing Water). The intraocular pressure did not show a significant change compared to the control group during the follow-up period up to the 28th day. (Bar = standard deviation)

Corneal endothelial cell density Figure 9 shows the changes in corneal endothelial cell density before and after anterior chamber injection of 1 1-deoxycortisol or BSF. The 1-deoxycortisol anterior chamber injection group showed no significant change in corneal endothelial cell density as compared to the control group.

(bar = standard deviation)

Corneal endothelial ultrastructure

Figures 10 to 13 show the fine morphology of corneal endothelial cells on day 2 and day 28 after intra-atrial injection of 1 1 -deoxycortisol or man-made water (BSs). The fine morphology of corneal endothelial cells on the second day (Fig. 10) and 28th day (Fig. 11) after injection of 1 1-deoxycortisol into the anterior chamber is the result of intercellular junctions and subcellular organelles. There was no difference between the 2nd day (Fig. 1 2) and 2 8th day (Fig. 1 3) of the man-in-the- workshop water injection group. The group injected with 11-deoxycortisol into the anterior chamber had no effect on the fine morphology of corneal endothelial cells as compared to the control group. (Bar = standard deviation) Summary

Injection of a suspension of 11-deoxycortisol into the anterior chamber of the white rabbit showed no ocular toxicity in the range searched. Industrial applicability

According to the present invention, it is possible to visualize the vitreous body without causing complications such as elevated intraocular pressure, glaucoma, cataracts, endophthalmitis and the like, so that not only vitrectomy becomes easy, but the vitreous body is thoroughly It can be removed to minimize the amount of residual vitreous, and it can enhance the therapeutic effect of ocular diseases in which the glass body is involved in pathogenesis and the surgical outcome of vitrectomy. Furthermore, according to the present invention, it is possible to eliminate ocular toxicity caused by additives such as emulsifiers and preservatives.

Claims

The scope of the claims

1. Glass comprising a suspension of a steroid derivative having (1) a steroid skeleton, (2) no action as glucocorticoid or electrolytic corticoid, and (3) no ocular or systemic toxicity. Body visualization agent.

2. The steroid derivatives are cholesterol, 1-deoxycortisol, 17α-hydroxyprogesterone, progesterone, predaneronone, estrone, estradioone nore, estorio nore, testosterone, tetrahydodro S,

11. The visualizing agent according to claim 1, which is selected from 1 α-epich droxycortisol and cortexolone.

3. The visualization agent according to claim 1 or 2, which does not contain an emulsifier and a preservative.

4. (1) Suspending a steroid derivative having a steroid skeleton, (2) not acting as glucocorticoid or electrolytic corticoid, and (3) having no ocular or systemic toxicity in an aqueous medium A method of producing a vitreous visualization agent comprising:

5. Steroloid derivatives such as cholesterol nol, 1 1 deoxycortisol, 17 α-hydroxy progesterone, progesterone, pregnenolone, estrone, estradiol nol, estrio nore, testosterone, tetrahydro S, 1 5. The method according to claim 4, wherein 1-alpha-epich droxicortisol or cortexolone is selected.

6. The method according to claim 4 or 5, comprising suspending the steroid derivative which has been recrystallized in an aqueous medium after filter-filtering the solution of the steroid derivative in an aqueous medium.

7. A method of visualizing a vitreous comprising using the visualizing agent according to any one of claims 1 to 3 as a vitreous visualizing agent.