JPH10158171A - Intraocular administrating agent formulating vitamin d compound therein - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an intraocular administrating agent capable of alleviating a complication causing visual disorder after intraocular operation by administering the agent into eye in intraocular operation by including a specific vitamin D compound. SOLUTION: This intraocular administrating agent is obtained by formulating, applying, bonding or embedding a vitamin D compound selected from ergocalciferol, cholecalciferol, an active type vitamin D derivative, a vitamin D2 analogue, a vitamin D3 analogue, an active type vitamin D2 analogue and an active type vitamin D3 analogue in which at least one in the 1st carbon and 25th side-chain carbon in ring A of sterol ring is hydroxylated to an intraocular injection, a viscoelastic substance, an intraocular lens, a substitute vitreous body, a tube for intraocular transplantation, a subtained release agent of medicine for intraocular transplantation, etc. The resultant intraocular administering agent is administered or transplanted into eye in intraoculr operation such as cataract operation, intraocular lens plantation operation, operation of cornea diseases, operation of glaucoma, operation of eye injury, operation of vitreous body disease or retinopexy.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD [0001] The present invention relates to an intraocular preparation containing vitamin D or active vitamin D as an active ingredient and used at the time of ophthalmic surgery for regulating intraocular cell activity.

[Background Art] Natural vitamin D having a high physiological activity and active vitamin D studied thereafter are widely used in bone diseases such as rickets, osteomalacia, osteoporosis, fibrous ostitis, osteosclerosis, etc. It is currently used to treat patients with malignant tumors such as breast cancer and colorectal cancer, and skin diseases such as psoriasis. Generally, when simply saying vitamin D, it refers to vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) having high anti-kulosis activity. The active vitamin D for treatment is administered by oral or intravenous injection, and in the case of dermatosis, it is administered by ointment. It has been known that vitamin D undergoes changes in its molecular structure in the liver and kidney, and becomes active vitamin D having high physiological activity. Calcitriol (1α, 25-) which is a derivative of cholecalciferol as active vitamin D3
After the discovery of dihydroxyvitamin D3), it has been found that active vitamin D has not only a calcium regulating effect but also other physiological activities. The active vitamin D is an active vitamin D in which at least one of the sterol ring A ring carbon C1 position and the side chain C25 position is hydroxylated,
Calcitriol (1α, 25-dihydroxyvitamin D3), 1α, 24-dihydroxyvitamin D3, alphacalcidol (1α-hydroxyvitamin D3),
Calcifedol (25-hydroxyvitamin D3),
1α, 24,25-trihydroxyvitamin D3,1
β, 25-dihydroxyvitamin D3, 22-oxacalcitriol, calcipotriol, KH1060 and the like. At present, about 820 kinds of analogs are considered including dihydrotatistrol. It has been found that there is an active vitamin D receptor in a certain kind of cell, and studies on the regulation of cell activity have been promoted since active vitamin D regulates the cytokine production of the cell.

[0003] Symptoms due to vitamin deficiency in ophthalmology include night blindness due to vitamin A deficiency, Bitot plaque of the bulbar conjunctiva, and conjunctival keratosis. Vitamin B1 deficiency results in beriberi amblyopia. It is known that retrobulbar optic neuritis and optic atrophy may appear, and vitamin C deficiency may cause bleeding in the eyelids, conjunctiva, and retina in scurvy. Nikkikai, 94
No., Rinzo 250, 1990, class I of active vitamin D to suppress rejection during corneal transplantation.
Experiments on the inhibitory effect on I antigen expression suggest that active vitamin D3 may act to suppress corneal transplant rejection. Japanese Patent Laid-Open Publication No. Hei 3-24016 describes that active vitamin D3 can be applied to the treatment of proliferative retinal diseases by inhibiting the growth of human retinal glial cells. Published Patent Publication No. 63-145233 discloses a cataract remedy containing active vitamin D3 as an active ingredient. U.S. Pat. No. 5,254,538,
Published Patent Public Relations, Hei 5-503922 and Hei 5-508
No. 655 describes that vitamin D compounds are effective for treating wounds on external epithelium such as cuts, punctures, and corneal lacerations, and ulcers such as ulcerative keratitis.

[0004] In general, among ophthalmic surgeries, intraocular surgery includes cataract surgery, intraocular lens transplantation surgery, corneal disease surgery, glaucoma surgery, eye trauma surgery, vitreous body surgery,
There are anterior segment and posterior segment intraocular surgery, such as retinal repositioning surgery and surgery for lacrimal canal disease. The activated cells after the invasion of intraocular surgery perform proliferation, extension and migration, repair and production of chemical inducers, and production of metabolites for repairing damage. As a complication after the operation, visual acuity may be reduced. BACKGROUND ART Conventionally, corticosteroids have been mainly used as anti-inflammatory agents in order to prevent visual impairment due to activated cells that have undergone surgical invasion. Although this steroid is very effective in inflammation, it also has systemic or local ocular side effects, and in particular, the use of steroids immediately after surgery tends to be avoided. Eisai Co., Ltd. Volume 43 No. 8 Small Magazine "Clinician", 19
August 1, 1996, pages 80-81, describes the corneal permeability of eye drops. According to this, a highly liposoluble drug having good corneal permeability is used at about 4% of the total dose, usually between 1% and 0.1%. The transfer to the blood is set at about 50% of the dose. Generally, when the corneal epithelial cells are normal, the corneal penetration barrier function against those foreign substances is high,
It is known that when these cells are damaged, inflamed, or removed, their barrier function is reduced.

[Problems to be Solved by the Invention] The first object of the present invention is to proliferate, spread or migrate active cells in the eye due to surgical invasion that occurs during ophthalmic surgery, and to overproduce or suppress chemical inducers, and It is to reduce visual impairment due to inhibition of intraocular transparency including ocular hypertension due to overproduction of metabolites. Since steroids currently administered as a coping therapy have a problem of side effects, an object of the present invention is to provide an agent for preventing visual impairment and ocular hypertension which can be administered at the time of surgery with less side effects. It is a second object of the present invention to adjust the activity of intraocular cells caused by invasion from ophthalmic surgery without time delay.

[Means for Solving the Problems] Accordingly, the present invention provides a method of administering a vitamin D compound to a local part of the eye during ophthalmic surgery, instead of instillation depending on the permeability of the cornea.
It is a means to solve the problem. And as the administration means, the dosage form is at least one of an intraocular injection, a viscoelastic substance, an intraocular lens, a vitreous substitute, an intraocular implant tube, and an intraocular implant drug sustained release agent. It is to administer according to the contents of the eye surgery. In the case of natural vitamin D, vitamin D, ergocalciferol or cholecalciferol administered locally to the eye directly regulates protein synthesis of ribonucleic acid (RNA) of intraocular cells activated by direct surgical invasion. Alternatively, the sterol ring A ring carbon C1 position or side chain C25 position, or both, are hydroxylated by mitochondrial or microsomal enzymes in active cells to become active vitamin D, and directly to the deoxyribonucleic acid (DNA ) And regulate cell activity. The present inventor has proposed that a sterol ring A ring carbon C1 position or a side chain C2 is higher than 1α, 25-dihydroxyvitamin D having high physiological activity
It is considered that active vitamin D hydroxylated at the 5-position is inferior in activities such as regulation of cell cytokine production and induction of cell differentiation, but it is considered that some physiological activity is still observed in ocular cells. In the case of active vitamin D, which is a derivative or analog of natural vitamin D, administration to the ocular topic directly affects DNA in the nucleus of active cells, regulates differentiation induction,
Alternatively, it has the effect of regulating the protein synthesis of RNA. Intraoperatively, vitamin D compounds to be administered intraocularly include ergocalciferol and cholecalciferol, and sterol ring A ring C1 position and side chain C as active vitamin D
Active Vitamin D Derivative, Vitamin D2 Analogue, Vitamin D3 Analogue, Activated Vitamin D2 Analogue, and Activated Vitamin D wherein at least One of the 25 Positions Has Been Hydroxylated
Vitamin D compounds selected from the group consisting of the three analogs are particularly effective. The active vitamin D analog, dihydrotatistrol, is also effective as the intraoperative intraocular agent of the present invention. Cholecalciferol sodium sulfate is also known as a vitamin D3 analog.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to the use of fat-soluble vitamin D or active vitamin D in intraocular injections, viscoelastic substances, intraocular lenses (or lens substitutes), vitreous substitutes, intraocular Mix, apply, adhere, or embed in a transplant tube or a sustained-release drug for ocular transplant. Then, the present agent is administered or transplanted into the eyes of mammals including humans at the time of ophthalmic surgery, and is characterized in that complications that cause visual impairment after ophthalmic surgery are reduced. The concentration of natural vitamin D in the intraocular preparation of the present invention is also topical administration. Intraocular injections and viscoelastic substances may have a concentration within about 100 μg / ml, and at least about 1 μg / ml. For intraocular implants and sustained-release preparations, this concentration range is not affected. The concentration of active vitamin D is also topical administration, and for intraocular injections and viscoelastic substances, it may be about 1 μg / ml or less, and at least about 0.1 ng / ml or more. For intraocular implants and sustained-release preparations, this concentration range is not affected.

In order to demonstrate the usefulness of the present invention, an experiment was performed on the regulation of the activity of intraocular cells, particularly corneal endothelial cells and lens epithelial cells, which had been invasive by surgery in cataract surgery and corneal incision surgery models using white rabbits. Was. As a result of this test,
The intraocular administration of the aqueous intraocular preparation or the viscoelastic substance of the present invention containing a vitamin D compound in comparison with the base administration control group has a low degree of lens capsular opacity or a defect of corneal endothelial cells. Recovery was promoted, suggesting a positive effect on vision after surgery. From these results, it was confirmed that the activity of damaged cells in the eye can be adjusted without time delay by directly administering the vitamin D compound into the eye during surgery. Unless administration of vitamin D or an active vitamin D preparation is at an abnormally high concentration, no cytotoxicity is observed, and it is considered that normal cells have almost no effect.

In the case of vitamin D, ergocalciferol, cholecalciferol, and the like, intraocular cells which have undergone surgical invasion, particularly cells in contact with the anterior / posterior chamber and the lens,
Activated vitamin D is converted to active vitamin D by its hydroxylase, and the activated vitamin D binds to its own or a nearby vitamin D receptor such as an invaded active cell and is taken into the nucleus, affecting DNA of the cell. To regulate the induction of differentiation or not bind to the vitamin D receptor.
Affects NA and regulates exudates such as various cytokines and proteins. In other words, the present inventor has considered that the intraocular lens, particularly the lens epithelial cells and the corneal endothelial cells, may be not only active vitamin D target cells but also active vitamin D producing cells.

[0010] Most preferably, the present invention is an aqueous intraocular formulation. Ophthalmic viscoelastic materials are indispensable tools for intraocular surgery to protect intraocular tissues from contact with surgical instruments and to maintain the ease of surgery. It is known that it takes about 3 to 7 days for the viscoelastic substance remaining in the eye to disappear, despite the removal of the viscoelastic substance from the eye after use. When a vitamin D compound is mixed with this ophthalmic viscoelastic substance, for example, when used in cataracts and intraocular lens transplantation surgery, active cells such as corneal endothelial cells and lens epithelial cells facing the anterior chamber, posterior chamber, and lens capsule are obtained. Highly effective for adjustment.
In intraocular lens transplantation, a vitamin D compound is applied, adhered, or embedded in the intraocular lens, and the activity of particularly the lens epithelial cells in contact with the intraocular lens is adjusted by the vitamin D compound. This allows the lens capsule and intraocular lens to remain transparent. In the vitreous substitute, the activity of particularly retinal glial cells in the vicinity of the vitreous substitute containing or embedded with a vitamin D compound is regulated, and visual impairment due to retinal glial cell proliferation or tractional retinal detachment is reduced. . In the intraocular transplant tube used for glaucoma surgery or lacrimal tract disease surgery, the activity of the cells in contact with the intraocular transplant tube coated, adhered, or embedded with a vitamin D compound is regulated, and the cell proliferation occurs. Scar hyperplasia is reduced. As for the sustained-release drug for intraocular transplantation, the sustained-release drug for intraocular transplantation containing or embedded with a vitamin D compound slowly releases the vitamin D compound from the drug and regulates adjacent active cells And suppresses cell hyperplasia or cell metabolite overproduction. When the sustained-release drug for intraocular transplantation is implanted, for example, under the conjunctival sac, the vitamin D compound exuded from the sustained-release agent mainly penetrates the cornea and regulates intraocular active cells. Conventionally, corticosteroids have been mainly used as anti-inflammatory agents, but steroid glaucoma, steroid cataracts, and new bacterial infections are expected to occur as ophthalmic side effects, and there is a tendency to avoid or reduce the use of steroids. It is in.

[0011] When a large amount of conventional vitamin D or active vitamin D preparation is orally administered, hypervitaminosis D is observed, blood calcium and phosphate increase, and soft tissues such as kidney, artery, smooth muscle, and lungs Calcification occurs. The vitamin D compound to be used as an intraocular agent of the present invention has a medicinal effect in a single administration during surgery, and even if the vitamin D compound enters the blood in the entire dose, it is unlikely that the conventional side effect will occur.

Hereinafter, the present invention will be described in more detail with reference to Formulation Examples and Test Examples. [Formulation Example 1] Activated vitamin D (calcitriol)
100 μg was diluted with 10 ml of ethanol (purity 99.9%), and 1 ml of the diluted solution was further diluted with polysorbate 80.
The aqueous solution (0.1% -Tween 80 ophthalmic aqueous solution) was further diluted 100-fold as a solvent to produce an intraocular preparation having an active vitamin D concentration of 0.1 μg / ml. The ophthalmic aqueous solution used was added to 100 ml of distilled water for injection, 780 mg of sodium chloride and 153 mg of potassium chloride, and sodium hydroxide was added to adjust pH to 7.4. [Formulation Example 2] Active vitamin D (calcitriol)
100 μg was diluted with 10 ml of ethanol (purity: 99.9%), and 20 μl of the diluted solution was further diluted and mixed 100 times with 2 ml of ophthalmic viscoelastic substance (1% -aqueous sodium hyaluronate solution) as a solvent. Vitamin D
An intraocular preparation having a concentration of 0.1 μg / ml was produced.

Test Example 1 The degree of opacity of the lens capsule after cataract surgery was tested in rabbits. Japanese native white rabbit, 2k
g, 6 birds were used. The right eye of the rabbit and the surgical eye were dilated with a mydriatic. After anesthesia by an analgesic / anaesthetic injection into the thigh muscle and ophthalmic anesthesia, the eyelids are opened, the sclerocorneal margin at 12:00 in the right eye of the rabbit is pierced, and a viscoelastic substance (1% aqueous solution of sodium hyaluronate) is applied. Fill the anterior chamber, anterior capsular resection about 5m in diameter
m as much as possible. Thereafter, the pierced sclerocorneal rim was expanded to a width of about 3.5 mm, and ultrasonic phacoemulsification was performed to aspirate and remove the lens nucleus and lens cortex. Three randomly selected birds were used as a drug administration group, and about 2 ml of the intraocular drug of Formulation Example 1 was slowly injected from the anterior chamber so as to fill the lens capsule and the anterior and posterior chambers. The other three birds were similarly injected with a polysorbate 80 aqueous solution (0.1% -Tween 80 aqueous solution) containing no active vitamin D as a control group. The sclerocorneal wound was sutured with one thread with 8-0 silk thread, and the operation was completed. After surgery, the eye was treated with ophthalmic and ointment antibiotics on the conjunctiva and cornea. For three days after the operation, antibiotics were administered to each operated eye three times a day and mydriatics were administered once a day. The postoperative opacification of the lens capsule was observed in each of the two drug-treated groups and the control group, which had no postoperative infection or pupillary adhesion and good anterior capsulotomy. Slit lamp microscopy of the surgical eye after mydriasis one week after the operation showed a band-like cloudiness in the margins of the anterior lens capsule resection, and the band-like cloudiness in the drug-administered group. Was slightly milder than the control group, and the width of the band-like cloudiness in the drug administration group was significantly narrower. The posterior capsule in the pupil region was also slightly more transparent in the drug-administered group.

Test Example 2 The degree of corneal edema after corneal full thickness incision was tested in rabbits. Japanese native white rabbit, 2
kg, four birds were used. The right eye of the rabbit and the surgical eye were dilated with a mydriatic. After anesthesia with thigh muscle injection of pain and anesthetic and ophthalmic anesthesia, the eyes are opened and the eyelid is opened. The cornea at a position of about 4 mm from the center of the cornea in the right eye of the rabbit at 12:00 is 3 mm wide with a lancet and an intracorneal valve. To the corneal tangent so that it can self-close
Puncture was performed at an angle of about 5 degrees toward the center of the pupil. Two randomly selected birds were used as a drug administration group, and about 1 ml of the intraocular formulation of Formulation Example 2 was slowly injected into the anterior chamber such that aqueous humor was replaced. No significant change in viscosity of the aqueous solution of sodium hyaluronate was observed with respect to ethanol in the intraocular preparation of Formulation Example 2. However, many bubbles were observed when the active vitamin D and the sodium hyaluronate aqueous solution were mixed. Using the other two birds as a control group, an aqueous solution of sodium hyaluronate containing no active vitamin D was injected in the same manner as in the drug administration group. After surgery, each eye was treated with eye drops and ointment antibiotics on the conjunctiva and cornea. For three days after the operation, antibiotics were administered to each operated eye three times a day and mydriatics were administered once a day.

One week after the operation, the degree of swelling of the injured part of the surgical eye was measured by a corneal shape measuring apparatus. The average was 10 diopters in the drug administration group and 18 diopters in the control group. These facts suggest that active vitamin D prevents abnormal refraction of the cornea in the local area of the eye. In addition, it suggests that it is strongly involved in the proliferation and extension of corneal endothelial cells despite single administration during surgery.

Vitamin D in Test Examples 1 and 2
No adverse effects such as corneal opacity, conjunctival hyperemia, fibrin deposition in the anterior chamber, endophthalmitis, etc. due to calcium adsorption to the cornea, which may be due to the compound, were not observed. It has been confirmed that administration of a vitamin D compound to the topical eye according to the present invention regulates the activity and metabolism of corneal endothelial cells or lens epithelial cells in the process of repairing damaged tissues in an inflammatory state and suppresses the overproduction of metabolites of those cells. Was done. These test results show that the intraoperative ophthalmic preparation is effective and safe in humans. It also suggests that an intraocular preparation containing, adhered to, or embedded with a vitamin D compound, which is an implant in the eye, is effective in regulating the activity of active cells in the eye.

[Effect of the Invention] The intraoperative intraocular administration of the vitamin D compound of the present invention is effective in reducing complications after ophthalmic surgery. Conventionally, side effects that are problematic with steroid eye drops can be avoided. It can be administered directly into the eye with no time delay in regulating the activity of intraocular cells due to surgical invasion. Ophthalmic patients,
In particular, many cataract surgery patients are elderly, and can administer drugs without particularly troublesome hands of the elderly. The intraoperative intraocular administration of the vitamin D compound of the present invention has a cell activity regulating effect by a single administration at the time of surgery. Oral vitamin D compounds,
By being able to administer directly to the site affected by the surgical operation by intravenous injection, administration by eye drops, etc., the regulating effect on active cells is ensured.

Claims (4)

[Claims] 1. Active vitamin D wherein at least one of ergocalciferol, cholecalciferol, sterol ring A ring carbon C1 position and side chain C25 position is hydroxylated.
An eye to which a vitamin D compound selected from the group consisting of a derivative, a vitamin D2 analog, a vitamin D3 analog, an active vitamin D2 analog, and an active vitamin D3 analog is used as an active ingredient and is administered intraocularly during ophthalmic surgery An intraocular agent for regulating intracellular activity. 2. Ophthalmic surgery includes cataract surgery, intraocular lens transplantation surgery, corneal disease surgery, glaucoma surgery, eye trauma surgery, vitreous disease surgery, retinal repositioning surgery, and lacrimal disease surgery. The intraocular agent according to claim 1, which is at least one. 3. A sterol ring A ring carbon C1 position and a side chain C2.
Active Vitamin D Derivative, Vitamin D2 Analogue, Vitamin D3 Analogue, Activated Vitamin D2 Analogue, and Activated Vitamin D wherein at least One of Positions 5 is Hydroxylated
The three analogs are calcitriol (1α, 25-dihydroxyvitamin D3), 1α, 24-dihydroxyvitamin D3, alpha-calcidol (1α-hydroxyvitamin D3), and calcifedol (25-hydroxyvitamin D3), 1α, 24, 25-trihydroxyvitamin D3,1, β, 25-dihydroxyvitamin D3,22-
Oxacalcitriol, calcipotriol, KH1
060, the agent for intraocular administration according to claim 1, which is selected from the group consisting of dihydrotatistrol. 4. The dosage form is selected from the group consisting of an intraocular injection, a viscoelastic substance, an intraocular lens, a vitreous substitute, an intraocular implant tube, and a drug sustained release agent for intraocular implant. Claim 1
2. The intraocular administration according to the above.