JP2009079041A - Therapeutic or prophylactic agent for posterior ocular disease comprising lithium salt as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To search a therapeutic or prophylactic agent for posterior ocular diseases. <P>SOLUTION: A lithium salt such as lithium carbonate exhibits an excellent angiogenesis inhibitory effect and an excellent vascular permeability sthenia inhibitory effect in a posterior ocular tissue such as a choroid or a retina, and is therefore useful as a therapeutic or prophylactic agent for a posterior ocular disease such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a therapeutic or preventive agent for posterior ocular diseases containing a lithium salt as an active ingredient.

Lithium salts act on neurotransmitters and their receptors in the central nervous system and are used to treat manic and manic depression. Known lithium salts used as pharmaceuticals include, for example, lithium carbonate, lithium citrate, and lithium orotate.
Posterior eye diseases generally refer to diseases in the vitreous body, retina, choroid, sclera, or optic nerve, and these diseases are deeply related to neovascularization and increased vascular permeability. In other words, in posterior ocular diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema, increased neovascularization and increased vascular permeability are the main causes of pathogenesis and pathological progression, which inhibits angiogenesis. In addition, it is known that suppressing the increase in vascular permeability is useful in the treatment of these diseases (Non-patent Documents 1 and 2).

  By the way, Patent Document 1 is an invention related to a therapeutic or preventive agent for neuronal cell death comprising a pharmaceutical preparation using a combination of lithium and a cell necrosis inhibitor such as a benzylaminosalicylic acid derivative or a tetrafluorobenzyl derivative. As one of the related diseases, eye diseases such as glaucoma are described. However, in Patent Document 1, there is no support by pharmacological tests for eye diseases, and eye diseases such as glaucoma are included in the target diseases because of the relationship between the nerve and the retina. Since factors such as vascular expression and increased vascular permeability are involved in the formation of pathological conditions in combination, it is not possible to expect therapeutic effects on these diseases only by inhibiting cell death.

On the other hand, with regard to lithium salts such as lithium carbonate, there are no reports of studying angiogenesis inhibitory action or vascular permeability enhancement action in posterior eye tissues such as choroid and retina, and lithium salts such as lithium carbonate are used alone. In addition, there is no report applied as a therapeutic or preventive agent for posterior ocular diseases such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema.
JP 2007-559999 A Journal of the Japan Association, 103, 923-947 (1999) New Illustrated Clinical Ophthalmology Vol.5 “Retinal Vitreous Disease”, P.184-189 and 232-237 (2000)

  Therefore, it is an interesting subject to search for new pharmaceutical uses for lithium salts such as lithium carbonate.

  The present inventors conducted extensive research to search for new pharmaceutical uses of lithium salts. Surprisingly, lithium carbonate and lithium chloride are excellent angiogenesis inhibitors in posterior ocular tissues such as choroid and retina. It has been found that it has an action and an inhibitory action on vascular permeability enhancement, and has led to the present invention.

  That is, the present invention relates to age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinitis pigmentosa, proliferative vitreoretinopathy, retina containing a lithium salt (hereinafter referred to as “the present compound”) as an active ingredient. Arterial occlusion, retinal vein occlusion, uveitis, label disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative chorioretinopathy, polypoidal choroidal vasculopathy , Treatment of posterior ocular diseases such as multiple choroiditis, neovascular maculopathy, retinal aneurysm, retinal hemangiomatous proliferation, optic neuropathy caused by these diseases, optic neuropathy caused by glaucoma, ischemic optic neuropathy or It is a prophylactic agent.

  The compound is not particularly limited as long as it is pharmaceutically acceptable. For example, lithium carbonate, lithium chloride, lithium citrate, lithium orotate, lithium fluoride, lithium bromide, lithium iodide, lithium sulfate, lithium nitrate. , Lithium sulfonate, and the like, and more preferably lithium carbonate, lithium chloride, lithium citrate, or lithium orotate.

  In the present invention, the posterior ocular disease refers to diseases in the vitreous, retina, choroid, sclera, or optic nerve, such as age-related macular degeneration (drusen formation in early age-related macular degeneration, atrophic age-related macular degeneration, exudation) Type age-related macular degeneration), diabetic retinopathy (simple diabetic retinopathy, preproliferative diabetic retinopathy, proliferative diabetic retinopathy), diabetic macular edema, retinitis pigmentosa, proliferative vitreoretinopathy, retinal artery occlusion, retina Venous occlusion, uveitis, label disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative chorioretinopathy, polypoidal choroidal vasculopathy, polychoidal inflammation And ocular diseases such as neovascular macular disease, retinal aneurysm, retinal hemangiomatous proliferation, optic neuropathy caused by these diseases, optic neuropathy caused by glaucoma, and ischemic optic neuropathy. Preferably, ocular diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema are exemplified. In addition, it is known that inhibiting angiogenesis and suppressing vascular permeability increase in the posterior eye tissues such as choroid and retina are useful for the above-mentioned diseases (Nipponkaikai, 103, 923-947). (1999), New Illustrated Clinical Ophthalmology, Vol. 5, “Retinal Vitreous Disease”, P.184-189 and 232-237 (2000)).

The compound can be formulated by adding a pharmaceutically acceptable additive as necessary and using a widely used technique.
This compound can be administered orally or parenterally to patients when used for the treatment or prevention of the aforementioned eye diseases. The administration forms include oral administration, topical administration to the eye (instillation administration). , Intraconjunctival sac administration, intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc., and if necessary, with pharmaceutically acceptable additives Formulated into a suitable dosage form. Examples of dosage forms suitable for oral administration include tablets, capsules, granules, powders, etc. Examples of dosage forms suitable for parenteral administration include injections, eye drops, eye ointments, and patches. Agents, gels, intercalating agents and the like. These can be prepared using conventional techniques widely used in the field. In addition to these preparations, this compound can also be made into preparations for DDS (drug delivery system) such as preparations for intraocular implants and microspheres.

  For example, the tablet is an excipient such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch , Disintegrating agents such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide , Lubricants such as hydrogenated oils; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl chloride Coating agents pyrrolidone; citric acid, aspartame, using ascorbic acid, appropriately selected and the like flavoring agent such as menthol, can be prepared.

  The injection is selected as necessary from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; and a thickener such as methylcellulose. Can be prepared.

  Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents; Stabilizers such as sodium citrate and sodium edetate; can be selected and used as needed from preservatives such as benzalkonium chloride and paraben, and pH is acceptable for ophthalmic preparations Although it should just exist in the range, the inside of the range of 4-8 is preferable normally. The eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.

  The intercalating agent is prepared by pulverizing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, together with the compound, and compressing the powder. If necessary, an excipient, a binder, a stabilizer, and a pH adjuster can be used. The preparation for intraocular implant can be prepared using a biodegradable polymer, for example, a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.

  The dose of this compound can be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, age, weight, doctor's judgment, etc. 0.01 to 5000 mg per day, preferably 0.1 to 2500 mg, more preferably 0.5 to 2000 mg can be administered in one or several divided doses. 0.0001 to 2000 mg can be administered once or divided into several times. In the case of eye drops or an intercalating agent, 0.000001 to 10% (w / v), preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.1% ( The active ingredient concentration of w / v) can be administered once or several times a day. Furthermore, in the case of a patch, a patch containing 0.0001 to 2000 mg can be applied to an adult. In the case of a preparation for an intraocular implant, 0.0001 to 2000 mg is contained for an adult. An intraocular implant formulation can be implanted in the eye.

  In the pharmacological test described below, lithium carbonate and lithium chloride significantly inhibited choroidal neovascularization by oral administration in a laser-induced rat choroidal neovascularization model, and lithium carbonate increased thrombin-induced rabbit retinal vascular permeability. In the model, retinal vascular permeability was significantly suppressed by intravitreal administration. That is, lithium salts such as lithium carbonate and lithium chloride are agents for treating or preventing posterior ocular diseases such as age-related macular degeneration, diabetic retinopathy, and diabetic macular edema, in which angiogenesis and increased vascular permeability are deeply involved in pathogenesis. Useful as.

  Although the result of a pharmacological test and a formulation example is shown below, these are for understanding this invention better, and do not limit the scope of the present invention.

[Pharmacological test 1]
A laser-induced choroidal neovascularization model is widely used as a pharmacological test model for examining the angiogenesis inhibitory effect in the choroid (Japanese Journal of Ophthalmology, 45, 853-856 (1994)). Therefore, the usefulness of lithium carbonate was evaluated using a laser-induced rat choroidal neovascularization model.

(Production method of krypton laser-induced rat choroidal neovascularization model)
Rats were anesthetized by intramuscular administration of 1 mL / kg of a mixture of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection (7: 1), 0.5% (W / V) After tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatic, photocoagulation was performed with a krypton laser photocoagulator. Photocoagulation was performed in a scattered manner at eight sites per eye in the posterior region of the fundus, avoiding thick retinal blood vessels and focusing on the deep retina. After photocoagulation, fundus photography was performed to confirm the laser irradiation site.

(Drug administration method)
Lithium carbonate was suspended in 1% (W / V) methylcellulose solution (prepared by dissolving methylcellulose in purified water) to a concentration of 20 mg / mL, and the lithium carbonate solution was operated at a dose of 100 mg / kg from the day of photocoagulation surgery. Orally administered once a day for 7 days including the day. A 1% (W / V) methylcellulose solution was similarly administered to the base administration group.

(Evaluation methods)
On day 7 after photocoagulation, rats were given a general anesthesia by intramuscular administration of 1 mL / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection. After 5% (W / V) tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatic, 0.1 ml of 10% sodium fluorescein solution was injected from the tail vein, and fluorescence fundus imaging was performed. In fluorescence fundus angiography, a spot where no fluorescent exposure was observed was judged negative (no angiogenesis), and a spot where fluorescent exposure was seen was judged positive. In addition, a photocoagulation site where slight fluorescence exposure was observed was determined to be positive (with angiogenesis) when two sites were present. Thereafter, the rate of choroidal neovascularization (%) was calculated from the number of positive spots for 8 spots irradiated with laser according to the formula (1), and the inhibition rate (%) of the evaluation drug was calculated according to the formula (2). The results are shown in Table 1. The number of lithium carbonate administration groups and base administration groups is 8.

(Results) As shown in Table 1, lithium carbonate suppressed choroidal neovascularization by about 51% in a laser-induced rat choroidal neovascularization model.

[Pharmacological test 2]
The usefulness of lithium chloride was evaluated using a laser-induced rat choroidal neovascularization model.

(Production method of krypton laser-induced rat choroidal neovascularization model)
A krypton laser-induced rat choroidal neovascularization model was prepared by the same method as Pharmacological Test 1.

(Drug administration method)
Lithium chloride was suspended in 1% (W / V) methylcellulose solution (prepared by dissolving methylcellulose in purified water) to a concentration of 1.2 mg / mL, and the lithium chloride solution was suspended at a dose of 6 mg / kg on the day of photocoagulation surgery. Orally administered once a day for 7 days including the day of surgery. In the base administration group, 50 μL of physiological saline was administered subconjunctivally once a day for 7 days from the photocoagulation surgery day including the surgery day.

(Evaluation methods)
With the same evaluation method as in Pharmacological Test 1, the inhibition rate (%) of the evaluation drug was calculated. The results are shown in Table 2. The number of examples in the lithium chloride administration group is 8, and the number of examples in the base administration group is 7.

(Results) As shown in Table 2, lithium chloride inhibited choroidal neovascularization by about 22% in a laser-induced rat choroidal neovascularization model.

[Pharmacological test 3]
Thrombin exposure to the epicardium induces vascular occlusion and induces increased retinal vascular permeability (Journal Journal, 93, 978-985 (1989)). Thrombin-induced rabbit retinal vascular permeability enhancement model Was used to evaluate the usefulness of lithium carbonate.

(Method of creating thrombin-induced rabbit retinal vascular permeability enhancement model)
Rabbits were intramuscularly anesthetized with 1 mL / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection, 0.5% (W / V) Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriasis, and then inserted into the vitreous cavity using a 1/4 vein needle and a microsyringe from the flat part of the ciliary body under fluoroscopy. For the drug group and the lithium carbonate administration group, 10 μL of a 1 KU / mL thrombin administration solution was dropped on the retinal blood vessel, and for the control group, 10 μL of physiological saline was dropped on the retinal blood vessel.

(Drug administration method)
Lithium carbonate was dissolved in physiological saline to 1% (W / V), and a lithium carbonate solution was administered intravitreally at a dose of 100 μg / eye 30 minutes before thrombin administration and 24 hours after thrombin administration. In the base group and the control group, physiological saline was similarly administered intravitreally.

(Evaluation methods)
48 hours after administration of thrombin, 0.1 mL / kg of 10% sodium fluorescein solution was administered from the ear vein, and after 1 hour and 45 minutes of administration, tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriatic, and then fluorescein. Two hours after administration of the sodium solution, the intraocular fluorescein concentration was measured using a vitreous fluorophotometer.
From the measurement results, the average fluorescence concentration in the vitreous was calculated and used as the fluorescence concentration in the vitreous. In addition, the inhibition rate (%) of the evaluation drug was calculated according to the formula (3). The results are shown in Table 2. The number of cases of the control group, the base administration group, and the lithium carbonate administration group is 5 or 6.

(Results) As shown in Table 3, lithium carbonate inhibited retinal vascular permeability enhancement by about 55% in a thrombin-induced rabbit retinal vascular permeability enhancement model.

(Discussion)
From the above results, it was shown that both lithium carbonate and lithium chloride have an excellent choroidal neovascularization inhibitory action. From this, it was shown that lithium ions are the active main body of these compound groups, and lithium salts represented by lithium carbonate and lithium chloride have an excellent choroidal neovascularization inhibitory action. In addition, lithium carbonate exhibited an excellent inhibitory effect on retinal vascular permeability, indicating that lithium salt is effective for enhancing retinal vascular permeability. From these, lithium salts typified by lithium carbonate and lithium chloride are a prominent preventive or posterior ocular disease involving angiogenesis and increased vascular permeability such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema, or It was shown to have an improving effect.

[Formulation example]
The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.

Formulation Example 1 Lithium carbonate 1mg in 100mg tablet
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 6mg
Magnesium stearate 0.6mg

  Lithium carbonate and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. Mix and compress with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, and 50 mg can be prepared by changing the addition amount of lithium carbonate.

Formulation Example 2 Injection 10ml Lithium citrate in 10ml
Sodium chloride 90mg
Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount

  An injection is prepared by dissolving lithium citrate and sodium chloride in sterile purified water. By changing the amount of lithium citrate added, injections containing 0.1 mg, 10 mg, and 50 mg in 10 mL can be prepared.

Formulation Example 3 Eye drops Lithium carbonate 10 mg in 100 mL
Sodium chloride 900mg
Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount

  Add lithium carbonate and other components to sterilized purified water and mix them thoroughly to prepare eye drops. By changing the amount of lithium carbonate added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / v) Eye drops can be prepared.

Formulation Example 4 Eye Ointment 100g Lithium Carbonate 0.3g
Liquid paraffin 10.0g
White petrolatum

  An eye ointment is prepared by adding lithium carbonate to uniformly melted white petrolatum and liquid paraffin, thoroughly mixing them, and then gradually cooling them. By changing the amount of lithium carbonate added, the concentration of 0.05% (w / v), 0.1% (w / v), 0.5% (w / v), 1% (w / w) An eye ointment can be prepared.

  It can be used as a therapeutic or preventive agent for posterior ocular diseases containing a lithium salt as an active ingredient.

Claims (8)

  A therapeutic or prophylactic agent for posterior eye diseases comprising a lithium salt as an active ingredient.   The lithium salt is lithium carbonate, lithium chloride, lithium citrate, lithium orotate, lithium fluoride, lithium bromide, lithium acetate, lithium succinate, lithium gluconate, lithium iodide, lithium sulfate, lithium nitrate or lithium sulfonate. The therapeutic or prophylactic agent according to claim 1.   The therapeutic or prophylactic agent according to claim 1, wherein the lithium salt is lithium carbonate, lithium chloride, lithium citrate or lithium orotate.   The therapeutic or prophylactic agent according to claim 1, wherein the posterior ocular disease is a disease in the vitreous, retina, choroid, sclera or optic nerve.   Posterior eye disease is age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinitis pigmentosa, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, uveitis, label disease, premature infant Retinopathy, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative choroidal retinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, neovascular maculopathy, retinal aneurysm, retinal hemangioma The therapeutic or prophylactic agent according to claim 1, which is symptomatic proliferation, optic neuropathy caused by these diseases, optic neuropathy caused by glaucoma, or ischemic optic neuropathy.   The therapeutic or prophylactic agent according to claim 1, wherein the posterior ocular disease is age-related macular degeneration, diabetic retinopathy or diabetic macular edema.   The therapeutic or prophylactic agent according to any one of claims 1 to 6, wherein the administration form is ophthalmic administration, intravitreal administration, subconjunctival administration, intraconjunctival sac administration, subtenon sac administration or oral administration.   The treatment or prevention agent according to any one of claims 1 to 6, wherein the dosage form is an eye drop, an eye ointment, an insertion agent, a patch, an injection, a tablet, a fine granule, or a capsule.