CN1155243A - Method of preventing and treating ophthalmic inflammation and/or wound - Google Patents
Method of preventing and treating ophthalmic inflammation and/or wound Download PDFInfo
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- CN1155243A CN1155243A CN 95194522 CN95194522A CN1155243A CN 1155243 A CN1155243 A CN 1155243A CN 95194522 CN95194522 CN 95194522 CN 95194522 A CN95194522 A CN 95194522A CN 1155243 A CN1155243 A CN 1155243A
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Abstract
A preventive and a remedy for ophthalmic inflammation and/or wound, which comprises at least one selected from carbostyril derivatives represented by formula (1), wherein R<1> and R<2> respectively indicate a lower alkyl group, and a bond between carbons of a carbostyril skeleton at the 3- and 4-positions indicates a single bond or a double bond, and salt thereof as an active ingredient.
Description
The present invention relates to the method for a kind of prevention and treatment eye inflammation and/or wound.
Carbostyril derivative with structural formula (1) is disclosed in Japanese patent application 60-26784:
[R wherein
1And R
2Represent low alkyl group respectively, and be singly-bound or two key at the 3-and the key between the carbon atom of 4-position of quinolinones skeleton] and salt can be effective as bronchodilator, peripheral vasodilator and antihypertensive.At United States Patent (USP) 4,322, also disclose above-claimed cpd in 425 and can be effective as glaucomatous therapeutic agent.And, above-claimed cpd is also disclosed in the disclosed patent application 64-52727 of Japanese unexamined as anti-allergy eye drop.
But the inflammation of eye and/or wound also not all are caused by the allergic effect reaction, also have other factors except that the allergic effect reaction.Like this, up to the present, needed to develop a kind of to not being inflammation and/or the good therapeutic agent of wound that reacts caused eye by allergic effect.
The inventor has furtherd investigate Carbostyril derivative and the salt thereof with formula (1).Found that Carbostyril derivative and salt thereof particularly the hydrochlorate of 8-hydroxyl-5-(1-hydroxyl-2-isopropyl amino butyl) quinolinones can promote the growth of the various cells of part tissue of eye such as the outer cell of cornea, conjunctival cells, keratocyte, endothelial cell, sclera fibroblast etc. and suppress the destruction of blood aqueous humour barrier or increase the thickness of cornea that they are effective to the inflammation and/or the wound of various not relevant with allergic effect reaction eyes thus.And, find also that these chemical compounds can promote the growth of tear amount and to the relevant many tear disease of the inflammation of simple property many tear disease or the various eyes not relevant and/or wound, keratoconjunctivitis sicca, sears optical or Sjogren syndrome that adherent lens causes are very effective by embedding with allergic effect reaction.Finished the present invention based on above-mentioned discovery.
That is to say, the invention provides the preventive and the therapeutic agent of a kind of eye inflammation and/or wound, it comprises that the hydrochlorate of Carbostyril derivative and salt thereof, particularly 8-hydroxyl-5-(the amino butyl of the 1-hydroxyl-2-isopropyl) quinolinones that formula (1) is represented is as active component.
The preventive of eye inflammation of the present invention and/or wound and therapeutic agent are applicable to eye inflammation and/or the wound except that allergia oculopathy; for example, blepharitis; conjunctivitis; keratitis; scleritis; episcleritis; the forward uveitis of eyes; operation back inflammation; chronic conjunctivitis; vernal conjunctivitis; stratiform keratitis; blepharitis; acute conjunctivitis; the secreted epiphora; herpetic keratitis; the prevention of the bitot's patches in the operated eye process and the protection of keratopathy; operated eye is (as cataract; vitreous body; glaucoma etc.) flushing of ophthalmic (perfusion) and bathing the time; myosis in the operation that in operation for glaucoma, causes; the existence of operation back inflammation; in the operation/operation back intercurrent disease; many tear disease; keratoconjunctivitis sicca; by embedding sears optical or sjogren ' the s syndrome that adherent lens causes.
Brief description
Fig. 1 is the figure that describes pharmacological testing 1 result in detail.
Fig. 2 is the figure that describes pharmacological testing 2 results in detail.
Fig. 3 is the figure that describes pharmacological testing 3 results in detail.
Fig. 4 is the figure that describes pharmacological testing 4 results in detail.
Realize the best mode of invention
In above-mentioned formula (1), by R1And R2Represented low alkyl group comprises having 1 to 6 The straight chain of carbon atom-or side chain-alkyl such as methyl, ethyl, propyl group, isopropyl, butyl, uncle's fourth Base, amyl group, hexyl etc.
In the present invention inner as the compound (1) of active component, the compound that contains acidic group can Form salt with acceptable alkali compounds on the pharmacology. The example of alkali compounds comprises the hydrogen-oxygen of metal Compound such as NaOH, potassium hydroxide, lithium hydroxide, calcium hydroxide etc.; Alkali-metal carbonate and Bicarbonate such as sodium carbonate, sodium acid carbonate etc.; Alkali alcoholate such as sodium methoxide, second potassium etc. And In the present invention inner as the compound (1) of active component, the compound that contains base can be easy Form salt with acceptable acid on the pharmacology. These sour examples comprise inorganic acid such as sulfuric acid, nitric acid, salt Acid, hydrobromic acid etc.; Organic acid such as p-methyl benzenesulfonic acid, ethyl sulfonic acid, oxalic acid, fumaric acid, citric acid, Butanedioic acid, benzoic acid etc. In the present invention, special preferred acid addition salts.
The example of the Carbostyril derivative of formula (1) expression comprises as follows: 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones.
Used general carrier can be prepared into the dosage form that is fit to dosage to the preventive of eye inflammation of the present invention and/or wound and therapeutic agent in Carbostyril derivative by hybrid (1) expression and salt and the eye preparation.As a kind of dosage form, can choose wantonly and use various normal forms.The example that is fit to topical comprises that the dosage form example of the rinse solution of eye ointment, eye drop, ophthalmic etc. and suitable whole body administration comprises tablet, granule, injection etc.Particularly preferably be medication preparation of the present invention is become eye drop or ophthalmic cleaning solution.
The dosage of medicine of the present invention and unrestricted, and its advantage is that the amount of active component in the medicine can be to adult patient every day 2-3 time, takes with 0.01 to 0.5mg preferred 0.05 to 0.1mg dosage every day.And the amount of active component is generally in 0.04 to 2% weight range in the preferred agents.
Use general method can produce medicine of the present invention.For example, mixing with a kind of suitable substrate, if necessary, add excipient and produce as the formula (1) of active component represented Carbostyril derivative and salt thereof.When making eye ointment, eye drop, injection etc., produce medicine of the present invention through a kind of extra sterilization treatment.The used substrate of different suitably selections according to pharmaceutical dosage form.For example, when producing eye ointment, can use conventional emulsible substrate, water-soluble base, suspensible substrate etc.The example of general substrate comprises white vaseline, lanoline grease, liquid paraffin etc.When producing the eye drop, generally use sterile distilled water to make substrate.
And, also can mix cosolvent, stabilizing agent, buffer agent, antioxidant, antibacterial etc. in the medicine of the present invention.The example of cosolvent comprises polyoxyethylene glycol ethers such as carbonyl methyl cellulose sodium, polyoxyethylene dodecane alcohol ether, polyoxyl 10 oleyl ether etc.; Polyoxyethylene fatty acid ester class such as polyoxyethylene glycol monolaurate, polyoxyethylene glycol high-grade aliphatic ester, polyoxyethylene sorbitan monolaurate, octadecanoic acid ester of polyethylene glycol etc.The example of stabilizing agent comprises hydroxypropyl emthylcellulose, polyvinyl alcohol, carbonyl methyl cellulose, hydroxyethyl-cellulose, glycerol, EDTA etc.The example of buffer agent comprises dibastic sodium phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate etc.Examples of antioxidants comprises sodium sulfite, sodium thiosulfite, ascorbic acid etc.The example of antibacterial comprises that chlorobutanol, benzalkonium chloride, chlorination cetyl pyrrole sting father-in-law, phenyl mercuric salt, thiomersalate, methyl butex, propylparaben etc.
But when medicine of the present invention forms the eye drop, preferably this drop and tear etc. are oozed.So, if necessary, preferably add isotonic agent such as sodium chloride etc.Preferably eye drop pH value is adjusted in 5.5 to 8.5, preferred .65 to 7.5.
Can select for use various medications to take resulting medicine of the present invention according to dosage form.If the eye drop, drip a device by a kind of suitable eye and it is splashed in the eye or by a kind of injection apparatus it is sprayed in the eye.If eye ointment is coated in it on eye.If tablet, capsule etc. are oral.If injection is by subcutaneous, intramuscular or intravenous administration.Under any circumstance, can both similarly reach ideal effect.
And when the present invention was used as intra-ocular flushing liquor, operation technique field component commonly used was prepared.The represented Carbostyril derivative of flushing liquor Chinese style (1) and the concentration of salt thereof approximately are 10 within the eye
-5To 10
-8M, and this intra-ocular flushing liquor is applicable to ophthalmologic operation, cleaning etc.This flushing generally can be carried out once in one day.
Embodiment
An amount of total amount 100ml of hydrochloric acid 0.2g benzalkonium chloride 0.01g sodium dihydrogen phosphate 0.56g potassium dihydrogen phosphate 0.8g distilled water of Preparation embodiment and pharmacological test example hereinafter will be described. Preparation Example 18-hydroxyl-5-(1-hydroxyl-2-isopropylamino butyl) quinolone
Said components is dissolved in the distilled water, then, resulting solution sterilization is also come the medicine of production eye drop of the present invention form with a kind of suitable filter paper filtering.The hydrochlorate 0.1g of preparation embodiment 28-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones
The plain 22g methylcellulose of lactose 55g corn starch 22g crystal fibre 0.8g
Use the conventional method mixing said ingredients, then resulting mixture is produced 1000 through the tabletting mould.Pharmacological testing 1 (increasing the test of tear effect)
Excise film nictation of Zelanian white rabbit and also select there is not a unusual animal.Begin test after one week.Measure the amount of tear with the basic step of the Schirmer test that improves.That is, this rabbit is fixed on that taper shape fixedly installs and after the animal peace and quiet, the 0.4% oxybuprocaine hydrochlorate of 50ul (0.4% oxybuprocaine, Santen Seiyaku company limited is produced) is instiled in right eye.After two minutes, the medicine of 50ul [concentration with 0.001% (by weight) is dissolved in the hydrochlorate (hydrochlorate of procaterol) of 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones in the distilled water] also is instilled in the right eye.Behind the instillation medicine 5 minutes, a slice Schirmer reagent paper is inserted eye conjunctiva partial interior.After 5 minutes, remove the length that the Schirmer reagent paper is measured the moistening reagent paper part of tear (behind the instillation medicine between 5 and 10 minutes 5 minutes).And, again the Schirmer reagent paper is inserted eye conjunctiva partial interior and measure behind the instillation medicine 10 to 15 minutes tear amount.
The results are shown in Figure 1.Pharmacological testing 2 (to the test of various cell growth-promoting activities)
(1) tissue samples
By the method for the pentobarbital intravenous administration of 250mg is killed white new zealand rabbit and is excised their eyeball.After removing the tunicle of conjunctiva ball, with ophthalmology scalpel isolated cornea and sclera.Cornea is placed in the phosphate-buffered saline (PBS) and at the stereoptics microscopically removes the Descemet film with tweezers.Fully wash from the cornea of eyeball sampling and cultivate these cells with the following step and measure the growth-promoting activity of medicine [hydrochlorate (procaterol hydrochloride) of 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones] with PBS various cells.
(2) the outer cell of cornea
Get the cornea of 2 to 3 square millimeters of a slices from cornea with a razor.This sheet cornea tightly pasted be placed in tissue culture's ware, the Eagle culture medium F12 (DEM/F-12 that adds the Dulbecoo improvement that contains 10% calf serum (FCS), 1: 1), behind a kind of epidermal growth factor (EGF) and 10ug/ml insulin of 10ng/ml, at 37 ℃ of 5%CO
2Under cultivated two days.After removing this sheet cornea, continue again to cultivate three days.That sheet cornea of removing is used for cultivating keratocyte.
(3) keratocyte
A slice cornea tightly pasted be placed on tissue culture's ware, contain the Eagle culture medium F12 (DMEM) of Dulbecoo improvement of 10%FCS in adding after, at 37 ℃ of 5%CO
2Under cultivate this sheet cornea to obtain sophisticated keratocyte.
(4) determination of activity of promotion growth
Make various cultured cells cell dissociate out through the processing of 0.25% trypsin-0.01%EDTA from the culture dish surface.In being used for cultivating in the culture medium of various cells, after 5 minutes, vacuum is removed culture medium with the 1000rpm centrifugalize the cell suspension that dissociates out.Again this cell granule is suspended in the culture medium, cell density is adjusted to 4 * 10
4Individual cells/ml.Then cell (0.51 milliliter/hole) is inoculated on the Tissue Culture Dish in 24 holes and at 37 ℃ of 5%CO
2Under cultivate a night.After fresh culture medium replacement, add the dilution group (2 * 10 of medicine [hydrochlorate of 8-hydroxyl-5-(the amino butyl of the 1-hydroxyl-2-isopropyl) quinolinones] aqueous solution of 5 microlitres/hole (n=3)
-5M, 2 * 10
-4M, 2 * 10
-3M and 2 * 10
-2M) and cell culture 2 to 3 days.Then, add 0.2% the 3-(4,5-dimethylthiazole-2-yl)-2 in 30 microlitres/hole, 5-diphenyl tetrazolium father-in-law's bromide (MTT) and after cultivating 4 hours, 20%SDS (sodium lauryl sulphate) solution that adds 150 microlitres dissolves this cell.Measure absorption value (570nm, the contrast: 690nm) of the solution of dissolved cell.And, organize in contrast according to the solution that the same procedure of having described obtains with removing not dosing beyond the region of objective existence.Calculate the effectiveness of medicine according to following formula:
The results are shown in Figure 2.Pharmacological testing 3 (Carbostyril derivative of lagophthalmos section operation back formula (1) is to the effect of blood-aqueous humour barrier)
Earlier rabbit (white is planted by New Zealand, and body weight 2 is to 3kg) is raised an about week again by the pentobarbital intravenous administration is killed.Then, with 10
-8M, 10
-7M, 10
-6M and 10M
-5Different concentration is dissolved in a kind of Carbostyril derivative (being the hydrochlorate (procaterol hydrochloride) of 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones) in the normal saline and with resulting flushing liquor flushing cup to measure proteinic amount from the cup eluent with Blo Rad albuminometry.
The results are shown in Figure 3.As shown in Figure 3, suppressing operation back blood-aqueous humour barrier destroys and depends on the dosage that is added to the Carbostyril derivative in the intra-ocular flushing liquor.Pharmacological testing 4 (Carbostyril derivative of formula (1) is to the effect of the edema of the corneosclera obtained from rabbit part)
Earlier rabbit (New Zealand's white race, body weight 2 is to 3kg) is raised an about week again by the pentobarbital intravenous administration is killed.Then, handle eyeball with preparation corneosclera part.With 10
-6The concentration of M is dissolved in a kind of Carbostyril derivative (being the hydrochlorate (procaterol hydrochloride) of 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl) quinolinones) in the normal saline and carries out the flushing of corneal endothelium face so that measure the thickness of cornea with sonigauge (UltrasonicPachmeter) with resulting flushing liquor.
The results are shown in Figure 4." Δ thickness " thickness in Fig. 4 for being meant that cornea increases.As shown in Figure 4, this Carbostyril derivative is joined to prevent in the intra-ocular flushing liquor that this has just caused having obtained inhibition with the increase of the corneal thickness of corneal edema with the hydatoid cornea conversion of endothelium healing keratopathy.
Claims (9)
1. the method for a prevention or treatment eye inflammation and/or wound, it comprises that part or whole body take a kind of at least a medicine that is selected from the Carbostyril derivative represented with following structural and salt thereof as active component that contains:
R wherein
1And R
2Represent low alkyl group respectively, the key between quinolinones skeleton 3-and 4-position carbon atom is singly-bound or two key, and condition is that the eye inflammation that is caused by anaphylaxis is foreclosed.
2. method that increases tear, it comprises that part or whole body take a kind of at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component that contains.
3. the flushing and the method for cleaning ophthalmic when operated eye, it comprises that part or whole body take a kind of at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component that contains.
4. method that promotes the outer cell of ocular tissue's cell such as cornea, conjunctival cells, keratocyte, sclera fibroblastic growth, it comprises that part or whole body are taken and contains at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component.
5. one kind is prevented and the treatment blepharitis, conjunctivitis, keratitis, scleritis, episcleritis, the forward uveitis of eyes, operation back inflammation, chronic conjunctivitis, vernal conjunctivitis, stratiform keratitis, blepharitis, acute conjunctivitis, the secreted epiphora, herpetic keratitis, bitot's patches in the operated eye process and keratopathy, myosis in the operation that in operation for glaucoma, causes, the existence of operation back inflammation, in the operation/operation back intercurrent disease, many tear disease, keratoconjunctivitis sicca, by embedding the sears optical that adherent lens causes or the method for Sjogren ' s syndrome, it comprises that part or whole body are taken and contains at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component that condition is that an eye inflammation that is caused by anaphylaxis is foreclosed.
6. one kind is suppressed blood-destructive method of aqueous humour barrier, and it comprises that part or whole body are taken and contains at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component.
7. one kind is suppressed the method that corneal thickness increases, and it comprises that part or whole body are taken and contains at least a medicine that is selected from the defined Carbostyril derivative of claim 1 and salt thereof as active component.
8. according to any method among the claim 1-7, wherein active component is the hydrochlorate of 8-hydroxyl-5-(the amino butyl of 1-hydroxyl-2-isopropyl)-2-quinolinol.
9. the preventive and the therapeutic agent of eye inflammation and/or wound, it contains at least a Carbostyril derivative represented with following structural and the salt thereof of being selected from as active component:
R wherein
1And R
2Represent low alkyl group respectively, the key between quinolinones skeleton 3-and 4-position carbon atom is singly-bound or two key, and condition is that the eye inflammation that is caused by anaphylaxis is foreclosed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95194522 CN1155243A (en) | 1994-08-10 | 1995-08-07 | Method of preventing and treating ophthalmic inflammation and/or wound |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP188303/94 | 1994-08-10 | ||
| CN 95194522 CN1155243A (en) | 1994-08-10 | 1995-08-07 | Method of preventing and treating ophthalmic inflammation and/or wound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1155243A true CN1155243A (en) | 1997-07-23 |
Family
ID=5082740
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95194522 Pending CN1155243A (en) | 1994-08-10 | 1995-08-07 | Method of preventing and treating ophthalmic inflammation and/or wound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1155243A (en) |
-
1995
- 1995-08-07 CN CN 95194522 patent/CN1155243A/en active Pending
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