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CN1087169C - Anti-inflammatory eyecrops - Google Patents

Anti-inflammatory eyecrops Download PDF

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Publication number
CN1087169C
CN1087169C CN95197387A CN95197387A CN1087169C CN 1087169 C CN1087169 C CN 1087169C CN 95197387 A CN95197387 A CN 95197387A CN 95197387 A CN95197387 A CN 95197387A CN 1087169 C CN1087169 C CN 1087169C
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Prior art keywords
cyd
diclofenac sodium
drop
volume
weight
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CN1173129A (en
Inventor
武内正史
丸山浩树
铃木浩惠
小熊徹
前田孚
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Wakamoto Pharmaceutical Co Ltd
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Wakamoto Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Ophthalmology & Optometry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

An anti-inflammatory eye drop comprises (a) 0.05 to 0.7 weight/volume % of diclofenac sodium; (b) 1 to 10 weight/volume % of gamma -cyclodextrin; (c) 1 to 20 weight/volume % of polyvinyl pyrrolidone; and (d) 0.002 to 0.01 weight/volume % of benzethonium chloride or 0.002 to 0.005 weight/volume % of benzalkonium chloride, and has a pH value ranging from 7.0 to 8.5. The anti-inflammatory eye drop may comprise diclofenac sodium in a wide range of concentration, is stable over a long time period and shows only a low degree of ocular irritation.Anti-inflammatory eyedrops comprising: (a) 0.05 to 0.7 w/v % of diclofenac sodium; (b) 1 to 10 w/v % of gamma -cyclodextrin; (c) 1 to 20 w/v % of polyvinylpyrrolidone; and (d) 0.002 to 0.01 w/v % of benzethonium chloride, or 0.002 to 0.005 w/v % of benzalkonium chloride; and having a pH value of 7.0 to 8.5. The eyedrops contain diclofenac sodium at a concentration over a wide range, remain stable for a long period of time, and little irritate the eyes.

Description

Anti-inflammatory eyecrops
The present invention relates to a kind of with the anti-inflammatory eyecrops of diclofenac sodium (hereinafter referred DFNa) as effective ingredient, be combined with the gamma-cyclodextrin that belongs to water soluble Beta-cyclodextrin (hereinafter referred γ-CyD) and polyvinylpyrrolidone (hereinafter referred PVP) in this drop, have secular storage stability, and can relax stimulation eyes.
The aqueous drop of non-steroidal anti-inflammatory agent DFNa because the biosynthesis of prostaglandin is had powerful blocking effect, therefore is used to prevent the inflammatory symptom of postoperative and in operation process and the complication of postoperative when implementing cataract operation.When non-steroidal anti-inflammatory agent during, almost all want stimulating mucosal and eyes bar none, and show intensive ophthalmalgia effect as drop.
Present inventors stimulate owing to the caused eye of non-steroidal anti-inflammatory agent with mitigation in the past or ophthalmalgia act as purpose, a kind of antiinflammatory drop is provided, it is characterized in that, wherein contain the non-steroidal anti-inflammatory agent from ibuprofen, indomethacin, Kai Tuoluofen, naproxen and flufenamic acid, selected as principal agent, and contain the salt that the acid that allows on calcium or magnesium and the physiology forms and stimulate demulcent (special fair 1-19362) as eye.In addition, also provide a kind of like this anti-inflammatory eyecrops, wherein,, contained the Tween-81 of 5～10 times of amounts (weight) or α and beta cyclodextrin as cosolvent (special fair 2-6329) with respect to DFNa.In addition, present inventors have also developed a kind of like this drop, wherein be combined with the beta-schardinger dextrin-that is used for DFNa is carried out chemical modification, therefore it does not stimulate eyes behind eye dripping, and its storage stability is also good, now this drop has been proposed patent application (spy opens flat 6-16547).
In addition, a kind of curative is also disclosed, it is characterized in that, wherein contain DFNa as active component, and in the aqueous solution of forming by buffer agent, cosolvent and preservative agent, contain the stabilizing agent 2-amino-2-methylol-1 that active component and preservative agent is played Stabilization, ammediol or in its thing of the same clan, have the chemical compound (spy opens clear 62-242617) that is not more than 10 carbon atoms.On the other hand, about being combined with the drop of cyclodextrin, following patent literature being disclosed: contains 2-(2-fluoro-4-xenyl) propanoic acid or its salt and beta-schardinger dextrin-(hereinafter to be referred as β-CyD) or the anti-inflammatory eye solution of γ-CyD (special fair 3-30571); The anti-inflammatory eye solution (spy opens clear 60-136516) that contains 2-(2-fluoro-4-xenyl) propanoic acid or its salt, β-CyD or γ-CyD and calcium salt or magnesium salt; Or containing 3,4-dihydro-2,8-diisopropyl-3-sulfo--2H-1,4-benzoxazinyl-4-acetic acid or its salt be as principal agent, and contain the aqueous liquor (spy opens flat 5-213757) of cyclodextrin.
Yet, though the calcium salt or the magnesium salt that are generated by the acid that allows on the physiology demonstrate satisfied effect in mitigation aspect the stimulation of eyes, lacking the stability of long preservation, this is its shortcoming.Disclosed alpha-cyclodextrin stimulates for the eye that is caused by DFNa among the special fair 2-6329 does not have abirritation, stimulates abirritation though β-CyD has weak eye, and this effect is insufficient.Afterwards, present inventors find, as long as the water-soluble beta-CyD that will play the chemical modification effect is according to respect to DFNa being 7～50 times of mol ratios cooperations, just can obtain good result's (spy opens flat 6-16547) aspect eye stimulation mitigation, the storage stability two, but, when DFNa concentration surpasses 0.1%, just abundant inadequately to the abirritation of eye irritation.Showing goodish effect aspect the storage stability though open the clear 62-242617 drop shown in the example of passing the imperial examinations at the provincial level, after eye dripping, producing strong impulse the spy, therefore can not be satisfactory.
In addition, β-CyD is disclosed among clear 60-136516 and the flat 5-213757 of Te Kai and γ-CyD has the abirritation that eye stimulates for the effective ingredient in the drop opening as the spy to the improvement patent application of the fair 3-30571 of above-mentioned spy, but, all do not obtain ideal effect in either side for γ-CyD.
On the other hand, compare with the water-soluble beta-CyD of chemical modification, known γ-CyD has same degree or higher Local security's [going up still, Japanese drug technique (Pharm.Tech.Japan), 7 (2), 143,1991].In the past, because γ-CyD is difficult to mass production, so its price is very high, and being about β-CyD is 100 times, considers almost can't utilize from economic aspect.But,, therefore, it is being caused people's concern as drug additive owing to, can provide γ-CyD product at a low price recently to the exploitation of new manufacturing technology.
Present inventors, for develop a kind of γ of use-CyD, after eye dripping to eye non-stimulated, have long preservation stability and can use DFNa to carry out deep research by wide range of concentrations as the drop of principal agent, found that, by with DFNa, γ-CyD, PVP and as the benzethonium chloride of antiseptic or the benzyl chloride alkanamine is used in combination and pH value is adjusted in 7.0～8.5 the scope and just can reaches above-mentioned purpose, so far just finished the present invention.That is to say that the pH value that the present invention relates to a kind of DFNa of containing, γ-CyD, PVP and benzethonium chloride or benzyl chloride alkanamine is 7.0～8.5 anti-inflammatory eyecrops.
DFNa became strong in DFNa concentration greater than 0.05% o'clock usually to the stimulation of eye.Present inventors find, usually also be adjusted to 7.0～8.5 with γ-CyD and with pH value, can relax stimulation significantly to eyes, and can make high concentration in order to bring into play its therapeutic effect fully according to the symptom of various persons suffering from ocular disorders, and, wherein contain PVP jointly and as the benzethonium chloride or the benzyl chloride alkanamine of antiseptic by making, can make it become drop steady in a long-term,, thereby finish the present invention based on this brand-new discovery.
Because DFNa has very strong stimulation to eyes, therefore, the past is as the goods of drop, generally all the upper limit of concentration of DFNa is decided to be 0.1%.But, in drop of the present invention, use γ-CyD of 1～10% by merging, simultaneously pH value is adjusted to 7.0～8.5, can relax stimulation significantly, thereby can realize high concentration, therefore enlarge its scope of application significantly up to 0.7% to eyes.
Because the DFNa of high concentration can show ophthalmic prostaglandin inhibitory action and atropine mydriasis effect more significantly, therefore can not only be in the surgical operation (cataract of ophthalmology, glaucoma, ablatio retinae, vitreous body is extractd, stravismus etc.) demonstrate the therapeutic effect that keeps mydriasis and antiinflammatory or postoperative the time significantly, and to general ophthalmic diseases, just with the endogenous uvea inflammation headed by the Behcet, outer eye diseases associated with inflammation (conjunctivitis, keratitis, go up strong film inflammation, the pinguecula inflammation, hordeolums etc.) etc. the symptom relevant with prostaglandin has good therapeutic effect.
The preferred plan that is used to carry out an invention
γ-the CyD that uses among the present invention can relax the caused eye irritation of wide range of concentrations DFNa from low concentration to high concentration significantly.The effect of this wide region is that γ-CyD institute is inherent, and is that other water soluble Beta-cyclodextrins are unexistent.
The PVP that uses among the present invention can prevent the insoluble production of foreign matters from the γ-CyD in the prescription.For example polyvinyl alcohol, hydroxyethyl-cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, sodium carboxymethyl cellulose, Polyethylene Glycol etc. also have the effect that prevents that insoluble foreign body from producing to open the water soluble polymer that discloses except that PVP other among the flat 5-213757 the spy, but when trying out this technology, present inventors find, water soluble polymer beyond the PVP does not have this effect, and this is the inherent effect of PVP.
The PVP that uses among the present invention, the K value of its Fei Kenxieer (hereinafter referred K value) is preferably in 10～95 scope.Such PVP can be buied with trade name Kollidon 12PF, 17PF, 25,30 and 90 and be changed into industry (strain) by Tokyo and buy with trade name PVP K15, K30, K60 and K90 by BASF JAPAN (strain), and each commodity can both easily be buied.
The antiseptic that uses among the present invention, its objective is to provide the drop with long preservation stability, wherein especially preferably uses benzethonium chloride or benzyl chloride alkanamine.That is to say,, can from table 3, find out very significantly that benzethonium chloride or benzyl chloride alkanamine have the effect that prevent foreign body generation better than other antiseptic according to present inventors' experiment.
The compound method of drop of the present invention is, at first DFNa and γ-CyD is dissolved in the Purified Water, cooperates then to add PVP and benzethonium chloride or benzyl chloride alkanamine and with buffer agent and pH regulator agent pH value is adjusted to 7.0～8.5 and make.
DFNa concentration in the final composition of the present invention is preferably 0.05～0.7% (weight/volume %, down together), is preferably 0.1～0.5% especially.When the concentration of DFNa is lower than 0.05%, the effect of its anti-inflammatory a little less than, therefore do not have practicality; And if be higher than 0.7%, then the preparation of compositions is had any problem.
γ in the final composition of the present invention-CyD concentration is preferably 1～10%, is preferably 3～10% especially.In the concentration range of above-mentioned DFNa, if the concentration of γ-CyD is lower than 1%, then can not relax stimulation to eyes, if it is surpass 10%, then unfavorable aspect preparation and economy.
PVP concentration in final composition of the present invention is preferably 1～20%, is preferably 2～10% especially.If the concentration of PVP is lower than 1%, then can produce insoluble foreign body and lack storage stability, in addition,, then the intensive sensation that is clamminess is at the moment arranged at point if surpass 20%, therefore also bad.
The pH value of drop of the present invention is preferably 7.0～8.5, be preferably especially 7.5～8.5. when pH value 6.5 when following, even the concentration of γ-CyD is 5～10% also can not obtain to relax fully the effect of eye irritation.In addition, if pH value more than 8.5, has then departed from physiological pH value, therefore also bad.In order to carry out the adjusting of pH, can use buffer agent and pH regulator agent such as sodium hydroxide solution or dilute hydrochloric acid such as borate buffer solution or phosphate buffer according to conventional method, unqualified to this.
Benzethonium chloride that uses among the present invention and benzyl chloride alkanamine can prevent that drop is in use by microbial contamination and have bactericidal action.About their concentration, for benzethonium chloride, be preferably 0.002～0.01%, if the concentration of benzethonium chloride is lower than 0.002%, then a little less than its bactericidal action excessively, in addition,, then can cause more for a long time that in frequency of utilization corneal epithelium is impaired if surpass 0.01%.For the benzyl chloride alkanamine, be preferably 0.002～0.005%, if the concentration of benzyl chloride alkanamine is lower than 0.002%, then a little less than its bactericidal action excessively, in addition, if surpass 0.005%, drop generation emulsifying then of the present invention can't be prepared.
In drop of the present invention, except above-mentioned various compositions, can also contain other compositions that usually in drop, use, only otherwise violating purpose of the present invention gets final product.For example can contain buffer agent, isotonic agent, surfactant, chelating agen etc.As buffer agent, can use phosphate, borate and organic base.As isotonic agent, can enumerate sodium chloride, potassium chloride, boric acid and Borax etc.As surfactant, can enumerate polysorbate 80 and polyoxyethylene hardened castor oil 60 etc.In addition, as chelating agen, can enumerate disodiumedetate and sodium citrate etc.
Enumerate embodiment below and explain the present invention in more detail, but the present invention is not subjected to the qualification of these examples with the prescription example.
Embodiment 1
Diclofenac sodium 0.1g
γ-CyD 3.0g
(Wacker Chemicals East Asia Co.，Ltd.)
Boric acid 1.30g
Borax 0.88g
PVP K30 2.0g
(Kollidon BASF JAPAN Co., Ltd. (strain) system)
Benzethonium chloride 0.005g
0.1N HCl/0.1N NaOH transfers to pH8.0
Purified Water complements to 100ml
In the 80ml Purified Water, add diclofenac sodium, γ-CyD, boric acid, Borax, PVP K30, benzethonium chloride, it is dissolved fully.With 0.1N hydrochloric acid or 0.1N hydrochlorinate sodium pH value is adjusted to 8.0, complements to 100ml, promptly obtain drop after after the filtration sterilization with Purified Water.
Embodiment 2
Diclofenac sodium 0.05g
γ-CyD 10.0g
(Wacker Chemicals East Asia Co.，Ltd.)
Boric acid 1.60g
Borax 0.16g
PVP K25 10.0g
(Kllidon BASF JAPAN Co.，Ltd.，)
Benzethonium chloride 0.005g
0.1N HCl/0.1N NaOH transfers to pH7.0
Purified Water complements to 100ml
By above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 3
Diclofenac sodium 0.05g
γ-CyD 1.0g
(Wacker chemicals East Asia Co.，Ltd.)
Boric acid 1.10g
Borax 2.10g
PVP K90 1.0g
(Kollidon BASF JAPAN Co.，Ltd.)
Benzethonium chloride 0.005g
0.1N HCl/0.1N NaOH transfers to pH8.5
Purified Water complements to 100ml
By above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 4
Diclofenac sodium 0.1g
γ-CyD 3.0g
(Wacker chemicals East Asia Co.，Ltd.)
Boric acid 1.10g Borax 2.10gPVP K255.0g (Kollidon BASF JAPAN Co., Ltd.) benzyl chloride alkanamine 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 5 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K253.0g (Kollidon BASF JAPAN Co., Ltd.) benzyl chloride alkanamine 0.002g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 6 diclofenac sodium 0.5g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.10g Borax 2.10gPVP K2510.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 7 diclofenac sodium 0.7g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.10g Borax 2.10gPVP K2510.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.01g0.1N HCl/0.1N NaOH transfers to the pH8.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 8 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.45g Borax 0.35gPVP K2510.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.002g0.1N HCl/0.1N NaOH transfers to the pH7.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 9 diclofenac sodium 0.05g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.10g Borax 2.10gPVP K1220.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.002g0.1N HCl/0.1N NaOH transfers to the pH8.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 10 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K901.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 11 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K253.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 12 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K255.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 13 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K257.0g (Kollidon BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 14 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K2510.0g (Kollidon 25:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.
Embodiment 15 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker Chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K1712.0g (Kollidon BASF JAPAN Co., Ltd. (strain) system) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, carry out similarly to Example 1, operation obtains drop.
Embodiment 16 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker Chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K1515.0g (Tokyo changes into industry (strain) system) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, carry out similarly to Example 1, operation obtains drop.
Embodiment 17 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K1220.0g (Kollidon 12PF:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 1 diclofenac sodium 0.05g boric acid 1.30g Borax 0.88g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 2 diclofenac sodium 0.1g γ-CyD 0.7g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.45g Borax 0.35gPVP K253.0g (Kollidon 25:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH7.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 3 diclofenac sodium 0.1g γ-CyD 10.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.70g Borax 0.07gPVP K2510.0g (Kollidon 25:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH6.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, (CELDEX: japanese food chemical industry (strain) system) boric acid 1.30g borax 0.88g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription obtain drop. comparative example 4 C14H10Cl2NNaO2 0.1g α-CyD 5.0g; Operate similarly to Example 1, obtain drop. Comparative example 5 diclofenac sodium 0.1g β-CyD 1.0g (RINGDEX BR:Mercian Co., Ltd.) boric acid 1.30g Borax 0.88g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 6 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVPK2523.0g (Kollidon 25:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 7 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K1225.0g (Kollidon 12PF:BASF JAPAN Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 8 γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 9 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88g benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 10 diclofenac sodium 0.05g α-CyD 1.0gCELDEX: japanese food chemical industry (strain) system) boric acid 1.60g Borax 0.16gPVP K252.0g (Kollidon 25:BASF JAPAN Co., Ltd.) 0.1N HCl/0.1N NaOH transfers to the pH7.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 11 diclofenac sodium 0.05g β-CyD 0.9g (RINGDEX BR:Mercian Co., Ltd.) boric acid 1.60g Borax 0.16gPVP K252.0g (Kollidon 25:BASF JAPAN Co., Ltd.) 0.1N HCl/0.1N NaOH transfers to the pH7.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 12 diclofenac sodium 0.05g α-CyD 1.0g (CELDEX: japanese food chemical industry (strain) system) boric acid 1.60g Borax 0.16gPVP K252.0g (Kollidon25:BASF JAPAN Co.; Ltd.) disodium ethylene diamine tetraacetate 0.1g0.1N HCl/0.1N NaOH transfers to the pH7.0 Purified Water and complements to 100ml comparative example 13 C14H10Cl2NNaO2 0.05g β-CyD 0.9g (RING DEX BR:Mercian Co., Ltd.) boric acid 1.60g borax 0.16gPVPK252.0g (Kollidon 25:BASF JAPAN Co., Ltd.) disodiumedetate 0.1g0.1N HCl/0.1N NaOH transfers to the pH7.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 14 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.45g Borax 0.35g hydroxyethyl-cellulose 0.5g (FUJICHEMI HEC CF-G:Fuji Chemical Co., Ltd.) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH7.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 15 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.45g Borax 0.35gMETOLOSE SM400 0.5g (SHIN-ETSU HANTOTAI's chemistry (strain) system) benzethonium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH7.5 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 16 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K253.0g (Kollidon 25:BASF JAPAN Co., Ltd.) hexadecylpyridinium chloride 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 17 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K253.0g (Kollidon 25:BASF JAPAN Co., Ltd.) glucosan hibitane 0.005g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml by above-mentioned prescription, operate similarly to Example 1, obtain drop.Comparative example 18 diclofenac sodium 0.1g γ-CyD 3.0g (Wacker chemicals East Asia Co., Ltd.) boric acid 1.30g Borax 0.88gPVP K253.0g (Kollidon 25:BASF JAPAN Co., Ltd.) methyl parahydroxybenzoate 0.026g propyl p-hydroxybenzoate 0.014g0.1N HCl/0.1N NaOH transfers to the pH8.0 Purified Water and complements to 100ml add methyl parahydroxybenzoate, propyl p-hydroxybenzoate in being preheated to about 60 ℃ Purified Water 80ml, fully stirs so that it dissolves fully.After treating that this solution is cooled to room temperature, to wherein adding γ-CyD, boric acid, Borax, diclofenac sodium, PVP K25And with its dissolving.With pH regulator to 8.0, complement to 100ml with Purified Water with 0.1N HCl or 0.1N NaOH, filtration sterilization obtains drop.
Below by the test example the abirritation that eye irritation rose of preparation of the present invention to diclofenac sodium is described.
Test example 1 (people's usability test (eye stimulates))
To 1 of people (10 people) eye dripping, estimate the usability (eye stimulates) behind the eye dripping to 3 minute with the preparation of normal saline solution, embodiment 1～9 and comparative example 1～5.The results are shown in the table 1.The determinating reference of listed usability is as follows in the table 1:
0: non-stimulated
1: slightly feel twinge
2: twinge
3: pain or strong twinge
Table 1
People's usability (eye stimulates) Add up to On average
1 2 3 4 5 6 7 8 9 10
Normal saline solution 0 0 0 0 0 0 0 0 1 0 1 0.1
Embodiment 1 0 0 1 0 0 0 0 0 1 0 2 0.2
2 1 0 1 0 0 0 1 0 2 0 5 0.5
3 0 0 1 0 0 0 0 1 1 0 3 0.3
4 0 0 0 0 0 0 0 0 1 0 1 0.1
5 1 0 1 0 0 0 0 0 1 0 3 0.3
6 1 0 1 0 0 1 0 0 1 0 4 0.4
7 1 0 1 0 0 1 0 0 2 0 5 0.5
8 1 0 1 0 0 1 0 0 1 0 4 0.4
9 0 0 1 0 0 0 0 0 1 0 2 0.2
Comparative example 1 3 3 3 3 3 3 3 3 3 3 30 3.0
2 2 1 2 3 2 2 2 3 3 2 22 2.2
3 3 2 3 3 2 2 3 3 3 2 26 2.6
4 3 2 3 3 3 2 3 3 3 2 27 2.7
5 3 2 2 2 2 2 2 3 3 2 23 2.3
Result according to table 1 can prove that preparation of the present invention can alleviate the eye that is caused by diclofenac sodium significantly and stimulate, and its stimulation equates with normal saline solution.
These test examples show that the concentration of the PVP that uses in the preparation of the present invention serves as suitable with 1～20%.
Test example 2 (people's usability test (being clamminess))
To 1 of people (10 people) eye dripping, estimate the usability (being clamminess) behind the eye dripping to 3 minute with the preparation of normal saline solution, embodiment 10～17 and comparative example 6～7.The results are shown in the table 2.The determinating reference of listed usability is as follows in the table 2:
0: be not clamminess no unplessantness displeasure
1: slightly be clamminess, but do not have unplessantness displeasure
2: be clamminess slightly, slightly unplessantness displeasure
3: be clamminess, unplessantness displeasure is arranged
Table 2
People's usability (being clamminess) Add up to On average
1 2 3 4 5 6 7 8 9 10
Normal saline solution 0 0 1 0 0 0 0 0 1 0 2 0.2
Embodiment 10 1 1 1 0 1 1 2 0 1 1 9 0.9
11 1 1 1 0 1 0 2 0 1 1 8 0.8
12 1 1 1 1 1 1 2 1 1 1 11 1.1
13 2 1 2 1 1 1 1 1 1 1 12 1.2
14 2 2 1 1 2 1 2 1 1 1 14 1.4
15 2 1 2 1 1 1 2 1 1 1 13 1.3
16 2 1 2 1 2 1 2 1 1 1 14 1.4
17 2 1 2 1 1 1 2 1 2 1 14 1.4
Comparative example 6 3 3 3 2 2 2 3 1 3 2 24 2.4
7 3 2 2 2 2 2 2 1 2 2 20 2.0
Result according to table 2 can prove, when the PVP concentration of using in the preparation of the present invention is 1～20%, and the sense of almost not being clamminess.
These test examples show, even preparation of the present invention also is stable under exacting terms, can not produce insoluble foreign body.
Test example 3 (storage stability test)
The preparation of embodiment 1～9, comparative example 1 and comparative example 8～18 is encapsulated in the glass ampule, preserved 1 month down, observe the situation that insoluble foreign body produces at 40 ℃.The results are shown in the table 3.Metewand in the table 3 is as follows.
-: there is not insoluble foreign body
*: insoluble foreign body is arranged
In addition,, its preparation is encapsulated in the glass ampule at 40 ℃ preserved 6 months down, measure the survival rate of the fragrant phenol sodium of two chlorine, the results are shown in the table 4 for embodiment 1～8.
Table 3
Insoluble foreign body
Embodiment 1 -
2 -
3 -
4 -
5 -
6 -
7 -
8 -
9 -
Comparative example 1 -
8 *
9 *
10 *
11 *
12 *
13 *
14 *
15 *
16 *
17 *
18 *
Table 4
The survival rate of diclofenac sodium (%)
Embodiment 1 99.8
2 98.2
3 100.3
4 101.1
5 99.6
6 98.2
7 98.0
8 100.1
From the result of table 3 and table 4 as can be seen, even preparation of the present invention also is stable under harsh conditions.
The possibility of utilizing on the industry
According to the present invention, a kind of DFNa of containing can be provided, in long-time, stablize, eyes are not had excitant and can use by wide range of concentrations the anti-inflammatory eyecrops of DFNa. Said drop can be used for keeping mydriasis when the eye surgery of cataract, ablatio retinae, vitreum excision, stravismus etc., and the treatment that can be used for anti-inflammatory or postoperative, perhaps to Behcets disease, endogenous uvea inflammation and conjunctivitis, keratitis, on strong film scorching, pinguecula is scorching, use as effective drop in the treatment of the outer eye diseases associated with inflammation of sty etc.

Claims (6)

1.一种抗炎症点眼剂，其中在作为基质的水中含有：1. An anti-inflammatory eye drop containing in water as a base: (a)双氯芬酸钠0.05～0.7重量/体积％、(a) Diclofenac Sodium 0.05～0.7% by weight/volume, (b)γ-环糊精1～10重量/体积％、(b) γ-cyclodextrin 1-10% by weight/volume, (c)聚乙烯吡咯烷酮1～20重量/体积％、(c) 1 to 20% by weight/volume of polyvinylpyrrolidone, (d)苄索氯铵0.002～0.01重量/体积％或氯苄烷胺0.002～0.005重量/体积％，(d) benzethonium chloride 0.002～0.01% by weight/volume or benzalkonium chloride 0.002～0.005% by weight/volume, 该抗炎症点眼剂的pH值为7.0～8.5。The pH value of the anti-inflammatory eye drop is 7.0-8.5. 2.如权利要求1所述的点眼剂，其中双氯芬酸钠的含量为0.1～0.5重量/体积％。2. The eye drop as claimed in claim 1, wherein the content of diclofenac sodium is 0.1-0.5% by weight/volume. 3.如权利要求1或2所述的点眼剂，其中γ-环糊精的含量为3～10重量/体积％。3. The eye drop according to claim 1 or 2, wherein the content of γ-cyclodextrin is 3 to 10% by weight/volume. 4.如权利要求1～3中任一项所述的点眼剂，其中聚乙烯吡咯烷酮的含量为2～10重量/体积％。4. The eye drop according to any one of claims 1 to 3, wherein the content of polyvinylpyrrolidone is 2 to 10% by weight/volume. 5.如权利要求1～4中任一项所述的点眼剂，其pH值为7.5～8.5。5. The eye drop according to any one of claims 1 to 4, which has a pH of 7.5 to 8.5. 6.如权利要求1～5中任一项所述的点眼剂，其中聚乙烯吡咯烷酮的费肯歇尔的K值为10～95。6. The eye drop according to any one of claims 1 to 5, wherein the Fekenscher K value of polyvinylpyrrolidone is 10 to 95.
CN95197387A 1995-01-20 1995-12-26 Anti-inflammatory eyecrops Expired - Fee Related CN1087169C (en)

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CN109908125A (en) * 2013-12-25 2019-06-21 日本株式会社Ltt生物医药 Dry eye treatment eye drops
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Publication number Priority date Publication date Assignee Title
JPS6416728A (en) * 1987-07-07 1989-01-20 Santen Pharmaceutical Co Ltd Aqueous preparation
JPH0616547A (en) * 1992-07-01 1994-01-25 Wakamoto Pharmaceut Co Ltd Anti-inflammatory eye drops

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TW200402B (en) * 1990-08-13 1993-02-21 Senju Pharma Co

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6416728A (en) * 1987-07-07 1989-01-20 Santen Pharmaceutical Co Ltd Aqueous preparation
JPH0616547A (en) * 1992-07-01 1994-01-25 Wakamoto Pharmaceut Co Ltd Anti-inflammatory eye drops

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