CN1514735A - Ophthalmic composition comprising hyaluronic acid - Google Patents

Ophthalmic composition comprising hyaluronic acid Download PDF

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Publication number
CN1514735A
CN1514735A CNA028115317A CN02811531A CN1514735A CN 1514735 A CN1514735 A CN 1514735A CN A028115317 A CNA028115317 A CN A028115317A CN 02811531 A CN02811531 A CN 02811531A CN 1514735 A CN1514735 A CN 1514735A
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described compositions
compositions
treatment
ketotifen
eyes
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M・巴比奥勒索尼耶
M·巴比奥勒索尼耶
仍罂
J-C·比泽克
A·费茨
C·肖赫
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Novartis AG
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

Ophthalmic compositions comprising an ophthalmic drug, e.g. ketotifen, and a linear polysaccharide compound, e.g. a hyaluronic acid compound, are useful for topical once-a-day administration to the eye.

Description

Contain hyaluronic eye medicine combination
The present invention relates to the method for the unusual or ophthalmic diseases of pharmaceutical composition, particularly eye medicine combination example gel, and applying said compositions treatment eye.
Eye medicine combination, (said composition is known, for example, is recorded in WO01/07049, and is available commercially, for example with trade (brand) name Zaditen for example to comprise the eye medicine combination of ketotifen Or Zaditor Obtain) use for several times, be generally two to four times the every day of having to usually.So administration repeatedly is unsatisfactory in actual use, because for example patient has to medicine is carried, but also can be disturbed for several times in one day because need to use medicine.Therefore, the multiple dosing of medicine, especially eye medicine combination tends to cause the excessive and/or insufficient problem of drug use.And the excessive stimulation that may cause eyes usually of drug use, the drug dose deficiency then may cause the recurrence of symptom usually.
So, the medicament for the eyes that need be administered once a kind of so-called every day.The present invention finds, can make the pharmaceutical composition that be administered once such every day, particularly eye medicine combination.Described compositions can provide their contained drugs, for example medicament for the eyes as the therapeutic effect of ketotifen about 24 hours at eye.Said composition has beat all well tolerable property, and produces very reliable and repeated fabulous clinical effectiveness in using the patient of said composition.
Therefore, on the one hand, the invention provides a kind of eye medicine combination, especially for topical every day compositions once, said composition comprises a kind of medicament for the eyes and a kind of linear polysaccharide chemical compound, preferred a kind of hyaluronic acid chemical compound (hereinafter referred to as compositions of the present invention).
The ophthalmic medicine that is fit to comprises anti-inflammation drugs, for example: indometacin, diclofenac, tenoxicam, piroxicam, hydrocortisone, medrysone, prednisolone, methyl meticortelone, betamethasone, triamcinolone acetonide, dexamethasone, fluorometholone; Claritin, for example: ketotifen, antazoline, cromoglycate; Treat glaucomatous medicine, for example: timolol, betaxolol, carteolol, befunolol, levobunolol, pilocarpine, Unoprostone, latanoprost, valsartan; Miotic is for example: pilocarpine, aceclidine, carbachol, acetylcholine; Mydriatic, for example: tropicamide, atropine, phyenlephrinium, cyclopentolate, scopolamine, melyltropeine, naphazoline; Antibiotic, for example: lomefloxacin, pefloxacin, gentamycin, sulfacetamide, sulfadicramide, sulfadiazine, neomycin, framycitine, polymyxin B, kanamycin, tobramycin, amikacin, tetracycline, oxytetracycline (oxytetracycline), subtilin, chloromycetin, doxycycline, minocycline, erythromycin, rifamycin, streptomycin; Antiviral drugs, for example: idoxuridine, 5-iodo-2 '-deoxycytidine, vidarabine, trifluridine, acyclovir (acycloguanosine), phosphine formic acid, interferon; Anesthetis, for example tetracaine, oxybuprocaine, lignocaine; Antifungal, for example: amphotericin B, nystatin, flucytosine, griseofulvin; Antibacterial such as chlohexidine, picloxydine; And nutrition medicament for example ascorbic acid (vitamin C), vitamin A.Preferred medicament for the eyes can be selected from: diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvin, ascorbic acid and retinal, especially ketotifen.
The medicament for the eyes that is fit to can be, for example, and the form of their free alkali or acid, or a kind of form of its officinal salt, and can be with two or more medication combined use.
The concentration of medicament for the eyes preferably approximately is 0.005-5%, preferred 0.01-2%, more preferably 0.01-1%, as 0.01-0.2%, as 0.01-0.1%, and particularly from 0.01 to 0.05%, preferred 0.02-0.04%, more than each percentage ratio be percetage by weight based on composition total weight.
Medicine is preferably the form of solution.Yet if desired, compositions of the present invention also can be the form of suspension, for example, contains average particulate diameter and is for example particulate suspension of medicament for the eyes of 200 to 25000 nanometers.
Compositions of the present invention can comprise pharmaceutically acceptable and be suitable for the excipient of eye medicine combination.Generally, the excipient of the present composition and compositions itself would not be damaged lachrymal gland system and tear film.
Information about performance, specification, feature has description in the textbook of for example standard, referring to for example: Fiedler, H.P.; 1996; Lexikon der Hilfsstoffe f ü r Pharmazie, Kosmetik Und angrenzende GebieteEditio Cantor Verlag Aulendorf (Germany), and Kibbe, A.H.; 2000; Handbook of pharmaceutical excipients (Handbook of pharmaceutical Excipients), London (Britain) medicine publishing house and Washington (U.S.) united states drug association combined publication; And the handbook of manufacturer, here the content with these files is incorporated herein by reference.
The linear polysaccharide chemical compound of the present composition preferably comprises a kind of hyaluronic acid chemical compound (hyaluronic acid; Fiedler, The same, 763 pages), as is known and for example hyaluronic acid Pentapharm by name that can be purchased or the chemical compound of hyaluronic acid BT from the Vitrolife AB of Sweden or from the Pentapharm AG of Switzerland.More the linear polysaccharide chemical compound of preferred compositions is a kind of hyaluronic acid chemical compound.Preferably, this hyaluronic acid chemical compound is a kind of hyaluronic basic salt, for example hyaluronate sodium.Hyaluronic acid can pass through people's known method, for example obtains from the cockscomb of cock, or obtains by biological technique method.Molecular weight is for example about 0.4 * 10 6To about 3 * 10 6Gram/mole or to 4 * 10 6Gram/mole.Preferred molecular weight is about 0.75 * 10 6More than the gram/mole, be more preferably about 2.6 * 10 6Gram/mole.
The definite amount of compound of polysaccharide, particularly hyalomitome chemical compound can change in a big way, to produce the present composition of a kind of its viscosity in following preferable range.For example, the amount of chemical compound can be 0.05% to 10% of whole composition weight, for example, and from 0.1% to 10%, preferably from 0.1% to 2%.
In addition, compositions of the present invention can comprise (2.) a kind of tension-elevating agent commonly used.The tension-elevating agent that is fit to is, for example:
2.1 ionic compound is as alkali metal or alkaline-earth halide, for example CaCl 2, KBr, KCl, LiCl, NaI, NaBr or NaCl, or boric acid, and/or
2.2 non-ionic compound is carbamide, glycerol, sorbitol, mannitol, propylene glycol or glucose for example.
Easily, the tension-elevating agent that adds capacity in the ophthalmic composition of making makes its osmolality be approximately 50 to 1000mOsmol, is preferably 100 to 400mOsmol, more preferably, be more preferably 280 to 350mOsmol from 200 to 400mOsmol.
Reach the physiology pH value in order to regulate pH value, to be preferably, add (3.) pH regulator agent or pharmaceutically useful buffer system.Suitable pH regulator agent comprises, for example sodium hydroxide, for example form of its 1 mol solution.The example of buffer substance be acetate, Ascorbate, borate, bicarbonate/carbonate, citrate, gluconate, lactate, phosphate, propionate and tromethane (three-(hydroxymethyl)-aminomethane, TRIS) buffer agent.Preferred tromethane buffer agent.Be generally and guarantee and keep the pH scope that a physiology can tolerate and add an amount of buffer substance.This pH scope normally from 4 to 9, preferably from 4.5 to 8.5, more preferably from 5.0 to 8.2.
Compositions of the present invention can further comprise (4.) a kind of antiseptic, for example in order to preserve or suppress microbial growth for to make said composition be exposed in the air opening the hermetic container that said composition is housed after.Antiseptic can be selected from usually, for example:
4.1 quaternary ammonium compound, for example: Benasept (N-benzyl-N-(C 8-C 18-alkyl)-N, the N-alkyl dimethyl ammonium chloride), benzoxonium chloride, cetrimonium bromide (cetab) etc.
4.2 the alkyl mercuric salt of thiosalicylic acid, for example thimerosal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate.
4.3 p-Hydroxybenzoate, for example: methyl parahydroxybenzoate, propyl p-hydroxybenzoate.
4.4 alcohols, for example: chlorobutanol, benzylalcohol or phenethanol.
4.5 Biguanide derivative, for example chlohexidine or polihexanide.
4.6 Dexol
4.7 known and can trade name Germal  II be purchased imidazolidinyl urea.
4.8 sorbic acid
4.9 stable oxychloride (oxychloro) complex is for example known and commercially available, commodity are called Purite 
4.10 Polyethylene Glycol-polyamines condensation resin is for example known and commercially available, the Polyquart  of Henkel KGaA for example, and/or
4.11 by the mixture that becomes to be grouped into arbitrarily in 4.1 to 4.10
Preferred antiseptic is a quaternary ammonium compound, especially Benasept and cetrimonium bromide.If suitably, can in eye medicine combination, add the antiseptic of capacity, to guarantee to prevent that in use for example, the consumption of preferred preservative is about 0.001-0.02% by antibacterial and the pollution of fungus-caused secondary.
Compositions of the present invention can contain (5.) a kind of solubilizing agent in addition, particularly when active component or non-active ingredient are tending towards forming a kind of suspension or emulsion.For compositions above-mentioned, suitable solubilizing agent is, for example:
5.1 known and commercially available Octylphenoxy-poly-(oxygen ethylene)-ethanol (alevaire), trade mark is called Triton , for example: and Triton  WR 1339, (Fiedler, The same, 1609 pages),
5.2 polyethylene glycol glycerol fatty acid ester.Fatty acid ester can comprise list and/or two and/or tri-fatty acid ester.Fatty acid composition can be that carbon chain lengths is the saturated or undersaturated fatty acid of 8 to 20 carbon.Polyethylene Glycol can have for example 5 to 40 [CH 2-CH 2-O] unit, for example 5 to 30 units.Particularly suitable is Polyethylene Glycol (15) glyceryl monostearate or Polyethylene Glycol (15) glycerin mono-fatty acid ester as being purchased from Nikko chemistry company limited, and trade name is respectively TGMS -15 or TGMO -15.More suitable is Polyethylene Glycol (30) glycerin mono-fatty acid ester that for example can be purchased from Goldschmidt, commodity Tagat  O by name (H.Fiedler, The same, the 2nd volume, 1502-1503 page or leaf).More suitable is to contain 5 to 10, as 7 [CH 2-CH 2-O] the polyethylene glycol glycerol C of unit 8-C 10Fatty acid ester, as Cetiol  HE, or Labrasol .
5.3 C 8-20Polyoxyethylene carboxylate, for example: known and commercially available polyoxyethylene stearic acid ester, commodity be called Myrj  (Fiedler, The same, 2, 1042 pages) or Brij  (Fiedler, The same, 259 pages; Handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), The same, 367 pages).This series products particularly preferably is Myrj  52, its D 25Value is about 1.1, and fusing point is about 40 to 44 ℃, and the HLB value is about 16.9, and acidity value is approximately 0 to 1, and saponification number is approximately 25 to 35.
5.4 glycerin ether (Fiedler, The same, 701 pages).
5.5 cyclodextrin, as α-, β-or gamma-cyclodextrin, alkyl, hydroxyalkyl, carboxyalkyl or alkoxy carbonyl-alkylating derivant for example, or list or diglycosyl-α-, β-or gamma-cyclodextrin, single or two malt-bases-α-, β-or gamma-cyclodextrin or glucosyl group malt-base-cyclodextrin, for example known and the Cavamax  or the Cavasol  that can be purchased from WackerChemie.The preferred especially hydroxypropyl of this series products-X-cyclodextrin, for example known and can trade name Cavasol  W7 HP or Cavasol  W8 HP be purchased.Also can use the mixture of cyclodextrin.
5.6 polyoxyethylene-anhydro sorbitol-C 8-C 20Fatty acid ester (Polysorbate), for example by fatty acid ester with oxirane and sorbitol and anhydro compounds thereof, for example single-and three-laurate, cetylate, stearate and oleate copolymerization and the product that obtains, for example known and can trade name Tween  be purchased (Fiedler The same, 1615 pages), comprise product Tween 
20[polyoxyethylene (20) sorbitol anhydride monolaurate],
21[polyoxyethylene (4) sorbitol anhydride monolaurate],
40[polyoxyethylene (20) sorbitol anhydride monopalmitate],
60[polyoxyethylene (20) sorbitan monostearate],
65[polyoxyethylene (20) sorbitol anhydride tristearate],
80[polyoxyethylene (20) sorbitan mono-oleic acid ester],
81[polyoxyethylene (5) sorbitan mono-oleic acid ester],
85[polyoxyethylene (20) sorbitol anhydride trioleate].
Particularly preferably be Tween  20 and Tween  80 in this series products.5.7 product natural or hydrogenated vegetable oil and ethylene glycol, i.e. natural the or hydrogenated vegetable oil of polyoxyethylene glycolization, for example, the natural or castor oil hydrogenated of polyoxyethylene glycolization.These products can obtain by known method, for example by will be natural or castor oil hydrogenated or its fraction and oxirane reacted in about 1: 35 to about 1: 60 according to mol ratio, randomly from product, remove free Polyethylene Glycol composition after the reaction, for example according to German publication number 1,182,388 and 1,518,819 described methods make.What especially be fit to is the various surfactants of the commodity Cremophor by name that can purchase.Particularly suitable is products C remophor RH 40, the about 50-60 of its saponification number, acidity=＜1, iodine number=＜1, water content (Fischer)=＜2%, n D 60Approximate 1,453-1,457, HLB approximates 14-16; And Cremophor RH 60, the about 40-50 of its saponification number, acidity=＜1, iodine number=＜1, water content (Fischer) approximates 4.5-5.5%, n D 25Approximate 1.453-1,457, HLB approximates 15-17; And Cremophor EL, its molecular weight (being recorded by the water vapour penetration platen press) approximates 1630, and saponification number is about 65-70, and acidity approximates 2, and iodine number approximates 28-32, n D 25Approximate 1.471 (referring to Fiedler, the same, the 326-327 page or leaf).The kinds of surface activating agent that commodity Nikkol by name is arranged that this apoplexy due to endogenous wind is suitable for equally, as: Nikkol HCO-60.Described product Nikkol HCO-60 is the product of castor oil hydrogenated and oxirane, and it has following characteristic: acidity approximates 0.3; Saponification number approximates 47.4; Hydroxyl value approximates 42.5; PH (5%) approximates 4.6; Color APHA approximates 40; M.p. approximate 36.0 ℃; Freezing point approximates 32.4 ℃; H 2O content (% KF) approximates 0.03, and/or
5.8 by 5.1 to 5.7 one-tenth mixture that are grouped into.
Particularly preferred solubilizing agent is Cremophor EL, Cremophor RH 40, alevaire and cyclodextrin.The concentration of its use is decided on the concentration of active component usually.The amount that adds is enough to the lytic activity composition usually.For example, the concentration of solubilizing agent is 0.1 to 5000 times of active component, preferred 0.5 to 1000 times, and as 1 to 500 times.
Find in addition, well-known Benasept (can cause described chemical compound several seconds inside irreversible ground after contacting to form colourless precipitation with hyaluronic acid chemical compound, the particularly incompatibility between the hyaluronate sodium, this incompatibility is used always widely, even be used for titration glycosaminoglycan (Harris etc., J.Lab.Clin.Med., Vol.74 (1969), 527-535)) can be by adding above-mentioned solubilizing agent, particularly being selected from the solubilizing agent of the product of natural or hydrogenated oil and fat and ethylene glycol, preferred Chremophor for example EL and Octylphenoxy-poly-(oxygen ethylene)-ethanol (alevaire) overcomes.
Can also comprise other excipient in the compositions of the present invention, these excipient specifically can play the effect of the stabilizing agent/solubilizing agent of associating.Additional stabilizers/the solubilizing agent of this associating has, for example the mixture of cyclodextrin or cyclodextrin.Preferred cyclodextrin specifically is selected from: alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, HP-, hydroxypropyl-gamma-cyclodextrin, DM-, methylated beta-schardinger dextrin-and dimethyl-gamma-cyclodextrin at random.Its consumption is generally about 0.01 to about 90% (weight), more preferably 0.1-20% (weight).
This ophthalmic composition can also comprise other pharmaceutically acceptable excipient, (6.) emulsifying agent for example, (7.) wetting agent or (8.) filler, for example Polyethylene Glycol (Fiedler, The same, 2108 pages, handbook of pharmaceutical excipients (Handbook of Pharmaceutical Excipients), The same, 392 pages) and as PEG200,300,400 and 600, or Carbowax  1000,1500,4000,6000 and 10000.
Below listed be operable other excipient under the situation of needs, but listed be not to be any restriction to be arranged for scope to the excipient that may use.Especially, they are (9.) chelating agent, as disodiumedetate, ethylenediaminetetraacetic acid (EDTA); (10.) antioxidant is as ascorbic acid, acetylcysteine, cysteine, sodium sulfite, butylated hydroxyanisole (BHA), butylated hydroxytoluene or acetic acid alpha-tocopherol; (11.) stabilizing agent is as thiourea, sulfo-sorbitol, dioctyl sodium sulphosuccinate or thioglycerol; Or (12.) other excipient, as: lauric acid sorbitol ester, triethanolamine oleate or cetylate.Preferred excipient is a chelating agent, as the EDTA disodium.The amount and the kind of the excipient that adds depend on specific requirement, arrive in the scope of about 90% (weight) about 0.0001 usually.
In another embodiment, compositions provided by the invention further comprises (13.) a kind of medicament for the eyes carrier.Such carrier is particularly useful for topical, below is its example:
13.1 water,
13.2 water and solvent such as the C easily miscible with water 1-C 7The mixture of-alkanol,
13.3 contain hydroxyethyl-cellulose, ethyl oleate, the carboxymethyl cellulose of 0.5 to 5% (weight), the vegetable oil or the mineral oil of polyvinylpyrrolidone,
13.4 the water-soluble polymer that medicament for the eyes is used, for example alkali metal salt of cellulose derivative such as methylcellulose, carboxymethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, methyl hydroxypropyl-cellulose and hydroxypropyl cellulose,
13.5 acrylate or methacrylate, as salt, the polyacrylamide of polyacrylic acid or ethyl acrylate,
13.6 natural product, for example, gelatin, alginate, pectin, tragacanth, karaya, gellan gum be Gelrite , xanthan gum, carrageenin, agar and Radix Acaciae senegalis for example,
13.7 starch derivatives, for example, amylcose acetate and hydroxypropyl starch,
13.8 synthetic product, for example, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyoxyethylene, or
13.9 these mixture of polymers.
Preferred carrier is a water, cellulose derivative such as methylcellulose, the alkali metal salt of carboxymethyl cellulose, hydroxy methocel, hydroxyethyl-cellulose, methylhydroxypropylcellulose and hydroxypropyl cellulose, or the mixture of above material.The concentration of carrier is for example 1 of activity component concentration to 100000 times.
Be appreciated that, although abovely excipient is described with reference to its specific function, yet any specific excipient can have other even multiple function, and for example, the mixture of cyclodextrin or cyclodextrin can be used as stabilizing agent, chelating agent and/or solubilizing agent.
The applicant finds to have the viscosity of appropriateness, for example from 500 to 2000, and comfortable especially in use as compositions of the present invention under 20-25 ℃ from about 1000 to 2000mPas.In the time of in dripping to eyes, the viscosity of the present composition can reduce because of the dilution of tear usually.Yet, particularly surprisingly, in being instilled into eyes after, compositions of the present invention still has good even outstanding retention property.
As needs, can select the excipient and the consumption thereof of the present composition, thereby make when temperature temperature 32-34 ℃ from storage temperature such as 20C to ocular surface, the viscosity of compositions increases, the viscosity of compositions when container is for example in the drop bottle is relatively low like this, and the viscosity in eyes can be within above-mentioned scope.This can realize by adding for example thermoreversible polymer.
Mensuration by routine shows that compositions of the present invention is stable, and these mensuration have, for example: under stress condition, for example 80 ℃ following 15 hours or following 1 month at 40 ℃.Compositions of the present invention can keep down stablizing more than 2 years even 3 years at 20 to 30 ℃, is no more than 5% medicament for the eyes degraded and only have.
A particularly preferred embodiment of the present composition comprises ketotifen or its officinal salt, particularly ketotifen difumarate as medicament for the eyes, account for the percentage ratio of composition total weight according to its weight, its concentration preferably from 0.005 to 0.2%, more preferably from 0.01% to 0.1%, for example 0.01% to 0.05%, for example 0.01% to 0.04%, particularly from 0.02% to 0.04%, the concentration that is more preferably is about 0.025%.
These compositionss comprise the hyaluronic acid chemical compound, preferably clear matter acid sodium, and for example its concentration is 0.05 to 10% of composition total weight, preferably from 0.1 to 2%.
A particular type of above-mentioned composition further comprises Benasept as antiseptic; And a kind of solubilizing agent, it specifically is selected from product and Octylphenoxy-poly-(oxygen ethylene) ethanol of natural or hydrogenated oil and fat and ethylene glycol.
Eye medicine combination of the present invention can prepare according to conventional method, for example: with medicament for the eyes and suitable mixed with excipients.
Compositions of the present invention is preferably transparent, and the solution of preferably clear or gel form are as transparent gel.
Filling can or be carried out after the sterilization before with the mixture sterilization of gained.The present composition and the sterilization of packing just can realize in order to method down, for example: gamma-rays radiation, with ethylene oxide treatment, with electron beam irradiation, autoclaving, microwave treatment, filter or steam sterilization with sterilizing filter.
The present composition can be packed according to conventional method.The present composition can be stored with single or multiple unit dosage forms, for example: airtight bottle, pipe or other container, these containers are by glass, plastics, and for example the combination of polyethylene, polyethylene terephthalate, polypropylene, metal or above material is made.For example, can contain in the bottle and have an appointment 1 to 5ml compositions of the present invention.Can load onto a dropper on the container so that administration.
Compositions of the present invention can be prepared with traditional mode, as is specially adapted to the mode of the topical of eyes.This not special description, these methods are known in the art for the method for preparation, and are perhaps similar with methods known in the art or method described herein.Representational method is documented in for example Remington ' s Pharmaceutical Sciences, and the 19th edition, Mack publishing house, 1995, H.Sucker etc.; Pharmazeutische Technologie, second edition, Thieme, 1991, R:H.Mueller etc.; Pharmazeutische Technologie:ModerneArzneimittelformen, second edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1998, L.Lachman etc.; The industrial principle of pharmacy and application (The Theory andPractice of Industrial Pharmacy), the third edition, 1986 and Hagers Handbuch derpharmazeutischen Praxis, the 4th edition the 7th volume, (Springer Verlag, 1971) and later version, above all the elements are all incorporated this paper into as a reference.
Used excipient can be for example known in the art those, for example be recorded in the following document those: Lexikon der Hilfsstoffe f ü r Pharmazie, Kosmetik und angrenzende Gebiete" handbook of pharmaceutical excipients ( Handbook of Pharmaceutical Excipients) ", the content of reference is referring to above; Or with the similar excipient of the known excipient in field, or have to prior art in or the new excipient of the similar function of excipient described herein.
Compositions of the present invention can be used for treating ophthalmic diseases/ophthalmic uncomfortable, concrete curative effect depends on the medicine that compositions is contained, for example show the infection that said composition can be treated inflammation, allergy, glaucoma, contracted pupil, numbness, be caused by virus, fungus or microorganism by standard animal experiment and clinical trial.Contain ketotifen and can be used for the temporary ophthalmic pruritus that causes by anaphylaxis conjunctivitis of preventing as the present composition of medicine, and the ophthalmic pruritus that causes of particularly seasonal anaphylaxis conjunctivitis, and, show that by standard animal and clinical trial it can be used for preventing and treating the sign and the symptom of seasonal anaphylaxis conjunctivitis.
An animal experiment is included in the Draize test of the improvement of carrying out on three albino rabbits, wherein, shows the toleration of eyes after 15 minutes and 1,2,7 day after the present composition of the dosage (50 μ L) that instils arrives ocular surface.Toleration is based on vision-based detection and consider following parameter: the turbidity of, chemosis (enlargement) rubescent, cornea and cornea relevant range by nictation or part/ophthalmic uncomfortable of judging of closing one's eyes fully, uncomfortable time, ejection, the conjunctiva (eyelid and bulbar conjunctiva) that continues, and the pathologic of iris changes.
Can carry out effect and the toleration of clinical trial with the test present composition, wherein, with 10 to 25 healthy volunteers or oculopathy or ophthalmic uncomfortable patient to be treated is the test crowd, be administered once in one day, the present composition that about 30 to 40 μ l are comprised 0.025% medicament for the eyes is instilled into eyeball surface at every turn, as the palpebra inferior inboard.Test duration 8 days.
By checking that the experimenter determines the curative effect to conjunctivitis, for example: the rapid onset of efficacy of a drug effect and permanent lasting and good tolerability for example significantly do not stimulate or redden.
In addition, bioavailability and the dosage form of commercially available one day administered twice of compositions of the present invention in above-mentioned test is suitable, and described bioavailability is to be determined by the absorption of conjunctiva or its surrounding tissue.
The bioavailability of the eye medicine combination that be administered once above-mentioned every day is measured by pharmacokinetic analysis described below:
With certain volume, for example the ophthalmic preparation of 50 μ l splashes into the top of rabbit conjunctiva.After 5,15,30 minutes or 1,8,16,20 hour, take a sample from conjunctiva, cornea, sclera.Extract sample to measure the ratio of medicine with respect to tissue wet.Medicament contg is by measuring with the liquid chromatograph (LC-MS) that links to each other with mass spectrograph.
Medicine, for example the definite consumption of ketotifen depends on numerous factors, for example the order of severity of the characteristic of the selection of salt, excipient, preparation and disease.Easily, compositions of the present invention can for example early be applied to cornea once a day after meal.Preferably use about 25 to 75 μ l, for example about 50 to 75 μ l for example use the dropper administration.
The daily dose of medicine depends on the kind and the indication of medicine.For example, ketotifen, the dosage of every kg body weight are approximately 1 approximately to 5 micrograms.For large mammal, the mammal of 70 kilogram weights people for example for example, recommended doses is about 100 to about 300 micrograms.
Therefore, the present invention provides on the other hand:
● above-described compositions, be used for the treatment of ophthalmic diseases/ophthalmic uncomfortable, the infection of for example treating inflammation, allergy, glaucoma, contracted pupil, numbness or causing by virus, fungus or microorganism,
● the above-described compositions that contains ketotifen, be used for the treatment of anaphylaxis conjunctivitis and, particularly treat and prevent seasonal anaphylaxis conjunctivitis or available ketotifen the treatment disease,
● the method for treatment ophthalmic diseases/discomfort, the method of the infection of for example treating inflammation, allergy, glaucoma, contracted pupil, numbness or causing by virus, fungus or microorganism, comprise above-described compositions topical once a day, thereby provide the drug effect of the medicine in the above-mentioned composition above about 24 hours at eye
● the treatment anaphylaxis conjunctivitis, particularly treat and prevent the method for the disease that seasonal anaphylaxis conjunctivitis or available ketotifen treat, comprise once a day in the patient's of this treatment of needs eye and use the above-described compositions that contains ketotifen,
● above-mentioned composition is used for the treatment of ophthalmic diseases/ophthalmic uncomfortable in preparation, for example, the purposes in the medicine of treatment inflammation, allergy, glaucoma, contracted pupil, numbness or the infection that causes by viral, fungus or microorganism and
● the above-mentioned compositions that contains ketotifen is used for the treatment of anaphylaxis conjunctivitis, particularly treats and prevent purposes in the medicine of the disease that seasonal anaphylaxis conjunctivitis or available ketotifen treat in preparation.
Except indicating part especially, all percentage ratios of mentioning here all are w/w percentage ratio.Below only be illustrating to the present composition.
Embodiment 1-4:
Excipient (its consumption is represented with w/w percentage ratio in following table) is added in the entry and with mixture successively and stirs.
Embodiment 1 embodiment 2 embodiment 3 embodiment 4
Ketotifen difumarate 0.0345 0.0345 0.0345 0.0345
Hyaluronate sodium 0.10 0.50 1.00 0.10
D-sorbitol (2.2) 5.40 5.08 4.50 4.50
Cetrimonium bromide (4.1) 0.005 0.005 0.005-
Benasept (10%; 4.1)---0.01
Alevaire---0.1
EDTA(9.) - - - 0.05
Water (13.) is added to 100 and is added to 100 and is added to 100 and is added to 100
The compositions of embodiment 1 to 4 is stable and transparent colourless solution.They demonstrate good in medium toleration in the eyes of rabbit, and when carrying out administration by above description, effective to seasonal anaphylaxis conjunctivitis.
The compositions of embodiment 3 and example 4 shows that behind single dose administration, they compare Zaditen in the bioavailability of conjunctiva, cornea and sclera Increase.With the preparation of embodiment 3 and 4 behind eyeball surface single topical 50 μ l, the bioavailability (AUC of ketotifen 0.08-20h[μ gg -1H]) improvement as shown in the table.
Embodiment conjunctiva corneosclera toleration
Embodiment 3 9.71 31.39 11.14 is medium
Embodiment 4 8.70 25.14 13.47 is medium
Zaditen 5.74 14.27 8.76 is good
(contrast)

Claims (18)

1. eye medicine combination, especially for to eyes topical every day compositions once, it comprises a kind of medicament for the eyes and a kind of linear polysaccharide chemical compound.
2. according to the described compositions of claim 1, linear polysaccharide chemical compound wherein is hyaluronic acid chemical compound, particularly hyaluronate sodium.
3. according to claim 1 or 2 described compositionss, further comprise one or more tension-elevating agents, buffer agent, antiseptic, solubilizing agent and/or chelating agent.
4. according to any one described compositions of claim 1 to 3, further comprise a kind of medicament for the eyes carrier.
5. according to any one described compositions of claim 1 to 4, medicament for the eyes wherein is selected from diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvin, anti-bad thrombosis, retinal and their officinal salt.
6. according to the described eye medicine combination of claim 5, contain ketotifen or its officinal salt.
7. according to the described compositions of claim 6, contain the ketotifen difumarate.
8. according to the described compositions of claim 6, it contains Benasept as antiseptic, and contains solubilizing agent, the product of preferred natural or hydrogenated oil and fat and ethylene glycol, perhaps Octylphenoxy-gather (oxygen ethylene) ethanol particularly.
9. according to the described compositions of claim 1, wherein the concentration of medicament for the eyes is 0.005 to 5%, in the gross weight of compositions.
10. according to the described compositions of claim 1, wherein the hyaluronic acid compound concentrations is 0.05 to 10%, and is preferred 0.1 to 2%, in the gross weight of compositions.
11. according to the described compositions of claim 6, wherein the concentration of ketotifen or its officinal salt is 0.005 to 0.2%, and is preferred 0.02 to 0.04%, in the gross weight of compositions.
12. according to the described compositions of claim 1, wherein in the time of 20-25 ℃, the viscosity of compositions is 500 to 2000mpas.
13. according to the described compositions of claim 1, be used for the treatment of ophthalmic diseases/ophthalmic uncomfortable, for example, treatment inflammation, allergy, glaucoma, contracted pupil, numbness or the infection that causes by virus, fungus or microorganism.
14. according to the described compositions of claim 6, be used for the treatment of anaphylaxis conjunctivitis and, particularly treat and prevent seasonal anaphylaxis conjunctivitis or available ketotifen the treatment disease.
15. the method for treatment ophthalmic diseases/ophthalmic uncomfortable, the method of the infection of for example treating inflammation, allergy, glaucoma, contracted pupil, numbness or causing by virus, fungus or microorganism, comprise the described compositions of claim 1 topical once a day, thereby provide the drug effect of the medicine in the described compositions above about 24 hours at eye.
16. the treatment anaphylaxis conjunctivitis, particularly treat and prevent the method for the disease that seasonal anaphylaxis conjunctivitis or available ketotifen treat, comprise once a day in the patient's of this treatment of needs eye and use the described compositions of claim 5.
17. be used for the treatment of ophthalmic diseases/ophthalmic uncomfortable according to the described compositions of claim 1 in preparation, for example, the purposes in the medicine of treatment inflammation, allergy, glaucoma, contracted pupil, numbness or the infection that causes by viral, fungus or microorganism.
18. be used for the treatment of anaphylaxis conjunctivitis, particularly treat and prevent purposes in the medicine of the disease that seasonal anaphylaxis conjunctivitis or available ketotifen treat in preparation according to the described compositions of claim 5.
CNA028115317A 2001-06-08 2002-06-07 Ophthalmic composition comprising hyaluronic acid Pending CN1514735A (en)

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