CN1514735A - Ophthalmic composition containing hyaluronic acid - Google Patents

Abstract

An ophthalmic composition comprising an ophthalmic drug, such as ketotifen, and a linear polysaccharide compound, such as hyaluronic acid, is disclosed, which can be used for topical administration to the eye once daily.

Description

Ophthalmic composition containing hyaluronic acid

The present invention relates to pharmaceutical compositions, particularly ophthalmic compositions such as gels, and methods of administering said compositions for the treatment of ocular abnormalities or ophthalmic diseases.

Ophthalmic compositions, e.g. ophthalmic compositions comprising ketotifen (such compositions are well known, e.g. described in WO 01/07049 and commercially available, e.g. under the trade names Zaditen® ^{or Zaditor®} ) generally do not Do not use several times a day, usually two to four times. Such repeated dosing is not ideal in practice because, for example, the patient has to carry the medicine with him and is interrupted several times a day to administer the medicine. Thus, multiple administrations of drugs, especially ophthalmic compositions, often lead to problems of overdose and/or underuse of the drug. While overdose can often cause eye irritation, underdose can often lead to recurrence of symptoms.

Therefore, there is a need for a so-called once-daily ophthalmic drug. The present invention has discovered that such once-daily pharmaceutical compositions, particularly ophthalmic compositions, can be formulated. The compositions can provide the therapeutic effect of the drug they contain, for example an ophthalmic drug such as ketotifen, in the eye for about 24 hours. The composition is surprisingly well tolerated and produces very reliable and reproducible clinical results in patients administered the composition.

Thus, in one aspect, the present invention provides an ophthalmic composition, in particular for once-daily topical administration, comprising an ophthalmic and a linear polysaccharide compound, preferably a hyaluronic acid acid compound (hereinafter referred to as the composition of the present invention).

Suitable ophthalmic medications include anti-inflammatory drugs such as: indomethacin, diclofenac, tenoxicam, piroxicam, hydrocortisone, medrison, prednisolone, methylprednisolone, betamethasone, trichomonas Acetide, dexamethasone, fluorometholone; anti-allergic drugs such as ketotifen, antazoline, cromoglycate; drugs for glaucoma such as timolol, betaxolol, cartisol Lol, benzfurolol, levobunolol, pilocarpine, unoprostone, latanoprost, valsartan; miotics such as: pilocarpine, aceclidine, carbachol, acetylcholine; mydriatic Agents, such as: tropicamide, atropine, phenylephrine, cyclopentolate, scopolamine, homatropine, naphazoline; antibiotics, such as: lomefloxacin, pefloxacin, gentamicin, Sulfaacetamide, sulfapentene, sulfadiazine, neomycin, framycitine, polymyxin B, kanamycin, tobramycin, amikacin, tetracycline, oxytetracycline (oxytetracycline), subtilis chloramphenicol, doxycycline, minocycline, erythromycin, rifamycin, streptomycin; Glucoadenosine, trifluridine, acyclovir (acyclovir), foscarnet, interferon; anesthetics such as tetracaine, oxybucaine, lidocaine; antifungal agents such as amphotericin B, nystatin, flucytosine, griseofulvin; fungicides such as chlorhexidine, perchloridine; and nutritional agents such as ascorbic acid (vitamin C), vitamin A. Preferred ophthalmic agents may be selected from: diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvin, ascorbic acid and retinal, especially ketotifen.

Suitable ophthalmic agents may be, for example, in their free base or acid form, or in the form of one of their pharmaceutically acceptable salts, and two or more drugs may be used in combination.

The concentration of the ophthalmic drug is preferably about 0.005-5%, preferably 0.01-2%, more preferably 0.01-1%, such as 0.01-0.2%, such as 0.01-0.1%, and especially from 0.01 to 0.05%, preferably 0.02-0.04 %, the above percentages are percentages by weight based on the total weight of the composition.

The drug is preferably in the form of a solution. However, the compositions of the present invention may, if desired, also be in the form of a suspension, for example, a suspension containing ophthalmic particles having an average particle diameter of, for example, 200 to 25000 nm.

The compositions of the present invention may contain excipients which are pharmaceutically acceptable and suitable for ophthalmic compositions. In general, the excipients of the composition of the present invention, as well as the composition itself, should not damage the lacrimal system and tear film.

Information about properties, specifications, characteristics is described in e.g. standard textbooks, see e.g. Fiedler, HP; 1996; Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angerzende Gebiete ; Editio Cantor Verlag Aulendorf (Germany), and Kibbe, AH; 2000; Handbook of Pharmaceutical Excipients , a joint publication of Pharmaceutical Press, London (UK) and the American Pharmaceutical Association, Washington (USA); and Manufacturer's Handbook, the contents of these documents are hereby incorporated by reference.

The linear polysaccharide compound of the composition according to the invention preferably comprises a hyaluronic acid compound (hyaluronic acid; Fiedler, supra , p. 763), as known and commercially available from Vitrolife AB, Sweden, or from Pentapharm AG, Switzerland under the name Hyaluronic Acid. Compounds such as hyaluronic acid Pentapharm or hyaluronic acid BT. A more preferred linear polysaccharide compound of the composition is a hyaluronic acid compound. Preferably, the hyaluronic acid compound is a basic salt of hyaluronic acid, such as sodium hyaluronate. Hyaluronic acid can be obtained by known methods, for example, from rooster combs, or by biotechnology methods. The molecular weight is, for example, from about 0.4 x ¹⁰⁶ to about 3 x ¹⁰⁶ g/mole or to 4 x ¹⁰⁶ g/mole. Preferably the molecular weight is above about 0.75 x ¹⁰⁶ g/mole, more preferably about 2.6 x ¹⁰⁶ g/mole.

The exact amount of the polysaccharide compound, especially the hyaluronic compound, can vary widely to produce a composition of the invention having a viscosity within the preferred range described below. For example, the amount of compound may be from 0.05% to 10% by weight of the total composition, for example, from 0.1% to 10%, preferably from 0.1% to 2%.

In addition, the composition of the present invention may contain (2.) a commonly used tonicity enhancing agent. Suitable tonicity enhancing agents are, for example:

2.1 Ionic compounds, such as alkali metal or alkaline earth metal halides, such as _CaCl2 , KBr, KCl, LiCl, NaI, NaBr or NaCl, or boric acid, and/or

2.2 Non-ionic compounds such as urea, glycerin, sorbitol, mannitol, propylene glycol or glucose.

Conveniently, sufficient tonicity enhancing agent is added to the prepared ophthalmic composition to have an osmolality of from about 50 to 1000 mOsmol, preferably from 100 to 400 mOsmol, more preferably from 200 to 400 mOsmol, still more preferably 280 to 350 mOsmol.

In order to adjust the pH value, preferably to reach a physiological pH value, (3.) pH regulators or pharmaceutically acceptable buffer systems are added. Suitable pH adjusting agents include, for example, sodium hydroxide, for example in the form of a 1 mole/liter solution. Examples of buffer substances are acetate, ascorbate, borate, bicarbonate/carbonate, citrate, gluconate, lactate, phosphate, propionate, and tromethamine (tri- (Hydroxymethyl)-aminomethane, TRIS) buffer. Tromethamine buffer is preferred. Usually, an appropriate amount of buffer substances is added to ensure and maintain a physiologically tolerable pH range. This pH range is generally from 4 to 9, preferably from 4.5 to 8.5, more preferably from 5.0 to 8.2.

The composition of the present invention may further comprise (4.) a preservative, eg, for storage or to inhibit the growth of microorganisms after the composition is exposed to air after opening a closed container containing the composition. Preservatives can generally be selected from, for example:

4.1 Quaternary ammonium compounds, such as: benzalkonium chloride (N-benzyl-N-(C ₈ -C ₁₈ -alkyl)-N,N-dimethylammonium chloride), benzoxonium chloride, cetromet Ammonium bromide (cetyltrimethylammonium bromide), etc.

4.2 Alkyl mercury salts of thiosalicylic acid, such as thimerosal, phenylmercuric nitrate, phenylmercuric acetate, and phenylmercuric borate.

4.3 Parabens, for example: methyl paraben, propyl paraben.

4.4 Alcohols, such as: chlorobutanol, benzyl alcohol or phenethyl alcohol.

4.5 Biguanide derivatives, such as chlorhexidine or polyhexidine.

4.6 Sodium perborate

4.7 Imidazolidinyl urea known and commercially available under the trade name Germal(R) II.

4.8 Sorbic acid

4.9 Stable oxychloro complexes, such as known and commercially available under the trade name Purite(R)

4.10 Polyethylene glycol-polyamine condensation resins, such as known and commercially available, such as Polyquart® from Henkel KGaA, and/or

4.11 Mixtures consisting of any of the ingredients in 4.1 to 4.10

Preferred preservatives are quaternary ammonium compounds, especially benzalkonium chloride and cetrimonium bromide. If appropriate, a sufficient amount of preservative can be added to the ophthalmic composition to ensure that secondary contamination caused by bacteria and fungi can be prevented during use, for example, the preferred amount of preservative is about 0.001-0.02%.

The compositions according to the invention may additionally contain (5.) a solubilizer, especially when the active or inactive ingredients tend to form a suspension or emulsion. Suitable solubilizers for the compositions mentioned above are, for example:

5.1 Known and commercially available octylphenoxy-poly(oxyethylene)-ethanol (tetratyloxapol), trade name Triton®, for example: Triton® WR 1339, (Fiedler, supra , p. 1609),

5.2 Polyethylene glycol glycerol fatty acid ester. Fatty acid esters may include mono and/or di and/or tri fatty acid esters. The fatty acid component may be a saturated or unsaturated fatty acid with a carbon chain length of 8 to 20 carbons. Polyethylene glycol may have, for example, 5 to 40 [ _CH2 - _CH2 -O] units, such as 5 to 30 units. Particularly suitable are polyethylene glycol (15) glyceryl monostearate or polyethylene glycol (15) glyceryl monooleate as commercially available from Nikko Chemical Co., Ltd. under the trade names TGMS®-15 or TGMO(R)-15. More suitable is, for example, polyethylene glycol (30) glycerol monooleate commercially available from Goldschmidt under the tradename Tagat(R) O (H. Fiedler, supra , Vol. 2, pp. 1502-1503). More suitable are polyethylene glycol glycerol C ₈ -C ₁₀ fatty acid esters containing 5 to 10, eg 7 [CH ₂ -CH ₂ -O] units, such as Cetiol(R) HE, or Labrasol(R).

5.3 C _8-20 fatty acid polyoxyethylene ester, for example: known and commercially available polyoxyethylene stearate, trade name Myrj (Fiedler, supra , 2 , 1042 pages) or Brij (Fiedler, supra , 259 pages; Handbook of Pharmaceutical Excipients, supra , page 367). A particularly preferred product of this type is Myrj 52, which has a ^D25 value of about 1.1, a melting point of about 40 to 44°C, an HLB value of about 16.9, an acidity value of about 0 to 1, and a saponification number of about 25 to 35.

5.4 Glyceryl ethers (Fiedler, supra , p. 701).

5.5 Cyclodextrins, such as α-, β- or γ-cyclodextrins, for example alkyl, hydroxyalkyl, carboxyalkyl or alkoxycarbonyl-alkylated derivatives, or mono- or diglycosyl-α -, β- or γ-cyclodextrin, mono- or dimaltosyl-α-, β- or γ-cyclodextrin or glucosylmaltosyl-cyclodextrin, such as Cavamax® known and commercially available from WackerChemie or Cavasol(R). Such products are particularly preferably hydroxypropyl-X-cyclodextrins, such as are known and are commercially available under the trade names Cavasol® W7 HP or Cavasol® W8 HP. Mixtures of cyclodextrins may also be used.

5.6 Polyoxyethylene-sorbitan- _C8 - _C20 fatty acid esters (polysorbates), for example by combining ethylene oxide with sorbitol and fatty acid esters of its dehydrating compounds, such as mono- and tri-lauric acid Copolymerization of esters, palmitate, stearate and oleate, such as known and commercially available under the trade name Tween® (Fiedler, supra , p. 1615), including the product Tween®

20 [polyoxyethylene (20) sorbitan monolaurate],

21 [Polyoxyethylene (4) sorbitan monolaurate],

40 [polyoxyethylene (20) sorbitan monopalmitate],

60 [polyoxyethylene (20) sorbitan monostearate],

65 [polyoxyethylene (20) sorbitan tristearate],

80 [polyoxyethylene (20) sorbitan monooleate],

81 [Polyoxyethylene(5) sorbitan monooleate],

85 [Polyoxyethylene (20) sorbitan trioleate].

Particularly preferred among such products are Tween® 20 and Tween® 80. 5.7 Reaction products of natural or hydrogenated vegetable oils and glycols, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, e.g. polyoxyethylene glycolated natural or hydrogenated castor oil. These products can be obtained by known methods, for example by reacting natural or hydrogenated castor oil or fractions thereof with ethylene oxide in a molar ratio of about 1:35 to about 1:60, optionally removing free The polyethylene glycol component is prepared, for example, according to the methods described in German Laid-Open Nos. 1,182,388 and 1,518,819. Particularly suitable are the various surfactants commercially available under the name Cremophor. Particularly suitable is the product Cremophor RH 40 with a saponification value of about 50-60, acidity=<1, iodine value=<1, water content (Fischer)=<2%, n _D ⁶⁰ about 1,453-1,457, HLB about 14-16; and Cremophor RH 60, its saponification value is about 40-50, acidity=<1, iodine value=<1, water content (Fischer) is about 4.5-5.5%, n _D ²⁵ is about 1.453-1,457, HLB It is approximately equal to 15-17; and Cremophor EL, its molecular weight (measured by vapor osmotic pressure method) is approximately equal to 1630, the saponification value is approximately 65-70, the acidity is approximately equal to 2, the iodine value is approximately equal to 28-32, n _D ²⁵ is approximately Equal to 1.471 (see Fiedler, supra, pp. 326-327). Also suitable in this class are various surfactants with the trade name Nikkol, such as: Nikkol HCO-60. Described product Nikkol HCO-60 is the reaction product of hydrogenated castor oil and oxirane, and it has following characteristic: acidity is equal to 0.3 approximately; Saponification value equals approximately 47.4; Hydroxyl value approximately equals 42.5; pH (5%) approximately equals 4.6; color APHA is approximately equal to 40; mp is approximately equal to 36.0°C; freezing point is approximately equal to 32.4°C; H ₂ O content (%, KF) is approximately equal to 0.03, and/or

5.8 Mixtures consisting of ingredients from 5.1 to 5.7.

Particularly preferred solubilizers are Cremophor EL, Cremophor RH 40, tyloxapol and cyclodextrin. The concentration used usually depends on the concentration of the active ingredient. The amount added is usually sufficient to dissolve the active ingredient. For example, the concentration of the solubilizing agent is 0.1 to 5000 times that of the active ingredient, preferably 0.5 to 1000 times, such as 1 to 500 times.

Furthermore, it was found that the well-known incompatibility between benzalkonium chloride and hyaluronic acid compounds, especially sodium hyaluronate (which can lead to the irreversible formation of a colorless precipitate of said compound within seconds after contact, this Incompatibility has been widely used, even for titration of glycosaminoglycans (Harris et al., J.Lab.Clin.Med., Vol.74(1969), 527-535)) can be obtained by adding the above-mentioned increasing Solvents, especially solubilizers selected from the reaction products of natural or hydrogenated oils with ethylene glycol, such as the preferred ^Chremophor® EL and octylphenoxy-poly(oxyethylene)-ethanol (tetratyloxapol).

Other excipients may also be included in the compositions of the invention, which may in particular act as combined stabilizers/solubilizers. Additional stabilizers/solubilizers for this combination are, for example, cyclodextrins or mixtures of cyclodextrins. Preferred cyclodextrins are specifically selected from the group consisting of: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, dimethyl - beta-cyclodextrin, randomly methylated beta-cyclodextrin and dimethyl-gamma-cyclodextrin. It is usually used in an amount of about 0.01 to about 90% by weight, more preferably 0.1 to 20% by weight.

The ophthalmic composition may also contain other pharmaceutically acceptable excipients such as (6.) emulsifiers, (7.) wetting agents or (8.) fillers such as polyethylene glycol (Fiedler, supra , 2108, Handbook of Pharmaceutical Excipients (Handbook of Pharmaceutical Excipients), supra , page 392) such as PEG 200, 300, 400 and 600, or Carbowax(R) 1000, 1500, 4000, 6000 and 10000.

Listed below are other excipients which may be used if desired, but the list is not intended to limit in any way the range of excipients which may be used. In particular, they are (9.) complexing agents such as disodium edetate, ethylenediaminetetraacetic acid (EDTA); (10.) antioxidants such as ascorbic acid, acetylcysteine, cysteine acid, sodium bisulfite, butylated hydroxyanisole, butylated hydroxytoluene or alpha-tocopheryl acetate; (11.) Stabilizers such as thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or Thioglycerol; or (12.) other excipients, such as: sorbitan laurate, triethanolamine oleate or palmitate. Preferred excipients are complexing agents such as disodium EDTA. The amount and type of excipients to be added depends on the particular requirements and generally ranges from about 0.0001 to about 90% by weight.

In another embodiment, the composition provided by the present invention further comprises (13.) an ophthalmic carrier. Such carriers are particularly useful for topical administration, the following are examples of:

13.1 water,

13.2 Mixtures of water and water miscible solvents such as C ₁ -C ₇ -alkanols,

13.3 Vegetable or mineral oils containing 0.5 to 5% by weight of hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone,

13.4 Water-soluble polymers for ophthalmic use, e.g. cellulose derivatives such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl-cellulose and hydroxypropyl cellulose,

13.5 Acrylates or methacrylates, such as polyacrylic or ethyl acrylate salts, polyacrylamides,

13.6 Natural products, for example, gelatin, alginates, pectin, tragacanth, karaya, gellan gums such as Gelrite®, xanthan gum, carrageenan, agar and gum arabic,

13.7 Starch derivatives, for example, starch acetate and hydroxypropyl starch,

13.8 Synthetic products, for example, polyvinyl alcohol, polyvinylpyrrolidone, polyvinylmethyl ether, polyoxyethylene, or

13.9 Mixtures of these polymers.

Preferred carriers are water, cellulose derivatives such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose and hydroxypropylcellulose element, or a mixture of the above substances. The concentration of the carrier is, for example, 1 to 100000 times the concentration of the active ingredient.

It will be appreciated that although excipients are described above with reference to their specific function, any one specific excipient may have additional, even multiple functions, e.g. cyclodextrin or mixture of cyclodextrins Can act as a stabilizer, complexing agent and/or solubilizer.

Applicants have found that compositions of the invention having a moderate viscosity, for example from 500 to 2000, such as from about 1000 to 2000 mPas at 20-25°C, are particularly comfortable to use. When instilled in the eye, the viscosity of the compositions of the present invention will generally be reduced by dilution of the tear fluid. However, it is particularly surprising that after instillation into the eye, the compositions according to the invention still have good, or even better, retention properties.

If desired, the excipients and the amount thereof used in the composition of the present invention can be selected such that the viscosity of the composition increases when the temperature is from a storage temperature such as 20°C to a temperature of 32-34°C on the surface of the eye, so that the composition is stored in a container such as The viscosity in the dropper bottle is relatively low, and the viscosity in the eyes can be within the above-mentioned range. This can be achieved by adding eg thermoreversible polymers.

The compositions of the invention are shown to be stable by routine tests, for example, under stress conditions, eg at 80°C for 15 hours or at 40°C for 1 month. The composition of the present invention can be kept stable for two years or even more than three years at 20 to 30°C, and only no more than 5% of the ophthalmic drug is degraded.

A particularly preferred embodiment of the composition of the present invention comprises ketotifen or a pharmaceutically acceptable salt thereof, especially ketotifen hydrogen fumarate as an ophthalmic drug, in a concentration of preferably From 0.005 to 0.2%, more preferably from 0.01% to 0.1%, such as 0.01% to 0.05%, such as 0.01% to 0.04%, especially from 0.02% to 0.04%, more preferably about 0.025%.

These compositions comprise a hyaluronic acid compound, preferably sodium hyaluronate, for example in a concentration of from 0.05 to 10%, preferably from 0.1 to 2%, of the total weight of the composition.

A particular type of the above composition further comprises benzalkonium chloride as a preservative; and a solubilizer selected in particular from reaction products of natural or hydrogenated oils with ethylene glycol and octylphenoxy-poly(oxyethylene) ethanol.

The ophthalmic composition of the present invention can be prepared according to conventional methods, for example, mixing ophthalmic medicine and suitable excipients.

The composition of the invention is preferably clear, preferably in the form of a clear solution or gel, such as a clear gel.

Filling can be performed before or after sterilizing the resulting mixture. Sterilization of the compositions of the invention and primary packaging can be achieved by methods such as gamma radiation, treatment with ethylene oxide, irradiation with electron beams, autoclaving, microwave treatment, filtration with sterile filters or steam sterilization bacteria.

The composition of the present invention can be packaged according to conventional methods. Compositions of the present invention may be stored in single or multiple unit dose form, for example: airtight bottles, tubes or other containers made of glass, plastics such as polyethylene, polyethylene terephthalate, polypropylene, metal or Combination of the above substances. For example, a bottle may contain about 1 to 5 ml of a composition of the invention. A dropper may be attached to the container to facilitate administration.

The compositions of the present invention may be formulated in conventional manner, such as are particularly suitable for topical administration to the eye. Methods of formulation are not specifically described herein, and such methods are known in the art, or are similar to methods known in the art or described herein. Representative methods are described, for example, in Remington's Pharmaceutical Sciences, 19th ed., Mack Press, 1995, H. Sucker et al.; Pharmazeutische Technologie, 2nd ed., Thieme, 1991, R: H. Mueller et al.; Second Edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1998, L.Lachman et al.; The Theory and Practice of Industrial Pharmacy, Third Edition, 1986 and Hagers Handbuch derpharmazeutischen Praxis, Fourth Edition, Volume 7, (Springer Verlag, 1971) and subsequent editions, all of which are hereby incorporated by reference.

The excipients used may be, for example, those known in the art, for example those described in: Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angerzende Gebiete and " Handbook of Pharmaceutical Excipients ", References are made above; either an excipient similar to an excipient known in the art, or a new excipient having a similar function to an excipient described in the prior art or herein agent.

The composition of the present invention can be used to treat ophthalmic diseases/eye discomfort, and the specific curative effect depends on the drugs contained in the composition, for example, it has been shown by standard animal experiments and clinical trials that the composition can treat inflammation, allergy, glaucoma, miosis , numbness, infections caused by viruses, fungi, or microorganisms. The composition of the present invention containing ketotifen as a medicament is useful for the temporary prevention of eye itching caused by allergic conjunctivitis, and especially seasonal allergic conjunctivitis, and, by standard animal and clinical tests It has been shown to be useful in the prevention and treatment of signs and symptoms of seasonal allergic conjunctivitis.

One animal test consisted of a modified Draize test carried out on three albino rabbits, in which the eyes were shown 15 minutes after instillation of a dose (50 μL) of the composition of the invention onto the eye surface and after 1, 2, 7 days. tolerance. Tolerability is based on visual inspection and takes into account the following parameters: ocular discomfort judged by blinking or partial/complete eye closure, duration of discomfort, discharge, conjunctival (eyelid and bulbar) redness, bulbar conjunctival edema (swollen ), opacity of the cornea and related areas of the cornea, and pathological changes of the iris.

Clinical trials can be carried out to test the effect and tolerance of the composition of the present invention, wherein, 10 to 25 healthy volunteers or patients with eye diseases or eye discomfort to be treated are used as the test population, administered once a day, each time about 30 to 40 µl of the composition of the present invention containing 0.025% ophthalmic drug is instilled onto the surface of the eyeball, the inner side of the lower eyelid. The test lasted 8 days.

Efficacy against conjunctivitis is determined by examining subjects, eg, rapid onset and long duration of action and good tolerability, eg, no significant irritation or reddening.

Furthermore, the bioavailability of the composition of the present invention in the above-mentioned test is comparable to that of the commercially available twice-daily dosage form, said bioavailability being determined by absorption in the conjunctiva or its surrounding tissues.

The bioavailability of the above once-daily ophthalmic compositions was determined by the pharmacokinetic analysis described below:

A certain volume, eg 50 µl, of the ophthalmic preparation is instilled into the upper part of the rabbit conjunctiva. Samples were taken from the conjunctiva, cornea, sclera after 5, 15, 30 minutes or 1, 8, 16, 20 hours. Samples were taken to determine the ratio of drug to tissue wet weight. Drug content was determined by liquid chromatography (LC-MS) coupled to a mass spectrometer.

The exact amount of drug, eg ketotifen, to be used will depend on numerous factors such as salt, choice of excipients, nature of the formulation and severity of the condition. Conveniently, the composition of the invention may be applied to the cornea once daily, for example after breakfast. Preferably about 25 to 75 [mu]l, eg about 50 to 75 [mu]l are administered, eg with a dropper.

The daily dose of the medicine depends on the type and indication of the medicine. For example, ketotifen is administered at a dose of about 1 to about 5 micrograms per kilogram of body weight. For a large mammal, such as a 70 kg mammal such as a human, the suggested dose is about 100 to about 300 micrograms.

Therefore, the present invention provides in another aspect:

a composition as described above for the treatment of ophthalmic diseases/disorders of the eye, for example in the treatment of inflammation, allergies, glaucoma, miosis, numbness or infections caused by viruses, fungi or microorganisms,

ketotifen-containing compositions as described above for the treatment of allergic conjunctivitis and, in particular, for the treatment and prophylaxis of seasonal allergic conjunctivitis or conditions treatable with ketotifen,

A method of treating an ophthalmic disease/disorder, such as a method of treating inflammation, allergy, glaucoma, miosis, numbness, or infection caused by a virus, fungus, or microorganism, comprising topically administering a composition as described above once daily, whereby providing the effect of the drug in the above composition in the eye for more than about 24 hours,

A method of treating allergic conjunctivitis, particularly the treatment and prophylaxis of seasonal allergic conjunctivitis or a condition treatable with ketotifen, comprising administering to the eyes of a patient in need of such treatment a ketotifen-containing compound as described above once a day. fen composition,

the use of the composition described above for the preparation of a medicament for the treatment of ophthalmic diseases/discomforts, for example, the treatment of inflammation, allergy, glaucoma, miosis, numbness or infections caused by viruses, fungi or microorganisms, and

●Use of the above-mentioned ketotifen-containing composition in the preparation of a medicament for treating allergic conjunctivitis, especially treating and preventing seasonal allergic conjunctivitis or diseases that can be treated with ketotifen.

All percentages mentioned herein are weight/weight percentages unless otherwise noted. The following are merely illustrative of the compositions of the present invention.

Embodiment 1-4:

The excipients (the amounts of which are expressed in weight/weight percentages in the table below) were sequentially added to the water and the mixture was stirred.

Example 1 Example 2 Example 3 Example 4

Ketotifen hydrogen fumarate 0.0345 0.0345 0.0345 0.0345

Sodium Hyaluronate 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 -

Benzalkonium chloride (10%; 4.1) - - - - - 0.01

Tetratyloxapol - - - - - 0.1

EDTA(9.) - - - - - 0.05

Water (13.) Add to 100 Add to 100 Add to 100 Add to 100

The compositions of Examples 1 to 4 were stable and clear colorless solutions. They were shown to be well to moderately tolerated in the eyes of rabbits and were effective in seasonal allergic conjunctivitis when administered as described above.

The compositions of Examples 3 and 4 showed improved bioavailability in the conjunctiva, cornea and sclera compared to Zaditen( ^R) after single dose administration. After a single topical administration of 50 μl of the formulations of Examples 3 and 4 on the surface of the eyeball, the bioavailability of ketotifen (AUC _0.08-20h [μg·g ⁻¹ ·h]) was improved as shown in the table below.

Examples Conjunctiva Cornea Sclera Tolerance

Example 3 9.71 31.39 11.14 Moderate

Example 4 8.70 25.14 13.47 Moderate

^Zaditen® 5.74 14.27 8.76 Good

(comparison)

Claims (18)

CLAIMS 1. An ophthalmic composition, particularly for once-daily topical administration to the eye, comprising an ophthalmic drug and a linear polysaccharide compound. 2. Composition according to claim 1, wherein the linear polysaccharide compound is a hyaluronic acid compound, especially sodium hyaluronate. 3. A composition according to claim 1 or 2, further comprising one or more tonicity enhancing agents, buffers, preservatives, solubilizers and/or complexing agents. 4. The composition according to any one of claims 1 to 3, further comprising an ophthalmic carrier. 5. According to the composition described in any one of claims 1 to 4, wherein the ophthalmic medicine is selected from diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvin, ascorbic acid Thrombosis, retinal and their pharmaceutically acceptable salts. 6. The ophthalmic composition according to claim 5, comprising ketotifen or a pharmaceutically acceptable salt thereof. 7. The composition according to claim 6, comprising ketotifen hydrogen fumarate. 8. Composition according to claim 6, which contains benzalkonium chloride as preservative and contains solubilizers, preferably reaction products of natural or hydrogenated oils with ethylene glycol, or especially octylphenoxy-poly (oxyethylene) ethanol. 9. The composition according to claim 1, wherein the concentration of the ophthalmic drug is 0.005 to 5%, based on the total weight of the composition. 10. The composition according to claim 1, wherein the concentration of the hyaluronic acid compound is 0.05 to 10%, preferably 0.1 to 2%, based on the total weight of the composition. 11. The composition according to claim 6, wherein the concentration of ketotifen or a pharmaceutically acceptable salt thereof is 0.005 to 0.2%, preferably 0.02 to 0.04%, based on the total weight of the composition. 12. The composition according to claim 1, wherein the composition has a viscosity of 500 to 2000 mpas at 20-25°C. 13. The composition according to claim 1, for use in the treatment of ophthalmic diseases/disorders of the eye, for example, in the treatment of inflammation, allergy, glaucoma, miosis, numbness or infections caused by viruses, fungi or microorganisms. 14. Composition according to claim 6 for use in the treatment of allergic conjunctivitis and, in particular, in the treatment and prophylaxis of seasonal allergic conjunctivitis or conditions treatable with ketotifen. 15. A method for the treatment of ophthalmic diseases/discomforts, such as inflammation, allergy, glaucoma, miosis, numbness or infections caused by viruses, fungi or microorganisms, comprising administering the composition of claim 1 once a day Topical administration provides the effect of the drug in the composition in the eye for more than about 24 hours. 16. A method for treating allergic conjunctivitis, especially treating and preventing seasonal allergic conjunctivitis or a disease that can be treated with ketotifen, comprising applying claim 5 to the eyes of a patient in need of the treatment once a day Compositions. 17. Use of the composition according to claim 1 in the preparation of a medicament for the treatment of ophthalmic diseases/eye discomforts, for example, for the treatment of inflammation, allergy, glaucoma, miosis, numbness or infections caused by viruses, fungi or microorganisms use. 18. Use of the composition according to claim 5 in the preparation of a medicament for treating allergic conjunctivitis, especially treating and preventing seasonal allergic conjunctivitis or a disease that can be treated with ketotifen.