CA2449213A1 - Ophthalmic compositions comprising hyaluronic acid - Google Patents

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

Pharmaceutical Compositions The invention relates to pharmaceutical, in particular ophthalmic compositions, e.g. gels and a method for treating ocular disorders/diseases by administration of said compositions.
Ophthalmic compositions have often to be applied several, typically two to four times a day, like, for instance, ophthalmic compositions comprising ketotifen which are known, e.g. from .
WO 01/07049 and commercially available, e.g. under the trademark Zaditen~ or Zaditor~.
Such repeated administration is not optimal in practice because the patient has, for instance, to have the medicament always available and is disrupted several times a day by the need of administering the composition. Therefore such multiple administration of a drug, in particular of an ophthalmic composition, generally leads to the problem of overdosing and/or underdosing. Overdosing, however, may typically generate ocular irritation, whereas underdosing may typically lead to re-occurrence of the symptoms.
There is thus a need for a so-called once-a-day administration of ophthalmic drugs. It has now been found that pharmaceutical compositions, in particular ophthalmic compositions, can be formulated for once-a-day administration. Said compositions provide the therapeutic effect the drug they comprise, for instance of an ophthalmic drug like ketotifen, at the eye over about 24 hours. Such compositions are surprisingly well tolerated, and produce a highly reliable and strongly reproducible clinical result in a patient treated therewith.
Therefore, in one aspect the present invention provides an ophthalmic composition, particularly for topical once-a-day administration, which comprises an ophthalmic drug and a linear polysaccharide compound, preferably a hyaluronic acid compound (hereinafter compositions of the present invention).
Suitable ophthalmic drugs include anti-inflammatory drugs such as indomethacin, diclofenac, tenoxicam, piroxicam, hydrocortisone, medrysone, prednisolone, methylprednisolone, betamethasone, triamcinolone acetonide, dexamethasone, fluorometholone; drugs against allergy such as ketotifen, antazoline, cromoglycate; drugs for treatment of glaucoma such as timoloi, betaxolol, carteoloi, befunolol, tevobunoiol, pilocarpine, unoprostone, latanoprost, valsartan; miotics such as pilocarpine, aceclidine, carbachol, acetycholine;
mydriatics such as tropicamide, atropine, phenylephrine, cyclopentolate, scopolamine, homatropine, napha-zoline; antibiotics such as lomefloxacine, pefloxacine, gentamicine, sulfacetamide, sulfadi-cramide, sulfadiazine, neomycine, framycitine, polymixine B, kanamycine, tobramycine, amikacine, tetracycline, oxytetracycline, bacitracine, chloramphenicol, doxycicline, minocycline, erythromycine, rifamycine, streptomycine; antiviral drugs such as idoxuridine, 5-iodo-2'-deoxycytidine, vidarabine, trifluridine, acyclovir, foscarnet, interferon; anaesthetics such as tetracaine, oxybuprocaine, lidocaine; antimycotics such as amphotericine B, nystatine, fluorocytosine, griseofulvine; antiseptics such as chlorhexidine, picloxidine; and trophic agents such as ascorbic acid, retinol. Preferably the ophthalmic drug is selected from diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvine, ascorbic acid and retinal, or is, very particularly, ketotifen.
Suitable ophthalmic drugs may be e.g. in their free base or acid form, or in form of a pharmaceutically acceptable salt thereof and may be used in combination of two or more than two.
The concentration of ophthalmic drug is preferably from about 0.005 - 5%, preferably 0.01 -2%, even more preferably from 0.01 - 1 %, e.g. 0.01 to 0.2%, e.g. 0.01 to 0.1 % and in particular from 0.01 to 0.05, preferably 0.02 - 0.04%, in each case by weight based on the total weight of the composition.
A drug is preferably in solution. If desired, however, the compositions of the present invention may be in the form of a suspension, e.g. containing particles of ophthalmic drug e.g. with a mean particle diameter of 200 to 25000 nm.
The compositions of the present invention may comprise pharmaceutically acceptable excipients, which are suitable for ophthalmic compositions. The excipients of the compositions of the present invention and the compositions themselves should, in general, not detrimentally affect the lacrimal system nor the ocular tear film.
Information on the properties, specifications and characteristics are described e.g in standard texts such as Fiedler, H.P.; 1996; Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik and angrenzende Gebiete; Editio Cantor Verlag Aulendort (Germany), and Kibbe, A.H.;
2000; Handbook of Pharmaceutical Excipients, a joint publication of Pharmaceutical Press, London (UK), and American Pharmaceutical Association, Washington (US) as well as manufacturers' brochures, the contents of which are incorporated herein by reference.
The linear polysaccharide compound of the compositions of the instant invention preferably comprises a hyaluronic acid compound (hyaluronan; Fiedler, loc. cit., p. 763) such as known and commercially available from Vitrolife AB, Sweden, or from Pentapharm AG, Switzerland, e.g. under the names hyaluronic acid Pentapharm or hyaluronic acid BT. Even more preferably the linear polysaccharide compound of the compositions is a hyaluronic acid compound. Preferably, the hyaluronic acid compound is an alkali salt of hyaluronic acids, e.g. sodium hyaluronate. The hyaluronic acid may be obtained in a way known per se, e.g.
from cocks combs or biotechnically. The molecular weight is e.g. from about 0.4*10s to about 3*106 g/mol or to about 4*106 g/mol. Preferred molecular weights are above about 0.75*10g g/mol, even more preferably about 2.6*106 g/moi.
The exact amounts of polysaccharide compound, in particular of hyaluronic compound may vary within wide limits, e.g. in order to produce a composition according to the present invention which has a viscosity within the preferred range indicated below.
For example, the amount may be from 0.05 to 10%, e.g. 0.1 to 10%, preferably from 0.1 to 2% by weight of the total composition.
Furthermore, the compositions of the present invention may comprise (2.) an usual tonicity enhancing agent. Suitable tonicity enhancing agents are, e.g.
2.1 ionic compounds, such as alkali metal or alkaline earth metal halides, such as CaCh, KBr, KCI, LiCI, Nal, NaBr or NaCI, or boric acid, and/or 2.2 non-ionic compounds such as urea, glycerol, sorbitol, mannitol, propylene glycol, or dextrose.
Conveniently, sufficient tonicity enhancing agent is added to impart to the ready-for-use ophthalmic composition an osmolality of approximately from 50 to 1000 mOsmol, preferred from 100 to 400 mOsmol, more preferred from 200 to 400 mOsmol and even more preferred from 280 to 350 mOsmol.
For the adjustment of the pH, preferably to a physiological pH, addition of (3.) pH modifying agents or a pharmaceutically acceptable buffer system. A suitable pH-modifying agent includes e.g. sodium hydroxide e.g. in form of a one molar solution. Examples of buffer substances are acetate, ascorbate, borate, hydrogen carbonatelcarbonate, citrate, gluconate, lactate, phosphate, propionate and tromethamine (tris-(hydroxymethyl)-amino-methane, TRIS) buffers. Tromethamine buffer is preferred. The buffer substance added is typically of an amount to ensure and maintain a physiologically tolerable pH
range. The pH
range is generally in the range of from 4 to 9, preferably from 4.5 to 8.5 and more preferably fromS.Oto8.2.
The compositions of the present invention may further comprise (4.) a preservative, e.g. on storage or to inhibit microbial growth after opening a closed container holding such a composition and exposing such a composition to the air. A preservative may typically be selected from e.g.
4.1 a quaternary ammonium compound such as e.g. benzalkonium chloride (N-benzyl-N-(C$-C~$-alkyl)-N,N-dimethylammonium chloride), benzoxonium chloride, cetrimide (hexadecyl-trimethylammonium bromide) or the like.
4.2 alkyl-mercury salts of thiosalicylic acid, such as e.g. thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, 4.3 parabens, such as e.g. methylparaben or propylparaben, 4.4 alcohols, such as e.g. chlorobutanol, benzyl alcohol or phenyl ethanol, 4.5 biguanide derivatives, such as e.g. chlorohexidine or polyhexamethylene biguanide, 4.6 sodium perborate, 4.7 imidazolidinyl urea as known and commercially available under the trade name Germal~ll, 4.8 sorbic acid, 4.9 stabilized oxychloro complexes such as known and commercially available under the trade name Purite~, 4.10 polyglycol-polyamine condensation resins, such as known and commercially available e.g. under the trade name Polyquart~ from Henkel KGaA, and/or 4.11 a mixture of any components 4,1 to 4.10.
Preferred preservatives are quaternary ammonium compounds, in particular benzalkonium chloride and cetrimide. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by bacteria and fungi, e.g. the preferred preservatives are present in an amount of about 0.001-0.02%.
The compositions according to the instant invention may additionally require the presence of (5.) a solubilizer, in particular if the active or the inactive ingredients tends to form a suspension or an emulsion. A solubilizer suitable for an above concerned composition is e.g.
5.1 octylphenoxy-poly(ethylenoxy)-ethanol (tyloxapol) known and commercially available under the trade name Triton, e.g. Triton ~ WR 1339, (Fiedler, loc. cit., p 1609), 5.2 polyethylene glycol glyceryl fatty acid ester. The fatty acid ester may include mono and/or di and/or tri fatty acid ester. The fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from e.g. C$-Czo. The polyethylene glycols may have e.g. from 5 to 40 [CH2-CH2-O] units, e.g. 5 or 30 units.
Particularly suitable is polyethylene glycol (15) glyceryl monostearate or polyethylene glycol (15) glyceryl monooleate which is commercially available, e.g. under the trade name TGMS~-15 or TGMO~-15, respectively, e.g. from Nikko Chemicals Co., Ltd.
Further suitable is polyethylene glycol (30) glyceryl monooleate which is commercially available, e.g. under the trade name Tagat~ O, e.g. from Goldschmidt (H.
Fiedler, loc cit, vol. 2, p. 1502-1503). Further suitable are polyethylene glycol glyceryl C8-Coo fatty acid ester with from 5 to 10 (CH2-CH2-Ol units, e.g. 7 units, e.g. Cetiol~ HE, or Labrasol~
5.3 polyoxyethylene C8_2o fatty acid esters, e.g. polyoxyethylene stearic acid esters of the type known and commercially available under the trade name Myrj~ (Fiedler, loc. cit., 2, p. 1042) or Brij~ (Fiedler, loc. cit., p. 259; Handbook of Pharmaceutical Excipients, loc. cit., p. 367). An especially preferred product of this class is Myrj~ 52 having a D~5 of about 1.1, a melting point of about 40 to 44°C, an HLB value of about 16.9, an acid value of about 0 to 1 and a saponification value of about 25 to 35, 5.4 glycerol ethers (Fiedler, loc. cit., p.701 ), 5.5 cyclodextrins, e.g. a-, (3- or y-cyclodextrin, e.g. alkylated, hydroxyalkylated, carboxy-alkylated or alkyloxycarbonyl-alkylated derivatives, or mono- or digiycosyl-a-, (i- or y-cyclodextrin, mono- or dimaltosyl-a-, (3- or y- cyclodextrin or panosyl-cyclodextrin, e.g.
such as known and commercially available under the trade name CavamaxC~ or Cavasol~ from Wacker Chemie. An especially preferred product of this class is hydroxypropyl-x-cyclodextrin, e.g. as known and commercially available under the trade name Cavasol~ W7 HP or Cavasol~ W8 HP. A mixture of cyclodextrins may also be used.
5.6 polyoxyethylene-sorbitan- C8_2o fatty acid esters (polysorbates) e.g.
produced by co-polymerising ethylene oxide with fatty acid esters of a sorbitol and its anhydrides of e.g. mono- and tri- lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name Tween~ (Fiedler, loc.cit., p.1615) including the products Tween~
20 [polyoxyethylene(20)sorbitanmonolaurate], 21 [polyoxyethylene(4)sorbitanmonolaurate], 40 [polyoxyethylene(20)sorbitanmonopalmitate], 60 [polyoxyethylene(20)sorbitanmonostearate], 65 [polyoxyethylene(20)sorbitantristearate], 80 [polyoxyethylene(20)sorbitanmonooleate], 81 [polyoxyethylene(5)sorbitanmonooleate], 85 [polyoxyethylene(20)sorbitantrioleate].
Especially preferred products of this class are Tween~20 and Tween~80.
5.7 reaction products of natural or hydrogenated vegetable oils and ethylene glycol, i.e.
polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example poly-oxyethylene glycolated natural or hydrogenated castor oils. Such products may be obtained in known manner, e.g. by reaction of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, with optional removal of free polyethylene glycol components from the product, e.g. in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Especially suitable are the various tensides available under the trade name Cremophor. Particularly suitable are the products Cremophor RH 40 having a saponification no. ca. 50-60, an acid no.=<1, an iodine no.=<1, a water content (Fischer)=<2%, an nDSO =ca.1,453-1,457 and an HLB=ca. 14-16; Cremophor RH 60 having a saponification no.=ca. 40-50, an acid no. =<1, an iodine no.=<1, a water content (Fischer)=ca. 4.5-5.5%, an np~s=ca.1.453-1,457 and an HLB=ca.15-17;
and Cremophor EL having a molecular weight (by steam osmometry)=ca. 1630, a saponification no.=ca. 65-70, an acid no.=ca. 2, an iodine no.=ca. 28-32 and an noes =ca.1.471 (c.f. Fiedler loc. cit. p. 326-327). Also suitable for use in this category are the various tensides available under the trade name Nikkol, e.g. Nikkol HCO-60.
The said product NIKKOL HCO-60 is a reaction product of hydrogenated castor oil and ethylene oxide exhibiting the following characteristics: acid no.=ca. 0.3;
saponification no.=ca.
47.4; hydroxy value=ca. 42.5. pH (5%)=ca. 4.6; Color APHA=ca. 40; m.p.=ca.
36.0°C.;
Freezing point=ca. 32.4°C.; H20 content (%, KF)=ca. 0.03, and/or 5.8 mixtures of the components 5.1 to 5.7.
Especially preferred solubilizers are Cremophor EL, Cremophor RH 40, tyloxapol and cyclodextrins. The concentration used depends especially on the concentration of the active ingredient. The amount added is typically sufficient to solubilize the active ingredient. For example, the concentration of the solubilizer is from 0.1 to 5000 times the concentration of the active ingredient, preferably 0.5 to 1000, e.g. 1 to 500.
It has furthermore been found that the well-known incompatibility of benzalkonium chloride and hyaluronic acid compounds, in particular sodium hyaluronate, which leads to the irreversible formation of a colourless precipitate within a few seconds after contact of said compounds which has widely been exploited even for titrating glucosaminoglycans (Harris et al. J. Lab. Clin. Med., Vol. 74(1969), p. 527-535) can be overcome by addition of solubilizers like those mentioned, in particular a solubilizers selected from reaction products of natural or hydrogenated oils and ethylene glycol, for example Chremophor~EL, and octylphenoxy-poly(ethylenoxy)ethanol (tyloxapol) which is preferred.
Further excipients may be comprised in the compositions of the present invention, which may in particular function as a combined stabilizer/solubilizer. Such a combined additional stabilizer/soiubilizer is for example a cyclodextrin or a mixture of cyclodextrins. A preferred cyclodextrin is in particular selected from the group of a-cyclodextrin, (3-cyclodextrin, y-cyclo-dextrin, hydroxypropyl-~i-cyclodextrin, hydroxypropyl-y-cyclodextrin, dimethyl-(3-cyclodextrin, randomly methylated (3-cyclodextrin and dimethyl-y-cyclodextrin. The amount is generally in the range of from approximately 0.01 to approximately 90% by weight, more preferably in the range of from 0.1 - 20% by weight.
The ophthalmic compositions may comprise further pharmaceutically acceptable excipients, such as (6.) emulsifiers, (7.) wetting agents or (8.) fillers, such as, e.g.
the polyethylene glycols (Fiedler, loc. cit., p. 2108, Handbook of Pharmaceutical Excipients, loc. cit., p 392) such as PEG 200, 300, 400 and 600, or Carbowax~ 1000, 1500, 4000, 6000 and 10000.

_g_ Other excipients that may be used if desired are listed below but they are not intended to limit in any way the scope of the possible excipients. They are especially (9.) complexing agents, such as disodium-ethylenediamine tetraacetate, ethylenediamine tetraacetic acid (EDTA), (10.) antioxidants, such as ascorbic acid, acetylcysteine, cysteine, sodium hydrogen sulfite, butylated hydroxyanisole, butylated hydroxytoluene or alpha-tocopherol acetate; (11.) stabilizers, such thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol; or (12.) other excipients, such as, for example, lauric acid sorbitol ester, triethanol amine oleate or palmitic acid ester. Preferred exipients are complexing agents, such as disodium-EDTA.
The amount and type of excipient added is in accordance with the particular requirements and is generally in the range of from about 0.0001 to about 90% by weight.
In another embodiment, the present invention provides for compositions further comprising (13.) an ophthalmic carrier. Such carriers are typically adapted for topical administration, and are for example 13.1 water, 13.2 mixtures of water and water-miscible solvents, such as C~- to C~-alkanols, 13.3 vegetable oils or mineral oils comprising from 0.5 to 5% by weight hydroxyethyl-cellulose, ethyl oleate, carboxymethyl-cellulose, polyvinyl-pyrrolidone, 13.4 water-soluble polymers for ophthalmic uses, such as, for example, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxy-methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylhydroxypropyl-cellulose and hydroxypropylcellulose, 13.5 acrylates or methacrylates, such as salts of polyacrylic acid or ethyl acrylate, poly-acrylamides, 13.6 natural products, such as gelatin, alginates, pectins, tragacanth, karaya gum, gellan gum such as Gelrite~, xanthan gum, carrageenin, agar and acacia, 13.7 starch derivatives, such as starch acetate and hydroxypropyl starch, 13.3 synthetic products, such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, or 13.9 mixtures of those polymers.
Preferred carriers are water, cellulose derivatives, such as methylcellulose, alkali metal salts of carboxymethylcellulose, hydroxymethylce!lulose, hydroxyethylcellulose, methylhydroxy-_g_ propylcellulose and hydroxypropylcellulose, or mixtures thereof. The concentration of the carrier is, for example, from 1 to 100 000 times the concentration of the active ingredient.
It will be appreciated that although the excipients have been described above by reference to a particular function any particular excipient may have alternative or multiple functions, e.g.
cyclodextrin or a mixture of cyclodextrins may act as e.g. stabilizer, complexing agent and/or solubilizer.
Applicants have found that compositions of the present invention with moderate viscosity, e.g. from 500 to 2000, e.g. about 1000 to 2000, mPa s at 20-25°C are particularly comfortable to apply. Upon instillation into the eye, the viscosity of the compositions of the present invention generally decreases, due to dilution with tear liquid.
Nevertheless, and particularly surprising, the compositions of the present invention still have a good or even excellent retention after instillation into the eye.
If desired, the excipients of the compositions of the present invention and the amounts thereof may be chosen such, that the viscosity of the compositions increases from storage temperatures, e.g. 20°C, to the temperatures at the surface of the eyes, e.g. 32-34°C, so that the compositions are of relatively low viscosity when in the container, for instance a drop bottle, and have a viscosity in the range indicated above on the eye. This can e. g. be achieved by incorporation of thermo-reversible polymers.
The compositions of the present invention are stable, as indicated by conventional tests, e.g.
under stressed conditions, such as 15h at 80°C or 1 month at 40°C. The compositions of the present invention are stable over 2, even 3, years showing less than 5 %
degradation of the ophthalmic drug at 20 to 30°C.
An expressly preferred embodiment of the compositions according to the instant invention comprises ketotifen or a pharmaceutically acceptable salt thereof as the ophthalmic drug, in particular, ketotifen hydrogen fumarate, preferably in a concentration from 0.005 to 0.2%, even more preferably from 0.01 - 0.1 %, e.g. 0.01 to 0.05%, e.g. 0.01 to 0.04%
and in particular from 0.02 - 0.04%, even more preferably about O.Q25%, by weight based on the total weight of the composition.

These composition comprise the hyaluronic acid compound, preferably sodium hya(uronate, for instance in a concentration of 0.05 to 10%, preferably from 0.1 to 2%, based on the total weight of the composition.
A specific type of the aforementioned compositions furthermore comprises benzalkonium chloride as preservative, and a solubilizer, in particular selected from a reaction product of natural or hydrogenated oils and ethylene glycol and octylphenoxy-poly(ethylenoxy)ethanol.
The ophthalmic compositions of the present invention may be prepared in conventional manner e.g. by mixing the ophthalmic drug and appropriate excipients.
The compositions of the present invention are preferably clear, preferably in form of clear solution or gel, e.g. clear gel.
Filling may be effected before or after sterilization of the resulting mixture. Sterilization of the composition of the present invention and the primary package can be effected e.g. by gamma irradiation, by ethylene oxide treatment, by electron beam, by autoclaving, by microwave treatment, by filtration through a sterile filter, or by steam sterilization.
The compositions of the present invention may be packaged in conventional manner. The compositions of the present invention may be stored in single or multiple unit dosage form, e.g. closed bottles, tubes or other containers made from glass, plastic such as e.g. poly-ethylene, polyethylene terephthalate, or polypropylene, or metal or combinations thereof. For example bottles may contain about 1 to 5 ml of the compositions of the present invention.
The container may be fitted with a dropper to facilitate administration.
The compositions of the present invention may be formulated in conventional manner e.g. to be particularly adapted for topical ophthalmic use. In so far as the procedures for formulation are not particularly described herein such formulation procedures may for example be known in the art, or analogous to those known in the art or to procedures described herein.
Representative procedures are disclosed in for example, Remington's Pharmaceutical Sciences, 19th Ed., Mack Publ., Co., 1995, H. Sucker et al, Pharmazeutische Technologie, 2nd Edition, Thieme, 1991, R: H. Mueller et al, Pharmazeutische Technologies Moderne Arzneimittelformen, 2nd Edition, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1998, L.

Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rd Ed, 1986, and Halters Handbuch der pharmazeutischen Praxis, 4th Ed. Vol. 7, (Springer Verlag, 1971 ) as well as later editions, the contents of all of which are incorporated herein by reference.
The excipients used may e.g. be those known in the art e.g in the Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik and angrenzende Gebiete; and Handbook of Pharmaceutical Excipients, references referred to above, or analogous to those known in the art or new excipients having analogous function to those described in the art or herein.
The compositions of the present invention are useful for the treatment of ophthalmic diseases/disorders, dependent on the drug comprised in the compositions for the treatment e.g. of inflammation, allergy, glaucoma, miosis, anaesthesia, viruses, fungi or microorganism as indicated e.g. in standard animal trials and clinical trials. The compositions of the present invention comprising ketotifen as drug are useful for the temporary prevention of itching of the eye due to allergic conjunctivitis, and in particular of seasonal allergic conjunctivitis, and may be used for the treatment and prevention of signs and symptoms of seasonal allergic conjunctivitis as also indicated in standard animal trials and clinical trials.
One animal test comprises a modified Draize test on three albino rabbits wherein the ocular tolerability after a single dose instillation of 50 microlitres of compositions of the present invention on the ocular surface is shown for the 15 minutes after instillation then after 1, 2 and 7 days. The tolerability was based on visual examination considering the following parameters: discomfort as judged by blinking or partial/complete closure of the eye, duration of discomfort, discharge, redness of conjunctiva (palpebral and bulbar conjunctiva), chemosis of conjunctiva (swelling), degree of opacity of cornea and area of cornea involved, and pathological modification of the iris.
A clinical trig! may be effected to test the effrcacy and tolerability of about 30 to 40 microlitre of compositions of the present invention containing 0.025% of drug administered once a day by instillation onto the ocular surface, e.g. to the inside lower lid, to groups of, e.g. 10 to 25, healthy volunteers, or patients suffering from ophthalmic disease/disorder to be treated. The trial lasts e.g. 8 days.

The subjects are examined to determine the effect against conjunctivitis, e.g.
fast onset of action and long duration of action and good tolerability, e.g. lack of significant irritation or reddening.
Additionally the bioavailability of the compositions of the present invention in the above trials as determined by absorption in the conjunctiva or surrounding tissues are comparable with commercially available forms which are administered twice a day.
The bioavailability of an addressed once-a-day ophthalmic composition was assessed with the pharmacokinetic assay described infra:
A fixed volume, e.g. 50 microliters, of the ophthalmic formulation was instilled onto the upper part of the conjunctiva of rabbits. Bulbar conjunctiva, cornea and sclera were sampled after either 5, 15, 30 minutes, or, 1, 8, 16, or 20 h. Samples were extracted for drug determination related to the wet weight amount of tissue. Content of drug was determined using a liquid chromatography linked to mass spectrography (LC-MS) validated method.
The exact amount of drug, for instance ketotifen, to be administered will naturally depend on a variety of factors, e.g. choice of salt, excipients, formulation properties, and severity of the condition. Conveniently, the composition of the present invention is administered to the cornea once a day, e.g. after breakfast. Preferably from about 25 to about 75 microlitres, e.g. from about 50 to about 75 microlitres, is administered, e.g. using a dropper.
The daily dose of the drug depends on the kind of drug and on the indication.
Ketotifen, for example, is to be administered in doses from about 1 microgramslkg to about 5 micrograms/kg. For larger mammals, e.g. a 70 kg mammal such as a human, a dose of from about 100 to about 300 micrograms, is indicated.
Therefore, in a further aspect the present invention provides:
~ a composition as described above for use in the treatment of ophthalmic diseases/disorders, for instance, treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganisms, ~ a composition as described above comprising ketotifen for use in the treatment of allergic conjunctivitis and, in particular, of treatment and prevention of seasonal allergic conjunctivitis, or a condition treatable by ketotifen therapy, ~ a method for treating ophthalmic diseases/disorders, for instance, treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganism, including a topics! once-a-day administration of a composition as described above, thereby providing the therapeutic effect of the drug in said composition at the eye over about 24 hours, ~ a method for treating allergic conjunctivitis, in particular for treating and preventing seasonal allergic conjunctivitis or a condition treatable by ketotifen therapy, including a once-a-day administration of a composition as described above comprising ketotifen to the eye of a patient in need thereof, ~ the use of a composition as described above in the preparation of a medicament for the treatment of ophthalmic diseases/disorders, for instance, the treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganisms, and ~ the use of a composition as described above comprising ketotifen in the preparation of a medicament for the treatment of allergic conjunctivitis, in particular, for treatment and prevention of seasonal allergic conjunctivitis or a condition treatable by ketotifen therapy.
All percentages referred to herein are weight/weight except where otherwise indicated.
Following is a description by way of example only of compositions of the present invention.
Examples 1 - 4:
The excipients (amounts given in % weight/ weight as described in table below) are added in turn to the water and the mixture stirred.
Ex.1 Ex.2 Ex.3 Ex.4 ketotifen hydrogen fumarate0.03450.03450.03450.0345 sodium hyaluronate 0.10 0.50 1.00 0.10 D-sorbitol (2.2) 5,40 5.08 4.50 4.50 cetrimide (4.1 ) 0.005 0.005 0.005-benzalkonium chloride - - - 0.01 (10%; 4.1) tyloxapol (5.1 ) - - - 0.1 EDTA (9.) - - - 0.05 water (13.) ad ad ad ad The compositions of examples 1 to 4 are stable clear, colourless solutions.
They show a good to moderate tolerability in rabbit eye and are effective against seasonal allergic conjunctivitis as administered as described above.
The compositions of Example 3 and 4 demonstrate an improvement of the bioavailabi(ity in conjunctiva, cornea and sclera as compared to Zaditen~ after single dose application. The improvement of ketotifen bioavai(ability (AUCo.os-aon [N~g~g'v]) after 50p1 single topical application of the formulations according to Ex. 3 and 4 to the ocular surface are shown in the following table.
Example Conjunctiva Cornea Sclera Tolerability Ex.3 9.71 31.39 11.14 Moderate Ex.4 8.70 25.14 13.47 Moderate Zaditen~ 5.74 14.27 8.76 Good (Comparison)

Claims (18)

Claims

1. An ophthalmic composition, in particular for topical once-a-day administration to the eye, comprising an ophthalmic drug and a linear polysaccharide compound.

2. A composition according to claim 1 wherein the linear polysaccharide compound is a hyularonic acid compound, in particular sodium hyaluronate.

3. A composition according to claim 1 or 2, further comprising one or more tonicity enhancing agent, buffer, preservative, solubilizer and/or complexing agent.

4. A composition according to any one of claims 1 to 3 further comprising an ophthalmic carrier.

5. A composition according to any one of claims 1 to 4 wherein the ophthalmic drug is selected from diclofenac, prednisolone, ketotifen, timolol, valsartan, griseofulvine, ascorbic acid, retinal and a pharmaceutically acceptable salt thereof.

6. An ophthalmic composition according to claim 5 comprising ketotifen or a pharmaceutically acceptable salt thereof.

7. A composition according to claim 6 comprising ketotifen hydrogen fumarate.

8. A composition according to claim 6 comprising benzalkonium chloride as preservative and a solubilizer, preferably a reaction product of natural or hydrogenated oils and ethylene glycol or, in particular octylphenoxy-poly(ethylenoxy)ethanol.

9. A composition according to claim 1, wherein the concentration of the ophthalmic drug is from 0.005 to 5 %, based on the total weight of the composition.

10. A composition according to claim 1 wherein the concentration of the hyaluronic acid compound is from 0.05 to 10, preferably from 0.1 to 2%, based on the total weight of the composition.

11. A composition according to claim 6, wherein the concentration of ketotifen or the pharmaceutically acceptable salt thereof is from 0.005 to 0.2%, preferably from 0.02 to 0.04%, based on the total weight of the composition.

12. A composition according to claim 1, wherein the viscosity of the composition ranges from 500 to 2000 mPa s at 20-25°C.

13. A composition according to claim 1 for use in the treatment of ophthalmic diseases/disorders, for instance, treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganisms

14. A composition according to claim 6 for use in the treatment of allergic conjunctivitis and, in particular, of treatment and prevention of seasonal allergic conjunctivitis, or a condition treatable by ketotifen therapy.

15. A method for treating ophthalmic diseases/disorders, for instance, treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganism, including a topical once-a-day administration of a composition according to claim 1, thereby providing the therapeutic effect of the drug in said composition at the eye over about 24 hours.

16. A method for treating allergic conjunctivitis, in particular for treating and preventing seasonal allergic conjunctivitis or a condition treatable by ketotifen therapy, including a once-a-day administration of a composition according to claim 5 to the eye of a patient in need thereof.

17. The use of a composition according to claim 1 in the preparation of a medicament for the treatment of ophthalmic diseases/disorders, for instance, the treatment of inflammation, allergy, glaucoma, miosis, anaesthesia or infections caused by viruses, fungi or microorganisms.

18. The use of a composition according to claim 5 in the preparation of a medicament for the treatment of allergic conjunctivitis, in particular, for treatment and prevention of seasonal allergic conjunctivitis or a condition treatable by ketotifen therapy.