HK1242197B - Polyaphrons and palpebral administration thereof - Google Patents

Description

Multifoam and eyelid application thereof

Technical Field

The present invention relates to an easy-to-apply polyamphron (polyamphron) in the general field of galenic formulations. In particular, the present invention relates to a composition comprising at least one polyaphron for topical application, preferably for eyelid application.

Background

Introduction to Multifoam

The polyaphron is a dispersion. In the meaning of the present invention, "dispersion" means a system in which liquid droplets or solid particles are dispersed in a continuous phase. In the present invention, the term "polyaphron" refers to droplets of a liquid, called "foam", dispersed in a continuous phase in which the foam is immiscible. The dispersed phase may be a hydrophilic phase or a hydrophobic phase, provided that the foam remains immiscible in the continuous phase. The continuous phase may be a fluid, liquid or gel.

More specifically, the dispersed phase of the multiple foam may be comprised of a syntactic foam dispersed in a continuous phase, the foam having:

-a core consisting of a material immiscible with the continuous phase;

-an intermediate layer consisting of the same material as the continuous phase;

-an outer layer comprising a surfactant.

For example, in an oil-in-water multi-foam, the foam may include an inner core that is hydrophobic beads; an intermediate layer made of an aqueous solution; and an outer layer comprising a surfactant. In oil-in-water muloam, the hydrophobic phase may comprise up to 98 wt.% based on the total weight of the muloam, and the muloam includes a very low amount of surfactant (typically in the range of 0.05 wt.% to 5 wt.%, or 0.1 wt.% to 3 wt.%, based on the total weight of the muloam) in view of the large amount of dispersed phase.

As another example, in a water-in-oil multi-foam, the foam may include an inner core that is an aqueous bead; an intermediate layer made of a hydrophobic solution; and an outer layer comprising a surfactant. In water-in-oil polyaphrons, the hydrophilic phase may comprise up to 98 wt.% based on the total weight of the polyaphron.

Notably, contrary to emulsions characterized by a single interface, multi-foams can have a multi-layered structure configuration that can impart significant stability to them.

Background

Multiple foams were first described about 40 years ago. US 4,486,333 discloses a process for preparing a multifoam, in particular an oil-in-water multifoam, using kerosene, petroleum ether, carbon tetrachloride, a carbon tetrachloride-cyclohexane mixture as hydrophobic phase and water or methanol as hydrophilic phase.

The multi-foam composition is referred to as an oral drug delivery system. For example, WO 2005/011628 discloses the delivery of lipophilic poorly water soluble drugs as a multi-foam composition in an immediate dosage form.

The multi-foam composition may be used as a topical drug delivery system for the delivery of active ingredients. For example, US 4,999,198 discloses the delivery of scopolamine (scopolamine) dissolved in peanut oil and mineral oil to another medium; WO 2008/110826 discloses the delivery of a corticosteroid in combination with vitamin E by topical application through dermal application; EP1970049 discloses topical compositions for use in the dermis comprising compositions comprising vitamin D to treat a number of skin conditions such as psoriasis or dermatitis.

Recently, multi-foam dispersions have been used for ophthalmic purposes. For example, WO 2012/123515 discloses a method for delivering different active ingredients such as antibiotics (cyclosporine, vancomycin), anti-inflammatory compounds (flurbiprofen, fluticasone), prostaglandins (latanoprost). WO 2012/123515 discloses eye drops to be administered topically to the cornea of a human/animal.

Technical problem

The applicant has observed that various problems arise when eye drops are topically applied directly to the surface of the eye of a patient. First, some patients cannot self-administer eye drops. Problems with topical application can occur. Further, when dispensing eye drops, the patient wants to know whether at least one eye drop has reached the target (cornea and/or conjunctiva); this problem is exacerbated in the elderly and children. Therefore, a problem of accurate quantification arises. Furthermore, even when drops are properly delivered to the surface of the eye, the patient may still experience some discomfort or experience blurred vision. Instillation of eye drops on the ocular surface typically triggers a reflex blink, washing away most of the eye drops within a few seconds. It is recognized that over 95% of the eye drops are washed off the ocular surface within 2 minutes after administration.

More importantly, direct application of the composition to the ocular surface may cause irritation, particularly corneal and/or conjunctival irritation, due to the presence of irritating ingredients in the formulation. Such consequences can be a real problem when the primary target of treatment is the eye.

Another key issue in eye treatment is the frequency of administration. Administering eye drops several times per day may become a real burden for some patients and patient compliance with treatment may be significantly reduced.

These different problems associated with eye treatment compositions have led the applicant to conceive and implement easily applicable polyaphrons that are capable of targeting the eye while avoiding direct application of the composition to the cornea and also avoiding discomfort, blurred vision and irritation.

Another problem in ocular treatment is achieving prolonged release of a therapeutic agent on the eye to deliver the therapeutic agent gradually into the targeted portion of the eye. Administration of large amounts of active agent to the eye over a short duration of time may produce toxic concentrations and thus may be harmful to the targeted portion of the eye.

Thus, it is contemplated that an amount of therapeutic agent is released over a sustained period of time sufficient to achieve therapeutic efficacy without releasing an excessive amount of therapeutic agent that may cause local toxicity. Another advantage of extending the duration of delivery is that the frequency of administration may be reduced and compliance thereby increased.

Surprisingly, the applicant has realised that a polyfoam may be an effective vehicle for sustained and/or controlled release of a drug substance to the eye of a subject by eyelid administration. This finding enables the applicant to conceive and implement a polyaphron capable of prolonged release of a drug substance onto the eye of a subject in a sustainable and/or controlled manner.

Disclosure of Invention

Thus, in a first aspect, the present invention relates to a composition which is or comprises a multi-foam for topical application to at least one eyelid of a subject. In one embodiment, the multi-foam comprises an active ingredient.

In one embodiment, the present invention relates to a composition comprising at least one multifoam surrounding an ingredient for eyelid administration of the ingredient to an eye of a subject by means of topical application of the multifoam onto at least one eyelid of the subject. In one embodiment, the ingredient is an active ingredient.

In a second aspect, the present invention relates to a method for transdermal delivery of a polyaphron or a component thereof to an eye of a subject to treat an eye disease or eye condition in the subject. The methods of the present invention can be used to deliver at least one component of a polyaphron to the surface of the eye or the anterior segment of the eye.

In a third aspect, the present invention relates to a process for making at least one polyaphron of the present invention.

In a fourth aspect, the present invention relates to a device for applying a composition for use onto the eyelid of a subject, wherein the composition is deposited or impregnated or coated onto the device.

In a fifth aspect, the invention relates to a kit comprising a device of the invention and a composition for use.

In a sixth aspect, the present invention relates to a method for sustained and/or controlled release of an ingredient onto the eye of a subject to treat an eye disease or eye condition in said subject.

Detailed Description

Multi-foam body

The present invention therefore relates to a polyaphron comprising at least one hydrophilic phase, at least one hydrophobic phase and at least one surfactant. More preferably, the multi-foam of the present invention comprises:

-at least one hydrophilic phase;

-at least one hydrophobic phase;

-at least one surfactant selected from ionic surfactants and/or non-ionic surfactants;

-optionally at least one additive selected from the group consisting of antioxidants, osmotic agents, viscosity modifiers, pH modifiers, buffers, preservatives, solubilizers, chelating agents;

-optionally at least one active ingredient.

Hydrophilic phase

According to one embodiment, the polyaphron of the invention is a polyaphron wherein the hydrophilic phase is an aqueous composition or water.

The aqueous composition may comprise a water-miscible surfactant or polymer, and water.

Hydrophobic phase

According to one embodiment, the polyaphron of the invention is a polyaphron wherein the hydrophobic phase comprises at least one of the group selected from short chain (C4 to C6) fatty acid mono-, di-and tri-esters of glycerol; medium chain (C8 to C12) fatty acid mono-, di-, and tri-esters of glycerol; long chain (C14 and longer) saturated fatty acid mono-, di-, and tri-esters of glycerol; long chain (C14 and longer) unsaturated fatty acid mono-, di-, and tri-esters of glycerol; a vegetable oil; almond oil; babassu oil (babassu oil); black currant seed oil; borage oil; canola oil (canola oil); castor oil; coconut oil; cod liver oil; corn oil; cottonseed oil; evening primrose oil; fish oil; grape seed oil; mustard seed oil (rapeseed oil); oat oil; olive oil; palm kernel oil; palm oil; peanut oil; rapeseed oil (rapeseed oil); safflower oil; sesame oil; shark liver oil; squalane; soybean oil; sunflower oil; walnut oil; wheat germ oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated cottonseed oil; hydrogenated palm oil; hydrogenated soybean oil; partially hydrogenated soybean oil; hydrogenated vegetable oil; fatty acid esters (e.g., ethyl oleate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate … …); short chain (C4 to C6) fatty acid monoesters and diesters of propylene glycol; medium chain (C8 to C12) fatty acid monoesters and diesters of propylene glycol; long chain (C14 and longer) saturated fatty acid mono-and diesters of propylene glycol; long chain (C14 and longer) unsaturated fatty acid mono-and diesters of propylene glycol; fatty alcohols (e.g., myristyl alcohol, oleyl alcohol … …); branched fatty alcohols (e.g., octyldodecanol … …); silicone oil; mineral oil; petrolatum; a vitamin E; vitamin E acetate; a tocopherol; tocopheryl acetate; a saturated fatty acid; unsaturated fatty acids; a phospholipid.

Preferably, the hydrophobic phase of the polyaphron of the invention is or comprises a pharmaceutically acceptable oil or a mixture of pharmaceutically acceptable oils.

In one embodiment, the hydrophobic phase of the present polyaphron is free of phospholipids.

In one embodiment, the hydrophobic phase of the polycoam of the invention comprises MCT. In one embodiment, the hydrophobic phase of the polyaphron of the present invention consists of MCT.

In one embodiment, the hydrophobic phase of the present multi-foams comprises mineral oil. In one embodiment, the hydrophobic phase of the present multifoam consists of mineral oil.

In one embodiment, the hydrophobic phase of the present polycoam comprises glyceryl triacetate.

Surface active agent

Nonionic surfactant

In one embodiment, the present multi-foams comprise at least one nonionic surfactant. Advantageously, said at least one nonionic surfactant is selected from the group of: alkyl polyglycol ethers; an alkyl polyglycol ester; an ethoxylated alcohol; polyoxyethylene sorbitan fatty acid esters; a castor oil derivative; polyoxyethylene fatty acid esters; polyoxyethylene glycol hydrogenated castor oil; polyoxyethyleneglycol castor oil; sorbitan fatty acid esters (e.g., sorbitan monolaurate, sorbitan monooleate); block copolymers of ethylene oxide and propylene oxide (e.g., poloxamer 188, poloxamer 407); a poloxamer; tyloxapol (tyloxapol); a polysorbate; sucrose alkyl esters; sucrose alkyl ethers; short chain (C4 to C6) fatty acid mono-and diesters of glycerol; medium chain (C8 to C12) fatty acid mono-and diesters of glycerol; long chain (C14 and longer) saturated fatty acid mono-and diesters of glycerol; long chain (C14 and longer) unsaturated fatty acid mono-and diesters of glycerol; short chain (C4 to C6) fatty acid monoesters of propylene glycol; medium chain (C8 to C12) fatty acid monoesters of propylene glycol; long chain (C14 and longer) saturated fatty acid monoesters of propylene glycol; long chain (C14 and longer) unsaturated fatty acid monoesters of propylene glycol; a polyoxylglyceride; polyoxyethylene alkyl esters; polyoxyethylene ethers; vitamin E polyethylene glycol succinate; an alkyl polyglycoside.

Ionic surfactant

In one embodiment, the multi-foam comprises at least one ionic surfactant. The ionic surfactant may be a cationic surfactant or an anionic surfactant.

Advantageously, said at least one ionic surfactant is a cationic surfactant selected from the group of: C10-C24 primary alkylamines, tertiary aliphatic amines, quaternary ammonium compounds, cationic lipids (e.g., phosphatidylcholine), aminoalcohols, biguanide salts, cationic polymers, and mixtures of two or more thereof. In a preferred embodiment, the at least one cationic agent is a quaternary ammonium compound, preferably selected from the group consisting of: benzalkonium halide, lauralkylkonium halide, cetrimide, cetyltrimethylammonium halide, tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide, cetrimonium halide, benzethonium halide, behenylbenzyldimethylammonium halide, cetrolodonmonium halide, cetearyldimethylammonium halide, cetylpyridinium halide, benzalkonium halide, chloroallylurotropinonium halide, myristylmethylammonium halide, myristylbenzyldimethylammonium halide, stearylbenzyldimethylammonium halide, or a mixture of two or more thereof, preferably a chloride or a chloride.

In one embodiment, the at least one ionic surfactant is an anionic surfactant selected from the group of: phospholipids, lecithin, perfluorooctanoates, perfluorooctanesulfonates, alkyl sulfates, sodium lauryl ether sulfate, alkylbenzenesulfonates, soaps or fatty acid salts or mixtures thereof.

Amount of surfactant

The present multi-foams comprise at least one surfactant. Advantageously, the amount of surfactant in the present multi-foam ranges from 0.005% to 5% by weight, preferably from 0.05% to 5% by weight, based on the total weight of the multi-foam. Generally, in conventional emulsions, the surfactant to oil ratio is in the range of 1/10 to 2/1. In the present multi-foams, the surfactant to oil ratio in the multi-foam is in the range of 1/50 to 1/40; thus, the amount of surfactant in the present multiple foams is much lower than in conventional emulsions. This difference gives the present multi-foams a distinct advantage over emulsions in terms of limited surfactant-related side effects.

Additive agent

In one embodiment, the multi-foam comprises an additive selected from the group of: antioxidants, penetrants, viscosity modifiers, pH modifiers or buffers, preservatives, solubilizers, chelating agents. The amount of additive can be calculated by one skilled in the art according to pharmacopoeial and biological criteria.

Antioxidant agent

In one embodiment, the multi-foam comprises an antioxidant selected from the group of: vitamin E, sodium bisulfite, sodium metabisulfite, anhydrous sodium thiosulfate, citric acid monohydrate, ascorbyl palmitate and ascorbic acid, butyl hydroxytoluene, butyl hydroxyanisole, propyl gallate. These antioxidants may be used alone or in combination. The amount of antioxidant can be calculated by one skilled in the art according to pharmacopoeial and biological criteria.

Penetrant

In one embodiment, the multi-foam comprises at least one osmotic agent selected from the group of: glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol, xylitol, and the like. Likewise, the amount of osmotic agent is determined according to pharmacopoeial and biological standards.

Viscosity modifier-viscosity of the Polyfoam of the invention

In one embodiment, the multi-foam comprises at least one viscosity modifier selected from the group of: carbomers (carbomers), polycarbophil (polycarbophil), cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose … …), povidone (povidone), copovidone (copovidone), natural gums (e.g., gellan gum, guar gum, xanthan gum, agar, xyloglucan … …), poloxamers, and the like. These viscosity modifiers may be used alone or in combination in amounts meeting the requirements of pharmacopoeial standards (in europe and the usa) and biological standards.

In one embodiment, the present polyaphron exhibits very low shear rates (less than 0.1 s)^-1) A viscosity of better than 1 Pa.s. In one embodiment, the multi-foams of the present invention exhibit a viscosity of better than 1pa.s at zero shear rate.

The viscosity of the multi-foams was measured at 25 ℃ to 35 ℃ at atmospheric pressure (1atm) using a rheometer apparatus known to those skilled in the art, such as the rotational rheometer Kinexus from Malvern UK.

In one embodiment, the polyaphron exhibits shear-thinning behavior and characteristics of a thixotropic material that make it easier and more convenient to apply to at least one eyelid of a subject.

pH regulators or buffers

In one embodiment, the polyaphron comprises at least one pH adjuster or buffer selected from: hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium bicarbonate, and the like. The amount of pH modifier varies with the final pH, which includes 3.5 to 7.5. Likewise, the amount of pH adjusting agent is used according to pharmacopoeial and biological standards.

Preservative

In one embodiment, the multi-foam comprises at least one preservative selected from the following, as such or in combination: benzalkonium chloride (benzalkonium chloride), benzyl alcohol, mercuric salts, thimerosal, chlorhexidine (chlorexidine), boric acid and/or its salts, and the like. Also, the amount of preservative is used according to pharmacopoeial and biological standards.

Solubilizer

In one embodiment, the multi-foam comprises at least one solubilizer selected from the group consisting of: ethanol, polyethylene glycol, glycerol, propylene glycol, N-methyl pyrrolidone, glycogen furfural and dimethyl isosorbide. Likewise, the amount of solubilizer is used according to pharmacopoeial and biological standards.

Chelating agents

In one embodiment, the polycoam comprises at least one chelating agent selected from: edetic acid and salts thereof; ethylene glycol tetraacetic acid and salts thereof; citric acid, metaphosphoric acid, pyrophosphoric acid, polyphosphoric acid, malic acid, tartaric acid, phytic acid, and salts thereof; more preferably, at least one type selected from the group consisting of: edetic acid, citric acid, metaphosphoric acid, polyphosphoric acid, and salts thereof; and salts of edetic acid are particularly preferred. Also, the amount of chelating agent is used according to pharmacopoeial and biological standards.

Oil-in-water multi-foams and methods of manufacture

In one embodiment, the polyaphron is an oil-in-water polyaphron wherein the continuous phase comprises or consists of water or a hydrophilic phase and the dispersed phase comprises or consists of a foam having a hydrophobic core. In this embodiment, the amount of continuous phase may range from 2 to 50 wt%, preferably from 2 to 20 wt% of the aqueous composition, based on the total weight of the polyaphron; the amount of foam may be in the range of 50 to 98 wt% w/w, preferably in the range of 70 to 98 wt% w/w, even more preferably in the range of 80 to 98 wt% w/w, based on the total weight of the multi-foam. In one embodiment, the oil-in-water multi-foam comprises a foam having an average diameter in the range of 0.1 μm to 100 μm.

In one embodiment, the oil-in-water multi-foams of the present invention are made following the following process: the aqueous solution was stirred and then the hydrophobic phase was added dropwise. Preferably, the aqueous solution is stirred at 200 to 1000rpm using a magnetic stirrer or propeller at room temperature and the hydrophobic phase is added at a specific rate that allows autocatalytic formation of the foam.

Water-in-oil froths and method of manufacture

In one embodiment, the multi-foam is a water-in-oil multi-foam, wherein the continuous phase is a hydrophobic phase and the dispersed phase comprises or consists of a foam having a hydrophilic inner core. In this embodiment, the amount of continuous phase may range from 2 to 50 wt%, preferably from 2 to 20 wt% of hydrophobic phase, based on the total weight of the polyaphron; the amount of foam may be in the range of 50 to 98 wt% w/w, preferably in the range of 70 to 98 wt% w/w, even more preferably in the range of 80 to 98 wt% w/w, based on the total weight of the multi-foam. In one embodiment, the water-in-oil froths comprise froths having an average diameter in the range of 0.1 μm to 100 μm.

In one embodiment, the water-in-oil froths of the invention are manufactured following the following process: the oil phase was stirred and then the aqueous solution was added dropwise. Preferably, the aqueous solution is stirred at 200rpm to 1000rpm using a magnetic stirrer or propeller at room temperature and the oil phase is added at a specific rate that allows autocatalytic formation of the foam.

Multifoams without active ingredients

In one embodiment, the polyaphron is free of any active ingredient, i.e. free of drug.

In this embodiment, the polyaphron may be considered a pharmaceutically acceptable vehicle.

In this embodiment, the polycoam is particularly useful in treating dry eye conditions, such as, for example, dry eye syndrome or Chronic Dry Eye Disease (CDED), both of which are clinically referred to as keratoconjunctivitis sicca (KCS).

Multifoam with active ingredient

In one embodiment, the multi-foam comprises an active ingredient. In one embodiment, the active ingredient is a therapeutically significant molecule.

In one embodiment, the active ingredient is selected from:

anti-allergic agents, such as cromolyn sodium, antazoline (antazoline), chlorpheniramine (chlorpheniramine), cetirizine (cetirizine), olopatadine (olapatadine), epinastine (epinastine), ketotifen (ketotifen), azelastine (azelastine), emedastine (emedastine), levocabastine (levocabastine), terfenadine (terfenadine) and loratadine (loratadine);

anti-inflammatory agents, such as cortisone (cortisone), hydrocortisone (hydrocortisone), hydrocortisone acetate (hydrocortisone acetate), dexamethasone (dexamethasone), dexamethasone 21-phosphate, dexamethasone palmitate, fluocinolone (fluorominolone), prednisone (prednisone), methylprednisole (methylprednisone), prednisolone acetate (prednisone acetate), fluorometholone (fluomethylone), triamcinolone (triamcinolone), betamethasone (betamethasone), loteprednol (loteprednol), flumethasone (fluumethosone), beclomethasone (difluprednate), and triamcinolone acetonide (triamcinolone acetonide) and their derivatives;

non-steroidal anti-inflammatory agents, such as salicylates, indomethacin (indomethacin), ibuprofen (ibuprofen), diclofenac (diclofenac), flurbiprofen, oxicams (oxicams), piroxicam (piroxicam) and COX2 inhibitors, such as rofecoxib, nimesulide (nimesulide), nepafenac (nepafenac);

-beta adrenergic blockers such as timolol (timolol) and salts thereof, including timolol maleate; levobunolol hydrochloride (levobunolol hydrochloride) and betaxolol hydrochloride (betaxolol hydrochloride), betaxolol, atenolol (atenolol), fendol (befandol), metipranolol (metipranolol), forskolin (forskolin), carteolol (carteolol);

-cytokines, interleukins, prostaglandins (and anti-prostaglandins and prostaglandin precursors), such as latanoprost, bimatoprost, tafluprost or travoprost;

-cyclosporine, sirolimus (sirolimus), tacrolimus (tacrolimus);

antioxidants, such as lutein; vitamins, especially vitamin a; coenzyme Q10, polyunsaturated fatty acids and derivatives thereof;

carbonic anhydrase inhibitors, such as brinzolamide (brinzolamide), dorzolamide (dorzolamide), acetazolamide (acetazolamide), methazolamide (methazolamide), dichlorobenzenesulfonamide (dichlorophenamide);

antiviral agents, such as idoxuridine (idoxuridine), trifluorothymidine (triflutomycin), acyclovir (acyclovir), valacyclovir (valaciclovir), ganciclovir (ganciclovir), cidofovir (cidofovir) and interferons;

antibiotics, such as aminoglycosides, carbacephem (carbapenems), carbapenems (carbapenems), cephalosporins (cephalosporins), glycopeptides, penicillins (penicilins), polypeptides, quinolones (quinolones), sulfonamides, tetracyclines (tetracyclines), chlorotetracycline (chlorocyclene), bacitracin (bacitracin), neomycin (neomycin), polymyxin, gramicidin (gramicidin), cephalexin (cephalexin), oxytetracycline (oxytetracycline), chloramphenicol (chloreniconic), kanamycin (kanamycin), rifampicin (rifampicin), tobramycin (tobramycin), gentamicin (gentamitamycin), ciprofloxacin (ciprofloxacin), aminosugars (amisidesaturates), erythromycin (erythromycin), cephalosporins (cephalosporins), vancomycin (penicillium), and vancomycin; macrolides (macrolides), azithromycin (azithromycin), clarithromycin (clarithromycin), fluoroquinolones (fluoroquinolones);

antibacterial agents, such as sulfonamides (sulfonamides), sulfadiazine (sulfadiazine), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethizole), sulfisoxazoleOxazole (sulfisozole), nitrofurazone (nitrofurazone), and sodium propionate;

-and/or derivatives thereof; and/or prodrugs thereof; and/or precursors thereof; and/or acceptable salts thereof; alone or in combination.

In one embodiment, the active ingredient is selected from latanoprost, tafluprost, timolol, dorzolamide, olopatadine, epinastine, azithromycin, clarithromycin, cyclosporin a, and sirolimus, dexamethasone palmitate.

In one embodiment, the active ingredient is olopatadine. In one embodiment, the active ingredient is epinastine. In one embodiment, the active ingredient is clarithromycin. In one embodiment, the active ingredient is cyclosporin a. In one embodiment, the active ingredient is dexamethasone palmitate.

In one embodiment, the multi-foam stabilizes and/or preserves the active ingredient.

Sterilization

In one embodiment, the multi-foam may be sterilized.

Non-limiting examples of sterilization methods are heating, such as by autoclaving; filtering, irradiating and gas sterilizing.

Form(s) of

In one embodiment, the present multi-foams may be a liquid, fluid, gel, powder, ointment, cream, patch, film formulation or any delivery formulation suitable for eyelid administration.

Preferably, the multi-foam has a viscosity suitable for topical application to the skin of the eyelid and is dispensed or applied to the subject in a gel or cream, or ointment, or patch, or in any form suitable for application through the eyelid for ophthalmic use.

Package (I)

In one embodiment, the multi-foam is packaged in a single dose; in another embodiment, the polyaphron is packaged in a suitable multi-dose container.

Method

Application to eyelid-kit

In one aspect, the present invention relates to a method for topically applying a multi-foam to at least one eyelid, upper eyelid, and/or lower eyelid of a subject.

In one embodiment, the multi-foam is applied by topical application to the skin surrounding the eye of the subject. In one embodiment, the multi-foam is applied by coating on the eyelid of the subject. In one embodiment, the multi-foam is applied by coating on the upper eyelid of the subject. In one embodiment, the multi-foam is applied by coating on the lower eyelid of the subject.

In another embodiment, the multi-foam is applied using an application device, such as, for example, a brush or an applicator.

The invention also relates to a kit comprising a container containing a polyaphron of the invention and an application device as described above.

Transdermal delivery

In another aspect, the present invention relates to a method for transdermal delivery of a polyaphron or a component thereof to an eye of a subject to treat an eye disease or eye condition in the subject.

In one embodiment, the methods of the present invention can be used to deliver a polyaphron or a component thereof to the surface of the eye or the anterior segment of the eye.

In one embodiment, the methods of the present invention are useful for eye care.

In one embodiment, the polycoam comprises a penetration enhancer, i.e., a compound that enhances the transdermal penetration of the polycoam or a component thereof into the surface of the eye or the anterior segment of the eye, as an additive.

Sustained and/or controlled release of ingredients

In another aspect, the invention relates to methods for sustained and/or controlled release of an ingredient onto an eye of a subject to treat an eye disease or eye condition in the subject.

In one embodiment, said sustained and/or controlled release is obtained by applying the multi-foam of the invention containing said ingredients onto at least one eyelid, upper eyelid and/or lower eyelid of the subject.

In one embodiment, the methods of the present invention are effective to achieve sustained and/or controlled release administration of the therapeutic agent.

In one embodiment, the ingredients are released in a sustained and/or controlled manner for a period of time ranging from 1 hour to 2 weeks, preferably from 6 hours to 1 week, preferably from 12 hours to 5 days. In a particular embodiment, the ingredients are released in a sustained and/or controlled manner for a period ranging from 1 day to 3 days.

In one embodiment, the sustained and/or controlled release kinetics may depend on the formulation of the polyaphron. In a particular embodiment, the release rate is dependent on the nature of the hydrophilic phase of the polyaphron. In a particular embodiment, the release rate is dependent on the nature of the hydrophobic phase of the polyaphron. In a particular embodiment, the release rate depends on the nature of the surfactant or mixture of surfactants contained in the polyaphron. In a particular embodiment, the release rate is dependent on the concentration of the surfactant or mixture of surfactants contained in the polyaphron.

In one embodiment, the sustained and/or controlled release kinetics may depend on the viscosity of the polyaphron. In a particular embodiment, the release rate decreases as the viscosity of the polyaphron increases.

In one embodiment, the sustained and/or controlled release kinetics may depend on the average bead size of the polyaphron. In a particular embodiment, the release rate decreases as the average bead size of the polyaphron decreases.

In one embodiment, the sustained and/or controlled release kinetics can be dependent on the volume of the multifoam administered onto the eye of the subject.

In one embodiment, the sustained and/or controlled release kinetics can be tailored to the exact needs of the subject. In a specific embodiment, the release kinetics can be adapted to the exact needs of the subject by selecting the surfactant or mixture of surfactants to be included in the multifoam. In a specific embodiment, the release kinetics can be tailored to the exact needs of the subject by selecting the appropriate concentration of the surfactant or mixture of surfactants to be included in the multifoam. In a particular embodiment, the release kinetics can be tailored to the exact needs of the subject by varying the viscosity and/or average bead size of the multifoam.

In one embodiment, the methods of the present invention can be used to provide sustained and/or controlled release of the ingredient to the surface of the eye or to the anterior segment of the eye.

In one embodiment, the methods of the present invention are useful for eye care.

Eye diseases or eye conditions

In the meaning of the present invention, an eye disease or eye condition is a dry eye condition, such as for example dry eye syndrome or chronic dry eye diseases, such as keratoconjunctivitis sicca (KCS), Atopic Keratoconjunctivitis (AKC) and Vernal Keratoconjunctivitis (VKC); glaucoma, and glaucoma; ocular inflammatory conditions such as, for example, keratitis, corneal epithelial erosion, uveitis (including anterior uveitis), intraocular inflammation, allergy, and dry eye syndrome ocular infections, ocular allergies, corneal or conjunctival disorders, cancerous growths, diabetic macular edema, age-related macular degeneration, corneal anesthesia, mydriasis.

In one embodiment, the ocular condition may be blepharitis, glaucoma, a Meibomian gland (Meibomian gland) disorder, such as, for example, Meibomian Gland Dysfunction (MGD); and dry eye conditions such as, for example, dry eye syndrome or chronic dry eye; diabetic keratopathy or neurotrophic keratopathy.

In one embodiment, the condition may be associated with a demodex folliculorum (demodex folliculorum) infection. In one embodiment, the condition is glaucoma. In one embodiment, the condition is anterior uveitis.

In another aspect, the polyaphron of the invention is used to treat an eye disease or condition.

In another aspect, the polyaphron of the invention is used in the manufacture of a medicament or medicament for the treatment of an eye disease or condition.

In another aspect, the invention relates to a method of treating an ocular disease or condition, wherein a therapeutically active amount of a therapeutic agent is administered to a patient in need thereof by topically applying a multifoam comprising the therapeutic agent. In one embodiment, the method comprises the step of topically applying a composition comprising a multi-foam to the upper eyelid and/or lower eyelid of the subject. In one embodiment, the topical application is an eyelid application.

In one embodiment, the multi-foam is applied once daily for 4 weeks.

In one embodiment, eyelid administration by multiple foams reduces toxicity and/or side effects of the treatment to the patient.

Definition of

In the present invention, the following terms have the following meanings:

"foam" refers to a composite bead consisting of: an outer layer comprising a surfactant, said outer layer surrounding an intermediate layer consisting of the same material as the continuous phase, said intermediate layer itself surrounding a core made of a phase immiscible with the continuous phase.

"continuous phase" means the phase surrounding the dispersed phase.

"dispersed phase" means droplets dispersed in a continuous phase.

- "eyelid" includes the upper eyelid, starting from the eyebrows to the lower limit determined by the base of the eyelashes; and a lower eyelid starting from the infraorbital region to a limit determined by the base of the eyelashes.

- "MCT" means medium chain triglycerides.

"therapeutically significant molecule" means any molecule of particular interest for the treatment of a disease or disorder.

- "ND" means "not determined".

"eyelid application" refers to topical application to the outer surface of at least one eyelid of a subject.

"Polyfoam" refers to liquid droplets called foam dispersed in a continuous phase.

Drawings

Fig. 1 is a graph showing the results of in vitro efficacy tests of clarithromycin-loaded polyaphron No. 28, oily solution No. 29, and ointment No. 30 (example 6).

Figure 2 is a graph showing the results of in vitro permeation tests for dexamethasone-loaded multiple foams No. 31 to No. 33 (example 7).

Fig. 3 is a graph showing the results of in vitro skin penetration tests of olopatadine hydrochloride-loaded multiple foams nos. 21 to 23 (example 8).

Fig. 4 is a histogram showing the results of in vivo efficacy tests for clarithromycin loaded polycoam number 34 and solution number 39 (example 10).

Fig. 5 is a histogram showing the results of in vivo efficacy tests for clarithromycin loaded multi-foam No. 34 and ointment No. 40 (example 11).

Fig. 6 is a histogram showing the results of in vivo efficacy tests for clarithromycin loaded polycoam number 34 and emulsion number 41 (example 12).

Examples

The invention is further illustrated by the following examples.

Example 1: the oil-in-water multi-foams without drug substances according to the invention

Composition numbering	1	2	3	4	5	6
							MCT	90	90	90	90	90	45
Glycerol triacetate						45
							Poloxamer 188	0.1	1.0
Poloxamer 407			0.1	1.0
							Polyoxyl-40 stearate					1.0	0.1
Sorbitan oleate						0.9
							Water (W)	Qs 100	Qs 100	Qs 100	Qs 100	Qs 100	Qs 100

Table 1: compositions of multi-foams No. 1 to No. 6 (amounts are indicated in% weight/weight).

Example 2: oil-in-water polyaphrons comprising cyclosporin A according to the invention

Table 2: compositions of multi-foams No. 7 to No. 15 (amounts are indicated in% weight/weight).

Example 3: oil-in-water multifoams comprising dexamethasone palmitate according to the invention

Composition numbering	16	17	18
				Dexamethasone palmitate	0.8	0.8	0.8
MCT	88.3	89.2	89.2
				Sorbitan oleate	0.9
Poloxamer 407		1	0.1
				Polyoxyl-40 stearate	0.1
Water (W)	qs 100	qs 100	qs 100

Table 3: compositions of the multi-foams No. 16 to No. 18 (amounts are indicated in% weight/weight).

Example 4: according to the invention, the composition comprises sodium fluorescein as a hydrophilic marker or hydrochloric acid as a drug substance Oil pack of olopatadineAqueous multi-foams

Composition numbering	19	20	21	22	23
						Fluorescein sodium salt	0.0005	0.05
Olopatadine hydrochloride			0.5	0.5	0.5
						Light mineral oil	19	19	17.9	17.9	17.9
Sorbitan oleate	1	1	2	2	2
						Sucrose tristearate			0.1	0.1	0.1
Glycerol				5.0
						PEG 400					5.0
Water (I)	qs 100	qs 100	Qs 100	Qs 100	Qs 100

Table 4: composition of multiple foams No. 19 and No. 23 (amounts are indicated in% weight/weight).

Example 5: water-in-oil polyaphron according to the invention comprising epinastine as drug substance

Composition numbering	24	25	26	27
					Epinastine hydrochloride	0.5	0.5	0.5	0.5
Light mineral oil	17.9	17.9	16.9	17.9
					Sorbitan oleate	2	2	2	2
Sucrose tristearate	0.1	0.1	0.1	0.1
					Myristic acid isopropyl ester			1
Glycerol				5
					Diethylene glycol monoethyl ether		2.5
PEG 400	5	2.5	5
					Water (W)	Qs 100	Qs 100	Qs 100	Qs 100

Table 5: compositions of multi-foams No. 24 to No. 27 (amounts are indicated as% weight/weight).

The bead size distribution of each of the multiple foams was measured using a prior art laser diffraction device (Helos Sympatec, Germany). The particle size distribution is determined on the basis of volume (Dv). The viscosity of each of the multiple foams has been measured using a prior art rheometer (Kinexus, malvern, uk).

Based on the physical properties of the compositions shown on table 6, a correlation occurs between the bead size distribution and the viscosity of the system: when the composition is more viscous, the bead size distribution is smaller. These characteristics may depend on the qualitative or quantitative composition of the multiple foams.

Composition numbering	24	25	26	27
					Bead size distribution (μm)
D(v,10)(μm)	1.8	2.9	2.5	1.8
					D(v,50)(μm)	7.2	16.7	12.3	7.7
D(v,90)(μm)	37.9	48.8	38.3	33.6
					Viscosity (Pa.s)
Initial viscosity eta0(Pa.s)	4549	3398	5662	6744

Table 6: physical Properties of Polyfoam Nos. 24 to 27

Example 6: in vitro evaluation of penetration of oil-in-water Polyfoam comprising Clarithromycin

Transdermal permeation of clarithromycin was evaluated using a Franz cell device fitted with a Strat-M membrane purchased from Millipore (molscheim, France), France. The Strat-M membrane is a synthetic membrane used for in vitro tests to simulate skin penetration.

The diffusion of clarithromycin from the polyfoam (composition No. 28) was compared to the diffusion from the oily solution (composition No. 29) and the diffusion from the ointment (composition No. 30). The concentration of clarithromycin in the receiving compartment over 72 hours was measured by Ultra Performance Liquid Chromatography (UPLC).

The following formulations were evaluated:

composition numbering	28	29	30
				Clarithromycin	1	1	1
Capmul PG8	50	56
				MCT	39	43
Light mineral oil			25
				Heavy mineral oil			25
Petrolatum			49
				CKC	0.005
Polysorbate 80	1
				Water (W)	Qs 100

Table 7: compositions of Polyfoam Nos. 28 to 30 (amounts are indicated as% weight/weight)

As disclosed on fig. 1, application of ointment No. 30 did not cause transdermal penetration, whereas clarithromycin diffused from the multi-foam No. 28. Thus, this experiment clearly demonstrates the superiority of the multifoam in skin penetration of the therapeutic agent over the ointment.

Clarithromycin diffuses from the oily solution No. 29 through the membrane, but such a composition is not suitable for topical application to the eyelid because its viscosity (25mpa.s-33mpa.s) is not high enough to allow the oily solution to remain on the eyelid. The oily solution will flow along the eyelid and/or into the eye. In contrast, the multi-foam No. 28 is suitable for eyelid application because its viscosity (>1pa.s) is high enough to remain on the eyelid.

Furthermore, as also shown in fig. 1, the frothy 28 was surprisingly able to release clarithromycin effectively over 72 hours, while oily solution 29 released clarithromycin immediately. This demonstrates that the use of a multi-foam can allow for sustained and controlled release of the therapeutic agent through the skin.

Example 7: in vitro evaluation of the penetration of oil-in-water Multifoams comprising dexamethasone

Transdermal permeation of dexamethasone was assessed using a Franz cell apparatus fitted with Strat-M membranes from millipore (morsem, france). The Strat-M membrane is a synthetic membrane used for in vitro tests to simulate skin penetration.

The bead size distribution of each of the multiple foams was measured using a prior art laser diffraction apparatus (heronsultak, germany). The particle size distribution is determined on the basis of volume (Dv). The viscosity of each of the multiple foams has been measured using a prior art rheometer (Kinexus, malvern, uk).

The diffusion of dexamethasone from multiple foams (composition No. 31 to No. 33) with different compositions was compared. The concentration of dexamethasone in the receiving compartment over the course of 48 hours was measured by Ultra Performance Liquid Chromatography (UPLC).

The following formulations were evaluated:

composition numbering	31	32	33
				Dexamethasone	0.024	0.024	0.024
MCT	89	90	90
				Sorbitan oleate	0.9
Poloxamer 407		1	0.1
				PEG-40 stearate	0.1
Water (W)	Qs 100	Qs 100	Qs 100

Table 8: compositions of Polyfoam Nos. 31 to 33 (amounts are indicated as% weight/weight)

Based on the physical properties of the compositions shown on table 9, a correlation occurs between the bead size distribution and the viscosity of the system: when the composition is more viscous, the bead size distribution is smaller. These characteristics may depend on the qualitative or quantitative composition of the polyaphron.

Composition numbering	31	32	33
				Bead size distribution (μm)
D(v,10)(μm)	4.7	1.5	14.9
				D(v,50)(μm)	20.3	3.8	32.7
D(v,90)(μm)	29.3	8.7	51.5
				Viscosity (Pa.s)
Initial viscosity eta0(Pa.s)	22	300	5

Table 9: physical Properties of Polyfoam Nos. 31 to 33

The results disclosed on figure 2 clearly demonstrate that the multifoam is capable of sustained release of dexamethasone through the skin over 48 hours. In addition, they demonstrated that the composition of the polyfoam affected the release profile of dexamethasone.

Surprisingly, the release kinetics depend on the nature of the surfactant. Release was faster in case of multiple foam No. 31 where the surfactant was a mixture of PEG-40 stearate and sorbitan oleate than in case of compositions No. 32 and No. 33 where the surfactant was poloxamer.

Surprisingly, the release kinetics also have a correlation with the viscosity of the composition and the bead size distribution. Comparing compositions nos. 32 and 33, increasing the relative concentration of surfactant reduced the bead size distribution and increased the viscosity. This allows the more viscous multi-foam No. 32 with smaller particle size to have slower kinetics than the less viscous multi-foam No. 33 with higher particle size.

Thus, the qualitative and/or quantitative formulation of the froths may be varied to control the release kinetics from the froths, for example by acting on the nature and/or concentration of the surfactant.

Example 8: for water-in-oil multivesicular containing olopatadine hydrochlorideIn vitro evaluation of the penetration of foam

Transdermal permeation of olopatadine hydrochloride was evaluated using a Franz cell apparatus equipped with Strat-M membranes purchased from millipore (morsem, france). The Strat-M membrane is a synthetic membrane used for in vitro tests to simulate skin penetration.

The diffusion of olopatadine hydrochloride from multiple foams (compositions nos. 21-23) having different compositions disclosed in table 4 of example 4 was compared. The concentration of olopatadine hydrochloride in the receiving compartment over 48 hours was measured by Ultra Performance Liquid Chromatography (UPLC).

As shown in fig. 3, sustained and controlled release was also obtained when olopatadine hydrochloride diffused through the multifoam.

Surprisingly, the addition of a hydrophilic co-solvent (e.g., glycerol, PEG 400) enhances permeation through the Strat-M membrane in vitro, thereby acting as a permeation enhancer.

Example 9: method for manufacturing multi-foam No. 34 to No. 38

In vivo evaluation was performed using the multi-foams No. 34 to No. 38 containing clarithromycin (examples 10 to 13 below).

The following procedure was followed to make the multi-foam No. 34 of table 10 below: to an aqueous phase (8.995g) containing polysorbate 80SR (1g) stirred at 200rpm was added dropwise an oil phase MCT (39g) containing CKC (0.005g), propylene glycol monocaprylate (50g) and clarithromycin (1 g). The rate of addition of the oil phase at the beginning of the process was slow (about one drop per 7 seconds), but after 20% of the oil phase had been added, accelerated so that the total time to prepare the multi-foam was about 20 minutes.

The multi-foams No. 35 to No. 38 of table 10 below were prepared according to the same manufacturing method.

	34	35	36	37	38
						Clarithromycin	1	0.3	0.25	0.5	-
MCT	39	39	47.88	47.75	39
						Propylene glycol monocaprylate	50	50	41.89	41.78	50
Polysorbate 80SR	1	1	0.2	0.2	1
						Water (W)	qs 100	qs 100	qs 100	qs 100	qs 100

Table 10: compositions of Multifoam Nos. 34 to 38 (amounts are indicated as% weight/weight)

The clarithromycin containing emulsions and ointments nos. 39 through 42 of table 11 below have been prepared for comparison.

	Solution 39	Ointment 40	Emulsion 41	Emulsion 42
					Clarithromycin	1	3	1	0.5
MCT	39	-
					Propylene glycol monocaprylate	50	-	25	25
White petrolatum	-	77.5	-	-
					Mineral oil	-	12.1	-	-
Polysorbate 80SR		-	2.5	2.5
					PEG-40 stearate	0.1	-	-	-
Sorbitan monooleate	-	-	2.5	2.5
					Sodium hydrogen phosphate	0.1
Glycerol	2	-	1.2	1.2
					Water (W)	qs 100	-	qs 100	qs 100

Table 11: formulation Nos. 39 to 42 (amounts are indicated as% w/w)

Example 10: in vivo experiment-eyelid application of Multifoam No. 34 and dispensing solution No. 39 onto cornea And (6) comparing.

Meibomian gland occlusion is Meibomian Gland Dysfunction (MGD), which often causes dry eye and may also lead to blepharitis.

Polyfoam number 34 (1% w/w clarithromycin) was topically applied once daily to the eyelids of subjects presenting with occluded meibomian glands for 4 weeks. For comparison, solution No. 39 (1% w/w clarithromycin) was dispensed onto the cornea of the subject 3 times a day for 4 weeks. Each formulation was evaluated on 6 eyes (n-6). The results are shown in FIG. 4.

Polyfoam number 34 (1% w/w clarithromycin) reduced the number of occluded glands after four weeks of treatment in the same ratio as solution number 39 (1% w/w clarithromycin) dispensed on the cornea.

In addition, it was clinically observed that the toxicity of the multi-foam No. 34 applied topically to the eyelid was lower than that of the solution No. 39 dispensed directly onto the cornea. The solution instilled onto the cornea triggered irritation and necrosis of the corneal epithelium, while no signs of corneal toxicity were reported for eyelid application of multi-foam No. 34.

Example 11: in vivo experiment-ratio of eyelid application for Polyfoam No. 34 to eyelid application for ointment No. 40 Then the obtained product is obtained.

Polyfoam No. 34 (1% w/w clarithromycin) was topically applied once daily to the eyelids of subjects presenting occluded meibomian glands for 4 weeks. In contrast, ointment No. 40 (3% w/w clarithromycin) was topically applied to the subject's eyelid once daily for 4 weeks. Each formulation was evaluated on 6 eyes (n-6). The results are shown on figure 5.

Polyfoam number 34 reduced the number of occluded glands after four weeks of treatment in the same ratio as ointment number 40. However, the reduction in the number of occluded cells must be balanced by the fact that ointment number 40 is three times the concentration of polyfoam number 34. Thus, when using polycoam No. 34, a reduced amount of clarithromycin in the polycoam compared to ointment No. 40 was required to induce the same efficacy.

The toxicity profile of Multifoam No. 34 is similar to that of ointment No. 40, although the concentration of clarithromycin in the ointment is three times that of the Multifoam. No corneal toxicity was observed for multi-foam No. 34.

Thus, the use of multiple foam 34 numbers for the eyelids allows for a reduced amount of clarithromycin to be used and exhibits better safety characteristics.

Example 12: in vivo experiment-ratio of eyelid application of Multifoam No. 34 to corneal application of emulsion No. 41 Then the obtained product is obtained.

Polyfoam number 34 (1% w/w clarithromycin) was topically applied once daily to the eyelids of subjects presenting with occluded meibomian glands for 4 weeks. In contrast, emulsion No. 41 (1% w/w clarithromycin) was topically applied to the eyelids of the subject 3 times a day for 4 weeks. Each formulation was evaluated on 6 eyes (n-6). The results are shown on figure 6.

Polyfoam number 34 reduced the number of occluded glands to a greater extent than emulsion number 41 after one week of treatment.

In addition, multiple foam No. 34 exhibited improved safety characteristics compared to emulsion No. 41 instilled on the cornea. Indeed, no signs of corneal toxicity were reported after application of multi-foam No. 34 to the eyelid, while severe toxicity (i.e., corneal epithelial necrosis) was reported after instillation of emulsion No. 41.

Example 13: quantitative analysis of clarithromycin in Polyfoam No. 37 and oil-in-water emulsion No. 42 Stability measurements performed

Polyfoam No. 37 (0.5% w/w clarithromycin) and oil-in-water emulsion No. 42 (0.5% w/w clarithromycin) were heated at 40 ℃ and 60 ℃ for one week. The amount of clarithromycin was measured at the end of the experiment and compared to the initial amount. The results are indicated as a percentage relative to the initial amount of clarithromycin and are presented in table 12.

Table 12: stability of Polyfoam No. 37 and emulsion No. 42 after one week of experiment

At 40 ℃, after one week of the experiment, 99% of the active ingredient was recovered in the frothy 37, and only 90% in the oil-in-water emulsion 42. At 60 ℃, only 72% of the active ingredient was recovered in oil-in-water emulsion No. 42, while multi-foam No. 37 still contained 96% of the active ingredient.

Polyfoam No. 37 thus provides for enhanced stability of clarithromycin compared to oil-in-water emulsion No. 42.

Claims (43)

1. Use of a composition comprising a polyaphron in the manufacture of a medicament for treating an ocular disease or condition in a subject,

wherein the multi-foam comprises:

at least one hydrophilic phase selected from aqueous compositions or water,

at least one hydrophobic phase selected from the group consisting of medium chain fatty acid mono-, di-and tri-esters of glycerol, glyceryl triacetate, medium chain fatty acid mono-and di-esters of propylene glycol and mineral oil,

at least one nonionic surfactant selected from the group consisting of alkyl polyglycol ethers, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, poloxamers, polysorbates, sucrose alkyl esters, vitamin E polyethylene glycol succinates, and alkylpolyglycosides,

at least one active ingredient selected from the group consisting of,

optionally at least one additive selected from the group consisting of antioxidants, osmotic agents, viscosity modifiers, pH modifiers, buffers, preservatives, solubilizers, and chelating agents;

wherein the multi-foam is:

-an oil-in-water multi-foam, wherein the amount of the continuous phase ranges from 2 to 50 wt% and the amount of the foam ranges from 50 to 98 wt%, based on the total weight of the multi-foam; or

-a water-in-oil polyaphron, wherein the amount of continuous phase ranges from 2 wt% to 50 wt% and the amount of polyaphron ranges from 50 wt% to 98 wt%, based on the total weight of polyaphron;

wherein the amount of surfactant in the polyaphron ranges from 0.005 wt.% to 5 wt.%, based on the total weight of the polyaphron;

wherein the eye disease or condition is a disease or condition of the eyelid; and is

Wherein the medicament is applied to the external surface of the upper eyelid and/or lower eyelid of the subject by eyelid administration.

2. The use of claim 1, wherein the composition is a fluid, gel, or cream.

3. The use according to claim 2, wherein the composition is a liquid.

4. Use according to claim 1 or 2, wherein the frothy body comprises beads having an average size in the range of 0.1 μm to 100 μm.

5. Use according to claim 1, wherein the at least one nonionic surfactant is selected from polyoxyethylene (4) lauryl ether; polyoxyl-40 stearate; sorbitan monooleate; poloxamer 188; poloxamer 407; polysorbate 80; sucrose laurate; sucrose palmitate; sucrose stearate; sucrose tristearate; vitamin E polyethylene glycol succinate and alkyl polyglycoside.

6. Use according to claim 1, wherein the hydrophobic phase is selected from triglycerides (MCT); glyceryl triacetate; propylene glycol monocaprylate and light mineral oil.

7. Use according to claim 1, wherein the active ingredient is selected from anti-allergic agents.

8. Use according to claim 7, wherein the active ingredient is selected from cromolyn sodium, chlorpheniramine, cetirizine, olopatadine, ketotifen, azelastine, emedastine, terfenadine, loratadine, and/or acceptable salts thereof, alone or in combination.

9. Use according to claim 1, wherein the active ingredient is antazoline or an acceptable salt thereof.

10. The use according to claim 1, wherein the active ingredient is selected from anti-inflammatory agents.

11. Use according to claim 10, wherein the active ingredient is selected from cortisone, hydrocortisone acetate, dexamethasone 21-phosphate, dexamethasone palmitate, fluocinolone, prednisone, methylprednisolone, prednisolone acetate, fluorometholone, triamcinolone, betamethasone, loteprednol etabonate, flumethasone, beclomethasone, difluprednate and triamcinolone acetonide, and/or acceptable salts thereof, alone or in combination.

12. Use according to claim 1, wherein the active ingredient is selected from non-steroidal anti-inflammatory agents.

13. Use according to claim 12, wherein the active ingredient is selected from salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, oxicams and other COX2 inhibitors, and/or acceptable salts thereof, alone or in combination.

14. Use according to claim 13, wherein the active ingredient is piroxicam or an acceptable salt thereof.

15. The use according to claim 1, wherein the active ingredient is selected from beta adrenergic blockers.

16. The use according to claim 15, wherein the active ingredient is selected from timolol, betaxolol, atenolol, benzfurolol, metiprolol, carteolol, and/or acceptable salts thereof, alone or in combination.

17. Use according to claim 1, wherein the active ingredient is forskolin or an acceptable salt thereof.

18. Use according to claim 1, wherein the active ingredient is selected from cytokines, prostaglandins and anti-prostaglandins.

19. The use according to claim 18, wherein the active ingredient is an interleukin.

20. The use of claim 18, wherein the active ingredient is selected from latanoprost, bimatoprost, travoprost, and/or acceptable salts thereof, alone or in combination.

21. Use according to claim 1, wherein the active ingredient is selected from cyclosporines.

22. The use according to claim 21, wherein the active ingredient is cyclosporin a or an acceptable salt thereof.

23. Use according to claim 1, wherein the active ingredient is selected from sirolimus, tacrolimus, and/or acceptable salts thereof, alone or in combination.

24. Use according to claim 1, wherein the active ingredient is selected from antioxidants.

25. The use according to claim 24, wherein the active ingredient is selected from lutein, vitamins, coenzyme Q10, polyunsaturated fatty acids, and/or acceptable salts thereof, alone or in combination.

26. Use according to claim 1, wherein the active ingredient is selected from carbonic anhydrase inhibitors.

27. The use according to claim 26, wherein the active ingredient is selected from brinzolamide, dorzolamide, acetazolamide, methazolamide, dichlorphenamide, and/or acceptable salts thereof, alone or in combination.

28. The use according to claim 1, wherein the active ingredient is selected from antiviral agents.

29. Use according to claim 28, wherein the active ingredient is selected from idoxuridine, trifluorothymidine, acyclovir, valacyclovir, ganciclovir, cidofovir and interferon, and/or acceptable salts thereof, alone or in combination.

30. Use according to claim 1, wherein the active ingredient is selected from antibiotics.

31. The use according to claim 30, wherein the active ingredient is selected from aminoglycoside antibiotics, carbacephem, carbapenem antibiotics, cephalosporin antibiotics, glycopeptide antibiotics, penicillin antibiotics, polypeptide antibiotics, quinolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics, bacitracin, chloramphenicol, rifampicin, macrolide antibiotics, and/or acceptable salts thereof, alone or in combination.

32. The use according to claim 31, wherein the active ingredient is selected from oxytetracycline, tobramycin, erythromycin, imipenem, and/or acceptable salts thereof, alone or in combination.

33. The use according to claim 30, wherein the active ingredient is selected from the group consisting of chlortetracycline, neomycin, polymyxin, gramicidin, cephalexin, kanamycin, gentamicin, ceftazidime, vancomycin, clarithromycin, azithromycin, fluoroquinolone antibiotics, and/or acceptable salts thereof, alone or in combination.

34. Use according to claim 30, wherein the active ingredient is selected from ciprofloxacin and/or an acceptable salt thereof.

35. The use of claim 1, wherein the active ingredient is selected from antibacterial agents.

36. Use according to claim 35, wherein the active ingredient is selected from sulfonamide antibacterial agents, nitrofurazone and sodium propionate, and/or acceptable salts thereof, alone or in combination.

37. The use according to claim 35, wherein the active ingredient is selected from sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, and/or acceptable salts thereof, alone or in combination.

38. The use of claim 1, wherein the active ingredient is selected from the group consisting of latanoprost, timolol, dorzolamide, olopatadine, azithromycin, clarithromycin, cyclosporin a, sirolimus, dexamethasone, and dexamethasone palmitate.

39. Use according to claim 1, wherein the active ingredient is released in a controlled and/or sustained manner for a period ranging from 12 hours to 5 days.

40. Use according to claim 39, wherein the active ingredient is released in a controlled and/or sustained manner for a period ranging from 1 day to 3 days.

41. Use according to claim 1, wherein the amount of surfactant in the polyaphron ranges from 0.05 wt% to 5 wt%, based on the total weight of the polyaphron.

42. A device comprising a brush or applicator for use according to any one of claims 1 to 41, whereby a composition is applied via eyelid application onto the outer surface of the upper and/or lower eyelid of a subject, wherein the composition is deposited or impregnated or coated onto the device.

43. A kit comprising the device of claim 42.