HK1180944A - A water-in-oil type emulsion for treating a disease of the eye - Google Patents

Description

Water-in-oil emulsions for treating ocular disorders

Technical Field

The present invention relates to the field of treating eye disorders or diseases by intraocular administration of therapeutic agents.

Background

The treatment of eye disorders by injecting therapeutic agents directly into the vitreous cavity has shown promising results in the past.(oligonucleotides) and(monoclonal antibodies) are pharmaceutical products that can be used effectively for the treatment of retinal diseases.

However, their half-life in the vitreous is relatively short, resulting in the need for repeated injections in order to maintain efficacy. These products are quickly removed because the vitreous humor is renewed over time.

This problem has been solved in the prior art: for example, WO2009/046198 describes a method of administering a therapeutic agent in the vitreous with sustained release kinetics; this method involves forming a macroscopic gel-like structure comprising the therapeutic agent in the vitreous cavity. In addition, EP2187980 describes the injection of a therapeutic agent in the vitreous cavity in combination with a polymer precursor which will form in situ a hydrogel suitable for achieving controlled release of the therapeutic agent.

However, injecting a gel or gel-like structure in the vitreous of a subject as described in these patent applications may cause visual discomfort to the subject because the field of vision is invaded by the gel or gel-like structure.

In other prior art documents, solid implants may be injected into the eye of a subject to release the active ingredient within months. However, this form of administration introduces solids into the patient's eye, which in some cases is undesirable. Furthermore, this method is more suitable for administration of lipophilic agents than hydrophilic agents and cannot be selected for administration of biological agents, such as proteins and monoclonal antibodies.

Thus, there is a need for a method for sustained release of a composition comprising a hydrophilic therapeutic agent (e.g., a protein or nucleic acid) in a vitreous cavity. How to ensure the visual comfort of the patient when the composition is located within the vitreous is another problem.

Surprisingly, applicants have recognized that water-in-oil emulsions can be an effective vehicle for administering hydrophilic therapeutic agents. Water-in-oil emulsions are two-phase systems in which water droplets are dispersed within an oil phase.

The use of water-in-oil emulsions as vehicles for sustained release of therapeutic agents is well known in the art. For example, WO01/89479 discloses the use of water-in-oil emulsions for parenteral administration of hydrophilic active ingredients with sustained release kinetics.

The present invention thus relates to the intraocular administration of a therapeutic agent to a subject in need thereof using a water-in-oil emulsion, thereby providing sustained release kinetics and avoiding any invasion of the subject's visual field in daily life or safety issues.

One advantage of the solutions proposed by the applicant is that when injected intraocularly, the water-in-oil emulsion of the invention forms a reservoir of therapeutic agent, which may be in the form of a layer or in the form of a blister and is of lower density than the vitreous humor. Thus, when injected, the composition will move up rapidly (within 0.5 seconds to 1 minute) from the injection site to the upper part of the vitreous. Thus, such a liquid reservoir will float on the vitreous outside the visual field, avoiding any visual discomfort to the subject to whom the composition is administered. The therapeutic agent is then released from the reservoir continuously over a period of time ranging from two weeks to 6 months. The compositions of the present invention have another advantage in that they are in physical contact with the vitreous and the targeted tissue (e.g., choroid or retina), thereby achieving targeted release of the therapeutic agent.

Definition of

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

- "emulsion": a colloidal system consisting of two immiscible components such as oil and water. One component (dispersed phase) is dispersed in the form of droplets in the other component constituting the continuous phase.

- "water-in-oil emulsion": emulsions are made up of water or water droplets (i.e., the dispersed phase) dispersed in an oil phase (i.e., the continuous phase). To avoid phase separation, the water-in-oil emulsion also comprises a surfactant (as defined below).

- "sustained release kinetics": the kinetics of slow release of a compound over an extended period at a predetermined rate is described.

- "intraocular administration": the product is injected directly into the eyeball, i.e., in the anterior or posterior chamber (vitreous cavity) of the eye.

- "surfactants": a substance is defined that reduces the interfacial tension between two liquids.

- "bioabsorbable": compounds that gradually disappear in a biological environment are defined.

- "therapeutic agent": describes an ability to slow or stop the development, exacerbation or worsening of one or more symptoms of a disease or disorder when administered in an appropriate amount; alleviating a symptom of the disease or disorder; molecules or substances, preferably biomolecules, such as oligonucleotides, siRNA, miRNA, DNA fragments, aptamers (aptamers), peptides, antibodies, proteins, etc., or chemical entities, that cure a disease or disorder.

- "therapeutically effective amount": for slowing or stopping the development, exacerbation, or worsening of one or more symptoms of the disease or disorder; alleviating a symptom of the disease or disorder; an amount of therapeutic agent necessary and sufficient to cure the disease or condition.

- "hydrophilic": defines a molecule or portion of a molecule that typically has a charge polarity and is capable of hydrogen bonding, and thus is more soluble in water than in an oil or other solvent.

- "lipophilic": refers to compounds that are soluble in fats, oils, lipids and non-polar solvents.

- "immiscible": a liquid that does not bind or mix with another liquid, or does not immediately bind or mix with another liquid.

"implant" is a solid dosage form, usually consisting of a polymer, implanted in biological tissues, in which the active ingredient is incorporated for slow release.

"depot" is a reservoir of active ingredient, which may be solid or liquid.

Disclosure of Invention

The present invention relates to a composition for use in the treatment of a disease or condition of the eye of a patient in need thereof by the intraocular route, preferably by intraocular injection, wherein the composition is a water-in-oil emulsion comprising an oil phase, a lipophilic surfactant dissolved in the oil phase, an aqueous phase dispersed in the oil phase, a hydrophilic therapeutic agent dissolved in the dispersed aqueous phase, wherein the composition has a density of less than 1, preferably in the range of 0.91 to 0.97g/cm³Within the range of (1). The density is measured by filling a calibrated volumetric flask with the emulsion and weighing on a balance. The volume/mass ratio is then calculated.

In a preferred embodiment, the viscosity of the composition at 20 ℃ is in the range of 25 to 10000mpa.s, as measured using Kinexus Pro from Malvern u.k. at 20 ℃.

Preferably, the average water droplet size is in the range of 20nm to 600 nm. In one embodiment, the average water droplet size is in the range of 25nm to 500nm, preferably 30nm to 200nm, more preferably 50-100 nm. In another embodiment, the average water droplet size is in the range of 20nm to 100 nm. The average particle size of the emulsion droplets was determined by quasi-elastic light scattering after dilution in water using a High performance particle size analyzer (Malvern Instruments, UK).

The composition provides sustained release of the hydrophilic therapeutic agent in the eye.

In a preferred embodiment, the composition of the invention is used for treating an eye disease or condition in a patient by the intraocular route, wherein the composition is a water-in-oil emulsion comprisingAn oil phase, a lipophilic surfactant dissolved in the oil phase, an aqueous phase dispersed in the oil phase, a hydrophilic therapeutic agent dissolved in the dispersed aqueous phase, and wherein the composition has a density of less than 1, preferably in the range of 0.91 to 0.97g/cm³And wherein the viscosity of the composition is in the range of 25 to 10000mpa.s at 20 ℃ and wherein the water droplet size is in the range of 20nm to 600nm, and wherein the use by the intraocular route is intraocular injection.

According to one embodiment, the oil phase is selected from the group comprising: triglycerides such as medium or long chain triglycerides, monoglycerides, diglycerides, vegetable or mineral oils.

Preferably, the lipophilic surfactant is selected from the group comprising: sorbitan esters such as sorbitan stearate, sorbitan laurate and sorbitan monopalmitate; bentonite; glycerol monostearate; propylene glycol monolaurate; and mixtures thereof.

In a preferred embodiment, the aqueous phase is present in the composition of the invention in an amount in the range of from 0.1 to 70% by weight, preferably from 2 to 50% w/w, more preferably from 10 to 30% w/w, relative to the total weight of the composition.

Preferably, the hydrophilic therapeutic agent is selected from the group comprising: monoclonal antibodies (whole or Fab fragments), such as ranibizumab (ranibizumab), bevacizumab (bevacizumab), trastuzumab (trastuzumab), cetuximab (cituximab), or rituximab (rituximab);

anti-angiogenic molecules, such as pegaptanib;

ROCK (Rho-kinase) inhibitors, such as fasudil (fasudil);

proteins such as WNT3A protein that are anti-CD 160S-HLA-G or that activate WNT (wingless integration site) for photoreceptor cell survival;

growth factors, such as Epithelial Growth Factor (EGF), anti-EGF or TGF (transforming growth factor);

siRNA, e.g., siRNA anti-arginase;

miRNA；

oligonucleotides, such as antisense DNA or antisense RNA;

iron-chelating molecules such as deferiprone (deferiprone) and salicylaldiphonyl hydrazone (salicylaldehyde isonicotinoyl hydrazone);

anti-inflammatory molecules, such as epigallocatechin gallate (epigallocatechin gallate);

antibiotics for combating eye infections, such as linezolid, clavulanic acid, macrolides;

an anti-inflammatory molecule, preferably selected from the group comprising: corticosteroids, such as dexamethasone (dexamethasone) and hydrophilic derivatives thereof; and mixtures thereof.

In one embodiment of the invention, the composition further comprises a lipophilic therapeutic agent in the oil phase, selected from the group comprising: cyclosporin a, lutein, alpha-tocopherol and dexamethasone palmitate.

According to the invention, the composition may additionally comprise a viscosity modifier, such as a hydrogel of sodium hyaluronate, carbopol gel, hydroxyethylcellulose, dextran (dextran), carboxymethylcellulose, polyethylene glycol, polyvinyl alcohol, collagen, and/or a pH buffer, such as a phosphate buffer, citrate buffer, tris buffer, histidine buffer or acetate buffer, and/or an osmolality modifier, such as NaCl, KCl, CaCl₂Glycerol, mannitol, alpha-trehalose or propylene glycol.

In a preferred embodiment, the composition of the invention may be injected intravitreally.

The diseases or conditions of the eye that can be treated with the compositions of the present invention are preferably selected from the group comprising: glaucoma, anterior uveitis, retinal oxidation, age-related macular degeneration, posterior uveitis, diabetic macular edema, and central vein occlusion.

The invention also relates to a pharmaceutical composition comprising the composition of the invention, and additionally comprising one or more pharmaceutically acceptable excipients.

The invention also relates to a medicament comprising a water-in-oil emulsion as described above.

The invention also relates to a method for treating a condition or disease of the eye comprising administering to a patient in need thereof by an intraocular route a composition of the invention wherein a therapeutic amount of a hydrophilic therapeutic agent is dissolved in the dispersed aqueous phase. In the methods of the invention, the therapeutic agent is released continuously within the eye of the patient.

In one embodiment, the volume of composition injected is in the range of 5 to 250 microliters.

In one embodiment, the composition or drug is injected into the vitreous cavity or into the anterior chamber of a patient's eye.

The invention also relates to a device comprising a composition or a medicament according to the invention. According to one embodiment, the device comprises a volume of the composition of the invention of 20 to 350 microlitres.

According to a preferred embodiment, the composition, pharmaceutical composition, medicament or device is not an implant.

Detailed Description

The present invention therefore relates to a composition for use in the treatment of a disease or condition of the eye by the intraocular route, wherein the composition is a water-in-oil emulsion comprising an oil phase, a lipophilic surfactant dissolved in the oil phase, an aqueous phase dispersed in the oil phase and a hydrophilic therapeutic agent dissolved in the dispersed aqueous phase, the composition having a density of less than 1, a viscosity in the range of 25 to 10000mpa.s at 20 ℃, wherein the average size of the water droplets is in the range of 20nm to 600nm, the composition continuously releasing the hydrophilic therapeutic agent, and wherein the use by the intraocular route is intraocular injection.

In one embodiment of the invention, the oil phase of the water-in-oil emulsion comprises an oil selected from the group comprising: triglycerides, such as semisynthetic oils: medium Chain Triglycerides (MCT) or long chain triglycerides; a monoglyceride; a diglyceride; or vegetable oils such as castor oil or mineral oil. According to a particular embodiment of the invention, the emulsion is free of ethyl oleate, soybean oil or mixtures thereof.

In a particular embodiment of the invention, the amount of oil phase in the water-in-oil emulsion is in the range of from 30 to 99.9% by weight, preferably from 50 to 98% w/w, more preferably from 70 to 90% w/w, relative to the weight of the total emulsion.

In one embodiment of the invention, the emulsion comprises one or more lipophilic surfactants in an amount sufficient to ensure water-in-oil type of the emulsion. In a particular embodiment of the invention, the lipophilic surfactant is selected from the group comprising: sorbitan esters such as sorbitan stearate and sorbitan monopalmitate, bentonite, glycerol monostearate, glycerol monooleate and propylene glycol monolaurate or mixtures thereof, poloxamer (poloxamer)188, poloxamer 282, poloxamer 407, tyloxapol (tyloxapol), vitamin ED polyethylene glycol succinate (vitamin ED-polyethylene glycol succinate), cetostearyl alcohol, cholesterol, ethylene glycol palmitate stearate, lauric acid, myristic alcohol, linoleic acid, oleic acid, palmitic acid, stearic acid, oleyl alcohol. According to one embodiment, the emulsion is free of at least one surfactant selected from the group consisting of: sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polysorbate 20(Tween20), sorbitan trioleate (Span85), phospholipids such as egg lecithin, or mixtures thereof.

In a particular embodiment of the invention, the HLB (hydrophilic-lipophilic balance) of the surfactant of the composition is in the range of 0 to 9, preferably 2 to 8.

In a particular embodiment of the invention, the amount of lipophilic surfactant in the water-in-oil emulsion is in the range of 0.1 to 10% by weight, preferably 0.5 to 5% w/w, more preferably 1 to 2% w/w, relative to the weight of the total emulsion.

In one embodiment of the invention the aqueous phase in the water-in-oil emulsion is present in an amount in the range of from 0.1 to less than 50% by weight, preferably from 0.5 to 15% w/w, more preferably from 2 to 10% w/w, relative to the weight of the total emulsion. Preferably, the aqueous phase is water or consists essentially of water.

In a particular embodiment of the invention, the composition comprises one or more hydrophilic therapeutic agents, said therapeutic agents being present in the water droplets of the water-in-oil emulsion.

In one embodiment of the invention, the hydrophilic therapeutic agent is selected from the group comprising: monoclonal antibodies (whole or fragment Fab) such as ranibizumab, bevacizumab, trastuzumab, cetuximab, and rituximab; anti-angiogenic molecules, such as pegaptanib; ROCK (Rho-kinase) inhibitors, such as fasudil; proteins, such as anti-CD 160S-HLA-G; WNT3A protein that activates WNT (wingless integration site) for photoreceptor cell survival; growth factors, such as Epithelial Growth Factor (EGF), anti-EGF or TGF (transforming growth factor); siRNA, e.g., siRNA anti-arginase, miRNA; oligonucleotides, such as antisense DNA or antisense RNA; iron-chelating molecules such as deferiprone and salicylaldehyde isonicotinyl hydrazone; anti-inflammatory molecules, such as epigallocatechin gallate; or antibiotics for combating eye infections, such as linezolid, clavulanic acid, macrolides; an anti-inflammatory molecule, preferably selected from the group comprising: corticosteroids such as dexamethasone and hydrophilic derivatives thereof; and mixtures thereof.

In one embodiment of the invention, the amount of hydrophilic therapeutic ingredient in the emulsion is in the range of 0.01 to 10% by weight, preferably 0.05 to 5% w/w, more preferably 0.1 to 1% w/w, relative to the total weight of the emulsion.

In a particular embodiment of the invention, the hydrophilic therapeutic agent is not a drug complex comprising a therapeutic agent and a polymer.

In one embodiment of the invention, the emulsion further comprises one or more lipophilic therapeutic agents in the oil phase. In a preferred embodiment of the present invention, the lipophilic therapeutic agent is selected from the group comprising: cyclosporin a, lutein, alpha-tocopherol and dexamethasone palmitate.

In a preferred embodiment, the amount of lipophilic therapeutic ingredient in the emulsion is in the range of 0.01 to 10% by weight, preferably 0.05 to 5% w/w, more preferably 1 to 2% w/w, relative to the total weight of the emulsion.

In a particular embodiment of the invention, the lipophilic therapeutic agent is not a drug complex comprising the therapeutic agent and a polymer.

In a specific embodiment of the invention, the water-in-oil emulsion is free of at least one metabolic degrading enzyme inhibitor selected from the group consisting of: CYP3A inhibitor, protease inhibitor such as aprotinin (aprotinin), chymotrypsin inhibitor (chymostatin), bacitracin (bacitracin), benzamidine, phosphodipeptide (phosphoramidon), leupeptin (leupeptin), bestatin (bestatin), cystatin (cystatin), amastatin (amastatin), pepstatin (pepstatin), potato carboxypeptidase, soybean trypsin inhibitor, diisopropyl fluorophosphate or EDTA. In another specific embodiment of the invention, the water-in-oil emulsion is free of at least one drug export P-glycoprotein inhibitor selected from the group consisting of: flavonoids contained in fruit juices, such as naringenin (naringenin), isoquercitin (isoquercetin), quercetin (quercetin) or vitamin E tocopheryl glycol succinate (TPGS).

The water-in-oil emulsion of the invention has a density lower than that of the vitreous humor, which corresponds to (if not equal to) the density of water. According to the invention, the water-in-oil emulsion of the invention has a density of less than 1. Preferably, the density of the water-in-oil emulsion is in the range of 0.90 to 0.99, preferably 0.91 to 0.97, more preferably 0.93 to 0.96. Thus, when injected into the vitreous, the emulsion will be located above the vitreous humor.

In addition, the composition will form a non-breakable depot upon injection. According to one embodiment, the reservoir has the form of a blister. The fact that the bubbles do not break up into droplets is related to the surface tension, interfacial tension and viscosity of the composition. These three physicochemical properties of the composition can be considered to be close to the properties of the oil phase used in the composition. As an example, Medium Chain Triglycerides (MCT) exhibit a surface tension of 30mN/m, an interfacial tension of 45mN/m and a viscosity of 27 to 33mpa.s at 20 ℃, and this combination of physicochemical properties avoids the MCT breaking into several oil droplets.

According to one embodiment, the viscosity of the composition is in the range of 5 to 10000mpa.s at 20 ℃, preferably in the range of 25 to 5000mpa.s at 20 ℃, preferably in the range of 24 to 1000mpa.s at 20 ℃, preferably in the range of 25 to 500mpa.s at 20 ℃, depending on the amount of emulsified water in the oil. According to one embodiment, the viscosity of the composition is in the range of 5 to 100mpa.s at 20 ℃, preferably in the range of 5 to 50mpa.s at 20 ℃, more preferably in the range of 5 to 20mpa.s at 20 ℃. According to another embodiment, the viscosity of the composition is in the range of 100 to 10000mPa.s at 20 ℃, preferably in the range of 500 to 10000mPa.s at 20 ℃, more preferably in the range of 5000 to 10000mPa.s at 20 ℃. According to the invention, the viscosity is measured using Kinexus Pro from Malvern u.k. at 20 ℃.

According to one embodiment, the surface tension of the composition is in the range of 0 to 30mN/m, preferably in the range of 5 to 20mN/m, more preferably in the range of 10 to 15 mN/m.

According to one embodiment, the interfacial tension of the composition is in the range of 0 to 45mN/m, preferably in the range of 5 to 30mN/m, more preferably in the range of 10 to 20 mN/m.

The water-in-oil emulsion of the present invention is effective for sustained release administration of a therapeutic agent. According to one embodiment, the therapeutic agent is released for a period in the range of 2 weeks to 12 months, preferably 1 month to 6 months.

The sustained release effect is provided by the migration of water droplets dispersed in the continuous oil phase to the surface of the oil reservoir formed by the emulsion when injected into the eye. In one embodiment of the invention, the sustained release kinetics can be tailored to the specific needs of the patient.

In a first embodiment of the invention, the sustained release kinetics may depend on the viscosity of the oil phase. Indeed, the more viscous the oil phase, the more the release duration can be extended, as evidenced by stokes law (stokes law):

wherein:

●v_sis the settling velocity (m/s) of the particles (vertically downward if ρ p > ρ f, vertically upward if ρ p < ρ f),

● g is the acceleration of gravity (m/s²)，

● ρ p is the mass density of the particles (kg/m)³) And is and

● ρ f is the mass density of the continuous phase (kg/m)³)，

● R is the radius of the particles,

● μ is the viscosity of the continuous phase.

Stokes law states that the speed of movement of particles (water droplets) in the continuous phase (oil phase) is inversely proportional to the viscosity (μ) of the continuous phase. Thus, the higher the viscosity of the oil phase of the emulsion, the slower the water droplets move to the oil reservoir surface to release the therapeutic agent. The release of the therapeutic agent can be extended to one year using viscous oils such as long chain triglycerides. According to one embodiment the viscosity of the oil phase is in the range of 1 to 10000mpa.s at 20 ℃, preferably in the range of 10 to 5000mpa.s at 20 ℃, even more preferably in the range of 25 to 1000mpa.s at 20 ℃.

In a second embodiment of the invention, the sustained release kinetics may depend on the size of the water droplets dispersed in the oil phase. In fact, as described by Stokes' law, larger water droplets move faster than smaller water droplets. Thus, the smaller the water droplets, the longer they will migrate to the surface of the injected reservoir, and thus the longer the duration of release of the therapeutic agent can be extended. For example, for the composition of the invention to be comparable in terms of ingredients, an emulsion with a droplet size of more than 1 μm may release the therapeutic agent in about 1 week to 2 months, while when the droplet size is below 500nm, the release may be extended to more than 2 months. According to one embodiment, the size of the water droplets in the emulsion of the invention is in the range of 1 to 2000nm, preferably 10 to 1000nm, more preferably 20 to 600 nm.

In a third embodiment of the invention, the sustained release kinetics can be adjusted by the volume of the water-in-oil emulsion injected. The larger the emulsion depot, the more the release duration can be extended. In fact, the larger the emulsion reservoir, the longer the path for the water droplets to reach the reservoir surface. Preferably, the injection volume of the composition of the invention is in the range of 5 to 250. mu.L, preferably 10 to 100. mu.L, more preferably about 50. mu.L.

In a fourth embodiment of the invention, the viscosity of the aqueous phase is increased in order to enhance sustained release. In a particular embodiment of the invention, the viscosity is increased by adding a viscosity modifier selected from the group comprising: sodium hyaluronate, carbopol gel, hydroxyethyl cellulose, dextran, carboxymethyl cellulose, PEG, polyvinyl alcohol and collagen. In a preferred embodiment of the present invention, the hydrogel is composed of cellulose, hyaluronic acid and/or collagen.

In a particular embodiment of the invention, the water-in-oil emulsion is free of organic gelling agents (organogelling agents), such as amino acid derivatives, in particular fatty acid ester derivatives of amino acids, more particularly alanine ester derivatives. In this particular embodiment, organogelators refer to molecules that are capable of spontaneously self-assembling via low energy bonds, thereby forming a matrix that immobilizes a hydrophobic organic liquid. In a particular embodiment, the water-in-oil emulsion of the present invention is not a phase change system.

In a fifth embodiment of the invention, the means for sustained release of the therapeutic agent as described in the first to fourth embodiments above may be combined with each other or all together in order to modulate the sustained release effect.

According to one embodiment of the invention, the aqueous phase of the emulsion additionally comprises a pH adjusting agent or a pH buffering agent. In a preferred embodiment, the pH buffer is selected from the group comprising: phosphate buffer, citrate buffer, tris buffer, histidine buffer, or acetate buffer. In a preferred embodiment, the pH buffer is a phosphate buffer. In one embodiment of the invention, the amount of said agent for adjusting the pH of the aqueous phase is in the range of 0.05 to 10% by weight, preferably 0.01 to 5% w/w, more preferably 0.1 to 1% w/w, relative to the total weight of the aqueous phase.

According to one embodiment of the invention, the aqueous phase of the emulsion additionally comprises an agent for adjusting the osmolality of the aqueous phase of the emulsion. In a first embodiment, the reagent for adjusting osmolality is selected from the group comprising NaCl, KCl and CaCl₂The group of (1). In a second embodiment, the osmolality of the composition is adjusted by adding a compound selected from the group comprising neutral compounds such as, but not limited to, glycerol, mannitol, alpha-trehalose or propylene glycol. In a preferred embodiment, the osmolality of the composition is adjusted by adding 0.5-2%, preferably 0.9% w/w NaCl and 0.5-10%, preferably 3-5% w/w alpha-trehalose or mannitol or propylene glycol by weight relative to the total emulsion weight.

In a particular embodiment, the water-in-oil emulsion of the present invention is not a double emulsion (i.e., water-in-oil-in-water or oil-in-water-in-oil emulsion).

According to one embodiment, the composition may be injected intraocularly. Preferably, the composition can be injected intravitreally.

The water-in-oil emulsion according to the invention is bioabsorbable. In one embodiment of the invention, the oil depot is absorbed within a period of 1 to 24 months after injection, preferably within a range of 6 to 18 months after injection, more preferably within a period of about 12 months after injection.

The water-in-oil emulsion according to the invention is used for the treatment of diseases or disorders of the eye. In one embodiment of the invention, the eye disease or disorder is selected from the group comprising: glaucoma, anterior uveitis, retinal oxidation, age-related macular degeneration, posterior uveitis, diabetic macular edema, and central vein occlusion.

The invention also relates to a pharmaceutical composition of the water-in-oil emulsion according to the invention. In one embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

The invention also relates to a medicament of a water-in-oil emulsion according to the invention.

The invention also relates to a device for administering the water-in-oil emulsion, the pharmaceutical composition or the medicament according to the invention. Preferably, the device is a pre-filled syringe containing from 20 μ L to 350 μ L of a composition of the invention. In one embodiment of the invention, the device contains a pharmaceutical composition or medicament according to the invention.

In addition, the present invention relates to a method for treating a condition or disease of the eye comprising intraocular administration of a therapeutic amount of a composition or medicament of the present invention. Preferably, the method of the invention comprises injecting (preferably in the vitreous cavity) a volume in the range of 5 to 250 μ L, preferably 10 to 100 μ L, more preferably about 50 μ L. In a preferred embodiment, the composition or medicament is injected less than once a week, preferably less than once a month, more preferably less than once every six months. According to one embodiment, the injected composition forms a depot in situ, within which the aqueous phase migrates toward the surface of the depot, allowing sustained release of the therapeutic agent to the vitreous cavity or to the targeted tissue. According to one embodiment, the reservoir has the form of a blister. According to another embodiment, the reservoir has the form of a spread bubble (spread bubble). According to another embodiment, the reservoir has the form of a layer, floating above the vitreous humor.

The water-in-oil emulsion of the present invention can be manufactured by a conventional process or by a process called membrane emulsification.

In a conventional process, the oil phase components are weighed sequentially in the same beaker and then magnetically stirred with slight heating (30-50 ℃, preferably 40 ℃) until a slightly viscous phase is obtained. The aqueous phase components are weighed in turn in the same beaker and then magnetically stirred with slight heating (30-50 ℃, preferably 40 ℃) until a clear and clear fluid phase is obtained. The two phases are heated (to 50-80 ℃, preferably 65 ℃). The emulsion droplet size can be reduced by high shear mixing with POLYTRON PT6100 for 5 minutes. The emulsion may be homogenized in a high pressure nanofiuidizer (C5, Avestin).

An alternative manufacturing process is membrane emulsification: the emulsions of the invention may also be made by membrane emulsification as described in Serguei (Serguei R.Kosvintsev, Gilda Gasparini, Richard G.Holdic, Membrane interaction: droplet size and unity in the presence of surface skin, Journal of Membrane Science, Vol. 313, stages 1-2, 2008, 4/10 days, pp. 182. 189). In this alternative process, the oil phase components are weighed sequentially in the same beaker and then magnetically stirred with slight heating (30-50 ℃, preferably 40 ℃) until a slightly viscous phase is obtained. The aqueous phase components are weighed in turn in the same beaker and then magnetically stirred with slight heating (30-50 ℃, preferably 40 ℃) until a clear and clear fluid phase is obtained. The two phases are heated (to 50-80 ℃, preferably 65 ℃). The aqueous phase was forced through a membrane with 1 μm pores. The water droplets are collected by the continuous flow of the oil phase.

Drawings

FIG. 1 shows photographs showing the behavior of the composition of example 1 injected at 60 μ L in a glass vial of water, and at 16 seconds (FIG. 1A), 24 seconds (FIG. 1B), and 1 minute (FIG. 1C) after injection.

Examples

The invention is further illustrated by the following examples.

Example 1: composition comprising a metal oxide and a metal oxide

This composition is a water-in-oil emulsion described in this specification, obtained by any of the manufacturing processes described below and using the following ingredients in the amounts specified:

the manufacturing process comprises the following steps:

the oil phase components were weighed in turn in the same beaker and then magnetically stirred with slight heating until a slightly viscous phase was obtained. The aqueous phase components were weighed in turn in the same beaker and then magnetically stirred with slight heating (40 ℃) until a clear and clear fluid phase was obtained. Both phases were heated to 65 ℃. The macroemulsion is formed by rapidly adding the aqueous phase to the oil phase. The emulsion was white and slightly transparent. The emulsion droplet size was reduced by applying high shear mixing with POLYTRON PT6100 for 5 minutes. The emulsion turned milky. The emulsion temperature was cooled to 20 ℃.

The final emulsion was obtained by homogenization in a high pressure nano-homogenizer (C5, Avestin) using continuous cycles of 5 minutes at 10000psi pressure. The emulsion was milky and very fluid. The emulsion temperature was reduced to 25 ℃.

And (3) characterization:

the emulsion was conditioned by bubbling nitrogen in a glass bottle and then sterilized in an autoclave at 121 ℃ for 20 minutes. The average particle size of the emulsion droplets was determined by quasielastic light scattering using a high performance particle size analyzer (Malvern Instruments, UK) after dilution in water. Electrophoretic mobility was measured in a Malvern Zetasizer2000(Malvern instruments, UK) at 25 ℃ after 1: 200 dilution in double distilled water as detailed above and converted to zeta potential by the smichowskiequ equation (smoluchowskiequification). Viscosity was measured using Kinexus Pro from Malvern u.k. at 20 ℃. The density is measured by filling a calibrated volumetric flask with the emulsion and weighing on a balance. The volume/mass ratio is then calculated.

Specifications for the composition of example 1:

size of water droplet	Density of	Time to release ranibizumab ex vivo
			500nm	0.94g/cm3	2 months old

The in vitro release test was performed by incubating 20 μ L of the composition in 4mL of water at 37 ℃. The active ingredient release in water was quantified by HPLC. At 2 months, the entire amount of ranibizumab was released into the water.

In vitro injection testing was performed by injecting 60 μ L of the composition of example 1 into water. As shown in fig. 1, the composition reaches the surface as soon as it is injected into an aqueous medium. This result is related to the composition having a density lower than that of water.

Example 2: compositions comprising pegaptanib sodium

Specifications for the composition of example 2:

the in vitro release test was performed by incubating 20 μ L of the composition in 4mL of water at 37 ℃ as in example 1. Quantification was performed by HPLC.

Compared to example 1, the release time doubled due to the reduction of the water droplet size according to stokes' law, which confirms that the size of the dispersed droplets is a key factor for the release rate of the hydrophilic active ingredient.

Claims (14)

1. A composition for use in the treatment of a disease or condition of the eye by the intraocular route,

wherein the composition is a water-in-oil emulsion comprising an oil phase, a lipophilic surfactant dissolved in the oil phase, an aqueous phase dispersed in the oil phase, a hydrophilic therapeutic agent dissolved in the dispersed aqueous phase, and

wherein the density of the composition is less than 1, preferably in the range of 0.91 to 0.97g/cm³In the range of (a) to (b),

wherein the viscosity of the composition is in the range of 25 to 10000mPa.s at 20 ℃,

wherein the size of the water droplets is in the range of 20nm to 600nm,

and wherein the use by the intraocular route is intraocular injection.

2. The composition of claim 1, wherein the oil phase is selected from the group comprising: triglycerides such as medium or long chain triglycerides, monoglycerides, diglycerides, vegetable or mineral oils.

3. The composition according to any one of claim 1 or claim 2, wherein the lipophilic surfactant is selected from the group comprising: sorbitan esters such as sorbitan stearate, sorbitan laurate and sorbitan monopalmitate; bentonite; glycerol monostearate; propylene glycol monolaurate; and mixtures thereof.

4. The composition according to any one of claims 1 to 3, wherein the aqueous phase is present in an amount ranging from 0.1 to less than 50% by weight, preferably from 0.5 to 15% w/w, more preferably from 2 to 10% w/w, relative to the total weight of the composition.

5. The composition of any one of claims 1-4, wherein the hydrophilic therapeutic agent is selected from the group comprising: monoclonal antibodies (whole or fragment Fab) such as ranibizumab, bevacizumab, trastuzumab, cetuximab, or rituximab; anti-angiogenic molecules, such as pegaptanib; ROCK (Rho-kinase) inhibitors, such as fasudil (fasudil); proteins, such as anti-CD 160S-HLA-G; WNT3A protein, which activates WNT (wingless integration site) for photoreceptor cell survival; growth factors, such as Epithelial Growth Factor (EGF), anti-EGF or TGF (transforming growth factor); siRNA, e.g., siRNA anti-arginase, miRNA; oligonucleotides, such as antisense DNA or antisense RNA; iron-chelating molecules such as deferiprone and salicylaldehyde isonicotinyl hydrazone; anti-inflammatory molecules, such as epigallocatechin gallate; or antibiotics for combating eye infections, such as linezolid, clavulanic acid, macrolides; an anti-inflammatory molecule, preferably selected from the group comprising: corticosteroids, such as dexamethasone and hydrophilic derivatives thereof; or mixtures thereof.

6. The composition of any one of claims 1-5, further comprising a lipophilic therapeutic agent dissolved in the oil phase, the lipophilic therapeutic agent selected from the group comprising: cyclosporin a, lutein, alpha-tocopherol and dexamethasone palmitate.

7. The composition according to any one of claims 1 to 6, additionally comprising a viscosity modifier, such as a hydrogel of sodium hyaluronate, carbopol (carbopo1) gel, hydroxyethylcellulose, dextran, carboxymethylcellulose, PEG, polyvinyl alcohol, collagen, and/or a pH buffer, such as a phosphate buffer, citrate buffer, tris buffer, histidine buffer or acetate buffer, and/or a osmolality modifier, such as NaCl, KCl, CaCl₂Glycerol, mannitol, alpha-trehalose or propylene glycol.

8. The composition according to any one of claims 1 to 7, wherein the use by intraocular route is intravitreal injection.

9. The composition according to any one of claims 1 to 8, wherein the ocular disease or disorder to be treated is selected from the group comprising: glaucoma, anterior uveitis, retinal oxidation, age-related macular degeneration, posterior uveitis, diabetic macular edema, and central vein occlusion.

10. A pharmaceutical composition comprising the composition of any one of claims 1-9 in combination with one or more pharmaceutically acceptable excipients.

11. A medicament comprising the composition of any one of claims 1-9.

12. The composition according to claim 10 or the medicament according to claim 11 for use in a method of treating an ocular condition or disease in a patient in need thereof, the method comprising administering to a patient in need thereof by an intraocular route a volume of the composition in the range of 5 to 250 microliters, wherein a therapeutic amount of a hydrophilic therapeutic agent is dissolved in the dispersed aqueous phase.

13. A device comprising the composition or medicament of any one of claims 1-12.

14. The device of claim 13, comprising the composition or medicament of any one of claims 1-12 in a volume of 20 to 350 microliters.