Ophthalmic composition in gel form comprising polycarbophil

Abstract

The present invention relates to an ophthalmic composition for the prevention and treatment of elevated intraocular pressure, in gel form comprising polycarbophil as the sole gelling agent. The ophthalmic compositions comprise one or more active agents for the prevention and treatment of elevated intraocular pressure, such as glaucoma.

Description

[0001] Description

[0002] Title: Ophthalmic composition in gel form comprising polycarbophil

[0003] FIELD OF INVENTION

[0004] The present invention relates to an ophthalmic composition for the prevention and treatment of ocular hypertension in the form of a gel comprising polycarbophil as the sole gelling agent. Ophthalmic compositions comprise one or more active ingredients for the prevention and treatment of ocular hypertension, such as glaucoma. PRIOR TECHNOLOGY

[0005] Ophthalmic compositions in gel form are well-known and generally include carbomers as gelling agents. Carbomers are polyacrylates widely used as thickeners in the preparation of gels for pharmaceutical and cosmetic formulations. Examples include gels for the prevention and treatment of dry eye, such as those marketed under the names Aquarest, Lacrinorm, and Liposic (Laboratoire Chauvin SA), Gel-Larmes and Siccafluid (Laboratoire Théa Pharma), Lacrifluid and Lacrigel (Laboratoire Europhta), and Lacryvisc (Laboratoire Alcon). In these cases, the carbomer itself is the active ingredient due to its film-forming properties. Various carbomers are used, such as Carbomer 974P and Carbomer 980.Carbomers can also be used as gelling excipients in formulations containing other active ingredients, such as antifungal agents for the treatment of eye or eyelid infections. An example is the fusidic acid composition marketed under the name Fucithalmic (CSP Laboratory). Antiglaucoma ophthalmic gels are also known, such as the timolol gel marketed under the name Geltim LP (Théa Pharma Laboratory). Gels containing bimatoprost are also described in patent application WO 2016 / 198434 (MedProject Pharma). These gels, such as Geltim, also include a carbomer as a gelling agent, but due to stability issues, require the addition of a second polymer to improve gel stability, such as polyvinylpyrrolidone (PVP), dextran, polyethylene glycol (PEG), carboxymethylcellulose or poly(vinyl alcohol) (PVA).It is also recommended to use salts to adjust the viscosity of the carbomer. The use of crosslinked polymers such as polycarbophile is also described for the preparation of ophthalmic gels. While polycarbophile is often cited among the thickening / gelling agents that can be used in ophthalmic compositions, along with other polyacrylates, it is rarely used (WO2013 / 115844) and is generally used in combination with a second polymer, as is the case for all polyacrylates (WO 2010 / 102192). More recently, the combination of an anionic polymer, such as polycarbophile, with a cationic polymer, such as chitosan, has been recommended (WO 2023 / 172240).Although identified among the polymers that could be used, it is rarely used or only under very specific conditions, either for keeping solid active ingredients in suspension in the form of particles (WO 2016 / 123079), or for preparing acidic pH forms for antibiotic penetration tests (Lehr & al., Investigative Ophthalmology & Visual Science, May 1994, Vol. 35, No. 6).

[0006] The complex compositions recommended in the state of the art to solve the problem of gel stability can lead to manufacturing problems, stability problems, but also additional risks of side effects brought about by the multiplication of excipients in the final formulation.

[0007] The invention provides a solution to these problems for the preparation of a stable ophthalmic formulation in gel form by selecting a gelling polymer that does not require the addition of another polymer to stabilize the gel, nor a salt to adjust its viscosity.

[0008] BRIEF DESCRIPTION

[0009] According to one aspect, the invention relates to an ophthalmic composition in the form of an aqueous gel comprising a water-soluble active ingredient and a single gelling agent, wherein the gelling agent consists of a polycarbophil. The antiglaucoma agent is selected from beta-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, and mixtures thereof.

[0010] the composition includes 0.15 to 0.4% by weight of polycarbophil relative to the total weight of the composition, and the composition does not include any preservative.

[0011] According to another aspect, the invention relates to an ophthalmic composition in gel form comprising

[0012] At least one water-soluble active ingredient

[0013] Polycarbophile as the sole gelling agent

[0014] A toning agent, and water.

[0015] According to a particular method, the gel composition comprising polycarbophil as the sole gelling agent does not include a pH buffer.

[0016] According to another aspect, the invention relates to an ophthalmic composition in gel form which consists of

[0017] At least one water-soluble active ingredient

[0018] Polycarbophile as the sole gelling agent

[0019] A toning agent,

[0020] An acid or a base to adjust the pH from 6 to 7 and

[0021] Water.

[0022] According to another aspect, the invention relates to an ophthalmic composition in the form of an aqueous gel comprising at least one antiglaucoma agent and a single gelling agent in which the gelling agent consists of a polycarbophil.

[0023] According to another aspect, the invention relates to an ophthalmic composition in the form of an aqueous gel comprising bimatoprost and timolol and a single gelling agent in which the gelling agent consists of a polycarbophil.

[0024] DEFINITIONS

[0025] In the present invention, the terms below are defined as follows:

[0026] "Ophthalmic composition" refers to a topical pharmaceutical composition intended for application to the eye, the ocular mucosa, or the area near the eye, such as the eyelids, where the product may migrate onto the eye and ocular mucosa. For ophthalmic compositions, particular attention is paid to the choice of excipients, their qualities, and the preparation methods to minimize the risk of microbial contamination and / or side effects such as eye irritation due to the fragility of the eye and ocular mucosa.

[0027] "Gelling agent", "gelling agent", "viscosity enhancer", "viscosity agent" or "viscosity agent" used interchangeably refer to a compound which, when added to water alone, causes an increase in the viscosity of the water until a gel is formed.

[0028] "Gel" refers to a liquid dosage form gelled with one or more gelling agents, used for the administration of at least one active ingredient. The gelling agent(s) are uniformly dispersed in a continuous liquid phase in which the active ingredient is dissolved or dispersed. According to the invention, the hydrophilic liquid phase essentially comprises water.

[0029] "Ophthalmic composition in gel form" means a gel formulated and prepared appropriately for use as an ophthalmic composition. The viscosity of the gel is measured according to the recommendations of the European Pharmacopoeia 7.0 using a cone-and-plane rheometer at 25°C with a 60 mm / 0.5° cone and a shear rate of 100 s⁻¹. 1 The ophthalmic composition in gel form has a viscosity of 100 to 500 mPa at 100 s' 1, in particular, from 100 to 450 mPa, 150 to 450 mPa, 200 to 450 mPa, 250 to 450 mPa, 300 to 450 mPa, 350 to 450 mPa, 100 to 400 mPa, 150 to 400 mPa, 200 to 400 mPa, 250 to 400 mPa, 300 to 400 mPa, 350 to 400 mPa, 100 to 200 mPa, 150 to 250 mPa, 200 to 300 mPa, 250 to 350 mPa, 300 to 400 mPa, 350 to 450 mPa, 400 to 500 mPa, 125, 130, 135, 140, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 210, 215, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 465, 470, 475, 480, 485, 490, 495 or 500 mPa.

[0030] "Polycarbophile" refers to a high molecular weight polyacrylic acid crosslinked with divinyl glycol. The molecular weight of polycarbophiles ranges from 700,000 to 3-4 billion (Handbook of Pharmaceutical Excipients, pages 509-512, 2009, Pharmaceutical Press). Polycarbophiles differ from crosslinked carbomers, which are polyacrylic acids crosslinked with alkylated sucroses or pentaerythritol alkyl ethers (Handbook of Pharmaceutical Excipients, pages 110-114, 2009, Pharmaceutical Press).

[0031] "Single gelling agent" means that the gel formation results from the addition of a single gelling agent to the liquid phase, the polycarbophile, and not from a combination of at least two gelling agents or a gelling agent with another stabilizing polymer. In the compositions according to the invention, the gelling agent consists solely of the polycarbophile.

[0032] "Other gelling agent" or "stabilizing polymer" means a gelling agent other than polycarbophil, in particular another polyacrylate, carbomer of the type Carbomer 974P or Carbomer 980, or another polymer such as polyvinylpyrrolidone (PVP), dextran, polyethylene glycol (PEG), carboxymethylcellulose, or polyvinyl alcohol (PVA). "Comprising" is an open-ended term, meaning that the composition to which it refers may include components other than those expressly listed in the definition that follows. However, it is understood that a composition comprising only one gelling agent does not include other gelling agents, in accordance with the definition of "only gelling agent," the open-ended meaning referring to other components that may fall within the definition of the composition.

[0033] "Preservative" or "preservative," in the singular or plural, refers to compounds used in topical compositions (pharmaceuticals, cosmetics, etc.) to prevent contamination by germs, such as quaternary ammonium compounds, including benzalkonium chloride, alkyl-dimethyl-benzylammonium, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzothonium chloride, cetalkonium chloride; mercurial preservatives, such as phenylmercuric nitrate / acetate / borate, thiomersal; alcoholic preservatives, such as ethanol, chlorobutanol, benzyl alcohol, phenyl ethanol, phenylethyl alcohol; carboxylic acids, such as sorbic acid; phenols, particularly methyl / propylparaben; amidines, for example chlorhexidine digluconate; and / or other agents chelating agent such as EDTA in association with at least one other preservative.

[0034] "Preservative-free" refers to a composition substantially devoid of such preservatives to meet the "preservative-free" claim. Its preservative content is preferably 0 ppm, with no preservatives being used in its composition.

[0035] "Excessive intraocular pressure" refers to a condition characterized by an abnormal increase in the pressure of the fluids inside the eye, which, if left untreated, can lead to blindness. The increased intraocular pressure causes the degeneration of nerve fibers responsible for transmitting information from the retina to the brain, potentially resulting in blindness in the affected eye. This excess pressure is known as glaucoma. There are generally two forms of glaucoma: chronic glaucoma, also called open-angle glaucoma, and acute glaucoma, also called closed-angle glaucoma."Surfactants" refers to surfactants commonly used in the preparation of emulsions, in particular chemically synthesized products, especially those chosen from the list of products authorized by regulations, such as polysorbates, polyethylene glycol and their derivatives, polyoxyethylene-40-stearate, sorbitan esters, polyoxyethylene-polyoxypropylene copolymers, polyvinyl alcohols, and polyvinylpyrrolidone polymers.

[0036] "Surfactant-free" refers to a composition, particularly in the form of an emulsion, substantially devoid of such additional surfactants or agents that could increase its stability, and may be characterized as "surfactant-free," "surfactant-free," or "surfactant-free." Its surfactant content is preferably equal to 0 ppm, with no surfactant being included in its composition.

[0037] DETAILED DESCRIPTION

[0038] The present invention relates to an ophthalmic composition in the form of an aqueous gel comprising a water-soluble active ingredient and a single gelling agent in which the gelling agent consists of a polycarbophil.

[0039] Polycarbophile as the sole gelling agent

[0040] Various polycarbophiles are commercially available for use as gelling agents in pharmaceutical compositions, particularly ophthalmic ones. One example is the polycarbophile marketed under the name Noveon® by the Lubrizol company.

[0041] A person skilled in the art will be able to choose the polycarbophil and its content in the ophthalmic composition in gel form according to the invention according to the desired viscosity of the gel.

[0042] In particular, the polycarbophile content in the composition according to the invention ranges from 0.15 to 0.4% by weight relative to the total weight of the composition. Advantageously, the polycarbophile content ranges from 0.25 to 0.35% by weight, in particular 0.25, 0.26, 0.27, 0.28, 0.29 or 0.3% by weight.

[0043] Antiglaucoma Agents

[0044] According to the invention, the ophthalmic composition in gel form comprises at least one antiglaucoma agent as water-soluble active ingredient(s). "Antiglaucoma agent" refers to an active ingredient used for the treatment of glaucoma. Antiglaucoma agents include, in particular, beta-blockers, which act by decreasing the secretion of aqueous humor; prostaglandin analogs, which increase the drainage of aqueous humor; and carbonic anhydrase inhibitors, which reduce the formation of aqueous humor, used alone or in combination. The active ingredients are generally used in saline form, with a salt commonly used in pharmacies. In this description, and unless otherwise indicated, the term "active ingredient" includes both the active ingredient alone and its saline forms.

[0045] Among the beta-blockers used to treat glaucoma are timolol, levobunolol, betaxolol, and carteolol. Beta-blockers are generally administered in saline form, with a commonly available salt, such as timolol maleate, levobunolol hydrochloride, betaxolol hydrochloride, and carteolol hydrochloride. Timolol, and more specifically timolol maleate, is the preferred beta-blocker.

[0046] Among the prostaglandin analogs used to treat glaucoma are bimatoprost, travoprost, latanoprost, and tafluprost, with bimatoprost, travoprost, and latanoprost being the preferred analog. According to a preferred method of administration, bimatoprost is the prostaglandin analog.

[0047] Examples of carbonic anhydrase inhibitors used to treat glaucoma include brinzolamide and dorzolamide.

[0048] According to a preferred method, the ophthalmic composition in gel form includes a beta-blocking agent and / or an analogue of the prostaglandins defined above as antiglaucoma agent(s).

[0049] According to another preferred formulation, the ophthalmic gel composition comprises a beta-blocking agent and another antiglaucoma agent selected from among the prostaglandin analogs and carbonic anhydrase inhibitors defined above. Specifically, the ophthalmic gel composition comprises a combination of a beta-blocking agent and a prostaglandin analog selected from timolol and bimatoprost, timolol and latanoprost, and timolol and travoprost. Most preferably, the timolol is in the form of timolol maleate.

[0050] The levels of antiglaucoma agents in the ophthalmic compositions according to the invention conform to the levels used in prior art formulations. They generally range from 0.0025 to 2% by weight relative to the total weight of the composition for all the antiglaucoma agents present in the composition. In a particular method, the beta-blocking agent content ranges from 0.1 to 0.5% by weight for use as the sole antiglaucoma agent. Specifically, the content ranges from 0.1 to 0.5% by weight. When in the saline form of timolol maleate, the percentage is given relative to the timolol portion of the salt alone.

[0051] According to another specific formulation, the prostaglandin analogue content ranges from 0.0025% to 0.03% by weight for use as a sole antiglaucoma agent. Specifically, the bimatoprost content ranges from 0.01% to 0.03% by weight, the travoprost content from 0.003% to 0.004% by weight, and the latanoprost content from 0.0025% to 0.005% by weight.

[0052] According to another specific formulation, the carbonic anhydrase inhibitor content ranges from 0.5 to 2% by weight for use as a sole antiglaucoma agent. Specifically, the brinzolamide content is 0.5 to 1% by weight and the dorzolamide content is 1 to 2% by weight.

[0053] Depending on the specific combination of a beta-blocker and a prostaglandin analogue, the beta-blocker content ranges from 0.1 to 0.5% by weight, and the prostaglandin analogue content ranges from 0.0025 to 0.03% by weight. Specifically, for a timolol + bimatoprost combination, the timolol content ranges from 0.1 to 0.5% by weight, and the bimatoprost content ranges from 0.01 to 0.03% by weight.

[0054] In a particular formulation, anti-glocaum agents consist of a combination of timolol and bimatoprost. The timolol content is advantageously 0.1% by weight (0.137% when timolol is in its saline form of timolol maleate) and the bimatoprost content is 0.01% by weight.

[0055] Tonic agent

[0056] The ophthalmic composition in gel form according to the invention also includes a tonicity agent in an appropriate quantity to obtain an osmolality greater than 180 mOsm / kg, advantageously from 250 to 350 mOsm / kg.

[0057] The tonic agents used in ophthalmic compositions are chosen from salts or polyalcohols, in particular sodium chloride, potassium chloride, sodium bicarbonate, potassium bicarbonate or glycerol, trehalose, erythritol, sorbitol or mannitol.

[0058] According to an advantageous method, the tonic agent is trehalose, more particularly added in its form of trehalose dihydrate. The trehalose content in the composition according to the invention advantageously ranges from 8 to 10% by weight relative to the total weight of the composition.

[0059] pH adjuster

[0060] The gel composition according to the invention has a pH ranging from 5.5 to 8. According to one embodiment, the pH of the composition is between 6 and 8 and preferably between 6 and 7.

[0061] The pH of the composition is adjusted by adding an acid or base commonly used in ophthalmic preparations, such as sodium hydroxide or hydrochloric acid. The composition may also include a buffer, such as phosphate, borate, acetate, or citrate buffer. The buffer is added to the composition in an appropriate amount to adjust the pH to the desired value.

[0062] According to a particular method, the gel composition with the polycarbophile as the sole gelling agent does not include a buffer, the polycarbophile playing this buffer role due to its composition having multiple carboxylic acid groups.

[0063] Other components

[0064] The composition according to the invention may also include other common components used in the composition of ophthalmic formulations such as an antioxidant agent, such as lipoic acid or its sodium salt, taurine, vitamin C, vitamin A, vitamin E, vitamin D or riboflavin.

[0065] The ophthalmic gel composition according to the invention must, in particular, be sterile to avoid introducing pathogens that could cause ophthalmic complications. According to the invention, the term "sterile" means the absence of germs as defined in European Pharmacopoeia 2.6.1.

[0066] Many ophthalmic compositions include preservatives to prevent or limit contamination.

[0067] According to another aspect of the invention, the composition may include at least one preservative, but preferably at a low concentration. In this case, the preservative content is less than or equal to 0.1% by weight relative to the total weight of the emulsion, in particular less than or equal to 0.05% by weight, or even less than or equal to 0.01% by weight.

[0068] According to one particular embodiment of the invention, the gel composition is not an emulsion. According to another particular embodiment, the composition does not comprise surfactants. In particular, this surfactant-free composition is not an emulsion.

[0069] Compositions in gel form

[0070] According to a preferred embodiment of the invention, the gel composition comprises only

[0071] At least one water-soluble active ingredient as defined above

[0072] Polycarbophile as the sole gelling agent, as defined above

[0073] A previously defined tonic agent, in particular trehalose,

[0074] An acid or a base to adjust the pH from 6 to 7 and

[0075] Water.

[0076] More specifically, the composition according to the invention comprises or is constituted by timolol and bimatoprost as antiglaucoma agents,

[0077] Polycarbophilic as the sole gelling agent,

[0078] Trehalose

[0079] An acid or a base to adjust the pH from 6 to 7 and

[0080] Water.

[0081] More specifically, the composition according to the invention comprises or is constituted by

[0082] 0.1% by weight of timolol in the form of timolol maleate, and 0.01% by weight of bimatoprost as antiglaucoma agents,

[0083] 0.25 to 0.3% by weight of polycarbophil as the sole gelling agent,

[0084] 8 to 10% by weight of trehalose,

[0085] An acid (HCl) or a base (NaOH) to adjust the pH from 6 to 7 and

[0086] Water up to 100 ml.

[0087] The ophthalmic composition in gel form is stored in single-dose vials for a single application, or multi-dose vials for multiple applications.

[0088] Applications

[0089] The ophthalmic composition in gel form according to the invention is used for the treatment of glaucoma, according to the usual practice of applying at least one drop of said composition on or in the eye, and repeating this application according to an appropriate treatment regimen depending on the severity of the condition. The invention also relates to a method for the prevention and treatment of glaucoma in a person who requires such treatment, the method consisting of applying an appropriate amount of the ophthalmic composition in gel form according to the invention on or in the eye at regular intervals.

[0090] The formula is particularly suitable for the treatment of open-angle glaucoma. The recommended dosage for glaucoma treatment is one or two drops per day, in the affected eye(s), depending on the active ingredient(s) used. Preparation of the formula

[0091] The preparation of the ophthalmic composition in gel form according to the invention comprises the preparation of a first solution, called solution A or "gel phase" on the one hand, and a second solution, called solution B or "active phase" on the other hand, and then mixing the two solutions until a homogeneous composition is obtained.

[0092] Solution A comprises water, a polycarbophil, and, if necessary, a tonic agent and a base or acid to adjust the pH. If necessary, the tonic agent, particularly trehalose dihydrate, is first dissolved in an appropriate amount of water before adding the polycarbophil while stirring. The pH of the solution is then adjusted by adding a base or acid, particularly a base, before thoroughly mixing the mixture until a homogeneous gel is obtained.

[0093] Solution B comprises water in which the antiglaucoma active ingredient(s) are dissolved.

[0094] Generally, solutions A and B are sterilized before being mixed.

[0095] Advantageously, the mixing is done by adding solution B into solution A.

[0096] EXAMPLES

[0097] Different gel compositions were prepared to analyze their behavior (buffering capacity, stability) and to compare them with a commercial reference product. The gelling agents used were as follows:

[0098] Polycarbophil (PCP): Noveon AAI marketed by Lubrizol

[0099] Carbomer: Carbopol 974P marketed by Lubrizol

[0100] Carboxymethyl Cellulose (CMC): Blanose 9H4XF marketed by Ashland. Example 1 - Buffering capacities of gelling agents

[0101] The buffering capacity of different gel compositions was studied by preparing the following gels obtained by dissolving the listed ingredients in water: Gel 1: 0.9% sodium carboxymethyl cellulose (CMC), 20mM citrate.

[0102] Gel 2: 0.7% polycarbophil (PCP), 20mM citrate.

[0103] Gel 3: 0.3% polycarbophil (PCP).

[0104] The pH of each gel is adjusted from 6.5 to 5.5 by adding a 0.1 N HCl solution to 5 g of each gel. The gels have a viscosity of 350 mPa·s at 100 s' 1 measured according to the European Pharmacopoeia (EP 2.2.10) by rotational rheometry, at 25 °C.

[0105] The buffering capacity is calculated by the ratio of the amount of 0.1N HCl solution added to 5 g of gel required to lower the pH by one unit. The results are given in Table 1.

[0106] [Table 1]

[0107]

[0108] The results show that polycarbophilic Gel 3 as the sole gelling agent has a buffering capacity of the same order of magnitude as a CMC gel buffered with 20 mM citrate.

[0109] Example 2 - Stability of Compositions

[0110] Several gel compositions with viscosities ranging from 300 to 350 mPa·s at 100 s⁻¹ were prepared, comprising 0.137 wt% timolol maleate (0.10 wt% timolol) and 0.010 wt% bimatoprost. These compositions were prepared with various gelling agents and, where necessary, buffers and an osmolarity agent (trehalose). The compositions are given in Table 2 below.

[0111] [Table 2]

[0112]

[0113]

[0114] The various gel compositions are bottled in Novelia® type containers (marketed by Nemera) and stored upright. Stability tests are carried out for 12 months at 25°C and 60% humidity (25°C / 60%RH) and 24 months at 40°C and 75% humidity (40°C / 75%RH).

[0115] Appearance - A yellow color is observed for Gel 7 at 25°C / 60%RH and 40°C / 75%RH. The other compositions remain colorless (Gel 4, Gel 5 and Gel 6).

[0116] Stability of active ingredients (Gel 4, Gel 5 and Gel 6) - The active ingredients remain stable in the 3 compositions (measurements of the content of active ingredients and degradation products).

[0117] pH Stability (Gel 4, Gel 5, and Gel 6) – The pH remained stable for all three compositions. The test confirms that buffering is not necessary for compositions containing polycarbophil as the sole gelling agent.

[0118] Osmolality stability (Gel 4, Gel 5 and Gel 6) - Osmolality remains stable for all 3 compositions.

[0119] Usage - Drop Reproducibility and Container Sagging (Gel 4, Gel 5 and Gel 6)

[0120] A usage study to analyze drop reproducibility and container settling was conducted over one month with the compositions in gel form in 11 mL Novelia®-type bottles, filled with 8 mL of gel, with a standard closure, without shaking before use (Trial 1) and with a ventilated closure and shaking before use (Trial 2). The results are given in Table 3 below.

[0121] [Table 3]

[0122]

[0123] Gel 4 (invention) exhibits good drop stability regardless of the closure system and does not exhibit bottle collapse, unlike Gel 5 and Gel 6 which have a viscosifying agent different from polycarbophil.

[0124] Example 3 - Comparison with Geltim® LP

[0125] The Geltim® LP formulation is an ophthalmic composition in the form of a gel comprising timolol (as timolol maleate) with the achievement and maintenance of viscosity by the combination of a viscosifying agent (carbomer 974 P) and a co-viscosifying agent (PVA), according to the teaching of application WO 2016 / 198434.

[0126] The viscosity of two batches of Geltim® was measured after 12 and 24 months at room temperature. A viscosity loss of 8% was measured at 12 months and 12% at 24 months. For the composition according to the invention with the polycarbophil as the sole viscosifier, a loss of between 5 and 7% was measured in a laboratory batch after 24 months at 25°C.

[0127] In the case of a composition according to the invention comprising the combination of timolol and bimatoprost (Gel 4), a loss of viscosity of only 5% at 12 months and 6% at 24 months, at 25°C, is observed for an industrial batch.

[0128] Example 4 - Pharmacokinetic Tests

[0129] The pharmacokinetics of the composition according to the invention (Gel 4) is compared to that of the commercial product Ganfort® (timolol 0.5% + bimatoprost 0.03%) and to Geltim® LP under GLP conditions according to the usual protocols.

[0130] After a single instillation, the concentrations of timolol on the one hand and bimatoprost (free acid form) on the other are measured in the aqueous humor, the iris / ciliary body after 30', 1h, 2h, 4h, 8h and 24h.

[0131] The results are shown in Figures 1 to 4. With respect to the concentrations, a penetration profile is observed in favour of the gel composition according to the invention (Gel 4), for both timolol and bimatoprost in the aqueous humors and the iris / ciliary body.

Claims

DEMANDS 1. Ophthalmic composition in the form of an aqueous gel comprising at least one water-soluble active ingredient selected from antiglaucoma agents and a single gelling agent, in which the gelling agent consists of a polycarbophil, characterized in that the antiglaucoma agent is chosen from among beta-blockers, prostaglandin analogues, carbonic anhydrase inhibitors and mixtures thereof, the composition comprises 0.15 to 0.4% by weight of polycarbophil relative to the total weight of the composition, and The composition does not include any preservatives.

2. Composition according to claim 1, characterized in that it comprises At least one water-soluble active ingredient chosen from among the antiglaucoma agents Polycarbophile as the sole gelling agent A tonic agent, and Water.

3. Composition according to claim 1 or 2, characterized in that it comprises from 0.0025 to 2% by weight of anti-glocaum agent(s) relative to the total weight of the composition.

4. Ophthalmic composition according to any one of claims 1 to 3, characterized in that the antiglaucoma agent is a mixture of beta-blocking agent and prostaglandin analogue.

5. Composition according to claim 4, characterized in that the beta-blocking agent is timolol and the prostaglandin analogue is bimatoprost.

6. Composition according to claim 5, characterized in that it comprises 0.1 to 0.5% by weight of timolol and 0.01 to 0.03% by weight of bimatoprost.

7. Composition according to any one of claims 1 to 5, characterized in that the tonic agent is trehalose.

8. Composition according to claim 7, characterized in that it comprises 8 to 10% by weight of trehalose relative to the total weight of the composition.

9. Composition according to any one of claims 1 to 8, characterized in that it does not comprise a buffer.

10. Composition according to any one of claims 1 to 9, characterized in that it consists of at least one water-soluble active ingredient selected from antiglaucoma agents, polycarbophil as the sole gelling agent, tonicity agent, an acid or a base to adjust the pH from 6 to 7 and water.

11. Composition according to any one of claims 1 to 10, characterized in that it does not comprise a surfactant.

12. Composition according to any one of claims 1 to 11, for its use in the treatment of glaucoma.

13. A method for preparing a composition according to any one of claims 1 to 11, characterized in that it comprises preparing a first solution, called solution A or "gel phase" comprising water, polycarbophil and where appropriate the tonic agent on the one hand, and a second solution, called solution B or "active phase" comprising water in which the antiglaucoma active ingredient(s) are dissolved on the other hand, and then mixing the two solutions until a homogeneous composition is obtained.

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