Aqueous gel composition

Abstract

The present invention discloses an aqueous gel composition useful for administration of a medicament active agent, particularly for transtympanic administration of a medicament active agent. The aqueous gel composition comprises at least one first surfactant in an amount of 10% to 30% by weight based on the total weight of the composition, at least one second surfactant in an amount of 5% to 20% by weight based on the total weight of the composition, at least one alcohol in an amount of 5% to 20% by weight based on the total weight of the composition, and water in an amount of at least 30% by weight based on the total weight of the composition.

Description

[Technical Field]

[0001] The present invention relates to novel aqueous gel compositions, particularly those useful as carriers for pharmaceutically active agents. The present invention also relates to pharmaceutical compositions or medicaments comprising the aqueous gel compositions, particularly those with sustained release of pharmaceutically active agents, and to the use of the aqueous gel compositions in the prevention or treatment of inner ear disorders. [Background technology]

[0002] Due to their viscosity characteristics, gel compositions are often used as carriers for topical and oral administration of pharmaceutically active agents.Important for the administration of gel compositions are, for example, easy application by syringe, particularly sufficient syringeability, i.e., the ability to be dispensed from a syringe and / or taken up into a syringe, or specific viscosity characteristics that allow easy application by a spatula; and good solubilization of the pharmaceutically active agent, which allows the gel composition to function as a depot with sustained release of the pharmaceutically active agent, particularly for at least 3 days, preferably at least 5 days, after a single administration to the organic tissue, and good adhesion of the composition to the organic tissue.

[0003] Therefore, thermoreversible non-aqueous gel compositions are often used that contain primarily a particulate gel matrix with a sufficient amount of viscosity-increasing thickener to provide a gelation temperature near body temperature, and that change viscosity at a characteristic temperature.

[0004] However, although non-aqueous particulate gel compositions are good carriers for pharmaceutically active agents with relatively poor water solubility, they exhibit the drawback of being unable to maintain the viscosity characteristics and uniform distribution of particles over a long period of time due to particle settling. This drawback is particularly evident in gel compositions (e.g., oleogels) containing an oily matrix and a thickener that remains undissolved. Furthermore, thickener settling results in an unevenly distributed pharmaceutically active agent, which carries the risk of inconsistent release of the pharmaceutically active agent. Therefore, subsequent pretreatment, particularly involving heating and ultrasonication, is often used to ensure rehomogenization of the pharmaceutically active agent immediately before application. However, this pretreatment is difficult to implement in daily clinical practice and is therefore undesirable.

[0005] Aqueous gel compositions offer a good alternative as gels with viscosity properties that allow for sustained good syringeability and good adhesion to organic tissues. Furthermore, due to the uniform distribution and good solubility of most pharmaceutically active agents in the aqueous gel composition, the aqueous gel composition allows for a constant, sustained release of the pharmaceutically active agent.

[0006] However, for pharmaceutically active agents that have relatively poor water solubility properties, conventional aqueous gel compositions lack these properties and are not suitable carriers.

[0007] In particular, for administration of gel compositions in internal organs, pharmaceutical compositions containing pharmaceutically active agents with relatively poor water solubility properties must be administered with a syringe. Furthermore, internal organs such as the eyes, ears, nose, mouth, lips, vagina, urethra, and anus are mostly covered with mucus or mucous membranes, making adhesion (mucoadhesion) difficult.

[0008] Thus, conventional aqueous gel compositions are unable to facilitate both adequate viscosity to allow good syringeability along with good adhesion in organic tissues and good administration along with sustained release of pharmaceutically active agents that have relatively poor water solubility properties.

[0009] Thermoreversible aqueous gel compositions are known from EP 3501521(A1) and WO 2019 / 210107. The corresponding compositions contain a pharmaceutically active agent such as cisplatin, carboplatin, oxaliplatin or a corticosteroid, in particular dexamethasone or a JNK (c-Jun N-terminal kinase) inhibitor, for the treatment or prevention of drug-induced ototoxicity.

[0010] U.S. Patent Application Publication No. 2018 / 0000950(A1) describes a non-aqueous gel composition comprising a therapeutic agent, a triglyceride, and at least one viscosity modifier. The triglyceride is present in an amount sufficient to stabilize the therapeutic agent for injection into the ear. Preferably, the at least one viscosity modifier is silicon dioxide.

[0011] There are several patent publications, such as WO 2014 / 076569 A2 and EP 0530965 A1, which include non-aqueous thermoreversible gels for use in the treatment of various diseases.

[0012] European Patent No. 0530965(A1) describes a composition for nasal application, which comprises at least one sex hormone drug, at least one lipophilic carrier, and a surfactant. Furthermore, the composition contains a viscosity adjusting agent, which is colloidal silicon dioxide.

[0013] U.S. Patent Application Publication No. 2013 / 150410(A1) describes a method for treating an ear disorder selected from the group consisting of Meniere's disease, endolymphatic hydrops, progressive hearing loss, lightheadedness, vertigo, and tinnitus, comprising transtympanic administration into the ear of a sterile pharmaceutical composition. The composition contains a multiparticulate ion channel modulating agent such that sustained release of the ion channel modulating agent into the ear occurs over a period of at least five days.

[0014] U.S. Patent Application Publication No. 2019 / 038469(A1) claims a system for delivering a therapeutic composition to the inner ear. The system further describes a delivery sheath having a lumen and a cannula configured to be inserted through the lumen of the delivery sheath. The cannula has a lumen for delivering the therapeutic composition and a distal tip for puncturing the tympanic membrane to deliver the therapeutic composition to the round window membrane so that the composition adheres to the round window membrane. The composition further includes a therapeutic agent for treating an inner ear disorder and a thixotropic material that allows the therapeutic composition to remain in liquid form while being injected through the cannula.

[0015] An object of the present invention is to provide a novel gel composition having superior properties compared to conventional gel compositions. Summary of the Invention

[0016] The above and further objects are solved by an aqueous gel composition according to claim 1, a pharmaceutical composition or medicament according to claim 20, and an aqueous gel composition for use in the prevention or treatment of inner ear diseases according to claim 21. Preferred embodiments are defined in the dependent claims. Preferably, but not necessarily, the aqueous gel composition is particularly suitable for transtympanic administration and comprises a pharmaceutically active agent with relatively poor water solubility properties, as defined in the dependent claims.

[0017] According to a first aspect, the present invention provides an aqueous gel composition comprising: - at least one first surfactant in an amount of 10% to 30% by weight, based on the total weight of the composition; at least one second surfactant in an amount of 5% to 20% by weight, based on the total weight of the composition; at least one alcohol in an amount of 5% to 20% by weight, based on the total weight of the composition; water in an amount of at least 30% by weight, based on the total weight of the composition; The present invention relates to an aqueous gel composition comprising or consisting of:

[0018] The present invention is based inter alia on the following surprising findings: - In contrast to conventional thermoreversible gels, the aqueous gel composition described in the present application is a suitable thermoreversible gel whose sol (liquid)-gel transition temperature can be adjusted in a relatively wide range by changing the amounts and ratios of at least one first surfactant, at least one second surfactant, and at least one alcohol; the aqueous gel compositions described in the present application show increased tolerability by patients resulting in no or only minor side effects due to the biodegradable compounds of the aqueous gel compositions of the present invention; all compounds of the aqueous gel compositions described in the present application are biodegradable and therefore do not leave any residues, in particular non-degradable residues, that may result in side effects after administration, in particular after transtympanic administration, thus positively impacting the pharmaceutical application; the aqueous gel compositions described in the present application have improved stability compared to conventional gel compositions and are therefore able to maintain the viscosity characteristics and uniform distribution of their components, preferably pharmaceutically active agents, more preferably pharmaceutically active agents with low solubility, over an extended period of time; The aqueous gel composition described in the present application is easily adjustable in terms of its solution of the pharmaceutically active agent and thus its sustained release of the pharmaceutically active agent by adapting the physicochemical properties of the gel through the selection of the different components and their ratios.

[0019] Preferably, the aqueous gel compositions of the present invention comprise or consist of a hydrophobic portion, preferably comprising at least one first surfactant and at least one second surfactant, and a hydrophilic portion, preferably comprising water and at least one alcohol.

[0020] Preferably, the aqueous gel compositions of the present invention are sterile.

[0021] Furthermore, the aqueous gel composition of the present invention may be a surfactant gel.

[0022] Terms used in the claims and throughout the specification are defined as follows:

[0023] As used herein, the term "aqueous composition" means a composition that includes water.

[0024] As used herein, the term "surfactant gel" refers to a semi-solid aqueous gel composition with viscoelastic properties that is based on surfactants, particularly formed by the aggregation of hydrated or solvated surfactant molecules.

[0025] As used herein, the term "surfactant" refers to a compound that reduces the surface tension between two liquids or between a liquid and a solid in a composition, allows or supports the formation of a dispersion, and improves the wetting properties of the composition. Surfactants can also act as detergents, emulsifiers, and foaming agents.

[0026] As used herein, the term "region or structure of the ear" means a region of the ear, in particular the middle ear region of the ear, or a structure of the ear, in particular the round window structure of the ear, which structure of the ear is part of said region of the ear.

[0027] As used herein, the term "transtympanic administration" refers to injection into the middle ear through the tympanic membrane for administration to the middle ear, particularly the round window membrane, to facilitate diffusion across the round window membrane.

[0028] As used herein, the term "sustained release gel" refers to a gel composition comprising at least one pharmaceutically active agent that provides an even, sustained and controlled release, particularly release, of at least one pharmaceutically active agent into the body, particularly the human body and its tissues.

[0029] As used herein, the term "multiparticulate" means a plurality of particles of at least one pharmaceutically active agent, the particles being of the same diameter or of different diameters.

[0030] As used herein, the term "micronized" refers to a substance, particularly a pharmaceutically active agent, that has been reduced in diameter to particles measured in μm.

[0031] As used herein, the term "sterile" means free from living bacteria or microorganisms, especially aseptic.

[0032] As used herein, the term "mucoadhesion" refers to adhesion in organic tissues that are largely covered by mucus or mucous membranes, such as the eyes, ears, nose, mouth, lips, vagina, urethral opening and anus.

[0033] As used herein, the term "thermoreversible gel" refers to a gel composition whose viscosity changes at a characteristic temperature. This thermal behavior includes the gel's properties being unaffected by repeated heating and cooling, and the gel's viscosity being reversible back to its initial state. Thermoreversible gels, particularly thermoreversible aqueous gels, contain both hydrophobic and hydrophilic components, and the thermoreversible effect results from a delicate balance between the hydrophobic and hydrophilic portions of the composition. Temperature can change the interaction between the hydrophilic and hydrophobic segments with water molecules, thus inducing a change in the solubility of the crosslinked network, causing a transition from a sol phase to a gel phase or vice versa. Changing the balance of hydrophilicity and hydrophobicity determines the macroscopic dissolution state of the crosslinked network in aqueous solution.

[0034] The term "sol phase" as used in accordance with the present invention refers to a flowing fluid, while the term "gel phase" as used in accordance with the present invention refers to a non-flowing composition that maintains its integrity.

[0035] The term "biodegradable" as used in accordance with the present invention refers to any physical or chemical change in an aqueous gel composition caused by any environmental factor, including light, heat, moisture, wind, chemical conditions, or biological activity. Typically, the aqueous gel composition of the present invention decomposes into carbon dioxide, water, and biomass as a result of the action of water and / or organisms and / or enzymes.

[0036] Thus, most or all of the compounds in the aqueous gel compositions of the present invention preferably have "GRAS" status (Generally Recognized As Safe status established by the FDA (Food and Drug Administration)) and / or are FDA approved and listed in the US and European Pharmacopoeias (European collection of recognized medicinal substances).

[0037] According to the present invention, the viscosity of the aqueous gel composition of the present invention at a temperature of 9°C to 15°C, particularly 10°C, is preferably 100 mPas to 250 mPas, more preferably 150 mPas to 200 mPas.

[0038] In one embodiment of the invention, the viscosity of the aqueous gel composition of the invention at a temperature of 25° C. is between 1400 mPas and 2300 mPas, more preferably between 1600 mPas and 2000 mPas. Within the last-mentioned range, a viscosity of between 1700 mPas and 1800 mPas is even more preferred.

[0039] According to the present invention, the viscosity of the aqueous gel composition of the present invention at a temperature of 37°C is preferably 500 to 1200 mPas, more preferably 700 to 1000 mPas.

[0040] Alternatively, the viscosity of the aqueous gel composition of the present invention at a temperature of 37° C. is preferably 1400 mPas to 2300 mPas, more preferably 1600 mPas to 2000 mPas. Within the last-mentioned range, a viscosity of 1700 mPas to 1800 mPas is even more preferred.

[0041] Alternatively and / or in combination, the viscosity of the aqueous gel composition of the present invention at a temperature of 25° C. is preferably 500 to 1200 mPas, more preferably 700 to 1000 mPas.

[0042] Preferably, the viscosity of the aqueous gel composition of the present invention at a temperature of 10°C is lower than the viscosity at 25°C, and the viscosity of the aqueous gel composition of the present invention at a temperature of 25°C is lower than the viscosity at 37°C, and more preferably, the viscosity increases from 10°C to 37°C.

[0043] Preferably, the aqueous gel composition of the present invention gels at room temperature (15° C. to 25° C.) but is liquid below room temperature (below 15° C.), particularly 4° C. to 15° C., and preferably 5° C. to 14° C. More preferably, the aqueous gel composition of the present invention gels at room temperature (15° C. to 25° C.) and maintains this state at body temperature (approximately 37° C.), but is liquid below room temperature (below 15° C.).

[0044] In contrast to conventional gel compositions, the aqueous gel compositions of the present invention have the advantage of providing a thermoreversible gel composition that changes viscosity at a characteristic temperature.

[0045] The thermoreversible viscosity characteristics described above provide aqueous gel compositions with a viscosity that makes them particularly useful in pharmaceutical compositions or topical medicaments. They provide a viscosity that is sufficient for syringeability, i.e., the ability to be dispensed from and / or taken up into a syringe, at (pharmaceutical) room temperature of 15°C to 25°C, as well as a viscosity that allows for good adhesion of the topical composition to organic tissue, particularly for at least three days, preferably at least five days, at about body temperature, typically 35°C to 38°C, after a single administration to the organic tissue. In particular, the aqueous gel compositions of the present invention are particularly useful for being drawn up into a syringe in a liquid state, preferably <10°C, dispensed at room temperature, and gelling at body temperature after administration.

[0046] This is particularly advantageous for administration of gel compositions in internal organs and / or septa, taking into account both the need to administer the composition with a syringe and the need for good adhesion, particularly good mucoadhesion.

[0047] The aqueous gel composition of the present invention preferably has a viscosity and gel structure that are useful for application through a suitable needle diameter of 18 to 27 gauge (Birmingham gauge), more preferably 20 to 23 gauge, and particularly 20 gauge. The aqueous gel composition of the present invention is also suitable for application in small volumes of 20 μL to 300 μL, preferably 30 μL to 300 μL, and more preferably 30 μL to 200 μL, to the inner ear, for example, and particularly to the middle ear to diffuse a pharmaceutically active agent into the inner ear.

[0048] Viscosity is usually measured with a viscometer, in particular a rheometer. A rheometer is usually a laboratory device that measures the flow properties of a liquid, suspension, or slurry in response to an applied force. A common type of device is the so-called shear rheometer, in which a shear stress is applied to the corresponding material. An apparatus that can be used to measure the viscosity of the aqueous gel composition according to the present invention is a Brookfield rheometer (AMETEK Brookfield).

[0049] Preferably, the aqueous gel composition of the present invention does not contain any organic polymers such as hydroxyethyl cellulose, colloidal solid particles, preferably inorganic colloidal solid particles, colloidal silica, ethylene glycol dioxide, zinc stearate, aluminum stearate and / or organically modified hectorite (Bentone).

[0050] In a further embodiment of the invention, the at least one first surfactant comprises or consists of at least one copolymer, in particular at least one block copolymer.

[0051] Preferably, the at least one first surfactant is a different surfactant from the at least one second surfactant.

[0052] Preferably, the at least one first surfactant is a non-ionic surfactant, more preferably a non-ionic copolymer, even more preferably a non-ionic block copolymer.

[0053] Furthermore, the at least one first surfactant is preferably an amphiphilic surfactant, more preferably an amphiphilic copolymer, and even more preferably an amphiphilic block copolymer.

[0054] Preferably, the at least one first surfactant is a non-ionic amphiphilic surfactant, more preferably a non-ionic amphiphilic copolymer, even more preferably a non-ionic amphiphilic block copolymer.

[0055] The term "copolymer" as used in accordance with the present invention refers to a polymer that comprises or consists of at least two different polymers.

[0056] The term "copolymer block" as used in accordance with the present invention refers to a polymer comprising or consisting of at least two different polymer blocks. Preferably, the polymer block is a homopolymer block or a copolymer block. A homopolymer block is a polymer block comprising or consisting of one monomer compound. When at least two different monomers are linked in one block, the structure is called a block copolymer.

[0057] Copolymers, especially block copolymers, have the advantage of being able to create amphiphilic structures that have the property of dissolving in both polar and nonpolar solvents. Thus, the copolymers can be both hydrophilic and lipophilic. The amphiphilic properties of the copolymers can lead to the self-aggregation of the copolymers into micelles with an inner core composed of hydrophobic blocks and an outer shell composed of hydrophilic units.

[0058] In a further embodiment of the invention, the at least one block copolymer comprises or consists of at least two different polymer blocks selected from the group consisting of a poly(ethylene oxide) (PEO) block, a poly(D,L-lactic-co-glycolic acid) (PLGA) block, a poly(l-caprolactone) block (PCL), a poly(L-lactic acid) (PLA) block, a poly(ether ester amide) (PEEA) block, a poly(propylene oxide) (PPO) block, a poly(N-isoprolylacrylamide) (pNiPAAm) block, a poly(ethylene glycol) block (PEG), a poly(propylene glycol) (PPG) block, a poly(methacrylic acid) (PMAA) block, a poly(vinyl alcohol) (PVA) block, a poly(vinylpyrrolidone) (PVP) block, and a mixture of at least two of the foregoing polymer blocks.

[0059] Preferably, the at least one block copolymer comprises or consists of at least one poly(ethylene oxide) block and at least one poly(propylene oxide) block.

[0060] More preferably, at least one block copolymer is a poloxamer, in particular poloxamer 407, where the last digit (7) multiplied by a factor of 10 indicates the relative mass fraction of the poly(ethylene oxide) blocks in percent, and the previous digit (40) multiplied by a factor of 100 encodes the relative molecular weight of the poly(propylene oxide) blocks.

[0061] Poloxamer 407, also known as Pluronic® F 127, Kolliphor P 407, or Lutrol F 127, preferably comprises or consists of a central poly(ethylene oxide) block connected at both ends to poly(propylene oxide) blocks.

[0062] Preferably, the central poly(ethylene oxide) block comprises or consists of 15 to 67 poly(ethylene oxide) monomers, preferably 56 poly(ethylene oxide) monomers, and the poly(propylene oxide) blocks attached to both ends of the central poly(ethylene oxide) block each or together comprise or consist of 2 to 130 poly(ethylene oxide) monomers, preferably 101 poly(ethylene oxide) monomers. Preferably, the number of monomers in each poly(ethylene oxide) block may be different or the same.

[0063] Poloxamer 407 is an amphiphilic structure with the property of being soluble in both polar and non-polar solvents, and therefore has the advantage of being both hydrophilic and lipophilic.

[0064] In a further embodiment of the invention, the at least one second surfactant comprises or consists of at least one phospholipid.

[0065] Preferably, the at least one second surfactant is a different surfactant from the at least one first surfactant.

[0066] Furthermore, the at least one first surfactant and the at least one second surfactant are preferably both amphiphilic surfactants.

[0067] The at least one first surfactant and the at least one second surfactant preferably comprise or consist of a surfactant selected from the group consisting of ionic, nonionic and zwitterionic surfactants.

[0068] Furthermore, the at least one second surfactant is preferably an amphiphilic surfactant, in particular an amphiphilic phospholipid, more preferably an amphiphilic phosphatidylcholine.

[0069] Furthermore, the at least one second surfactant is preferably an ionic surfactant, in particular a zwitterionic surfactant, more preferably a zwitterionic phospholipid, even more preferably a zwitterionic phosphatidylcholine.

[0070] Preferably, the at least one second surfactant is a zwitterionic amphiphilic surfactant, more preferably a zwitterionic amphiphilic phospholipid, and even more preferably a zwitterionic amphiphilic phosphatidylcholine.

[0071] Preferably, the phospholipid comprises or consists of a glycerol backbone or an amino-alcohol sphingosine backbone esterified to at least one, preferably two, fatty acids, a phosphate group, and a hydrophilic residue. Phospholipids with two esterified fatty acids are called diacylphospholipids, while phospholipids with one fatty acid are called monoacylphospholipids or lysophospholipids.

[0072] In a further embodiment of the invention, the at least one phospholipid is selected from the group consisting of phosphatidylcholine, cholesterol, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and a mixture of at least two of the foregoing phospholipids.

[0073] Preferably, the at least one phospholipid is at least one phosphatidylcholine.

[0074] Furthermore, the phosphatidylcholine is preferably diacyl- or monoacyl-phosphatidylcholine, more preferably natural phosphatidylcholine or synthetic phosphatidylcholine, in particular natural diacyl- or monoacyl-phosphatidylcholine or synthetic diacyl- or monoacyl-phosphatidylcholine.

[0075] As used herein, the term "natural phosphatidylcholine" refers to phosphatidylcholine derived from plants, particularly soybean plants.

[0076] Phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol are negatively charged at physiological pH, and phosphatidylethanolamine is negatively charged at basic pH and zwitterionic at physiological pH, whereas phosphatidylcholine has the advantage of being soluble in both polar and non-polar solvents and being zwitterionic and amphiphilic at physiological pH.Thus, phosphatidylcholine is both hydrophilic and lipophilic.

[0077] In a further embodiment of the present invention, the at least one alcohol comprises or consists of at least one polyol, in particular at least one diol.

[0078] In a further embodiment of the invention, the at least one diol is an alkanediol selected from the group consisting of ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, 1,2-pentylene glycol, pentamethylene glycol, 1,2-hexylene glycol, hexamethylene glycol, heptamethylene glycol, 1,2-octylene glycol, octamethylene glycol, ethylhexylene glycol, nonamethylene glycol, decamethylene glycol, lauryl glycol, and mixtures of at least two of the aforementioned diols.

[0079] The most important common advantageous feature of diols, especially alkanols, is their hydrophilicity. This property decreases with increasing alkyl group length and increases with the number of hydroxyl groups. Diols have higher hydrophilicity than monohydric (single hydroxyl group) alcohols, especially monohydric alkanols. Short-chain diols, especially alkanols such as propylene glycol, are particularly advantageous as solvents due to their amphiphilic nature.

[0080] Preferably, the at least one diol is at least one propylene glycol.

[0081] Furthermore, propylene glycol is miscible with water and is amphiphilic, which is particularly advantageous in combination with at least one amphiphilic first surfactant and at least one amphiphilic second surfactant, resulting in optimal interaction with the at least one first surfactant and at least one second surfactant in the aqueous gel composition of the present invention, thus contributing to the gel structure.

[0082] Preferably, at least one alcohol and at least one second surfactant are in the form of a premix composition.A useful premix composition is commercially available, for example, under the name Phosal®, preferably Phosal® 50PG.Phosal® 50PG comprises or consists of phosphatidylcholine, particularly phosphatidylcholine derived from soybean plants, and propylene glycol, preferably in a weight ratio of 1:1.

[0083] In a further embodiment of the invention, the at least one first surfactant is present in an amount of 10% to 25% by weight, preferably 12% to 22% by weight, more preferably 14% to 16% by weight, based on the total weight of the composition.

[0084] It has been found that the amount of the at least one first surfactant in the aqueous gel composition is important to ensure the formation of a thermoreversible gel having the required sol phase to gel phase transition temperature, good loading of the pharmaceutically active agent in the aqueous gel composition of the present invention, particularly good encapsulation capacity of the pharmaceutically active agent in the aqueous gel composition of the present invention, mucoadhesive properties, and sustained release of the pharmaceutically active agent from the aqueous gel composition of the present invention, particularly good sustained release kinetics.

[0085] In a further embodiment of the invention, the at least one second surfactant is present in an amount of from 6% to 20% by weight, preferably from 6% to 15% by weight, more preferably from 6% to 10% by weight, based on the total weight of the composition.

[0086] In a further embodiment of the invention, the at least one alcohol is present in an amount of 6% to 20% by weight, preferably 6% to 15% by weight, more preferably 6% to 10% by weight, based on the total weight of the composition.

[0087] Preferably, the at least one alcohol and the at least one second surfactant are present in the composition in a weight ratio of 1:1, 30:70, or 70:30.

[0088] The amounts of at least one second surfactant and at least one alcohol in the aqueous gel composition have been found to be particularly advantageous for ensuring the formation of a thermoreversible gel having the required sol phase to gel phase transition temperature, good loading of the pharmaceutically active agent in the aqueous gel composition of the present invention, in particular good encapsulation capacity of the pharmaceutically active agent in the aqueous gel composition of the present invention, mucoadhesive properties, and sustained release of the pharmaceutically active agent from the aqueous gel composition of the present invention, in particular good sustained release kinetics.

[0089] In a further embodiment of the present invention, the aqueous gel composition preferably comprises: the at least one first surfactant is a poloxamer, in particular present in an amount of 14% to 16% by weight, based on the total weight of the composition; the at least one second surfactant is a phospholipid, preferably a natural phosphatidylcholine, in particular present in an amount between 6% and 10% by weight, based on the total weight of the composition; and the at least one alcohol is propylene glycol, in particular present in an amount of 6% to 10% by weight, based on the total weight of the composition;

[0090] The aqueous gel compositions of the present invention have been found to be particularly useful for providing a sustained in vivo release of a therapeutically effective amount of a pharmaceutically active agent after administration, preferably in an internal organ and / or septum, particularly after transtympanic administration, for application to the middle ear to allow diffusion of the pharmaceutically active agent to the inner ear for at least 3 days, preferably at least 5 days, after a single administration to the organic tissue.

[0091] In a further embodiment of the invention, the aqueous gel composition further comprises at least one pharmaceutically active agent.

[0092] Preferably, the aqueous gel composition of the present invention is a sustained release gel comprising at least one pharmaceutically active agent, which provides an even, sustained and controlled release, in particular release, of the at least one pharmaceutically active agent into the body, in particular the human body, over a period of at least 3 days, preferably at least 5 days, more preferably at least 1 month, in particular after a single administration in an organic tissue.

[0093] The at least one pharmaceutically active agent is preferably present in an amount of 0.05% to 10% by weight, preferably 0.1% to 10% by weight, more preferably 2% to 10% by weight, and even more preferably 2% to 5% by weight, based on the total weight of the composition.

[0094] The above amounts of at least one pharmaceutically active agent have been found to be particularly useful for providing a sustained release gel for at least 3 days, and preferably at least 5 days, after a single administration to organic tissue, to release the pharmaceutically active agent from the aqueous gel compositions of the present invention.

[0095] Furthermore, the at least one pharmaceutically active agent may in particular be in the form of particles and / or have an average particle size of between 0.01 μm and 100 μm, preferably between 5 μm and 80 μm, more preferably between 20 μm and 50 μm.

[0096] The term "average particle size" as used herein refers to particles of at least one pharmaceutically active agent or 50% (D50) of all particles, whose size, in particular their diameter, preferably the average diameter, is in the range of 0.01 μm to 100 μm, preferably 5 μm to 80 μm, more preferably 20 μm to 50 μm. In this context, the term "diameter" should be understood to mean, in the case of spherical particles, the diameter of the sphere, i.e., twice the radius of the sphere. In the case of non-spherical particles, the term "diameter" should be understood as the maximum possible distance that two points along the circumference of the particle can be from each other.

[0097] More preferably, the at least one pharmaceutically active agent is in the form of particles, and 90% (D90) of all particles of the at least one pharmaceutically active agent are smaller than a particle size, especially a mean particle size, of 0.01 μm to 100 μm, preferably 1 μm to 50 μm, more preferably 5 μm to 20 μm, even more preferably 11 μm or 7 μm.

[0098] More preferably, the at least one pharmaceutically active agent is in the form of particles, wherein 50% (D50) of all particles of the at least one pharmaceutically active agent have a particle size, in particular a mean particle size, of 0.01 μm to 100 μm, preferably 1 μm to 50 μm, more preferably 5 μm to 10 μm, and even more preferably 5 μm.

[0099] The average particle size distribution is preferably obtained by laser diffraction. During laser diffraction measurement, a laser beam is passed through a dispersed particulate sample, and the angular variation in the intensity of the scattered light is measured. Large particles scatter light at small angles relative to the laser beam, while small particles scatter light at large angles. The angular scattered intensity data is then analyzed to calculate the diameter of the particle that produced the scattering pattern using the Mie theory of light scattering. Particle size is reported as the volume-equivalent spherical diameter. The folded optical design of the Mastersizer 3000 (Malvern Panalytical) used in the particular measurement provides a particle size range from 10 nm to 3.5 mm using a single optical measurement path. The Mastersizer 3000 uses a sequential combination of red and blue light source measurements to measure across the entire particle size range.

[0100] The above average particle sizes of the at least one pharmaceutically active agent have been found to be particularly useful for obtaining a uniform distribution of the at least one pharmaceutically active agent in the aqueous gel composition.

[0101] Preferably, the desired particle size of the at least one pharmaceutically active agent is obtained by grinding, ball milling, high pressure homogenization, homogenization, micronization, or a combination of at least two of the methods described.

[0102] Furthermore, due to the above particle size of the at least one pharmaceutically active agent, the uptake of the at least one pharmaceutically active agent from the compositions of the present invention into the body after administration to organic tissue is particularly advantageous compared to other conventional gel compositions containing pharmaceutically active agents. Due to the advantageous uptake of the pharmaceutically active agent from the aqueous gel compositions of the present invention into the body, a lower amount of the pharmaceutically active agent in the composition is required to achieve the same therapeutic effect as conventional gel compositions.

[0103] Alternatively, at least one pharmaceutically active agent may not be specifically micronized.

[0104] As used herein, the term "uptake of a pharmaceutically active agent into the body" means uptake of a pharmaceutically active agent into the mammalian body, particularly the human and / or animal body, particularly into the perilymph and / or endolymph of the mammalian body, particularly the human and / or animal body.

[0105] Preferably, the aqueous gel compositions of the present invention comprise a multiparticulate suspension of the pharmaceutically active agent, based on the concentration of the pharmaceutically active agent.

[0106] In a preferred embodiment of the present invention, the aqueous gel composition of the present invention preferably comprises a solution of a pharmaceutically active agent.

[0107] Preferably, the at least one pharmaceutically active agent has a (low) solubility in water at room temperature (22-26°C) of less than 1 mg / mL, preferably less than 0.1 mg / mL, more preferably less than 0.01 mg / mL, in particular between 0.01 mg / mL and 1 mg / mL.

[0108] The low solubility of a pharmaceutically active agent adversely affects the uptake of the pharmaceutically active agent into the body, particularly into the perilymph and / or endolymph of the body, after administration, particularly in internal organs, e.g., after transtympanic administration. As a result, the therapeutic effect cannot be achieved by a single administration, but a local depot formulation should be developed that uses the inherent low solubility of the pharmaceutically active agent in a suitable gel composition to obtain sustained uptake of the pharmaceutically active agent over a desired time interval.

[0109] The aqueous gel compositions of the present invention exhibit the advantage that they are particularly useful for carrying pharmaceutically active agents with (low) solubility as described above, especially for topical administration.

[0110] Preferably, at least one first surfactant, particularly a poloxamer, and at least one second surfactant, particularly a phospholipid, are both amphiphilic compounds that act as surfactants and combine to form a lamellar structure in the aqueous gel composition of the present invention. The different carbon chain lengths of the at least one first surfactant, particularly a poloxamer, and the at least one second surfactant, particularly a phospholipid, preferably create cavities in the lamellar structure into which drug substances can be intercalated. Thus, the pharmaceutically active agent is preferably encapsulated in the aqueous gel composition of the present invention. This can increase the solubilizing effect of the formulation and increase the drug loading of the pharmaceutically active agent, especially a pharmaceutically active agent with low water solubility, and enable the solubilization of even less water-soluble pharmaceutically active agents in the aqueous gel composition of the present invention.

[0111] The term "lamellar structure" as used herein means a microstructure comprising alternating layers of different materials, in particular at least one first surfactant, preferably a poloxamer, and at least one second surfactant, preferably a phospholipid.

[0112] Additionally, the aqueous gel compositions of the present invention can be administered to form a local depot to obtain sustained uptake of the pharmaceutically active agent for at least 3 days, preferably at least 5 days, particularly after a single administration to organic tissue.

[0113] Preferably, at least one pharmaceutically active agent is a substance comprising low solubility and high permeability characteristics.

[0114] In a further embodiment of the invention, the at least one pharmaceutically active agent preferably has formula I, [ka] During the ceremony, -n=1, -RL is a substituent selected from the group consisting of substituted cyclopentathienyl groups, which are substituted with at least one F or Cl atom, and unsubstituted or substituted indanyl groups, which are substituted with at least one F or Cl atom; -RR is a substituted phenyl group, the substituted phenyl group comprising at least one substituent selected from F, SF5, CF3, and OCF3.

[0115] In a further embodiment of the invention, the at least one pharmaceutically active agent is (S)-3-(3,4-difluorophenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3-pentafluorosulfanylphenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, and (S)-1-(5-chloro-2,3-dihydro-1-H-inden-1-yl)-1-methyl-3-(3-pentafluorosulfanylphenyl)urea, and mixtures of at least two of the foregoing pharmaceutically active agents.

[0116] Preferably, the at least one pharmaceutically active agent is (S)-3-(3,4-difluorophenyl)-1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1-methylurea.

[0117] The pharmaceutically active agents listed above preferably function as potassium channel openers, particularly as openers of the Kv7.4 potassium channel, and thus belong to a class of compounds that are particularly useful in the treatment of disorders associated with abnormal potassium activity, such as Alzheimer's disease and Parkinson's disease. Further disorders are neurological conditions such as epilepsy, or cognitive and psychiatric disorders such as depression, mania, and schizophrenia. In particular, potassium channels are known to play an important role in the normal function of outer hair cells (OHCs) in the organ of Corti of the cochlea. Therefore, the pharmaceutically active agents listed above are promising candidates for the treatment of hearing loss and / or the prevention of hearing loss, for example, before treatment with drugs that induce ototoxicity.

[0118] In a further embodiment of the invention, the at least one pharmaceutically active agent preferably has formula II, [ka] During the ceremony, -R is an unsubstituted cycloalkyl group, in particular a bicycloalkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted thienyl group, the substituted thienyl group or phenyl group being preferably substituted with at least one halogen atom selected from the group consisting of at least one F atom, Cl atom, Br atom, or I atom, more preferably at least one F atom or at least one Cl atom, -R1 is F, SF5, CF3 or OCF3.

[0119] According to the present invention, the at least one pharmaceutically active agent is preferably (1R,2R,4S)-rel-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or Stereoisomers or tautomers of (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, especially the enantiomer (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or Racemic mixture (1SR,2SR,4RS)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide), (1R,2R,4S)-rel-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, p-chloro-N-(4-trifluoromethoxy)benzyl)benzamide, p-chloro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-fluoro-N-(4-trifluoromethoxy)benzyl)benzamide, p-fluoro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-chloro-N-(4-(trifluoromethyl)benzyl)benzamide, p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, and mixtures of at least two of the foregoing pharmaceutically active agents.

[0120] Preferably, the at least one pharmaceutically active agent is (1R,2R,4S)-rel-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or (1S,2S,4R)—N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide.

[0121] The pharmaceutically active agents listed above preferably function as potassium channel openers, particularly as openers of the Kv7.4 potassium channel, and thus belong to a class of compounds that are particularly useful in the treatment of disorders associated with abnormal potassium activity, such as Alzheimer's disease and Parkinson's disease. Further disorders are neurological conditions such as epilepsy, or cognitive and psychiatric disorders such as depression, mania, and schizophrenia. In particular, potassium channels are known to play an important role in the normal function of outer hair cells (OHCs) in the organ of Corti of the cochlea. Therefore, the pharmaceutically active agents listed above are promising candidates for the treatment of hearing loss and / or the prevention of hearing loss, for example, before treatment with drugs that induce ototoxicity.

[0122] The above-mentioned pharmaceutically active agents, in particular (1SR,2SR,4RS)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (hereinafter referred to as Compound A) and its enantiomer (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (hereinafter referred to as Compound B), exhibit (low) solubilities of less than 1 mg / mL, preferably less than 0.1 mg / mL, more preferably less than 0.01 mg / mL, and particularly 0.01 mg / mL to 1 mg / mL at room temperature (22 to 26°C).

[0123] Furthermore, the aqueous gel composition preferably comprises: the at least one first surfactant is a poloxamer, in particular present in an amount of 14% to 16% by weight, based on the total weight of the composition; the at least one second surfactant is a phospholipid, preferably a natural phosphatidylcholine, in particular present in an amount between 6% and 10% by weight, based on the total weight of the composition; the at least one alcohol is propylene glycol, in particular present in an amount of from 6% to 10% by weight, based on the total weight of the composition; the viscosity of the composition, in particular at a temperature of 25°C or 37°C, is between 1400 and 2300 mPas, preferably between 1600 and 2000 mPas, and at least one pharmaceutically active agent is (S)-3-(3,4-difluorophenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3-pentafluorosulfanylphenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, and (S)-1-(5-chloro-2,3-dihydro-1-H-inden-1-yl)-1-methyl-3-(3-pentafluorosulfanylphenyl)urea, (1R,2R,4S)-rel-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or Stereoisomers or tautomers of (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, especially, Enantiomer (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide or Racemic mixture (1SR,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide), (1R,2R,4S)-rel-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, p-chloro-N-(4-trifluoromethoxy)benzyl)benzamide, p-chloro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-fluoro-N-(4-trifluoromethoxy)benzyl)benzamide, p-fluoro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-chloro-N-(4-(trifluoromethyl)benzyl)benzamide, p-Fluoro-N-(4-(trifluoromethyl)benzyl)benzamide and mixtures of at least two of the foregoing pharmaceutically active agents.

[0124] The above compositions have been found to be particularly advantageous with respect to adhesive and viscosity properties, as well as uptake of pharmaceutically active agents into the body from the aqueous gel compositions of the present invention, which provide sustained release of the compound for at least 3 days, and preferably at least 5 days, after a single administration to organic tissue.

[0125] According to a second aspect, the present invention relates to a container, in particular a discharge device, which preferably contains, and is preferably filled with, an aqueous gel composition, in particular an aqueous gel composition according to the first aspect of the invention.

[0126] The container may be in the form of a vial or a syringe.

[0127] Preferably, the discharge device is connected to a needle suitable for transtympanic administration, preferably having a diameter of 18 to 27 gauge (Birmingham gauge), more preferably 20 to 23 gauge, especially 20 gauge, and particularly suitable for applying small amounts of the aqueous gel composition of the present invention, in the range of 20 μL to 200 μL, for transtympanic administration.

[0128] Furthermore, the ejection device is preferably a cycloolefin polymer (COP) syringe, which presents the advantage of not risking the inclusion of any residual glass particles from the manufacturing process.

[0129] Preferably, the ejection device includes a stopper and a plunger.

[0130] Furthermore, the ejection device preferably comprises a syringe holder, in particular a plastic or cardboard syringe holder, which is particularly useful to avoid any damage to the syringe during transport.

[0131] Furthermore, the discharge device, particularly the syringe, is preferably filled under aseptic conditions with the sterile aqueous gel composition of the present invention.

[0132] With regard to further features and advantages of the evacuation device, in particular with regard to the aqueous gel composition, reference is made in general to the features and advantages described with respect to the aqueous gel composition according to the first aspect of the invention. The features and advantages described with respect to the first aspect of the invention apply mutatis mutandis with regard to the evacuation device according to the second aspect of the invention.

[0133] According to a third aspect, the present invention relates to a pharmaceutical composition or medicament comprising an aqueous gel composition, in particular comprising an aqueous gel composition according to the first aspect of the invention.

[0134] With regard to further features and advantages of the pharmaceutical composition or medicament, in particular with regard to the aqueous gel composition, reference is made generally to the features and advantages described with regard to the aqueous gel composition according to the first aspect of the invention and with regard to the use according to the fourth aspect of the invention. The features and advantages described with reference to the first, second and fourth aspects of the invention apply mutatis mutandis with regard to the pharmaceutical composition or medicament according to the fourth aspect of the invention.

[0135] According to a fourth aspect, the present invention relates to an aqueous gel composition for use in the prevention or treatment of an inner ear disease, in particular an aqueous gel composition according to the first aspect of the invention, or a pharmaceutical composition or medicament for use in the prevention or treatment of an inner ear disease, preferably provided for transtympanic administration.

[0136] Preferably, the aqueous gel composition comprising at least one pharmaceutically active agent is administered via transtympanic administration, which provides sustained release of the pharmaceutically active agent to the ear, preferably the inner ear, for at least three days, preferably at least five days, particularly after a single administration. Due to its viscosity characteristics described above, the aqueous gel composition of the present invention is particularly useful for sustained release of pharmaceutically active agents via transtympanic administration for the treatment of otopathies, including, but not limited to, induced hearing loss, particularly sensorineural hearing loss, and drug-induced ototoxicity.

[0137] Furthermore, the aqueous gel compositions of the present invention advantageously exhibit a well-controlled viscosity and gel structure that makes them particularly suitable for administration as drops. After transtympanic administration, the compositions, preferably in the form of drops, preferably containing the aqueous gel compositions of the present invention in a volume of 20 μL to 300 μL, preferably 30 μL to 300 μL, more preferably 30 μL to 200 μL, adhere to the round window membrane or adjuvant mucosa and are not washed away from the middle ear and / or round window membrane, thus providing a sustained release of the pharmaceutically active agent for at least 3 days, preferably at least 5 days, after a single administration to the organic tissue, thereby avoiding frequent transtympanic administration to the patient's ear.

[0138] With regard to further features and advantages of the use in pharmaceutical compositions or medicaments, and in particular with regard to aqueous gel compositions, reference is made in general to the features and advantages described with regard to the aqueous gel compositions according to the first aspect of the invention. The features and advantages described with reference to the first and second aspects of the invention apply mutatis mutandis with regard to the use according to the fourth aspect of the invention.

[0139] Further features and advantages of the present invention will become apparent from the following description of preferred embodiments in the form of examples, in conjunction with the subject matter of the dependent claims. Individual features can be realized either alone or in combination in one embodiment of the present invention. The preferred embodiments merely serve to illustrate and better understand the present invention and should not be understood as limiting the invention in any way.

[0140] The diagram shows: [Brief explanation of the drawings]

[0141] [Figure 1a] Temperature-induced increase in viscosity of aqueous gel compositions of the present invention without a pharmaceutically active agent, with different poloxamer 407 contents. [Figure 1b] Temperature-induced increase in viscosity of aqueous gel compositions of the present invention without a pharmaceutically active agent, with different poloxamer 407 contents. [Figure 1c]Temperature-induced increase in viscosity of aqueous gel compositions of the present invention without a pharmaceutically active agent, with different poloxamer 407 contents. [Figure 1d] Temperature-induced increase in viscosity of aqueous gel compositions of the present invention without a pharmaceutically active agent, with different poloxamer 407 contents. [Figure 2a] Temperature-induced increase in viscosity of an aqueous gel composition of the present invention containing 15% poloxamer 407 (a, left) compared to the same aqueous gel composition of the present invention containing 2% pharmaceutically active agent (API), which is (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (ACOU085) (b, right). [Figure 2b] Temperature-induced increase in viscosity of an aqueous gel composition of the present invention containing 15% poloxamer 407 (a, left) compared to the same aqueous gel composition of the present invention containing 2% pharmaceutically active agent (API), which is (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (ACOU085) (b, right). [Figure 3a] Adhesion test: Photograph of gel formulation applied to microscope objective slide. [Figure 3b] Adhesion test: Photograph of gel formulation applied to microscope objective slide. [Figure 4] In vitro drug release study: Time-release relationship of compositions in Table 1 (new) containing 2% ACOU085 and 3% ACOU085 (200 μL dose) in triplicate. [Figure 5] In vitro drug release study: Time-release relationship of the compositions in Table 1 (new) containing 2% ACOU085 (300 μL application) and the reference formulation (ref) containing 3% ACOU085 (200 μL application) in triplicate. [Figure 6] In vitro drug release study: Time-release relationship of the compositions in Table 1 (new) containing 3% ACOU085 (200 μL application) and the reference formulation (ref) containing 2% ACOU085 (300 μL application) in triplicate. [Figure 7]Comparisons of 300 μL or 200 μL of the compositions in Table 1 apply. [Figure 8] A comparison of 300 μL or 200 μL of the reference formulation is applied. [Example]

[0142] Viscosity Test: The temperature-induced increase in viscosity of the suspension was tested using aqueous gel compositions of the present invention (according to Table 1) containing 13.9%, 15%, 17.9%, and 20% poloxamer 407 without a pharmaceutically active agent (Figures 1a-d and 2a).

[0143] Note: The maximum viscosity is the same for all formulations (according to this test method). Figures 1a-1d show that the tipping point at which viscosity rapidly increases with increasing temperature depends on the percentage of poloxamer. The composition containing 15% poloxamer exhibits optimal viscosity characteristics, as the viscosity increases rapidly at 20°C, which is preferable for medical applications.

[0144] Figures 2a and 2b show that the pharmaceutically active agent (API) did not affect the viscosity-temperature relationship of the formulations.

[0145] Adhesion Test: In an initial adhesion test, aqueous gel compositions of the present invention (according to Table 1) containing 14%, 15%, 17.9%, and 20% poloxamer 407 were each applied to a finger. The composition containing 14% poloxamer 407 exhibited dripping of the composition from the finger. This dripping was not observed with the 15%, 17.9%, and 20% compositions.

[0146] A final, more accurate adhesion test was performed using an aqueous gel composition of the present invention (according to Table 1) containing 14% poloxamer and no pharmaceutically active agent. 300 μL of this composition was applied horizontally to a microscope objective slide at room temperature. The slide was placed in a 37°C oven, and at several time points (30 seconds, 1 minute, 1.5 minutes, 2 minutes, 3 minutes, 5 minutes, and 6 minutes), the slide was turned upright. Subsequent visual inspection showed that the composition remained in place at 37°C, and no dripping was detected at any time point (see Figures 3a and 3b).

[0147] Since the aqueous gel composition of the present invention containing no pharmaceutically active agent and 14% poloxamer (according to Table 1) did not show any dripping in the final, more accurate adhesion test, it can be inferred that formulations with higher poloxamer concentrations will also stay on the microscope slide, since higher poloxamer content gives a viscous composition at lower temperatures.

[0148] composition [Table 1] Composition of the Aqueous Gel Compositions of the Invention. Compositions used in the examples that deviate from the percentages or ingredients listed in the tables were adjusted accordingly by adding or omitting water. * :Exact percentages are not rounded numbers. ** The (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (ACOU085) used in the formulation is a GMP material with the following particle size: D90: 32 μm. D90 means that 90% of all particles are smaller than this diameter. D50: 13 μm. D50 means that 50% of all particles are smaller than this diameter. - D10: 3.5 μm. D10 means that 10% of all particles are smaller than this diameter.

[0149] Composition for one vial of 550 mg: [Table 2] Composition (mg) of the aqueous gel composition of the present invention. ** :+(1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide

[0150] preparation 1. Mix Phosal 50PG (premixed phosphatidylcholine and propylene glycol, 1:1) with (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (ACOU085). 2. Slowly add water while stirring with an overhead stirrer (phase inversion from water-in-oil emulsion to oil-in-water emulsion). 3. Cool the mixture on ice. 4. Slowly add Kolliphor P407 (Poloxamer 407) powder while stirring with an overhead stirrer. 5. Keep the mixture cool while stirring and adding the poloxamer. 6. Continue stirring the mixture for at least 1 hour until all of the Kolliphor P407 has dissolved.

[0151] Stability (stress) test: Compositions prepared from Table 1 were stored at room temperature for 6 months and visually examined for appearance and showed no signs of decomposition and / or precipitation.

[0152] a) Analysis method In vitro drug release testing: The optimal media and membrane materials were determined: i) Membrane: a. Polysulfone membranes were identified as the best performing membranes in this study because they exhibited excellent diffusion properties (see Figures 4-7).

[0153] ii) Medium: Several media were tested and the optimal medium was selected. PBS buffer pH 7.4 and 3% SDS was selected as the optimal medium due to its properties, good ACOU085 solubility, and the fact that air bubbles do not easily form under the membrane (see Figures 4 to 7).

[0154] b) Needle passability: The aqueous gel compositions of the present invention shown in Table 1 can be passed through a 1 mL syringe equipped with a 21 G or 25 G needle.

[0155] In vitro release data: The in vitro release data (Figures 4-8 and Tables 2-6) were obtained using a Franz diffusion cell for permeation experiments. This device consists of two compartments with a fixed membrane (diffusion barrier) between them. The substance to be tested is applied directly to the top of the membrane, and the concentration of the permeating compound can be detected in the opposite (acceptor) compartment.

[0156] When a reference composition was used, the reference composition was the following non-aqueous oleogel composition: ACOU085 present in an amount of 2% or 3% by weight, castor oil present in an amount of 92.5% by weight or 91.5% by weight, Labrafil® (oleoyl macrogolglycerides) present in an amount of 3.50% by weight, and - Silica, colloidal anhydrous, present in an amount of 2.00% by weight.

[0157] [Table 3]

[0158] Figure 4 and Table 2 show that the formulations provide sustained, dose-dependent release across the test membrane into the medium. Over 144 hours, release ranged from 76.5-80.5% (2% ACOU085 formulation) to 82.2-88.4% (3% ACOU085 formulation) of the formulated pharmaceutically active agent.

[0159] [Table 4]

[0160] [Table 5]

[0161] Figure 5, Tables 3, and 4 show that both formulations provide sustained release across the test membrane into the medium. However, over 144 hours, release from the aqueous gel composition of the present invention results in significantly higher drug concentrations in the receiving medium and more complete release than from the reference formulation, despite the same overall amount of pharmaceutically active agent. The in vitro release curves for the reference and aqueous gel compositions of the present invention (newly developed formulations) show similar profiles. However, initially (up to 12 hours), the reference shows slightly faster release, but ultimately, the aqueous gel composition of the present invention provides the highest concentration (Figure 5).

[0162] [Table 6]

[0163] [Table 7]

[0164] Figure 6 and Tables 5 and 6 show that both formulations provide sustained release across the test membrane into the recipient medium. However, over 144 hours, release from the aqueous gel composition of the present invention results in significantly higher drug concentrations in the recipient medium and more complete release than from the reference formulation, despite the same overall amount of pharmaceutically active agent. This advantage was unaffected by varying the formulation volume / pharmaceutical active agent content between the aqueous gel composition of the present invention and the reference oleogel formulation (300 μL / 2% ACOU085 vs. 200 μL / 3% ACOU085), respectively. Figures 7 and 8 show that the higher achieved pharmaceutically active agent concentration in the recipient medium and more complete release of the loaded pharmaceutically active agent was specific to the aqueous gel composition of the present invention compared to the reference composition and was independent of the volume / pharmaceutical active agent concentration combination at a constant drug loading for each formulation.

[0165] Effect of solubilizer to water ratio on pharmaceutically active agents with relatively poor water solubility properties Solubility enhancers are explored to improve the solubility of pharmaceutically active agents that have relatively poor water solubility properties in water.

[0166] (1S,2S,4R)-N-(3-(pentafluorosulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (ACOU085) was used as the pharmaceutically active agent, which has relatively poor solubility properties in water.

[0167] Initially, six mixtures are prepared to see if emulsions with ACOU085 in water are a viable approach. Once a stable emulsion is formed, the mixture can be further stabilized with other compounds added to the water phase, particularly poloxamer 407. Poloxamer 407 introduces thermoreversible properties to the mixture.

[0168] [Table 8]

[0169] Mixture 1: Composition 1 drop of premix Phosal 50PG + ACOU085 + 10 mL of MilliQ water.

[0170] Preparation method: 1. Pipette 1 drop of Phosal 50PG containing ACOU085 into 10 mL of water. 2. Flakes form but are not stable. 3. After 10 minutes of sonication, a white or pale blue turbidity typical of micro / nano emulsions forms.

[0171] After adding the premix to water, flake formation occurred. These flakes were removed by ultrasonic treatment for 10 minutes. After ultrasonic treatment, a white or pale blue turbidity, typical of micro / nano emulsions, was formed.

[0172] Mixture 2: Composition: 1 mL of premix Phosal 50PG + ACOU085 + 10 mL of MilliQ water.

[0173] Preparation: 1. Pipette 1 mL of Phosal 50PG containing ACOU085 into 10 mL of water. 2. Large flakes formed, but were not stable. 3. Sonication for 10 minutes resulted in the formation of a milky emulsion. 4. Precipitation occurred after several days, but was not stable.

[0174] After adding the premix to water, flake formation occurs. After 10 minutes of sonication, a milky emulsion is formed, but precipitation occurs after several days. Therefore, the mixture is not stable. Furthermore, a micrograph of Mixture 2 shows large ACOU085 particles that are not incorporated into the formed emulsion or precipitate immediately after preparation.

[0175] Mixture 3: Composition 1 drop of premix Phosal 50PG + ACOU085 + 10 mL of MilliQ water + 1 drop of Cremophor RH40 at 40°C.

[0176] Preparation: 1. 40°C water with Cremophor. 2. Pipette 1 drop of Phosal + ACOU085 into the stirring mixture. 3. Flakes will form, but with further stirring the flakes will dissolve.

[0177] After adding the premix to the water and Cremophor mixture, flakes form, but after stirring, these flakes dissolve. The mixture remains opaque and stable. Micrographs show no visible ACOU085 particles.

[0178] Mixture 4: Composition 1 g of premix Phosal 50PG + ACOU085 + 0.25 g of Polysorbate 80 + 9 g of MilliQ water.

[0179] Preparation method: 1. Mix Phosal 50PG + ACOU085 with 0.25g Polysorbate 80. 2. Add water slowly under stirring. 3. Phase inversion, first forming a w / o emulsion, then adding more water to form an o / w (oil-in-water) emulsion. The mixture was prepared using the phase inversion technique. A water-in-oil emulsion is formed first, and after adding more water, an oil-in-water emulsion is formed. The formulation is a milky white emulsion that remains stable initially but precipitates after 10 days. A few particles of ACOU085 are visible in the micrograph.

[0180] Mixture 5: Composition: 1 mL Phosal 50PG + 20 mL MilliQ water.

[0181] Preparation method: 1. Stir the water. 2. Slowly add Phosal 50PG to the water phase. 3. Stir after each addition until homogeneous. Mix 5 was prepared without ACOU085 to get an initial idea of ​​if it is feasible to prepare a stable emulsion with Phosal 50PG and water. 4. Mix the water and slowly add Phosal 50PG.

[0182] Mixture 6: Composition: 1 mL Phosal 50PG + 5 g MilliQ water.

[0183] Preparation method: 1. Stir Phosal 50PG. 2. Slowly add water. 3. Phase inversion from w / o emulsion to o / w emulsion, product is liquid.

[0184] Attempts to prepare a stable emulsion in Mixture 5 were unsuccessful. Therefore, a different approach is used to prepare a stable emulsion. This mixture was also prepared without ACOU085 to get an initial idea of ​​whether the phase inversion technique might work. Phosal 50PG was added first, and water was slowly added while stirring the Phosal 50PG. The mixture became a viscous water-in-oil emulsion, and after further water addition, an oil-in-water emulsion formed. The mixture was a milky-white emulsion that remained stable (see Figure 10). In the micrograph, a typical image of the emulsion is shown with small, evenly distributed droplets.

[0185] conclusion Of these six mixtures, it can be concluded that the emulsion of Mixture 6 exhibited the best stability and was capable of emulsifying a sufficient amount of ACOU085 to produce a workable final formulation. This mixture was prepared using a phase inversion technique, resulting in small, uniformly distributed droplets. This mixture will be used as a basis for further development of formulations with thermoreversible properties. Apparently, a Phosal:water ratio of 1:5, preferably 1:1 to 1:10, and more preferably 1:1.5 to 1:3, exhibited the best stability.

[0186] Mixture 6 containing ACOU085 and a compound having thermoreversible properties To see if a stable and homogeneous suspension with thermoreversible properties is possible, three formulations were prepared according to the ratio of Phosal 50G to water described in Mixture 6.

[0187] [Table 9]

[0188] These formulations result in stable formulations with desirable thermoreversible properties. However, formulations containing Labrafill exhibited impaired thermoreversible properties compared to formulations containing Kolliphor P407 (also known as Poloxamer 407).

[0189] In vivo release data Eighteen female Sprague Dawley rats participated in a pharmacokinetic study to determine the distribution of a 6% thermoreversible ACOU085 formulation at a dose of 1.2 mg / animal following unilateral transtympanic administration in peripheral plasma, inner ear, perilymph, brain, and CSF. At 4, 24, 48, 96, 168, and 336 hours after administration, n=3 rats from all groups were euthanized with carbon dioxide, peripheral and terminal blood samples and brains were collected, and inner ears were dissected for analysis of ACOU085 concentrations. Body weights were assessed on days 1-4, 7, and 14. Animals were examined for any clinical signs related to test substance toxicity.

[0190] No visible signs of pain, behavioral changes, or adverse reactions were observed after treatment with the sponsor test article, and all animals survived the scheduled study period. Only minor defensive reactions, such as head scratching, were observed immediately after injection. This reaction is believed to be due to fluid remaining in the middle ear after injection. This lack of an obvious, macroscopically detectable reaction suggests that the sponsor test article did not cause adverse effects that led to animal responses (pain, discomfort, loss of balance) when applied transtympanically to the middle ear of female Sprague-Dawley rats at a dose of 1.2 mg / animal.

[0191] [Table 10]

[0192] [Table 11]

[0193] The uptake of ACOU085 into the brain and plasma was low, as indicated by the lower concentrations measured in these organs compared to the inner ear tissue and perilymph: in fact, the maximum mean concentrations measured were only 45 nmol / L in plasma and 82 nmol / L in brain.

[0194] [Table 12]

[0195] [Table 13]

[0196] Although ACOU085 was still present at detectable levels in plasma (26 nmol / L) after 7 days, concentrations steadily decreased, reaching 4 nmol / L 14 days after administration. In the brain, ACOU085 concentrations consistently increased after treatment (Figure 3), peaking at 96 hours after injection. After 96 hours, ACOU085 concentrations steadily decreased, similar to those in plasma, until they were nearly undetectable (8 nmol / L) 14 days after administration.

[0197] conclusion The plasma pharmacokinetics (PK) and distribution of a pharmaceutically active agent using 6% ACOU085 in a thermoreversible aqueous gel composition of the present invention administered unilaterally transtympanically to female Sprague Dawley rats showed improved tolerability and release profiles compared to other formulations, resulting in sustained release of the pharmaceutically active agent with few or no side effects. Examples of embodiments of the present invention are listed in the following items [Aspect 1] to [Aspect 21]. [Aspect 1] 1. An aqueous gel composition comprising: - at least one first surfactant in an amount of 10% to 30% by weight, based on the total weight of the composition; - at least one second surfactant in an amount of 5% to 20% by weight, based on the total weight of the composition; at least one alcohol in an amount of 5% to 20% by weight, based on the total weight of the composition; - water in an amount of at least 30% by weight, based on the total weight of the composition, Aqueous gel compositions. [Aspect 2] 2. The aqueous gel composition according to claim 1, wherein the viscosity of the composition at a temperature of 25° C. is from 1400 mPas to 2300 mPas, preferably from 1600 mPas to 2000 mPas. [Aspect 3] 3. The aqueous gel composition of any one of the preceding aspects, wherein the at least one first surfactant comprises at least one copolymer, in particular at least one block copolymer. [Aspect 4] 4. The aqueous gel composition of embodiment 3, wherein the at least one block copolymer comprises at least two different polymer blocks selected from the group consisting of poly(ethylene oxide) blocks, poly(D,L-lactic-co-glycolic acid) blocks, poly(l-caprolactone) blocks, poly(L-lactic acid) blocks, poly(ether ester amide) blocks, poly(propylene oxide) blocks, poly(N-isoprolylacrylamide) blocks, poly(ethylene glycol) blocks, poly(propylene glycol) blocks, poly(methacrylic acid) blocks, poly(vinyl alcohol) blocks, poly(vinylpyrrolidone) blocks, and mixtures of at least two of the said polymer blocks. [Aspect 5] 5. The aqueous gel composition of any one of aspects 1 to 4, wherein the at least one second surfactant comprises at least one phospholipid. [Aspect 6] 6. The aqueous gel composition of embodiment 5, wherein the at least one phospholipid is selected from the group consisting of phosphatidylcholine, cholesterol, phosphatidylethanolamine, phosphatidylserine, and a mixture of at least two of the foregoing phospholipids. [Aspect 7] 7. The aqueous gel composition according to any one of the preceding aspects, wherein the at least one alcohol comprises at least one polyol, in particular at least one diol. [Aspect 8] 8. The aqueous gel composition of claim 7, wherein the at least one diol is an alkanediol selected from the group consisting of ethylene glycol, propylene glycol, trimethylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, tetramethylene glycol, 2,3-butylene glycol, 1,2-pentylene glycol, pentamethylene glycol, 1,2-hexylene glycol, hexamethylene glycol, heptamethylene glycol, 1,2-octylene glycol, octamethylene glycol, ethylhexylene glycol, nonamethylene glycol, decamethylene glycol, lauryl glycol, and a mixture of at least two of the said diols. [Aspect 9] 9. The aqueous gel composition of any one of aspects 1 to 8, wherein the at least one first surfactant is present in an amount of 10 wt. % to 25 wt. %, preferably 12 wt. % to 22 wt. %, and more preferably 14 wt. % to 16 wt. %, based on the total weight of the composition. [Aspect 10] 10. The aqueous gel composition of any one of the preceding aspects, wherein the at least one second surfactant is present in an amount of 6% to 20% by weight, preferably 6% to 15% by weight, and more preferably 6% to 10% by weight, based on the total weight of the composition. [Aspect 11] 11. The aqueous gel composition of any one of aspects 1 to 10, wherein the at least one alcohol is present in an amount of 6 wt. % to 20 wt. %, preferably 6 wt. % to 15 wt. %, and more preferably 6 wt. % to 10 wt. %, based on the total weight of the composition. [Aspect 12] said at least one first surfactant is a poloxamer; said at least one second surfactant is a phospholipid, preferably a natural phosphatidylcholine; said at least one alcohol is propylene glycol; 12. The aqueous gel composition according to any one of aspects 1 to 11. [Aspect 13] the at least one first surfactant is a poloxamer, in particular present in an amount of 14% to 16% by weight, based on the total weight of the composition; the at least one second surfactant is a phospholipid, preferably a natural phosphatidylcholine, in particular present in an amount between 6% and 10% by weight, based on the total weight of the composition; the at least one alcohol is propylene glycol, in particular present in an amount of from 6% to 10% by weight, based on the total weight of the composition; Aspect 12: The aqueous gel composition according to any one of aspects 1 to 12. [Aspect 14] 14. The aqueous gel composition of any one of Aspects 1 to 13, further comprising at least one pharmaceutically active agent, preferably in an amount of 0.05% to 10% by weight, preferably 0.1% to 10% by weight, and more preferably 2% to 10% by weight, based on the total weight of the composition. [Aspect 15] 15. The aqueous gel composition according to aspect 14, wherein the at least one pharmaceutically active agent has an average particle size of 0.01 μm to 100 μm, preferably 5 μm to 80 μm, and more preferably 20 μm to 50 μm. [Aspect 16] The at least one pharmaceutically active agent has the formula I:

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Claims

1. 1. An aqueous gel composition comprising: - at least one first surfactant in an amount of from 10% to 30% by weight, based on the total weight of the composition; - at least one second surfactant in an amount of from 5% to 20% by weight, based on the total weight of the composition; at least one alcohol in an amount of from 5% to 20% by weight, based on the total weight of the composition; water in an amount of at least 30% by weight, based on the total weight of the composition; - at least one pharmaceutically active agent having an average particle size of 0.01 μm to 100 μm, - said at least one first surfactant is a poloxamer; - said at least one second surfactant is a phospholipid; said at least one alcohol is propylene glycol; said at least one pharmaceutically active agent has formula I, 【Chemical 1】 During the ceremony, -n=1, -RL is a substituent selected from the group consisting of a substituted cyclopentathienyl group, said substituted cyclopentathienyl group being substituted with at least one F or Cl atom, and an unsubstituted or substituted indanyl group, said substituted indanyl group being substituted with at least one F or Cl atom; -RR is a substituted phenyl group, said substituted phenyl group containing at least one substituent selected from F, SF5, CF3, and OCF3; or - said at least one pharmaceutically active agent has formula II: 【Chemistry 2】 During the ceremony, -R is an unsubstituted cycloalkyl group, in particular a bicycloalkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted thienyl group, said substituted thienyl group or phenyl group being substituted with at least one halogen, R 1 is F, SF 5 , CF 3 or OCF 3 ; Aqueous gel compositions.

2. 10. The aqueous gel composition of claim 1, wherein the viscosity of the composition at a temperature of 25°C is from 1400 mPas to 2300 mPas.

3. 3. The aqueous gel composition of claim 1, wherein the at least one phospholipid is selected from the group consisting of phosphatidylcholine, cholesterol, phosphatidylethanolamine, phosphatidylserine, and a mixture of at least two of the phospholipids.

4. 3. The aqueous gel composition of claim 1, wherein the at least one first surfactant is present in an amount of 10% to 25% by weight, based on the total weight of the composition.

5. 3. The aqueous gel composition of claim 1, wherein the at least one second surfactant is present in an amount of from 6% to 20% by weight, based on the total weight of the composition.

6. 3. The aqueous gel composition of claim 1, wherein the at least one alcohol is present in an amount of from 6% to 20% by weight, based on the total weight of the composition.

7. the poloxamer is present in an amount of 14% to 16% by weight, based on the total weight of the composition; - the phospholipids are present in an amount of 6% to 10% by weight, based on the total weight of the composition; the propylene glycol is present in an amount of from 6% to 10% by weight, based on the total weight of the composition; The aqueous gel composition according to claim 1 or 2.

8. The aqueous gel composition of claim 1, wherein the at least one pharmaceutically active agent is present in an amount of 0.05% to 10% by weight based on the total weight of the composition.

9. 3. The aqueous gel composition of claim 1, wherein the at least one pharmaceutically active agent has an average particle size of from 5 μm to 80 μm.

10. The at least one pharmaceutically active agent has Formula I: (S)-3-(3,4-difluorophenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3-pentafluorosulfanylphenyl)-1-(2-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, (S)-3-(3,4-difluorophenyl)-1-(5-fluoro-2,3-dihydro-1H-inden-1-yl)-1-methylurea, and (S)-1-(5-chloro-2,3-dihydro-1-H-inden-1-yl)-1-methyl-3-(3-pentafluorosulfanylphenyl)urea, and mixtures of at least two of said pharmaceutically active agents, 3. The aqueous gel composition according to claim 1, wherein the aqueous gel composition is selected from the group consisting of:

11. The at least one pharmaceutically active agent has Formula II: (1R,2R,4S)-rel-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfanyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1S,2S,4R)-N-(3-(trifluoromethoxy)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, p-chloro-N-(4-trifluoromethoxy)benzyl)benzamide, p-chloro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-fluoro-N-(4-trifluoromethoxy)benzyl)benzamide, p-fluoro-N-(4-(pentafluorosulfanyl)benzyl)benzamide, p-chloro-N-(4-(trifluoromethyl)benzyl)benzamide, p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, and a mixture of at least two of said pharmaceutically active agents; 3. The aqueous gel composition according to claim 1, wherein the aqueous gel composition is selected from the group consisting of:

12. A pharmaceutical composition or drug comprising the aqueous gel composition of claim 1 or 2.

13. 13. An aqueous gel composition according to claim 1 or 2 for use in the prevention or treatment of an inner ear disease, or a pharmaceutical composition according to claim 12 for use in the prevention or treatment of an inner ear disease.

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