Non-aqueous gel composition

Abstract

The present invention discloses a non-aqueous gel composition useful for the administration of pharmaceutically active agents, particularly for transtympanic administration of pharmaceutically active agents, comprising: castor oil, present in an amount of 85-95% by weight based on the total weight of the composition; oleoyl macrogolglycerides, preferably Labrafil®, present in an amount of 2-6% by weight based on the total weight of the composition; and at least one thickening agent, preferably silicon dioxide, more preferably colloidal silicon dioxide, present in an amount of 1-6% by weight based on the total weight of the composition, wherein the viscosity of the composition at a temperature of −25° C. is 1400-2400 mPas, preferably 1400-1800 mPas.

Description

[Technical field]

[0001] Technical field and prior art The present invention relates to novel non-aqueous gel compositions, particularly useful as carriers for pharma- ceutical active agents. The present invention also relates to delivery devices comprising the non-aqueous gel compositions, and to the use of the non-aqueous gel compositions as components of pharmaceutical compositions or medicaments. [Background technology]

[0002] Due to their viscosity characteristics, gel compositions are often used as carriers for topical and oral application of medicamentously active agents.Important for the administration of gel compositions are, for example, specific viscosity characteristics that, on the one hand, allow sufficient syringeability, i.e., the ability to be dispensed and / or drawn from a syringe, and, on the other hand, allow good adhesion of the composition to organic tissues at or around body temperature, especially for a period of at least 3 days, preferably at least 5 days, after a single administration to organic tissues.

[0003] Therefore, thermoreversible aqueous gel compositions that change viscosity at a characteristic temperature, primarily comprising a copolymer in an amount sufficient to provide a gelling temperature at about body temperature, are often used.

[0004] However, despite their good viscosity properties, aqueous gel compositions exhibit the disadvantage that they are unable to carry pharmacologic active agents that have relatively poor water solubility properties if those pharmacologic active agents cannot be administered as a suspension in the gel.

[0005] Non-aqueous gel compositions offer a good alternative as carriers for said pharmacologic active agents that have relatively poor aqueous solubility properties. Moreover, due to their lipophilicity, non-aqueous gel compositions can provide the possibility for the pharmacologic active agents to at least partially cross cell membranes.

[0006] However, when it comes to viscosity properties that allow for good syringeability and good adhesion in organic tissue, conventional non-aqueous gel compositions lack their thermoreversible properties.

[0007] In particular, for administration of the gel composition in the internal organs, it is necessary to administer the pharmaceutical composition using a syringe. Moreover, internal organs such as the eyes, ears, nose, mouth, lips, vagina, urethral opening and anus are largely covered by mucus or mucous membranes that make adhesion (mucoadhesion) difficult.

[0008] As such, conventional non-aqueous gel compositions are unable to promote both suitable viscosity characteristics that would allow for good syringeability and good adhesion in organic tissue.

[0009] Thermoreversible aqueous gel compositions are known from EP 3501521 A1 and WO 2019210107. The corresponding compositions comprise a medicamentously active agent such as cisplatin, carboplatin, oxyplatin 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] US20180000950A1 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, for example WO2014076569A2 and EP0530965A1, which include non-aqueous thermoreversible gels for use in the treatment of various diseases.

[0012] EP0530965A1 describes a nasal application of a composition comprising at least one reproductive hormone drug, at least one lipophilic carrier and a surfactant, and further comprising a viscosity property adjusting agent, which is colloidal silicon dioxide.

[0013] US2013150410A1 describes a method of treating an ear disorder selected from the group consisting of Meniere's disease, endolymphatic hydrops, progressive hearing loss, dizziness, vertigo and tinnitus, comprising transtympanic administration into the ear of a sterile pharmaceutical composition comprising 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] US2019038469A1 claims a system for delivery of a therapeutic composition to the inner ear. Further, the system includes 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 delivery of the therapeutic composition and a distal tip for piercing the tympanic membrane for delivery of the therapeutic composition to the round window membrane such that the composition adheres to the round window membrane. Further, the composition includes a therapeutic agent for treating an inner ear disorder and a thixotropic material that allows the therapeutic composition to exist in a liquid state while being injected through the cannula.

[0015] It is an object of the present invention to provide a novel gel composition that has superior properties compared to conventional gel compositions. Summary of the Invention

[0016] The above and further objects are solved by a non-aqueous gel composition according to claim 1, a delivery device according to claim 9 and a non-aqueous gel composition for use in a pharmaceutical composition or medicament according to claim 10. Preferred embodiments are defined in the dependent claims. Preferably, but not necessarily, the non-aqueous gel composition, as defined in the dependent claims, is particularly suitable for transtympanic administration and comprises a pharma- ceutical active agent having relatively poor water solubility.

[0017] The present invention relates to a non-aqueous gel composition comprising: castor oil, present in an amount ranging from 85 to 95% by weight, based on the total weight of the composition, oleoyl macrogolglycerides, preferably Labrafil®, present in an amount ranging from 2 to 6% by weight based on the total weight of the composition, at least one thickening agent, preferably silicon dioxide, more preferably colloidal silicon dioxide, present in an amount ranging from 1 to 6% by weight, based on the total weight of the composition; and wherein The viscosity of the composition at a temperature of -25°C is 1400 to 2400 mPas, preferably 1400 to 1800 mPas. A non-aqueous gel composition is provided. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 graphically depicts in vitro dissolution data (US Paddle II apparatus, 37° C.) of non-aqueous gel compositions (described in Tables 4 and 5) containing 0.6% Compound B (initial, 3 months, and 6 months). [Diagram 2] FIG. 2 graphically depicts in vitro dissolution data (US Paddle II apparatus, 37° C.) of non-aqueous gel compositions (described in Tables 4 and 5) containing 6% Compound B (initial and 3 months). [Diagram 3] FIG. 3 illustrates a pharmacokinetic (pk) study of pharmacologic active agent levels in guinea pigs for non-aqueous gel compositions containing 6% Compound B (described in Tables 4 and 5). [Figure 4] FIG. 4 illustrates a schematic of pharmacologic active agent level testing (inner ear tissue, mean values) in guinea pigs using non-aqueous gel compositions containing 6% Compound B (described in Tables 4 and 5). [Diagram 5] FIG. 5 shows graphically an example of the particle size distribution (PSD) of a Compound B batch for use in a non-aqueous gel composition of the present invention (Master Sizer results). [Figure 6] FIG. 6 shows stability data for a non-aqueous gel composition containing 0.6% Compound B in a syringe stored at 2-8° C. for 6 months. [Figure 7]FIG. 7 shows stability data for non-aqueous gel compositions containing 0.6% Compound B in syringes stored at 25° C. / 60% rh (relative humidity) for 6 months. [Figure 8] FIG. 8 graphically illustrates the viscosity of non-aqueous gel compositions containing 0.6% and 6% Compound B with shear stress. [Figure 9] FIG. 9 graphically depicts the in vitro dissolution profile (US Paddle II apparatus, 37° C.) of a non-aqueous gel formulation containing 0.6% Compound B. [Figure 10] FIG. 10 shows diagrammatically the viscosity measurements of F1-F3, F5 and F6 (listed in the specification as V1, V2, V3, V5, V6) at 25° C. [Figure 11] FIG. 11 shows diagrammatically the viscosity measurements of F1-F3, F5 and F6 (listed in the specification as V1, V2, V3, V5, V6) at 37° C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] In this composition, the castor oil has the function of lipophilic carrier and the oleoyl macrogolglyceride, preferably Labrafil®, has the function of surfactant.

[0020] In a preferred embodiment of the present invention, the non-aqueous gel compositions of the present invention are sterile.

[0021] In another preferred embodiment of the present invention, the non-aqueous gel composition of the present invention is an oleogel.

[0022] Terms used in the claims and general description are defined as follows:

[0023] The term "non-aqueous composition" as used herein means a composition that is free of water or substantially free of water.

[0024] The term "oleogel" as used herein means a lipid, especially fat, based semi-solid non-aqueous gel composition having viscoelastic properties.

[0025] The term "lipophilic carrier", as used herein, means a substrate, preferably a lipophilic substrate, used in the process of delivery of a pharma- ceutical active compound, and which serves to improve the administration of various lipophilic pharma- ceutical active agents.

[0026] The term "surfactant" as used herein means a compound that reduces the surface tension between two liquids or between a liquid and a solid in a composition, and allows or assists in the formation of a dispersion and improves the wetting of the composition. The surfactant may also act as a cleaning agent, an emulsifier, and a foaming agent.

[0027] The term "thickener" as used herein means a substance that enhances the viscosity characteristics of a liquid composition without substantially altering its other performance. Preferably, the thickener acts as a gallant that forms a viscous internal structure, especially a gel, and is therefore also known as a gelling agent.

[0028] The term "part or structure of the ear" as used herein means the ear, in particular the middle ear, or a structure of the ear, in particular the round window structure of the ear, wherein said ear structure is part of said ear.

[0029] The term "transtympanic administration" as used herein refers to injection through the tympanic membrane into the middle ear for administration in the middle ear, particularly onto the round window membrane, to facilitate diffusion across the membrane.

[0030] The term "sustained release gel", as used herein, means a gel composition comprising at least one pharma- ceutical active compound, and which provides for a uniform, sustained and controlled release, particularly release, of the at least one pharma- ceutical active compound into the body, particularly the human body, and its tissues.

[0031] The term "multiparticulate," as used herein, means a plurality of particles of at least one pharma- ceutical active agent, where the particles are of the same size or of different sizes.

[0032] The term "micronized" as used herein means a substance, particularly a pharma- ceutical active agent, that has been reduced in size to particles measured in microns.

[0033] The term "sterile" as used herein means free from live pathogens or microorganisms, especially sterile.

[0034] The term "mucoadhesion" as used herein means adhesion in organic tissues that are largely covered by mucus or mucous membranes, such as the eyes, ears, nose, mouth, lips, vagina, urethral meatus and anus.

[0035] The term "thermoreversible gel" as used herein means a gel composition that changes its viscosity characteristics at a characteristic temperature. This thermal behavior includes that the gel's properties are not affected by repeated heating and cooling, and that the viscosity of the gel is reversible to its initial state.

[0036] In a preferred embodiment of the invention, the viscosity of the inventive non-aqueous gel composition at a temperature of 25° C. is between 1400 and 2300 mPas, more preferably between 1600 and 2000 mPas. Even more preferred is the last-mentioned viscosity range of 1700 to 1800 mPas.

[0037] According to the present invention, the viscosity of the nonaqueous gel composition of the present invention at a temperature of 37° C. is preferably 500 to 1200 mPas, more preferably 700 to 1000 mPas.

[0038] In contrast to conventional gel compositions, the non-aqueous gel compositions of the present invention have the advantage of providing a thermoreversible gel composition, which changes its viscosity at a characteristic temperature.

[0039] The thermoreversible viscosity properties provide a non-aqueous gel composition with a viscosity that makes it particularly useful for pharmaceutical compositions or medicaments for topical administration: a viscosity that is sufficient for syringeability, i.e., the ability to be dispensed from and / or drawn into a syringe, at (medical) room temperature of 15°C to 25°C, as well as a viscosity that allows good adhesion of the composition for topical administration in organic tissue, for example at about body temperature, typically 35°C to 38°C, after a single administration in organic tissue, in particular over a period of at least 3 days, preferably at least 5 days.

[0040] This is particularly advantageous for administration of gel compositions in internal organs, given both the need to administer the composition using a syringe and the need for good adhesion, especially good mucoadhesion.

[0041] The non-aqueous gel compositions of the present invention preferably comprise a viscosity and gel structure useful for application through a suitable needle diameter of 18 to 27 gauge (Birmingham gauge), more preferably 20 to 23 gauge, especially 20 gauge. The non-aqueous gel compositions of the present invention are also suitable for application in small volumes, for example, 20 μL to 200 μL, to the inner ear and / or middle ear.

[0042] According to the present invention, the viscosity is usually measured using a viscometer, in particular a rheometer. A rheometer is a laboratory tool that usually measures the flow properties of a liquid, suspension or slurry in response to an applied force. A common type of equipment is the so-called shear rheometer, in which a shear stress is applied to the corresponding material. The device used to measure the viscosity of the non-aqueous gel composition according to the present invention is a rheometer manufactured by Brookfield (AMETEK Brookfield).

[0043] In another embodiment of the present invention, the non-aqueous gel composition of the present invention is preferably free of polymers, including copolymers.

[0044] In another embodiment of the present invention, the castor oil of the non-aqueous gel composition of the present invention may comprise at least one further lipophilic carrier, preferably at least one glyceride ester, selected from the group comprising monoglyceride esters, diglyceride esters, triglyceride esters, and mixtures thereof, wherein preferably the glyceride ester is a triglyceride ester.

[0045] According to the invention, the at least one triglyceride ester comprises at least one unsaturated or saturated, preferably unsaturated, fatty acid, preferably having a chain length of 16 to 20 C atoms, preferably 18 C atoms.

[0046] In a preferred embodiment of the invention, the at least one fatty acid is preferably selected from the group comprising ricinoleic acid, oleic acid, stearic acid, linoleic acid, palmic acid.

[0047] In another preferred embodiment of the present invention, the at least one further lipophilic carrier preferably comprises a triglyceride ester comprising three unsaturated fatty acids with a fatty acid chain length containing 18 C atoms, wherein said fatty acid is ricinoleic acid.

[0048] According to the present invention, the at least one further lipophilic carrier comprising at least one glyceride ester is preferably selected from the group comprising almond oil, linseed oil, canola oil, corn oil, cottonseed oil, palm oil, peanut oil, poppy seed oil, soybean oil and mixtures thereof.

[0049] In a preferred embodiment of the present invention, the at least one further lipophilic carrier comprising at least one glyceride ester is selected from the group comprising natural oils, synthetic oils, semi-synthetic oils and mixtures thereof.

[0050] In another embodiment of the present invention, the oleoyl macrogolglycerides, preferably Labrafil®, of the non-aqueous gel composition of the present invention may comprise at least one further surfactant, preferably selected from the group comprising oleoyl macrogolglycerides, acylglycerols, lecithin, polyoxyethylene, polyoxyethylene sorbitan, polyglycerol, polyethylene glycol and mixtures thereof.

[0051] The surfactants described above, and in particular the oleoyl macrogol glycerides, are particularly useful in improving the wettability of the non-aqueous gel compositions of the present invention to ensure uniform distribution of hydrophobic particles, preferably hydrophobic pharma- ceutical active agent particles, in the compositions.

[0052] According to the present invention, the oleoyl macrogol glyceride is preferably Labrafil®, more preferably Labrafil® M 1944 CS. Labrafil® M 1944 CS is an oleoyl polyoxy-6-glyceride.

[0053] Labrafil® is a registered trademark of Gattefosse. The Labrafil® series includes Labrafil® M 1944 CS, Labrafil® M2125CS (linoleoyl polyoxyl-6 glyceride) and Labrafil® M2130CS (lauroyl polyoxyl-6 glyceride).

[0054] According to the present invention, the at least one thickening agent is preferably silicon dioxide, more preferably colloidal silicon dioxide.In another embodiment of the present invention, the at least one thickening agent is preferably selected from the group comprising stearates, colloidal silicon dioxide, mesoporous silicon dioxide and mixtures thereof.

[0055] The above thickening agents, in particular colloidal silicon dioxide, are particularly useful for improving the adhesive properties of the non-aqueous gel compositions of the present invention on organic tissue at about body temperature (usually 35-38° C.), especially after a single administration on the organic tissue, in particular over a period of at least 3 days, preferably at least 5 days.

[0056] In a preferred embodiment of the present invention, the at least one thickening agent is preferably colloidal silicon dioxide.

[0057] In another preferred embodiment of the present invention, at least one thickening agent is preferably not dissolved but dispersed in the non-aqueous gel composition of the present invention, resulting in a thixotropic gel structure and a non-aqueous gel composition that exhibits high viscosity over a period of time when a certain shear stress is applied to the composition.

[0058] The castor oil according to the present invention is present in the non-aqueous gel composition of the present invention in an amount of 85 to 95% by weight, preferably in an amount of 91 to 94% by weight, more preferably in an amount of 94% by weight, based on the total weight of the composition.

[0059] In a preferred embodiment, the at least one further lipophilic carrier is present in the castor oil in an amount of less than 5%.

[0060] According to the invention, the oleoyl macroglyceride, preferably Labrafil®, is present in the non-aqueous gel composition of the invention in an amount of 2-6% by weight, preferably 3.5% by weight, based on the total weight of the composition.

[0061] In a preferred embodiment, the at least one further surfactant is present in the oleoyl macroglyceride, preferably Labrafil®, in an amount of less than 5%.

[0062] It has been found that the amount of surfactant, especially oleoyl macroglyceride, preferably Labrafil®, in non-aqueous gel composition is important for ensuring good wettability, but does not negatively affect the adhesive properties of said non-aqueous gel composition.As mentioned above, it has been found that the amount of at least one surfactant, especially oleoyl macroglyceride, preferably Labrafil®, is particularly useful for ensuring good wettability and good adhesion of said non-aqueous gel composition.

[0063] According to the present invention, at least one further thickening agent, preferably silicon dioxide, more preferably colloidal silicon dioxide, is present in the non-aqueous gel composition of the present invention in an amount of 1 to 6% by weight, preferably in an amount of 2% by weight, based on the total weight of the composition.

[0064] The amount of at least one viscosity increasing agent, in particular colloidal silicon dioxide, contained in the non-aqueous gel composition of the present invention described above is particularly useful for providing sufficient syringeability of the composition at room temperature (see above).

[0065] The non-aqueous gel compositions of the present invention have been found to be particularly useful in providing sustained release in vivo of a therapeutically effective amount of a medicamentously active agent after a single administration in organic tissue, over a period of at least 3 days, preferably at least 5 days, preferably after administration in a visceral organ, in particular after transtympanic administration.

[0066] In accordance with the present invention, the non-aqueous gel compositions of the present invention preferably further comprise at least one pharma- ceutical active agent.

[0067] In one embodiment of the present invention, the non-aqueous gel composition of the present invention is preferably a sustained release gel, which comprises at least one pharma- ceutical active compound, and which provides a uniform, sustained and controlled release, particularly release, of the at least one pharma- ceutical active compound into the body, particularly the human body, particularly in organic tissue, over a period of at least 3 days, preferably at least 5 days, and more preferably at least 1 month, after a single administration.

[0068] According to the present invention, the at least one pharma- ceutical active agent is preferably present in an amount of 0.05-10% by weight, preferably 0.1-10% by weight, more preferably 0.5-5% by weight, more preferably 0.6% or 3% by weight, or alternatively 3-10% by weight, preferably 6-10% by weight, based on the total weight of the composition, including the active agent.

[0069] The amounts of at least one pharma- ceutical active agent described above have been found to be particularly useful in providing a sustained release gel that releases the pharma- ceutical active agent from the non-aqueous gel composition of the present invention over a period of at least 3 days, and preferably at least 5 days, following a single administration in organic tissue.

[0070] According to the present invention, it is preferred that the at least one pharma- ceutical active agent has an average particle size of 0.01 to 100 μm, preferably 5 to 80 μm, more preferably 20 to 50 μm.

[0071] The term "average particle size" as used herein means particles whose dimensions, in particular diameter, preferably average diameter, are in the range of 0.01 to 100 μm, preferably 5 to 80 μm, more preferably 20 to 50 μm. In this context, the term "diameter" shall be understood to mean, in the case of spherical particles, the diameter of a sphere, i.e. twice the radius of the sphere. In the case of non-spherical particles, the term "diameter" shall be understood to mean the longest possible distance between two points along the circumference of the particle.

[0072] The average particle size distribution is preferably obtained by laser diffraction. During laser diffraction measurement, a laser beam is passed through a dispersed particle sample and the angular change in the intensity of the scattered light is measured. Large particles scatter light at small angles to the laser beam and small particles scatter light at large angles. The angular scattering intensity data is then analyzed to calculate the size of the particles that produced the scattering pattern using the Mie theory of light scattering. Particle size is reported as the diameter of a sphere of equivalent volume. The folded optical design of the Mastersizer3000 (Malvern Panalytical) used specifically for this measurement provides a particle size measurement range from 10 nm up to 3.5 mm using a single optical measurement path. The Mastersizer3000 uses a combination of sequential measurements using red and blue light sources to measure across the entire particle size range.

[0073] The above-described average particle sizes of the at least one pharma- ceutical active agent have been found to be particularly useful for obtaining a uniform distribution of the at least one pharma- ceutical active agent in the non-aqueous gel composition.

[0074] In certain embodiments of the present invention, the desired particle size of the at least one pharma- ceutical active agent is preferably obtained by grinding, ball milling, high pressure homogenization, homogenization, micronization or a combination of at least two of the mentioned methods.

[0075] Furthermore, due to the particle size of the at least one pharma- ceutical active agent described above, the uptake of the at least one pharma- ceutical active agent from the composition of the present invention into the body after administration in organic tissue is particularly advantageous compared to other conventional gel compositions containing pharma- ceutical active agents.Due to the advantageous uptake of the pharma- ceutical active agent from the non-aqueous gel composition of the present invention into the body, a smaller amount of the pharma- ceutical active agent is required in the composition to achieve the same therapeutic effect as that of conventional gel compositions.

[0076] The term "uptake of a medicamentously active agent into the body", as used herein, means uptake of a medicamentously active agent into a mammalian body, particularly a human and / or animal body, and / or into the perilymph and / or endolymph of a mammalian body, particularly a human and / or animal body.

[0077] In one embodiment of the invention, the non-aqueous gel composition of the invention comprises a multiparticulate suspension of the pharma- ceutical active agent based on the concentration of the pharma- ceutical active agent.

[0078] In a preferred embodiment of the present invention, the non-aqueous gel compositions of the present invention preferably comprise a solution of a pharma- ceutical active agent.

[0079] According to the present invention, at least one pharma- ceutical active agent preferably has a (low) water solubility of <1 mg / mL, preferably <0.1 mg / mL at room temperature (22-26°C).

[0080] The poor solubility of a medicamentously active agent negatively affects the uptake of the medicamentously active agent into the body, especially after administration in the internal organs, for example after transtympanic administration, especially in the perilymph and / or endolymph of the body. As a result, the therapeutic effect could not be achieved by a single administration, but instead local depot formulations had to be developed that use the inherent poor solubility of the medicamentously active agent in a suitable gel composition to obtain sustained uptake of the medicamentously active agent over a desired time interval.

[0081] The non-aqueous gel composition of the present invention exhibits the advantage of being particularly useful for carrying pharmacologic active agents having (low) solubility as described above, especially for topical administration.Furthermore, the non-aqueous gel composition of the present invention can be administered to form a local depot to obtain sustained uptake of the pharmacologic active agent, especially after a single administration in organic tissue, for a period of at least 3 days, preferably at least 5 days.

[0082] In a preferred embodiment of the present invention, the at least one pharma- ceutical active agent is a Biopharmaceutic Classification System Class II (BCS Class II) substance, preferably comprising poor solubility and high permeability characteristics, wherein the classification is based on the Biopharmaceutic Classification (BCS) system.

[0083] The BCS system was introduced for a more thorough characterization of pharmacologic active agents with poor solubility. The BCS system distinguishes between four categories based on the solubility and permeability of pharmacologic active agents:

[0084] According to the present invention, at least one pharma- ceutical active agent has the following formula (I): [ka] {In the formula, -R is an unsubstituted cycloalkyl group, in particular a bicycloalkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted thienyl group, where the substituted thienyl or phenyl group is preferably substituted with at least one halogen, preferably selected from the group comprising at least one F, Cl, Br or I atom, more preferably at least one F atom or at least one Cl atom, and - R1 is F, SF5, CF3 or OCF3} It is preferred that the compound has the formula:

[0085] According to the present invention, at least one pharma- ceutical active agent is one of the following: (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-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or Racemic mixture (1SR,2SR,4RS)-N-(3-(pentafluoro-λ6-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluormethyl)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, and p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, It is preferably selected from the group comprising:

[0086] The above-listed medicamentously active agents belong to a group of compounds that preferably function as potassium channel openers, in particular as openers of the Kv7.4 potassium channel, and are therefore particularly useful for the treatment of disorders related to abnormal potassium activity, such as Alzheimer's disease and Parkinson's disease. Further disorders are neurological conditions such as epilepsy or cognitive psychiatric disorders, such as depression, mania and schizophrenia. In particular, it is known that potassium channels play an important role in the normal function of the outer hair cells (OHC) of the organ of Corti. Therefore, the above-listed medicamentously active agents are promising candidates for the treatment and / or prevention of hearing loss, for example before treatment with ototoxicity-inducing drugs.

[0087] The above mentioned pharma- ceutical 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-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, hereinafter referred to as compound B, show a (low) solubility in water of <1 mg / mL, preferably <0.1 mg / mL at room temperature (22-26° C.) and are therefore classified as BCS class II drug substances.

[0088] According to the present invention, non-aqueous gel compositions are preferred, wherein: the castor oil is present in an amount ranging from 85 to 95% by weight, based on the total weight of the composition; the oleoyl macrogolglycerides, preferably Labrafil®, are present in an amount ranging from 2 to 6% by weight based on the total weight of the composition; at least one thickening agent, preferably silicon dioxide, more preferably colloidal silicon dioxide, is present in an amount ranging from 1 to 6% by weight, based on the total weight of the composition; The viscosity of the composition at a temperature of -25°C is 1400 to 2400 mPas, preferably 1400 to 1800 mPas, and - at least one pharma- ceutical active agent is selected from the group consisting of: (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, the enantiomer (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, or Racemic mixture (1SR,2S,4R)-N-(3-(pentafluoro-λ6-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide, (1R,2R,4S)-rel-N-(3-(trifluormethyl)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, and p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, The compound is selected from the group consisting of:

[0089] The above mentioned compositions have been found to be particularly advantageous with respect to adhesion and viscosity properties, as well as uptake of pharma- ceutical active agents into the body from the non-aqueous gel compositions of the present invention, which provide sustained release of the compound over a period of at least 3 days, preferably at least 5 days, following a single administration in organic tissue.

[0090] The present invention further provides a delivery device, in particular a syringe, wherein said delivery device is filled with the non-aqueous gel composition as claimed and defined above.

[0091] In one embodiment of the invention, the delivery device is preferably connected to a needle suitable for transtympanic administration, which is suitable for applying small volumes of the non-aqueous gel composition of the invention, in particular for transtympanic administration, of 20 μL to 200 μL, preferably having a diameter of 18 to 27 gauge (Birmingham gauge), more preferably 20 to 23 gauge, in particular 20 gauge.

[0092] In another embodiment of the invention, the delivery device is preferably a CycloOlefinPolymer (COP) syringe, which presents the advantage of not running the risk of including any residual glass particles from the manufacturing process involved.

[0093] In another embodiment of the present invention, the discharge device preferably includes a stopper and a plunger.

[0094] Furthermore, the discharge device preferably includes a syringe holder, especially a plastic or cardboard syringe holder, which is particularly useful for avoiding any damage to the syringe during transport.

[0095] In a further embodiment of the invention, the delivery device, in particular a syringe, is preferably filled under aseptic conditions with a sterile, non-aqueous gel composition of the invention.

[0096] For further features and advantages of the delivery device, particularly with regard to non-aqueous gel compositions, reference is made generally to the above description.

[0097] Finally, the present invention provides a non-aqueous gel composition comprising at least one pharma- ceutical active agent as claimed and defined above, for use in a pharmaceutical composition or medicament, wherein preferably said use is for the prevention or treatment of an inner ear disease, and wherein preferably said non-aqueous gel composition is provided for transtympanic administration.

[0098] In certain embodiments of the present invention, the non-aqueous gel composition comprising at least one pharma- ceutical active agent is preferably administered via transtympanic administration, which provides sustained release of the pharma- ceutical active agent into the ear, preferably into the inner ear, over a period of at least 3 days, preferably at least 5 days, particularly after a single administration.Due to the viscosity described above, the non-aqueous gel composition of the present invention is particularly useful for sustained release of pharma- ceutical active agents, particularly for transtympanic administration, for the treatment of otic disorders, including, but not limited to, induced hearing loss and drug-induced ototoxicity.

[0099] In addition, advantageously, the non-aqueous gel composition of the present invention exhibits a well-adjusted viscosity and gel structure, particularly suitable for administration as drops. Following transtympanic administration, the composition preferably adheres to the round window membrane or adjuvant mucus, particularly in the form of drops, so that it is not removed from the middle ear and / or the round window membrane, and thus provides a sustained release of the medicamentously active agent for a period of at least 3 days, preferably at least 5 days, after a single administration in the organic tissue, thereby avoiding frequent transtympanic administration into the ear of the patient.

[0100] For further features and advantages of use, particularly with respect to non-aqueous gel compositions, reference is made in general to the above description.

[0101] Further features and advantages of the present invention will become apparent from the following examples in conjunction with the subject matter of the dependent claims. The individual features may be realized either alone or in combination in one embodiment of the present invention. The preferred embodiments are merely useful for illustrating and better understanding the present invention and should not be understood as limiting the present invention in any way. EXAMPLES

[0102] Laboratory scale testing: As the pharma- ceutical active agent, (1SR,2SR,4RS)-N-(3-(pentafluoro-λ6-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (Compound A) or (1S,2S,4R)-N-(3-(pentafluoro-λ6-sulfaneyl)benzyl)bicyclo[2.2.1]heptane-2-carboxamide (Compound B) were used in the study.

[0103] The pharma- ceutical active agent is ground with a mortar / pestle system to an appropriate particle size prior to its use.

[0104] The milled pharma- ceutical active agent is then vigorously mixed with the surfactant to obtain nearly completely hydrated pharma- ceutical active agent particles. The mixing is carried out in a double-jacketed glass reactor. The pre-heated (at about 50°C) lipophilic carrier is then added stepwise under vigorous mixing. The suspension is stirred for an appropriate time to ensure homogeneous suspension of the pharma- ceutical active agent. Finally, the thickener is carefully added under stirring at about 50°C until it is completely dispersed and the non-aqueous gel composition is formed. The final non-aqueous gel composition is placed in a glass bottle and the entrapped air bubbles are removed under reduced pressure (initially about 150-80 mbar, then about 18-20 mbar). If filling is performed, the final non-aqueous gel composition is filled into an appropriate size (e.g., 0.5, 1.0, 2.25, 3.0 ml) transparent, e.g., Luer-lock CycloOlefinPolymer or CycloOlefinCopolymer (COP or COC) syringe or I-type glass syringe, using a filling system, and finally, a stopper is placed on the non-aqueous gel composition to close the syringe. The syringe is stored horizontally or vertically under appropriate conditions (e.g., at 2-8°C or ≦25°C) until use.

[0105] Pilot scale testing under sterile conditions: All manipulations must be performed in a sterile environment via an isolator system. Sterile starting materials must be prepared before the process begins. Additionally, samples for bioburden must be taken prior to sterilization of the material.

[0106] The additive Labrafil® M 1944 CS and refined castor oil are sterilized in-line by sterile filtration using two filter capsules each. A polyethersulfone (PES) membrane consisting of one layer with 0.65 μm and 0.2 μm was found to be optimal, but other membranes may be used as well. Filter integrity tests are performed before and after filtration. Each individual filter is tested. An integrity test before sterile filtration is performed with the membrane wetted with water. The water is removed before performing the sterile filtration. An appropriate pre-flow of sterile filtration material is discarded.

[0107] When the sterile filtration is complete, another membrane integrity test is performed.

[0108] To facilitate filtration, the castor oil and Labrafil® M 1944 CS are preheated to approximately 50-55° C. Filtration should be performed immediately before production begins.

[0109] Depending on the concentration of the active pharmaceutical ingredient in the oleogel, the active pharmaceutical ingredient (API) was added to a mixture of castor oil and Labrafil® M 1944 CS and sterile filtered. If the concentration of the API exceeds the solubilization limit of the oleogel, the castor oil and Labrafil® M 1944 CS must be sterile filtered separately and the API must be gamma irradiated before being added to the sterile filtered mixture of castor oil and Labrafil® M 1944 CS in a sterile environment.

[0110] Silicon dioxide is an insoluble solid that must be gamma irradiated to obtain its sterility prior to manufacturing. Active pharmaceutical ingredients can only be gamma irradiated at high, solubility limit concentrations. The amount required for batch production is pre-weighed to the exact mass required for the current batch size and then gamma irradiated. The container with the irradiated material is stored until production begins.

[0111] In the case of a solution of an active pharmaceutical ingredient in an oily matrix, the following manufacturing steps apply: The preparation of the oleogel is carried out in a double jacketed glass reactor. In the first step, Labrafil® M 1944 CS and castor oil are premixed at about 50-55° C. and the active pharmaceutical ingredient is dissolved in the mixture. The mixture is then sterile filtered into a jacketed glass reactor (solution 1). The reactor is preheated to about 50-55° C.

[0112] Dispersion of sterile silicon dioxide must be performed quickly to avoid high viscosity of the dispersion before all the silicon dioxide is watered. After the entire amount of silicon dioxide is dispersed in solution 1, homogenization of the composition is completed using Ultra-Turrax and further mixed.

[0113] The removal of the trapped air, which is carried out in situ in the glass reactor, is then carried out by applying a reduced pressure (about 25 mbar) for a specific period of time after connection to a suitable vacuum pump and separation of the reactor with a sterile air filter, which must be carried out with a careful control of the rise of the bubbles in order to avoid a delay in boiling.

[0114] Finally, the glass reactor is connected to a suitable filling pump. Filling of the syringes is carried out and finally stoppering is carried out. The syringes are placed back into their nests and removed from the isolator.

[0115] The syringe is labeled with a clear label with two markings that confirm precise application of the intended small volume (eg, 100 μl).

[0116] Examples of Non-Aqueous Gel Compositions Several laboratory scale batches were prepared according to the general procedure described above with and without the addition of pharma- ceutical active agents. Tables 1-3 below provide an overview of some relevant batches:

[0117] [Table 1]

[0118] [Table 2]

[0119] [Table 3]

[0120] Capmul® is an acylglycerol. Capmul® GMO50 is glycerol monooleate. Capmul® is a registered trademark of ABITEC. The Capmul® series includes Capmul® GMO50, Capmul® 708G (glyceryl monocaprylate), Capmul® MCM (medium chain, mono- and diglycerides) and Capmul® MCM C8 (glyceryl monocaprylate), Capmul® PG-8 (propylene glycol monocaprylate), Capmul® PG-12 (propylene glycol monolaurate), Capmul® PG-2L (propylene glycol dilaurate), and Capmul® S12L (sodium lauroyl lactylate).

[0121] SILSOL® is 6035 mesoporous silicon dioxide and is a product of WR Grace & Co.-Conn.

[0122] In another embodiment, laboratory scale batches with final selected compositions were produced as described above. As representative examples, two batches are described:

[0123] Lab Scale Batch A Batch size: approx. 250g Concentration: 0.6% active ingredient compound B Composition (Table 4)

[0124] [Table 4]

[0125] Laboratory Scale Batch B Batch size: approx. 250g Concentration: 6.0% active ingredient compound B Composition (Table 5)

[0126] [Table 5]

[0127] Pilot scale batches under sterile conditions were manufactured as described above. By way of example, two representative batches are described: Pilot Scale Batch A Batch size: approx. 2200g Concentration: 0.6% active ingredient compound B Composition (Table 6)

[0128] [Table 6]

[0129] Pilot Scale Batch B Batch size: approx. 2200g Concentration: 6.0% active ingredient compound B Composition (Table 7)

[0130] [Table 7]

[0131] Fluid dynamics and needle penetration measurements Viscosity is measured using a Brookfield RST Cone Plate Rheometer. A shear rate of 500 1 / s with constant rotation can be used. The preferred measurement time is 120 seconds. Measurement temperatures of 25°C and 37°C are used.

[0132] For sample preparation and measurement, the rheometer is preheated to the desired measurement temperature by a thermostat. The sample (0.6 ml) is then dropped onto the sample plate by means of a graduated pipette, an Eppendorf Pipette or a suitable syringe to achieve complete filling of the measurement gap of the rheometer. After removing excess sample material, the sample is also preheated to the desired temperature and measured.

[0133] In a further embodiment, some of the formulation batches listed above were tested for adhesion properties, viscosity and syringeability:

[0134] [Table 8]

[0135] The relative viscosity values ​​of F1 to F6 are as follows: [Table 9]

[0136] In another embodiment, a non-aqueous gel composition containing, inter alia, castor oil, oleoyl macrogol glycerides (Labrafil® M 1944 CS) and silicon dioxide (Aerosil 200PH, also known as Aerosil® Pharma, product of Evonik Operations GmbH) was subjected to syringeability and adhesion tests:

[0137] [Table 10]

[0138] Particle size distribution (PSD) of non-aqueous gel compositions containing Compound B In some embodiments, the PSD (particle size distribution) of the pharma- ceutical active agent was measured using a Malvern MasterSizer 2000 or 3000 (water as dispersion medium, stirrer speed 1500 rpm, Mie presentation) with the following results (Table 11). The PSD of the active ingredient remained unchanged in the non-aqueous gel composition. A portion of the milled batch is reported with the full PSD profile in Figure 5:

[0139] [Table 11-1]

[0140] Several laboratory scale batches are prepared according to the general procedure described above with or without the addition of oleoyl macrogol glyceride Labrafil® and with or without the addition of pharma- ceutical active agents (APIs). Tables 11a and 11b below provide an overview of several relevant batches. Tables 11a and 11b show that Labrafil® in the non-aqueous gel compositions of the present invention has the advantage over Capmul®, resulting in compositions with better syringeability and better flow-out tendency.

[0141] Batches F6, F2, F7b and 6 containing Labrafil® provide compositions with light or moderate resistance during application with a 23G needle (at about 25° C.), and therefore are easy to dispense from and / or draw into a syringe. In comparison, batches F7a, F10aI, F8b and 7 containing Capmul® provide compositions with no resistance during application with a 23G needle (at about 25° C.), and therefore are less suitable for application during use, as they drip out of the syringe without applying high pressure to the syringe.

[0142] Similar results were obtained when testing the run-off tendency of droplets in an adhesion test that simulates the adhesion of the composition on organic tissue.Batches F6, F2, F7b and 6 containing Labrafil® provide compositions with low run-off tendency, and therefore are suitable for adhesion to organic tissue.Batches F7a, F10a, F8b and 7 containing Capmul® provide compositions with high or moderate run-off tendency, and therefore are less suitable for adhesion to organic tissue, especially after a single administration, over a period of at least 3 days.

[0143] For the adhesion test, a drop of each composition was placed on a Petri dish, which was then placed vertically to check the possible run-off effect of the drop, and then a further drop was placed on a Petri dish filled with water to check the possible peeling effect of the drop.

[0144] [Table 11-2]

[0145] [Table 11-3]

[0146] sterile The following conditions were used for the silicon dioxide: origin: 60 Co Packaging: Amber glass bottles or HDPE (High Density Poly Ethylene) bottles with X-ray radiation resistant caps were packed in dry ice. Exposure dose: 25-50kGy (standard range)

[0147] PES filters were used for the sterile filtration of castor oil and Labrafil® or castor oil / Labrafil mixtures. ISO 5 class certified isolators were used for the sterile environment. Sterility of silicon dioxide and final product was verified using validated Ph.Eur (European Pharmacopoeia) methods.

[0148] Impurity profile of active ingredient before and after gamma irradiation In some embodiments, the impurity profile of Compound B was investigated by HPLC before and after gamma irradiation, and it was demonstrated that gamma irradiation (standard conditions) had only a small effect on the quality of the active ingredient when dry ice was used for cooling.

[0149] [Table 12]

[0150] Dissolution Profile In a further embodiment, in vitro dissolution was tested using a Sotax T7 Smart US Paddle System at 100 rpm at 37° C. in pH 7.4 (Phosphate Buffered Saline (PBS)) with 3% sodium dodecyl sulfate (SDS). Defined amounts of various non-aqueous gel compositions were spread evenly on a watch glass (8 cm diameter) and the watch glass was placed at the bottom of the dissolution vessel. Results are reported representatively in Figures 1, 2 and 9 or tabulated below for stability samples.

[0151] stability In another embodiment, the stability of the non-aqueous gel compositions of the present invention was investigated. Results are reported representatively for the 0.6% non-aqueous gel composition formulations set forth in Tables 4 and 5. The results shown demonstrate excellent stability over the study interval at 2-8° C. and 25° C. / 60% relative humidity.

[0152] Pharmacokinetic profile Guinea pig testing Applicable Applied transtympanically as a single dose of 100 μL Animal specifications Species: Dunkin Hartley Guinea Pig Gender: Female Experimental groups and doses Groups: 3 per time point Dose: 100 μL of 0.6% non-aqueous gel composition (as described in Tables 4 and 5) or 100 μL of 6% non-aqueous gel composition (as described in Tables 4 and 5) / animal / ear

[0153] For a better understanding of what is disclosed, some drawings are attached, which show, diagrammatically or illustratively, or merely non-limiting examples, practical cases of embodiments of the invention.

[0154] FIG. 1 graphically depicts in vitro dissolution data (US Paddle II apparatus, 37° C.) of non-aqueous gel compositions (described in Tables 4 and 5) containing 0.6% Compound B (initial, 3 months, and 6 months).

[0155] FIG. 2 graphically depicts in vitro dissolution data (US Paddle II apparatus, 37° C.) of non-aqueous gel compositions (described in Tables 4 and 5) containing 6% Compound B (initial and 3 months).

[0156] FIG. 3 illustrates a pharmacokinetic (pk) study of pharmacologic active agent levels in guinea pigs for non-aqueous gel compositions containing 6% Compound B (described in Tables 4 and 5).

[0157] FIG. 4 illustrates a schematic of pharmacologic active agent level testing (inner ear tissue, mean values) in guinea pigs using non-aqueous gel compositions containing 6% Compound B (described in Tables 4 and 5).

[0158] FIG. 5 shows graphically an example of the particle size distribution (PSD) of a Compound B batch for use in a non-aqueous gel composition of the present invention (Master Sizer results).

[0159] FIG. 6 shows stability data for a non-aqueous gel composition containing 0.6% Compound B in a syringe stored at 2-8° C. for 6 months.

[0160] FIG. 7 shows stability data for non-aqueous gel compositions containing 0.6% Compound B in syringes stored at 25° C. / 60% rh (relative humidity) for 6 months.

[0161] FIG. 8 graphically illustrates the viscosity of non-aqueous gel compositions containing 0.6% and 6% Compound B with shear stress.

[0162] FIG. 9 graphically depicts the in vitro dissolution profile (US Paddle II apparatus, 37° C.) of a non-aqueous gel formulation containing 0.6% Compound B.

[0163] FIG. 10 shows diagrammatically the viscosity measurements of F1-F3, F5 and F6 (listed in the specification as V1, V2, V3, V5, V6) at 25° C.

[0164] FIG. 11 shows diagrammatically the viscosity measurements of F1-F3, F5 and F6 (listed in the specification as V1, V2, V3, V5, V6) at 37° C.

[0165] Figure 1 is explained as follows: Figure 1 demonstrates consistent release profiles of non-aqueous gel compositions containing 0.6% Compound B over 22 hours at 37°C by US Paddle II method after storage at 2-8°C and 25°C / 60r.h. over 1 month (1M) and 3 months (3M). Mean values ​​alone and n=3 are presented compared to the initial release profile (MWt0).

[0166] "Released API" means "released active pharmaceutical ingredient."

[0167] FIG. 2 is explained as follows: FIG. 2 demonstrates the effect of heat treatment at 50° C. for 2 hours followed by ultrasonic (US) treatment for 15 minutes (with possible rehomogenization) on a non-aqueous gel composition containing 6% compound B stored at 2-8° C. for a period of 3 months (3M) as well as the impact on the dissolution profile at 37° C. by US-paddle apparatus compared to the initial release profile (MWt0).

[0168] FIG. 3 is described as follows: FIG. 3 shows pk testing of guinea pig tissue and perilymph concentration levels of pharmacologic active agent in ng / ml for a non-aqueous gel composition containing 6% Compound B, demonstrating sustained release efficacy over a period of >150 hours.

[0169] FIG. 4 is interpreted as follows: FIG. 4 shows PK studies of guinea pig tissues and perilymph of non-aqueous gel compositions containing an average of 6% Compound B at concentration levels of pharmacologic active agent in nM units, demonstrating sustained release effects over a period of >150 hours.

[0170] FIG. 5 is explained as follows: FIG. 5 shows diagrammatically examples of particle size distributions (PSD) (MasterSizer results) of Compound B batches used in the non-aqueous gel compositions of the present invention, with reported d10 values ​​of 4.4 or 6.5 microns, d50 values ​​of 18 or 32 microns, respectively, and d90 values ​​of 44 or 72 microns, respectively, for hand-ground samples (top and middle examples), and d10 values ​​of 3.4 microns, d50 values ​​of 12.4 microns, and d90 values ​​of 26.3 microns for micronized samples using a jet mill for micronized samples (bottom examples).

[0171] FIG. 6 is interpreted as follows: FIG. 6 shows the stability data of a non-aqueous gel composition containing 0.6% Compound B in a syringe stored at 2-8° C. for 6 months and analyzed for the indicated parameters, assay (by HPLC), viscosity, degradation (by HPLC) and dissolution at 37° C. (US Paddle Type II), demonstrating good stability of the non-aqueous gel over the period studied.

[0172] FIG. 7 is interpreted as follows: FIG. 7 shows the stability data of a non-aqueous gel composition containing 0.6% Compound B in a syringe stored at 25° C. / 60% rh for 6 months and analyzed for the indicated parameters, assay (by HPLC), viscosity, degradation (by HPLC) and dissolution at 37° C. (US Paddle Type II), demonstrating good stability of the non-aqueous gel over the studied period.

[0173] FIG. 8 is explained as follows: FIG. 8 (top graph) illustrates the viscosity of a non-aqueous gel composition containing 0.6% Compound B at temperatures between 20° C. and 25° C. with shear stress and demonstrates that the stress increase and stress decrease curves are nearly identical, thus demonstrating that the viscosity decreases from an initial value of about 2100-2200 mPa*s to a steady state level of about 1500-1600 mPa*s with increasing shear rate (stress) as is typical of a thixotropic medium and reversible effects.

[0174] FIG. 8 (lower trace) illustrates the viscosity of a non-aqueous gel composition containing 6% Compound B at temperatures between 20° C. and 25° C. with shear stress and demonstrates that from an initial value of about 71,500 mPa*s, the viscosity decreases to a steady state level of about 1,500 mPa*s with increasing shear rate (stress) as is typical of a thixotropic medium, but maintains the shear effect over an extended period of time and remains at a low viscosity level (due to the high loading of Compound B) as the shear rate is reduced.

[0175] FIG. 9 is described as follows: FIG. 9 illustrates the in vitro dissolution profiles (US Paddle II apparatus, 37° C.) of two non-aqueous gel formulations containing 0.6% Compound B, as well as the effect of varying the surfactant in the composition on the release profile (see Tables 1 and 2; V5 is identical to F5 and V9e is identical to F9e as the original batch).

[0176] Figure 10 is explained as follows: Figure 10 shows diagrammatically the viscosity measurements of F1, F2, F3, F5 and F6 (listed in the specification as V1, V2, V3, V5 and V6) of Table 1 at 25°C. The compositions of F1, F2, F3, F5 and F6 are identical to V1, V2, V3, V5 and V6. The modified allocations in this figure relate to new experiments. The graph shows the dependency of the viscosity increase on the composition of the non-aqueous gels.

[0177] Consistent with previous statements, viscosity measurements were performed using a Brookfield RST-CPS (Cone Plate) rheometer at a temperature of 25° C. A shear rate of 500 1 / s was used.

[0178] Figure 11 is explained as follows: Figure 11 shows diagrammatically the viscosity measurements of F1, F2, F3, F5 and F6 (listed in the specification as V1, V2, V3, V5 and V6) at 37°C. The compositions of F1, F2, F3, F5 and F6 are identical to V1, V2, V3, V5 and V6. The modified assignments in this figure relate to new experiments. The graph shows the dependency of the viscosity increase on the composition of the non-aqueous gels. The same equipment and conditions (but at 37°C) were used as previously described in Figure 10.

Claims

1. A non-aqueous gel composition for transtympanic administration, comprising: castor oil, present in an amount ranging from 85 to 95% by weight, based on the total weight of the composition, oleoyl polyoxy-6-glycerides, present in an amount ranging from 2 to 6% by weight based on the total weight of the composition, at least one thickening agent, present in an amount ranging from 1 to 6% by weight, based on the total weight of the composition, and wherein The viscosity of the composition at a temperature of -25°C is 1400 to 2400 mPas; the non-aqueous gel composition further comprises at least one pharma- ceutical active agent having an average particle size of 0.01 to 100 μm; The at least one pharma- ceutical active agent has the following formula (I): 【Chemistry 1】 {During the ceremony, -R is an unsubstituted cycloalkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted thienyl group, wherein the substituted thienyl group or phenyl group is substituted with at least one halogen; and - R 1 is F, SF 5 , CF 3 or OCF 3 . having Non-aqueous gel compositions.

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

3. 3. The non-aqueous gel composition of claim 1 or 2, wherein the at least one pharma- ceutical active agent has an average particle size of 5 to 80 μm.

4. 4. The non-aqueous gel composition according to any one of claims 1 to 3, wherein the at least one pharma- ceutical active agent has a (low) water solubility of < 1 mg / mL at room temperature.

5. The at least one pharma- ceutical active agent is selected from the group consisting of: (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-(trifluormethyl)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, and p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, The non-aqueous gel composition according to any one of claims 1 to 4, selected from the group comprising:

6. 6. The non-aqueous gel composition of claim 5, comprising: - castor oil is present in an amount ranging from 85 to 95% by weight, based on the total weight of the composition; - oleoyl polyoxy-6-glycerides are present in an amount of 2 to 6% by weight based on the total weight of the composition, at least one thickening agent is present in an amount of 1 to 6% by weight, based on the total weight of the composition; The viscosity of the composition at a temperature of -25°C is 1400 to 2400 mPas; and - said non-aqueous gel composition further comprises at least one pharma- ceutically active agent having an average particle size of 0.01 to 100 μm; at least one pharma- ceutical active agent is (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-(trifluormethyl)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, and p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, A non-aqueous gel composition selected from the group comprising:

7. 6. The non-aqueous gel composition of claim 5, comprising: castor oil, present in an amount ranging from 85 to 95% by weight, based on the total weight of the composition, oleoyl polyoxy-6-glycerides, present in an amount ranging from 2 to 6% by weight based on the total weight of the composition, at least one thickening agent, present in an amount ranging from 1 to 6% by weight, based on the total weight of the composition, at least one pharma- ceutically active agent having a mean particle size between 0.01 and 100 μm, -below: (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-(trifluormethyl)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, and p-fluoro-N-(4-(trifluoromethyl)benzyl)benzamide, at least one pharma- ceutically active agent selected from the group comprising: where: The viscosity of the composition at a temperature of -25°C is 1400 to 2400 mPas; Non-aqueous gel compositions.

8. A delivery device filled with the non-aqueous gel composition according to any one of claims 1 to 7.

9. 6. The non-aqueous gel composition according to any one of claims 1 to 5 for use as a pharmaceutical composition or medicament, wherein said use is for the prevention or treatment of an inner ear disease.

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