Oral aqueous suspension formulations comprising carbamate compound and uses thereof

Abstract

This disclosure relates to an aqueous formulation comprising a carbamate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, poloxamer, and an aqueous carrier, wherein the aqueous formulation is in the form of a suspension.

Description

[Technical Field]

[0001] This disclosure relates to a pharmaceutical composition and a method of using the pharmaceutical composition, and particularly to an aqueous preparation comprising a carbamate compound represented by Formula 1 or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and poloxamer:

[0001]

[0001] Among them,

[0001] R1, R2, A1 and A2 are as defined herein. [Previous Technology]

[0002] PCT Publications WO 2006 / 112685 A1, WO 2010 / 150946 A1 and WO 2011 / 046380 A2 describe carbamic acid compounds of Formula 1 and methods for their preparation, and the disclosures of the aforementioned patent documents are incorporated herein by reference. In one specific example, the carbamic acid compound of Formula 1 is carbamic acid(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester having the chemical structure of Formula 2:

[0002]

[0003] It is known that the carbamate compound of Formula 1 is an effective anticonvulsant for central nervous system diseases.

[0004] Formulations containing these compounds are suitable for repeated administration over a longer period of treatment to ensure a uniform concentration of the active ingredient in the blood. However, solid oral dosage forms such as capsules or tablets are typically prepared for adults who can easily swallow large tablets. Therefore, there is a need to develop a formulation that can be easily administered to patients who have difficulty swallowing capsules or tablets (e.g., pediatric patients) and adults who have difficulty swallowing and using them through the digestive tract.

[0005] Tablets and capsules are preferred dosage forms due to their ease of preparation into solid dosage forms. Currently, FDA-approved cenobamate (the carbamate compound discussed here) products are in solid dosage forms, i.e., tablets. An unmet need is for suitable oral liquid cenobamate formulations as an additional treatment option, primarily for children and the elderly. Liquid dosage forms present greater challenges due to the solubility and stability of solutions with various excipients and solvents, as well as the physical stability of oral suspensions. This disclosure partially addresses the physical stability issues of oral suspensions. Liquid dosage forms also present challenges in screening suitable sweeteners and flavorings to make the formulation more palatable to the target population. These properties are intended to improve patient compliance. Specific combinations of sweeteners, flavorings, and bitterness masking agents need to be selected through taste testing of various combinations to address the bitterness issue of the compound. Appropriate preservatives are required for this formulation, as its aqueous properties are within acceptable limits for pediatric populations. Furthermore, the buffering system should exhibit an optimal pH to ensure the effectiveness of the preservatives while also contributing to the overall stability of the formulation. Therefore, in various embodiments, this disclosure provides an oral aqueous suspension formulation comprising an aminocarbamate compound of formula 1 or 2 as an active ingredient, wherein the formulation has controllable and optimal solubility to suspend insoluble particles in an aqueous buffer system, and the active ingredient has excellent storage stability. The potential for crystal growth and bitterness due to supersaturated solubility is intended to be overcome through specific formulation strategies.

[0006] This disclosure provides an aqueous formulation comprising a carbamate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, a solvate or hydrate, poloxamer, and an aqueous carrier:

[0006]

[0006] Among them,

[0006] R1 and R2 are each independently selected from the group consisting of -H, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy; and

[0006] One of A1 and A2 is CH, and the other is N.

[0006] The aqueous preparation is in the form of a suspension preparation.

[0007] This disclosure also provides an aqueous formulation comprising a carbamate compound of formula 1 or a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, smectite clay and an aqueous carrier, wherein the aqueous formulation is in the form of a suspension.

[0008] This disclosure also provides an aqueous preparation described herein as an antispasmodic agent.

[0009] According to one embodiment, the aqueous preparation is used to treat central nervous system disorders, such as anxiety, depression, convulsions, epilepsy, migraine, bipolar disorder, drug abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration and / or muscle spasms.

[0010] The aqueous suspending agent disclosed herein can uniformly disperse and suspend active compounds in a structured carrier, exhibiting good physical and chemical stability during storage. The structured carrier can be configured to provide a system of aqueous buffers, surfactants, and / or one or more viscosity modifiers to control the viscosity, pH value, and / or particle size of the active compounds in the formulation. In some embodiments, the formulation may selectively use a suitable combination of sweeteners, bitterness masking agents, and / or flavoring agents to address bitterness associated with the active compounds. In some embodiments, the formulation includes a preservative proven by suitable antimicrobial efficacy testing at a concentration of up to 75% and 85% as required, exhibiting antimicrobial effects in the formulation.

[0011] In certain embodiments, poloxamer is included in the suspension formulation along with the active compound, making it usable over a wide pH range even at low concentrations. In some embodiments, bentonite exhibits synergistic effects with cellulosic viscosity modifiers or xanthan gum on the redispersibility / suspension of the suspension formulation. [Simplified Explanation of the Diagram]

[0012] Figure 1 shows images of the sedimentation patterns of senosides containing different concentrations of poloxamer 188 in phosphate buffer.

[0013] Figure 2 shows an image of the sedimentation pattern of senoside ester containing 0.1 mg / mL poloxamer 188 in citrate buffer.

[0014] Figure 3 is a PSD histogram of Formulation I stored at 40°C / 75%RH for 6 months in an upright manner.

[0015] Figure 4 is a PSD histogram of Formulation II stored at 40°C / 75%RH for 6 months in an inverted manner.

[0016] Figure 5 shows the XRD results of formulation I at T=0.

[0017] Figure 6 shows the XRD results of Formulation I stored at 40°C / 75%RH for 6 months in an upright manner.

[0018] Figure 7 shows the XRD results of formulation II at T=0.

[0019] Figure 8 shows the superimposed XRD results of Formulation II in an inverted manner at T=0 and under storage conditions of 40°C / 75%RH for 6 months.

Implementation Method

[0020] The contents of this disclosure will be detailed below.

[0021] Oral suspensions can be selected as a formulation alternative to oral liquids. The advantage of oral suspensions is that the active ingredient is in particulate form and the use of a solubilizer will not cause it to dissolve beyond its saturation solubility; therefore, compared to solutions, the active ingredient has less potential for crystal growth. The dosage form requires less active ingredient in a dissolved state, thus helping to reduce bitterness.

[0022] This disclosure provides an aqueous formulation comprising a carbamate compound of formula 1 as an active ingredient, or a pharmaceutically acceptable salt, solvate or hydrate thereof, poloxamer, and an aqueous carrier:

[0022]

[0022] Among them,

[0022] R1 and R2 are each independently selected from the group consisting of -H, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy;

[0022] One of A1 and A2 is CH, and the other is N.

[0022] The aqueous formulation is in the form of a suspension. In one embodiment, the aqueous formulation is for oral administration.

[0023] In one embodiment, in Formula 1, R1 and R2 are each independently selected from the group consisting of -H, halogens and C1-C8 alkyl groups.

[0024] In one embodiment, the halogenated C1-C8 alkyl group is a perfluoroalkyl group.

[0025] In one embodiment, the carbamate compound of Formula 1 is carbamate (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of Formula 2:

[0025]

[0026] The aminocarbamate (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of Formula 2, senoside, is an antiepileptic drug used to treat partial seizures. It is known to reduce neuronal excitability by blocking the inactive state of electrically gated sodium ion channels and to increase the inhibitory effect of the γ-aminobutyric acid (GABA) system by enhancing the presynaptic release of GABA.

[0027] The terms "compound" or "active ingredient" are used to encompass not only the compound itself, but also its isomers, or pharmaceutically acceptable salts, solvates, and hydrates thereof. Therefore, as used herein, a carbamate compound of Formula 1 refers not only to the compound itself, but also to its isomers or pharmaceutically acceptable salts, solvates, or hydrates thereof. Similarly, as used herein, a carbamate compound of Formula 2 refers not only to (R)-1-(2-chlorophenyl)-2-tetrazol-2-ethyl carbamate, but also to its isomers, or pharmaceutically acceptable salts, solvates, or hydrates thereof.

[0028] Examples of pharmaceutically acceptable salts of carbamate compounds of Formula 1 independently include acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoloyl arsanilate, hexylresorcinate, and hydravamine. Hydrobromide, hydrochloric acid, bicarbonate, hydroxynaphthoate, iodide, isethionate, lactic acid, lactobionic acid, malic acid, maleic acid, mandelate, methanesulfonate, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / bisphosphonate, polygalacturonate, salicylate, stearate, hypoacetate, succinate, hemisuccinate, sulfate or hemisulfate, tannate, tartrate, oxalate or hemitartrate, teoclate, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium, and zinc.

[0029] Those skilled in the art of compound synthesis can prepare carbamate compounds of Formula 1 and Formula 2 using known compounds or compounds readily prepared therefrom. In particular, methods for preparing compounds of Formula 1 are detailed in PCT Publications WO 2006 / 112685 A1, WO 2010 / 150946 A1 and WO 2011 / 046380 A2, the disclosures of which are incorporated herein by reference. Compounds of Formula 1 can be chemically synthesized by any of the methods described in the aforementioned documents; however, these methods are merely exemplary, and the order of unit operations may be selectively changed if necessary. Therefore, the above methods are not intended to limit the scope of the invention.

[0030] The content of the carbamate compound of formula 1 or 2 in the oral aqueous suspension may vary depending on the application of the formulation. In one embodiment, the oral aqueous suspension contains the carbamate compound of formula 1 or 2 at a concentration of about 1 mg / ml to about 100 mg / ml. In one embodiment, the oral aqueous suspension contains the carbamate compound of formula 1 or 2 at a concentration of about 1 mg / ml to about 50 mg / ml. In one embodiment, the oral aqueous suspension contains the carbamate compound of formula 1 or 2 at a concentration of about 5 mg / ml to about 20 mg / ml. In one embodiment, the oral aqueous suspension contains the carbamate compound of formula 1 or 2 at a concentration of about 5 mg / ml to about 12 mg / ml. In one embodiment, the oral aqueous suspension formulation contains the carbamate compound of formula 1 or 2 at a concentration of about 8 mg / ml to about 12 mg / ml. In one embodiment, the oral aqueous suspension contains the carbamate compound of formula 1 or 2 at a concentration of about 9 mg / ml to about 11 mg / ml.

[0031] In various embodiments, the pharmaceutical composition in suspension form comprises a carbamate compound or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients and an aqueous carrier. The aqueous carrier is selected from the group consisting of water and mixtures of water and water-soluble organic solvents. In one embodiment, the organic solvent is selected from the group consisting of ethanol, vinyl bromide, butanol, acetone, chloroform, 2-ethylhexanol, methyl ethyl ketone, vinyl chloride, isobutanol, glycerol, methyl isobutyl ketone, dichloromethane, isopropanol, methyl isopropyl ketone, tetrachloroethylene, methanol, methyl methyl oxide, carbon tetrachloride, propanol, trichloroethylene, propylene glycol, 1,4-dioxane, butyl ether, dimethylformamide, diethyl ether, diisopropyl ether, dimethyl sulfoxide, tetrahydrofuran, tert-butyl methyl ether, pyridyne, acetonitrile, ethyl acetate, cyclohexane, toluene, hexane, xylene, other suitable solvents, and combinations thereof. In another embodiment, the aqueous carrier comprises water, water buffered to a specific pH value with phosphate or carbonate ions, and a combination of an aqueous solvent and one or more organic solvents. In a particular embodiment, the aqueous carrier is water. In some embodiments, the aqueous formulation includes an aqueous carrier in an amount of 40% to 99%, 70% to 98%, or 90% to 95% of the formulation weight.

[0032] In one embodiment, poloxamer is an ABA block copolymer composed of 75 to 85% polyethylene oxide (PEO) units and 15 to 25% polypropylene oxide (PPO) units. In one embodiment, poloxamer is an ABA block copolymer composed of about 80% A blocks of polyethylene oxide (PEO) units and about 20% B blocks of polypropylene oxide (PPO) units. In one embodiment, poloxamer is poloxamer 188 (P188). In one embodiment, the aqueous formulation contains poloxamer at a concentration of about 0.1 mg / ml to about 1.5 mg / ml. In one embodiment, the aqueous formulation contains poloxamer at a concentration of about 0.8 mg / ml to about 1.2 mg / ml. In one embodiment, the aqueous formulation contains poloxamer at a concentration of about 0.1 mg / ml to about 0.5 mg / ml. In some implementations, poloxamer is added to provide sufficient spacing between the sedimented particles of the active ingredient and to allow the active ingredient to be redispersed with minimal effort over a wide pH range, regardless of the type of buffer.

[0033] In one embodiment, the aqueous formulation further includes bentonite. Bentonite can be added to the aqueous formulation as a suspending agent to improve its suspension and viscosity properties. Bentonite can prevent the particle sedimentation of the active ingredient and impart viscosity to the formulation. In one embodiment, the bentonite is selected from the group consisting of aluminum silicates such as montmorillonite (bentonite, hectorite, and their derivatives); magnesium aluminum silicate (Veegum® of various grades, commercially available from RTVanderbilt); sodium magnesium silicate (Laponite® of varying grades, commercially available); and organically modified bentonite including tetraalkyl and / or trialkylammonium bentonite (organically modified clay), such as quaternary-18 bentonite, quaternary-18 hectorite, stearalkonium bentonite, and stearalkonium hectorite, and mixtures thereof. In one embodiment, the bentonite is purified. In one embodiment, the bentonite is magnesium aluminum silicate. Specifically, the bentonite may be type I magnesium aluminum silicate, and more specifically, the bentonite may be Veegum HV, Veegum R, Veegum K, or any combination thereof. In one embodiment, the aqueous formulation contains bentonite at a concentration of about 2.5 mg / ml to about 7.0 mg / ml. In another embodiment, the aqueous formulation contains bentonite at a concentration of about 4 mg / ml to about 6 mg / ml. In low-solids suspensions, specific grades may be required to establish viscosity, and the grades or quantities may need to be modified according to the desired concentration and solids content of the final formulation.

[0034] In one embodiment, the aqueous formulation further includes a viscosity modifier. A viscosity modifier may be added to reduce the sedimentation rate of particles in the formulation. The viscosity modifier may be used synergistically with one or more excipients herein to improve the suspension and redispersibility of the formulation. In one embodiment, the aqueous formulation includes a viscosity modifier at a concentration of about 1 mg / ml to about 25 mg / ml. A viscosity modifier that has a synergistic effect with bentonite may be selected. In one embodiment, the viscosity modifier may be a recrystallization inhibitor determined from PSD data.

[0035] In one embodiment, the viscosity modifier is selected from the group consisting of cellulose or its derivatives and xanthan gum. In one embodiment, the aqueous formulation contains xanthan gum at a concentration of about 1 mg / ml to about 10 mg / ml, about 2 mg / ml to about 6 mg / ml, or about 3 mg / ml to about 5 mg / ml. In one embodiment, the viscosity modifier is cellulose or its derivatives. In one embodiment, the cellulose derivative is selected from the group consisting of methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), microcrystalline cellulose (MCC), cellulose acetate (CA), cellulose acetate phthalate (CAP), cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), and combinations thereof. In one embodiment, a mixture of carboxymethylcellulose (CMC) and microcrystalline cellulose (MCC) is selected. In one embodiment, the aqueous formulation comprises cellulose or a derivative thereof at a concentration of about 1 mg / mL to about 25 mg / mL. In another embodiment, the aqueous formulation comprises cellulose or a derivative thereof at a concentration of about 15 mg / mL to about 25 mg / mL or about 15 mg / mL to about 20 mg / mL. In another embodiment, the aqueous formulation contains cellulose or a derivative thereof at a concentration of about 5 mg / mL to about 14 mg / mL or about 8 mg / mL to about 12 mg / mL. In one embodiment, the aqueous formulation further comprises a sweetener. In one embodiment, the sweetener is selected from the group consisting of sorbitol, mannitol, maltitol, xylitol, and mixtures thereof. In one embodiment, the oral aqueous formulation contains a sweetener at a concentration of about 10 mg / mL to about 30 mg / mL. In one embodiment, the sweetener may be used as a recrystallization and cryoprotectant, and to ensure the consistency of the formulation. In one embodiment, the formulation comprises a suitable combination of a sweetener, a bitterness masking agent, and an evaluated flavoring agent to overcome the bitterness of the active ingredient, where applicable. In one embodiment, the sweetener is selected from the group consisting of sugar alcohols, substituted disaccharide derivatives, and salts of glycyrrhizic acid. In this regard, the sweetener is used in combination with flavoring agents such as raspberry, cherry, mint, orange, strawberry, grape, black cherry, and apple.

[0036] In one embodiment, the aqueous formulation further includes one or more of a recrystallization inhibitor, a flavoring agent, a bitterness masking agent, a preservative, and a buffer. In one embodiment, the recrystallization inhibitor is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC). In one embodiment, the aqueous formulation contains polyvinylpyrrolidone (PVP) at a concentration of about 20 mg / mL to about 40 mg / mL. In one embodiment, the aqueous formulation contains hydroxypropyl methylcellulose (HPMC) at a concentration of about 1 mg / mL to about 5 mg / mL. In one embodiment, the buffer is a citrate buffer or a phosphate buffer.

[0037] In one embodiment, the aqueous suspension includes at least one preservative, particularly selected from the group consisting of p-hydroxybenzoic acid, benzoic acid, boric acid, sorbic acid, their salts, and combinations thereof, preferably sodium benzoate, at a concentration of about 0.5 mg / mL to about 5.0 mg / mL, or about 1.0 mg / mL to about 2.0 mg / mL, or about 1.3 mg / mL to about 1.7 mg / mL. In one embodiment, the aqueous suspension is stable for twelve months or longer at 25°C / 60%RH and 40°C / 75%RH. In one embodiment, the aqueous suspension is stable for 18 months or longer at 25°C / 60%RH and 40°C / 75%RH. In one embodiment, the aqueous formulation may include a carbamate compound of formula 1 or 2 with a particle size distribution range of D10 of 1 μm to 15 μm, 1.4 μm to 10 μm or 1.5 μm to 5 μm, more specifically, 1 μm to 3 μm, 1.5 μm to 3 μm, 3 μm to 6 μm, 6 μm to 9 μm, 9 μm to 12 μm, or 12 μm to 15 μm. In one embodiment, the aqueous formulation may include a carbamate compound of formula 1 or 2 with a particle size distribution range of 1 to 2: D50 of 1 μm to 20 μm, 1 μm to 15 μm or 5 μm to 10 μm, more specifically, 1.5 μm to 3 μm, 3 μm to 6 μm, 4 μm to 9 μm, 5 μm to 9 μm, 6 μm to 9 μm, 9 μm to 12 μm, 12 μm to 15 μm, 15 μm to 18 μm, 18 μm to 20 μm. In one embodiment, the aqueous formulation may include a carbamate compound of formula 1 or 2 within the particle size distribution range described below: D90 of 1 μm to 60 μm, 5 μm to 50 μm, or 10 μm to 45 μm, more specifically, 10 μm to 15 μm, 10 μm to 20 μm, 20 μm to 30 μm, 30 μm to 45 μm, or 40 μm to 50 μm. In one embodiment, the particle size of the carbamate compound of formula 1 or 2 may be controlled by milling or other available processes. In one embodiment, the aqueous formulation includes a carbamate compound of formula 1 or 2 having the above-described particle size distribution range to ensure uniformity in the oral aqueous suspension formulation.

[0038] In one embodiment, the particle size of the carbamate compound of formula 1 or 2 that can be used to prepare an oral aqueous formulation is as follows: D10 is 1 μm to 30 μm, 1.4 μm to 28 μm or 1.5 μm to 27 μm, more specifically, 1.5 μm to 3 μm, 3 μm to 6 μm, 6 μm to 9 μm, 9 μm to 12 μm, 12 μm to 15 μm, 15 μm to 18 μm, 18 μm to 21 μm, 21 μm to 24 μm or 24 μm to 27 μm. In one embodiment, the particle size of the carbamate compound of formula 1 or 2 that can be used to prepare an oral aqueous formulation is as follows: D50 is 3 μm to 60 μm, 3.2 μm to 58 μm or 3.5 μm to 55 μm, more specifically, 3.5 μm to 5.0 μm, 5.0 μm to 10 μm, 10 μm to 15 μm, 15 μm to 20 μm, 20 μm to 25 μm, 25 μm to 30 μm, 35 μm to 40 μm, 40 μm to 45 μm, 45 μm to 50 μm or 50 μm to 55 μm. In one embodiment, the particle size of the carbamate compound of formula 1 or 2 that can be used to prepare an oral aqueous formulation is as follows: D90 is 5 μm to 120 μm, 7 μm to 110 μm or 8 μm to 100 μm, more specifically, 10 μm to 20 μm, 20 μm to 30 μm, 30 μm to 40 μm, 40 μm to 50 μm, 50 μm to 60 μm, 60 μm to 70 μm, 70 μm to 80 μm, 80 μm to 90 μm or 90 μm to 100 μm.

[0039] As used herein, D10, D50, and D90 represent the median or 10th, 50th, and 90th percentiles of the particle size distribution by volume, respectively. This means that the term "D50" is defined as a size in micrometers where, by volume, 50% of the particles are smaller than that size, and similarly, the term "D90" is defined as a size in micrometers where, by volume, 90% of the particles are smaller than that size. Particle size can be determined by laser light scattering, for example, using a particle size analyzer such as the proprietary Mie scattering, Cilas 1180.

[0040] In one embodiment, the aqueous formulation has a pH value of about 3.5 to about 7.0, about 3.5 to about 6.0, or about 3.5 to about 5.5.

[0041] The obtained oral suspension can be tested using appropriate analytical methods to ensure physical and chemical stability. Examples of analytical methods include, but are not limited to, appearance, pH, viscosity, determination of related substances, physical purity determination, homogeneity, redispersibility, solubility, particle size, and XRD.

[0042] Wetting / dispersibility indices can be used to analyze formulations to optimize wetting agents and viscosity modifiers, such as controlling the settling volume after stirring, the redispersibility and wettability of the powder in water, and visually observing whether the sample shows signs of agglomeration, flocculation, and compound dispersion. The volume of the settling layer is an indicator of the interparticle spacing within the settling layer. Sufficient spacing between particles is necessary because these particles need to move to achieve uniform dispersion.

[0043] In one embodiment, the aqueous preparation is used as an antispasmodic and can be used to treat anxiety, depression, convulsions, epilepsy, migraine, bipolar disorder, substance abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration and / or muscle spasms.

[0044] The dosage of carbamate compounds of formula 1 or 2 used for the prevention, relief, or treatment of the aforementioned diseases can generally vary depending on the severity of the disease, the subject's weight, and metabolic status. The "therapeutic effective amount" for an individual patient refers to the amount of active ingredient sufficient to achieve a therapeutic effect. Specifically, depending on the free form and once-daily administration to humans, the therapeutic effective amount of the active ingredient is 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 100 mg to 400 mg, 100 mg to 300 mg, 50 mg to 200 mg, or 100 mg to 200 mg. A therapeutic effective amount is preferably 50 mg to 400 mg, more preferably 50 mg to 200 mg.

[0045] This disclosure provides an aqueous formulation comprising, as an active ingredient, an amino carbamate compound of formula 1, or a pharmaceutically acceptable salt thereof, a solvate or hydrate thereof, poloxamer, and an aqueous carrier:

[0045]

[0045] Among them,

[0045] R1 and R2 are each independently selected from the group consisting of -H, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy, and C1-C8 alkoxy; and

[0045] One of A1 and A2 is CH, and the other is N.

[0045] The aqueous formulation is in the form of a suspension. In one embodiment, the aqueous formulation is a formulation for oral administration.

[0046] The carbamate compound and bentonite are as previously described. In one embodiment, the aqueous formulation further comprises the above-described poloxamer. In one embodiment, the aqueous formulation further comprises one or more excipients as described herein.

[0047] The present invention will be explained in more detail below through embodiments. However, the following working examples are intended to illustrate one or more embodiments only and are not intended to limit the scope of the invention.

[0047] Example

[0047] Preparation Example: Synthesis of (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamate

[0048] The compound of formula 2 (xenoamine ester) was prepared according to the method described in Preparation Example 50 of International Publication No. WO 2010 / 150946.

[0048] Example 1

[0049] The sedimentation volume, dispersibility, and wettability of poloxamer 188 dispersions containing thioamine esters in pure citrate or phosphate buffers at pH 3 to 7 were evaluated at different concentrations. In phosphate buffer at pH 4.2, approximately 100 mg of thioamine ester was dispersed in 10 mL of poloxamer liquid (concentrations of 0.10 mg / mL, 0.5 mg / mL, 1.00 mg / mL, and 1.50 mg / mL, respectively), and the sedimentation volume, redispersibility, and wettability of the dispersions were evaluated. Images are shown in Figure 1. Furthermore, individual samples containing 0.1 mg / mL poloxamer 188 were prepared in citrate buffers at different pH values ​​(pH 3.5, 4.2, and 5.2) and evaluated in the same manner. Images are shown in Figure 2.

[0050] The volume of the settling layer is an indicator of the spacing between particles within the settling layer. Physical property observations show that these dispersions settle rapidly but form a loose layer that is very easily redispersible after inversion and / or shaking (Figures 1 and 2). Good wettability of senoamine esters was also observed in the presence of poloxamer 188, as assessed by the time required for the senoamine esters to descend below the surface.

[0050]

[0051] Poloxamer 188 dispersion exhibited near-immediate flocculation and provided sufficient interparticle spacing for redispersible drug substances with minimal effort across the entire pH range between pH 3.5 and pH 5.2, regardless of buffer type. The expected effects were as follows: upon addition of thiocyanate to the poloxamer solution, most of the material was immediately wetted, and initial precipitation occurred rapidly and loosely within the first 30 minutes to 1 hour, based on the precipitate volume to total volume ratio, without clumping, and redispersible effectively. The material dispersed rapidly after shaking the precipitated sample for 10 seconds.

[0051] Example 2

[0052] Different combinations of poloxamer 188, viscosity modifier and bentonite were tried in a semi-factor design, and the suspension, redispersibility and viscosity were evaluated.

[0053] Twelve separate experimental-scale batches were prepared to determine the effects of the composition of poloxamer, bentonite, and / or viscosity modifiers on the uniformity, suspension, and redispersibility of senoamine ester, as shown below. The type and concentration of the viscosity modifier, and the concentrations of bentonite and poloxamer 188, varied according to Table 2. As shown in Table 3, the remaining formulation components were fixed.

[0053]

[0053]

[0054] Homogeneity, suspension and redispersibility are measured by the following procedure:

[0054] Uniformity

[0054] 1. Shake the bottle by hand.

[0054] 2. Invert the bottle and check the bottom for clumps. If clumps have formed on the sample, be careful when performing the analysis.

[0054] 3. Using a syringe and cannula, samples were taken from the top and bottom of the bottle for quantification of senosides (assay), and diluted according to the assay method for analysis.

[0054] 4. Compare the results at the top and bottom of the bottle to determine the absolute difference in uniformity.

[0054] Suspension

[0054] 1. After sampling evenly, seal the bottle and place it undisturbed.

[0054] 2. Without shaking or otherwise mixing the sample, obtain additional aliquots from the bottom of the vial for use in the quantification of senosides.

[0054] 3. After dilution, analyze according to the method.

[0054] 4. Compare this result with the uniformity of the bottom quantification to determine the absolute difference in suspension.

[0054] Re-dispersibility

[0054] 1. Shake the sample by hand and immediately transfer it into a conical tube.

[0054] 2. Centrifuge the sample.

[0054] 3. Remove the sample from the centrifuge and shake it by hand.

[0054] 4. Collect the sample from the center of the test tube for quantification.

[0054] 5. Compare these results with the average quantitative results to determine the percentage of redispersibility.

[0055] Viscosity measurements and any correlation between viscosity and suspension and redispersibility were performed based on Stokes' law, which describes the final velocity of a sphere falling through a liquid. According to the data in Table 4, these formulations exhibit acceptable physical stability. Overall, the average homogeneity of the various formulations ranged from 91.1 to 100.8, and the absolute differences (%) among the formulations selected throughout the experimental design ranged from 0.0 to 3.9.

[0055]

[0055] Example 3

[0056] Based on the results of Examples 1 and 2, the formulations shown in Table 5 were prepared.

[0056]

[0056] Example 4

[0057] The stability of formulations I and II was evaluated by testing pH, quantification of senosides, suspension, content of related compounds, solubility, particle size, and XRD. The formulations (upright and inverted) were stored at 25°C / 60%RH for 12 months and at room temperature at 40°C / 75%RH for 6 months.

[0058] High-performance liquid chromatography (HPLC) was used to determine the quantification of senoamine esters and related compounds. Suspension determination was performed as in Example 2. Dissolution tests were performed using a USP instrument 2 (paddle, 900 mL, 75 rpm, 37°C, 5 to 45 minutes). Particle size was measured using Mie scattering.

[0059] Results showed that formulations I and II (upright / inverted) were stable for at least 6 months at 25°C / 60%RH and 40°C / 75%RH, and stable for 12 months at 25°C / 60%RH. Stability results were provided under inverted conditions (representing greater interaction between the formulation and the packaging).

[0059] ND = Not detected, N / A = Not applicable, NT = Not measured, Abs.Diff.: Absolute difference from quantitative value, RRT: Relative residence time

[0059] ND = Not detected, N / A = Not applicable, NT = Not measured, Abs.Diff.: Absolute difference from quantitative value, RRT: Relative residence time

[0059] ND = Not detected, N / A = Not applicable, NT = Not measured, Abs.Diff.: Absolute difference from quantitative value, RRT: Relative residence time

[0059] ND = Not detected, N / A = Not applicable, NT = Not measured, Abs.Diff.: Absolute difference from quantitative value, RRT: Relative residence time

[0060] Formulations I and II are stable for 12 months at 25°C / 60%RH and for 6 months at 40°C / 75%RH.

Claims

1. An aqueous formulation comprising a carbamate compound of formula 1 or a pharmaceutically acceptable salt, solvate or hydrate thereof, poloxamer, smectite clay, and an aqueous carrier: [Formula 1] wherein, R1 and R2 are each independently selected from the group consisting of -H, halogens and C1-C8 alkyl groups; and one of A1 and A2 is CH and the other is N, wherein the aqueous formulation is in the form of a suspension.

2. The aqueous formulation as described in claim 1, wherein, The carbamate compound of Formula 1 is carbamate (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester.

3. The aqueous formulation as described in claim 1, wherein the pharmaceutically acceptable salt is selected from acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoloyl arsanilate, hexylresorcinate, and hydravamine. The group consisting of hydrobromide, hydrochloric acid, bicarbonate, hydroxynaphthoate, iodide, isethionate, lactic acid, lactobionic acid, malic acid, maleic acid, mandelate, methanesulfonate, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / bisphosphate, polygalacturonate, salicylate, stearate, hypoacetate, succinate, hemisuccinate, sulfate or hemisulfate, tannate, tartrate, oxalate or hemitartrate, teoclate, procaine, aluminum, ammonium, tetramethylammonium, calcium, lithium, magnesium, potassium, sodium and zinc.

4. The aqueous formulation as claimed in claim 1, comprising a carbamate compound of formula 1 at a concentration of about 1 mg / ml to about 100 mg / ml.

5. The aqueous formulation as described in claim 1, wherein, This poloxamer is an ABA block copolymer composed of 75 to 85% polyethylene oxide (PEO) units and 15 to 25% polypropylene oxide (PPO) units.

6. The aqueous formulation as described in claim 1, wherein, This poloxamer is an ABA block copolymer composed of 80% polyethylene oxide (PEO) units and 20% polypropylene oxide (PPO) units.

7. The aqueous formulation as described in claim 6, wherein, The polosham is polosham 188.

8. The aqueous formulation as claimed in claim 1, which contains poloxamer at a concentration of about 0.1 mg / ml to about 1.5 mg / ml.

9. The aqueous formulation as claimed in claim 1, wherein the bentonite is selected from the group consisting of aluminum silicate, magnesium aluminum silicate, sodium magnesium silicate, organically modified bentonite, and mixtures thereof.

10. The aqueous formulation as described in claim 9, wherein, The bentonite is magnesium aluminum silicate.

11. The aqueous formulation as claimed in claim 1, which contains bentonite at a concentration of about 2.5 mg / ml to about 7.0 mg / ml.

12. The aqueous formulation as described in claim 1 further includes a viscosity modifier.

13. The aqueous formulation as described in claim 12, wherein, The viscosity modifier is selected from the group consisting of cellulose or its derivatives and xanthan gum, wherein the cellulose derivative is selected from the group consisting of methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), microcrystalline cellulose (MCC), cellulose acetate (CA), cellulose acetate phthalate (CAP), cellulose acetate butyrate (CAB), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), and combinations thereof.

14. The aqueous formulation as described in claim 13, wherein, This cellulose derivative is a mixture of CMC and MCC.

15. The aqueous formulation as claimed in claim 12, containing the viscosity modifier at a concentration of about 1 mg / ml to about 25 mg / ml.

16. The aqueous formulation as described in claim 13, containing xanthan gum at a concentration of about 1 mg / ml to about 10 mg / ml.

17. The aqueous formulation as claimed in claim 13, comprising the cellulose or a derivative thereof in a concentration of about 5 mg / ml to about 14 mg / ml.

18. The aqueous formulation as claimed in claim 13, comprising the cellulose or a derivative thereof at a concentration of about 15 mg / ml to about 25 mg / ml.

19. The aqueous formulation as described in claim 1 further includes a sweetener.

20. The aqueous formulation as described in claim 19, containing the sweetener at a concentration of about 10 mg / ml to about 30 mg / ml.

21. The aqueous formulation as claimed in claim 1 further includes at least one selected from the group consisting of recrystallization inhibitors, flavorings, bitterness masking agents, preservatives and buffers.

22. The aqueous formulation as described in claim 21, wherein, The recrystallization inhibitor is polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC).

23. The aqueous formulation as described in claim 22, containing PVP at a concentration of about 20 mg / ml to about 40 mg / ml.

24. The aqueous formulation as described in claim 22, containing HPMC at a concentration of about 1 mg / ml to about 5 mg / ml.

25. The aqueous formulation as described in claim 21, wherein, The buffer is either citrate buffer or phosphate buffer.

26. The aqueous formulation as described in claim 1, having a pH value of 3.5 to 5.

5.

27. The aqueous formulation as described in claim 1, wherein, The aqueous carrier is water, or a mixture of water and a water-miscible organic solvent.

28. The aqueous formulation as described in claim 1, wherein, The D90 of the compound of formula 1 used in the preparation of aqueous formulations is 10 μm to 20 μm, 20 μm to 30 μm, 30 μm to 40 μm, 40 μm to 50 μm, 50 μm to 60 μm, 60 μm to 70 μm, 70 μm to 80 μm, 80 μm to 90 μm, or 90 μm to 100 μm.

29. The aqueous formulation as described in claim 1 is a formulation for oral administration.

30. The aqueous formulation as claimed in claim 1, comprising about 8 mg / ml to 12 mg / ml of cenobamate, about 0.1 mg / ml to about 1.5 mg / ml of poloxamer, about 2.5 mg / ml to about 7.0 mg / ml of bentonite, and water.

31. Use of an aqueous formulation as described in claim 1 in the preparation of a medicament for treating a central nervous system disease in a subject.

32. The use as described in claim 31, wherein, The selected central nervous system disorders are grouped together as anxiety, depression, convulsions, epilepsy, migraine, bipolar disorder, substance abuse, attention deficit hyperactivity disorder (ADHD), sleep disorders, neuropathic pain, stroke, cognitive impairment, neurodegeneration, and muscle spasms.

33. The use as described in claim 31, wherein, This subject is for pediatric or adult patients with difficulty swallowing.

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