Liquid tasimelteon preparation and method of using the same

Abstract

To provide aqueous suspensions of tasimelteon.SOLUTION: The present invention provides a homogeneous aqueous suspension of tasimelteon, comprising 1-6 mg / mL of tasimelteon, 1-15 mg / mL of hydroxypropyl methylcellulose, 200-400 mg / mL of mannitol, 50-200 mg / mL of sorbitol, a high-intensity sweetener, a flavoring agent, a preservative and an antioxidant.SELECTED DRAWING: None

Description

[Technical Field] 【0001】 The present invention provides a pharmaceutically refined formulation comprising a liquid suspension of tasimerteon (see U.S. Patent 5,856,529, Claim 7), namely trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropan-1-yl]methyl]propanamide. Tasimerteon is the active ingredient of HETLIOZ®, a drug approved for use in non-24-hour sleep-wake disorders (Non-24) and is commercially available in solid oral dosage form, i.e., capsules containing 20 mg of tasimerteon. [Background technology] 【0002】 Cross-references to related applications This application claims priority from the co-pending U.S. Provisional Patent Application No. 62 / 947,774 filed on 13 December 2019, U.S. Provisional Patent Application No. 62 / 972,902 filed on 11 February 2020, and U.S. Provisional Patent Application No. 63 / 119,488 filed on 30 November 2020, the contents of each of these U.S. Provisional Patent Applications being incorporated in their entirety by reference as if their contents were fully described. 【0003】 The preparation of pharmaceutically sophisticated suspensions of drugs suitable for administration to patients, especially as liquid formulations, presents numerous challenges. Typical challenges include physical stability. The contents may exhibit uniformity, precipitation, caking, resuspendability, crystal growth, and undesirable taste or odor. (Refer to Alok K. Kulshreshtha, Onkar N. Singh, and G. Michael Wall (eds.), "Pharmaceutical Suspensions: From Formulation Development to Manufacturing") See reference. The preparation of pharmaceutically refined liquid suspensions of tasimerteon suitable for administration to patients, especially pediatric patients, is particularly complex due to factors such as the unpleasant taste of tasimerteon, the need to achieve a viscosity suitable for measuring and administering effective unit doses in appropriate volumes of liquid, the chemical stability of liquid tasimerteon formulations, their dissolution rate and solubility in liquid vehicles, and the opacity of liquid formulations prepared as tasimerteon suspensions. Achieving a pharmaceutically refined formulation of tasimerteon requires successfully addressing each of these complex factors while simultaneously ensuring that the resulting formulation is easily manufacturable. 【0004】 Previously, U.S. Patent 5,856,529 (e.g., column 17) reported that pharmaceutical compositions of drugs such as tasimerteon can be prepared as formulations suitable for oral administration, and such formulations include compositions comprising a liquid carrier used for preparing a syrup or aqueous liquid suspension, wherein conventional additives such as suspending agents, emulsifiers, wetting agents, and preservatives, as well as flavorings and / or colorings, may be used in the liquid carrier. 【0005】 [ka] Tasimertheon 【0006】 As is well known in this industry, tasimeltheone can be prepared as a white to off-white powder with a melting point (DSC) of approximately 78°C. It is highly soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, and polyethylene glycol (PEG-300 and PEG-400), but has low solubility in water. The original pH of a saturated solution of tasimeltheone in water is 8.5, and its water solubility is not significantly affected by pH. [Overview of the Initiative] [Means for solving the problem] 【0007】 The invention described in the present disclosure is a pharmaceutically refined liquid composition containing tasimelteon in the state of an aqueous suspension, wherein a predetermined volume (for example, 0.35 to 10 mL) of this pharmaceutical composition provides a unit volume of the active ingredient suspended therein, whereby one or more such unit volumes administered to an individual provide an amount of tasimelteon effective to treat or prevent a disease or symptom for the purpose of pharmaceutical administration. The above-mentioned liquid composition is provided. 【0008】 The pharmaceutical composition of the present invention provides a homogeneous aqueous suspension of tasimelteon, which may contain one or more suspending agents and one or more taste masking agents. An example As such, such a composition may contain a cellulose-based suspending agent as a suspending agent. The general viscosity of the suspending agent is about 150 centipoise (cps) or less under ambient conditions. 【0009】 The above-mentioned pharmaceutical composition may be formulated to have a specific gravity of greater than 1 to about 1.5 under ambient conditions. In addition, such a formulation may additionally contain one or more opacity imparting agents and one or more surfactants such as nonionic surfactants. The nonionic surfactant is, for example, polysorbate 80. 【0010】 The above pharmaceutical composition may be a pharmaceutical composition in which the useful suspending agent in the composition is one or more of methylcellulose, hydroxypropylmethylcellulose (HPMC), carboxypropylmethylcellulose sodium (CPMC), or sodium carboxymethylcellulose and microcrystalline cellulose. For example, the pharmaceutical composition of the present invention may be one in which the suspending agent is microcrystalline cellulose and carboxymethylcellulose, or a salt thereof, and the pharmaceutical composition contains an opacifying agent, a sweetening agent, and an antioxidant. Alternatively, the suspending agent may be microcrystalline cellulose and sodium carboxymethylcellulose. For example, the suspending agent may be (1) microcrystalline cellulose in which 60% of the particle size of the microcrystalline cellulose particles is less than 0.2 μm (its D 60 (is) less than 0.2 μm and (2) sodium carboxymethylcellulose. 【0011】 The above pharmaceutical composition may also be a pharmaceutical composition in which the suspending agent is Avicel (registered trademark) RC-591 microcrystalline cellulose and sodium carboxymethylcellulose. 【0012】 An example of the pharmaceutical composition of the present invention is a pharmaceutical composition containing an opacifying agent that is mannitol. 【0013】 The above pharmaceutical composition may be a pharmaceutical composition in which the flavoring agent is a sweetening agent. The sweetening agent may contain a monosaccharide or disaccharide, and a high-intensity sweetener, such as stevia, aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin, advantame, or cyclamate. More specifically, the monosaccharide or disaccharide is sucrose, and the total solid content is less than 500 mg / mL. For example, the concentration of mannitol may be less than 200 mg / mL, the concentration of sucrose may be less than 300 mg / mL. For example, the concentration of mannitol may be 100 mg / mL or less, the concentration of sucrose may be 200 mg / mL or less, and the total solid content may be 350 mg / mL or less. 【0014】 In accordance with the above, these tasimeltheone-containing compositions are (1) A nonionic surfactant which is polysorbate 80, present at a concentration of 0.5 to 5 mg / mL, for example, 1 to 3 mg / mL (or more preferably 1 to 2 mg / mL or most preferably about 1 mg / mL); the above pharmaceutical composition may include pharmaceutical compositions in which tasimelteon is present at a concentration of 1 to 6 mg / mL, 2 to 5 mg / mL, 1 mg / mL, or 4 mg / mL. (2) Suspensions containing tasimelteon in concentrations of 1-6 mg / mL, 2-5 mg / mL, 1 mg / mL, or 4 mg / mL, and (1) microcrystalline cellulose and sodium carboxymethylcellulose in concentrations of 0-30 mg / mL, 10-20 mg / mL, or 20 mg / mL. (3) Mannitol present as an opacity imparting agent at concentrations of (1) 200 mg / mL or less, (2) less than 200 mg / mL, (3) 50 to 100 mg / mL, or (4) 100 mg / mL; Sucrose present as a sweetener at concentrations of (1) 300 mg / mL or less, (2) less than 300 mg / mL, (3) 150 to 250 mg / mL, or (4) 200 mg / mL; High-intensity sweeteners; Polysorbate present as a nonionic surfactant at concentrations of (1) 1 to 5 mg / mL, (2) 1 to 3 mg / mL, or (3) 2 mg / mL; Antioxidants, sodium chloride, and flavorings. It may include. 【0015】 The above compositions may be formulated to exhibit a target pH level. Preferably, these compositions are formulated to achieve a target pH of 4.0 ± 0.5. In addition, compositions formulated according to the above specifications are targeted to exhibit the following release specifications. (1) Stability: After storage at (1) 5±3℃, (2) 25±2℃ (relative humidity 60±5%), and (3) 40±2℃ (relative humidity 75±5%) for a successive period of 1 month, 2 months, or 3 months, the total amount of impurities measured by high-performance liquid chromatography (HPLC) is 1.5% by weight or less for known impurities, 0.5% by weight or less for known impurities, and 0.2% by weight or less for unspecified impurities. (2) Viscosity: 5 to 30 centipoises (cP or cps) (under ambient conditions), for example, about 20 cps (3) Specific gravity: 1.1~1.3mg / mL (4) pH: 4.0~5.0 (5) Particle size distribution: D 90 =100~150μm, D 50 = 50~70 μm, and D 10 = 15~40μm (6) Dissolution: More than 90% after paddling in 1 N HCl (at 50 revolutions per minute (rpm)) for 15 minutes. 【0016】 The above explanation regarding "particle size distribution" indicates the percentage of particles in the sample that have a diameter greater than, smaller than, or equal to the indicated physical side, for example, D 50 =50~70μm refers to a sample in which 50% of the particles in the same batch have a diameter of 50~70μm. In this disclosure, particle size distribution refers to measurements performed on tasimelteon particles suspended in the pharmaceutical formulation described herein. Such particle size measurements can be performed using laser diffraction techniques, such as laser light scattering detection using a Malvern Mastersizer 2000 or Malvern Mastersizer 3000. 【0017】 Another aspect of the present invention provides a method for treating Smith-Magenis syndrome (SMS) in a patient requiring treatment, the method comprising measuring the patient's body mass; The following is included: if the patient's weight is 28 kg or less, administer a first dose of tasimerteon equal to 0.7 mg / kg to the patient once daily; or if the patient's weight is greater than 28 kg, administer a second dose of tasimerteon equal to 20 mg to the patient once daily. [Brief explanation of the drawing] 【0018】 These and other features of the present invention will be more readily understood from the following detailed description of various embodiments of the invention, which will be read in conjunction with the accompanying drawings illustrating various embodiments and aspects of the invention. [Figure 1] The graph shows the effective dose of tasimerteon liquid formulation as a function of the patient's body mass. [Figure 2] This diagram illustrates the various steps involved in administering a liquid formulation of tasimelteon according to an embodiment of the present invention. 【0019】 Furthermore, the drawings are not to scale, and are intended to depict only typical embodiments of the present invention; therefore, they should not be construed as limiting the scope of the present invention. [Modes for carrying out the invention] 【0020】 Preparing pharmaceutically refined liquid formulations of tasimelteon presents several challenges, each of which is addressed in the compositions described below. 【0021】 taste The solubility of tasimelteon in water is approximately 1 mg / mL. However, in the presence of formulation excipients, this drug is likely to be substantially insoluble in most suspension formulations. Nevertheless, a trace amount dissolves, imparting a bitter taste to the formulation. This bitterness is difficult to mask. Therefore, the following formulation techniques are considered to improve the taste. ● Contains a combination of sucrose, sucralose, and sodium chloride as sweeteners / flavoring agents. ● Contains Avicel® RC-591, a hydrophilic polymer, as a suspension agent. This hydrophilic polymer hydrates and swells in the presence of water. Some amount of water is required to properly hydrate and disperse this polymer, and additional water is needed to dissolve the ascorbic acid and sodium benzoate. As a result, the amount of water available to dissolve sucrose is limited. Therefore, 200 mg / mL of sucrose was identified as the maximum amount that can be dissolved. ●Since the sucrose concentration cannot be increased to more than 200 mg / mL, sucralose is also included as a sweetener at 1 mg / mL. This makes the taste sweeter, which helps to better mask the bitterness. ●In addition, the inclusion of sodium chloride masks the bitterness and also improves the overall taste at a concentration of 5 mg / mL. 【0022】 viscosity To maintain a uniform suspension of tasimelteon drug particles during shaking, it is necessary to identify an appropriate viscosity building agent and its optimal concentration. Methylcellulose A15C, methylcellulose A4M, and Avicel® RC-591 (microcrystalline cellulose / carboxymethylcellulose (CMC) sodium) are useful as suspending agents. Both grades of methylcellulose produce suspensions containing polymer particles that are not fully hydrated, resulting in higher viscosity, which has negatively affected their dissolution rate. 【0023】 Avicel® RC-591 at a concentration of 6 mg / mL without homogenization exhibits desirable physicochemical properties, including rapid dissolution, complete redispersion upon gentle shaking of the stored suspension bottle, and sufficient uniformity of content. 【0024】 chemical stability Tasimelteon is susceptible to oxidative degradation, producing three degradation products, thus requiring antioxidants in the formulation. Antioxidants such as sodium bisulfite and sodium sulfite were initially considered, but they may cause allergic reactions in children. 【0025】 Ascorbic acid is preferentially oxidized, thereby preventing the oxidation of tasimelteon, but this causes yellowing of the suspension during storage, particularly after more than 3 months at 40°C / 75% relative humidity. Storage at 40°C / 75% relative humidity for more than 3 months is the accelerated storage condition for products stored at room temperature (satisfactory stability for 6 months at 40°C / 75% relative humidity is required for long-term storage at room temperature / 25°C / 60% relative humidity to be justifiable). Due to the color change from white / off-white to yellow after 3 months of storage at 40°C / 75% relative humidity, it is necessary to store the suspension at 5°C. For storage at 5°C, the accelerated storage condition is 25°C / 60% relative humidity, and data on satisfactory stability up to 6 months under this storage condition is available (i.e., the color change is from white / off-white to a faint yellow). 【0026】 Dissolution The initial dissolution rate of the prototype suspension formulation was rapid (i.e., similar to the HETLIOZ® capsule formulation), but the dissolution rate slowed down during storage for the stored samples. When polysorbate 80 was evaluated as a surfactant / solubility enhancer, it was found to improve the initial solubility profile. However, upon storage, several prototype formulations containing polysorbate 80 showed slower solubility. 【0027】 Only one prototype formulation (containing 4 mg / mL tasimerteon, 200 mg / mL sucrose, 100 mg / mL mannitol, 20 mg / mL Avicel® RC-591, 5 mg / mL cherry flavor, 3 mg / mL ascorbic acid, 3 mg / mL sodium benzoate, 1 mg / mL sucralose, and an appropriate amount of purified water to make 1 mL) yielded satisfactory results in terms of suspension appearance, tasimerteon assay, solubility, impurities / degradation products, and redispersibility. Based on these favorable stability results, this formulation was selected for use in clinical research. 【0028】 opacity Since the concentration of tasimelteon in the suspension is only 4 mg / mL, the appearance of the suspension is rather translucent, far from resembling a proper suspension. Therefore, 100 mg / mL of mannitol is used as an opacity enhancer. While mannitol has a water solubility of approximately 200 mg / mL, its solubility in formulations is likely much lower due to the presence of sucrose, ascorbic acid, sodium benzoate, and Avicel® RC591, which dissolve or hydrate it. This limits the solubility of mannitol in formulations, leaving undissolved particles that impart opacity to the suspension. A small amount of mannitol is likely to dissolve in the suspension formulation, increasing the overall sweetness. 【0029】 Manufacturing process Since the formulation contains several components dissolved or dispersed in a batch volume of purified water, separate portions of the formulation components were prepared (i.e., sucrose was dissolved in hot water (portion 1); tasimelteon, sodium benzoate, ascorbic acid, sucralose, polysorbate 80, and mannitol were dissolved / dispersed and homogenized (portion 2); and Avicel® RC-591 was dispersed in water simply by stirring without homogenization (portion 3)). These three portions were then mixed to obtain the final homogeneous suspension. 【0030】 Avicel® RC-591 polymer dispersions are prepared without homogenization, simply by stirring the polymer in a portion of the batch water. Homogenization of polymer dispersions makes them excessively viscous, which negatively affects the dissolution rate. 【0031】 Due to the low melting point of tasimelteon (approximately 70°C), it is necessary to maintain the temperature of the suspension in the range of 50°C to 55°C to prevent the drug from dissolving. Preparing a liquid pharmaceutical formulation of tasimerteon for oral administration may require an undesirably large amount of solvent to ensure that the active ingredient remains homogeneously dissolved. This is especially true when the water solubility of the active ingredient in the formulation is limited. To address the possibility of requiring unacceptable levels of solvent, the present invention provides a pharmaceutical composition comprising tasimerteon formulated as an aqueous liquid suspension that allows one or more unit doses of tasimerteon to be contained in an optimal volume (e.g., 0.35 mL per 10 mL of liquid suspension). More specifically, one embodiment of the present invention allows one unit dose to contain an effective amount of tasimerteon to treat the individual to whom the drug is administered. 【0032】 Such suspensions are prepared by mixing tasimelteon with a suspending agent in water. The resulting suspensions are homogeneous—that is, uniformly dispersed—and highly stable. These tasimelteon liquid suspensions utilize finely ground tasimelteon that is dispersible within the suspension. Furthermore, the suspended tasimelteon is substantially undissolved in the aqueous vehicle of the formulation (e.g., at least 50%, 75%, or 90% undissolved). 【0033】 In exemplary embodiments, tasimelteon is dispersed homogeneously or substantially homogeneously during shaking or stirring of the pharmaceutical composition. The pharmaceutical composition can be ported for oral administration using a spoon, cup, syringe, straw, pharmaceutical dropper, etc., and has a sufficiently low viscosity to be easily swallowed, including in individuals who have difficulty swallowing pills or capsules, such as pediatric patients, elderly patients, or patients with disabilities. 【0034】 In exemplary embodiments, as described above, the concentration of tasimeltheone in the liquid suspension of the present invention is 1 to 6 mg / mL. Such embodiments include concentrations of 2 to 5 mg / mL, or about 4 mg / mL (e.g., 3.5 to 4.5 mg / mL), or about 1 mg / mL (e.g., 0.5 to 1.5 mg / mL). 【0035】 In exemplary embodiments, the liquid vehicle is an aqueous solution containing a suspending agent and a flavoring agent. The suspending agent is a substance added to the suspension to increase viscosity and slow sedimentation. Examples of such agents include cellulosic suspending agents, clays (e.g., bentonite and silicate), polysaccharide gums (xanthan gum, acacia or gum arabic, and tragacanth), other polysaccharides (agar and carrageenan), synthetic polymers (carbomer, polyvinylpyrrolidone or PVP, and PVP-vinegar). Examples include vinyl acid or PVP copolymers such as PVP-VA, and gelatin. The suspension agent in the pharmaceutical composition is generally effective when present in a concentration range of 1 to 5%. 【0036】 Cellulosic suspensions can impart improved properties to pharmaceutical compositions compared to other types of suspensions. These include better stability, reduced sedimentation, or better homogeneity. Examples of cellulosic suspensions include methylcellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxypropyl methylcellulose (CPMC), hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and powdered cellulose. Pharmaceutical compositions with particularly advantageous properties can be obtained using Methylcellulose A15C hydroxypropyl methylcellulose, or using Avicel® RC-591 microcrystalline cellulose + sodium carboxymethylcellulose. 【0037】 In one exemplary embodiment, the suspension comprises compacted powder particles containing microcrystalline cellulose (MCC) and carboxymethylcellulose sodium (CMC) microcrystals. The powder particles have, for example, a particle size D 60 This product, marketed as Avicel® RC-591 MCC+CMC sodium (FMC Corporation, Philadelphia, Pennsylvania), contains microcrystalline particles smaller than 0.2 μm, and the particles are sufficiently compressed so that each 30 μm diameter particle contains approximately 600 million MCC+CMC microcrystals with a diameter of approximately 0.1 μm. Other MCC+CMC suspensions include the product VivaPur® MCG MCC+CMC sodium (JRS Pharma, Rosenberg, Germany), which is currently on the market. 【0038】 Examples of flavoring agents include sugars (saccharides), polyols such as mannitol and sorbitol, and sweeteners such as synthetic sweeteners like saccharin and aspartame. Flavorings or flavorants (e.g., strawberry flavoring) may also be added to mask the taste of tasimelteon and to make the suspension more palatable, especially for children. 【0039】 Other excipients in aqueous solutions include opacity enhancers, colorants, surfactants (especially nonionic surfactants acting as wetting agents), sweeteners, antioxidants, and preservatives. These and other types of agents optionally contribute to the stability and homogeneity of tasimelteon in the pharmaceutical composition, and more generally to the stability and homogeneity of the suspension, and optionally contribute to the acceptability of the taste and appearance of the suspension (e.g., flavorings and colorants). 【0040】 High-intensity sweeteners are compounds that are several times sweeter than sucrose, and examples include stevia, aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin, and advantame. 【0041】 Opacifiers, also known as opacifying agents, include pharmaceutically acceptable insoluble (or sparingly soluble) particulate solids that reduce translucency and give a suspended appearance. Optionally, an agent may be included in the formulation to adjust its pH. Such agents may be, for example, acids, bases, or buffers, such as sodium hydroxide, phosphoric acid, or citric acid. 【0042】 While different categories of agents are identified by the function they perform in a formulation, various excipients may play multiple roles in a pharmaceutical composition. Furthermore, the pharmaceutical compositions disclosed herein are limited to the specific particle sizes disclosed herein. It's not necessary. 【0043】 Tasimelteon, which is used as an active ingredient in a pharmaceutical composition, is prepared using the same chemistry and manufacturing methods as those known for the preparation of the Tasimelteon active ingredient used, for example, to prepare solid oral dosage forms such as capsules. See, for example, U.S. Patent Application Publication 2009 / 0105333 and PCT Application Publication WO2015 / 123389. Acceptable particle sizes include those described in these publications, which are, for example, D 50 is less than 100 μm, for example D 50 is 20 - 40 μm or 30 - 50 μm. Other exemplary particle size specifications for the Tasimelteon active ingredient are, in particular, D 10 ≦ 30 μm D 50 ≦ 100 μm D 90 ≦ 200 μm or, D 10 ≦ 15 μm D 50 ≦ 45 μm D 90 ≦ 105 μm. are included. 【0044】 The above particle size measurement can be performed using laser diffraction such as laser light scattering detection using a Malvern Mastercizer, for example. In an exemplary particle size analysis using such equipment, a dispersion is prepared by mixing 10 mg of polysorbate 80 and 1 g of tasimelteon in 1 L of distilled water, and then filtered through a 0.2 μm filter. The sampler accessory (Hydro 2000S(A) module) was filled with a dispersant to obtain a background measurement. Then, 80 - 90 mg of the sample dispersed in about 15 mL of the dispersant was slowly added to the sampler accessory until an absorbance (obscuration) of about 15% (e.g., 10% - 20%) was obtained. Before starting the measurement of this sample, it is recirculated at about 2000 rpm for about 5 seconds. Two sample runs are performed and the average result is calculated for D 90 D 50 and / or D10 Get the value. 【0045】 To prepare the suspensions disclosed herein, all components except tasimelteon and other water-insoluble components (e.g., ascorbic acid or sodium benzoate) may be dissolved in purified water and optionally sparged with nitrogen for 30 minutes beforehand. Tasimelteon and other water-insoluble components, such as mannitol, may be sieved, for example, through a 40-mesh screen, to form one or more dispersed phases, which are then dispersed in the solution of the other formulation components. The dispersed phase containing tasimelteon is preferably maintained well below the melting temperature of tasimelteon (about 71°C), for example, below 35°C. The final aqueous suspension may be filled, for example, into 50 mL or 100 mL amber-colored polyethylene terephthalate (PET) bottles and optionally purged with nitrogen before closing the bottles. 【0046】 Aqueous suspensions of tasimelteon containing a cellulosic suspending agent (methylcellulose A15C), an opacity enhancer, a thickener / sweetener, a high-intensity sweetener, a flavoring agent, an antioxidant, and a preservative, such as those described below, may have improved viscosity and sedimentation profiles compared to those using crospovidone + povidone (crospovidone XL-10 + povidone K30), a thickener / sweetener, a high-intensity sweetener, a flavoring agent, an antioxidant, and a preservative. Viscosity measurements can be taken, for example, using a Brookfield viscometer DV-III Ultra 2 hours and 24 hours after each aqueous suspension is prepared. Exemplary pharmaceutical compositions containing PVP and PVP / VA as suspending agents are shown in Table 1. 【0047】 [Table 1] 【0048】 The compositions in Table 1 exhibit acceptable stability. Compositions containing cellulosic suspension agents have improved properties such as increased viscosity and reduced sedimentation. Exemplary compositions are shown in Table 2. [Table 2] 【0049】 A composition containing sucrose instead of sorbitol and also containing sodium chloride may have improved taste and reduced bitterness (or burning sensation). 【0050】 Suspensions of microcrystalline cellulose + carboxymethylcellulose (CMC) sodium at concentrations of 10-30 mg / mL, particularly 20 mg / mL, can provide improved stability and physical appearance (homogeneity). Mannitol is useful as an opacity-imparting agent, for example, when used at 100–300 mg / mL. The range of 100–200 mg / mL, especially 100 mg / mL, results in improved solubility and viscosity, particularly when combined with a reduction in sucrose from 300 mg / mL to 200 mg / mL. The dissolution of tasimelteon is handled by US Pharmacopeia (USP <711> ) can be determined according to, for example, Device: Device 2 (Paddle) Container size / type: 1000mL, clear glass, round bottom Rotation speed: 50 rpm Test temperature: 37±0.5℃ Dissolution medium: 0.1N HCl Sample volume (pull volume): 5 mL Exchange: None Sinker: None Cannula: Stainless steel Filter: Whatman GF / F 0.7μm pore size, syringe filter Discard volume: 2 mL 【0051】 Dissolution within 10-15 minutes is generally 50% or more, for example, 70% or more, for example, 90% or more. 【0052】 Short-term stability tests can be performed for 1 to 3 months under the following storage conditions: (1) 5±3℃, (2) 25±2℃ (relative humidity 60±5%), and 40±2℃ (relative humidity 75±5%). Under these conditions, the total impurities determined by HPLC for pharmaceutically acceptable compositions are, for example, 2.0% or less by weight or 0.5% or less by weight for known impurities, and 0.2% or less by weight for unspecified impurities. 【0053】 Viscosity measurements can be performed, for example, using a Brookfield DV-III Ultra viscometer, 2 hours and 24 hours after each aqueous suspension is prepared. Viscosity values ​​may generally be less than or equal to about 150 cps under ambient environmental conditions (i.e., about 18°C ​​to about 24°C, e.g., about 20°C, and about 1 atm), but viscosity levels in some embodiments are 5 to 100 cps, e.g., 5 to 50 cps or 5 to 20 cps. 【0054】 The specific gravity (relative density) of the suspension is typically greater than 1 mg / mL and about 1.5 mg / mL or less under ambient environmental conditions, for example, 1.1 to 1.3 mg / mL. A satisfactory pH is generally in the range of pH 3 to pH 7, for example, pH 4 to pH 5 or pH 4.0 to pH 4.5. 【0055】 Regarding particle size, the improved result is D 90 ≤150 μm, e.g., 100-150 μm; D 50 ≤80 μm, e.g., 50-70 μm; D 10 It is obtained with particle sizes including ≤50 μm, for example, 15-40 μm. 【0056】 Therefore, in one embodiment, the formulation of the present invention satisfies at least the following specifications for release for commercial distribution. Stability: After storage for 1 month, 2 months, or 3 months under the storage conditions of (1) 5±3℃, (2) 25±2℃ (relative humidity 60±5%), and 40±2℃ (relative humidity 75±5%), the total impurities (HPLC) were 1.5% by weight or less for known impurities and 0.5% by weight or less for unspecified impurities. Viscosity: 5-30 cps, e.g., 20 cps (under ambient environmental conditions) Specific gravity: 1.1~1.3mg / mL pH: 4.0~5.0 Particle size: D 90 =100~150μm, D 50 = 50~70 μm, and D 10 = 15~40μm Dissolution: More than 90% after paddling at 50 rpm for 15 minutes in 1N HCl. 【0057】 As described above, alternative suspension agents include polysaccharide gums. For example, promising results have been obtained using xanthan gum in concentrations of, for example, 1 to 25 mg / mL, preferably 1 to 5 mg / mL. Exemplary compositions containing polysaccharide gum as a suspension agent and titanium dioxide as an opacity imparting agent are given in Table 3. 【0058】 [Table 3] 【0059】 Dosage determination and administration Smith-Magenis syndrome (SMS) is a rare, clinically recognizable syndrome characterized by a distinct pattern of mild craniofacial and skeletal abnormalities, severe speech / language developmental delay, psychomotor and developmental delay, and marked neurobehavioral phenotypes (stereotypic, self-injurious, and aggressive behaviors). SMS and its treatment with tasimertheon are described, for example, in PCT publication number WO2016 / 036619, which is incorporated into this disclosure by reference. 【0060】 One common symptom of SMS is a chronically disrupted sleep pattern, which is seen in all age groups. In a study to determine the efficacy of tasimerteon in treating abnormalities, including SMS, oral formulations (20 mg capsules or 4 mg / mL suspension) and intravenous formulations (0.4 mg / mL) were administered once daily before bedtime to pediatric patients aged 3 to 17 years. 【0061】 The therapeutic effects include improved nighttime sleep (i.e., reduced nighttime behavior that interrupts sleep; improved sleep efficiency; reduced variability in falling asleep; reduced variability in waking up in the morning; and / or improved sleep quality), reduced daytime sleepiness, and reduced behavioral problems (i.e., reduced aggressive behavior, reduced temper tantrums, reduced hyperactivity, and / or reduced The assessment was based on a slight lack of attention. 【0062】 Surprisingly, the consistently effective tasimerteon dose was found to be proportional to body mass (0.7 mg / kg) for patients weighing 28 kg or less, but 20 mg for patients weighing over 28 kg. In other words, the apparent clearance in children weighing over 28 kg was constant and similar to that in adults. This result was unexpected but consistent and independent of other variables, including patient age and sex. 【0063】 Figure 1 shows a graph of the effective dose of tasimerteon as a function of patient weight (measured as apparent clearance; the reverse is systemic exposure). As can be seen, the effective dose is proportional to body weight up to 28 kg (0.7 mg / kg), but thereafter the corresponding effective dose remains constant at 20 mg. 【0064】 Such dosing is applicable to any of the liquid formulations containing tasimerteon described herein, or to any other formulation suitable for administration according to such dosing regimens. For example, the liquid formulation can be used to administer a daily dose of 0.7 mg / kg to patients weighing 28 kg or less, and to administer a daily dose of 20 mg to patients weighing more than 28 kg. Alternatively, the liquid formulation according to the present invention may be used to administer a daily dose of 0.7 mg / kg to patients weighing 28 kg or less, and other tasimerteon formulations, such as capsules, tablets, or intravenous formulations, may be used to administer a daily dose of 20 mg to patients weighing more than 28 kg. 【0065】 Figure 2 is a series of diagrams illustrating various steps of a suitable method for administering a liquid formulation of tasimerteon according to an embodiment of the present invention. In panel A, the bottle containing the liquid formulation of tasimerteon, such as the above formulation, is shaken well for at least 15 seconds (e.g., about 30 seconds or more) before use. This step is shown to be important to ensure that the components in the formulation, including tasimerteon, are thoroughly mixed in order to achieve the benefits described above and enable consistent and accurate dosing of tasimerteon. 【0066】 In both Panel B and Panel C, the bottle cap is removed after shaking, and a bottle adapter is inserted into the neck of the bottle. As those skilled in the art will understand, the use of the bottle adapter is neither important nor necessary, but it is often useful when using a syringe to administer all types of liquid formulations, including the liquid formulation of tasimelteon according to the embodiments of the present invention, as described below. 【0067】 In panels D and E, the syringe is inserted into the opening of the bottle adapter, and both the bottle and the inserted syringe are inverted so that a predetermined amount of liquid formulation can be drawn into the syringe. The drawn dose may then be administered to the patient (not shown) orally, directly from the syringe, or in other ways. In step F, the cap is repositioned onto the bottle until it is ready for reuse. 【0068】 Further exemplary embodiments of the present invention are described in the following set of claims. As with the formulations and methods illustrated above, they are intended to be illustrative and not to limit the present invention. The present invention also includes modifications of such exemplary embodiments. This includes variations. Exemplary embodiments of the present invention are described below. <1> A homogeneous aqueous suspension of tasimerteon, such that one or more unit doses having a volume of 0.35 mL to 10 mL contain a concentration of tasimerteon effective in treating an individual to whom said one or more unit doses are administered; Suspension; Flavoring agent; Opacity-imparting agents; and surfactants A pharmaceutical composition containing, Under ambient environmental conditions, the composition has a viscosity of 150 cps or less and a specific gravity greater than 1 to 1.5. The aforementioned pharmaceutical composition. <2> The suspension comprises at least one cellulosic suspension agent. <1> The composition described above. <3> The at least one cellulosic suspension is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxypropyl methylcellulose sodium (CPMC), carboxymethylcellulose sodium, and microcrystalline cellulose. <2> The composition described above. <4> The above-mentioned at least one cellulosic suspension comprises microcrystalline cellulose and sodium carboxymethylcellulose. <3> The composition described above. <5> The aforementioned microcrystalline cellulose has a diameter of less than 0.2 μm. 60 Having, <4> The composition described above. <6> The opacity imparting agent is selected from the group consisting of insoluble particulate solids and sparingly soluble particulate solids. <1> The composition described above. <7> The opacity-imparting agent is mannitol. <1> The composition described above. <8> The aforementioned flavoring agent is a sweetener selected from the group consisting of monosaccharides, disaccharides, and high-intensity sweeteners. <1> The composition described above. <9> The aforementioned sweetener is sucrose. <8> The composition described above. <10> The total solids content is less than 500 mg / mL. <9> The composition described above. <11> The aforementioned high-intensity sweeteners include stevia, aspartame, sucralose, neotame, acesulfame potassium, saccharin, advantame, and cyclamate. Selected from the following groups, <8> The composition described above. <12> The surfactant is a nonionic surfactant. <1> The composition described above. <13> The nonionic surfactant is polysorbate 80. <12> The composition described above. <14> The polysorbate 80 is present in an amount of 0.5 to 5 mg / mL. <13> The composition described above. <15> The polysorbate 80 is present in an amount of 1 to 3 mg / mL. <14> The composition described above. <16> The aforementioned polysorbate 80 is present in an amount of 1 to 2 mg / mL. <15> The composition described above. <17> The polysorbate 80 is present in an amount of approximately 1 mg / mL. <16> The composition described above. <18> The aforementioned tasimelteon is present at a concentration of 1 to 6 mg / mL, or The aforementioned tasimelteon is present at a concentration of 2-5 mg / mL, or The aforementioned tasimelteon is present at a concentration of 1 mg / mL, or The aforementioned tasimelteon is present at a concentration of 4 mg / mL. <1> ~ <17> A composition described in any one of the following. <19> The aforementioned Tasimertheon 1-6 mg / mL, or 2-5 mg / mL, or 1 mg / mL, or 4 mg / mL It exists at this concentration, The suspension is composed of microcrystalline cellulose and sodium carboxymethylcellulose, 10-30 mg / mL, or 10-20 mg / mL, or 20 mg / mL It exists at this concentration. <1> The composition described above. <20> Mannitol as the opacity imparted agent 200 mg / mL or less, Less than 200 mg / mL, or 50-100 mg / mL, or 100 mg / mL At this concentration, As the aforementioned flavoring agent, sucrose 300 mg / mL or less, Less than 300 mg / mL, or 150-250 mg / mL, or 200 mg / mL At this concentration, High-intensity sweeteners, Polysorbate 80 is used as the surfactant. 1-5 mg / mL, or 1-3 mg / mL, or 2 mg / mL At this concentration, Antioxidants, Sodium chloride, and Flavoring including, <19> The composition described above. <21> Having a pH of 4.0 ± 0.5, <1> ~ <20> A composition described in any one of the following. <22> The following release specifications are met: <1> ~ <21> The composition described in any one of the following: Stability: After storage for 1 month, 2 months, or 3 months at 5±3°C, 25±2°C / 60±5% relative humidity, and 40±2°C / 75±5% relative humidity, the total impurity amount (HPLC) is 1.5% or less by weight for known impurities, 0.5% or less by weight for known impurities, and 0.2% or less by weight for unspecified impurities; Viscosity: 5-30 cps, for example, approximately 20 cps (under ambient conditions) Specific gravity: 1.1~1.3mg / mL pH: 4.0~5.0 Particle size distribution:D 90 =100~150μm, D 50 = 50~70 μm, and D 10 = 15~40μm Dissolution: After 15 minutes of paddling at 50 rpm in 1 N HCl, the solution should be 90 or higher. <23> It contains tasimelteon and a suspension agent, and further, Sugar alcohols, sweetener, Flavoring agent, Flavorings, preservatives, Nonionic surfactants, and Antioxidant Including one or more of the following: A homogeneous aqueous suspension of tasimeltheone. <24> This includes sugar alcohols that are C5 or C6 sugar alcohols, such as C6 sugar alcohols, or specifically mannitol. <23> The composition described above. <25> The aforementioned mannitol 50-500 mg / mL 50-300 mg / mL 100-200 mg / mL, or 100 mg / mL It exists at this concentration. <24> The composition described above. <26> For example, it includes C5 or C6 sugars such as C6 monosaccharides or disaccharides, specifically sucrose. <23> The composition described above. <27> The aforementioned sugar 100-400 mg / mL 150-350 mg / mL, or 300 mg / mL It exists at this concentration. <25> or <26> The composition described above. <28> Furthermore, it contains sodium chloride, <23> ~ <27> A composition described in any one of the following. <29> The NaCl 1-10 mg / mL 3-8 mg / mL, or 5 mg / mL It exists at this concentration. <28> The composition described above. <30> Furthermore, it includes sugar substitutes such as high-intensity sweeteners. <23> ~ <29> A composition described in any one of the following. <31> The particle size of the aforementioned tasimeltheon is D 90 <200 μm, D50 <100、 D 10 <50μm; or D 90 =100~150μm, D 50 = 50~100 μm, D 10 = 5~50μm; or D 90 <150 μm, D 50 <75μm, D 10 <35μm; or D 90 =100~135μm, D 50 = 50~75μm, D 10 = 20~35μm The composition described in any one of <23-30>. <32> Tasimerteon at 1-6 mg / mL, 1-15 mg / mL of hydroxypropyl methylcellulose (HPMC), Mannitol at 200-400 mg / mL, 50-200 mg / mL of sorbitol, Antioxidants, preservatives, High-intensity sweeteners, and Flavoring including, <23> The composition described above. <33> Tasimerteon at 1-6 mg / mL, 5-40 mg / mL of microcrystalline cellulose and sodium carboxymethylcellulose, Mannitol at 100-400 mg / mL, 200-400 mg / mL of sucrose, 1-10 mg / mL of NaCl, Antioxidants, Preservatives, and Flavoring including, <23> The composition described above. <34> Tasimerteon at 1-6 mg / mL, 10-20 mg / mL of microcrystalline cellulose and sodium carboxymethylcellulose, Mannitol at 100-200 mg / mL, 250-350 mg / mL of sucrose, 2-8 mg / mL of NaCl, Antioxidants, Preservatives, and Flavoring including, <23> The composition described above. <35> Having a pH of 4.0 ± 0.5, <1> ~ <34> A composition described in any one of the following. <36> One or more of the following release specifications must be met: <23> ~ <35> The composition described in any one of the following: Stability: After storage for 1 month, 2 months, or 3 months at 5±3°C, 25±2°C / 60±5% relative humidity, and 40±2°C / 75±5% relative humidity, the total impurity amount (HPLC) is 1.5% by weight or less for known impurities and 0.2% by weight or less for unspecified impurities. Viscosity: 5-30 cps, for example, 5-20 cps (under ambient conditions) Specific gravity: 1.1~1.3mg / mL pH: 4.0~5.0 Particle size distribution:D 90 =100~150μm, D 50 = 50~70 μm, and D 10 = 15~40μm Dissolution: After 15 minutes of paddling at 50 rpm in 1 N HCl, the solution should be 90 or higher. <37> Measuring the patient's body mass, and If the patient's weight is 28 kg or less, administer to the patient a first dose of tasimerteon equal to 0.7 mg / kg once daily, or If the patient's weight exceeds 28 kg, the patient should be given a dose of tasimertheon equal to 20 mg. Administer dose 2 once daily. A method for treating Smith-Magenis syndrome (SMS) in patients requiring treatment, including [mention specific treatment details]. <38> The first dose of tasimerteon is administered in liquid form. <37> Methods used. <39> The aforementioned liquid formulation Homogeneous aqueous suspension of tasimeltheone, Suspension, Flavoring agent, Opacity-imparting agent, and surfactants Includes, Under ambient environmental conditions, the composition has a viscosity of 150 cps or less and a specific gravity greater than 1 to 1.5. <38> Methods used. <40> The suspension comprises at least one cellulosic suspension agent. <39> Methods used. <41> The at least one cellulosic suspension is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose (HPMC), carboxypropyl methylcellulose sodium (CPMC), carboxymethylcellulose sodium, and microcrystalline cellulose. <40> Methods used. <42> The above-mentioned at least one cellulosic suspension comprises microcrystalline cellulose and sodium carboxymethylcellulose. <41> Methods used. <43> The aforementioned microcrystalline cellulose has a diameter of less than 0.2 μm. 60 Having, <42> Methods used. <44> The opacity imparting agent is selected from the group consisting of insoluble particulate solids and sparingly soluble particulate solids. <39> Methods used. <45> The opacity-imparting agent is mannitol. <39> Methods used. <46> The aforementioned flavoring agent is a sweetener selected from the group consisting of monosaccharides, disaccharides, and high-intensity sweeteners. <39> Methods used. <47> The aforementioned sweetener is sucrose. <46> Methods used. <48> The total solids content is less than 500 mg / mL. <47> Methods used. <49> The aforementioned high-intensity sweeteners include stevia, aspartame, sucralose, neotame, acesulfame potassium, saccharin, advantame, and cyclamate. Selected from the following groups, <46> Methods used. <50> The surfactant is a nonionic surfactant. <39> Methods used. <51> The nonionic surfactant is polysorbate 80. <50> Methods used. <52> The polysorbate 80 is present in an amount of 0.5 to 5 mg / mL. <51> Those listed Law. <53> The polysorbate 80 is present in an amount of 1 to 3 mg / mL. <52> Methods used. <54> The aforementioned polysorbate 80 is present in an amount of 1 to 2 mg / mL. <53> Methods used. <55> The polysorbate 80 is present in an amount of approximately 1 mg / mL. <54> Methods used. <56> The tasimeltheon in the liquid formulation 1-6 mg / mL, or 2-5 mg / mL, or 1 mg / mL, or 4 mg / mL It exists at this concentration. <38> ~ <55> Any one of the following methods. <57> The suspension is composed of microcrystalline cellulose and sodium carboxymethylcellulose, 10-30 mg / mL, or 10-20 mg / mL, or 20 mg / mL It exists at this concentration. <56> Methods used. <58> The aforementioned liquid formulation is Mannitol as the opacity imparted agent 200 mg / mL or less, Less than 200 mg / mL, or 50-100 mg / mL, or 100 mg / mL At this concentration, As the aforementioned flavoring agent, sucrose 300 mg / mL or less, Less than 300 mg / mL, or 150-250 mg / mL, or 200 mg / mL At this concentration, High-intensity sweeteners, Polysorbate 80 is used as the surfactant. 1-5 mg / mL, or 1-3 mg / mL, or 2 mg / mL At this concentration, Antioxidants, Sodium chloride, and Flavoring including, <57> Methods used. <59> The liquid formulation has a pH of 4.0 ± 0.5. <38> ~ <58> Any one of the following methods. <60> The aforementioned liquid formulation satisfies the following release specifications: <38> ~ <59> The method described in any one of the following: Stability: After storage for 1 month, 2 months, or 3 months at 5±3°C, 25±2°C / 60±5% relative humidity, and 40±2°C / 75±5% relative humidity, the total impurity amount (HPLC) is 1.5% or less by weight for known impurities, 0.5% or less by weight for known impurities, and 0.2% or less by weight for unspecified impurities; Viscosity: 5-30 cps, for example, approximately 20 cps (under ambient conditions) Specific gravity: 1.1~1.3mg / mL pH: 4.0~5.0 Particle size distribution:D 90 =100~150μm, D 50 = 50~70 μm, and D 10 = 15~40μm Dissolution: After 15 minutes of paddling at 50 rpm in 1 N HCl, the solution should be 90 or higher. <61> The further step is to shake the liquid preparation for at least 15 seconds before administering it to the patient. <38> ~ <60> Any one of the following methods. <62> Shaking the liquid formulation for 15 seconds or more before administering it to the patient includes shaking the liquid formulation for 30 seconds or more before administering it to the patient. <61> Methods used.

Claims

[Claim 1] Tasimerteon in doses of 1-6 mg / mL, 1-15 mg / mL of hydroxypropyl methylcellulose, Mannitol at 200-400 mg / mL, 50-200 mg / mL of sorbitol, High-intensity sweeteners, Flavorings, Preservatives, and Antioxidant A homogeneous aqueous suspension of tasimeltheone, containing [the specified substance].

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