RU2806302C1 - Liquid compositions containing tasimelteon and methods of their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to liquid suspensions containing tasimelteon. The pharmaceutical composition of tasimelteon is a homogeneous aqueous suspension and contains tasimelteon at a concentration of 1 to 6 mg/ml; a suspending agent containing microcrystalline cellulose and sodium carboxymethylcellulose, at a concentration of 10 to 30 mg/ml; taste masking agent; opacity agent; and surfactant. Also the following is disclosed: homogeneous aqueous suspensions containing tasimelteon.

EFFECT: group of inventions provides a stable homogeneous aqueous suspension of tasimelteon.

13 cl, 2 dwg, 3 tbl, 1 ex

Description

Cross reference to related applications

This application claims priority over concurrently pending U.S. provisional patent applications. Nos. 62/947774, filed Dec. 13, 2019, 62/972902, filed Feb. 11, 2020, and 63/119488, filed Nov. 30, 2020, each of which is incorporated herein in its entirety as if it were fully brought.

State of the art

The present invention relates to pharmaceutically attractive preparations including liquid suspensions containing tasimelteon (see US patent 5856529, claim 7) or trans-N-[[2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1- yl]methyl]propanamide, which is the active ingredient in HETLIOZ ^® , a medicinal product approved for the treatment of non-24-hour sleep-wake disorder and is commercially available in an oral solid dosage form, those. capsules containing 20 mg of tasimelteon.

In preparing a pharmaceutically attractive suspension containing a drug that is suitable for administration to patients, particularly in the form of a liquid preparation, a number of difficulties arise, typical difficulties may include ensuring physical stability, uniform distribution of the contents, preventing sedimentation, solidification, ensuring redispersibility, preventing crystal growth and unpleasant taste or odor. See Alok K. Kulshreshtha, Onkar N. Singh, and G. Michael Wall (Eds.), “Pharmaceutical Suspensions: From Formulation Development to Manufacturing.” Preparation of a pharmaceutically attractive suspension containing tasimelteon suitable for administration to patients, in particular pediatric patients, is particularly difficult due to factors such as the unpleasant taste of tasimelteon, the need to provide a viscosity suitable for selection and administration of an effective single dose included in a suitable volume of liquid , the need to ensure the chemical stability of preparations containing tasimelteon, the rate of its dissolution and its solubility in a liquid diluent, and the opacity of preparations prepared as suspensions containing tasimelteon. To develop a pharmaceutically attractive drug containing tasimelteon. it is necessary to successfully overcome each of these difficulties and at the same time ensure that the resulting preparation can be easily manufactured.

Previously, U.S. Pat. 5,856,529 (e.g., column 17) discloses that pharmaceutical compositions containing drugs such as tasimelteon can be formulated into preparations suitable for oral administration, including compositions containing a liquid carrier used for the preparation of a syrup or a liquid aqueous suspension, in which may use conventional additives such as suspending agents, emulsifying agents, wetting agents and preservatives, as well as flavoring and/or coloring agents.

Tasimelteon

As is otherwise known in the art, tasimelteon can be obtained as a white to off-white powder having a melting point of about 78° C. (DSC). It is highly soluble in 95% ethanol, methanol, acetonitrile, ethyl acetate, isopropanol, polyethylene glycols (PEG-300 and PEG-400), but slightly soluble in water. The characteristic pH value of a saturated solution of tasimelteon in water is 8.5, and its solubility in water is significantly influenced by the pH value.

Summary of the invention

The present invention as disclosed herein relates to pharmaceutically attractive liquid compositions containing tasimelteon in an aqueous suspension, wherein a pharmaceutical composition having a predetermined volume (for example, 0.35-10 ml) provides a single dose of the active ingredient suspended therein such that, through one or more doses administered to an individual, an amount of tasimelteon is provided that is effective to treat or prevent the disease or condition for which the drug is being administered.

The pharmaceutical compositions of the present invention are tasimelteon-containing homogeneous aqueous suspensions that may contain one or more suspending agents and one or more taste-masking agents. For example, such compositions may contain a cellulose-based suspending agent as a suspending agent. Typical suspension viscosities at ambient conditions are less than or equal to approximately 150 centipoise (cP).

The pharmaceutical composition described above can be formulated to provide an ambient density of greater than 1 to about 1.5. In addition, such preparations may further contain one or more opacifying agents and one or more surfactants, such as a nonionic surfactant, for example, polysorbate 80.

The pharmaceutical composition described above may be one in which the suspending agents useful in the compositions of the present invention are one or more of the following: methylcellulose, hydroxypropylmethylcellulose (HPMC), sodium carboxypropylmethylcellulose (CPMC) or sodium carboxymethylcellulose and microcrystalline cellulose. For example, the pharmaceutical composition of the present invention may contain an opacifying agent, a sweetener and an antioxidant, wherein the suspending agent is microcrystalline cellulose and carboxymethylcellulose or salts thereof. Alternatively, the suspending agent may be microcrystalline cellulose and sodium carboxymethylcellulose. For example, the suspending agents may be (1) microcrystalline cellulose, wherein the diameter of 60% of the microcrystalline cellulose particles (D ₆₀ value) is less than 0.2 microns, and (2) sodium carboxymethyl cellulose.

The pharmaceutical composition described above may be one in which the suspending agents may be ^Avicel® RC-591 (microcrystalline cellulose and sodium carboxymethylcellulose).

An example of a pharmaceutical composition according to the present invention is one that contains an opacifying agent, which is mannitol.

The pharmaceutical composition described above may be one in which the taste-masking agent is a sweetener. The sweetener may include a mono- or disaccharide and a high intensity sweetener, for example, stevioside, aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin, advantam or cyclamate. More specifically, the mono- or disaccharide may be sucrose and the total solids concentration is less than 500 mg/ml. Thus, for example, the concentration of mannitol may be less than 200 mg/ml and the concentration of sucrose may be <300 mg/ml, for example, the concentration of mannitol may be no more than 100 mg/ml and the concentration of sucrose may be no more than 200 mg/ml, and the total the concentration of solids may not exceed 350 mg/ml.

As stated above, these tasimelteon-containing compositions may contain:

(1) a nonionic surfactant, which is polysorbate 80, which is contained at a concentration of 0.5 to 5 mg/ml, including a concentration of 1 to 3 mg/ml (or more preferably 1 to 2 mg /ml, or most preferably about 1 mg/ml). The pharmaceutical composition described above may include one in which: tasimelteon is contained at a concentration of 1 to 6 mg/ml, 2 to 5 mg/ml, 1 mg/ml or 4 mg/ml.

(2) tasimelteon contained at a concentration of 1 to 6 mg/ml or 2 to 5 mg/ml or 1 mg/ml or 4 mg/ml, and a suspending agent which is microcrystalline cellulose and sodium carboxymethylcellulose , which is contained at a concentration equal to (1) from 0 to 30 mg/ml or (2) from 10 to 20 mg/ml, or (3) 20 mg/ml.

(3) mannitol, contained as an opacifying agent, at a concentration equal to (1) not more than 200 mg/ml, or (2) less than 200 mg/ml, or (3) from 50 to 100 mg/ml, or ( 4) 100 mg/ml; sucrose contained as a sweetener at a concentration equal to (1) not more than 300 mg/ml or (2) less than 300 mg/ml, or (3) from 150 to 250 mg/ml, or (4) 200 mg/ml; high intensity sweetener; a polysorbate contained as a nonionic surfactant at a concentration of (1) 1 to 5 mg/ml or (2) 1 to 3 mg/ml or (3) 2 mg/ml; antioxidant, sodium chloride and flavoring agent.

The above compositions can be formulated to achieve the target pH value. Preferably, these compositions are formulated to achieve a target pH of 4.0 ± 0.5. In addition, the compositions are formulated to provide the above characteristics so that they comply with the following release specifications:

(1) stability: after storage under all of the following conditions: (1) at 5±3°C, (2) at 25±2°C (at a relative humidity of 60±5%) and (3) at 40±2 °C (at a relative humidity of 75 ± 5%) for successive periods of 1, 2 or 3 months, the total amount of impurities determined by high performance liquid chromatography (HPLC) is not more than 1.5 wt. %, the amount of known impurities is no more than 0.5 wt. % and the amount of unknown impurities is no more than 0.2 wt. %;

(2) viscosity: 5 to 30 centipoise (cP), for example about 20 cP (at ambient conditions);

(3) density: 1.1 to 1.3 mg/ml;

(4) pH value: 4.0 to 5.0;

(5) particle size distribution: D ₉₀ = 100 to 150 μm, D ₅₀ = 50 to 70 μm and D ₁₀ = 15 to 40 μm;

(6) dissolution: greater than or equal to 90% after stirring in 1N. HCl solution using a paddle device (at a speed of 50 revolutions per minute (rpm)) for 15 minutes.

The above description relating to "particle size distribution" means, expressed as a percentage, the number of particles contained in a sample that have a diameter that is greater than, less than, or equal to a specified value of a physical quantity, for example, D ₅₀ = from 50 up to 70 µm means that 50% of the particles of the same batch contained in the sample have a diameter between 50 and 70 µm. As used in the present invention, "particle size distribution" means obtained by examining tasimelteon particles suspended in the pharmaceutical preparations described in the present invention. This particle size determination can be performed using laser diffraction techniques such as laser light scattering using a Malvern Mastersizer 2000 or Malvern Mastersizer 3000 instrument.

Another aspect of the present invention is a method of treating Smith-Magenis syndrome (CMC) in a patient in need thereof, the method comprising: determining the patient's body weight; and, in the case where the patient's body weight is less than or equal to 28 kg, administering to the patient once daily a first dose of tasimelteon equal to 0.7 mg/kg; or, in the case where the patient's body weight is more than 28 kg, administering to the patient a second dose of tasimelteon equal to 20 mg once daily.

Brief description of drawings

These and other features of the present invention will be better understood by reference to the following detailed description of various aspects of the present invention in conjunction with the accompanying drawings, in which various embodiments and aspects of the present invention are illustrated, in which:

in fig. Figure 1 shows the dependence of the effective dose of liquid preparations containing tasimelteon on the patient’s body weight.

in fig. 2 is a graphical representation of various stages of administration of tasimelteon-containing liquid preparations according to embodiments of the present invention.

It should be noted that the drawings are not drawn to scale. The drawings are intended to illustrate only representative aspects of the present invention and therefore should not be construed as limiting the scope of the present invention.

Detailed Description of the Invention

A number of difficulties arise in the preparation of a pharmaceutically attractive tasimelteon-containing liquid suspension, all of which are overcome in the case of the compositions described below.

Taste

The solubility of tasimelteon in water is ~1 mg/ml. However, in the presence of excipients contained in the formulation, the drug is likely to be substantially insoluble in most suspension formulations. However, trace amounts dissolve and give the drug a bitter taste that is difficult to mask. Accordingly, the following approaches used in the preparation of the drug are believed to improve the taste.

- Inclusion of a combination of sucrose, sucralose and sodium chloride used as sweeteners/flavor masking agents.

- Inclusion of a hydrophilic polymer used as a suspending agent, Avicel ^® RC-591, which hydrates and swells in the presence of water. A certain amount of water is required to properly hydrate and disperse the polymer, and additional water is required to dissolve the ascorbic acid and sodium benzoate. As a result, the amount of water that is available to dissolve the sucrose is limited, so an amount of sucrose of 200 mg/ml is determined to be the maximum amount that can be dissolved.

- Since the concentration of sucrose cannot be increased to more than 200 mg/ml, sucralose as a sweetener is also included at a concentration of 1 mg/ml, this provides a sweet taste and thus helps to better mask the bitter taste.

- Additionally, the inclusion of sodium chloride at a concentration of 5 mg/ml masks the bitter taste and also improves the overall taste.

Viscosity

To ensure that the tasimelteon drug particles are maintained uniformly dispersed after shaking, it is necessary to determine the appropriate viscosity increasing agent and its optimal amount.

Methylcellulose-A15C, methylcellulose-A4M and ^Avicel® RC-591 (microcrystalline cellulose/sodium CMC (carboxymethylcellulose)) are suitable for use as suspending agents. The use of both grades of methylcellulose produces suspensions that contain polymer particles that are not fully hydrated and their viscosities are high, which has a negative impact on their dissolution rates.

The use of Avicel ^® RC-591 at a concentration of 6 mg/ml and without homogenization provides the necessary physicochemical characteristics such as rapid dissolution, complete redispersion when gently shaking the bottles in which the suspension is stored, and satisfactory uniformity of the contents.

Chemical stability

Tasimelteon is susceptible to oxidative decomposition, leading to the formation of three decomposition products, so the use of an antioxidant is necessary in the preparation.

Antioxidants such as sodium bisulfite and sodium sulfite were initially considered, but these may cause allergic reactions in children.

Ascorbic acid oxidizes preferentially, this prevents oxidation of tasimelteon, however it also gives the suspension a yellow color during storage, particularly if stored at 40°C/RH=75% for >3 months, these conditions are the conditions accelerated storage for products stored at room temperature (satisfactory stability at 40°C/75% RH for 6 months is required to confirm long-term storage at room temperature/25°C/60% RH). Since after storage at 40°C/OB=75% for 3 months the color changes from white/almost white to yellow, the suspension must be stored at 5°C, for these conditions the accelerated storage conditions are as follows: i25°C/OB=60 %, and for these storage conditions there are results indicating satisfactory stability for up to 6 months (ie a change from white/almost white to pale yellow). Dissolution

The initial dissolution rate for the experimental suspension formulations was high (i.e., similar to the capsule formulations, HETLIOZ ^® ), but dissolution slowed down during storage of the stability tested samples.

The use of polysorbate 80 as a surfactant/dissolution enhancer was investigated and found to improve the initial dissolution profile, however, after storage of several experimental formulations containing polysorbate 80, they exhibited slower dissolution.

Only one experimental product (containing 4 mg/ml tasimelteon; 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 purified water, ST (as required) to provide a volume of 1 ml) satisfactory results are provided, such as the appearance of the suspension, determination of tasimelteon content, dissolution, amount of impurities/ degradation products and redispersibility. Due to the satisfactory results obtained in the stability study, this drug was selected for use in clinical trials.

Opacity

Since the concentration of tasimelteon contained in the suspension is only 4 mg/ml, the suspension appears rather clear and does not quite look like a suspension, so mannitol is used as an opacifying agent at a concentration of 100 mg/ml.

Although the solubility of mannitol in water is ~200 mg/ml, its solubility in the formulation is likely to be significantly lower due to the presence of sucrose, ascorbic acid, sodium benzoate and Avicel ^® RC-591, which dissolve or hydrate. This limits the solubility of mannitol in the preparation; it remains in the form of undissolved particles and makes the suspension opaque. It is likely that a small amount of mannitol dissolves in the suspension preparation and thus enhances the overall sweet taste.

Cooking method

Since the drug contains several ingredients that are dissolved or dispersed in purified water, the amount of which is necessary to prepare the batch, prepare separate components containing the drug ingredients (i.e., sucrose dissolved in hot water (component 1); tasimelteon, sodium benzoate, ascorbic acid acid, sucralose, polysorbate 80 and mannitol are dissolved/dispersed and (B) homogenized (component 2), and Avicel ^® RC-591 is dispersed in water by simple stirring without homogenization (component 3)). Then the three components are mixed and a homogeneous suspension is obtained.

Avicel ^® RC-591 polymer dispersion is prepared by simply mixing the polymer in a portion of water taken from the quantity required for batch preparation, without homogenization. If the polymer dispersion is homogenized, it becomes too viscous and this has an adverse effect on the dissolution rate.

Due to the low melting point of tasimelteon (~70°C), it is necessary to maintain the temperature of the suspension in the range of 50-55°C to prevent melting of the drug.

When preparing liquid pharmaceutical preparations containing tasimelteon intended for oral administration, undesirably large quantities of solvent may be required to ensure that the active ingredient remains in a uniformly distributed dissolved form, particularly if the active ingredient contained in the preparation has limited solubility in water . To eliminate the possibility that unacceptable amounts of solvent may be required, the present invention provides a pharmaceutical composition containing tasimelteon that is formulated as a liquid aqueous suspension that allows one or more unit doses of tasimelteon to be contained in an optimal volume (e.g., 0. 35 to 10 ml liquid suspension). More specifically, one embodiment of the present invention allows for one single dose to contain an amount of tasimelteon that is effective for treating the individual being administered the drug.

This suspension is prepared by mixing tasimelteon with a suspending agent in water. Suspensions are obtained that are homogeneous, i.e. tasimelteon is homogeneously dispersed and which can be extremely stable. These tasimelteon-containing liquid suspensions contain tasimelteon, which has fine particles and can be dispersed in suspension. In addition, the suspended tasimelteon is substantially undissolved in the aqueous diluent contained in the formulation (eg, at least more than 50% or 75% or 90% is undissolved).

In illustrative embodiments, tasimelteon is uniformly or substantially uniformly dispersed upon shaking or stirring of the pharmaceutical composition. The pharmaceutical composition has a viscosity low enough to be administered orally using a spoon, cup, syringe, straw, pharmaceutical dropper, etc., and is easy to swallow, including for individuals who have difficulty swallowing a tablet or capsule , for example, some pediatric, elderly, or incapacitated patients.

In illustrative embodiments, as noted above, the concentration of tasimelteon contained in the liquid suspensions of the present invention is from 1 to 6 mg/ml. Such embodiments include the use of concentrations that are from 2 to 5 mg/ml, or about 4 mg/ml (for example, from 3.5 to 4.5 mg/ml), or about 1 mg/ml (for example, from 0. 5 to 1.5 mg/ml).

In illustrative embodiments, the liquid diluent is an aqueous solution containing a suspending agent and a taste masking agent. Suspending agents are substances that are added to a suspension to increase viscosity and retard sedimentation. Examples of such agents include cellulose-based suspending agents, clays (including, for example, bentonite and silicates), polysaccharide gums (including xanthan gum, acacia or gum arabic and gum tragacanth), other polysaccharides (including agar-agar and carrageenan), synthetic polymers (including carbomer, polyvinylpyrrolidone or PVP and PVP copolymers such as PVP-vinyl acetate or PVP-VA) and gelatin. Suspending agents contained in pharmaceutical compositions are generally effective if they are contained at a concentration ranging from 1 to 5%.

Compared to other types of suspending agents, cellulose-based suspending agents can impart improved characteristics to a pharmaceutical composition. These include better stability, reduced amount of sediment and better uniformity. Examples of cellulose-based suspending agents are methylcellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxypropyl methylcellulose (CPMC), hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose and powdered cellulose. Pharmaceutical compositions with particularly favorable characteristics can be prepared using methylcellulose A15C, hydroxypropyl methylcellulose, and also using ^Avicel® RC-591 (microcrystalline cellulose + sodium carboxymethylcellulose).

In one illustrative embodiment, the suspending agent includes particles of a compacted powder substance containing microcrystals of microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (CMC), for example, a product sold under the name Avicel ^® RC-591 (MCC + sodium CMC) (FMC Corporation , Philadelphia, RA), which includes particles consisting of microcrystals having a D ₆₀ size of <0.2 μm, where the particles are sufficiently compacted so that a particle having a diameter of 30 μm contains approximately 600 million MCC+ microcrystals CMCs, which have a diameter of approximately 0.1 μm. Other MCC+CMC suspending agents include the product sold under the name ^VivaPur® MCG (MCC + CMC sodium salt) (JRS Pharma, Rosenberg, Germany).

Flavor-masking agents include sweeteners such as saccharides, polyols such as mannitol and sorbitol, and synthetic sweeteners such as saccharin and aspartame. Flavoring agents or flavoring agents (eg cherry flavoring) may also be added to mask the taste of tasimelteon and to make the suspension more palatable, particularly to children.

Other excipients contained in the aqueous solution may include opacifiers, coloring agents, surfactants (particularly nonionic surfactants that act as wetting agents), sweeteners, antioxidants, and preservatives. These agents and other types of agents do not necessarily contribute to the stability and uniformity of distribution of tasimelteon in the pharmaceutical composition and more generally the stability and uniformity of the suspension, and do not necessarily contribute to the acceptability of the taste and appearance of the suspension, for example, in the case of flavoring agents and coloring agents.

High-intensity sweeteners are compounds that are several times sweeter than sucrose and include, for example, stevioside, aspartame, sucralose, neotame, acesulfame potassium (Ace-K), saccharin and advantame.

Opacifying agents, also known as opacifying agents or opacifiers, include pharmaceutically acceptable insoluble (or slightly soluble) particulate solids that reduce clarity and thereby impart a suspension-like appearance.

The preparation optionally includes agents to adjust its pH value, for example, acids, bases or buffers, including sodium hydroxide, phosphoric acid or citric acid.

Although the different categories of agents are defined above according to the function they perform in a formulation, various excipients may perform more than one function in a pharmaceutical preparation. Moreover, the pharmaceutical compositions disclosed herein should not be limited to those that include the specific particle sizes disclosed herein.

Tasimelteon used in pharmaceutical compositions as an active ingredient is prepared, for example, using the same chemical techniques or preparation techniques as known for preparing the active ingredient tasimelteon used for the preparation of solid oral dosage forms, for example, capsules. See, for example, published application US 20090105333 and published PCT application WO 2015/123389. Suitable particle sizes include those described in these publications, for example, D ₅₀ is less than 100 microns, for example, D ₅₀ is from 20 to 40 microns or from 30 to 50 microns. Other exemplary particle size characteristics for the active ingredient tasimelteon include, but are not limited to:

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.

The particle size determination described above can be carried out, for example, using laser diffraction, such as laser light scattering, using a Malvern Mastersizer.

In an exemplary particle size analysis using such an instrument, a dispersion is prepared by mixing 10 mg of polysorbate 80 and 1 g of tasimelteon in 1 L of distilled water and then filtering through a 0.2 μm filter. A dispersant is added to the sampling device (Hydro 2000S(A) module) and the background value is obtained. Then, about 80 to 90 mg of sample dispersed in about 15 mL of dispersing agent is slowly added to the sample collection device until the turbidity is about 15% (eg, 10 to 20%). The sample is rotated at a speed of approximately 2000 rpm for approximately 5 s, then tests are carried out. Two samples are examined and the average values are calculated to obtain D ₉₀ , D ₅₀ and/or D ₁₀ values.

To prepare the suspensions of the present invention, all ingredients of the drug, with the exception of tasimelteon and other poorly water-soluble ingredients (for example, ascorbic acid or sodium benzoate), can be dissolved in purified water, optionally pre-flushed with nitrogen for 30 minutes. Tasimelteon and other slightly water-soluble ingredients, such as mannitol, can be sifted through a 40 mesh sieve to form one or more dispersible phases, and then dispersed in a solution containing the other formulation ingredients. The temperature of the dispersible phases containing tasimelteon is preferably maintained well below the melting point of tasimelteon (~71°C), for example, <35°C. The finished aqueous suspension can be filtered, for example, into amber 50 ml or 100 ml bottles made of polyethylene terephthalate (PET) and optionally purged with nitrogen before closing the bottles.

A tasimelteon-containing aqueous suspension containing a cellulose-based suspending agent (methylcellulose A15C), an opacity agent, a thickener/sweetener, a high-intensity sweetener, a flavoring agent, an antioxidant and a preservative, such as those described below, may have an improved viscosity and sedimentation profile than those containing crospovidone + povidone (crospovidone XL-10 + povidone KZO), thickening agent/sweetener, high intensity sweetener, flavoring agent, antioxidant and preservative. Viscosity studies can be carried out, for example, using a Brookfield DV-III Ultra viscometer at 2 hours and 24 hours after preparation of each aqueous suspension. An exemplary pharmaceutical composition containing PVP and PVP/VA as suspending agents is presented in Table 1.

The composition shown in Table 1 has acceptable stability. Compositions containing cellulose-based suspending agents have improved characteristics such as increased viscosity and reduced sludge formation. Illustrative compositions are presented in Table 2.

Compositions containing sucrose instead of sorbitol and containing sodium chloride may have improved taste and reduced bitterness (or less burning sensation).

The use of microcrystalline cellulose + sodium carboxymethylcellulose (CMC) suspending agent in an amount of 10 to 30 mg/ml, preferably 20 mg/ml, can provide improved stability and appearance (uniformity).

Mannitol is suitable for use as an opacifying agent, for example, when used in an amount of 100 to 300 mg/ml. Using an amount in the range of 100 to 200 mg/ml, preferably 100 mg/ml, provides improved dissolution and viscosity, especially in combination with a reduction in the amount of sucrose from 300 to 200 mg/ml.

The dissolution of tasimelteon is determined in accordance with the United States Pharmacopeia (USP <711>), for example, under the following conditions:

Apparatus: apparatus 2 (with blades)

Vessel size/type: 1000 ml, clear glass, round bottom

Stirring speed: 50 rpm

Test temperature: 37±0.5°C

Solvent medium: 0.1 N. HCl solution

Added volume: 5 ml

Replacement: none

Cargo: none

Cannula: stainless steel

Filter: Whatman GF/F, pore size: 0.7 micron, syringe filter

Excluded volume: 2ml

The amount of dissolved substance after 10-15 minutes is usually at least 50%, for example, at least 70%, for example, at least 90%.

Short-term stability studies can be conducted using the following storage conditions: (1) at 5±3°C, (2) at 25±2°C (relative humidity equal to 60±5%) and (3) at 40±2°C C (at a relative humidity of 75±5%) for 1 to 3 months. When using such conditions, the total amount of impurities for pharmaceutically acceptable compositions, determined by HPLC, is, for example, the following: not more than 2.0 wt. % or not more than 0.5 wt. % of known impurities and not more than 0.2 wt. % unknown impurities.

Viscosity studies can be performed, for example, using a Brookfield DV-III Ultra viscometer at 2 hours and 24 hours after preparation of each aqueous suspension. Viscosity values at ambient conditions (i.e., at a temperature of ~18 to ~24°C, for example at ~20°C, and a pressure of about 1 atm) can typically be up to about 150 cP, however, in some embodiments, the viscosity values may range from 5 to 100 cP, such as from 5 to 50 cP or from 5 to 20 cP.

The density (relative density) of the suspension at ambient conditions is typically greater than 1 and up to about 1.5 mg/ml, such as 1.1 to 1.3 mg/ml.

A satisfactory pH value is usually in the range of 3 to 7, for example 4 to 5 or 4.0 to 4.5.

In terms of particle size, improved results can be obtained using a particle size that includes D ₉₀ ≤150 μm, for example 100 to 150 μm; D ₅₀ ≤80 µm, for example from 50 to 70 µm; D ₁₀ ≤50 µm, for example from 15 to 40 µm.

Thus, in one embodiment, the drug of the present invention meets at least the following specifications for release for commercial distribution: stability: after storage (1) at 5±3°C, (2) at 25±2°C ( at a relative humidity of 60 ± 5%) and (3) at 40 ± 2°C (at a relative humidity of 75 ± 5%) for 1, 2 or 3 months, the total amount of impurities (as determined by HPLC) is not more than 1.5 wt. %, the amount of known impurities is no more than 0.5 wt. % and the amount of unknown impurities is no more than 0.2 wt. %;

Viscosity: 5 to 30 cP, e.g. 20 cP (at ambient conditions);

density: from 1.1 to 1.3 mg/ml;

pH value: from 4.0 to 5.0;

particle size: D ₉₀ = 100 to 150 μm, D ₅₀ = 50 to 70 μm and D ₁₀ = 15 to 40 μm;

solubility: ≥90% after stirring in 1N. HCl solution using a paddle device at a speed of 50 rpm for 15 minutes.

As described above, alternative suspending agents include polysaccharide gums. For example, promising results have been obtained using xanthan gum in an amount of, for example, 1 to 25 mg/ml, preferably 1 to 5 mg/ml. Exemplary compositions containing polysaccharide gum as a suspending agent and titanium dioxide as an opacifying agent are presented in Table 3.

Dosage and Administration

Smith-Magenis syndrome (CMC) is a rare, clinically recognizable syndrome characterized by a distinct form of minor craniofacial and skeletal anomalies, delays in expressive speech/language development, delayed psychomotor development and growth, and a remarkable neurobehavioral phenotype (stereotypies, self-injury, and aggressive behavior). behavior). CMC and its treatment using tasimelteon are described, for example, in PCT publication WO 2016/036619, which is incorporated herein by reference.

One common symptom of CMC is chronic sleep disturbance, which occurs at any age. In studies designed to determine the effectiveness of tasimelteon for the treatment of disorders including CMC, pediatric patients aged 3–17 years were administered oral formulations (20 mg capsule or 4 mg/mL suspension) once daily at bedtime. ) and intravenous administration (0.4 mg/ml).

Treatment efficacy was assessed based on improvements in nighttime sleep (i.e., reduction in nighttime sleep-interrupting activities, improvement in sleep efficiency, reduction in sleep onset variation, reduction in morning wake-up time variation, and/or improvement in sleep quality), decreased sleepiness during the day, reducing behavioral problems (i.e., reducing aggressive behavior, reducing temper tantrums, reducing hyperactivity, and/or reducing attention deficits).

Surprisingly, the consistent efficacy dose of tasimelteon was found to be proportional to body weight (0.7 mg/kg) for those patients weighing 28 kg or less, but 20 mg for those patients weighing more than 28 kg. . This means that the apparent clearance in children weighing more than 28 kg is constant and similar to that observed in adults. This result is unexpected, but it is consistent and independent of other parameters, including patient age and gender.

In fig. Figure 1 shows the dependence of the effective dose of tasimelteon (defined as apparent clearance, for which the opposite parameter is systemic exposure) on the patient’s body weight. As can be seen, the effective dose is proportional to body weight (0.7 mg/kg) up to a body weight of 28 kg, then the corresponding effective dose is constant at 20 mg.

Such dosage is applicable in the case of any of the tasimelteon-containing liquid preparations described in the present invention, or any other preparation suitable for administration in accordance with such a dosage regimen. For example, such liquid preparations can be used to administer to a patient weighing 28 kg or less a daily dose of 0.7 mg/kg, and to administer to a patient weighing more than 28 kg a daily dose of 0.7 mg/kg. dose equal to 20 mg. Alternatively, the liquid preparation of the present invention can be used to administer to a patient weighing 28 kg or less a daily dose of 0.7 mg/kg and another tasimelteon-containing preparation such as a capsule, tablet or formulation for intravenous administration, used for administration to a patient weighing more than 28 kg, a daily dose of 20 mg.

In fig. 2 is a series of graphical representations of various steps of a technique suitable for administering tasimelteon-containing liquid preparations according to embodiments of the present invention.

Box A indicates that a vial containing a liquid preparation containing tasimelteon, such as those described above, is shaken thoroughly for at least 15 seconds (eg, at least about 30 seconds) before use. This step has been shown to be important in ensuring that the drug components, including tasimelteon, are sufficiently mixed to provide the above benefits and consistent, accurate dosing of tasimelteon.

Boxes B and C, respectively, show that after shaking, the vial is opened and the vial adapter is inserted into the neck of the vial. It will be apparent to one skilled in the art that the use of a vial adapter is not critical or necessary, but is often useful when using the syringe described below when administering liquid formulations of all types, including tasimelteon containing liquid formulations consistent with embodiments of the present inventions.

In D and E, respectively, a syringe and vial are inserted into the vial adapter opening and the inserted syringe is inverted to allow the syringe to draw the prescribed amount of liquid drug. The collected dose can then be administered to the patient (not shown) orally, directly from a syringe, or by other means. Box F shows that the bottle is capped before reuse.

Additional illustrative embodiments of the present invention are described in the following claims. Like the preparations and methods described above, they are intended to illustrate and not limit the present invention, which includes modifications and variations of such illustrative embodiments.

Claims (56)

1. Pharmaceutical composition of tasimelteon, which is a homogeneous aqueous suspension containing: tasimelteon at a concentration of 1 to 6 mg/ml; a suspending agent containing microcrystalline cellulose and sodium carboxymethylcellulose, at a concentration of 10 to 30 mg/ml; taste masking agent; opacity agent; And surface-active substance. 2. The composition of claim 1, wherein the suspending agent further comprises at least one cellulose-based suspending agent selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose (HPMC) and sodium carboxypropylmethylcellulose (CPMC). 3. The composition according to claim 1, wherein the opacifying agent is mannitol. 4. The composition of claim 1, wherein the taste-masking agent is a sweetener selected from the group consisting of monosaccharides, disaccharides and high-intensity sweeteners. 5. The composition according to claim 4, in which the sweetener is sucrose. 6. The composition of claim 5, wherein the total solids content is less than 500 mg/ml. 7. The composition of claim 4, wherein the high-intensity sweetener is selected from the group consisting of the following: stevioside, aspartame, sucralose, neotame, acesulfame potassium, saccharin, advantame and cyclamate. 8. The composition according to claim 1, wherein the surfactant is a nonionic surfactant. 9. The composition according to claim 8, in which the nonionic surfactant is polysorbate 80. 10. The composition according to claim 9, in which polysorbate 80 is contained in an amount of from 0.5 to 5 mg/ml. 11. A composition according to claim 1, having, under ambient conditions, a viscosity of less than or equal to 150 cP and a density of greater than 1 and up to 1.5. 12. A homogeneous aqueous suspension containing tasimelteon, used for the preparation of a pharmaceutical composition containing from 1 to 6 mg/ml tasimelteon; from 1 to 15 mg/ml HPMC; from 200 to 400 mg/ml mannitol; from 50 to 200 mg/ml sorbitol; And antioxidant; preservative; high intensity sweetener; And flavoring substance. 13. The suspension according to claim 12, in which the particle size of tasimelteon is as follows: D90 < 200 µm; D50 < 100 µm; D10 < 50 µm; or D90 = 100 to 150 µm; D50 = 50 to 100 µm; D10 = 5 to 50 µm; or D90 < 150 µm; D50 < 75 µm; D10 < 35 µm; or D90 = 100 to 135 µm; D50 = 50 to 75 µm; D10 = 20 to 35 µm. 14. A homogeneous aqueous suspension containing tasimelteon, used for the preparation of a pharmaceutical composition, containing: from 1 to 6 mg/ml tasimelteon; from 5 to 40 mg/ml microcrystalline cellulose and carboxymethylcellulose sodium salt; from 100 to 400 mg/ml mannitol; from 200 to 400 mg/ml sucrose; from 1 to 10 mg/ml NaCl; antioxidant; preservative; And flavoring substance. 15. A homogeneous aqueous suspension containing tasimelteon, used for the preparation of a pharmaceutical composition, containing: from 1 to 6 mg/ml tasimelteon; from 10 to 20 mg/ml microcrystalline cellulose and carboxymethylcellulose sodium salt; from 100 to 200 mg/ml mannitol; from 250 to 350 mg/ml sucrose; from 2 to 8 mg/ml NaCl; antioxidant; preservative; And flavoring substance.