Treatment methods for social anxiety disorder using BNC210

Abstract

The present invention relates to a method for treating anxiety associated with social anxiety disorder (SAD), also known as social phobia, by administering BNC210 or its salts or prodrugs.

Description

Technical Field

[0001] Field The present invention generally relates to methods for treating social anxiety disorder (SAD), also known as social phobia.

Background Art

[0002] Background Social anxiety disorder (SAD) is a chronic mental health condition characterized by recurrent, disproportionate fear and irrational anxiety triggered by social interaction.

[0003] For people with SAD (also known as social phobia), everyday social interactions can trigger various levels of irrational anxiety, fear, self-consciousness, and embarrassment. Symptoms can include excessive fear of situations that may be judged (e.g., normal social or work settings such as giving a work presentation), concern about shame or humiliation, or fear of angering someone.

[0004] According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), there are a total of 10 diagnostic criteria for SAD: 1. Fear or anxiety specific to the social situation that occurs when a person feels they are being watched, observed, or scrutinized. In adults, this can include first dates, job interviews, meeting new people for the first time, oral presentations, or speaking in class or meetings. In children, the fear / avoidance behavior should occur in the context of interactions with peers rather than with adults and may be expressed by age-appropriate distress such as shrinking, crying, or showing obvious fear or discomfort. 2. Typically, an individual may fear expressing their anxiety and experiencing social rejection. 3. Social interactions can consistently cause distress. 4. Avoid social interactions or endure them reluctantly with distress. 5. Fear and anxiety are markedly disproportionate to the actual situation. 6. Fear, anxiety, or other distress related to a social situation that may last for more than six months. 7. In one or more areas, such as interpersonal functioning or occupational functioning, causing personal distress and impairment, 8. Fear or anxiety cannot be caused by a medical disorder, substance use, or harmful drug effect, or 9. Not attributable to another mental disorder, and 10. If there is another medical condition that may cause the individual to be overly self-conscious, such as a prominent facial scar, the fear and anxiety are unrelated or disproportionate. Clinicians may also include a designator that the social anxiety is specific to a performance situation (e.g., an oral presentation).

[0005] The median age of onset for social anxiety disorder (SAD) in the United States is approximately 13 years, and it has been reported that about 75% of SAD patients develop the disorder between the median age of 8 and 15 years. Onset can be either insidious or triggered by a specific event. The DSM-5 states that the overall annual prevalence of SAD in the United States is approximately 7% (both in children and adults).

[0006] The DSM-5 identifies temperamental traits such as low social standing and fear of inhibition as risk factors for developing SAD, and notes that child abuse (including peer abuse) is a correlated risk factor for SAD, although a causal relationship has not been established. While genetic factors may play a role, it can also be argued that SAD can be a learned behavior. Obesity has been identified as a risk factor for adolescents because obese teenagers may experience peer rejection and develop social anxiety as a learned behavior.

[0007] In efforts to treat social anxiety disorder (SAD), the use of exposure-focused cognitive behavioral therapy (CBT) may help reduce the symptoms of social anxiety disorder. Exposure therapy involves gradually placing the individual in anxiety-inducing situations and associating the feared stimulus with a relaxing or indifferent response. This is also known as systematic desensitization and has been shown to be effective to varying degrees. [Overview of the project] [Problems that the invention aims to solve]

[0008] Currently, there are no approved medications on the market for acute or as-needed (PRN) use when SAD patients face social situations that could otherwise be avoided or that they feel they cannot cope with. Therefore, there is a need to develop effective acute drug therapies to treat patients, particularly children and young adults diagnosed with SAD. [Means for solving the problem]

[0009] Summary of the Invention In one embodiment, the present invention provides at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS score (subjective units of the distress scale) by at least 5 units compared to a placebo control.

[0010] In another embodiment, the present invention relates to at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in a patient, comprising the step of administering a tablet containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and the single-dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) score by at least 5 units compared to the placebo control, and the tablet is administered to the patient at least about 20 minutes before the expected anxiety-provoking event.

[0011] In another aspect, the present invention provides a method for minimizing or reducing a recurrent episodic disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet comprising at least about 100 mg of a compound of formula (I):

Chemical formula

[0012] In a further aspect, the present invention provides a method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet comprising at least about 100 mg of a compound of formula (I):

Chemical formula

[0013] In a further aspect, the present invention provides a method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet comprising at least about 100 mg of a compound of formula (I):

Chemical formula

[0014] In another aspect, the present invention provides a method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be exacerbated by an anticipated anxiety-provoking event in a patient, comprising administering a tablet comprising at least about 100 mg of formula (I): [Chemical formula] administering a tablet comprising a compound or a salt or prodrug thereof, to provide a method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be exacerbated by an anticipated anxiety-provoking event in a patient, The patient is characterized by moderate to severe SAD, and a single-dose of the tablet can reduce the patient's STAI-State score (Spielberger's State-Trait Anxiety Inventory-State component) by 3 to 20 units compared to a placebo control, and the tablet is administered to the patient at least about 20 minutes before the anticipated anxiety-provoking event.

[0015] In another aspect, the present invention provides a method for minimizing or reducing a recurrent episodic disorder associated with social anxiety disorder (SAD) in a patient, comprising administering a tablet comprising at least about 100 mg of formula (I): [Chemical formula] administering a tablet comprising a compound or a salt or prodrug thereof, to provide a method for minimizing or reducing a recurrent episodic disorder associated with social anxiety disorder (SAD) in a patient, The patient is characterized by moderate to severe SAD, and a single-dose of the tablet can reduce the patient's STAI-State score (Spielberger's State-Trait Anxiety Inventory-State component) by 3 to 20 units compared to a placebo control.

[0016] In a further embodiment, the present invention provides at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by 3 to 20 units compared to a placebo control. The patient is administered the tablet at the first onset of panic symptoms.

[0017] In a further embodiment, the present invention provides at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control.

[0018] In another embodiment, the present invention relates to at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in a patient, comprising the step of administering a tablet containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control, and the patient is administered the tablet at least about 20 minutes before an anticipated anxiety-inducing event.

[0019] In another embodiment, the present invention relates to at least about 100 mg of formula (I): [ka] The present invention provides a method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control.

[0020] In a further embodiment, the present invention provides at least about 100 mg of formula (I): [ka] The present invention provides a method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control. The patient is administered the tablet at the time of the first onset of panic symptoms.

[0021] In one embodiment, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS score (subjective units of the distress scale) by at least 5 units compared to a placebo control.

[0022] In another aspect, the present invention relates to a formulation of at least about 100 mg of Formula (I) for use in reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) score by at least 5 units compared to a placebo control, and the patient is administered the tablet at least about 20 minutes before the expected anxiety-inducing event.

[0023] In another aspect, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of the Distress Scale) by at least 5 units compared to a placebo control.

[0024] In a further embodiment, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) by at least 5 units compared to a placebo control. The patient is administered the tablet at the first onset of panic symptoms.

[0025] In a further embodiment, the present invention relates to a formulation of formula (I) of at least about 100 mg for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by 3 to 20 units compared to a placebo control.

[0026] In another aspect, the present invention relates to a formulation of at least about 100 mg of Formula (I) for use in reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State score (Spielberger State-Trait Anxiety Scale-State component) by 3 to 20 units compared to a placebo control, and the patient is administered the tablet at least about 20 minutes before an anticipated anxiety-inducing event.

[0027] In another aspect, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by 3 to 20 units compared to a placebo control.

[0028] In a further embodiment, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by 3 to 20 units compared to a placebo control. The patient is administered the tablet at the first onset of panic symptoms.

[0029] In a further embodiment, the present invention relates to a formulation of formula (I) of at least about 100 mg for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control.

[0030] In another aspect, the present invention relates to a formulation of at least about 100 mg of Formula (I) for use in reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control, and the patient is administered the tablet at least about 20 minutes before an anticipated anxiety-inducing event.

[0031] In another aspect, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control.

[0032] In a further embodiment, the present invention relates to a formulation of at least about 100 mg of formula (I) for use in reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound or a salt or prodrug thereof. The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control. The patient is administered the tablet at the time of the first onset of panic symptoms.

[0033] In one embodiment, a method is disclosed that follows any of the above embodiments, in which approximately 225 mg of the compound of formula (I) or a salt or prodrug thereof is administered. In a particular embodiment, the above method of use includes the administration of 225 mg of the compound of formula (I) or a salt or prodrug thereof.

[0034] In another embodiment, a method is disclosed that follows any of the above embodiments, in which approximately 450 mg of the compound of formula (I) or its salt or prodrug is administered. In a particular embodiment, the above method of use includes the administration of 450 mg of the compound of formula (I) or its salt or prodrug. In another embodiment, the method includes the administration of two tablets, each containing approximately 225 mg of the compound of formula (I) or its salt or prodrug.

[0035] In yet another embodiment, a method is disclosed that follows any of the above embodiments, in which approximately 675 mg of the compound of formula (I) or its salt or prodrug is administered. In a particular embodiment, the above method of use includes the administration of 675 mg of the compound of formula (I) or its salt or prodrug. In another embodiment, the method includes the administration of three tablets, each containing approximately 225 mg of the compound of formula (I) or its salt or prodrug.

[0036] In a further embodiment, the present invention relates to a formulation of formula (I) of approximately 225 mg for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: [ka] The present invention provides tablets containing the compound.

[0037] In one embodiment, the tablets can achieve the required reduction of anxiety within approximately 20 to 90 minutes of administration.

[0038] In one embodiment, the tablet can achieve the required reduction of anxiety within approximately 20 to 90 minutes of administration, and the reduction can be maintained for at least 5 hours from a single dose.

[0039] In one embodiment, the patient is under approximately 35 years of age.

[0040] In one embodiment, the patient is under approximately 30 years of age.

[0041] In one embodiment, the patient is approximately 13 to 25 years old.

[0042] In one embodiment, the patient is a pediatric patient.

[0043] In one embodiment, the patient is a child patient approximately 13 to 18 years of age.

[0044] In one embodiment, the tablets are administered in doses ranging from approximately 100 mg to approximately 300 mg.

[0045] In one embodiment, the tablets are administered in doses ranging from approximately 100 mg to approximately 300 mg to achieve an average Cmax plasma concentration of approximately 500 to 3000 ng / mL.

[0046] In one embodiment, the tablets are administered in doses ranging from approximately 300 mg to approximately 700 mg.

[0047] In one embodiment, the tablets are administered in doses ranging from approximately 300 mg to approximately 700 mg to achieve an average Cmax plasma concentration of approximately 3000 to 8000 ng / mL.

[0048] In certain embodiments, the tablets contain about 100 mg to 700 mg of the compound of formula (I) or a salt or prodrug thereof.

[0049] In certain embodiments, a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by 2 to 150 units compared to a placebo control.

[0050] In certain embodiments, patients are characterized by moderate to severe SAD with a Leibowitz Social Anxiety Scale (LSAS) score greater than approximately 60 and less than approximately 100. [Brief explanation of the drawing]

[0051] Brief explanation of the drawing [Figure 1] Graph of mDSC of spray-dried dispersion; reversible heat flow versus temperature. [Figure 2] XRPD graph of spray-dried dispersions; intensity vs. 2-theta. [Figure 3] Chart for designing a SAD speech challenge research project. [Figure 4] Graph showing the change in mean SUDS score from baseline relative to the amount of compound (I) and placebo tablets. [Figure 5] Area under the curve (AUC) of the mean change from the baseline SUDS score over time at various stages. [Modes for carrying out the invention]

[0052] Detailed explanation tablet The present invention is based on the effective administration of a solid-state drug formulation of a compound of formula (I), specifically, a tablet formulation comprising a solid dispersion.

[0053] The present invention also provides a solid drug formulation, specifically a tablet formulation, comprising the solid dispersion, prepared by dry granulation and compression.

[0054] In certain embodiments, the tablet comprises at least one pharmaceutically acceptable polymer, which is at least one crystallization inhibitor polymer.

[0055] In further embodiments, the tablet comprises an effective amount of (i) a compound of formula (I) or a salt or prodrug thereof, and (ii) a solid dispersion comprising a certain amount of at least one crystallization inhibitor polymer, wherein the ratio of (i):(ii) is about 10:90 to about 80:20 (wt / wt%).

[0056] During pre-formulation studies, the inventors noted that the compound of formula (I) exhibited a high melting point, low in vitro solubility of the crystalline form of compound I (a thermodynamically stable form observed when the amorphous form of compound I is exposed to water / moisture), and low oral exposure, which increased with the addition of 0.5% HPMC to the suspension formulation and depended on the feeding / fasting state of the subject. In connection with this, it was observed that there was a need to develop alternative formulations for further development focused on preventing (or at least substantially minimizing) the formation of poorly soluble crystalline forms, reducing the effects of food, and increasing oral exposure. Solid dispersion techniques such as thermal fusion extrusion (HME) and spray drying, lipid formulation, and nanosizing were considered methods to overcome the shortcomings of these formulations. Considering the target dose of the compound and its good solubility in a mixture of dichloromethane (DCM) and methanol, the inventors recognized that the compound of formula (I) could be suitable for spray drying. Undesirable drug / drug interactions leading to crystallization have been shown to be avoided, for example, when a specific crystallization inhibitor polymer is used in a spray-dried amorphous solid dispersion of a drug (compound of formula (I)) usable for tablet preparation (see Figure 1). Preferred ratios of compound (I) to polymer are discussed below and can result in a favorably high loading of the API in the subsequent tablet formulation. These resulting tablet formulations are shown to exhibit good in vivo solubility and avoid, or at least minimize, the effects of any adverse diet.

[0057] In certain embodiments, the present invention relates to a polymer matrix formed by a pharmaceutically acceptable polymer in which formula (I) is dispersed: [ka] The administration of tablets prepared from a solid dispersion containing the compound or a salt thereof or a prodrug.

[0058] In other embodiments, the present invention is (i) Formula (I) for at least 100 mg (e.g., 100 mg to 700 mg): [ka] A compound or a salt thereof or a prodrug, (ii) Crystallization inhibitor polymer and The administration of tablets containing [the substance] is included, and the ratio of (i):(ii) is approximately 10:90 to approximately 80:20 (wt / wt%).

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. For the purposes of the present invention, the following terms are defined below.

[0060] "BNC210" is represented by the following equation (I): [ka] It refers to the compound.

[0061] This compound and its salts can be prepared as defined in PCT / AU2007 / 001566 (International Publication No. 2008 / 046135), the entirety of which is incorporated herein by reference.

[0062] An “excipient” is a pharmaceutically inert substance that functions as a vehicle or medium for a drug or other active substance, and the “crystallization inhibitor polymer” as described herein is distinct from the use of the term “excipient” as used herein. Accordingly, in certain embodiments, the present invention envisions a composition comprising BNC210, at least one crystallization inhibitor polymer, and one or more excipients.

[0063] The terms “administer,” “give administration,” or “dosage” in relation to the compounds, compositions, or formulations of the present invention mean introducing the compound into the body of a patient requiring treatment. When the compounds of the present invention are provided in combination with one or more other active agents, “dosage” and its variations are understood to include the simultaneous and / or sequential introduction of the compound and the other active agents, respectively.

[0064] HPMC, also known as hypromellose, is the excipient hydroxypropyl methylcellulose. It is a semi-synthetic, inert, viscoelastic polymer. This is a nonionic, hydrophilic derivative of cellulose ether, stable over a pH range of 3 to 11. One preferred example is HPMC E15 LV (marketed by Dupont as METHCEL® E15 Industrial LV), a low-viscosity grade premium polymer with approximately 15 cP.

[0065] HPMCAS is the excipient hydroxypropyl methylcellulose acetate succinate (or hypromellose acetate succinate), primarily used as an enteric coating material for both conventional enteric coatings and sustained-release formulations, and contains varying amounts of acetyl and succinoyl groups in the polymer. Several types of HPMCAS exist that dissolve at various pH levels. Type L HPMCAS represents polymers with a high ratio of succinoyl substitutions to acetyl substitutions (S / A ratio), Type H represents polymers with a low S / A ratio, and Type M represents polymers with a moderate S / A ratio higher than that. Type L HPMCAS dissolves at a lower pH (≧5.5) compared to Type M at pH ≧6.0 and Type H at pH ≧6.8.

[0066] "Cellulose - microcrystalline" is an excipient, often called refined wood pulp, and is frequently used as a texturizer, anti-caking agent, suspending agent, and adsorbent. It is often sold under the trade name Avicel PH-105 as microcrystalline cellulose.

[0067] Croscarmellose sodium or sodium croscarmellose is the sodium salt of internally bonded carboxymethylcellulose and is used as a superdisintergrant. It is marketed, among other things, by FMC Biopolymer under the trade name Ac-Di-Sol SD711.

[0068] Colloidal silica (also known as silicon dioxide or colloidal silicon dioxide) is used in the preparation of tablets as an anti-caking agent, adsorbent, disintergrant, or flow enhancer, allowing for improved fluidity when tablets are processed. It is marketed, among other things, by Cabot under the trade name Cab-O-Sil MP.

[0069] Sodium stearyl fumarate (also known as monostearyl sodium fumarate or monooctadecyl sodium fumarate) is a water-soluble lubricant used to aid in tablet compression. It is marketed, among other things, by JRS Pharma under the trade name Pruv SSF.

[0070] "PVP-VA" (also known as PVP / VA copolymer, poly(l-vinylpyrrolidone-co-vinyl) acetate, copovidone, or PVP VA64) is a randomly linearly arranged vinylpyrrolidone-vinyl acetate copolymer (vinyl acetate-vinylpyrrolidone copolymer) produced by free radical polymerization of monomers in a vinyl acetate to vinylpyrrolidone ratio ranging from 70:30 to 30:70. It is also known by trade names such as Polectron 845, Luviskol VA 281, Kolima 10, 35, Ganhon S 860, or Ganex E313.

[0071] "CAP" (also known as cellulose acetate, ceracephate, 1,2-benzenedicarboxylate) is a cellulose acetate phthalate polymer that is insoluble in water, alcohol, hydrocarbons, and chlorinated hydrocarbons. It is often used as an enteric coating material.

[0072] "Eudragit" is a common trade name for copolymers derived from acrylic acid and methacrylic acid esters, containing methacrylate monomers in a ratio ranging from 2 to 3, such as methacrylic acid, methacrylic acid esters, and dimethylaminomethyl methacrylate.

[0073] Soluplus® is a polyvinylcaprolactam-polyvinyl acetate polyethylene glycol graft copolymer (PCL-PVAc-PEG) available from BASF. It is a water-soluble copolymer with an average molecular weight ranging from 90,000 to 140,000 g / mol and can solubilize poorly water-soluble drugs.

[0074] In the formulations of the present invention, the main active ingredient is a compound of formula (I) or a salt or prodrug thereof. The amount of compound of formula (I) contained in the formulation is effective in providing therapeutic plasma concentrations in the subject for up to 24 hours. In one embodiment, when presented as a tablet, the formulation contains about 100 mg to about 700 mg of the active ingredient. In one embodiment, when presented as a tablet, the formulation contains about 100 mg to about 300 mg of the active ingredient. In one embodiment, when presented as a tablet, the formulation contains about 200 mg to about 400 mg of the active ingredient. In another embodiment, the tablet formulation contains about 200 mg to about 500 mg of the active ingredient. In another embodiment, the tablet formulation contains about 225 mg of the active ingredient. In another embodiment, the tablet formulation contains about 450 mg of the active ingredient. In another embodiment, the tablet formulation contains about 675 mg of the active ingredient.

[0075] It will be recognized that the solid dispersion formulations disclosed herein comprise only the compound of formula (I) and at least one pharmaceutically acceptable polymer, i.e., at least one crystallization inhibitor polymer. This solid dispersion will ultimately be mixed with further excipients before tablet formation, and such formulations (i.e., the solid dispersion and added excipients) are referred herein to as pre-tablet formulations.

[0076] For example, a 1-gram tablet provided by the present invention may contain 60% solid dispersion and 40% other excipients (on a %wt / %wt basis), which will be discussed further herein. It will also be recognized that in the case of a 1.1 g tablet containing 225 mg of compound (I), 60% of the tablet may consist of a 60% wt / 40% wt solid dispersion / excipient mixture, and the solid dispersion may be calculated to have 35% wt of compound (I).

[0077] Accordingly, the tablet formulations of the present invention may also include combinations of formulation excipients that enable the immediate release of the active ingredient throughout the gastrointestinal tract. This is achieved through a rapid dissolution control process by swelling and matrix erosion under the influence of a medium, allowing the active ingredient to be released. In certain embodiments, the formulations disclosed herein are immediate-release formulations, exhibiting, for example, about 70% dissolution in the first 15 minutes.

[0078] The solid dispersions, pre-tablet formulations and tablet formulations discussed herein each contain an effective amount of the compound of formula (I) dispersed within a polymer matrix formed by at least one pharmaceutically acceptable polymer or crystallization inhibitor polymer (used interchangeably) to ensure that the compound of formula (I) is held in a substantially amorphous form.

[0079] In certain embodiments, the ratio of (i):(ii) is approximately 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, and approximately 80:20 wt / wt%.

[0080] In certain embodiments, the crystallization inhibitor polymer is a polymer excipient selected from the group consisting of HPMCAS-M, HPMCAS-H, HPMCAS-L, PVP-VA, HPMC (e.g., HPMC EI5LV), and Soluplus.

[0081] In certain embodiments, the crystallization inhibitor polymer is HPMCAS-H.

[0082] In certain embodiments, the crystallization inhibitor polymer is HPMCAS-M.

[0083] In certain embodiments, the crystallization inhibitor polymer is HPMC E15 LV.

[0084] In certain embodiments, the crystallization inhibitor polymer is HPMCAS-L.

[0085] In certain embodiments, the crystallization inhibitor polymer is PVP-VA.

[0086] In one embodiment, the solid dispersion formulations disclosed herein are produced by spray drying. In one embodiment, the total weight (wt%) of the solid in the solution to be spray-dried is 2 to 15% wt, for example, about 2 to 10% wt.

[0087] In certain embodiments, the spray-drying solvent includes dichloromethane.

[0088] In certain embodiments, the spray-drying solvent includes dichloromethane and methanol.

[0089] In certain embodiments, the spray-drying solvent contains dichloromethane and methanol in a weight-to-weight ratio of about 90:10 to 60:10, for example, about 85:15, 80:20, 75:25, 70:30, and about 65:35 wt / wt%.

[0090] In certain embodiments, the yield of the spray-dried dispersion is approximately 50-100%.

[0091] In one embodiment, the solid dispersion formulation disclosed herein is manufactured by fused thermal extrusion (HME). In a particular embodiment, the extruded material is manufactured at a temperature of approximately 160–190°C.

[0092] The pre-tablet formulation and the tablet formulation may also contain microcrystalline cellulose, which is known in the art to be purified partially hydrolyzed polymerized cellulose prepared by treating α-cellulose obtained as pulp from plant material with mineral acid. In one embodiment, the tablet formulation or pre-tablet formulation contains about 30% to about 60% (%wt / wt, based on the total weight of the tablet) of microcrystalline cellulose. In another embodiment, the tablet formulation or pre-tablet formulation contains about 35% to about 55% (%wt / wt) of microcrystalline cellulose. In yet another embodiment, the pre-tablet formulation and the tablet formulation contain about 40% to about 50% (%wt / wt) of microcrystalline cellulose.

[0093] In one embodiment, the pre-tablet formulation and the tablet formulation contain about 0.2% to about 2% (%wt / wt, based on the total weight of the tablet) of sodium stearyl fumarate (SSF). In another embodiment, the pre-tablet formulation and the tablet formulation contain about 0.3% to 1.5% (%wt / wt) of SSF. In yet another embodiment, the pre-tablet formulation and the tablet formulation contain about 0.5% to 1% (%wt / wt) of SSF. In yet another embodiment, the formulation contains about 0.5% to 0.8% (%wt / wt) of SSF.

[0094] In other embodiments, the pre-tablet formulation and the tablet formulation contain approximately 0.8% to 2.5% (%wt / wt) of croscarmellose sodium based on the total weight of the tablet. In yet another embodiment, the pre-tablet formulation and the tablet formulation contain approximately 1% to 2% (%wt / wt) of croscarmellose sodium. In yet another embodiment, the pre-tablet formulation and the tablet formulation contain approximately 1.2% to 1.8% (%wt / wt) of croscarmellose sodium.

[0095] In other embodiments, the pre-tablet formulation and the tablet formulation contain approximately 0.5% to approximately 2% (%wt / wt, based on the total weight of ferrous sulfate) of colloidal silica. In yet another embodiment, the pre-tablet formulation and the tablet formulation contain approximately 0.7% to approximately 1.5% (%wt / wt) of colloidal silica. In yet another embodiment, the formulation contains approximately 0.9% to approximately 1.3% (%wt / wt) of colloidal silica.

[0096] In certain embodiments, the tablet formulation includes a coated tablet. The coating component may therefore include polymers, plasticizers, and pigments, which are mixed together and finely dispersed as a film on the tablet to protect the tablet, maintain its shape, aid swallowing, and provide a glossy appearance. In the above formulation, a poly(vinyl alcohol) (PVA)-based coating formulation is used.

[0097] In other embodiments, to further aid solubility, the formulation may also include a surfactant selected from SLS (sodium lauryl sulfate) or sorbate. If added, the surfactant may be present in amounts less than 5% (wt / wt of the total formulation), for example, about 4%, about 3%, about 2%, about 1%, or less than 1%.

[0098] Surfactants can be added either during the solid dispersion or formulation stage.

[0099] Tablet Formation Process In certain embodiments, the excipients and solid dispersions (containing the compound of formula (I)) of the pre-tablet formulation can be combined and advantageously processed by a dry granulation process which may consist of intragranular blending, roller compression, de-lumping, and extragranular blending. This has been found to be advantageous because it further helps to maintain the compound of formula (I) in an amorphous state. Furthermore, such a process has been found to produce granules with flow properties suitable for compression in a tablet press. The granules can be compressed at compression pressures ranging from 80 to 200 MPa.

[0100] Treatment method This disclosure also aims to address SAD (or social phobia).

[0101] In certain embodiments, tablets containing compound (I) can be used to treat SAD, improve its signs and / or symptoms, prevent or otherwise delay its onset or progression.

[0102] Accordingly, this specification teaches the use of a tablet formulation containing compound (I) in the manufacture of a drug for treating and / or preventing SAD or its symptoms in patients in need.

[0103] In certain embodiments, the tablet formulations described herein are administered to the subject as monotherapy.

[0104] In certain embodiments, the tablet formulations disclosed herein offer further additional advantages over conventional treatments, namely, a reduction in sedative side effects that may adversely affect the quality of life of the subject. In certain embodiments, the tablet formulations disclosed herein are free from measurable sedative side effects.

[0105] The criteria and symptoms of social anxiety disorder include the following: • Concerns about feeling embarrassed or humiliated • Fear of situations where one might be judged negatively. • A strong fear of interacting with or talking to strangers. • The fear of others noticing that you appear anxious. • Fear of physical symptoms that may cause embarrassment, such as flushing, sweating, trembling, or a trembling voice. • Avoiding doing things or talking to people out of fear of embarrassment. Avoid situations that could draw attention. • Anxiety stemming from anticipating a feared activity or event. • Severe fear or anxiety in social situations • Analysis of one's performance after social situations and identification of shortcomings in one's communication skills. • Anticipating the worst possible outcomes from negative experiences in social situations.

[0106] In certain embodiments, the tablet formulations described herein may be used to treat or prevent one or more symptoms associated with social anxiety disorder, and the patient may be identified based on the Leibowitz Social Anxiety Scale (LSAS) score.

[0107] In one embodiment, the patient is characterized by a Leibowitz Social Anxiety Scale (LSAS) score of SAD that is greater than approximately 60 and less than approximately 100, for example, approximately 65, 70, 75, 80, 85, 90 or approximately 95, or in the range of approximately 60-90, approximately 60-85, approximately 60-80, approximately 60-75, approximately 70-80 or approximately 70-90.

[0108] A single dose of the aforementioned tablet can reduce a patient's SUDS (Subjective Units of the Pain Scale) by approximately 5 to 35 units compared to a placebo control, for example, by approximately 7 to 20, 9 to 20, 10 to 20, 12 to 20, 15 to 20, 20 to 30, 25 to 35, 5 to 10, and 5 to 8 units compared to a placebo control.

[0109] In one embodiment, the tablets can achieve the required reduction of anxiety within approximately 20 to 90 minutes after administration, for example, within approximately 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, or 85 minutes (or within the range of any two of the above times).

[0110] In one embodiment, the tablet can achieve the required reduction of anxiety within approximately 20 to 90 minutes of administration, and the reduction can be maintained for at least 5 hours, for example, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, or at least 10 hours from a single dose. In one embodiment, the tablet can achieve the required reduction of anxiety within approximately 20 to 90 minutes of administration, and the reduction can be maintained for approximately 5 to 10 hours.

[0111] In one embodiment, the patient is under approximately 35 years of age, for example, under 30 years of age.

[0112] In one embodiment, the patient is approximately 13 to 25 years old, for example, 15 to 20 years old.

[0113] In one embodiment, the patient is a pediatric patient (including adolescents).

[0114] In one embodiment, the patient is a child patient approximately 13 to 18 years of age.

[0115] In one embodiment, the tablet is administered in an amount of approximately 100 mg to approximately 300 mg of the compound of formula (I), for example, between 100 and 200 mg.

[0116] In one embodiment, the tablets are administered in doses ranging from approximately 100 mg to approximately 300 mg to achieve an average Cmax plasma concentration of approximately 500 to 3000 ng / mL, for example, 500 to 2500 ng / mL, 500 to 2000 ng / mL, 500 to 1500 ng / mL, 3000 to 2000 ng / mL, or 3000 to 1000 ng / mL.

[0117] In one embodiment, the tablets are administered in doses ranging from approximately 300 mg to approximately 700 mg.

[0118] In one embodiment, the tablets are administered in doses ranging from approximately 300 mg to approximately 700 mg to achieve a plasma concentration of average Cmax of approximately 3000 to 8000 ng / mL, for example, 3000 to 7500 ng / mL, 3000 to 7000 ng / mL, 3000 to 6000 ng / mL, 3000 to 5000 4000 to 8000 ng / mL, or 5000 to 7000 ng / mL.

[0119] In certain embodiments, the present invention relates to reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by anticipated anxiety-inducing events in patients.

[0120] In the context described above, the term "worsen" is intended to mean that, in the patient, an increase in the SUDS (Subjective Units of Distress Scale) score is expected in anticipation of an anxiety-inducing event.

[0121] In a particular embodiment, the expected anxiety-inducing event is the patient's speech performance.

[0122] In certain embodiments, the anticipated anxiety-inducing event is a potentially stressful interview situation, such as a job interview or a personal meeting (e.g., a romantic encounter).

[0123] It should be recognized that the tablet formulations described herein can be administered to a patient in a therapeutically effective dose. In some embodiments, the therapeutically effective dose is either a therapeutically effective dose or a preventively effective dose. As used herein, the term “therapeutically effective dose” means the amount of an active compound or pharmaceutical product that elicits a biological or medical response in a tissue, body, animal, or human, as determined by researchers, veterinarians, medical doctors, or other clinicians. The therapeutically effective dose of a compound administered will be controlled by such considerations and is the minimum amount necessary to improve, cure, or treat one or more of a disease or disorder or its symptoms. The term “preventively effective dose” means an amount that is effective in preventing or substantially reducing the opportunity to acquire a disease or disorder, or reducing the severity of a disease or disorder before it is acquired, or reducing the severity of one or more of its symptoms before they develop. Broadly speaking, preventive measures are divided into primary prevention (to prevent the development of a disease or symptom) and secondary prevention (when a disease or symptom has already developed and the subject is protected from the exacerbation of this process).

[0124] In all embodiments, the present invention involves administering a tablet containing about 100 mg to 700 mg of the compound of formula (I), for example, 120 mg, 140 mg, 160 mg, 180 mg, 190 mg, 200 mg, 220 mg, 225 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 625 mg, 640 mg, 650 mg, 660 mg, 675 mg, or about 700 mg (or any range between two of the above weights).

[0125] As used herein, the term “effective dose” refers to the amount of a tablet formulation that provides the desired therapeutic activity when administered according to a desired dosing regimen. Dosage may be given at intervals of minutes, hours, days, weeks, months or years, or continuously over any one of these periods. An appropriate dose is in the range of approximately 1.0 ng / kg body weight to 100 mg g / kg body weight per dose. The dose may be in the range of 1 μg to 100 mg / kg body weight per dose, for example, in the range of 1 mg to 100 mg / kg body weight per dose. In one embodiment, the dose may be in the range of 10 mg to 50 mg / kg body weight per dose. In another embodiment, the dose may be in the range of 1 mg to 50 mg / kg body weight per dose. In yet another embodiment, the dose may be in the range of 0.1 mg to 10 mg / kg body weight per dose, for example, up to 0.5 mg / kg body weight per dose (or any range between two of the above weights).

[0126] In certain embodiments, an effective dose of a tablet formulation for administration to a 70 kg adult once or more times daily may contain, per unit dosage form, about 1 mg to about 1000 mg, about 1 mg to about 800 mg, about 1 mg to about 700 mg, about 10 mg to about 700 mg, about 50 mg to about 700 mg, about 50 mg to about 800 mg, about 100 mg to about 900 mg, about 100 mg to about 500 mg, about 200 mg to about 700 mg, or about 100 mg to about 800 mg (or any range between two of the above weights).

[0127] The appropriate dosage and administration plan may be determined by the attending physician and may depend on the specific condition being treated, its severity, and the patient's overall age, health, and weight. It will be recognized that the dosage ranges described herein provide guidance for administering the provided pharmaceutical composition to adults. For example, the amount administered to children or adolescents may be determined by a physician or a person skilled in the art and may be less than or equal to the amount administered to adults.

[0128] The tablet formulations described herein can be used in combination therapy with one or more additional therapeutic agents. In combination therapy with two or more active agents, where the active agents are in separate drug formulations, the active agents may be administered separately or together. In addition, the administration of one element may be before, simultaneously with, or after the administration of the other element.

[0129] In certain embodiments, the tablet formulations and additional therapeutic agents described herein are administered in effective doses (i.e., doses that are therapeutically effective when administered individually). In other embodiments, the tablet formulations and additional therapeutic agents described herein are administered in doses that do not produce a therapeutic effect individually (doses less than or equal to the therapeutic dose). In yet another embodiment, the tablet formulations described herein may be administered in effective doses, and the additional therapeutic agents may be administered in doses less than or equal to the therapeutic dose. In yet another embodiment, the tablet formulations described herein may be administered in doses less than or equal to the therapeutic dose, and the additional therapeutic agents may be administered in effective doses.

[0130] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending on factors such as the species, age, and overall health of the subject, the severity of side effects or disorders, the uniqueness of the specific compound, and the method of administration. The desired dose may be delivered three times a day, twice a day, once a day, every two days, every three days, once a week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose may be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more doses).

[0131] No reference in this specification to any prior publication (or information derived therefrom) or any known matter shall be construed, and should not be construed, as confirmation, acknowledgment, or in any form of suggestion that such prior publication (or information derived therefrom) or known matter constitutes part of the common general knowledge in the field of the efforts relating to this specification.

[0132] Throughout this specification and the subsequent claims, unless the context requires otherwise, the word “comprise,” and its variations such as “comprises” and “comprising,” will be understood to mean the inclusion of the described integer or step or group of integers or steps, but not to exclude any other integer or step or group of integers or steps.

[0133] Throughout this specification and the subsequent claims, unless the context requires otherwise, the phrase "consisting essentially of" and variations such as "consists essentially of" will be understood to indicate that the described element is essential, i.e., a necessary element of the invention. This phrase allows for the presence of other undescribed elements that do not substantially affect the features of the invention, but excludes additional unspecified elements that may affect the basic and novel features of the defined method.

[0134] Throughout this specification, the objective has been to describe preferred embodiments of the invention without limiting the invention to any one embodiment or particular set of features. Accordingly, those skilled in the art will recognize that various modifications and changes can be made in light of this disclosure without departing from the scope of the invention in the specific embodiments illustrated. All such modifications and changes are intended to be included within the appended claims.

[0135] Further features of the present invention are described more fully in the following non-limiting embodiments. [Examples]

[0136] Examples Example 1 (Ex1): Preparation of a typical spray-dried dispersion (SDD) composition of the present invention Approximately 30.985 kg of compound (I), also known as "BNC210," was dissolved in 1192 L of a mixture of dichloromethane and methanol (70:30% v / v). 57.665 kg of polymer HPMCAS-M was added to this solution, and the mixture was stirred to obtain a homogeneous solution. The solution was spray-dried using a Buechi B290 spray dryer equipped with two-fluid nozzles. [ka]

[0137] Modulated differential scanning calorimetry (mDSC) and powder X-ray diffraction were used to characterize the spray-dry dispersion composition of the present invention. The data are shown in Table 1.

[0138] [Table 1]

[0139] Modulated differential scanning calorimetry (mDSC) was used to characterize the compositions of the present invention using the parameters shown in Table 2. Details of the mDSC method used in the tests are described below:

[0140] [Table 2]

[0141] The compositions of the present invention are given in Table 1 and, as shown in Figure 1, a single glass dislocation (T g ) Indicates temperature.

[0142] Powder X-ray diffraction (PXRD): The crystallinity of the spray-dried dispersion composition of the present invention was determined by powder X-ray diffraction (PXRD) using a Rigaku Miniflex 6G benchtop X-ray diffractometer. The recommended parameters for PXRD recording are shown below. - Tube: Cu: K-alpha (λ=1.5418 Å). - Generator: Voltage: 40kV; Current: 40mA. - Scanning range: 3-40 degrees; - Scanning speed: 9.5 degrees / minute - Sample rotation speed: 15 rpm

[0143] The spray-dried and heat-melt extruded dispersion compositions of the present invention exhibit very broad peaks in XRPD (Figure 2), indicating that the compositions are essentially amorphous.

[0144] Example 2: Formulation of BNC210SDD into BNC210 film-coated tablets Clinical batches of BNC210 film-coated tablets were manufactured using the dry granulation process outlined below:

[0145] Pre-blend 1. Prepare BNC210SDD, excipients, and coating system in a cleanroom. The quantities are as shown in the batch formulations in Table 3. 2. Mix 5,373.0 g of microcrystalline cellulose and 537.3 g of colloidal silica. Pass the mixture through a Comil and collect it in an LDPE bag. 3. Pass the remaining microcrystalline cellulose, granular croscarmellose sodium, and mannitol through the Comil and collect the mixture in an LDPE bag. 4. Place the LDPE bag material from Step 2 into a container (500L or equivalent), then add BNC210SDD. 5. Add the ingredients from step 3 to the container and blend the mixture at a blending speed of 10 rpm for about 20 minutes. 6. Using a komill, grind the mixture using the following target parameters and place it in an LDPE bag: Impeller speed = 960 rpm 7. Put the ingredients back into the container and blend at 10 rpm for about 20 minutes. 8. Sift the magnesium stearate from the granules using a 60-mesh screen or equivalent, and place it in a container. 9. Blend the mixture at 10 rpm for about 10 minutes.

[0146] Dry granulation 10. Using the following parameters, dry granulate the final blend from step 9 by roller compression: Target roll pressure = 4.0~6.0 MPa Target roll gap = 1.0~3.0mm Target roll speed = 4.0~8.0 rpm Target granulator RFG speed=60.0~100.0rpm 11. Release the granules into a double LDPE bag with a desiccant in between, then place it in an aluminum foil bag and heat seal it (net weight of granules = 102,128.5g).

[0147] Blending and lubrication 12. Based on the actual amount of final granule weight, reweigh the extragranules of croscarmellose sodium and magnesium stearate. 13. Add the final granules from step 11 to a mixing container (500L), and crush the croscarmellose sodium outside the granules using a crustacean and add it to the container. 14. Sift the granular magnesium stearate through a 60-mesh screen and place it in a container. 15. Blend the mixture at 10 rpm for about 10 minutes. 16. Dispense the blend from the container into a double LDPE bag with a desiccant in between, then place it in an aluminum foil bag and heat seal it.

[0148] Compression and coating 17. Add the granules from step 16 to the supply hopper and begin compression. 18. Release all the tablets that have passed through into a double LDPE bag with a desiccant in between, then place it in an aluminum foil bag and seal it. 19. Prepare the coating solution by adding the coating powder to water (final concentration = 15%). 20. Set up the coating machine and establish the parameters to achieve the specified spray rate of 60.0 g / min. 21. Adjust the parameters to maintain the floor temperature within 38-50°C and start the coating process until the weight increase is 3% (2.5-4.0%). 22. Once the target weight increase is achieved, stop spraying and pumping the solution. Dry / cool the tablets using inlet air at 25°C until the exhaust temperature reaches approximately 35°C. 23. Dispense the tablets into a double LDPE bag with a desiccant in between, then place it in an aluminum foil bag and heat seal it.

[0149] [Table 3]

[0150] Example 3: Speech Challenge: A phase 2 randomized, double-blind study to evaluate the efficacy and safety of BNC210 compared to placebo for the acute treatment of social anxiety disorder. The following examples are intended to illustrate the present invention, and not to limit it.

[0151] Participants will attend a screening visit at a designated clinic to confirm their eligibility. Approximately 150 participants who meet the eligibility criteria will return to the clinic within 14 days of their screening visit to be randomized and receive either 225 mg of BNC210, 675 mg of BNC210, or a corresponding placebo (in a 1:1:1 ratio). On the day of randomization (treatment day), participants' SUDS scores will be recorded, and participants will be administered a single oral dose of their assigned study drug and asked to rest for 55 minutes in an isolation / preparation room (rest phase). Participants' SUDS scores will be recorded again, and then they will be shown an instructional video regarding the speech challenge. Next, participants will be asked to select up to two topics from a given list and prepare a 2-minute speech on their chosen topics (preparation phase). After the instructional video ends, participants' SUDS scores will be recorded every minute (a total of 3 times) during the preparation phase. Next, participants will be led to a performance room and asked to speak for 5 minutes on their chosen topics (performance phase). Participants' SUDS scores were recorded at the start of their speech and every minute during the performance phase (a total of 6 times). At the end of the speech, participants were returned to the preparation room to complete the post-challenge assessment, where their SUDS scores were recorded every 10 minutes for a total of 30 minutes (a total of 3 times) (Figure 3 and Table 4: Activity Schedule for Treatment Day - Effectiveness Assessment). Data processing of SUDS scores, aggregation of descriptive statistics, calculation of estimated statistics, and graphing were primarily performed using SAS (release 9.4 or later).

[0152] [Table 4]

[0153] The SUDS is a standard tool for measuring the subjective intensity of distress or anxiety an individual is currently experiencing and for assessing social anxiety and performance anxiety in SAD patients in role-playing situations. Individuals self-assess their position on a scale of 0 to 100, with higher scores indicating greater anxiety / discomfort (Wolpe, 1969, Heimberg 1998, 2002). Wolpe J. The practice of behavior therapy. New York: Pergamon Press; 1969. Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, et al.Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome.Arch Gen Psychiatry.1998 Dec; 55(12):1133-41.

[0154] The mean SUDS score (BL score) obtained at baseline was subtracted from the SUDS scores obtained in the rest phase (R), expectation phase (A0, A1, and A2), performance phase (P0-P5), and post-challenge phase. A time-series graph of the mean change in SUDS score from baseline is shown for each treatment group at all time points in Figure 4, with error bars indicating the standard error. The change in SUDS score from baseline is a measure of improvement in SAD symptoms. Both treatment groups (BNC210 225 mg and BNC210 675 mg) showed consistent symptom improvement compared to placebo. For example, as highlighted at P0 below, patients' SUDS (subjective units of the distress scale) decreased by approximately 9 units compared to the placebo control (approximately 32 in the placebo control compared to approximately 23 with a single BNC tablet).

[0155] AUC was calculated using the trapezoidal rule: the mean of the SUDS scores observed between two adjacent time points was taken, multiplied by the time point difference (in minutes), and this was repeated over all time points and summed to obtain the total AUC for the expected and performance phases. An analysis of covariance (ANCOVA) model was used to analyze the difference in AUC of SUDS scores between BNC210 and placebo, combined for the expected and performance phases. This model included treatment as the main effect and baseline SUDS score, mask use, and sex as covariates. BNC210 225 mg and 675 mg were combined and compared to placebo, and the LS mean is reported along with the corresponding p-value (Figure 5). For example, the combined AUC of the expected and performance phases for all patients who received BNC210 was significantly different from placebo. The difference in AUC was -96.79, and the p-value was 0.044.

[0156] Example 4: Speech Challenge using STAI as an evaluation item The following examples are intended to illustrate the present invention, and not to limit it.

[0157] Participants will attend a screening visit at a designated clinic to confirm their eligibility. Approximately 150 participants who meet the eligibility criteria will return to the clinic within 14 days of their screening visit to be randomized and receive either 225 mg of BNC210, 675 mg of BNC210, or a corresponding placebo (in a 1:1:1 ratio). On the day of randomization (treatment day), participants' STAI-status scores will be recorded, and participants will be administered a single oral dose of their assigned research drug and asked to rest for 55 minutes in an isolation / preparation room (rest phase). Participants' STAI-status scores will be recorded again, and then participants will be shown an instructional video regarding a speech challenge. Next, participants will be asked to select up to two topics from a given list and prepare a 2-minute speech on their chosen topics (preparation phase). After the instructional video ends, participants' STAI-status scores will be recorded at the end of the preparation phase. Next, participants will be led to a performance room and asked to speak for 5 minutes on their chosen topics (performance phase). Participants' STAI-Status scores are recorded at the end of the performance phase. At the end of the speech, participants are returned to the preparation room to complete the post-challenge assessment, and their STAI-Status scores are recorded at the end of the post-challenge phase (Figure 3 and Table 5, Activity Schedule for Treatment Day - Effectiveness Assessment). Data processing of STAI-Status scores, aggregation of descriptive statistics, calculation of estimated statistics, and graphing were primarily performed using SAS (release 9.4 or later).

[0158] [Table 5]

[0159] The STAI (Spielberger 1983) is a widely used self-report scale for subjective anxiety in clinical practice. It consists of 20 items across two scales, asking participants to report their feelings of anxiety: the STAI-State scale requires reporting of feelings at the time of questionnaire completion, and the STAI-Trait scale requires reporting of how the subject typically feels. Responses are marked on a 4-point scale from "not at all" to "very much so." This study used the STAI-State component. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA.Manual for the State-Trait Anxiety Inventory: STAI (form Y).Palo Alto (CA): Consulting Psychological Press; 1983.

[0160] The least squares mean (LS mean) difference (treatment-placebo) and p-value in the STAI-status score were obtained from MMRM using the fixed effects of treatment, visits, interaction between treatment and visits, sex, mask use, and baseline STAI-status score as covariates. Intra-subject correlations were modeled using an unstructured covariance matrix. The mean difference in LS from the placebo group in STAI-status scores at the prediction stage was significantly lower in a subset of patients under 30 years of age treated with the lower dose (BNC210 225 mg) (Table 6). The mean difference in LS from the placebo control in STAI-status scores combined at the prediction and performance stages was significantly lower in a subset of patients under 30 years of age treated with the lower dose of 225 mg, demonstrating that BNC210 has pharmacological activity throughout the entire speech task (Table 6).

[0161] [Table 6]

[0162] Other embodiments All publications, patents, and patent applications referenced herein are incorporated herein by reference in whole to the same extent as each individual publication, patent, or patent application is specifically and individually incorporated herein by reference in whole. Where it is found that a term in this application is defined differently in a document incorporated herein by reference, the definition provided herein shall serve as the definition of that term.

[0163] While the present invention has been described in relation to its particular aspects, the present invention is subject to further modifications, and this application is intended to encompass any modifications, uses, or adaptations, including any deviations from this disclosure that are generally in principle within the scope of known or customary practices in the art to which the invention relates, applicable to the essential features described above and subject to the claims.

[0164] In addition to the various embodiments described herein, this disclosure includes the following embodiments. This list of embodiments is presented as an exemplary list, and this application is not limited to these embodiments.

[0165] E1. Formula (I) of at least approximately 100 mg: [ka] A method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, A method in which a patient characterized by moderate to severe SAD is able to reduce the patient's SUDS score (subjective units of the distress scale) by at least 5 units compared to a placebo control.

[0166] E2. Formula (I) of at least approximately 100 mg: [ka] A method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by an anticipated anxiety-inducing event in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) score by approximately 5 to 35 units compared to a placebo control, and the patient is administered the tablet at least approximately 20 minutes before an anticipated anxiety-inducing event.

[0167] E3. Formula (I) of at least approximately 100 mg: [ka] A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the single dose of the tablet can reduce the patient's SUDS (Subjective Units of the Distress Scale) by approximately 5 to 35 units compared to a placebo control.

[0168] E4. Formula (I) of at least approximately 100 mg: [ka] A method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) by at least approximately 5 units compared to a placebo control, and the patient is administered the tablet at the time of the first onset of panic symptoms.

[0169] E5. Formula (I) of at least approximately 100 mg: [ka] A method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, A method in which a patient characterized by moderate to severe SAD is able to reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by at least 3 units compared to a placebo control.

[0170] E6. Formula (I) of at least approximately 100 mg: [ka] A method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by an anticipated anxiety-inducing event in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by at least approximately 3 units compared to a placebo control, and the patient is administered the tablet at least approximately 20 minutes before an anticipated anxiety-inducing event.

[0171] E7. Formula (I) of at least approximately 100 mg: [ka] A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, A method in which the patient is characterized by moderate to severe SAD, and a single-dose of the tablet can reduce the patient's STAI-State score (Spielberger's State-Trait Anxiety Inventory-State component) by at least about 3 units compared to a placebo control.

[0172] E8. At least about 100 mg of formula (I):

Chemical formula

[0173] E9. At least about 100 mg of formula (I):

Chemical formula

[0174] E10. At least about 100 mg of formula (I):

Chemical formula

[0175] E11. Formula (I) of at least approximately 100 mg: [ka] A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, A method in which a patient characterized by moderate to severe SAD is given, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least about 25 units compared to a placebo control.

[0176] E12. Formula (I) of at least approximately 100 mg: [ka] A method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by 25 to 150 units compared to a placebo control, and the patient is administered the tablet at the time of the first onset of panic symptoms.

[0177] E13. A method for reducing anxiety associated with social anxiety disorder (SAD) in patients, wherein the amount is effective in reducing the severity of SAD in the subject by at least 5 units on the SUDS score compared to a placebo-controlled group, using formula (I): [ka] A method comprising administering a tablet containing a compound or a salt thereof or a prodrug.

[0178] E14. The patient has a Leibowitz Social Anxiety Scale (LSAS) score of approximately 60 or higher, following one of the methods in E1-E13.

[0179] E15. The patient has a Leibowitz Social Anxiety Scale (LSAS) score of less than approximately 100, following one of the methods E1-E14.

[0180] E16. The patient has a Leibowitz Social Anxiety Scale (LSAS) score between approximately 60 and less than approximately 100, following one of the methods E1-E15.

[0181] E17. The patient has a Leibowitz Social Anxiety Scale (LSAS) score of approximately 60 to less than approximately 87, following one of the methods E1-E16.

[0182] E18. The required reduction of anxiety is achieved within approximately 120 minutes of administration, following one of the methods described in E1-E17.

[0183] E19. The required reduction of anxiety is achieved within approximately 20-90 minutes of administration, following one of the methods described in E1-E18.

[0184] E20. The required reduction of anxiety is achieved within approximately 20–90 minutes of administration and is maintained for at least 5 hours from a single dose, according to the method described in E18 or E19.

[0185] A method according to any one of E1 to E20, wherein the patient is less than about 35 years old.

[0186] A method according to any one of E1 to E21, wherein the patient is less than about 30 years old.

[0187] A method according to any one of E1 to E22, wherein the patient is between about 13 years and 25 years of age.

[0188] A method according to any one of E1 to E23, wherein the tablet contains from about 100 mg to about 700 mg of a compound of formula (I):

Chemical formula

[0189] A method according to E24, wherein the tablet contains from about 100 mg to about 300 mg of a compound of formula (I) or a salt or prodrug thereof.

[0190] A method according to E24, wherein the tablet contains from about 300 mg to about 700 mg of a compound of formula (I) or a salt or prodrug thereof.

[0191] A method according to any one of E1 to E25, wherein about 225 mg of a compound of formula (I) or a salt or prodrug thereof is administered.

[0192] A method according to any one of E1 to E25 and E27, wherein 225 mg of a compound of formula (I) or a salt or prodrug thereof is administered.

[0193] A method according to any one of E1 to 24 and E26, wherein about 450 mg of a compound of formula (I) or a salt or prodrug thereof is administered.

[0194] A method according to any one of E1 to 24, E26 and E29, wherein 450 mg of a compound of formula (I) or a salt or prodrug thereof is administered.

[0195] E31. A method according to any one of E1-24 and E26, in which approximately 675 mg of the compound of formula (I) or its salt or prodrug is administered.

[0196] A method according to one of E1-24, E26, and E31, in which 2.675 mg of the compound of formula (I) or a salt or prodrug thereof is administered.

[0197] E33. The administered tablet contains approximately 100 mg to approximately 300 mg of the compound of formula (I) or its salt or prodrug, and a mean Cmax of the compound of formula (I) of approximately 500 to 3000 ng / mL is achieved in the patient's plasma, according to one of E1 to E32.

[0198] E34. The administered tablet contains approximately 300 mg to approximately 700 mg of the compound of formula (I) or its salt or prodrug, and a mean Cmax of the compound of formula (I) of approximately 3000 to 8000 ng / mL is achieved in the patient's plasma, according to one of E1 to E26 and E29 to E32.

[0199] E35. The tablets are administered in an amount effective to achieve an average Cmax of the compound of formula (I) of approximately 3000–8000 ng / mL in the patient's plasma, according to one of the methods E1–E34.

[0200] E36. Formula (I) of approximately 225 mg for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: [ka] Tablets containing the compound or its salt or prodrug.

Claims

1. Formula (I) of at least approximately 100 mg: 【Chemistry 1】 A method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, A method wherein the patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS score (subjective units of the distress scale) by at least 5 units compared to a placebo control.

2. Formula (I) of at least approximately 100 mg: 【Chemistry 2】 A method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by an anticipated anxiety-inducing event in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) score by approximately 5 to 35 units compared to a placebo control, and the patient is administered the tablet at least approximately 20 minutes before the expected anxiety-inducing event.

3. Formula (I) of at least approximately 100 mg: 【Transformation 3】 A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the method involves a single dose of the tablet that can reduce the patient's SUDS (Subjective Units of the Distress Scale) by approximately 5 to 35 units compared to a placebo control.

4. Formula (I) of at least approximately 100 mg: 【Chemistry 4】 A method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's SUDS (Subjective Units of Distress Scale) by at least about 5 units compared to a placebo control, and the tablet is administered to the patient at the first onset of panic symptoms.

5. Formula (I) of at least approximately 100 mg: 【Transformation 5】 A method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the method involves a single dose of the tablet that can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State component) by at least 3 units compared to a placebo control.

6. Formula (I) of at least approximately 100 mg: 【Transformation 6】 A method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by an anticipated anxiety-inducing event in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by at least about 3 units compared to a placebo control, and the tablet is administered to the patient at least about 20 minutes before the expected anxiety-inducing event.

7. Formula (I) of at least approximately 100 mg: 【Transformation 7】 A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the single-dose tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State component) by at least approximately 3 units compared to a placebo control.

8. Formula (I) of at least approximately 100 mg: 【Transformation 8】 A method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the patient's STAI-State Score (Spielberger State-Trait Anxiety Scale-State Component) by at least approximately 3 units compared to a placebo control, and the tablet is administered to the patient at the time of the first onset of panic symptoms.

9. Formula (I) of at least approximately 100 mg: 【Chemistry 9】 A method for reducing anxiety associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least 25 units compared to a placebo control.

10. Formula (I) of at least approximately 100 mg: 【Chemistry 10】 A method for reducing anxiety associated with social anxiety disorder (SAD) that is expected to be aggravated by an anticipated anxiety-inducing event in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least about 25 units compared to a placebo control, and the tablet is administered to the patient at least about 20 minutes before the expected anxiety-inducing event.

11. Formula (I) of at least approximately 100 mg: 【Chemistry 11】 A method for minimizing or reducing recurrent paroxysmal disorder associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and the single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by at least about 25 units compared to a placebo control.

12. Formula (I) of at least approximately 100 mg: 【Chemistry 12】 A method for reducing panic symptoms and panic intensity associated with social anxiety disorder (SAD) in a patient, comprising the step of administering a tablet containing a compound or a salt or prodrug thereof, The patient is characterized by moderate to severe SAD, and a single dose of the tablet can reduce the area under the curve of the patient's SUDS score over time by 25 to 150 units compared to a placebo control, and the tablet is administered to the patient at the time of the first onset of panic symptoms.

13. A method for reducing anxiety associated with social anxiety disorder (SAD) in patients, wherein the amount is effective in reducing the severity of SAD in the subjects by at least 5 units on the SUDS score compared to a placebo-controlled group, as given by formula (I): 【Chemistry 13】 A method comprising administering a tablet containing a compound or a salt thereof or a prodrug.

14. The method according to any one of claims 1 to 13, wherein the patient has a Leibowitz Social Anxiety Scale (LSAS) score greater than approximately 60.

15. The method according to any one of claims 1 to 14, wherein the patient has a Leibowitz Social Anxiety Scale (LSAS) score of less than approximately 100.

16. The method according to any one of claims 1 to 15, wherein the patient has a Leibowitz Social Anxiety Scale (LSAS) score between approximately 60 and less than approximately 100.

17. The method according to any one of claims 1 to 16, wherein the patient has a Leibowitz Social Anxiety Scale (LSAS) score of approximately 60 to less than approximately 87.

18. The method according to any one of claims 1 to 17, wherein the required reduction of anxiety is achieved within approximately 20 to 90 minutes after administration.

19. The method according to claim 18, wherein the required reduction of anxiety is achieved within approximately 20 to 90 minutes of administration and is maintained for at least 5 hours from a single dose.

20. The method according to any one of claims 1 to 19, wherein the patient is under approximately 35 years of age.

21. The method according to any one of claims 1 to 20, wherein the patient is under approximately 30 years of age.

22. The method according to any one of claims 1 to 21, wherein the patient is approximately 13 to 25 years of age.

23. The aforementioned tablets contain approximately 100 mg to approximately 700 mg of formula (I): 【Chemistry 14】 The method according to any one of claims 1 to 22, comprising the compound.

24. The aforementioned tablets contain approximately 100 mg to approximately 300 mg of formula (I): 【Chemistry 15】 The method according to any one of claims 1 to 23, comprising the compound.

25. The aforementioned tablets contain approximately 300 mg to approximately 700 mg of formula (I): 【Chemistry 16】 The method according to any one of claims 1 to 23, comprising the compound.

26. The method according to any one of claims 1 to 24, wherein approximately 225 mg of the compound of formula (I) is administered.

27. The method according to any one of claims 1 to 24 and 26, wherein 225 mg of the compound of formula (I) is administered.

28. The method according to any one of claims 1 to 23 and 25, wherein approximately 450 mg of the compound of formula (I) is administered.

29. The method according to any one of claims 1 to 23, 25, and 28, wherein 450 mg of the compound of formula (I) is administered.

30. The method according to any one of claims 1 to 23 and 25, wherein approximately 675 mg of the compound of formula (I) is administered.

31. The method according to any one of claims 1 to 23, 25, and 30, wherein 675 mg of the compound of formula (I) is administered.

32. The method according to any one of claims 1 to 27, wherein approximately 100 mg to approximately 300 mg of the compound of formula (I) is administered, and an average Cmax of approximately 500 to 3000 ng / mL of the compound of formula (I) is achieved in the plasma of the patient.

33. The method according to any one of claims 1 to 25 and 28 to 31, wherein approximately 300 mg to approximately 700 mg of the compound of formula (I) is administered, and an average Cmax of approximately 3000 to 8000 ng / mL of the compound of formula (I) is achieved in the plasma of the patient.

34. The method according to any one of claims 1 to 33, wherein the tablet is administered in an amount effective to achieve an average Cmax of the compound of formula (I) of about 3,000 to 8,000 ng / mL in the plasma of the patient.

35. Formula (I), approximately 225 mg, for use in reducing anxiety associated with social anxiety disorder (SAD) in patients: 【Chemistry 17】 A pharmaceutical composition comprising tablets containing the compound.

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