Enteric coated tiropride formulations and methods of use

Abstract

The present application relates generally to dosage forms (e.g., oral dosage forms) and pharmaceutical compositions comprising a pharmaceutically active agent comprising telotristat or a pharmaceutically acceptable salt, solvate, or hydrate thereof; an enteric coating; and optionally one or more pharmaceutically acceptable excipients; and to methods of using the dosage forms and pharmaceutical compositions, and methods of making the dosage forms and pharmaceutical compositions.

Description

Cross-references to related applications

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 590,678, filed October 16, 2023; U.S. Provisional Application No. 63 / 616,039, filed December 29, 2023; U.S. Provisional Application No. 63 / 679,270, filed August 5, 2024; and European Patent Application No. 24306216.3, filed July 18, 2024, the entire contents of which are incorporated herein by reference. Background Technology

[0002] Pitolisant preparations can be used to treat many diseases and conditions, especially sleep disorders such as excessive daytime sleepiness (EDS) and cataplexy. For example, WAKIX... ® (Telorissen monohydrochloride) is a prescription drug approved for the treatment of EDS or cataplexy in subjects with narcolepsy.

[0003] Existing telolide formulations are typically administered in titration over the first two weeks, starting at approximately 8.9 mg / day, then doubled after one week, and then doubled again after the second week to reach a dose of 35.6 mg / day, which can be reduced depending on patient tolerance. Summary of the Invention

[0004] This application generally relates to a dosage form (e.g., an oral dosage form) and a pharmaceutical composition comprising a pharmaceutically active agent, an enteric coating (also known as a delayed-release coating), and optionally one or more pharmaceutically acceptable excipients, wherein the pharmaceutically active agent comprises teloridine or a pharmaceutically acceptable salt, solvate, or hydrate thereof represented by the structure of formula (I): (I).

[0005] This application also discloses methods for using the dosage form and pharmaceutical composition (e.g., for treating a disease or condition), and methods for preparing the dosage form and pharmaceutical composition. The dosage form may further include a moisture barrier.

[0006] The dosage forms and pharmaceutical compositions of this application have the advantage that, when administered (e.g., orally), they may have reduced or no gastrointestinal side effects, such as nausea, vomiting, and stomach upset. For example, an equivalent amount of a non-enteric-coated dosage form or pharmaceutical composition (such as WAKIX) administered orally to a subject. ® Subjects receiving the dosage forms or pharmaceutical compositions disclosed herein via oral administration may experience minimal or no side effects, such as nausea, stomach upset, or vomiting.

[0007] Another advantage of the dosage form and pharmaceutical composition of this application is that, compared to the dosage forms or pharmaceutical compositions typically used in non-enteric-coated formulations or compositions (such as WAKIX), it offers advantages over other formulations. ® Based on the patient compliance observed in subjects receiving the formulations and pharmaceutical compositions disclosed herein, the dosage forms and pharmaceutical compositions of this application are able to improve patient compliance in subjects receiving them. This is partly attributed to the reduction in side effects experienced by subjects receiving the dosage forms or pharmaceutical compositions of this application (e.g., after oral administration). Because the side effects experienced by subjects receiving the dosage forms or pharmaceutical compositions disclosed herein may be very mild or nonexistent, subjects are more likely to adhere to the titration period and / or the prescribed dosing regimen and will be more likely to continue at the maximum recommended dose, thereby obtaining the full clinical benefit with very mild or no side effects.

[0008] Not wanting to be bound by theory, it is believed that the dosage forms and pharmaceutical compositions disclosed herein are equivalent in amount to dosage forms containing the same pharmaceutically active agent but without enteric coating (e.g., WAKIX). ® The formulations are bioequivalent. For example, oral administration of the disclosed dosage form or pharmaceutical composition to a subject provides substantially similar (i.e., approximately the same) teloratesen exposure, as determined by measuring the area under the curve (AUC) of teloratesen, compared to oral administration of an equivalent dose of WAKIX® disclosed herein. Furthermore, oral administration of an equivalent dose of WAKIX® to a subject provides substantially similar (i.e., approximately the same) teloratesen exposure. ® In comparison, oral administration of the dosage forms or pharmaceutical compositions disclosed herein can provide substantially similar C-values ​​of teloratesen. max Furthermore, it is equivalent to an oral dose of WAKIX. ® In comparison, oral administration of the dosage forms or pharmaceutical compositions disclosed herein can provide substantially similar T-cell efficacy to teloraterone. max This is surprising because, compared to their non-enteric-coated counterparts, enteric-coated dosage forms are generally expected to have a relatively delayed release of the pharmaceutically active agent, which is anticipated to cause non-bioequivalence, for example, due to delayed absorption of the pharmaceutically active agent and / or altered pharmacokinetics, such as desensitized C4. max Longer T max Or a modified AUC. However, the dosage forms and pharmaceutical compositions of this application comprise enteric coatings and may be compatible with their non-enteric-coated counterparts (such as WAKIX). ® They are essentially biologically equivalent; for example, they do not exhibit fundamentally different C values. max T max And / or exposure levels as determined by AUC.

[0009] In some aspects, this application relates to an oral dosage form comprising: a core; and an enteric coating surrounding the core, wherein the core comprises teloratesen or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and optionally one or more pharmaceutically acceptable excipients. The core may comprise teloratesen monohydrochloride (e.g., crystalline teloratesen monohydrochloride).

[0010] Enteric coatings may contain polymers. The polymers may contain ionizable functional groups, such as carboxylic acid groups. Enteric coatings may contain polymers such as cellulose materials (e.g., alkyl cellulose), acrylic polymers, acrylate polymers, methacrylic polymers, methacrylate polymers, or methacrylate copolymers (e.g., anionic methacrylate copolymers). For example, enteric coatings may contain EUDRAGIT. ® Polymers, such as EUDRAGIT® L 100-55, or enteric coatings may contain ACRYL-EZE ® It will be understood that enteric coating can also be referred to as delayed-release coating.

[0011] Enteric coatings may further contain plasticizers, such as polyethylene glycol (PEG), for example PEG8000, or triethyl citrate.

[0012] The dosage form of this application may include a moisture barrier. The moisture barrier may be located between the core and the enteric coating. For example, the dosage form may include a tablet core coated with a moisture barrier (to obtain a moisture-barrier-coated tablet), which itself is further coated with an enteric coating (to obtain an enteric-coated tablet). The moisture barrier may comprise a polymer, such as polyvinyl alcohol (PVA) or a cellulose-based polymer, such as HPMC. The moisture barrier may comprise OPADRY. ® Polymers, such as OPADRY ® amb II (e.g., purple OPADRY) ® amb II, or transparent OPADRY ® amb II).

[0013] Dosage forms may contain about 1 mg to about 25 mg (e.g., about 3 mg to about 7 mg, or about 18 mg to about 22 mg) of teloratesen or its pharmaceutically acceptable salts, solvates, or hydrates. For example, dosage forms may contain about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, or about 25 mg of teloratesen or its pharmaceutically acceptable salts, solvates, or hydrates. Teloratesen or its pharmaceutically acceptable salts, solvates, or hydrates may be contained within the core of the dosage form and may not be present in an enteric coating or moisture barrier. For example, a dosage form of this application may contain about 5 mg of teloratesen or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., 5 mg of teloratesen monohydrochloride). For example, a dosage form of this application may contain about 20 mg of teloratesen or a pharmaceutically acceptable salt, solvate, or hydrate thereof (e.g., 20 mg of teloratesen monohydrochloride).

[0014] The dosage form may contain pharmaceutically acceptable excipients. For example, pharmaceutically acceptable excipients may be microcrystalline cellulose, crospovidone, talc, magnesium stearate, or colloidal silica (e.g., anhydrous colloidal silica). For example, the dosage form of this application may contain a core, wherein the core comprises one or more of microcrystalline cellulose, crospovidone, talc, magnesium stearate, or colloidal silica (e.g., anhydrous colloidal silica).

[0015] The dosage form of this application may comprise crystalline teloliden monohydrochloride. The dosage form may further comprise pharmaceutically acceptable excipients. In some embodiments, the dosage form comprises a core, wherein the core comprises (e.g., substantially composed of, for example, teloliden monohydrochloride), microcrystalline cellulose, crospovidone, talc, magnesium stearate, and colloidal silica (e.g., anhydrous colloidal silica).

[0016] The dosage forms disclosed herein may have a core surrounded by a moisture barrier that comprises (e.g., substantially composed of, for example, a PVA-based polymer, such as OPADRY) ® amb II. The core, which has a moisture barrier, may be further surrounded by an enteric coating comprising (e.g., essentially composed of, for example, a copolymer of methacrylic acid and ethyl acrylate, such as EUDRAGIT) ® L 100-55 or ACRYL-EZE ® .

[0017] Telorissen or its pharmaceutically acceptable salts, solvates, or hydrates contained in the dosage forms of this application may have X-ray diffraction patterns including characteristic peaks (2θ) at 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°). For example, telorissen or its pharmaceutically acceptable salts, solvates, or hydrates may have X-ray diffraction patterns including characteristic peaks (2θ) at 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0°, and 46.0° (±0.2°). Figure 1 Exemplary X-ray diffraction patterns are provided. In some embodiments, teloratesen or its pharmaceutically acceptable salt, solvate, or hydrate present in the dosage form or pharmaceutical composition of this application has a similar effect to... Figure 1 The X-ray diffraction pattern provided is essentially the same.

[0018] The oral dosage form of this application may be a tablet.

[0019] The dosage form of this application may be similar to a dosage form containing approximately the same amount of telolide or its pharmaceutically acceptable salt, solvate, or hydrate, but without an enteric coating (e.g., WAKIX). ® () is biologically equivalent.

[0020] For example, oral administration of the dosage form of this application to a subject may be performed using telolide, C, provided by the subject. max Compared with oral administration to subjects of drugs without enteric coating (e.g., WAKIX) ® The C of teloridine produced after equal doses of ) max The basic structure is the same. As another embodiment, the once-daily oral administration of the dosage form of this application provides a steady-state C-level concentration of teloratesen for approximately 7 days. max Compared with oral administration without enteric coating (e.g., WAKIX) ® The steady-state C of teloratesen produced after approximately 7 days using an equal-volume formulation of the same drug) max They are basically the same.

[0021] The AUC of telolide provided by oral administration of the dosage form of this application to subjects is the same as that provided by oral administration without enteric coating (e.g., WAKIX). ® The AUC of teloratesen produced by equal-volume administration of the formulation of this application for approximately 7 days is substantially the same as that produced by once-daily oral administration of a formulation without enteric coating (e.g., WAKIX). As another example, the steady-state AUC of teloratesen provided by once-daily oral administration of the formulation of this application for approximately 7 days is comparable to that of once-daily oral administration of a formulation without enteric coating (e.g., WAKIX). ®The steady-state AUC of telorazole produced by equal doses of the same formulation after approximately 7 days was essentially the same.

[0022] The Tmax of telolide provided by oral administration of the dosage form of this application to subjects is equivalent to that of oral administration of an uncoated dose (e.g., WAKIX). ® The Tmax of telorazole obtained after the formulation of the other product was basically the same.

[0023] This application also relates to methods of treating a disease or condition, including: orally administering the oral dosage form of this application to a subject in need. The disease or condition may be a sleep disorder. For example, the disease or condition may be excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. In some embodiments, the disease or condition is excessive daytime sleepiness (EDS). In some embodiments, the disease or condition is cataplexy. In some embodiments, the method relates to treating a disease or condition in a subject suffering from narcolepsy (e.g., an adult suffering from narcolepsy).

[0024] This application also relates to dosage forms (e.g., oral dosage forms) described herein for treating a disease or condition, optionally wherein the disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. The disease or condition can occur in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

[0025] This application also relates to the use of the oral dosage form described herein in the preparation of a medicament for treating a disease or condition, optionally wherein the disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness. The disease or condition can occur in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

[0026] This application also relates to a method for preparing the oral dosage form described herein. The method may include the following steps: (a) blending teloride or a pharmaceutically acceptable salt, solvate, or hydrate thereof with one or more pharmaceutically acceptable excipients (e.g., microcrystalline cellulose, crospovidone, talc, magnesium stearate, colloidal silica (e.g., anhydrous colloidal silica) or combinations thereof) to provide a blend; (b) tableting the blend (e.g., using a tablet press) to provide a tablet core; (c) optionally coating the tablet core with a moisture barrier to provide a moisture-protected tablet; and (d) coating the tablet core of step (b) or the moisture-protected tablet of step (c) with enteric coating to provide an enteric-coated tablet.

[0027] The moisture barrier optionally applied in step (c) may include polymers such as polyvinyl alcohol (PVA) or HPMC, such as OPADRY® polymers, such as OPADRY® amb II. The enteric coating applied in step (d) may also contain polymers such as copolymers of methacrylic acid and ethyl acrylate, such as EUDRAGIT® L 100-55 or ACRYL-EZE®. The enteric coating applied in step (d) may also contain plasticizers such as triethyl citrate or PEG (e.g., PEG8000). Attached Figure Description

[0028] Figure 1 This is an X-ray diffraction pattern of the polymorph of the crystalline teloridine monohydrochloride suitable for use in the dosage form of this application.

[0029] Figure 2 This is a graph depicting the quality changes of the tablet core during the pressing process of batch 1.

[0030] Figure 3 This is a graph depicting the hardness changes of the tablet core during compression in batch 1.

[0031] Figure 4 It is a superimposed graph depicting the stability dissolution curves (average values) of batches 1-1 (10%GR), 1-2 (12%GR), and 1-3 (15%GR) under basket dissolution at 100 rpm, where each batch is an exemplary enteric-coated dosage form containing 20 mg telorisen HCl.

[0032] Figure 5 It is a superimposed graph depicting the stability dissolution curves (average values) of batches 3 to 6 under basket dissolution at 100 rpm, where each batch is an exemplary enteric-coated form containing 20 mg teloridine HCl.

[0033] Figure 6 It is an overlay plot of the stability dissolution curves (average) of batches 7-1 (10%GR), 7-2 (13%GR), 7-3 (15%GR) and 7-4 (17%GR), where each batch is an exemplary enteric-coated form containing 20 mg telorisen HCl.

[0034] Figure 7 This is a superimposed graph depicting the stability dissolution profiles (average values) of batch 8 (an exemplary enteric-coated form containing 20 mg telorisen HCl) at release and after 1 month at 5°C, 25°C / 60%RH, or 40°C / 75%RH.

[0035] Figure 8A and Figure 8BThis is a graph showing the dissolution profiles of two sub-batches of an exemplary enteric-coated dosage form (clinical batch LC23120A): Sub-batch 1 ( Figure 8A ) and sub-batch 2 ( Figure 8B ).

[0036] Figure 9 This is a graph showing the dissolution profile of an exemplary enteric-coated dosage form (clinical batch LC23120A) at release.

[0037] Figure 10 This is a graph showing the dissolution curves at release of an exemplary enteric-coated dosage form compared to the same batch (clinical batch LC23120A) after 3 months under different stability testing conditions. Detailed Implementation

[0038] This application generally relates to a dosage form (e.g., an oral dosage form) and a pharmaceutical composition comprising a pharmaceutically active agent, an enteric coating, and optionally one or more pharmaceutically acceptable excipients and an optional moisture-proof coating, wherein the pharmaceutically active agent comprises teloridine or a pharmaceutically acceptable salt, solvate, or hydrate thereof represented by formula (I): (I).

[0039] Compared to existing telolide formulations (such as WAKIX) ® Compared to other telolide dosage forms and pharmaceutical compositions, the enteric-coated formulations and pharmaceutical compositions of this application have numerous advantages. Specifically, compared to telolide dosage forms or pharmaceutical compositions without enteric coating, such as WAKIX... ® The dosage form and pharmaceutical composition of this application are more tolerable to subjects due to fewer or no side effects (e.g., gastrointestinal side effects such as stomach upset, nausea, and vomiting). Therefore, compared to receiving teloprene formulations without enteric coating (e.g., WAKIX), they are more readily tolerated. ® Subjects receiving the dosage form and pharmaceutical composition of this application showed better patient compliance. Another advantage of the dosage form and pharmaceutical composition of this application is their compatibility with WAKIX. ® The fact that a teloprecin-containing formulation of EDS and cataplexy, which is approved for the treatment of adult subjects with narcolepsy, is bioequivalent is unexpected.

[0040] definition The articles “a” and “an” used in this article refer to one or more of the grammatical objects of the article (i.e., at least one). For example, “element” means one or more elements.

[0041] The term “about” when referring to measurable values ​​(such as quantity, duration, etc.) means that it covers a variation of ±20% or less, or in some cases ±15% or less, or in some cases ±10% or less, or in some cases ±5% or less, or in some cases ±1% or less, or in some cases ±0.1% or less, compared to a specified value, because such variation is appropriate.

[0042] The phrase “and / or” as used herein should be understood to mean “any one or both” of the elements it connects, that is, elements that exist simultaneously in some cases and optionally in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements thus connected. In addition to the elements specifically indicated by the “and / or” clause, other elements may optionally exist, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “including,” the expression “A and / or B” may refer only to A (optionally including elements other than B) in one embodiment; only to B (optionally including elements other than A) in another embodiment; both A and B (optionally including other elements) in yet another embodiment, and so on.

[0043] As used herein, the terms “administer,” “administering,” or “administration” mean the introduction of a compound, dosage form, or pharmaceutical composition into the body through implantation, absorption, ingestion, injection, inhalation, or other means.

[0044] The terms “comprise,” “comprises,” and “comprising” as used herein are used in a non-exclusive sense unless the context otherwise requires. Similarly, the term “includes” and its grammatical variations are intended to be non-restrictive, such that the listing of items in a list does not exclude other similar items that may substitute for or be added to the listed items.

[0045] As used herein, the term "effective amount" or "therapeutic effective amount" means an amount of the compound, dosage form, or pharmaceutical composition described herein that is sufficient, under the conditions of administration, to achieve the desired result. For example, the effective amount of the compound, dosage form, or pharmaceutical composition disclosed herein for treating excessive sleep disorder (EDS), for example, in a subject suffering from narcolepsy, is an amount capable of reducing the effect of EDS and / or reducing or eliminating the severity of EDS-related symptoms. A skilled clinician may determine the appropriate dosage based on a variety of considerations, including the severity of the disease, the subject's age, weight, general health condition, and other considerations. The dosage forms or pharmaceutical compositions disclosed herein may be administered to provide amounts of about 0.01 mg to about 250 mg (e.g., about 0.1 mg to about 100 mg), such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg of a pharmaceutically active agent (e.g., teloprene or a pharmaceutically acceptable salt, solvate, or hydrate thereof). In some aspects, the dosage form or pharmaceutical composition of this application is administered to provide about 5 mg of teloliden hydrochloride. In some aspects, the dosage form or pharmaceutical composition of this application is administered to provide about 20 mg of teloliden hydrochloride.

[0046] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a non-toxic material that can be formulated with the compounds disclosed herein to provide a pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable excipients that can be used to prepare the pharmaceutical compositions disclosed herein are any excipients well known in the art, and include, but are not limited to, diluents, dispersants, granulators, surfactants, emulsifiers, disintegrants (sometimes referred to herein as disintegrants), binders (sometimes referred to herein as binders), flow agents, preservatives, buffers (sometimes referred to herein as buffers), lubricants (sometimes referred to herein as lubricants), flow aids, fillers, wetting agents, suspending agents, solvents, dispersion media, ion exchangers, salts, electrolytes, waxes, colorants, and / or oils, etc.

[0047] For example, pharmaceutically acceptable excipients may be alumina, phosphates (e.g., calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate), sulfates (e.g., calcium sulfate), cellulose (including, for example, cellulose derivatives, microcrystalline cellulose (including spray-dried microcrystalline cellulose), silicified microcrystalline cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose or salts thereof (e.g., sodium carboxymethyl cellulose or calcium carboxymethyl cellulose), kaolin, bentonite, VEEGUM ®Lactose (e.g., anhydrous lactose, spray-dried lactose, hydrated lactose), mannitol, sorbitol, sucrose, inositol, compressible sugars, trehalose, xylitol, gum arabic, gelatin, glucose, maltodextrin, starch (e.g., corn starch, potato starch), sodium starch glycolate, starch derivatives, amino acids (e.g., glycine or leucine), magnesium carbonate, polyvinylpyrrolidone (PVP, povidone) (e.g., cross-linked PVP, cross-linked povidone), polyvinyl alcohol, tragacanth gum, polyethylene glycol, polymethyl methacrylate, mineral clay powder, cross-linked carboxymethyl cellulose, poloxamer, fatty acids or their salts (e.g., lauric acid, sodium lauryl sulfate, hard... Fatty acids, calcium stearate, magnesium stearate, aluminum stearate, oleic acid), hydrogenated vegetable oil, talc, titanium dioxide, glyceryl behenate, silica (e.g., colloidal silica), silicates (e.g., magnesium trisilicate), lecithin, serum albumin (e.g., human serum albumin), sorbic acid, potassium sorbate, metal cation salts (e.g., sodium salts, such as sodium chloride; potassium salts, such as potassium chloride; magnesium salts, such as magnesium chloride; zinc salts, such as zinc chloride), water, dimethylacetamide, protamine sulfate, polyacrylate, lanolin, ethylenediaminetetraacetic acid (EDTA), cyclodextrin (e.g., CAPTISOL) ® ), KOLLIDON® CL, CELLACTOSE®, LUDIPRESS®, polysorbates (e.g., TWEEN) ® (e.g., TWEEN® 20 or TWEEN® 80) and combinations thereof.

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found on the corresponding compound. When the compounds involved in this application contain relatively basic functional groups (e.g., as in formula (I)), acid addition salts can be obtained by contacting a neutral form of such a compound with a sufficient amount of the desired acid in its pure form or in a suitable solvent (e.g., an inert solvent). For example, a neutral form of teloridesen can be contacted with gaseous hydrochloric acid to provide teloridesen monohydrochloride, which may be present in the dosage forms disclosed herein. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, succinic acid, fumaric acid, lactic acid, mandelic acid, paprika acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and oxalic acid. Salts of amino acids such as arginine and salts of organic acids such as glucuronic acid or galacturonic acid are also included. Other pharmaceutically acceptable salts known to those skilled in the art are suitable for the pharmaceutical compositions of this application.

[0049] As used herein, the term "solvent" refers to the form in which a compound typically associates with a solvent via a solvent decomposition reaction. This physical association can include hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, etc. The compounds of this application can be prepared, for example, in crystalline form and can be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0050] As used herein, the term "hydrate" refers to a compound associated with water. Generally, the number of water molecules in a hydrate of a compound is in a certain ratio to the number of compound molecules in the hydrate. Therefore, a hydrate of a compound can be represented, for example, by the general formula R·xH₂O, where R is the compound and x is a number greater than 0. A given compound can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and less than 1, such as hemihydrates (R·0.5 H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

[0051] As used herein, the term "subject" refers to any animal, such as any mammal, including but not limited to humans, non-human primates, rodents, dogs, etc. Non-human primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques (e.g., rhesus monkeys). Rodents include mice, rats, marmots, ferrets, rabbits, and hamsters. Domesticated and wild animals include cattle, horses, pigs, deer, bison, buffalo, felines (e.g., domestic cats), canines (e.g., dogs, foxes, wolves), birds, and fish. In some embodiments, the subject is a mammal (e.g., a human, rat, or mouse). The subject can be male or female. The subject can be of any age, including elderly subjects (e.g., 65 years or older), non-elderly subjects (e.g., less than 65 years old), or human pediatric subjects (e.g., less than 18 years old). In a preferred aspect, the subject is a human.

[0052] As used herein, the terms “treat,” “treatment,” “treating,” or grammatically related terms refer to methods for reducing the effects of a disease or condition. As is readily understood in the art, complete eradication of a disease, condition, or its symptoms is preferred, but not necessary for treatment. The desired effects of treatment include, but are not limited to: prevention of the occurrence or recurrence of the disease or condition; relief of symptoms; reduction of any direct or indirect pathological consequences of the disease or condition; or other improvements in any signs, symptoms, or consequences of the disease or condition, such as prolonged survival, reduced morbidity, and / or reduced side effects.

[0053] Throughout this application, various embodiments may be presented in range form (e.g., X to Y). It should be understood that the description in range form is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this application. Therefore, the description of a range should be considered as having specifically disclosed all possible sub-ranges and the individual values ​​within that range. For example, a description of a range such as 1 to 6 should be considered as disclosing specifically disclosed sub-ranges such as 1 to 5, 1 to 4, 1 to 3, 2 to 6, 2 to 4, 3 to 6, etc., and the individual values ​​within that range, such as 1, 2, 2.8, 3, 3.6, 4, 5, 5.4, and 6. As another example, a range such as 95% to 99% includes 95%, 96%, 97%, 98%, or 99% and all sub-ranges such as 96% to 99%, 96% to 98%, 96% to 97%, 97% to 99%, 97% to 98%, etc. This applies regardless of the width of the range.

[0054] All publications cited in this application (e.g., scientific journal articles, patent publications, etc.) are incorporated herein by reference in their entirety. If any material incorporated by reference contradicts or is inconsistent with this specification, this specification shall supersede any such material. Any reference cited herein does not constitute an endorsement that such reference is prior art. Various terms relating to aspects of this specification are used throughout the specification and claims. Unless otherwise stated, these terms shall be given their ordinary meaning in the art. Other specifically defined terms shall be interpreted in a manner consistent with the definitions provided herein.

[0055] The compounds disclosed herein (e.g., pharmaceutically active agents) may also contain one or more isotope substitutions. For example, hydrogen (H) may be included... 1 H, 2 H (D or deuterium), 3 Any isotopic form including H (T or tritium); carbon (C) can be any of the following forms: 12 C 13 C and 14 Any isotopic form including C; oxygen (O) can be any of the following forms:16 O and 18 Any isotopic form including O; nitrogen (N) can be any isotopic form including O; 14 N and 15 Any isotopic form including N; and chlorine (Cl) can be any isotopic form including N; 35 Cl and 37 Any isotopic form including Cl.

[0056] Various embodiments of the compounds, dosage forms, pharmaceutical compositions and methods described herein are described in more detail below, and additional definitions may be provided throughout the specification.

[0057] Dosage Forms and Pharmaceutical Compositions This document discloses dosage forms (e.g., oral dosage forms) and pharmaceutical compositions comprising a pharmaceutically active agent, an enteric coating, and optionally one or more pharmaceutically acceptable excipients. The pharmaceutically active agent is telolide, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, as represented by formula (I). (I).

[0058] Dosage form or pharmaceutical composition may contain a therapeutically effective amount of a pharmaceutically active agent. For example, dosage form or pharmaceutical composition may contain about 1 mg to about 200 mg of a pharmaceutically active agent, such as about 1 mg to about 100 mg, 1 mg to about 80 mg, 1 mg to about 60 mg, about 1 mg to about 50 mg, about 10 mg to about 25 mg, or about 1 mg to about 10 mg of a pharmaceutically active agent, such as about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg of a pharmaceutically active agent.

[0059] It should be understood that when the pharmaceutically active agent is a pharmaceutically acceptable salt of formula (I), the amount of the pharmaceutically active agent in the dosage form or pharmaceutical composition will be slightly higher than the amount of an equal amount of free base. For example, the dosage form or pharmaceutical composition disclosed herein containing 5 mg of teloristian hydrochloride will contain about 4.45 mg of teloristian (free base). In another embodiment, the dosage form or pharmaceutical composition disclosed herein containing 20 mg of teloristian hydrochloride contains about 17.8 mg of teloristian (free base). In some embodiments, the dosage form or pharmaceutical composition disclosed herein contains about 5 mg of teloristian monohydrochloride, or about 4.45 mg of teloristian (free base). In some embodiments, the dosage form or pharmaceutical composition disclosed herein contains about 20 mg of teloristian monohydrochloride, or about 17.8 mg of teloristian (free base).

[0060] The dosage form of this application can be tablets, capsules, suspensions, granules, powders, etc. Preferably, the dosage form of this application is enteric-coated tablets, enteric-coated capsules, enteric-coated capsules, etc. Tablets (e.g., enteric-coated tablets) can be round or biconvex tablets. Tablets can be engraved with, for example, numbers, letters, or both.

[0061] The dosage form or pharmaceutical composition of this application may further comprise one or more pharmaceutically acceptable excipients, such as diluents, dispersants, granulators, surfactants, emulsifiers, disintegrants (sometimes referred to herein as disintegrants), binders (sometimes referred to herein as binders), preservatives, buffers, lubricants (sometimes referred to herein as lubricants), glidants, adjuvants, fillers, wetting agents, suspending agents, solvents, dispersion media, ion exchangers, salts, electrolytes, waxes and / or oils, etc.

[0062] Non-limiting examples of pharmaceutically acceptable excipients suitable for the dosage forms or pharmaceutical compositions disclosed herein include alumina, phosphates (e.g., calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate), sulfates (e.g., calcium sulfate), cellulose, cellulose derivatives, microcrystalline cellulose (including spray-dried microcrystalline cellulose), silanized microcrystalline cellulose, hydroxypropyl methylcellulose, methylcellulose, carboxymethyl cellulose or salts thereof (e.g., sodium carboxymethyl cellulose or calcium carboxymethyl cellulose), kaolin, bentonite, and VEEGUM. ® Lactose (e.g., anhydrous lactose, spray-dried lactose, hydrated lactose), mannitol, sorbitol, sucrose, inositol, compressible sugars, trehalose, xylitol, gum arabic, gelatin, glucose, maltodextrin, starch (e.g., corn starch, potato starch), sodium starch glycolate, starch derivatives, amino acids (e.g., glycine or leucine), magnesium carbonate, polyvinylpyrrolidone (PVP, povidone) (e.g., cross-linked PVP, cross-linked povidone), polyvinyl alcohol, tragacanth gum, polyethylene glycol, polymethyl methacrylate, mineral clay powder, cross-linked carboxymethyl cellulose, poloxamer Brut, fatty acids or their salts (e.g., lauric acid, sodium lauryl sulfate, stearic acid, calcium stearate, magnesium stearate, aluminum stearate, oleic acid), hydrogenated vegetable oils, talc, titanium dioxide, glyceryl behenate, silica (e.g., colloidal silica), silicates (e.g., magnesium trisilicate), lecithin, serum proteins (e.g., human serum albumin), sorbic acid, potassium sorbate, metal cation salts (e.g., sodium salts, such as sodium chloride; potassium salts, such as potassium chloride; magnesium salts, such as magnesium chloride; zinc salts, such as zinc chloride), water, dimethylacetamide, protamine sulfate, polyacrylates, lanolin, ethylenediaminetetraacetic acid (EDTA), cyclodextrins (e.g., CAPTISOL) ®), KOLLIDON® CL, CELLACTOSE®, LUDIPRESS®, polysorbates (e.g., TWEEN) ® (e.g., TWEEN® 20 or TWEEN® 80) and combinations thereof.

[0063] In a preferred aspect, the dosage form (e.g., an oral dosage form) or pharmaceutical composition of this application comprises a combination of pharmaceutically acceptable excipients. For example, the dosage form or pharmaceutical composition of this application may comprise one or more of the following pharmaceutically acceptable excipients: microcrystalline cellulose (e.g., Vivapur 102), crospovidone (e.g., Polyplasdone XL), talc, magnesium stearate (e.g., Kemilub EM-FV), and colloidal silica. Pharmaceutically acceptable excipients may be present only in the core of the dosage form.

[0064] Each pharmaceutically acceptable excipient may be present in any suitable amount in the dosage form or pharmaceutical composition. For example, a pharmaceutically acceptable excipient may be present in the dosage form or pharmaceutical composition in an amount of about 1% to about 95% by weight, such as about 60% to 90% by weight, or about 80% to about 90% by weight.

[0065] For example, telolide may be present in the core of the dosage form in an amount of about 14 wt% to about 18 wt% (e.g., about 16 wt%), and pharmaceutically acceptable excipients may constitute the remaining weight of the core of the dosage form. One pharmaceutically acceptable excipient may be a diluent (e.g., microcrystalline cellulose) present in the core of the dosage form in an amount of about 60 wt% to about 70 wt% (e.g., about 65 wt%). Another pharmaceutically acceptable excipient may be a disintegrant (e.g., crospovidone) present in the core of the dosage form in an amount of about 6 wt% to about 10 wt% (e.g., about 8 wt%). Another pharmaceutically acceptable excipient may be a glidant (e.g., talc) present in the core of the dosage form in an amount of about 6 wt% to about 10 wt% (e.g., about 8 wt%). Another pharmaceutically acceptable excipient may be a lubricant (e.g., magnesium stearate) present in the core of the dosage form in an amount of about 1 wt% to about 4 wt% (e.g., about 2.4 wt%). Another pharmaceutically acceptable excipient may be a flow agent (e.g., colloidal silica) present in the core of the dosage form in an amount of about 0.1% to about 2% by weight (e.g., about 0.8% by weight).

[0066] Preferably, the dosage form or pharmaceutical composition of this application is for oral administration.

[0067] The preparation of the dosage form (e.g., oral dosage form) or pharmaceutical composition of this application may include conventional methods such as blending, filling, pressing (e.g., direct pressing, pressing of dry, wet or sintered particles), coating (e.g., coating by spray process), extrusion, granulation (e.g., wet or dry granulation), pelleting (e.g., direct pelleting), bonding, powder layering (e.g., on a neutral core or particle without active ingredient or pharmaceutical active agent), and rounding off.

[0068] For example, the dosage form of this application can be prepared by the following steps: (a) preparing a core blend comprising teloridesen and optionally one or more pharmaceutically acceptable excipients, for example, by blending a pharmaceutically active agent (e.g., crystalline powder) with one or more pharmaceutically acceptable excipients (e.g., binders, disintegrants, glidants, etc.). Additional sieving steps may be employed. The next step may include (b) forming a tablet core with the blend, for example, by tableting using a tableting machine. Optionally, the tablet core may be coated with a moisture barrier coating disclosed herein, for example, using a spray process. Finally, the tablet core coated with a moisture barrier may be further coated with an enteric coating material disclosed herein, for example, using a spray process. The coating step may include spraying the moisture barrier material or enteric coating material in the form of a solution, suspension, or dispersion (e.g., an organic solution or an aqueous dispersion).

[0069] Enteric coating The dosage forms (e.g., oral dosage forms) and pharmaceutical compositions disclosed herein comprise enteric coatings. Enteric coatings can be pH-dependent materials. For example, the dosage forms or pharmaceutical compositions disclosed herein can remain substantially intact in the stomach at a low pH (about 1.0 to 3.5) and release the pharmaceutically active agent upon entering the small intestine due to disintegration of the enteric coating at a relatively high pH (about 5.5 to 7.0) in the small intestine. In some aspects of this application, the enteric coating can disintegrate at higher pH levels, for example, to significantly release the pharmaceutically active agent in more distal portions of the small intestine at even higher pH levels (e.g., about 6.0 to 7.5). The pharmaceutical compositions or dosage forms of this application can significantly release the pharmaceutically active agent in the duodenum, jejunum, or both the duodenum and jejunum.

[0070] Enteric coatings can remain substantially undisintegrated in the stomach or gastric juices, for example, at a pH of about 1.0 to about 3.5. Enteric coatings can disintegrate in the intestine (e.g., the small intestine) to expose the pharmaceutically active agent, for example, after the dosage form or pharmaceutical composition has entered the intestine. For this purpose, enteric coatings can substantially disintegrate in the intestine (e.g., the small intestine) or intestinal juices or at a pH greater than 5 (e.g., greater than 5.5, greater than 6.0, greater than 6.5, greater than 7.0, or greater than 7.5).

[0071] The enteric coating of the dosage form or pharmaceutical composition of this application may be acid-resistant (gastric-tolerant) and prevent the release of more than 10% of the pharmaceutically active agent for at least 1 hour (e.g., 2 hours) when the dosage form is in the stomach, in hydrochloric acid solution (pH 1.2), gastric juice, or simulated gastric juice, for example, releasing less than 10%, less than 8%, less than 6%, less than 4%, less than 3%, less than 2%, or less than 1% of the pharmaceutically active agent by weight, or not releasing the pharmaceutically active agent. The temperature of the hydrochloric acid solution, gastric juice, or simulated gastric juice may be about 37°C. The dosage form or pharmaceutical composition, or its enteric coating, may substantially disintegrate after the dosage form or pharmaceutical composition is in the intestine (e.g., small intestine) or exposed to intestinal juice, simulated intestinal juice, or a solution (e.g., a buffer solution, such as phosphate buffer) with a pH greater than 5 (e.g., pH greater than 5.5, 6.0, 6.5, 7.0, 7.5, or higher).

[0072] The dosage form or pharmaceutical composition according to this application may be a delayed-release dosage form or pharmaceutical composition that conforms to the determination method and judgment criteria of United States Pharmacopeia (USP) 701 Delayed-Release Tablets and Capsules (tablets or capsules formulated with acid-resistant or enteric coating).

[0073] The enteric coating of the dosage forms or pharmaceutical compositions disclosed herein may comprise a polymer. For example, the polymer of the enteric coating may be a polymer containing ionizable functional groups (e.g., carboxylic acid groups), such as functional groups that are non-ionizable in the stomach or gastric juice or in solutions with a pH of about 1.0 to about 3.5. The functional group may be a group that is ionizable in the intestine (e.g., small intestine) or intestinal juice or in solutions with a pH greater than 5 (e.g., pH greater than 5.5, greater than 6.0, greater than 6.5, greater than 7.0, or greater than 7.5).

[0074] Enteric coatings may contain acrylic polymers, such as copolymers of acrylic acid and methacrylic acid, copolymers of methacrylates (e.g., copolymers of methyl methacrylate, butyl methacrylate and dimethyl methacrylate, copolymers of methyl methacrylate, ethyl acrylate and trimethylammonium methacrylate, copolymers of methyl methacrylate and ethyl acrylate); cellulose materials, such as alkyl cellulose, e.g., ethyl cellulose, AQUACOAT ® SURELEASE ® Hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, cellulose acetate phthalate, etc.; polyvinylpyrrolidone (PVP), polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, KOLLICOAT ® Polymers, starch, starch derivatives, polyvinyl acetate (PVAc), polyvinyl acetate phthalate (PVAP or COATERIC®), KOLLIDON ®Polymers, vinyl acetate-vinylpyrrolidone copolymers (e.g., KOLLIDON) ® VA64), vinyl acetate: crotonic acid copolymer (VAC:CRA), polyethylene glycol (e.g., polyethylene glycol with a molecular weight greater than 1000 g / mol), chitosan, cross-linked and / or non-cross-linked polyacrylic acid, sodium alginate, pectin, methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, poly(methacrylic acid), alkyl methacrylate copolymers, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate), polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, ammonium methacrylate copolymers, etc.; shellac, zein, etc.; combinations thereof. In some embodiments, the enteric coating comprises anionic polymers, such as anionic methacrylate copolymers. It should be understood that the polymer may not be anionic at sufficiently low pH (e.g., in gastric juice), but becomes ionized at elevated pH (e.g., in intestinal juice).

[0075] Enteric coating may contain EUDRAGIT ® Polymers, such as EUDRAGIT ® L polymers, such as EUDRAGIT ® L 30D-55, EUDRAGIT ® L 100-55, EUDRAGIT ® FL 30 D-55, EUDRAGIT ® L 100, EUDRAGIT ® L 12,5, or EUDRAGIT ® S polymers, such as EUDRAGIT ® S 100, EUDRAGIT ® S 12,5, EUDRAGIT ® FS 30 D, EUDRAGIT ® FS 100; EUDRAGIT ® RL polymers, such as EUDRAGIT ® RL PO, EUDRAGIT ® RL 100, EUDRAGIT ® RL 30D, EUDRAGIT ® RL 12,5; EUDRAGIT ® RS polymers, such as EUDRAGIT ® RS PO, EUDRAGIT ® RS 100, EUDRAGIT® RS 30 D or EUDRAGIT ® RS 12,5; EUDRAGIT ® NM polymers, such as EUDRAGIT ® NM 30, or combinations thereof.

[0076] Enteric coating may contain ACRYL-EZE ® Such as ACRYL-EZE ® transparent.

[0077] Enteric coatings may also contain plasticizers and stabilizers (such as oleic acid or polysorbates, such as TWEEN). ® 80) Lubricants, flow aids, release agents, or pigments (e.g., talc, titanium dioxide, or magnesium stearate). Examples of suitable plasticizers include sebacic acid esters (e.g., dibutyl sebacic acid), propylene glycol, polyethylene glycol (e.g., PEG8000), phthalates (e.g., diethyl phthalate or dibutyl phthalate) or phthalate derivatives, citrate esters (e.g., triethyl citrate or tributyl citrate), triacetin, acetylated monoglycerides, castor oil, propylene glycol, and polyethylene glycol. Examples of release agents include glyceryl monostearate or other suitable fatty acid derivatives, silica derivatives, and talc. Preferred stabilizers are PEG8000 and triethyl citrate.

[0078] Enteric coatings may include materials disclosed in US 2004 / 0028737, US 2005 / 0271778, WO 2005 / 044240, WO2007 / 006353, and WO 2008 / 135090, all of which are incorporated herein by reference in their entirety.

[0079] Moisture barrier The dosage forms (e.g., oral dosage forms) and pharmaceutical compositions disclosed herein may include a moisture barrier coating. A moisture barrier is different from an enteric coating, and in addition to an enteric coating, a moisture barrier may also be present in the dosage form or pharmaceutical composition. For example, the moisture barrier coating may be located around the core of the dosage form and below the enteric coating layer (i.e., between the outer surface of the core and the inner surface of the enteric coating layer). The moisture barrier may include any suitable material, such as a material that prevents moisture from the environment from easily penetrating the core of the dosage form before the dosage form is intended to dissolve (e.g., at the time of application).

[0080] Moisture barriers may include polymers. Suitable polymers include polyvinyl alcohol and hydroxypropyl methylcellulose. An exemplary moisture barrier material of this application is OPADRY. ® amb II (e.g., purple OPADRY) ®amb II, or transparent OPADRY ® amb II).

[0081] Pharmaceutical active agents The pharmaceutically active agent in the dosage forms (e.g., oral dosage forms) or pharmaceutical compositions disclosed herein is teloridine (1-{3-[3-(4-chlorophenyl)propoxy]propyl}-piperidine) or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Teloridine is represented by formula (I): (I).

[0082] The pharmaceutically active agent can be a free base of formula (I), or it can be any pharmaceutically acceptable salt of formula (I), such as those disclosed herein. For example, the pharmaceutically active agent can be a hydrochloride or oxalate of formula (I).

[0083] In a preferred aspect, the pharmaceutically active agent is a hydrochloride salt of formula (I), such as (1-{3-[3-(4-chlorophenyl)propoxy]propyl}-piperidine monohydrochloride; teloliden hydrochloride), represented by formula (Ia): (Ia).

[0084] Not wanting to be bound by theory, it is believed that teloraten can activate receptors in the stomach, such as histamine H3 receptors, which may lead to interactions with existing teloraten formulations (such as WAKIX). ® Related gastric side effects. The inventors have discovered that by formulating teloratesen dosage forms or pharmaceutical compositions with an enteric coating, gastric side effects can be significantly reduced or eliminated. Not wishing to be bound by theory, it is also believed that although the enteric coating prevents teloratesen from being released from the dosage form in the stomach or gastric juices, compared to comparative formulations such as WAKIX... ® Cmax or Tmax did not flatten, and the dosage form of this application is similar to WAKIX. ® The total exposure (as measured by AUC) is relatively the same between them. In other words, despite the enteric coating, the dosage forms and pharmaceutical compositions disclosed herein are substantially comparable to WAKIX. ® It is biologically equivalent.

[0085] The dosage forms and pharmaceutical compositions disclosed herein may comprise a monohydrochloride salt of formula (I) that has relatively high water solubility compared, for example, with other known pharmaceutically acceptable salts of formula (I) (e.g., teloroxygen oxalate). The water solubility of the pharmaceutically active agent at 23°C may be approximately 4 g / mL.

[0086] Pharmaceutical active agents (e.g., formula (I) or formula (Ia)) may be crystalline.

[0087] The water content of the pharmaceutical active agent may be 6% (±0.5%) or less by weight, for example less than 5%, less than 4%, less than 3%, less than 2% or less than 1%.

[0088] Pharmaceutical active agents can be found at 1112, 1101, 2936, 2868, 1455, 2647, 2551, 1492 and 802 cm⁻¹. -1 It has a characteristic IR peak at (±5).

[0089] The pharmaceutically active agent may be the crystalline form of teloliden hydrochloride. The pharmaceutically active agent may be the crystalline form of teloliden hydrochloride as described in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety.

[0090] The pharmaceutically active agent can be teloridine hydrochloride, obtained using X-ray diffraction techniques described in U.S. Patent No. 8,207,197, operating with a Nonius Kappa charge-coupled device system at -158°C and a wavelength of 0.71073 Å, with characteristic peaks (2θ) at 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°). The pharmaceutically active agent can have the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0091] The pharmaceutically active agent may be a compound disclosed in US 8,207,197, US 8,354,430, US 8,486,947, US 7,138,413, US 7,910,605 or US 7,169,928, all of which are incorporated herein by reference in their entirety.

[0092] Pharmacokinetics Not wanting to be bound by theory, it is believed that the oral dosage forms and pharmaceutical compositions disclosed herein, and their non-enteric-coated counterparts (such as WAKIX), are compatible. ® They are substantially bioequivalent and / or have substantially the same bioavailability. In other words, and not wishing to be bound by theory, it is believed that the presence of an enteric coating on the dosage forms or pharmaceutical compositions disclosed herein does not substantially affect their pharmacokinetics and / or bioavailability, and that upon administration, an equivalent amount of the dosage form or pharmaceutical composition (e.g., containing substantially the same amount of the same pharmaceutically active agent and pharmaceutically acceptable excipients) is obtained as with administration of a dosage form or pharmaceutical composition without an enteric coating, such as WAKIX. ® The expected similar biological effects, bioavailability, and / or pharmacokinetics.

[0093] For example, it is believed that oral administration of one or more dosage forms or pharmaceutical compositions disclosed herein to provide about 35.6 mg / day of teloratesen (free base) can achieve a steady-state Cg of about 49.2 ng / mL to about 126 ng / mL, such as about 73 ng / mL of teloratesen. max Similarly, it is believed that oral administration of one or more dosage forms or pharmaceutical compositions disclosed herein to provide approximately 35.6 mg / day of teloratesen (free base) can achieve a steady-state AUC of approximately 518 ng*hr / mL to approximately 1468 ng*hr / mL, for example, approximately 812 ng*hr / mL of teloratesen. It is further believed that after once-daily oral administration of one or more dosage forms or pharmaceutical compositions disclosed herein, steady-state AUC and C0 are reached on day 7. max .

[0094] The dosage forms (e.g., oral dosage forms) or pharmaceutical compositions disclosed herein may have the same amount as dosage forms or pharmaceutical compositions without enteric coating (e.g., WAKIX). ® The oral bioavailability is substantially the same. For example, not wishing to be bound by theory, it is believed that administration (e.g., oral administration) of the dosage forms or pharmaceutical compositions disclosed herein can achieve oral absorption of greater than 50%, such as about 75%, about 85%, about 90%, or higher. Further, it is believed that administration (e.g., oral administration) of the dosage forms or pharmaceutical compositions disclosed herein can achieve T-cell absorption of teloratesen for about 2 hours to about 5 hours (e.g., about 3.5 hours). max .

[0095] In some embodiments, when used with dosage forms that do not contain enteric coating (e.g., WAKIX) ® When the same molar dose of the therapeutic agent was administered, the rate and / or extent of absorption of teloratesen after administration of the dosage forms or pharmaceutical compositions disclosed herein did not show significant differences.

[0096] In some embodiments, the oral dosage forms or pharmaceutical compositions disclosed herein are compatible with WAKIX. ® It is bioequivalent, as determined by the bioequivalence guidance 94D-0401 provided by the U.S. Food and Drug Administration (FDA).

[0097] In some embodiments, the oral dosage forms or pharmaceutical compositions disclosed herein have similar properties to WAKIX. ® Essentially the same bioavailability.

[0098] Treatment This application also relates to methods for treating diseases or conditions, including administering a dosage form (e.g., an oral dosage form) or pharmaceutical composition disclosed herein to a subject in need. Diseases or conditions can be sleep disorders (e.g., excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness), central nervous system diseases (e.g., epilepsy, Alzheimer's disease, Parkinson's disease, dementia (e.g., Lewy body dementia and / or vascular dementia), attention deficit, arousal disorder, memory impairment, cognitive deficits (e.g., in older adults), psychopathology, depressive and asthenic states, vertigo and motion sickness, obesity, psychosomatic disorders. Disorders), respiratory diseases, allergic diseases, inflammatory diseases, heart diseases, gastrointestinal diseases, genitourinary diseases, skin diseases, stress, migraines, headaches, pain, mental illnesses, asthma, bronchitis, rhinitis, tracheitis, gastric ulcers, duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel syndrome, cystitis, endometritis, urinary incontinence, fecal incontinence, urticaria, pruritus, arthritis, conjunctivitis, premenstrual syndrome, prostatitis, reproductive disorders, rheumatic diseases, eye diseases, drooling, seizures, depression, hypothalamic-pituitary system diseases, cerebral circulatory diseases, and immune system diseases.

[0099] In a preferred aspect, the illness or condition is a sleep disorder. For example, the illness or condition could be excessive daytime sleepiness (EDS). EDS can occur in subjects with narcolepsy (e.g., adult subjects).

[0100] This application also relates to a method for preventing adverse side effects associated with the use of antipsychotic or antidepressant medications (e.g., aripiprazole, clozapine, olanzapine, risperidone, quetiapine, serindole, mirtazapine, amitriptyline, and paroxetine), the method comprising administering a dosage form or pharmaceutical composition of this application to a subject in need. Non-limiting examples of adverse side effects associated with the use of antipsychotic or antidepressant medications include weight gain, somnolence, and cognitive impairment.

[0101] This application also relates to methods for (i) inducing prolonged wakefulness; (ii) improving cognitive processes; (iii) reducing food intake; and / or (iv) normalizing vestibular reflexes, comprising administering the dosage form or pharmaceutical composition disclosed herein to a subject in need.

[0102] The dosage forms (e.g., oral dosage forms) or pharmaceutical compositions disclosed herein can be taken once daily, twice daily, or more frequently. More than one dosage form can be administered at once to achieve the desired dose. Preferably, the dosage form (or multiple dosage forms when using multiple dosage forms) or pharmaceutical composition is taken once daily. For example, one or more dosage forms disclosed herein can be administered orally once daily, such as upon waking in the morning. One or more dosage forms or pharmaceutical compositions disclosed herein can be taken at a frequency (e.g., once daily) such that the total amount of the pharmaceutically active agent administered is from about 10 mg / day to about 50 mg / day, for example, from about 15 mg / day to about 40 mg / day. One or more dosage forms or pharmaceutical compositions disclosed herein can be taken at a frequency (e.g., once daily) such that the total amount of teloprene administered (as free base) is from about 17.8 mg / day to about 35.6 mg / day. For example, a subject may be given two oral formulations once daily, each containing 4.45 mg of teloratesen (calculated as free base) to achieve a daily dose of 8.9 mg of teloratesen (calculated as free base). A subject may be given one oral formulation once daily, containing 17.8 mg of teloratesen (calculated as free base) to achieve a daily dose of 17.8 mg of teloratesen (calculated as free base). A subject may be given two oral formulations once daily, each containing 17.8 mg of teloratesen (calculated as free base) to achieve a daily dose of 35.6 mg of teloratesen (free base).

[0103] Example To provide a fuller understanding of the invention described herein, the following examples are provided. These examples are intended to illustrate dosage forms (e.g., enteric-coated dosage forms), methods of use, and methods of preparation, and should not be construed in any way as limiting its scope.

[0104] The compounds and dosage forms provided herein can be prepared from readily available starting materials using modifications to the specific methods described below, as is well known to those skilled in the art. It should be understood that, given typical or preferred process conditions, other process conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization.

[0105] Materials and methods Materials used in the following examples were purchased from commercial suppliers. Telorizen hydrochloride (API) was obtained from CordenPharma Chenove (MA-22-013). Telorizen hydrochloride can also be prepared according to the method described in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety. Microcrystalline cellulose (Vivapur 102) (diluent) was obtained from JRS Pharma (ME-19-093; ME-19-077). Cross-linked polyvinylpyrrolidone (Polyplasdone XL) (disintegrant) was obtained from BASF (0002356295). Talc (Luzenac Pharma) (flow aid) was obtained from IMI Fabi (TE142). Magnesium stearate (Kemilub EM-FV) (lubricant) was obtained from Peter Greven (241231). Anhydrous colloidal silica (Aerosil 200 Pharma) (flow agent) was obtained from Evonik (150061214). OPADRY ® amb II transparent (moisture barrier agent) is sourced from Colorcon (TKL53663). ACRYL-EZE ® The transparent (acid-resistant coating) is also available from Colorcon (TKL64755). Topmill Red 240.17 (colorant) is available from Biogrund (9030806-L). Water for injection (solvent) is available from Lavoisier (19KK18GC) (purified water may also be used). Triethyl citrate (TEC) and PEG8000 (plasticizer) are available from Colorcon (DTR527487 and DTR550141).

[0106] The weighing scales used included OGAL075, OGAL023, OGAL367, and OGAL351-1. Blending was performed using a Soneco blender OGAL112, a Soneco 100L container OGAL108, and an 800 μm manual sieve OGAL211-IV3. Tableting was performed using a FETTEP1200 tablet press OGAL035-1, a turntable B OGAL035-2, punches and dies D7.5R 9.2 and D7.5B 132 I / S / M, marked "20". Coating was performed using a Manesty OGAL117-1, a 330mm perforated coating pan OGAL117-4, a 0.8 mm nozzle, a pump OGAL236, a stirrer OAMA092, appropriate beakers, tubing 4.8-2.4, and a magnetic stirrer.

[0107] Example 1. Preparation of an exemplary telolide tablet core (batch 1 core). Production formula Use the production formulation described in Table 1 to prepare the tablet core.

[0108] Table 1. Production formula for batch 1 tablet core.

[0109]

[0110] Blending steps Before tableting, the production formulation undergoes screening and blending steps. Table 2 provides the production parameters used in these steps to provide the final blend for tableting.

[0111] Table 2. Blending parameters

[0112] Production formula The flowability and density of the final blends were tested (Table 3). For comparison, the flowability of the reference batch blend (batch 2) was measured. Although the flowability appeared to be poor in batch 1, no flow problems occurred during the pressing steps described below.

[0113] Table 3. IPC of the final mixture

[0114] NA: Not applicable; 1 The mixture flows when the funnel is tapped periodically. Tableting Batch 1 tablets were produced on a rotary tableting machine using a 5-punch D7.5R 9.2 machine marked with "20". The main compression force and filling volume were adjusted to achieve tablets with a hardness of 50N and a tablet mass of 125.0 mg. Tableting parameters are provided in Table 4.

[0115] Table 4. Tableting parameters and IPC results

[0116] Disintegration and friability test Subsequently, batch 1 tablets were subjected to disintegration and friability tests, the results of which are provided in Table 5.

[0117] Table 5. Results of disintegration and friability tests for batch 1 tablets.

[0118]

[0119] The quality changes during pressing were tested, and the results are provided in Figure 2 The tablet quality was very stable, with variations remaining below 1.5%. The increase in RSD over time was attributed to insufficient powder in the feeding system.

[0120] Tablet hardness was also assessed during the compression process, and the results are provided in Figure 3 Medium. The tablet hardness is as stable as the tablet quality.

[0121] The tablet cores of batch 1 met the requirements in terms of disintegration time and friability. Throughout the process, tablet quality and hardness remained very stable.

[0122] Example 2. Preparation of an exemplary enteric-coated telorazole (batch 1) First, the exemplary tablet core of Example 1 (batch 1 core) was coated with a moisture barrier, and then coated with an acid-resistant coating pack.

[0123] The nozzle is slid into the perforated disc using a 0.8 mm nozzle. The first layer of OPADRY is then applied. ® amb II (3%) (sublayer). A colorant was also added to this layer. Then ACRYL-EZE was used. ® Apply a gastric acid-resistant coating. The plasticizer used is TEC (12%). Prepare the suspension for coating using a magnetic rod and beaker stirring.

[0124] Moisture barrier coating process (batch 1) OPADRY ® The suspension of amb II is prepared according to the production formula provided in Table 6. Details of the suspension preparation are provided in Table 7.

[0125] Table 6. Production formula for Amb II coating.

[0126]

[0127] 1 15% solids, excess (x2) Table 7. Suspension Preparation (OPADRY® amb II)

[0128] The suspension was homogeneous, and the stirring speed was reduced to 300 rpm for coating.

[0129] The coating parameters for the moisture barrier layer (OPADRY® amb II) are provided in Table 8.

[0130] Table 8. Coating parameters of OPADRY® amb II

[0131] Acid-resistant coating process (batch 1) Prepare ACRYL-EZE according to the production formula provided in Table 9. ®Suspension. Details of suspension preparation are provided in Table 10.

[0132] Table 9. ACRYL-EZE ® The production formula for coating.

[0133]

[0134] 1 20% solids, excess (x2) Table 10. Suspension Preparation (ACRYL-EZE) ® )

[0135] The suspension was homogeneous, and the stirring speed was reduced to 300 rpm for coating.

[0136] Acid-resistant layer (ACRYL-EZE) ® The coating parameters are provided in Table 11.

[0137] Table 11. ACRYL-EZE ® Coating parameters

[0138] Final IPC was performed on the exemplary coated tablets. The results are provided in Table 12.

[0139] Table 12. IPC results of exemplary enteric-coated tablets

[0140] The addition of dye confirmed that the coating was uniform.

[0141] Example 3. Preparation of exemplary enteric-coated tablets (batch 3 to batch 6) Four more batches were prepared, as shown in Table 13. For each batch, the same tablet core prepared in Example 1 (batch 1 core) was used. Different coatings were applied according to the schemes shown below.

[0142] Table 13. Lots 3 to 6 containing varying amounts of acid-resistant layer (GR), moisture barrier layer (amb II), and plasticizer (PEG or TEC).

[0143]

[0144] Moisture barrier coating steps Prepare a 3% OPADRY® amb II suspension according to the production formula provided in Table 14, and a 5% OPADRY® amb II suspension according to the production formula provided in Table 15. Since the 3% and 5% OPADRY® amb II coatings were prepared on the same day, only one solution of each was prepared. Details of the suspension preparation are provided in Table 16.

[0145] Table 14.3% OPADRY® amb II coating production formula.

[0146]

[0147] 1 15% solids, excess (x2) Table 15.5% OPADRY® amb II coating production formula.

[0148]

[0149] 1 15% solids, excess (x2) Table 16. Suspension Preparation (OPADRY® amb II)

[0150] The suspension was homogeneous, and the stirring speed was reduced to 300 rpm for coating.

[0151] The moisture barrier layer (OPADRY® amb II) for batches 3 to 6 is provided in Table 17.

[0152] Table 17. Coating parameters for OPADRY® amb II coating in batches 3 to 6. Batch 1 is also listed for comparison.

[0153] Acid-resistant coating steps Based on the production formulas provided in Tables 18 to 21, ACRYL-EZE is prepared for each batch in batches 3-6. ® Suspension. Details of suspension preparation are provided in Table 22.

[0154] Table 18. ACRYL-EZE in Lot 3 ® The production formula for coating.

[0155]

[0156] 1 20% solids, excess (x2) Table 19. ACRYL-EZE in Lot 4 ® The production formula for coating.

[0157]

[0158] 1 20% solids, excess (x2) Table 20. ACRYL-EZE in Lot 5 ® The production formula for coating.

[0159]

[0160] 1 20% solids, excess (x2) Table 21. ACRYL-EZE in Lot 6 ® The production formula for coating.

[0161]

[0162] 1 20% solids, excess (x2) Table 22. Preparation of suspensions for batches 3-6 (ACRYL-EZE®)

[0163] The suspension is homogeneous, and the stirring speed is reduced to 250 / 300 rpm for coating.

[0164] Acid-resistant emulsion (ACRYL-EZE) applied to batches 3 to 6 ® The coating parameters are provided in Table 23.

[0165] Table 23. Lots 3 to 6 for ACRYL-EZE ® Coating parameters. Batch 1 is also listed for comparison.

[0166] After applying a moisture barrier coating (OPADRY® amb II) and after applying an acid-resistant coating (ACRYL-EZE) ® Following this, for batches 3-6, the exemplary tablets underwent final IPC. The results are provided in Table 24.

[0167] Table 24. IPC results for exemplary enteric-coated tablets. Batch 1 is also listed for comparison.

[0168]

[0169] Example 4. Preparation of an exemplary enteric-coated tablet (batch 7) Another batch of enteric-coated tablets (batch 7) was prepared according to the following protocol.

[0170] This batch used the same tablet core prepared in Example 1 (batch 1 core). First, it was coated with OPADRY® amb IIBEIGE (reference number 88A270004), then various percentages (up to 18%) of ACRYL-EZE were used. ® The product undergoes a second coating process. The plasticizer used in this batch is PEG8000 (8%).

[0171] Moisture barrier coating process (batch 7) Prepare the OPADRY® amb II BEIGE suspension according to the production formula provided in Table 25. Details of suspension preparation are provided in Table 26.

[0172] Table 25. Production formula for OPADRY® amb II BEIGE coating of batch 7.

[0173]

[0174] 1 15% solids, excess (x2) Table 26. Preparation of suspensions of OPADRY® amb II BEIGE coated in batch 7.

[0175]

[0176] The suspension was homogeneous, and the stirring speed was reduced to 300 rpm for coating.

[0177] The moisture barrier layer (OPADRY® amb II BEIGE) used in batch 7 is provided in Table 27.

[0178] Table 27. Coating parameters for OPADRY® amb II coating on lot 7. Lot 1 is also listed for comparison.

[0179] Acid-resistant coating process (batch 7) Based on the production formula provided in Table 28, ACRYL-EZE was prepared for batch 7. ® Suspension. Details of suspension preparation are provided in Table 29.

[0180] Table 28. ACRYL-EZE in Lot 7 ® The production formula for coating.

[0181]

[0182] 1 20% solids, excess (x2) Table 29. Suspension preparation details for batch 7.

[0183]

[0184] The acid-resistant coating (ACRYL-EZE) applied to batch 7 ® The coating parameters are provided in Table 30.

[0185] Table 30. Lot 7 for ACRYL-EZE ® Coating parameters. Batch 1 is also listed for comparison.

[0186] Example 5. Quality Control Testing Quality control tests were performed on batches 1 and 3-6, including disintegration, dissolution, and content uniformity. Additionally, stability tests were conducted on batches 3, 5, and 6, including appearance, average mass, water content, content determination, and purity.

[0187] Disintegration - Batch 1 Disintegration studies were conducted on n=6 tablets of representative samples from batch 1 with coatings of 10% GR (batch 1-1), 12% GR (batch 1-2), and 15% GR (batch 1-3). According to Ph.Eur. 2.9.1 / USP <711> The study was conducted in two steps: first, for 2 hours in 0.1 M HCl (without a disc), and then for 1 hour in phosphate buffer at pH 6.8 (with a disc).

[0188] The results are presented in Table 31. All disintegration results are consistent.

[0189] Table 31. Disintegration results of batches 1-1, 1-2 and 1-3

[0190] Disintegration - Batch 3-6 According to Ph.Eur. 2.9.1 / USP <711> Disintegration studies were conducted on n=6 tablets from representative samples of batches 3-6 in a two-step process: first, in 0.1 M HCl for 2 hours (without a disc), and then in phosphate buffer at pH 6.8 for 1 hour (with a disc). For batch 4, the disintegration results were unsatisfactory: 5 units ruptured after 120 minutes in 0.1 M HCl in acidic medium. For batch 6, 2 tablets swelled after 120 minutes in 0.1 M HCl. The remaining batches 3 and 5 met the requirements. The results are presented in Table 32.

[0191] Table 32. Disintegration studies of batches 3-6

[0192] Disintegration - Batch 7 Disintegration studies were conducted on n=6 tablets of representative samples from batch 7 with 10% GR (7-1), 12% GR (7-2), 15% GR (7-3), and 17% GR (7-4). According to Ph.Eur. 2.9.1 / USP <711> The study was conducted in two steps: first, for 2 hours in 0.1 M HCl (without a disc), and then for 1 hour in phosphate buffer at pH 6.8 (with a disc).

[0193] For batch 7, all tested amounts of GR coating (10% to 17%) showed consistent disintegration results in both acidic and phosphate-buffered media. The results are presented in Table 33.

[0194] Table 33. Disintegration results of batches 7-1, 7-2, 7-3 and 7-4

[0195] Dissolution - Batch 1 Dissolution tests were performed on representative samples (n=6 tablets) of acid-resistant film-coated tablets. The results are provided in Tables 34-36, showing a plateau at 100% dissolution and low variability observed between units. The dissolution results met Level 1 quality criteria. Comparisons of 10% GR (batch 1-1), 12% GR (batch 1-2), and 15% GR coatings (batch 1-3) showed no significant differences in dissolution profiles regardless of the amount of acid-resistant coating (GR).

[0196] Table 34. Dissolution results of batch 1-1

[0197] Table 35. Dissolution results of batches 1-2

[0198] Table 36. Dissolution results of batches 1-3

[0199] Figure 4 An overlay plot of dissolution curves for batches 1-1 to 1-3 is provided.

[0200] Dissolution - Batch 3-6 Dissolution tests were performed on representative samples (n=6 tablets) of acid-resistant film-coated tablets from batches 3-6. The results are provided in Tables 37-40. Except for batch 4, the dissolution results were satisfactory, with all units showing dissolution exceeding 10% after 120 minutes.

[0201] Table 37. Dissolution results of batch 3

[0202] Table 38. Dissolution results of batch 4

[0203] Table 39. Dissolution results of batch 5

[0204] Table 40. Dissolution results of batch 6

[0205] Figure 5 Overlay plots of dissolution curves for batches 4 to 6 are provided.

[0206] Dissolution - Batch 7 Dissolution tests were performed on representative samples (n=6) of seven tablets from batches with 10%GR (7-1), 12%GR (7-2), 15%GR (7-3), and 17%GR (7-4) of acid-resistant coated tablets. Except for batch 7-1 (10%GR coating), the dissolution results met the requirements. The results are provided in Tables 41 to 44.

[0207] Table 41. Dissolution results of batch 7-1 (10% GR coating)

[0208] Table 42. Dissolution results of batch 7-2 (13% GR coating)

[0209] Table 43. Dissolution results of batch 7-3 (15% GR coating)

[0210] Table 44. Dissolution results of batch 7-4 (17% GR coating)

[0211] Figure 6 Overlay plots of dissolution curves for batches 7-1 to 7-4 are provided.

[0212] Content uniformity - batch 1-3 Content uniformity was studied in 10 units of batches 1-3 (15% GR) using an isocratic model. According to Eur.Ph.2.9.40 / USP <905> Calculate the acceptable value (AV) for n=10 units. Content uniformity conforms to Ph.Eur.2.9.40 / USP. <905> The quality standard is ≤15.0. The results are provided in Table 45 and are consistent with the observations of dissolution results. There is no variation between tablets, and the target value is 100%. The content uniformity meets the quality standard of Ph.Eur. 2.9.40 / USP<905> (≤15.0).

[0213] Table 45. Content uniformity results for batches 1-3 (15%GR).

[0214]

[0215] Content uniformity - batch 3 to 6 For enteric-coated tablets in batches 3, 5, and 6, a gradient model was used to study the content uniformity of 10 units. According to Eur.Ph.2.9.40 / USP <905> Calculate the acceptable value (AV) for n=10 units. The content uniformity results listed in Table 46 conform to Eur.Ph.2.9.40 / USP. <905> The quality standard is ≤15.0.

[0216] Table 46. Results of content uniformity in batches 3 to 6 (20 mg teloristian HCl).

[0217]

[0218] Appearance Study Visual inspection was conducted using batches 3, 5, and 6, with n=10 tablets taken from a representative sample for appearance study. The results are presented in Table 47.

[0219] Table 47. Appearance of batches 3, 5 and 6

[0220] Average quality study By weighing, using Batches 3, 5, and 6, n = 10 tablets were taken from the representative samples for the average mass study. The results are provided in Table 48.

[0221] Table 48. Average Mass Results for Batches 3, 5, and 6

[0222] Water content study The water content of the representative samples (n = 3) was studied by volumetric Karl Fischer analysis. Batches 3, 5, and 6 were studied. The results are provided in Table 49.

[0223] Table 49. Water Content of Batches 3, 5, and 6

[0224] Content determination and purity Using the parameters provided in Table 50, n = 2 samples of Batches 3, 5, and 6 were assayed for content and examined for related substances by HPLC. A gradient method was developed to optimize the co-elution between the API (telotristat) and triethyl citrate (TEC) (an excipient present in some formulations).

[0225] Table 50. HPLC Parameters

[0226] The results of the assay for content and examination for related substances met the quality standards. The target value of 100% assay was achieved, and both individual impurities and total impurities were < LQ. The results of the assay for content and purity are provided in Table 51.

[0227] Table 51. Results of Assay for Content and Purity.

[0228]

[0229] LQ: Limit of Quantification (0.05%).

[0230] Summary of quality control research For Batch 1 (amb II 3%, TEC 12%), all results met the requirements regardless of the amount of ACRYL-EZE ® coating (10%, 12%, or 15%). For Batch 4 (ACRYL-EZE ® 10%, amb II 5%, PEG 8%), the disintegration and dissolution results obtained did not meet the requirements (disintegration: in acidic medium, 5 units disintegrated after 120 minutes; dissolution: all units dissolved more than 10% after 120 minutes). On the other hand, Batches 3, 5, and 6 all met the requirements. In acidic medium, the best formulation obtained was Batch 3 (ACRYL-EZE® (15%, AMB II 3%, PEG 8%). For batches 3 to 6, the content uniformity test all met the requirements, and the CU results showed that the batches had good homogeneity. The results are summarized in Table 52 below.

[0231] Table 52. Preliminary analysis summary of batches 3 to 6.

[0232]

[0233] Based on these initial analytical results, stability studies were conducted on batches 3, 5, and 6. Additional tests were performed based on batch 3.

[0234] Lot 7 was analyzed using color-modified OPADRY® amb II (BEIGE) as a support batch and to investigate variations in the amount of ACRYL-EZE® coating. Disintegration studies of lot 7 showed that for all batches meeting quality standards, disintegration time increased with increasing amounts of ACRYL-EZE® coating in the formulation.

[0235] Example 6. One-month stability test of enteric-coated formulation of teloliden HCl Following a similar scheme as described in Examples 1 and 2, cGMP-compliant enteric-coated 20 mg teloratesen HCl tablets (batch 8) and enteric-coated 5 mg teloratesen HCl tablets (batch 9) were produced.

[0236] The formulations for batches 8 and 9 are provided in Table 53.

[0237] Table 53. Exemplary enteric-coated dosage forms with 4.45 mg and 17.8 mg teloliden HCl

[0238] 1 15% suspension, weight gain = 5%; 2 20% suspension, weight gain = 15%; 3 PEG, 8% ACRYL-EZE® A 1-month stability test was performed on a representative sample of 8 tablets from the batch. The results are provided in Table 54.

[0239] Table 54. 1-month stability test of 8 tablets in batch with enteric coating.

[0240]

[0241] Figure 7Additional data are provided, showing the stability dissolution profiles (average) of an exemplary enteric-coated dosage form (batch 8) over one month at 5°C, 25°C / 60%RH, and 40°C / 75%RH.

[0242] Example 7. Preparation of an exemplary enteric-coated dosage form Acid-resistant (GR) film-coated tablets were prepared for a Phase I clinical trial (NF2 project). The tablets were packaged into 20 mL HDPE bottles (30 tablets per bottle), capped with PP and containing 2.4 g of desiccant. A batch size of 5000 g (actual yield 4519.9 g) of tablet cores was prepared.

[0243] First, two sub-batch coatings were performed using Opadry AMBII purple. Due to a slight color difference between sub-batch 1 and 2, a third sub-batch was prepared for hue evaluation for reference, but this was not continued. The reason for the hue difference when the formulation and parameters are similar between the sub-batch batches is unclear. The hue difference is cosmetic and does not affect the key quality attributes of acid-resistant tablets.

[0244] The following raw materials were used: crospovidone (Polyplasdone XL) (supplier lot number: 0002618775); anhydrous colloidal silica (Aerosil 200 pharma) (supplier lot number: M22120016), Opadry amb II purple, 88A200015 (supplier lot number: DT743323); Acryl eze 93A19346 clear (supplier lot number: DT738120); and microcrystalline cellulose (Vivapur 102) (supplier lot number: 56102212111). All these raw materials were released after production and found to meet the required quality standards. There was no impact on the clinical batch.

[0245] Production formula The actual production formulation of the tablet core (active batch, LC23120) is described in Table 55 below. When readjusting, the HCl content of telolide and the water content (98.19%) were taken into account (to compensate for cellulose). The equipment used is described in the Materials and Methods section above.

[0246] Table 55. Production formula for clinical batch LC23120.

[0247]

[0248] The production parameters used during the blending step are provided in Table 56. The blend was sampled five times (twice from the top, once from the middle, and twice from the bottom; approximately 625 mg each time) to test blend homogeneity. A fill weight of 30% was used, which is suitable for good mixing.

[0249] Table 56. Production parameters of active batch LC23120.

[0250]

[0251] *3.63 (min, cent) corresponds to 3 minutes and 38 seconds at 22 rpm, or 80 revolutions.

[0252] The yield of the blending step is shown in Table 57 and is very good (98.5%).

[0253] Table 57. Yields of the blending step.

[0254]

[0255] The final blend (25g) was tested for flowability and density. Although the flowability was characterized as poor, no problems occurred during tableting. Relevant parameters are provided in Table 58.

[0256] Table 58. Liquidity and density data.

[0257]

[0258] Tableting steps The rotary tablet press (Fette P1200) uses 8 punches for tableting.

[0259] Table 59 shows the tableting parameters and the IPC results obtained in terms of tablet weight, hardness, and thickness. The results of the friability and disintegration tests are shown in Table 60.

[0260] Table 59. Tableting parameters and IPC results.

[0261] Actual parameters of tablet compression

[0262] IPC Results

[0263] *At 15 minutes, increase the feeder speed from 20 rpm to 40 rpm.

[0264] Table 60. Results of disintegration and friability tests.

[0265]

[0266] The disintegration and friability IPC test results meet the standards. The LOD is quite high, which is known for this product.

[0267] The tableting yield exceeded 90%, which is excellent (see Table 61A). The tablet cores were divided into three sub-batches for coating: sub-batch 1 was 1004.8 g, sub-batch 2 was 1004.8 g, and sub-batch 3 was 1000.6 g (the latter was not further studied).

[0268] Table 61A. Tableting and overall evaluation.

[0269]

[0270] Coating steps Coating was performed using a 0.8 mm nozzle in a 330 mm perforated coating pan. Film coating was carried out in two steps for two sub-batches: a first layer of Opadry amb II (sub-layer) was applied, resulting in a 3% weight gain. Then, acid-resistant coating was performed with acryliceze, resulting in a 15% weight gain. For both ambII and acryliceze, excess suspensions were prepared at 15% or 20% solids (PEG corresponds to 8% acryliceze, x2.5 for ambII and x2.0 for acryliceze). Two 1000 g sub-batches were produced (sub-batches 1 and 2 were 1004.8 g each). See Tables 61B and 62 for details.

[0271] Table 61B. Suspension Preparation (amb II)

[0272] Table 62. Suspension Preparation (amb II)

[0273] Sub-batch 1 Amb II coating lasted 90 minutes, and sub-batch 2 Amb II coating lasted 80 minutes. During sub-batch 1, the spray gun clogged after 20 minutes. During spray gun cleaning, spraying was stopped and the pan speed was reduced to 15 rpm. Coating was restarted after 3 minutes. After 50 minutes of coating, the pan speed was reduced from 28 rpm to 26 rpm to prevent tablets from falling off the sides.

[0274] No issues were observed during sub-batch 2.

[0275] The coating parameters of both sub-batches are close to the target values, and sub-batches 1 and 2 are similar—see Tables 63A and 63B for details.

[0276] Table 63A. Coating Parameters (amb II)

[0277] Table 63B. Coating Parameters (amb II) (Continued)

[0278] For Acryl eze coating, suspensions were prepared according to Tables 64 and 65.

[0279] Table 64. Preparation of suspensions (acryl eze).

[0280]

[0281] Table 65. Suspension Preparation (acryl eze)

[0282] Coating was performed using a 0.8 mm nozzle in a 330 mm perforated coating pan. Sub-batch 1 lasted 207 minutes, while sub-batch 2 lasted 175 minutes. In sub-batch 1, the peristaltic pump malfunctioned after 180 minutes of coating. Spraying was stopped to clean the spray gun. Coating was restarted after a few minutes. No special problems occurred during sub-batch 2. The coating parameters of both sub-batches were close to the target values, and the results were similar between sub-batch 1 and 2, as detailed in Tables 66A and 66B.

[0283] Table 66A. Coating Parameters (acryl eze)

[0284] Table 66B. Coating Parameters (Acryl eze) (continued)

[0285] As shown in Table 67, the two sub-batches meet the requirements and have similar IPC results.

[0286] Table 67. IPC results for film-coated tablets.

[0287] ambII after coating

[0288] After Acryl eze coating

[0289] Overall yield is acceptable (Table 68).

[0290] Table 68. Coating Assessment. Due to an anomaly, the material balance exceeded the standard.

[0291]

[0292] Package batch LC23120 into 20mL HDPE bottles (30 tablets per bottle), seal with a PP child-tamper cap containing a desiccant (2.4 g) (LC23120A1), and then label with (LC23120A2). Prepare a carton containing 38 bottles.

[0293] Package the Wakix reference standard (manufacturer batch number 3831701) into 20mL HDPE bottles (30 tablets per bottle), seal them with child-tamper-evident PP caps containing a desiccant (2.4 g), and label them (LC23177A1). Prepare a carton containing 33 bottles.

[0294] Pantoprazole reference standard (2 labeled blister packs per box, 14 tablets per blister pack; manufacturer's batch number 535260) was labeled (LC23206A1). Five boxes were prepared, each with 2 blister packs.

[0295] Blending results after lubrication Analytical methods were used to prepare and quantify the blend homogeneity. Since approximately 625 mg of powder was sampled, the preparation method was the same as that used for the 20 mg tablet sample solution.

[0296] As observed in Table 69, the independent determination results of the blends were uniform and close to the target values.

[0297] Table 69. Blending homogeneity results for five units of the mixture at the top (n=2), middle (n=1), and bottom (n=2) of the mixture.

[0298]

[0299] Content uniformity (tablet core) Content uniformity tests were performed on the first 10 units of pressing, the middle 10 units of pressing, and the last 10 units of pressing. According to Ph. Eur. 2.9.40 / USP <905> Calculate the acceptable value (AV) for n=10 units.

[0300] The content uniformity results in Table 70 conform to Ph. Eur. 2.9.40 / USP <905> The standard is that the acceptable value is ≤15.0.

[0301] Table 70. Content uniformity results for 10 units at the start, middle, and end of pressing.

[0302]

[0303] Batch Analysis - Appearance Visual inspection was performed on representative samples (n=10 pieces) from each of the two sub-batches. Color differences were observed between the two sub-batches. Nevertheless, the results met the purple to light purple appearance standard.

[0304] Table 71. Appearance results of batch LC23120.

[0305]

[0306] Overall Analysis - Average Quality For the two sub-batches of LC23120, the average mass of representative samples (n=10 tablets) was determined by weighing. The average mass of sub-batch 1 was 150.2 mg, and the average mass of sub-batch 2 was 148.2 mg.

[0307] Overall Analysis - Water Content For the two sub-lots of LC23120, the moisture content of representative samples (n=2 tablets) was determined using the Karl Fischer method. The moisture content of sub-lot 1 was 4.2%, and the moisture content of sub-lot 2 was 4.0%.

[0308] Overall Analysis - Collapse During IPC, disintegration analysis (n=6 tablets) of sub-lots 1 and 2 of batch LC23120 was performed according to Eur. Ph. 2.9.1, and the results met the requirements.

[0309] Clinical batch LC23120 (acid-resistant film-coated tablet containing 20 mg telorissen hydrochloride) consisted of two sub-batches (two rounds of coating, test batch 1 and test batch 2). During manufacturing, two slightly different colors were observed in these two test batches (test batch 1 was purple, and test batch 2 was light purple). To investigate and evaluate the impact, it was decided to perform hydrochloric acid disintegration assays and QC dissolution tests on both test batches. However, during the initial analysis of the whole tablets, disintegration tests were performed again on sub-batches 1 and 2 of batch LC23120. Disintegration tests (n=6 tablets) were performed on representative samples of sub-batches 1 and 2 of batch LC23120 according to Eur. Ph. 2.9.1. For sub-batches 1, the disintegration results were satisfactory, with no tablets disintegrating in 0.1 M HCl; the results in phosphate buffer at pH 6.8 are for reference only. However, the disintegration results of the sub-batch did not meet the requirements, with 4 tablets disintegrating in 0.1 M HCl (see 011 / RHS / 2023).

[0310] During 011 / RHS / 2023, an investigation indicated that a methodological cause (GR tablets disintegrating in the presence of a small amount of water) appeared to be the most likely cause, but could not be confirmed. The results of the initial analysis were not invalidated. Sub-batch 2 (n=6 tablets) of batch LC23120 were retested using carefully cleaned and dried instrument grids, and the results were satisfactory. Prior to testing, the grids were washed, dried (with compressed air), and immersed in HCl for 3 seconds and 3 times (to remove residual water), and then tablets were dropped onto the grids. For the disintegration time test in 0.1 N HCl for 2 hours, no tablets showed signs of disintegration or cracks that allowed contents to escape. The membrane coating barrier remained unchanged.

[0311] Table 72. Disintegration time results of batch LC23120 during IPC, initial analysis and retesting.

[0312]

[0313]

[0314]

[0315] Overall analysis - dissolution Dissolution tests were performed on sub-lots 1 and 2 of the monolithic film-coated tablet batch LC23120 from representative samples. The results are shown in Tables 73 and 74.

[0316] Table 73. Dissolution results of sub-batch 1 of batch LC23120.

[0317]

[0318] The dissolution profile of sub-batch 1 of LC23120 is shown in Figure 8A middle.

[0319] Table 74. Dissolution results of sub-batch 2 of batch LC23120.

[0320]

[0321] The dissolution profile of sub-batch 2 of LC23120 is shown in Figure 8B middle.

[0322] Overall analysis - content determination and related substance detection Content determination and related substances testing were performed using sub-batch 1 and 2 tablets from the overall batch LC23120 of representative samples (n=2 samples). The results are shown in Table 75.

[0323] Table 75. Content determination and related substance detection of sub-batches 1 and 2 of batch LC23120.

[0324]

[0325] Release test of film-coated tablets (HDPE bottle, 30 units) Visual inspection was conducted on a representative sample (n=10 pieces) of this batch, each of the two sub-batches, and the overall packaged sample. The appearance of the packaged product LC23120A1 met the requirements.

[0326] Table 76. Appearance results of batch LC23120A1.

[0327]

[0328] The released batches were tested for average mass, water content, disintegration, identification, content and related substances, content uniformity and dissolution. The results were basically the same as the overall test values ​​mentioned above, within the quality standard and meeting the requirements.

[0329] Dissolution profiles for batch LC23120A1 are also provided. Figure 9 middle.

[0330] Microbiological tests were performed on representative tablet samples, and the results met the quality standards.

[0331] Table 77. Microbiological results.

[0332]

[0333] TAMC: Total aerobic microorganisms; TYMC: Total yeast and mold count. in conclusion In summary, the blending and tableting steps proceeded smoothly. There was a slight color difference between sub-batch 1 and sub-batch 2, but no difference in disintegration and dissolution tests. Regarding IPC analysis, all results were within the quality standard range. No trends were observed in the lubricated blends or between the start, middle, and end of compression. Content determination and content unit uniformity results met target values. Furthermore, release results met acceptable standards. Disintegration records are for reference only.

[0334] The production yielded qualified tablets: teloliden hydrochloride (20 mg acid-resistant film-coated tablets, equivalent to 17.8 mg of teloliden in the free base form).

[0335] Example 8. Stability study over three months.

[0336] A 3-month stability study was conducted on the enteric-coated dosage form from Example 7 (batch LC23120A1). The purpose of this study was to examine the stability of the product packaged in one package and to confirm the shelf life determined in supporting batches. Data obtained after 3 months of storage at 5°C, 25°C / 60%RH, and 40°C / 75%RH are summarized below.

[0337] Table 78. Telorisen HCl enteric-coated dosage form (prepared in Example 7).

[0338]

[0339] 1 15% suspension, weight gain = 3% 2 20% suspension, weight gain = 15% 3 PEG, 8% Acryl eze Table 79. Packaging Information.

[0340]

[0341] Table 80. Characteristics of Packaging Containers.

[0342]

[0343] Stability protocols, storage conditions, and stability testing Samples should be stored according to ICH conditions: long-term conditions 25°C / 60%RH; intermediate conditions 30°C / 65%RH; accelerated conditions 40°C / 75%RH; 5°C for reference.

[0344] Table 81. Storage conditions and stability tests

[0345] -: Not tested; []: Optional test; 1): Only when 40°C / 75%RH conditions are not met. After being removed from the climate chamber, all samples were stored at 15-25°C before and after analysis.

[0346] Telolidesen hydrochloride 20 mg gastric-resistant film-coated tablets, batch LC23120A1 at 5°C, 25°C / 60%RH and After 3 months of storage at 40°C / 75%RH Appearance: No changes in appearance were observed after 3 months at 5℃, 25℃ / 60%RH, and 40℃ / 75%RH. The appearance meets quality standards.

[0347] Mean weight: A slight decrease in mean weight was observed after 3 months at 5°C and 25°C / 60%RH (from an initial 148.0 mg to 146.9 mg and 147.0 mg, respectively). No significant change in mean weight was observed after 3 months at 40°C / 75%RH. The mean weight results are in line with quality standards.

[0348] Water content: A slight increase in water content was observed after 3 months under all conditions, while a slight decrease was observed after 2 months at 25°C / 60%RH and 40°C / 75%RH.

[0349] Dissolution: After 3 months at 25℃ / 60%RH and 40℃ / 75%RH, a slightly slower dissolution profile was observed at the start of dissolution in the buffer stage. No significant changes were observed at 5℃. The dissolution results met the quality standards. Figure 10 The image provides an overlay plot of stability dissolution curves.

[0350] Disintegration time: No significant change in disintegration time was observed after 3 months of storage at 5°C. Increases were observed after 1 month of storage at 25°C / 60%RH and 40°C / 75%RH. At the 3-month time point, disintegration was approximately 3 to 4 minutes longer than at the initial time point, showing differences between tablets.

[0351] Content determination / purity: Regarding content determination, no significant changes were observed after 3 months at 5℃, 25℃ / 60%RH, and 40℃ / 75%RH. The content determination results meet the quality standards.

[0352] Regarding purity, all individual impurities and total impurities remain <0.05%. The purity results meet the quality standards.

[0353] Microbiological testing: Initially, the microbiological results were within the quality standard range.

[0354] Conclusion: After 3 months of storage in HDPE bottles at 5°C, 25°C / 60%RH, and 40°C / 75%RH, the 20 mg teloliden hydrochloride acid-resistant film-coated tablet formulation (equivalent to 17.8 mg of teloliden free base) packaged in 20 mL HDPE bottles (sealed with PP caps containing 2.4 g desiccant) (30 tablets per bottle) is stable. Based on the obtained stability data, the 12-month shelf life of teloliden hydrochloride 20 mg acid-resistant film-coated tablets is currently met and stable under all storage conditions.

[0355] Equivalent statement Those skilled in the art will recognize or be able to determine many equivalent embodiments of the specific implementations disclosed herein using only conventional experiments. Those skilled in the art will understand that various changes or modifications can be made to this description without departing from the spirit or scope of this application as defined by the appended claims.

Claims

1. An oral dosage form comprising: core; and Enteric coating surrounding the core; in, The core comprises telolide or a pharmaceutically acceptable salt, solvate or hydrate thereof; and optionally one or more pharmaceutically acceptable excipients.

2. The dosage form according to claim 1, wherein, The core contains teloridine monohydrochloride.

3. The dosage form according to claim 1 or 2, wherein, The enteric coating comprises a polymer, optionally wherein the polymer comprises an ionizable functional group (e.g., a carboxylic acid group).

4. The dosage form according to any one of the preceding claims, wherein, The enteric coating comprises a cellulose material (e.g., alkyl cellulose), an acrylic or acrylate polymer, or a methacrylic acid or methacrylate copolymer (e.g., anionic methacrylate copolymer).

5. The dosage form according to any one of the preceding claims, wherein, The enteric coating contains EUDRAGIT. ® Polymers (such as EUDRAGIT® L 100-55) or ACRYL-EZE®.

6. The dosage form according to any one of the preceding claims, wherein, The enteric coating contains a plasticizer.

7. The dosage form according to claim 6, wherein, The plasticizers include: polyethylene glycol (PEG), such as PEG8000; or triethyl citrate.

8. The dosage form according to any one of the preceding claims further comprises a moisture barrier.

9. The dosage form according to claim 8, wherein, The moisture barrier is located between the core (e.g., the outer surface of the core) and the enteric coating (e.g., the inner surface of the enteric coating).

10. The dosage form according to claim 8 or 9, wherein, The moisture barrier contains polyvinyl alcohol (PVA) or HPMC.

11. The dosage form according to any one of claims 8 to 10, wherein, The moisture barrier contains OPADRY® polymers, such as OPADRY® amb II.

12. A dosage form according to any one of the preceding claims, comprising about 1 mg to about 25 mg (e.g., about 3 mg to about 7 mg, or about 18 mg to about 22 mg) of telorazole or a pharmaceutically acceptable salt, solvate or hydrate thereof.

13. The dosage form according to any one of the preceding claims comprises about 5 mg of telolide or a pharmaceutically acceptable salt, solvate or hydrate thereof.

14. The dosage form according to any one of the preceding claims comprises about 20 mg of teloratesen or a pharmaceutically acceptable salt, solvate or hydrate thereof.

15. The dosage form according to any one of the preceding claims comprises at least one pharmaceutically acceptable excipient.

16. The dosage form according to claim 15, wherein, The pharmaceutically acceptable excipients are selected from the group consisting of microcrystalline cellulose, crospovidone, talc, magnesium stearate, and colloidal silica (e.g., anhydrous colloidal silica).

17. The dosage form according to any one of the preceding claims, wherein the teloristian or its pharmaceutically acceptable salt, solvate or hydrate is crystalline teloristian monohydrochloride.

18. The dosage form according to any one of the preceding claims, wherein, The core comprises (e.g., substantially composed of, for example, telolide monohydrochloride, microcrystalline cellulose, crospovidone, talc, magnesium stearate, and colloidal silica (e.g., anhydrous colloidal silica).

19. The dosage form according to claim 18, wherein, The core is surrounded by a moisture barrier, which comprises (e.g., substantially composed of, for example, a PVA-based polymer, such as OPADRY) ® amb II.

20. The dosage form according to claim 19, wherein, The core, which has the aforementioned moisture barrier, is further surrounded by an enteric coating, the enteric coating comprising (e.g., substantially composed of, for example, a copolymer of methacrylic acid and ethyl acrylate, such as EUDRAGIT® L 100-55 or ACRYL-EZE) ® .

21. The dosage form according to claim 18, wherein, The core is surrounded by a moisture barrier, which contains (for example, substantially composed of) OPADRY® amb II.

22. The dosage form according to claim 19 or 21, wherein, The core, which has the moisture barrier, is further surrounded by an enteric coating, which contains (e.g., substantially composed of, for example, ACRYL-EZE®).

23. The dosage form according to any one of the preceding claims, wherein, The telolide or its pharmaceutically acceptable salt, solvate or hydrate has an X-ray diffraction pattern including characteristic peaks (2θ) at 11.2°, 19.9°, 20.7° and 34.1° (±0.2°).

24. The dosage form according to any one of the preceding claims comprises crystalline teloristine hydrochloride, said crystalline teloristine hydrochloride having an X-ray diffraction pattern including characteristic peaks (2θ) at 11.2°, 19.9°, 20.7° and 34.1° (±0.2°).

25. The dosage form according to any one of claims 1 to 22, wherein, The teloridine or its pharmaceutically acceptable salt, solvate or hydrate has an X-ray diffraction pattern containing characteristic peaks (2θ) at 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0° and 46.0° (±0.2°).

26. The dosage form according to any one of claims 1 to 22, comprising crystalline teloristian hydrochloride, said crystalline teloristian hydrochloride having an X-ray diffraction pattern including characteristic peaks (2θ) at 11.2°, 15.4°, 16.3°, 16.9°, 17.8°, 19.9°, 20.7°, 21.0°, 21.8°, 22.6°, 24.5°, 24.6°, 25.0°, 25.5°, 26.3°, 28.3°, 30.3°, 34.1°, 35.8°, 40.0°, and 46.0° (±0.2°).

27. The dosage form according to any one of the preceding claims, wherein, The oral dosage form is a tablet.

28. The dosage form according to any one of the preceding claims, wherein, The dosage form is bioequivalent to a dosage form containing the same amount of teloratesen or its pharmaceutically acceptable salts, solvates or hydrates but without enteric coating (e.g., WAKIX®).

29. The dosage form according to any one of the preceding claims, wherein, The Cmax of teloratesen provided in the subject by oral administration of the dosage form of the present invention was substantially the same as that provided by oral administration of an equivalent dosage form of teloratesen without enteric coating (e.g., WAKIX®) to the subject.

30. The dosage form according to any one of the preceding claims, wherein, The steady-state Cmax of teloratesen provided by once-daily oral administration of the aforementioned dosage form for approximately 7 days is substantially the same as that provided by once-daily oral administration of an equivalent dosage form without enteric coating (e.g., WAKIX®) for approximately 7 days.

31. The dosage form according to any one of the preceding claims, wherein, The AUC of teloratesen provided by oral administration of the aforementioned dosage form is substantially the same as that provided by oral administration of an equivalent dosage form without enteric coating (e.g., WAKIX®).

32. The dosage form according to any one of the preceding claims, wherein, The steady-state AUC of teloratesen provided by once-daily oral administration of the aforementioned dosage form for approximately 7 days is substantially the same as that provided by once-daily oral administration of an equivalent dosage form without enteric coating (such as WAKIX®) for approximately 7 days.

33. The dosage form according to any one of the preceding claims, wherein, The Tmax of teloratesen provided by oral administration of the aforementioned dosage form is substantially the same as that provided by oral administration of an equivalent dosage form of teloratesen without enteric coating (e.g., WAKIX®).

34. A method for treating a disease or symptom, comprising: The oral dosage form according to any one of claims 1 to 33 shall be administered orally to subjects in need.

35. The method according to claim 34, wherein, The disease or condition mentioned is a sleep disorder.

36. The method according to claim 34 or 35, wherein, The disease or condition mentioned is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness.

37. The method according to any one of claims 34 to 36, wherein, The disease or condition mentioned is excessive daytime sleepiness (EDS).

38. The method according to any one of claims 34 to 36, wherein, The disease or symptom mentioned is sudden collapse.

39. The method according to any one of claims 34 to 38, wherein, The subject suffers from narcolepsy (e.g., the subject is an adult with narcolepsy).

40. The dosage form (e.g., an oral dosage form) according to any one of claims 1 to 33, the dosage form being used to treat a disease or condition, optionally, wherein the disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness.

41. The dosage form for said application according to claim 40, wherein, The disease or condition is in subjects with narcolepsy (e.g., adult subjects with narcolepsy).

42. Use of the oral dosage form of any one of claims 1 to 33 in the preparation of a medicament for treating a disease or condition, optionally, wherein said disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness.

43. The use according to claim 42, wherein, The disease or condition is in subjects with narcolepsy (e.g., adult subjects with narcolepsy).

44. An oral dosage form comprising: nuclear; A moisture barrier surrounding the core; and The enteric coating surrounding the core and the moisture barrier, in, The core comprises crystalline telolide hydrochloride and one or more pharmaceutically acceptable excipients, wherein the moisture barrier comprises a polymer, and wherein the enteric coating comprises a polymer.

45. The oral dosage form according to claim 44, wherein, The moisture barrier contains (for example, substantially composed of, for example, OPADRY® polymers, such as OPADRY® amb II).

46. ​​The oral dosage form according to claim 44 or 45, wherein, The enteric coating contains (for example, substantially composed of) ACRYL-EZE® polymer.

47. A pharmaceutical composition comprising the oral dosage form of any one of claims 1 to 33, suitable for oral administration to a subject in need.

48. The dosage form (e.g., an oral dosage form) according to any one of claims 1 to 33, said dosage form for use in treating a disease or condition selected from sleep disorders.

49. The dosage form according to claim 48, wherein, The sleep disorders mentioned are excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (such as obstructive sleep apnea), sleep-induced apnea, or daytime sleepiness.

50. The dosage form of the application according to claim 48 or 49, wherein, The sleep disorder is in subjects with narcolepsy (e.g., adult subjects with narcolepsy).

51. The dosage form of the application according to any one of claims 48 to 50, wherein, The sleep disorder mentioned is excessive daytime sleepiness (EDS).

52. The dosage form of the application according to any one of claims 48 to 50, wherein, The sleep disorder mentioned is cataplexy.

53. A method for preparing an oral dosage form according to any one of claims 1 to 33.

54. The method of claim 53, comprising the following steps: a) Blending telolide or its pharmaceutically acceptable salt, solvate or hydrate with one or more pharmaceutically acceptable excipients (e.g. microcrystalline cellulose, crospovidone, talc, magnesium stearate, colloidal silica (e.g., anhydrous colloidal silica) or combinations thereof) to provide a blend; b) Compress the blend (e.g., using a tablet press) to provide a tablet core; c) Optionally, the tablet core is coated with a moisture barrier to provide a moisture-resistant coated tablet; and d) Coat the tablet core of step (b) or the moisture-proof coated tablet of step (c) with enteric coating to provide enteric coated tablets.

55. The method according to claim 54, wherein, The moisture barrier contains polyvinyl alcohol (PVA) or HPMC, such as OPADRY. ® Polymers, such as OPADRY ® amb II.

56. The method according to claim 54 or 55, wherein, The enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate, such as EUDRAGIT® L 100-55 or ACRYL-EZE®.

57. The method according to any one of claims 54 to 56, wherein, The enteric coating further comprises a plasticizer, such as triethyl citrate or PEG (e.g., PEG8000).

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