New formulations and methods of use of tiropride

Abstract

The present application relates to combinations, dosage forms, and pharmaceutical formulations comprising an active pharmaceutical ingredient (e.g., telotristat) and an alkalizing agent for improving absorption of the active pharmaceutical ingredient.

Description

[0001] Related applications 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 hydrochloride is a product of WAKIX. ® Marketed drug molecules can be used to treat various diseases and conditions, especially sleep disorders such as excessive daytime sleepiness (EDS) and cataplexy. WAKIX ® Contains crystalline telolide hydrochloride. Telolide is usually administered orally and absorbed, reaching peak plasma concentrations (C60) approximately 3 hours after oral administration. max The plasma elimination half-life of telolide is 8 to 11 hours.

[0003] To achieve its wakefulness-inducing effect without disrupting patients' nighttime sleep, it is desirable for teloratesen to take effect as quickly as possible after administration. Therefore, it is desirable to shorten the absorption time of teloratesen.

[0004] Doxepin hydrochloride is another drug molecule that was developed as an antidepressant but is also approved for the treatment of insomnia. Doxepin is usually administered orally, and peak plasma concentrations are reached 3.5 hours after oral administration. For doxepin to promote sleep, a rapid onset of action is required.

[0005] Shortening the absorption time of active pharmaceutical ingredients, especially those used to treat sleep disorders or diseases, particularly those administered orally, is a recognized but unmet need. Summary of the Invention

[0006] This application generally relates to combinations of active pharmaceutical ingredients (APIs) and alkalizing agents, as well as dosage forms and pharmaceutical compositions comprising them. Compared to administering APIs without combining them or in another dosage form or pharmaceutical composition, the combinations, dosage forms, and pharmaceutical compositions of this application, for example, after oral administration, can provide faster absorption of APIs.

[0007] It has now been found that active pharmaceutical ingredients, which are usually applied in the form of chloride salts, can be absorbed more quickly when applied in combination with alkalizing agents.

[0008] Without being bound by theory, it is believed that APIs, which are usually administered in the form of salts, such as hydrochlorides (e.g., teloridine hydrochloride or doxepin hydrochloride), are absorbed more rapidly when administered in combination with an alkalizing agent, for example, after oral administration. In particular, it has been shown that the plasma absorption peak of teloridine hydrochloride or doxepin hydrochloride occurs more quickly when co-administered with an alkalizing agent.

[0009] For example, it is believed that when co-administered with an alkalizing agent, the plasma absorption peak (or C10) of teloridine hydrochloride or doxepin hydrochloride is increased. max ) appear faster (i.e., T) max shorten).

[0010] This application generally relates to a novel use, particularly enabling the active pharmaceutical ingredient to cross the intestinal barrier more rapidly. More specifically, this application also generally relates to dosage forms and pharmaceutical compositions comprising a combination of an active pharmaceutical ingredient and an alkalizing agent, and their uses, particularly enabling the active pharmaceutical ingredient to be absorbed more rapidly, for example, after oral administration, or (e.g., from the gastrointestinal tract) cross the intestinal barrier and enter the bloodstream.

[0011] Specifically, this application relates to combinations of salts of active pharmaceutical ingredients and alkalizing agents. More specifically, this application relates to combinations of salts of active pharmaceutical ingredients and alkalizing agents, as well as dosage forms and pharmaceutical compositions comprising the same.

[0012] This application also relates to new formulations of APIs, such as teloprene (e.g., teloprene hydrochloride), which have improved API absorption (e.g., after oral administration of the formulation).

[0013] In its implementation, this application relates to an accelerated absorption formulation comprising an active pharmaceutical ingredient in salt form and an alkalizing agent.

[0014] In its implementation, this application relates to the use of an alkalizing agent to promote the absorption of an active pharmaceutical ingredient applied in salt form.

[0015] In some implementations, the salt is a hydrochloride salt.

[0016] In some embodiments, the active pharmaceutical ingredient administered in the form of a salt (such as hydrochloride) particularly involves telorazole or doxepin.

[0017] This application also relates to combinations of teloridine salts (such as teloridine hydrochloride) with alkalizing agents.

[0018] This application also relates to pharmaceutical compositions or dosage forms comprising a salt of teloratesen (e.g., teloratesen hydrochloride), an alkalizing agent as defined herein, and optionally one or more pharmaceutically acceptable excipients. Attached Figure Description

[0019] Figure 1Compared with the control, the cumulative apparent permeability (Papp) over time (0-120 minutes) of exemplary combinations of different amounts of telorazole and alkalizing agent (10) 6 A diagram showing the speed (cm / s).

[0020] Figure 2 This illustrates the cumulative apparent permeability (area under the curve, AUC) in terms of bioavailability for exemplary combinations (numbers 2-13) of teloroxygen hydrochloride with different amounts of alkalizing agent compared to the control (number 1). 0-120min (represented as a percentage relative to control).

[0021] Figure 3 This illustrates the apparent permeability (Papp) of doxepin hydrochloride over time (120 minutes) in an exemplary combination using doxepin hydrochloride compared to a control. 6 The graph shows the speed (cm / s). Detailed Implementation

[0022] This application relates to a combination of an active pharmaceutical ingredient (API) and an alkalizing agent, wherein the active pharmaceutical ingredient (API) may be in the form of a pharmaceutically acceptable salt (such as a hydrochloride salt). In some embodiments, this application relates to a combination of an active pharmaceutical ingredient in the form of a pharmaceutically acceptable salt (preferably a hydrochloride salt) and an alkalizing agent.

[0023] More specifically, this application relates to a combination of teloridine in the form of a pharmaceutically acceptable salt, preferably in the form of hydrochloride, with an alkalizing agent.

[0024] This application also relates to pharmaceutically acceptable salts, preferably combinations of doxepin in hydrochloride form with alkalizing agents.

[0025] This application also relates to dosage forms and pharmaceutical compositions that include combinations of the present application (e.g., a combination of teloridine hydrochloride and an alkalizing agent).

[0026] This application also relates to the use of combinations, dosage forms, and pharmaceutical compositions of this application, such as the use in treating a disease or condition in a subject in need.

[0027] Active pharmaceutical ingredients An active pharmaceutical ingredient generally refers to a component (e.g., a compound or a pharmaceutically acceptable salt thereof) in a combination, dosage form, or pharmaceutical composition of this application that provides a therapeutic effect. An active pharmaceutical ingredient may be referred to herein as an API, active ingredient, or drug.

[0028] The preferred active pharmaceutical ingredient of this application is a compound formulated as an acid addition salt (such as a hydrochloric acid addition salt). Hydrochloric acid addition salts may be referred to herein as hydrochloride salts or HCl salts.

[0029] In this embodiment, the active pharmaceutical ingredient is pitolisant, or more preferably, an acid addition salt of pitolisant, such as pitolisant hydrochloride.

[0030] The hydrochloric acid addition salt of telolide has the following formula: It may be referred to herein as telorissen hydrochloride, telorissen monohydrochloride, or telorissen HCl. It should be understood that these terms may cover telorissen hydrochloride in amorphous or crystalline forms (such as its polymorphic forms), including form I (disclosed, for example, in U.S. Patent No. 8,207,197, which is incorporated herein by reference in its entirety) and form II (disclosed in U.S. Patent Application No. 18 / 621,972, which is disclosed in U.S. Patent Publication No. 2024 / 0327366, and PCT / IB2024 / 000139, which is disclosed in WO2024 / 201139, each of which is incorporated herein by reference in its entirety).

[0031] In some embodiments, the active pharmaceutical ingredient is crystalline teloratesen hydrochloride. In some embodiments, the active pharmaceutical ingredient is form I polymorph of teloratesen hydrochloride. In some embodiments, the active pharmaceutical ingredient is crystalline teloratesen hydrochloride, whose X-ray diffraction pattern contains characteristic peaks (2θ) at 11.2°, 19.9°, 20.7°, and 34.1° (±0.2°), or more preferably 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°). In some embodiments, the active pharmaceutical ingredient is a polymorph of teloratesen as described and characterized in U.S. Patent No. 8,207,197.

[0032] In some embodiments, the active pharmaceutical ingredient is doxepin, or more preferably an acid addition salt of doxepin, such as doxepin hydrochloride.

[0033] The hydrochloric acid addition salt of doxepin has the following formula: It may be referred to herein as doxepin hydrochloride, doxepin monohydrochloride, or doxepin HCl. It should be understood that these terms may cover doxepin hydrochloride in amorphous or crystalline forms (such as its polymorphic forms).

[0034] The amount of active pharmaceutical ingredient in the combination, dosage form or pharmaceutical composition of this application can be expressed as the weight percentage (wt%) of the active ingredient in the total weight of the combination, dosage form or pharmaceutical composition. For example, the combination, dosage form, or pharmaceutical composition of this application may contain amounts from about 1 wt% to about 99 wt%, such as about 1 wt% to about 80 wt%, about 1 wt% to about 60 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about 10 wt%, about 10 wt% to about 15 wt%, such as about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18 wt%, about 19 wt%, about 20 wt%, about 21 wt%, about 22 wt%, about 23 wt%, about 24 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%. Active ingredients in wt%, approximately 50 wt%, approximately 60 wt%, approximately 70 wt%, approximately 80 wt%, approximately 90 wt%, approximately 95 wt%, approximately 97.5 wt%, or approximately 99 wt%.

[0035] Salt Salts generally refer to pharmaceutically acceptable salts of compounds (such as APIs), such as acid addition salts. Such salts are typically used to obtain the crystalline and / or solid form of a compound, which could otherwise be amorphous and / or liquid.

[0036] In some implementations, the salt is a hydrochloride salt. Such hydrochloric acid addition salts are generally considered pharmaceutically acceptable.

[0037] Salts can be obtained by contacting a neutral form of an active pharmaceutical ingredient with an acid (e.g., hydrochloric acid), either as a net contact or in a suitable solvent (e.g., an inert solvent). Methods for preparing such salts are known to those skilled in the art.

[0038] Alkalizing agent The combinations, dosage forms, and pharmaceutical compositions of this application contain alkalizing agents.

[0039] An alkalizing agent is a reagent that can raise the pH of a solution, such as an aqueous solution. Alkalizing agents can be salts, such as magnesium, calcium, or sodium salts with suitable counterions.

[0040] According to the embodiments, the counterions may include carbonate, citrate, bicarbonate, acetate, lactate, or oxide salts.

[0041] In embodiments, the alkalizing agent includes one or more of the following: tetraborate, hydroxide, oxide, carbonate, citrate, bicarbonate, acetate, lactate, arginine, lysine, choline, meglumine, tromethamine, potassium salt, magnesium salt, calcium salt, or sodium salt.

[0042] Preferably, the alkalizing agent is selected from magnesium carbonate, sodium carbonate, potassium bicarbonate, and magnesium oxide, or more preferably, the alkalizing agent is magnesium carbonate.

[0043] The amount of alkalizing agent in the combination, dosage form, or pharmaceutical composition of this application can be expressed as a weight percentage (wt%) of the alkalizing agent in the total weight of the combination, dosage form, or pharmaceutical composition. For example, the combination, dosage form, or pharmaceutical composition of this application may contain an amount from about 1 wt% to about 99 wt%, such as about 1 wt% to about 80 wt%, about 1 wt% to about 60 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 1 wt% to about 20 wt%, about 1 wt% to about 10 wt%, about 1 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 15 wt%, such as about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%. wt%, about 4wt%, about 4.5wt%, about 5wt%, about 6wt%, about 7wt%, about 8wt%, about 9wt%, about 10wt%, about 11wt%, about 12wt%, about 13wt%, about 14wt%, about 15wt%, about 16wt%, about 17wt%, about 18wt%, about 19wt%, about 20wt%, about 21wt%, about 22wt%, about 23wt%, about 24wt%, about 25wt%, about 30wt%, about 35wt%, about 40wt%, about 45wt%, or about 50wt%.

[0044] In a combination, dosage form, or pharmaceutical composition, the alkalizing agent may be provided with other components (e.g., the active pharmaceutical ingredient) in any desired ratio. For example, in a combination, dosage form, or pharmaceutical composition, the weight ratio of the alkalizing agent to the active pharmaceutical ingredient in the combination, dosage form, or pharmaceutical composition of this application may be about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 2:3, about 2:5, about 2:7, about 2:9, about 3:4, about 3:5, about 3:7, about 3:8, about 3:9, about 3:10, about 4:5, about 4:7, about 4:9, about 5:6, about 5:7, about 5:8, about 5:9, about 6:7, about 6:9, about 7:8, about 7:9, or about 8:9.

[0045] In the embodiments, the weight ratio (alkalizing agent / alkalizing agent + telostatin or alkalizing agent / alkalizing agent + doxepin) is between 5% and 99%, preferably between 15% and 95%, and more preferably between 15% and 70%.

[0046] According to embodiments, the combination, dosage form, or pharmaceutical composition has a pH between 7.5 and 11. For example, when the combination, dosage form, or pharmaceutical composition is exposed to a solution (e.g., an aqueous solution, typical drinking water, such as a standard volume of 250 mL of drinking water), the pH of the solution will change to a value between 7.5 and 11. In some embodiments, this pH change of the combination, dosage form, or pharmaceutical composition occurs in the microenvironment, such as in the gastrointestinal tract of a subject who has orally administered the combination, dosage form, or pharmaceutical composition.

[0047] Pharmacokinetics The combinations of this application generally exhibit faster absorption of the active ingredient in vivo than the combination of the active ingredient itself. More specifically, the combinations, dosage forms, and pharmaceutical compositions of this application can provide faster absorption of the active ingredient in vivo (e.g., after oral administration), for example, compared to administration of the active ingredient not in a combination form or in another dosage form or pharmaceutical composition.

[0048] In particular, and not wanting to be bound by theory, it is believed that when the active ingredient is administered in combination with an alkalizing agent, the plasma absorption peak of the active ingredient (e.g., telolide or doxepin) appears more quickly.

[0049] Therefore, the combination of this application accelerates absorption, i.e., the so-called T max The reduction. More specifically, the combinations, dosage forms, and pharmaceutical compositions of this application can provide accelerated absorption of the active ingredient and / or T. max Reduced (e.g., after oral administration), for example, relative to administration of the active ingredient not in combination or in another dosage form or pharmaceutical composition. It will be understood that T max It is the peak plasma concentration (C) of the active ingredient reached after application. max The shortest time measure.

[0050] The combinations, dosage forms, and pharmaceutical compositions of this application can provide C max The increase (e.g., after oral administration), such as C obtained after administration of the active ingredient not in combination or in another dosage form or pharmaceutical composition. max In some embodiments, such as when administered not in combination or in another dosage form or pharmaceutical composition, the corresponding active ingredient obtains C max Compared to the combined application of C maxIt can be 5% higher, preferably 10% or more higher, and even better 20% or more higher.

[0051] In some embodiments, such as when administered not in combination or in another dosage form or pharmaceutical composition, the corresponding active ingredient yields T max Compared to the combined application of T max It can be 5% or more lower, preferably 10% or more lower, or even more preferably 20% or more lower.

[0052] Without being bound by theory, it is believed that the combinations of this application can allow for greater absorption of the active ingredient. In particular, it is believed that the combinations, dosage forms, and pharmaceutical compositions of this application provide greater absorption of the active ingredient (e.g., after oral administration), for example, compared to when the same active ingredient is administered not in combination or in another dosage form or pharmaceutical composition.

[0053] Higher absorption can be determined by a higher integral (increased AUC) of the concentration-time curve. In embodiments, the AUC of the combination can be 5% or more higher than the AUC obtained by the corresponding active ingredient, preferably 10% or more, and even more preferably 20% or more. For example, the AUC obtained by administration (e.g., oral administration) of the combination, dosage form, or pharmaceutical composition of this application can be 5% or more higher than the AUC obtained by administration of the corresponding active ingredient, for example, not in combination form or in another dosage form or pharmaceutical composition.

[0054] Dosage Forms and Pharmaceutical Compositions This application also relates to dosage forms or pharmaceutical compositions comprising the combinations disclosed herein and optionally one or more pharmaceutically acceptable excipients.

[0055] This application also relates to dosage forms comprising the pharmaceutical compositions disclosed herein.

[0056] The dosage forms and pharmaceutical compositions of this application may contain teloristian salts (such as teloristian hydrochloride) and alkalizing agents, as well as optional one or more pharmaceutically acceptable excipients.

[0057] The pharmaceutical composition or dosage form of this application may be a tablet, caplet, capsule, suspension, granule, powder, etc. The pharmaceutical composition or dosage form of this application may be in tablet form. The pharmaceutical composition or dosage form of this application may be in capsule form.

[0058] Exemplary dosage forms or pharmaceutical compositions of this application comprise 0.5 wt% to 20 wt% of teloristian salt (e.g., teloristian hydrochloride) and 2 wt% to 50 wt% of an alkalizing agent, wherein the weight is based on the total weight of the dosage form or pharmaceutical composition. For example, an exemplary tablet of this application comprises (by weight): 0.5% to 20% teloristian salt (such as hydrochloride) and 2% to 50% alkalizing agent relative to the total weight of the tablet (e.g., a coated tablet).

[0059] The pharmaceutical compositions or dosage forms of this application may include a coating, such as a film (sometimes referred to herein as a coated film). In embodiments, the dosage form or pharmaceutical composition is a tablet comprising a core coated by a film, wherein the core comprises teloristian salt (e.g., teloristian hydrochloride) and an alkalizing agent. The core may further comprise one or more pharmaceutically acceptable excipients selected from, for example, microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, lactose, and croscarmellose sodium.

[0060] The coating film may contain one or more components, including, for example, polyvinyl alcohol, titanium dioxide, polyethylene glycol (macrogol), or talc. Suitable ready-to-use compositions for preparing the coating film (referred to herein as "coating systems") are commercially available, such as Opadry manufactured by Colorcon. ® ambII coating system.

[0061] The coating film can be a moisture barrier. It should be understood that a moisture barrier is different from a delayed-release coating (sometimes called an enteric coating). The moisture barrier coating can be located around the core of the pharmaceutical composition or dosage form of this application and may optionally be present together with a delayed-release (e.g., enteric) coating layer. For example, the dosage form or pharmaceutical composition of this application may contain a coating film between the outer surface of the core and the inner surface of the delayed-release coating layer. The moisture barrier can contain any suitable material, such as materials that prevent moisture from the environment from easily penetrating the core of the dosage form before it is intended to dissolve (e.g., at application). The moisture barrier may include polymers. Suitable polymers include polyvinyl alcohol and hydroxypropyl methylcellulose (hydroxypropyl methylcellulose). An exemplary moisture barrier material of this application is OPADRY. ® amb II.

[0062] Another exemplary pharmaceutical composition or dosage form of this application is a coated tablet comprising: a core comprising 3% to 15 wt% teloridine hydrochloride; 20 wt% to 50 wt% an alkalizing agent; 35 wt% to 50 wt% of one or more pharmaceutically acceptable excipients selected from microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, and lactose; and a coating film comprising 2 wt% to 5 wt% of the total weight of the coated tablet.

[0063] The dosage form or pharmaceutical composition of this application may be in the form of gastro-resistant tablets or capsules.

[0064] An exemplary acid-resistant tablet of this application comprises: a core comprising: 0.5 wt% to 20 wt% telolide hydrochloride; 2 wt% to 20 wt% alkalizing agent; 40 wt% to 60 wt% pharmaceutically acceptable excipients selected from microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, lactose, and croscarmellose sodium; a coating film comprising: 5 wt% to 15 wt% of one or more acid-resistant coating agents relative to the total weight of the coated tablet; and 2 wt% to 5 wt% of pharmaceutically acceptable excipients selected from coating systems and plasticizers relative to the total weight of the coated tablet.

[0065] As used herein, “acid-resistant coating agent” refers to a composition suitable for preparing an acid-resistant film. Suitable ready-to-use compositions for preparing such acid-resistant coatings are commercially available, such as propylene (Acryl) EZE® compositions manufactured by Colorcon.

[0066] Dosage forms or pharmaceutical compositions may contain a therapeutically effective amount of a salt of teloristine. For example, dosage forms or pharmaceutical compositions may contain about 1 mg to about 200 mg, such as about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 10 mg to about 25 mg, or about 1 mg to about 10 mg of teloristine hydrochloride, 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 teloristine hydrochloride.

[0067] The dosage form of the pharmaceutical composition may contain about 1 mg to about 400 mg of teloratesen or a pharmaceutically acceptable salt thereof (e.g., about 1 mg to about 250 mg, or about 20 mg to about 200 mg, such as about 10 mg, about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, or about 300 mg). The dosage form or pharmaceutical composition may contain about 1 mg to about 80 mg of teloratesen or a pharmaceutically acceptable salt thereof (e.g., about 1 mg to about 70 mg, about 1 mg to about 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about 20 mg to about 40 mg, about 40 mg to about 60 mg, or about 50 mg to about 70 mg). For example, the dosage form or pharmaceutical composition 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, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, etc. Tilorisen or its pharmaceutically acceptable salts in the following amounts: approximately 50 mg, approximately 51 mg, approximately 52 mg, approximately 53 mg, approximately 54 mg, approximately 55 mg, approximately 56 mg, approximately 57 mg, approximately 58 mg, approximately 59 mg, approximately 60 mg, approximately 61 mg, approximately 62 mg, approximately 63 mg, approximately 64 mg, approximately 65 mg, approximately 66 mg, approximately 67 mg, approximately 68 mg, approximately 69 mg, approximately 70 mg, approximately 71 mg, approximately 72 mg, approximately 73 mg, approximately 74 mg, or approximately 75 mg.

[0068] It should be understood that the amount of teloraten in the free base form of the dosage form or pharmaceutical composition will be slightly less than the equivalent amount described above. For example, a dosage form or pharmaceutical composition disclosed herein containing 5 mg of teloraten hydrochloride will contain about 4.45 mg of teloraten (free base). In another example, a dosage form or pharmaceutical composition disclosed herein containing 20 mg of teloraten hydrochloride contains about 17.8 mg of teloraten (free base). In some embodiments, the dosage forms or pharmaceutical compositions disclosed herein contain about 5 mg of teloraten monohydrochloride, or about 4.45 mg of teloraten (free base). In some embodiments, the dosage forms or pharmaceutical compositions disclosed herein contain about 20 mg of teloraten monohydrochloride, or about 17.8 mg of teloraten (free base).

[0069] The dosage form of this application may be tablets, capsules, suspensions, granules, powders, etc. For example, the dosage form of the pharmaceutical composition is tablets, and more particularly film-coated tablets.

[0070] The dosage form or pharmaceutical composition of this application may include a core, and optionally a coating surrounding the core. The core may include combinations of those of this application. According to embodiments, the core comprises a combination of teloridine hydrochloride and an alkalizing agent.

[0071] In some embodiments, the dosage form or pharmaceutical composition is a coated tablet, and the active pharmaceutical ingredient (e.g., teloridine HCl) is contained within the core of the tablet and is substantially absent from the coating. In some embodiments, the dosage form or pharmaceutical composition is a coated tablet, and an alkalizing agent is contained within the core of the tablet and is substantially absent from the coating. In some embodiments, the dosage form or pharmaceutical composition is a coated tablet, and both the active pharmaceutical ingredient (e.g., teloridine HCl) and the alkalizing agent are contained within the core of the tablet, and neither the active pharmaceutical ingredient nor the alkalizing agent is substantially absent from the coating.

[0072] In addition to the hydrochloride salt and alkalizing agent of the active pharmaceutical ingredient, the dosage form or pharmaceutical composition of this application may also contain 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), flow aids, adjuvants, fillers, wetting agents, suspensions, solvents, dispersion media, ion exchangers, salts, electrolytes, waxes and / or oils, etc.

[0073] Pharmaceutical compositions or dosage forms may contain pharmaceutically acceptable excipients disclosed herein or combinations thereof.

[0074] For example, the dosage form or pharmaceutical composition of this application may contain one or more of the following pharmaceutically acceptable excipients: colloidal silica, crospovidone, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

[0075] 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 0.01% to about 95% by weight, such as about 0.1% to about 25%, about 1% to about 10%, about 15% to about 95%, or about 0.01% to about 2% by weight.

[0076] The dosage forms and pharmaceutical compositions of this application can be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally, or via implantation. In some embodiments, the dosage forms and pharmaceutical compositions of this application are administered orally.

[0077] The preparation of dosage forms or pharmaceutical compositions 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 of a bead or pharmaceutical active agent that does not contain active ingredient), and rounding off.

[0078] Treatment This application also relates to combinations, dosage forms, or pharmaceutical compositions disclosed herein for the treatment of diseases or conditions, such as those disclosed herein.

[0079] This application also relates to methods for treating diseases or conditions, including administering the combinations, dosage forms or pharmaceutical compositions disclosed herein to a subject in need.

[0080] Diseases or conditions can include sleep disorders (e.g., excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea, sleep-induced apnea, daytime sleepiness), severe fatigue, idiopathic narcolepsy, central nervous system disorders (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), psychopathological states, depressive and asthenic states, vertigo and motion sickness, obesity, psychosomatic disorders, respiratory diseases, etc. Allergic diseases, inflammatory diseases, heart diseases, gastrointestinal diseases, urogenital diseases, skin diseases, stress, migraines, headaches, pain, mental disorders, asthma, bronchitis, rhinitis, tracheitis, gastric ulcers, duodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), cystitis, endometritis, urinary incontinence, fecal incontinence, urticaria, pruritus, arthritis, conjunctivitis, premenstrual syndrome, prostatitis, genital diseases, rheumatic diseases, eye diseases, drooling, seizures, depression, hypothalamic-pituitary system disorders, cerebral circulatory disorders, and immune system diseases.

[0081] Illnesses or conditions can be sleep disorders. For example, illnesses or conditions can be excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness, severe fatigue, or idiopathic narcolepsy.

[0082] In some embodiments, the disease or condition is excessive daytime sleepiness (EDS). In some embodiments, the disease or condition is cataplexy. In the methods disclosed herein, the subject to be treated may have narcolepsy, and / or may be an adult with narcolepsy. For example, a method of treating a disease or condition may include administering the combination or pharmaceutical composition of this application to the subject in need.

[0083] In some aspects, this application relates to combinations, dosage forms, or pharmaceutical compositions of salts of teloristian (e.g., teloristian hydrochloride) and alkalizing agents disclosed herein for the treatment of diseases or conditions (e.g., the diseases or conditions disclosed herein), optionally wherein the disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness, severe fatigue, or idiopathic narcolepsy. The disease or condition may occur in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

[0084] In some aspects, this application relates to the use of combinations or dosage forms or pharmaceutical compositions of the teloristian salts (e.g., teloristian hydrochloride) disclosed herein with an alkalizing agent in the preparation of a medicament for treating a disease or condition (e.g., the disease or condition disclosed herein), optionally wherein the disease or condition is excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness, severe fatigue, or idiopathic narcolepsy. The disease or condition may occur in a subject with narcolepsy (e.g., an adult subject with narcolepsy).

[0085] 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 the combination, 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.

[0086] 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, the method comprising administering to a subject in need the combination, dosage form, or pharmaceutical composition disclosed herein.

[0087] The illness or condition can be depression, anxiety, chronic urticaria, insomnia, or itching.

[0088] The combinations, dosage forms, or pharmaceutical compositions disclosed herein can be administered once daily, twice daily, or more frequently. More than one dosage form may be administered at one time to obtain the desired dose of the active ingredient. The combinations, dosage forms, or pharmaceutical compositions disclosed herein can be taken at frequencies and amounts such that the total amount of the active ingredient (e.g., teloprene, in terms of free base) administered is in the range of about 5 mg to about 100 mg per day, for example, about 5 mg to about 80 mg per day, for example, about 5 mg to about 70 mg per day, for example, about 10 mg to about 50 mg per day, for example, about 15 mg to about 40 mg per day. The combinations, dosage forms, or pharmaceutical compositions disclosed herein can be taken at frequencies and amounts such that the total amount of the active ingredient (e.g., teloprene, as a free base) administered is in the range of about 17.8 mg to about 35.6 mg per day. For example, a subject may orally administer two dosage forms once daily, each containing 4.45 mg of the active ingredient (e.g., teloratesen, calculated as free base), to achieve a daily dose of 8.9 mg of the active ingredient (e.g., teloratesen, calculated as free base). A subject may orally administer one dosage form once daily, containing 17.8 mg of the active ingredient (e.g., teloratesen, calculated as free base), to achieve a daily dose of 17.8 mg of the active ingredient (e.g., teloratesen, calculated as free base). A subject may orally administer two dosage forms once daily, each containing 17.8 mg of the active ingredient (e.g., teloratesen, calculated as free base), to achieve a daily dose of 35.6 mg of the active ingredient (e.g., teloratesen, calculated as free base).

[0089] In some embodiments, the combinations, dosage forms, or pharmaceutical compositions disclosed herein can be taken at frequencies and amounts such that the total amount of teloristine administered (calculated as free base) is in the range of about 10 mg to about 50 mg per day, for example, about 15 mg to about 40 mg per day. The combinations, dosage forms, or pharmaceutical compositions disclosed herein can be taken at frequencies and amounts such that the total amount of teloristine administered (calculated as free base) is in the range of about 17.8 mg to about 35.6 mg per day. For example, a subject may orally administer two dosage forms once daily, each containing 4.45 mg of teloristine (calculated as free base) to achieve a daily dose of 8.9 mg of teloristine (calculated as free base). A subject may orally administer one dosage form once daily, containing 17.8 mg of teloristine (calculated as free base) to achieve a daily dose of 17.8 mg of teloristine (calculated as free base). Subjects can be administered two dosage forms orally once daily, each containing 17.8 mg of teloratesen (as free base) to achieve a daily dose of 35.6 mg of teloratesen (free base).

[0090] Used to improve drug absorption This application also provides methods or uses for improving the absorption of active ingredients (e.g., teloprene or doxepin).

[0091] This application provides a method for improving the absorption of an active ingredient, the use of which includes administering the active ingredient in salt form together with an alkalizing agent, as defined above. For example, a method or use of this application for improving the absorption of an active ingredient (e.g., teloprene or doxepin) may include administering the active ingredient (optionally, in salt form) together with an alkalizing agent (such as the alkalizing agent of this application). This administration may be oral.

[0092] Methods or uses of this application for improving the absorption of an active ingredient (e.g., teloprene or doxepin) may include administering the combination, dosage form, or pharmaceutical composition of this application. This administration may be oral.

[0093] Improving absorption using the methods of this application may include accelerating the absorption of the active ingredient in the patient's body (e.g., after oral administration, such as absorption from the gastrointestinal tract into the bloodstream), for example by shortening T... max To determine. Improving absorption using the methods of this application may include increasing the amount of absorbed active ingredient (e.g., after oral administration, such as absorption from the gastrointestinal tract into the bloodstream), for example, through higher C... max Sure.

[0094] In some respects, this application relates to an accelerated absorption formulation comprising an active pharmaceutical ingredient (optionally in the form of a salt) in combination with an alkalizing agent.

[0095] definition The articles “a” and “an” are used in this text to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “element” means one or more elements.

[0096] The term “about” when referring to measurable values, such as quantities, durations, etc., is intended to cover variations of ±20% or less relative to a specified value, 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, because such variations are appropriate.

[0097] As used herein, the phrase “and / or” should be understood to mean “one or two” of the elements so joined together: that is, elements that exist together in some cases and separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, that is, “one or more” of the elements so joined together. 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 indicated. Thus, as a non-limiting example, when used in conjunction with open-ended language such as “including,” a reference to “A and / or B” may in one embodiment refer only to A (optionally including elements other than B); in another embodiment, it may refer only to B (optionally including elements other than A); in yet another embodiment, it may refer to both A and B (optionally including other elements), and so on.

[0098] As used herein, the terms “administer,” “administering,” or “administration” refer to the implantation, absorption, ingestion, injection, inhalation, or other introduction of a compound, dosage form, or pharmaceutical composition.

[0099] Unless the context otherwise requires, the terms “comprise,” “comprises,” and “comprising” are used in a non-exclusive sense herein. Similarly, the term “include” and its grammatical variations are intended to be non-restrictive, meaning that a listing of an item does not exclude other similar items that could substitute for or be added to the listed item.

[0100] As used herein, the term "effective amount" or "therapeutic effective amount" means an amount of the compound or pharmaceutical composition described herein that is sufficient to achieve the desired results under the conditions of administration. For example, an effective amount of the compound, combination, dosage form, or pharmaceutical composition disclosed herein for treating excessive sleep disorder (EDS) in a subject, for example, 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 can determine appropriate dosing based on a variety of considerations, including the severity of the disease, the subject's age, weight, general health condition, and other factors.

[0101] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a non-toxic material that can be formulated with the compounds or combinations disclosed herein (e.g., teloridine or doxepin in combination with an alkalizing agent) to provide a dosage form or pharmaceutical composition. Preferably, the pharmaceutically acceptable excipient is inert and does not interfere with the pharmacological activity of the compound (e.g., the active pharmaceutical ingredient) formulated therewith. Pharmaceutically acceptable excipients that can be used to prepare the dosage forms and pharmaceutical compositions disclosed herein are any excipients 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), preservatives, buffers (sometimes referred to herein as buffers), lubricants (sometimes referred to herein as lubricants), flow aids, adjuvants, fillers, wetting agents, suspensions, solvents, dispersion media, ion exchangers, salts, electrolytes, waxes and / or oils, etc.

[0102] For example, pharmaceutically acceptable excipients may include: alumina; phosphates (e.g., calcium phosphate, dicalcium phosphate, tricalcium phosphate, disodium hydrogen phosphate, potassium hydrogen phosphate); sulfates (e.g., calcium sulfate); cellulose; kaolin; bentonite; 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; polyvinylpyrrolidone (PVP, povidone) (e.g., cross-linked PVP, cross-linked povidone); polyvinyl alcohol; tragacanth gum; polyethylene glycol; mineral clay powder; crosslinked... Bicarboxymethyl cellulose; poloxamer; 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 zinc chloride); water; dimethylacetamide; protamine sulfate; lanolin; ethylenediaminetetraacetic acid (EDTA); cyclodextrins (e.g., CAPTISOL) ® ); polysorbates (e.g., Tween) ® For example, Twain ® 20 or Tween ® 80), and their combinations.

[0103] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a corresponding compound prepared with a relatively non-toxic acid or base, based on the specific substituents present on the compound. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound in its neutral form with the desired acid, either through net contact or in a suitable solvent (e.g., an inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids (such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphorous acid, etc.) and those 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, papoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, oxalic acid, etc.). Also included are amino acid salts (such as arginine salts) and organic acid salts (such as glucuronic acid or galacturonic acid). Other pharmaceutically acceptable salts known to those skilled in the art are also suitable for the pharmaceutical compositions of this application.

[0104] As used herein, the term "solvent" refers to a compound form that typically associates with a solvent via a solvent decomposition reaction. This physical association may 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, solvates will be able to be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0105] 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 proportional 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•0.5H₂O)), and polyhydrates (x is a number greater than 1, such as dihydrates (R•2H₂O) and hexahydrates (R•6H₂O)).

[0106] 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. Domestic and game 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., under 65 years of age), or human child subjects (e.g., under 18 years of age). In a preferred aspect, the subject is a human.

[0107] As used herein, the terms “treat,” “treatment,” “treating,” or grammatically related terms refer to methods for alleviating 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.

[0108] Throughout this application, various embodiments may exist in range form (e.g., from X to Y). It should be understood that the range form description is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of this application. Therefore, a range description should be considered as having specifically disclosed all possible subranges of that range and individual numerical values. For example, a description of a range such as 1 to 6 should be considered as specifically disclosing subranges such as 1 to 5, 1 to 4, 1 to 3, 2 to 6, 2 to 4, 3 to 6, etc., and individual numerical 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 subranges 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.

[0109] All publications cited in this application (e.g., scientific journal articles, patent publications, etc.) are incorporated herein by reference in their entirety. In the event of any inconsistency or contradiction between the material incorporated by reference and this specification, this specification shall prevail. Any citation of any reference herein does not imply an acceptance 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.

[0110] The compounds disclosed herein (e.g., pharmaceutically active agents) may also contain one or more isotopic substitutions. For example, hydrogen (H) can be in any isotopic form, including 1 H, 2 H (D or deuterium), 3 H (T or tritium); carbon (C) can be in any isotopic form, including 12 C 13 C and 14 C; Oxygen (O) can be in any isotopic form, including 16 O and 18 O; Nitrogen (N) can be in any isotopic form, including 14 N and 15 N; and chlorine (Cl) can be in any isotopic form, including 35 Cl and 37 Cl.

[0111] The various embodiments of the combinations, pharmaceutical compositions and methods described herein are further described in detail below, and additional definitions may be provided throughout the specification.

[0112] Example Example 1. An exemplary formulation comprising telorazole hydrochloride. Exemplary formulations comprising teloridine hydrochloride (40 mg), low and high doses of an alkalizing agent, and pharmaceutically acceptable excipients. Treatment A: 30 mg magnesium carbonate; Treatment B: 7.5 mg magnesium carbonate; Treatment C: 30 mg potassium bicarbonate; Treatment D: 30 mg sodium carbonate.

[0113] Each formulation is provided in tablet form coated with an acid-resistant film, details of which are shown in Table 1 below.

[0114] Table 1: Exemplary Formulations

[0115] aThe salt / base ratio is 1.1234—corresponding to 35.6 mg of teloristine. In this regimen, the teloristine dose is expressed as a teloristine-HCl dose. A 40 mg teloristine-HCl dose is equivalent to 35.6 mg of teloristine.

[0116] 1 15% suspension, weight gain = 3% 2 20% suspension, weight gain = 15% 3 PEG, with 8% propylene Eze Example 2. Clinical studies using the exemplary formulation of this application. Following a single oral administration in healthy male subjects, the exemplary teloraten HCl tablet formulation was compared to a reference teloraten HCl (WAKIX®) tablet formulation to determine the exemplary formulation (treatment A and treatment B) in an open-label, single-center, crossover randomized, relative bioavailability study. Sixteen (16) healthy, normal-weight male subjects were recruited to obtain at least twelve (12) complete evaluable subjects.

[0117] The bioequivalence of exemplary formulations A and B (treatment A and treatment B) disclosed in Example 1, which contain teloridine hydrochloride (40 mg) and high and low doses of an alkalizing agent, was determined and compared with a reference formulation as outlined in Table 2.

[0118] Table 2: Statistical Results of Bioequivalence Evaluation

[0119] GM: Geometric mean; GMR: Geometric mean ratio; CI: Confidence interval; BE: Bioequivalence; W-CV: Within-CV (%) of subjects Reference: Two 20 mg Wakix tablets ® tablet The above data indicate that magnesium carbonate increases the bioavailability of telolide by approximately 15% to 20% (AUC and / or C). max ) (Low dose 7.5 mg (treatment B) and high dose 30 mg (treatment A)).

[0120] Example 3. Apparent permeability of an exemplary teloridine-HCl combination over time The Caco-2 permeability assay was performed using an established method that measures the flux rate of a compound through a polarized Caco-2 cell monolayer. The resulting data can be used to predict drug absorption in vivo.

[0121] The Caco-2 cell line is derived from human colon cancer. These cells possess characteristics similar to intestinal epithelial cells, such as the formation of a polarized monolayer, a well-defined brush border on the apical surface, and intercellular junctions. Cells are grown on a semipermeable membrane in a Transwell™ system plate and form confluent polarized monolayers within 18 to 22 days. From days 18 to 22, the test compound is added to the apical side of the cell monolayer, and the flux of the compound across the monolayer into the basolateral receiving chamber is monitored up to a 2-hour incubation period (multiple intermediate time points).

[0122] The permeability coefficient (Papp) is calculated by the following formula: Papp=dQ / dtC0 x A Where Papp is the apparent permeability coefficient (cm / s x 10⁻⁶), dQ / dt is the rate of drug permeation through the cell (pmol / sec), C0 is the donor concentration at time zero (pmol / mL), and A is the area of ​​the cell monolayer (cm²). 2 ).

[0123] The apparent permeability of exemplary formulations containing teloliden hydrochloride (40 mg) with different alkalizing agents was determined and compared with a control (HBSS buffer, pH 7), and summarized in Table 3: Table 3: Exemplary combinations of teloroxygen hydrochloride used in apparent permeability studies.

[0124]

[0125] Figure 1 The table provides the apparent permeability of the formulation at a 540 µM teloridine HCl concentration (equivalent to a dose of 40 mg teloridine HCl tablet dissolved in 250 ml of standardized drinking water): • Under standard permeability test conditions (control): Teloridine HCl dissolved in HBSS buffer at pH 7; • Telorazole + potassium carbonate dissolved in water (7.5, 15, or 30 mg); and • Telorisen + magnesium oxide dissolved in water (7.5, 15, or 30 mg).

[0126] The results showed that, compared with the control (teloridine hydrochloride and buffer), the combination of teloridine hydrochloride and the alkalizing agent exhibited a relatively earlier peak (i.e., a shorter T value). max ), and increased permeability.

[0127] Example 4. Bioavailability of an exemplary teloroxygen HCl combination.

[0128] The bioavailability of telorate hydrochloride was assessed at a concentration of 540 µM (equivalent to a dose of 40 mg telorate hydrochloride tablet dissolved in 250 ml of standardized drinking water) under standard permeability assay conditions (telorate hydrochloride dissolved in HBSS buffer at pH 7) or with an alkalizing agent having a set pH.

[0129] As shown in Table 4, by measuring the area under the curve (AUC) 0-120 The bioavailability of an exemplary combination of teloridine hydrochloride and an alkalizing agent was determined by min (expressed as a percentage relative to the control).

[0130] Table 4: Exemplary combinations of teloratesen hydrochloride used in bioavailability studies.

[0131]

[0132] Figure 2 The results of bioavailability measurements are provided.

[0133] The results showed that the combination of teloridine hydrochloride and an alkalizing agent produced higher bioavailability compared to the control (teloridine hydrochloride and buffer).

[0134] Example 5. Apparent permeability of an exemplary doxepin HCl combination over time.

[0135] Apparent permeability was assessed using the Caco-2 permeability assay disclosed above. The apparent permeability of an exemplary combination of doxepin hydrochloride (10 mg) and magnesium carbonate (30 mg) at pH 7.5 was compared to a control (doxepin hydrochloride 10 mg / HBSS). Results are shown in... Figure 3 The document shows a combination containing doxepin hydrochloride at a concentration of 143 µM, corresponding to a dose of 10 mg doxepin hydrochloride tablets dissolved in a standardized volume of 250 mL of drinking water: Under standard permeability assay conditions (doxepin HCl dissolved in HBSS buffer at pH 7), and Doxepin + magnesium carbonate 30 mg dissolved in water Figure 3 The results showed that the combination of doxepin hydrochloride and an alkalizing agent produced higher bioavailability (+50% over 2 hours) compared to doxepin hydrochloride with buffer (Hankes Balanced Salt Solution, HBSS).

Claims

1. A combination of a salt of telolide and an alkalizing agent.

2. The combination according to claim 1, wherein, The salt of teloratesen is teloratesen hydrochloride.

3. The combination according to claim 1 or 2, wherein, The alkalizing agent includes one or more of the following: tetraborate, hydroxide, oxide, carbonate, citrate, bicarbonate, acetate, lactate, arginine, lysine, choline, meglumine, tromethamine, potassium salt, magnesium salt, calcium salt, or sodium salt.

4. The combination according to any one of the preceding claims, wherein, The alkalizing agent is magnesium carbonate or sodium carbonate, preferably magnesium carbonate.

5. The combination according to any one of the preceding claims, wherein, The weight ratio (alkalizing agent / alkalizing agent + teloridine salt) is between 5% and 99%, preferably between 15% and 95%, and more preferably between 15% and 70%.

6. The combination according to any one of the preceding claims, wherein the combination is used to treat or prevent a disease or condition selected from the group consisting of: excessive daytime sleepiness (EDS), cataplexy, narcolepsy, sleep apnea (e.g., obstructive sleep apnea), sleep-induced apnea, daytime sleepiness, severe fatigue, and idiopathic narcolepsy.

7. The combination according to any one of the preceding claims, wherein the combination is used to accelerate and / or enhance the absorption of teloratesen in a subject (e.g., absorption from the gastrointestinal tract into the bloodstream).

8. A pharmaceutical composition comprising the combination of any one of claims 1 to 5, and optionally one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in tablet form, and wherein, relative to the total weight of the coated tablets, the tablets comprise (by weight): 0.5% to 20% telostatin hydrochloride; 2% to 50% alkalizing agent.

10. The pharmaceutical composition according to claim 8 or 9, wherein, The tablet comprises a film-coated core, and wherein the core comprises teloridine hydrochloride and an alkalizing agent.

11. The pharmaceutical composition according to claim 10, wherein, The core also includes one or more pharmaceutically acceptable excipients, such as pharmaceutically acceptable excipients selected from the group consisting of microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, lactose, and croscarmellose sodium.

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the pharmaceutical composition is in the form of a coated tablet, comprising: The core comprises: 3% to 15% by weight of teloridine hydrochloride; 20% to 50% by weight of alkalizing agent; 35% to 50% by weight of a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, and lactose; and The coating film, wherein the coating film accounts for 2% to 5% by weight. All of these weights are relative to the total weight of the coated tablets.

13. The pharmaceutical composition according to any one of claims 8 to 11, wherein the pharmaceutical composition is in the form of an acid-resistant tablet, comprising: The core comprises: 0.5% to 20% by weight of teloridine hydrochloride; 2% to 20% by weight of alkalizing agent; 40% to 60% by weight of a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica, lactose, and croscarmellose sodium; and The coating film comprises: 5% to 15% by weight of one or more acid-resistant coating agents, and 2% to 5% by weight of a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is selected from coating systems and plasticizers; All of these weights are relative to the total weight of the coated tablets.

14. An accelerated absorption formulation comprising an active pharmaceutical ingredient (optionally, in the form of a salt) in combination with an alkalizing agent.

15. Uses of alkalizing agents in accelerating the absorption of active pharmaceutical ingredients, including: The active pharmaceutical ingredient (optionally in the form of a salt) is applied together with the alkalizing agent.

16. The accelerated absorption formulation according to claim 14 or the use according to claim 15, wherein, The active pharmaceutical ingredient is doxepin (e.g., doxepin hydrochloride).

17. The accelerated absorption formulation according to claim 14 or the use according to claim 15, wherein, The active pharmaceutical ingredient is teloratesen (e.g., teloratesen hydrochloride).

18. The accelerated absorption formulation or use according to any one of claims 14 to 17, wherein, The alkalizing agent is defined according to any one of claims 2 to 4.

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