Tablets comprising 6-((5-methyl-3-(6-methylpyridin-3-yl) isoxazol-4-yl) methoxy)-n-(tetrahydropyran-4-yl) pyridazine-3-carboxamide

Abstract

The present invention relates to: a tablet comprising 6-((5-methyl-3-(6-methylpyridin-3-yl) isoxazol-4-yl) methoxyl)-N-(tetrahydropyran-4-yl) pyridazine-3-carboxamide; and a pharmaceutical composition comprising the tablet. A process for the preparation of the tablet; a cartridge containing the tablet; and the use of the tablet in medical treatment.

Description

Technical Field

[0001] This invention relates to: tablets comprising 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazine-3-carboxamide; a method for preparing said tablets; a pharmaceutical package comprising said tablets; and the use of said tablets in medical treatment. Background Technology

[0002] 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide (I), also known as alogabat (WHO Drug Information, Vol. 35, No. 2, 2021, 366), is a small molecule selective γ-aminobutyric acid type A (GABAA) receptor 5-subunit allosteric modulator (PAM).

[0003] (I)

[0004] Alogabat is currently undergoing a Phase II clinical trial to investigate its pharmacokinetics and safety in children and adolescents with Angelman syndrome (AS), as well as its efficacy, safety, and tolerability in patients with autism spectrum disorder (ASD).

[0005] For the Phase I clinical trial, alogabat was administered in hard capsule form. However, hard capsules may not be suitable for administering the API to patients with AS or ASD, especially pediatric AS or ASD patients, as they are more prone to anxiety disorders than the general population and / or more sensitive to taste and texture, making it difficult for them to swallow hard capsules. Therefore, an alternative to the Phase I capsule formulation is needed.

[0006] WO2018104419 discloses a tablet formulation containing alogabat. However, the tablet formulation disclosed in WO2018104419 has the same drawbacks as the aforementioned capsule formulation. Furthermore, as described in WO2018104419, the use of lactose as a filler in the tablet formulation was found to be incompatible with the physical properties of the API, especially at high drug loadings (see Example 4). Additionally, as part of a Phase I clinical trial, taste evaluations were performed on five healthy volunteers, revealing an unpleasant bitter taste in the API. This could make swallowing alogabat-containing tablets even more challenging for patients with dysphagia, such as pediatric AS and ASD patients.

[0007] In summary, there is an unmet need for new formulations of alogabat. Summary of the Invention

[0008] As a solution to the problems associated with the Phase I capsule formulations and tablet formulations disclosed in WO2018104419 outlined above, this invention provides tablets that can be dispersed in a liquid (such as water or apple juice) prior to administration. This greatly facilitates the administration of alogabat to patients with ASD and Angelman syndrome, particularly pediatric patients with ASD and Angelman syndrome. Dispersing the tablets in an acidic beverage (such as apple juice) also overcomes the problem of the unpleasant bitterness of APIs, as APIs are found to have low solubility at acidic pH. In other words, when the tablets according to the invention are dispersed in an acidic beverage (such as apple juice), the APIs do not dissolve, thus preventing them from exhibiting their unpleasant bitterness. To promote the disintegration of the tablets in water and acidic beverages, respectively, a superdisintegrant is added to the formulation.

[0009] During the development of the tablet formulations of the present invention, it was surprisingly discovered that at high drug loadings (>25%), delamination and capping occurred when the formulation blends were compressed into tablet cores. This behavior is likely due to the inherent mechanical properties of the API. That is, the API was found to exhibit extreme plastic behavior even under low compaction pressures. Therefore, the tablets according to the present invention have a drug loading of ≤25%.

[0010] Furthermore, due to the plastic behavior and low tensile strength value of APIs, they are incompatible with excipients exhibiting low tensile strength and high compaction strength (such as lactose), especially in formulations with high drug loading. Therefore, when developing tablet formulations according to the present invention, excipients with low tensile strength and high compaction strength, such as lactose, are excluded.

[0011] In summary, in a first aspect, the present invention provides a tablet comprising a core and optional coating, wherein the core comprises:

[0012] (i) API 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide (I), or a pharmaceutically acceptable salt thereof,

[0013] (I);

[0014] (ii) Superdisintegrants;

[0015] (iii) First filler;

[0016] (iv) Second filler;

[0017] (v) Flow aids; and

[0018] (vi) Lubricant;

[0019] The amount of API relative to the total weight of the kernel is ≤25% ± 1%, preferably ≤20% ± 1% of the total weight of the kernel; and

[0020] The kernel described therein does not contain lactose.

[0021] The tablets according to the invention can be manufactured on an industrial scale, have low content standard deviation, and exhibit rapid disintegration. Attached Figure Description

[0022] Figure 1 is a flowchart depicting a method for manufacturing tablets according to the present invention.

[0023] Figure 2 is a flowchart depicting a method for manufacturing tablets containing sweeteners and flavoring agents according to the present invention.

[0024] Figure 3 is a flowchart depicting a method for manufacturing a tablet containing a sweetener according to the present invention.

[0025] Figure 4 depicts the dissolution profiles of tablets according to the invention with different dose intensities. Detailed Implementation

[0026] definition

[0027] Features, integers, properties, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for at least some mutually exclusive combinations of such features and / or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0028] As used herein, the term "dose intensity" refers to the absolute amount, expressed in milligrams (mg), of a Formula I compound contained in a tablet formulation according to the invention in the form of a free base. Therefore, if the Formula I compound is used in the form of a pharmaceutical salt, the term "dose intensity" refers to the corresponding free base equivalent.

[0029] As used herein, the term "filler" refers to a substance added to a pharmaceutical composition to increase the weight and / or size of the pharmaceutical composition. Pharmaceutically acceptable fillers are described in Remington's Pharmaceutical Sciences and listed in the Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of fillers are starch (e.g., pregelatinized starch), cellulose (e.g., microcrystalline cellulose), and lactose (e.g., lactose monohydrate). Preferred, but non-limiting examples of fillers are cellulose and lactose.

[0030] As used herein, the term "disintegrant" refers to a substance added to a pharmaceutical composition to aid in the breakdown (disintegration) (e.g., after administration) and release of the active ingredient. Pharmaceutically acceptable disintegrants are described in Remington's Pharmaceutical Sciences and listed in the Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. A non-limiting example of a disintegrant is low-substituted hydroxypropyl cellulose alginate. A preferred but non-limiting example of a disintegrant is alginate.

[0031] As used herein, the term "superdisintegrant" refers to a highly efficient disintegrant that, when used at low levels, provides rapid disintegration and dissolution in tablet or capsule dosage forms (see USP). <1059> "Excipient Properties" and USP 41-NF 36 General Rules <2040> (“superdisintegrant”). Preferred, but not limiting, examples of superdisintegrants are croscarmellose sodium and crospovidone. Particularly preferred examples of superdisintegrants are croscarmellose sodium.

[0032] As used herein, the term "lubricant" refers to a substance added to a pharmaceutical composition to help reduce the adhesion of powder particles to the surface of an equipment. Pharmaceutical lubricants are described in Remington's Pharmaceutical Sciences and listed in the Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of lubricants are sodium stearate and magnesium stearate. Preferred but non-limiting examples of lubricants are sodium stearate.

[0033] As used herein, the term "flow aid" refers to a substance added to a pharmaceutical composition to enhance product flow by reducing interparticle friction. Pharmaceutically acceptable flow aids are described in Remington's Pharmaceutical Sciences and listed in the Handbook of Pharmaceutical Excipients, Sheskey et al., 2017. Non-limiting examples of flow aids include silica (colloid), polyethylene glycol PEG 6000, and fumed silica Aerosil. ® 200, talc, etc. Preferred, but not limiting, examples of glidants are colloidal silica.

[0034] As used herein, the term "sweetener" refers to a substance that provides sweetness and has a sugar-like taste to make a product more palatable. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts, and any material that induces sweetness in an individual. Exemplary sweeteners include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, isomaltulose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, etc. Other exemplary sweeteners include glycerin, inulin, erythritol, acesulfame potassium and its salts (e.g., acesulfame potassium), alitane, aspartame, neotame, cyclamate, saccharin and its salts (e.g., sodium saccharin or calcium saccharin), neohesperidin dihydrochalcone, steviol, thomatose, etc. A particularly preferred sweetener is sucralose.

[0035] As used herein, the term "flavoring agent" refers to an active ingredient that can be used to mask unpleasant tastes and increase patient acceptance of completing a treatment course. Flavoring agents can be natural (e.g., fruit extracts) or artificial.

[0036] As used herein, the term “API” refers to an active pharmaceutical ingredient. The API used in the tablets according to the invention is 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide (I) or a pharmaceutically acceptable salt thereof, also known as alogabat or RO7017773.

[0037] (I).

[0038] As used in this article, the term "acidic" refers to pH < 7.

[0039] As used herein, the term “treatment” means the complete or partial relief of a symptom, disease, or condition, or of one or more symptoms associated with a symptom, disease, or condition; or the slowing or cessation of further progression or worsening of these symptoms; or the relief or elimination of the cause of the symptom, disease, or condition itself.

[0040] As used herein, the term “preventing” includes: preventing or delaying the onset of clinical symptoms of a disease, condition or illness in a mammal (especially a human) that may be susceptible to or be prone to a disease, condition or illness but has not yet experienced or presented clinical or subclinical symptoms of a disease, condition or illness.

[0041] As used in this article, the term "patient" refers to a person.

[0042] Tablet formulation

[0043] In a first aspect, the present invention provides a tablet comprising a core and optional coating, wherein the core comprises:

[0044] (i) API 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide (I), or a pharmaceutically acceptable salt thereof,

[0045] (I);

[0046] (ii) Superdisintegrants;

[0047] (iii) First filler;

[0048] (iv) Second filler;

[0049] (v) Flow aids; and

[0050] (vi) Lubricant;

[0051] The amount of API relative to the total weight of the kernel is ≤25% ± 1%, preferably ≤20% ± 1% of the total weight of the kernel; and

[0052] The kernel described therein does not contain lactose.

[0053] In one embodiment, the present invention provides a tablet as described herein, wherein

[0054] (i) The weight of the API accounts for 2% ± 1% to 20% ± 1% of the total weight of the kernel;

[0055] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0056] (iii) The weight of the first filler accounts for 46% ± 1% to 57% ± 1% of the total weight of the core;

[0057] (iv) The weight of the second filler accounts for 26% ± 1% to 32% ± 1% of the total weight of the core;

[0058] (v) The weight of the gliding agent accounts for 2% ± 1% of the total weight of the core; and

[0059] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core.

[0060] In one embodiment, the present invention provides a tablet as described herein, wherein

[0061] (i) The weight of the API accounts for 20% ± 1% of the total weight of the kernel;

[0062] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0063] (iii) The weight of the first filler accounts for 46% ± 1% of the total weight of the core;

[0064] (iv) The weight of the second filler accounts for 26% ± 1% of the total weight of the core;

[0065] (v) The weight of the gliding agent accounts for 2% ± 1% of the total weight of the core; and

[0066] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core.

[0067] As part of a Phase I clinical trial, taste evaluations were conducted on five healthy volunteers, revealing an unpleasant bitter taste in the API. This is another problem that the tablets of this invention aim to address. It was also found that the API has low solubility at acidic pH. Therefore, when the tablets according to the invention are dispersed in acidic beverages (such as apple juice), the API does not dissolve, thus preventing it from exhibiting its unpleasant taste.

[0068] In one aspect, the present invention provides a method of administering a tablet according to the invention to a patient, the method comprising dispersing the tablet in an acidic beverage.

[0069] In a preferred embodiment, the acidic beverage is apple juice.

[0070] As an alternative to dispersing tablets in acidic beverages, the bitterness of the API can be masked by adding sweeteners and / or flavoring agents to the tablet formulation. This is particularly useful if patients prefer to swallow the tablets whole rather than dispersing them in liquid before administration.

[0071] Therefore, in one embodiment, the present invention provides a tablet as described herein, which further comprises:

[0072] (vii) Sweeteners.

[0073] In one embodiment, the sweetener accounts for 0.3% ± 0.1% to 0.5% ± 0.1% of the total weight of the core.

[0074] In one embodiment, the sweetener is sucralose.

[0075] In one embodiment, the present invention provides a tablet as described herein, wherein

[0076] (i) The weight of the API accounts for 2% ± 1% of the total weight of the kernel;

[0077] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0078] (iii) The weight of the first filler accounts for 57% ± 1% of the total weight of the core;

[0079] (iv) The weight of the second filler accounts for 32% ± 1% of the total weight of the core;

[0080] (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core;

[0081] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and

[0082] (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

[0083] In one embodiment, the present invention provides a tablet as described herein, wherein

[0084] (i) The weight of the API accounts for 3% ± 1% of the total weight of the kernel;

[0085] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0086] (iii) The weight of the first filler accounts for 57% ± 1% of the total weight of the core;

[0087] (iv) The weight of the second filler accounts for 32% ± 1% of the total weight of the core;

[0088] (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core;

[0089] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and

[0090] (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

[0091] In one embodiment, the present invention provides a tablet as described herein, wherein

[0092] (i) The weight of the API accounts for 8% ± 1% of the total weight of the kernel;

[0093] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0094] (iii) The weight of the first filler accounts for 54% ± 1% of the total weight of the core;

[0095] (iv) The weight of the second filler accounts for 30% ± 1% of the total weight of the core;

[0096] (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core;

[0097] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and

[0098] (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

[0099] In one embodiment, the present invention provides a tablet as described herein, wherein

[0100] (i) The weight of the API accounts for 16% ± 1% of the total weight of the kernel;

[0101] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0102] (iii) The weight of the first filler accounts for 48% ± 1% of the total weight of the core;

[0103] (iv) The weight of the second filler accounts for 27% ± 1% of the total weight of the core;

[0104] (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core;

[0105] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and

[0106] (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

[0107] In one embodiment, the present invention provides a tablet as described herein, further comprising:

[0108] (viii) Flavoring agents.

[0109] In one embodiment, the flavoring agent accounts for 1% ± 0.5% of the total weight of the core.

[0110] In one embodiment, the flavoring agent is a strawberry flavoring agent.

[0111] In one embodiment, the present invention provides a tablet as described herein, further comprising:

[0112] (vii) sweeteners; and

[0113] (viii) Flavoring agents.

[0114] In one embodiment, the present invention provides a tablet as described herein, wherein:

[0115] (i) The weight of the API accounts for 20% ± 1% of the total weight of the kernel;

[0116] (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core;

[0117] (iii) The weight of the first filler accounts for 45% ± 1% of the total weight of the core;

[0118] (iv) The weight of the second filler accounts for 26% ± 1% of the total weight of the core;

[0119] (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core;

[0120] (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core;

[0121] (vii) The sweetener comprises 0.5% ± 0.1% of the total weight of the core; and

[0122] (viii) The flavoring agent accounts for 1% ± 0.5% of the total weight of the core.

[0123] In one embodiment, the present invention provides a tablet as described herein, wherein:

[0124] (ii) The disintegrant is croscarmellose sodium;

[0125] (iii) The first filler is isomaltitol;

[0126] (iv) The second filler is microcrystalline cellulose;

[0127] (v) The flow aid is colloidal silica; and

[0128] (vi) The lubricant is sodium stearate fumarate.

[0129] In one embodiment, the present invention provides tablets as described herein, wherein the dose strength is from 0.5 mg to 375 mg, preferably from 2.5 mg to 375 mg, more preferably from 3 mg to 200 mg, more preferably from 3 mg to 150 mg, and even more preferably from 3 mg to 125 mg, such as 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, or 125 mg.

[0130] In one embodiment, the present invention provides tablets as described herein, wherein the dose strength is from 2.5 mg to 375 mg.

[0131] In a preferred embodiment, the present invention provides tablets as described herein, wherein the dose strength is from 3 mg to 125 mg.

[0132] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 3 mg.

[0133] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 4 mg.

[0134] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 5 mg.

[0135] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 10 mg.

[0136] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 20 mg.

[0137] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 25 mg.

[0138] In a particularly preferred embodiment, the present invention provides a tablet as described herein, wherein the dose strength is 125 mg.

[0139] In a preferred embodiment, the present invention provides a tablet as described herein, which comprises a coating.

[0140] In one embodiment, the coating weighs 3% ± 1% of the weight of the core.

[0141] In one embodiment, the coating comprises:

[0142] (i) Hydroxypropyl methylcellulose;

[0143] (ii) Lactose monohydrate;

[0144] (iii) Titanium dioxide; and

[0145] (iv) Polyethylene glycol 3350.

[0146] In one implementation, within the coating:

[0147] (i) The weight of the hydroxypropyl methylcellulose accounts for 34% ± 1% of the total weight of the coating;

[0148] (ii) The weight of the lactose monohydrate accounts for 28% ± 1% of the total weight of the coating;

[0149] (iii) The titanium dioxide accounts for 26% ± 1% of the total weight of the coating; and

[0150] (iv) The weight of the polyethylene glycol 3350 accounts for 12% ± 1% of the total weight of the coating.

[0151] In a preferred embodiment, the coating is Opadry II White 32F280008.

[0152] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0153]

[0154] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0155]

[0156] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0157]

[0158] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0159]

[0160] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0161]

[0162] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0163]

[0164] In a particularly preferred embodiment, the present invention provides a tablet, which is:

[0165]

[0166] As mentioned above, it is important to find that the tablets according to the invention can be dispersed in water and acidic beverages (such as apple juice). This requirement is achieved in particular by adding a superdisintegrant to the formulation. In a particularly preferred embodiment, the invention provides tablets as described herein, wherein the tablets disintegrate in purified water at 37°C in a time of <3 minutes (see Example 3).

[0167] Manufacturing method

[0168] In one aspect, the present invention provides a method for manufacturing the tablets described herein, the method comprising:

[0169] (i) Weigh the API and the first filler and place them in a container, and sieve the two components to obtain a blend;

[0170] (ii) Add the second filler, the super-disintegrant, the gliding agent and optional sweetener and / or flavoring agent to the blend from step (i) and sieve all components;

[0171] (iii) The sieved material from step (ii) is blended to obtain a powder blend;

[0172] (iv) Sift the lubricant, add it to the powder blend from step (iii), and blend.

[0173] (v) Sift the material from step (iv);

[0174] (vi) Blend the sieved material from step (v);

[0175] (vii) Compress the blend from step (vi) into a tablet core; and

[0176] (viii) Spray the film-coated suspension onto the tablet core from step (vii).

[0177] In a preferred embodiment, the method according to the invention is shown in Figures 1 to 3.

[0178] use

[0179] In one aspect, the present invention provides the tablet described herein, which is used as a medicine.

[0180] In one aspect, the present invention provides a method for treating or preventing GABA in patients. A A method for treating α5 receptor-related diseases, which includes administering one or more tablets as described herein to a patient.

[0181] In one aspect, the present invention provides the tablets described herein for use in treating or preventing GABA in patients. A In methods for treating α5 receptor-related diseases.

[0182] In one aspect, the present invention provides the tablets described herein for the treatment or prevention of GABA in patients. A Applications in methods for treating α5 receptor-related diseases.

[0183] In one implementation, the GABA A Alpha-5 receptor-related diseases are selected from Alzheimer's disease, mild cognitive impairment (MCI), age-related cognitive decline, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome, P-W. syndrome, epilepsy, post-traumatic stress disorder (PTSD), amyotrophic lateral sclerosis (ALS), and Fragility X disorder.

[0184] In a preferred embodiment, the GABA A α5 receptor-related diseases are selected from autism spectrum disorders and Angelman syndrome.

[0185] In a particularly preferred embodiment, the GABA A α5 receptor-related diseases are autism spectrum disorders.

[0186] In a particularly preferred embodiment, the GABA A α5 receptor-related diseases include Angelman syndrome.

[0187] Example

[0188] The following examples are provided to illustrate the invention. They should not be considered as limiting the scope of the invention, but merely as examples.

[0189] Example 1 – Tablet Dissolution Behavior

[0190] Figure 4 highlights the release behavior of the formulation according to the invention in 500 mL citrate buffer. Dissolution was determined using a paddle apparatus in accordance with USP 711 and harmonized with Ph. Eur. 2.9.3. The test formulation was then tested by HPLC.

[0191] Example 2 – Manufacturability (Tablet Hardness / Solids Fraction Type)

[0192] Manufacturability of representative batches of tablets was assessed using the highest dose strength of 20 mg (see Example 7), as this was considered most critical for formulation performance. Solids fraction (SF) is the proportion of solids in the compact volume. Porosity is one minus the solids fraction. Mechanical properties can change by 10% to 20% for every 0.01% change in solids fraction. Therefore, it is crucial to compare materials with the same solids fraction (Hiestand, EN and Smith, DP, (1984). “Indices of tableting performance”, Powder Technology, 38(2), pp. 145-159).

[0193]

[0194] Example 3 – Tablet disintegration behavior dependent on tablet hardness

[0195] Tablet disintegration behavior was monitored during the routine manufacturing process of the batch. Adapted from USP 701 and Ph. Eur. 2.9.1 regarding dispersible tablets, disintegration was performed in purified water at 37°C using the "Apparatus A" method.

[0196]

[0197] Example 4 – Plastic Behavior of APIs

[0198] Measurements were performed on cubic samples pressed with three different solid fractions, repeated three times (or twice or a single measurement for a limited number of samples). The dynamic response of the material was characterized by high-speed indentation (dynamic hardness Hd) caused by a spherical pendulum impacting the main surface of the sample.

[0199] In summary, it is important to note that even at lower compaction pressures, API exhibits extreme plastic behavior, resulting in a dynamic hardness (Hd) of 40.4 MPa, exceeding the ideal range of 100 MPa to 200 MPa (Amidon, GE, (1995), “Physical and mechanical property characterization of powders”, in Brittany HG, ed., Physical Characterization of Pharmaceutical).

[0200] The tensile strength of a compact is determined by measuring the force required to induce tensile failure under transverse compression. This is similar to measuring the crushing force or hardness of tablets. In these studies, experimental conditions and compact formation were well controlled, making the results more reproducible and quantitative. The ideal tensile strength indicating strong compact formation is >1 MPa. This API was found to have a low tensile strength value of approximately 0.79 MPa.

[0201] In summary, due to the plastic behavior and low tensile strength of APIs, they are incompatible with excipients that exhibit low tensile strength and high compaction values, such as lactose, especially in formulations with high drug loading.

[0202] Example 5 – 125 mg film-coated tablets

[0203]

[0204] Example 6 – 125 mg film-coated tablets with added sweeteners and flavoring agents

[0205]

[0206] Example 7 – 20 mg film-coated tablets with added sweetener

[0207]

[0208] Example 8 – 10 mg film-coated tablets with added sweetener

[0209]

[0210] Example 9 – 4 mg film-coated tablets with added sweetener

[0211]

[0212] Example 10 – 3 mg film-coated tablets with added sweetener

[0213]

[0214] Example 11 – Method for tablet manufacturing

[0215] The method for manufacturing tablets according to the present invention is shown in Figures 1 to 3.

[0216] The method and steps can be summarized as follows:

[0217] (i) Weigh the API and isomaltose into a container and sieve the two components to obtain a blend;

[0218] (ii) Add microcrystalline cellulose, croscarmellose sodium, colloidal silica and optional sucralose and / or strawberry flavoring agent to the blend from step (i) and sieve all components;

[0219] (iii) The sieved material from step (ii) is blended to obtain a powder blend;

[0220] (iv) Sift sodium stearate, add it to the powder blend from step (iii), and blend.

[0221] (v) Sift the material from step (iv);

[0222] (vi) Blend the sieved material from step (v);

[0223] (vii) Compress the blend from step (vi) into a tablet core; and

[0224] (viii) Spray the film-coated suspension onto the tablet core from step (vii).

[0225] Screening can be performed mechanically or manually as needed.

[0226] Preferably, the blend from step (vi) is compressed into a tablet core by direct compression.

[0227] equipment

[0228] The container used in step (i) is a metal drum. The powder blend is mixed using a Servolift mixer. The tablet cores are compressed by direct compression using a Korsch XL100 Wipcon rotary tablet press. Film coating is performed using a Glatt GMPC 1 apparatus.

Claims

1. A tablet comprising a core and an optional coating, wherein the core comprises: (i) API 6-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methoxy)-N-(tetrahydropyran-4-yl)pyridazin-3-carboxamide (I), or a pharmaceutically acceptable salt thereof, (I)； (ii) Superdisintegrants; (iii) First filler; (iv) Second filler; (v) Flow aids; and (vi) Lubricant; The amount of API relative to the total weight of the kernel is ≤25% ± 1%, preferably ≤20% ± 1%; and The kernel described therein does not contain lactose.

2. The tablet according to claim 1, wherein... (i) The weight of the API accounts for 2% ± 1% to 20% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 46% ± 1% to 57% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 26% ± 1% to 32% ± 1% of the total weight of the core; (v) The weight of the gliding agent accounts for 2% ± 1% of the total weight of the core; and (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core.

3. The tablet according to claim 1, wherein... (i) The weight of the API accounts for 20% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 46% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 26% ± 1% of the total weight of the core; (v) The weight of the gliding agent accounts for 2% ± 1% of the total weight of the core; and (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core.

4. The tablet according to claim 1 or 2, further comprising: (vii) Sweeteners.

5. The tablet according to claim 4, wherein the sweetener accounts for 0.3% ± 0.1% to 0.5% ± 0.1% of the total weight of the core.

6. The tablet according to claim 4, wherein (i) The weight of the API accounts for 2% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 57% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 32% ± 1% of the total weight of the core; (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core; (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

7. The tablet according to claim 4, wherein (i) The weight of the API accounts for 3% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 57% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 32% ± 1% of the total weight of the core; (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core; (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

8. The tablet according to claim 4, wherein (i) The weight of the API accounts for 8% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 54% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 30% ± 1% of the total weight of the core; (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core; (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

9. The tablet according to claim 4, wherein (i) The weight of the API accounts for 16% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 48% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 27% ± 1% of the total weight of the core; (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core; (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; and (vii) The sweetener accounts for 0.3% ± 0.1% of the total weight of the core.

10. The tablet according to any one of claims 1, 2, 4 and 5, further comprising: (viii) Flavoring agents.

11. The tablet of claim 10, wherein the flavoring agent comprises 1% ± 0.5% of the total weight of the core.

12. The tablet according to claim 10, wherein (i) The weight of the API accounts for 20% ± 1% of the total weight of the kernel; (ii) The super-disintegrating agent accounts for 3% ± 1% of the total weight of the core; (iii) The weight of the first filler accounts for 45% ± 1% of the total weight of the core; (iv) The weight of the second filler accounts for 26% ± 1% of the total weight of the core; (v) The weight of the flow aid accounts for 2% ± 1% of the total weight of the core; (vi) The weight of the lubricant accounts for 3% ± 1% of the total weight of the core; (vii) The sweetener comprises 0.5% ± 0.1% of the total weight of the core; and (viii) The flavoring agent accounts for 1% ± 0.5% of the total weight of the core.

13. The tablet according to any one of claims 1 to 12, wherein: (ii) The superdisintegrant is croscarmellose sodium; (iii) The first filler is isomaltitol; (iv) The second filler is microcrystalline cellulose; (v) The flow aid is colloidal silica; and (vi) The lubricant is sodium stearate fumarate.

14. The tablet according to any one of claims 4 to 12, wherein the sweetener is sucralose.

15. The tablet according to any one of claims 10 to 12, wherein the flavoring agent is a strawberry flavoring agent.

16. The tablet according to any one of claims 1 to 15, wherein the dose strength is 0.5 mg to 375 mg, preferably 2.5 mg to 375 mg, more preferably 3 mg to 200 mg, more preferably 3 mg to 150 mg, more preferably 3 mg to 125 mg, for example 3 mg, 4 mg, 5 mg, 10 mg, 20 mg, 25 mg, or 125 mg.

17. The tablet according to any one of claims 1 to 16, comprising a coating.

18. The tablet of claim 17, wherein the weight of the coating is 3% ± 1% of the weight of the core.

19. The tablet of claim 17 or 18, wherein the coating comprises: (i) Hydroxypropyl methylcellulose; (ii) Lactose monohydrate; (iii) Titanium dioxide; and (iv) Polyethylene glycol 3350.

20. The tablet according to claim 19, wherein: (i) The weight of the hydroxypropyl methylcellulose accounts for 34% ± 1% of the total weight of the coating; (ii) The weight of the lactose monohydrate accounts for 28% ± 1% of the total weight of the coating; (iii) The titanium dioxide accounts for 26% ± 1% of the total weight of the coating; and (iv) The weight of the polyethylene glycol 3350 accounts for 12% ± 1% of the total weight of the coating.

21. The tablet according to any one of claims 1 to 20, wherein the tablet has a disintegration time of <3 minutes in purified water at 37°C.

22. A method for manufacturing a tablet according to any one of claims 1 to 21, comprising: (i) Weigh the API and the first filler and place them in a container and sieve the two components to obtain a blend; (ii) Add the second filler, the superdisintegrant, the flow aid and optional sweetener and / or flavoring agent to the blend from step (i) and sieve all components; (iii) The sieved material from step (ii) is blended to obtain a powder blend; (iv) The lubricant is sieved, added to the powder blend from step (iii), and blended. (v) Sift the material from step (iv); (vi) Blend the sieved material from step (v); (vii) The blend from step (vi) is compressed into a tablet core; as well as (viii) Spray the film-coated suspension onto the tablet core from step (vii).

23. A medicine box comprising: a tablet according to any one of claims 1 to 21, and instructions for using the tablet.

24. The tablet according to any one of claims 1 to 21, which is used as a medicine.

25. A GABA formulation for the treatment or prevention of disease in patients. A A method for treating α5 receptor-related diseases, the method comprising administering to the patient one or more tablets according to any one of claims 1 to 21.

26. The method of claim 25, wherein the application comprises dispersing the one or more tablets in a liquid.

27. The method of claim 26, wherein the liquid is water or an acidic beverage, particularly apple juice.

28. The tablet according to any one of claims 1 to 21, used in the method according to any one of claims 25 to 27.

29. Use of the tablet according to any one of claims 1 to 21 in the method according to any one of claims 25 to 27.

30. A method of administering a tablet according to any one of claims 1 to 21 to a patient, the method comprising dispersing the tablet in an acidic beverage.

31. The method of claim 30, wherein the acidic beverage is apple juice.

32. The present invention as described above.

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