AG10 formulation

Abstract

This disclosure provides high-load tablet formulations of AG10 or a pharmaceutically acceptable salt thereof. [Solution] In some embodiments, provided herein are tablet formulations of AG10 or a pharmaceutically acceptable salt thereof, comprising at least 40% by weight of AG10 and at least one pharmaceutical excipient selected from one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants.

Description

[Background technology]

[0001] Cross-references to related applications This application claims the benefit of priority under 35 U.S. SC § 119(e) to U.S. Provisional Application No. 62 / 765,154 filed on 17 August 2018, the disclosure thereof is incorporated herein by reference in its entirety.

[0002] Description of rights to inventions made under federal government-sponsored research and development. Not applicable

[0003] References to “sequence listings,” tables, or appendices to computer program listings submitted on compact discs. Not applicable

[0004] Abnormal protein interactions and aggregation, resulting from either protein misfolding or excessive activation of signaling pathways, are underlying causes of numerous human degenerative diseases. Therefore, targeting protein-protein interactions (PPIs) is therapeutically important.

[0005] To date, approved PPI inhibitors are proteins, not small molecule inhibitors. For example, therapeutic monoclonal antibodies (mAbs) are used to treat cancer, autoimmune diseases, infections, and neurodegenerative diseases. Therapeutic mAbs are expensive to manufacture, require administration by injection, and can illicit a patient's immune response. For these reasons, the development of small molecule inhibitors of PPIs remains of interest.

[0006] An example of abnormal protein aggregation is the soluble protein transthyretin (TTR or prealbumin). Wild-type (WT) TTR is a 55 kDa homotetrameric protein found in blood and cerebrospinal fluid. Upon dissociation from the homotetrameric form, the WT TTR dimer can be misfolded into an amyloid-forming monomer. The formation of amyloid-forming monomers has been observed in WT TTR and over 100 different mutant variants. Studies have shown that stabilizing the tetrameric form of TTR inhibits the misfolding of amyloid-forming monomers and subsequent TTR amyloid formation.

[0007] Recent studies have identified 3-(3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy)-4-fluorobenzoic acid (AG10) as a promising candidate for the treatment of TTR amyloid-related diseases, such as TTR amyloid cardiomyopathy and ATTR polyneuropathy. This compound is disclosed in International Publication No. 2014 / 100227. Despite the disclosure of this compound, improved pharmaceutical formulations that provide enhanced stability and consistent pharmacokinetic data remain unclear.

[0008] Therefore, there is a need to manufacture pharmaceutical formulations suitable for administration to humans or other animals. This disclosure addresses these needs and also provides related advantages. [Overview of the Initiative]

[0009] This disclosure provides high-concentration tablet formulations of AG10 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient selected from one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants. In some embodiments, the tablet formulations are coated with a coating agent. [Brief explanation of the drawing]

[0010] [Figure 1] Figure 1 shows a process flow diagram for preparing the AG10 formulation described in Example 2. [Figure 2] Figure 2 shows an image of the AG10 HCl coated tablets prepared in Example 2. [Figure 3] Figure 3 shows the dissolution profile of the AG10 solid tablet formulation described in Example 2. [Figure 4] Figure 4 shows a process flow diagram for preparing the AG10 formulation described in Example 3. [Figure 5] Figure 5 shows the process flow for the preparation of the aqueous coating suspension or the preparation of the AG10 formulation described in Example 3. [Figure 6] Figure 6 shows an "image" illustrating the absence of edge erosion of the tablets after the abrasion test of L018A (high hardness, left) and L018B (medium hardness, right) (with 33.0% AG10). [Figure 7] Figure 7 shows images of the edge erosion of the large tablets after the abrasion test of L016 (left) and L017 (right) (both formulations have a 40% AG10 formulation and maximum hardness). [Figure 8] Figure 8 shows a process flow diagram of the 33% AG10 HCl tablets described in Example 4. [Figure 9] Figure 9 shows a process flow diagram of the 66.7% AG10 HCl tablets described in Example 4. [Figure 10] Figure 10 shows the dissolution profile of the 33.3% AG10 HCl tablets after storage under 40°C / 75%RH conditions. T = 0 (white triangle); T = 1 month (white diamond); T = 3 months (black circle); T = 6 months (black square). [Figure 11] Figure 11 shows the dissolution profile of the 66.7% AG10 HCl tablets after storage under 4°C / 75%RH conditions. T = 0 (white triangle); T = 3 months (black circle); T = 6 months (black square).

Mode for Carrying Out the Invention

[0011] Detailed Description of the Invention I. Overview The present disclosure is based, in part, on the discovery that formulations containing 40% or more of AG10 can be successfully prepared as tablets. These tablets are particularly suitable for administration, regardless of whether the subject is human or animal, because these amounts meet the stability and pharmacokinetic requirements necessary for oral formulations. Other formulations, such as capsules, cannot meet these needs.

[0012] High-dose immediate-release AG10 tablets were successfully achieved using high-grade microcrystalline cellulose. In contrast, tablet formulations containing more than 33.3% AG10 using standard-grade microcrystalline cellulose showed signs of tablet erosion after the abrasion test and a decreased dissolution rate after long-term storage.

[0013] II. Definition Unless otherwise specified, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and shall also be able to be used in the practice of this invention for any method or material similar or equivalent to the methods or materials described herein. For the purposes of this invention, the following terms are defined.

[0014] As used herein, the terms "a," "an," or "the" include embodiments having only one member as well as embodiments having a plurality of members. For example, the singular forms "a," "an," or "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, and reference to "a agent" includes reference to one or more agents known to those of ordinary skill in the art and the like.

[0015] As used herein, the term “about” means a range of values ​​that includes a particular value and which a person skilled in the art would reasonably consider to be similar to that particular value. In some embodiments, the term “about” means within a standard deviation using measurements that are generally accepted in the art. In some embodiments, “about” means a range that extends to + / - 10% of a particular value. In some embodiments, “about” means a particular value.

[0016] The term “tablet” refers to solid pharmaceutical preparations, with or without a coating. The term “tablet” also refers to tablets having one, two, three, or more layers, each of the aforementioned types of tablets having or not having one or more coatings. In some embodiments, tablets of this disclosure can be prepared by roller compression or other preferred means known in the art. The term “tablet” also includes mini tablets, melt tablets, chewable tablets, effervescent tablets, and orally disintegrating tablets. A tablet comprises AG10 and at least one pharmaceutical excipient selected from one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants. Optionally, to calculate the weight percentage of a tablet preparation that also includes a coating, the amount of the coating is not included in the calculation. That is, the weight percentages reported herein are for uncoated tablets.

[0017] The term “salt” refers to an acidic or basic salt of the compounds of this disclosure. Exemplary examples of pharmaceutically acceptable salts include mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). It is understood that pharmaceutically acceptable salts are nontoxic. Additional information regarding preferred pharmaceutically acceptable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0018] III. Embodiments of the Disclosure This disclosure provides, in particular, tablet formulations of AG10 or pharmaceutically acceptable salts thereof. AG10 has the chemical formula:

[0019] [ka]

[0020] It is a compound that has [a certain characteristic].

[0021] In some embodiments, a pharmaceutically acceptable salt of AG10 is chemical formula I

[0022] [ka]

[0023] This corresponds to the following, where X is the pharmaceutically acceptable anion of the protonate.

[0024] Various protonic acids are suitable for forming pharmaceutically acceptable salts of chemical formula I. It is understood that the pharmaceutically acceptable anion of a protonic acid depends on the protonic acid used. For example, protonic acids useful in this disclosure include hydrochloric acid, hydrobromic acid, sulfonic acid, tosylic acid (p-toluenesulfonic acid), methanesulfonic acid, nitric acid, or acetic acid. Thus, the pharmaceutically acceptable anion of a protonic acid is the chloride anion (Cl - ), bromide anion (Br - ), sulfonate anion (HS(O)2O - ), tosylate anion (TsO - ), mesylate anion (MsO - ), nitrate anion (NO3 - ), and acetate anion (CH3C(O)O - ), or combinations thereof.

[0025] In some embodiments, the pharmaceutically acceptable anion of the protonate is the mesylate anion.

[0026] In some embodiments, the pharmaceutically acceptable anion of the protonate is the tosylate anion.

[0027] In some embodiments, the pharmaceutically acceptable anion of the protonic acid is the chloride ion, and the pharmaceutically acceptable salt of chemical formula I is chemical formula (Ia)

[0028] [ka]

[0029] It is represented as follows.

[0030] A pharmaceutically acceptable salt of chemical formula I can be prepared using many conventional means in the art. For example, the free acid form of the compound of chemical formula I may be brought into contact with a stoichiometric amount of a suitable acid, organic solvent, or mixture of the two in water. In some embodiments, a pharmaceutically acceptable salt of chemical formula I is prepared in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In some embodiments, a pharmaceutically acceptable salt of chemical formula I is prepared by dissolving the compound of chemical formula IX in water, adding a suitable amount of HX to form a mixture, and then adding a non-aqueous solvent such as the above-mentioned non-aqueous medium to crystallize the salt. In some embodiments, the suitable amount of HX is a stoichiometric amount. It is understood that HX contains hydrogen and X is a pharmaceutically acceptable anion of the protic acid as defined above.

[0031] The tablet formulations of this disclosure may, for example, contain about 40 to 85% by weight, or about 50 to 75% by weight, of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 50 to 70% by weight of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 50% by weight of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 66.7% by weight of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 75% by weight of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 80% by weight of AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablet formulation contains about 85% by weight of AG10 or a pharmaceutically acceptable salt thereof.

[0032] The amount of AG10 or a pharmaceutically acceptable salt in the tablet formulation may be about 0.1 to about 500 mg, about 0.1 to about 250 mg, or about 0.1 to about 100 mg. In some embodiments, the amount of AG10 present in the tablet formulation is about 10, 25, 50, 100, 200, 300, 400, or 500 mg. In some embodiments, the amount of AG10 present in the tablet formulation is about 50, 100, 200, or 400 mg. In some embodiments, the total weight of the tablet formulation (e.g., excluding the active ingredient and excipients-coatings) is about 50 to about 1500 mg. For example, the total weight of the solid dosage form is about 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, or 1500 mg.

[0033] The tablet formulations of this disclosure may comprise at least one component selected from one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants, or other components. In some embodiments, the tablet formulation comprises one or more excipients selected from high-grade microcrystalline cellulose fillers, inorganic salt fillers, and lubricants.

[0034] In some embodiments, the tablet formulations of the present disclosure include one or more fillers. Preferred fillers are as follows: In some embodiments, one or more fillers are present in an amount of about 1 to 60, 5 to 55, 10 to 50, or 15 to 45% by weight. In some embodiments, one or more fillers are present in an amount of about 42.5% by weight. In some embodiments, one or more fillers are present in an amount of about 25.8% by weight. In some embodiments, one or more fillers are present in an amount of about 17.5% by weight.

[0035] In some embodiments, the tablet formulations of the Disclosure comprise one to three fillers. In some embodiments, the tablet formulations of the Disclosure comprise one to two fillers. In some embodiments, the tablet formulations of the Disclosure comprise two fillers.

[0036] Suitable fillers include, for example, oligosaccharides (e.g., lactose), sugars, starch, modified starch, sugar alcohols (e.g., mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, hypromellose), calcium sulfate, aluminum silicate, and magnesium silicate complexes and oxides. Examples of inorganic salt fillers include phosphates such as dibasic calcium phosphate dehydrate, sulfates, and silicon dioxide. In some embodiments, one or more fillers include cellulose derivatives or alkaline earth metal salts such as chlorides, phosphates, and sulfates. In some embodiments, one or more fillers include cellulose derivatives and inorganic salts. In some embodiments, one or more fillers are microcrystalline cellulose and silicon dioxide. In some embodiments, one or more fillers are microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is high-grade microcrystalline cellulose.

[0037] High-grade microcrystalline cellulose is a cellulose-derived product that possesses specific properties not the primary characteristics of more standard preparations of microcrystalline cellulose. For example, in some embodiments, high-grade microcrystalline cellulose is characterized by cellulose polymers having a spherical morphology and a porous structure. These properties are found in CEOLUS®'s UF-grade microcrystalline cellulose (e.g., UF-702 and UF-711) and similar available products. In some embodiments, high-grade microcrystalline cellulose is characterized by cellulose polymers having a needle-like particle shape. These properties are found in CEOLUS®'s KG-grade microcrystalline cellulose (e.g., KG-802 and KG-1000).

[0038] High-grade cellulose filler may be present in an amount of about 1 to 60% by weight. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 5 to 55% by weight. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 10 to 50% by weight. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 15 to 45% by weight. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45% by weight. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 17%. In some embodiments, high-grade microcrystalline cellulose is present in an amount of about 26%. In some embodiments, high-grade microcrystalline cellulose is present in an amount of approximately 42%.

[0039] In some embodiments, the tablet formulations of the present disclosure include one or more binders. Preferred binders are as follows: In some embodiments, one or more binders are present in an amount of about 0.5 to 15%, about 0.5 to 10%, or about 1 to 10% by weight. In some embodiments, one or more binders are present in an amount of about 3 to 8% by weight. In some embodiments, one or more binders are present in an amount of about 5% by weight.

[0040] In some embodiments, the tablet formulations of the Disclosure comprise one to three binders. In some embodiments, the tablet formulations of the Disclosure comprise one binder.

[0041] Suitable binders include, for example, povidone, lactose, starch, modified starch, sugars, gum arabic, tragacanth gum, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone, gelatin, sodium alginate, etc. Non-cellulose binders include polymers lacking a cellulose backbone and other binders. Examples of non-cellulose binders include povidone, lactose, starch, modified starch, gum, guar gum, pectin, wax, gelatin, alginates, etc. In some embodiments, the formulation includes a non-cellulose binder such as povidone or copovidone. In some embodiments, the non-cellulose binder is copovidone.

[0042] In some embodiments, the tablet formulations of the present disclosure include one or more disintegrants. Preferred disintegrants are as follows: In some embodiments, one or more disintegrants are present in an amount of about 1 to 15, about 1 to about 12, or about 1 to about 10% by weight. In some embodiments, one or more disintegrants are present in an amount of about 3 to 8% by weight. In some embodiments, the formulation includes about 3, 4, 5, 6, 7, or 8% by weight of disintegrants. In some embodiments, the formulation includes about 6% by weight of disintegrants.

[0043] In some embodiments, the tablet formulations of the Disclosure comprise one to three disintegrants. In some embodiments, the tablet formulations of the Disclosure comprise one disintegrant.

[0044] Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, pyrinylpyrrolidone, sodium starch glycolate, and corn starch. In some embodiments, the formulation includes a disintegrant, such as sodium starch glycolate or crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

[0045] In some embodiments, the tablet formulations of the present disclosure include one or more lubricants. Preferred lubricants are as follows: In some embodiments, one or more lubricants are present in an amount of about 0.1 to 8, 0.5 to 5, or 0.5 to 3% by weight. In some embodiments, one or more lubricants are present in an amount of about 0.5, 0.75, 1, 1.5, 2, 3, 4, or 5% by weight. In some embodiments, one or more lubricants are present in an amount of about 2% by weight. In some embodiments, one or more lubricants are present in an amount of about 1.5% by weight.

[0046] In some embodiments, the tablet formulations of the Disclosure comprise one to three lubricants. In some embodiments, the tablet formulations of the Disclosure comprise one lubricant.

[0047] Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and sodium stearyl fumarate. In some embodiments, one or more lubricants are magnesium stearate and / or sodium stearyl fumarate. In some embodiments, one or more lubricants are magnesium stearate.

[0048] Other suitable fillers, disintegrants, lubricants, and other excipients that can be used are described in Handbook of Pharmaceutical Excipients, 2nd Edition, American Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, 2nd Edition, Lieberman, Herbert A., et al, 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 15th Edition, 1975, each of which is incorporated herein by reference in its entirety.

[0049] In some embodiments, the tablets are coated with a coating agent. Suitable coating agents include ethylcellulose, polymethacrylate, and coating products marketed by OPADRY®. In some embodiments, the coating agent is Opadry Clear, Opadry Blue 13B50579, Opadry White 33628707, Opadry QX 321A180025, or Opadry II (33G28707). In some embodiments, the coating agent is Opadry White 33628707. In some embodiments, the coating agent is Opadry QX 321A180025. In some embodiments, the coating agent is Opadry II (33G28707). The amount of coating agent is not included in the calculation of the weight percentage of the tablet formulation. That is, the weight percentages reported herein are for uncoated tablets.

[0050] In some embodiments, the tablet formulation comprises about 40-85% by weight of AG10 or a pharmaceutically acceptable salt thereof; about 5-55% by weight of one or more fillers; about 0-15% by weight of one or more binders; about 1-15% by weight of one or more disintegrants; and about 0.1-8% by weight of one or more lubricants. In some embodiments, the described formulation comprises a coating agent.

[0051] In some embodiments, the tablet formulation comprises about 50% by weight of AG10 or a pharmaceutically acceptable salt thereof; about 42.5% by weight of one or more fillers; about 6% by weight of a disintegrant; and about 1.5% by weight of a lubricant. In some embodiments, the described formulation comprises a coating agent.

[0052] In some embodiments, the tablet formulation comprises about 66.7% by weight of AG10 or a pharmaceutically acceptable salt thereof; about 25.8% by weight of one or more fillers; about 6% by weight of a disintegrant; and about 1.5% by weight of a lubricant. In some embodiments, the described formulation comprises a coating agent.

[0053] In some embodiments, the tablet formulations of the present disclosure are dissolved at least 75% after 10 minutes in a 0.1 N HCl solution at 37 ± 0.5°C in Apparatus II (Paddle) at a paddle speed of about 50 rpm. In some embodiments, the tablet formulations of the present disclosure are dissolved at least 85% after 10 minutes in a 0.1 N HCl solution at 37 ± 0.5°C in Apparatus II (Paddle) at a paddle speed of about 50 rpm. In some embodiments, the tablet formulations of the present disclosure are dissolved at least 95% after 10 minutes in a 0.1 N HCl solution at 37 ± 0.5°C in Apparatus II (Paddle) at a paddle speed of about 50 rpm. In some embodiments, the tablets to be tested were prepared within one week of the dissolution test. In some embodiments, the tablets to be tested were prepared at least one month before the dissolution test was conducted. In some embodiments, the tablets to be tested were prepared at least three months before the dissolution test was conducted. In some embodiments, the tablets to be tested were prepared at least six months prior to the dissolution test. In some embodiments, the tablets were incubated at 25°C for one month at 60% relative humidity (RH) before the dissolution test. In some embodiments, the tablets were incubated at 25°C for two months at 60% relative humidity (RH) before the dissolution test. In some embodiments, the tablets were incubated at 25°C for three months at 60% relative humidity (RH) before the dissolution test. In some embodiments, the tablets were incubated at 40°C for one month at 75% relative humidity (RH) before the dissolution test. In some embodiments, the tablets were incubated at 40°C for three months at 75% relative humidity (RH) before the dissolution test. In some embodiments, the tablets were incubated at 40°C for six months at 75% relative humidity (RH) before the dissolution test. [Examples]

[0054] IV. Examples The following embodiments are provided to illustrate the claimed invention, but are not limited thereto.

[0055] Example 1: Evaluation of capsules and tablets; capsules provide inconsistent oral pharmacokinetic data. The pharmacokinetics of AG10 were measured in dogs following once-daily forced oral administration at 20, 60, and 200 mg / kg for 3 days (Study No. 1). Each group consisted of 2 animals / sex / group. Blood samples were collected from each animal on Day 1 before dosing, at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing, on Day 3 before dosing, and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for AG10 by LC-MS / MS. Generally, no sex differences were observed in the mean C max and AUC 0-24 values. Therefore, the results of the 20 mg / kg dosing group are presented in Table 1 below as the total values by sex.

[0056] The pharmacokinetics of AG10 were also measured after oral administration to non-naive male and female beagle dogs (Study No. 2). The study design included three treatment groups (n = 2 / sex / group). Groups 1 and 2 were administered 5 mg / kg and 20 mg / kg of AG10, respectively, in a 0.5% methylcellulose (MC) formulation. Animals in Group 3 were administered 20 mg / kg of AG10 in gelatin capsules. Blood samples were collected before dosing and at approximately 2, 4, 6, 8, 12, and 24 hours after dosing. Plasma samples were analyzed for AG10 by LC-MS / MS. The plasma exposure (AUC 0-24 ) of AG10 in dogs administered 20 mg / kg of AG10 as a suspension in 0.5% methylcellulose was similar to that obtained in Study No. 1 (Table 1). The plasma exposure of AG10 was similar in dogs administered the same dose as either a suspension in 0.5% methylcellulose or gelatin capsules without excipients.

[0057] AG10 was orally administered to four male beagle dogs as 50 mg tablets, 200 mg tablets, and 200 mg capsules (No. 3). Blood samples were collected before administration and approximately 0.25, 0.5, 1, 2, 4, 8, 24, 48, 72, and 96 hours after administration. Plasma samples were analyzed for AG10 by LC-MS / MS. C10 was analyzed in dogs administered 200 mg tablets and 200 mg capsules. max and AUC 0-inf The values ​​did not show significant differences as determined by an unpaired t-test (P<0.05) (each C max and AUC 0-inf The p-values ​​are 0.0788 and 0.0995.

[0058] [Table 1]

[0059] In a dog study comparing methylcellulose formulations of AG10, the time to maximum concentration (Tmax) was 0.44 ± 0.38 hours in Study No. 1 and 2.5 ± 1 hour in Study No. 2. The capsules in Study No. 2 were formulated without excipients and showed less variability than the methylcellulose control (Tmax = 2 ± 0 hours). In Study No. 3, the maximum exposure of AG10 tablets was comparable to the maximum exposure of capsules, but the inter-animal variability in AG10 absorption was greater in the four animals orally administered capsules containing excipients. For the 50 mg tablet, the time to maximum concentration (Tmax) was 0.500 ± 0 hours, and for the 200 mg tablet, Tmax was 1.00 ± 0 hours. For the 200 mg capsule containing excipients, Tmax was more variable at 1.38 ± 0.750 hours. Therefore, in a direct comparison, tablets resulted in more consistent oral absorption of AG10.

[0060] Example 2: High-concentration immediate-release AG10 tablet formulation The following examples illustrate successful formulations of tablet formulations with a high AG10 content.

[0061] Tablet formulations containing different amounts of AG10 were prepared. Tablet 2 provides information on the relative amounts of the components used in each formulation.

[0062] [Table 2]

[0063] After compression, the tablets were coated with Opadry QX White.

[0064] The tablets were prepared using the general diagram provided in Figure 1. Table 3 below provides exemplary amounts used in the formulation of a tablet formulation containing 66.7% AG10 HCl (Batch 2), and Tables 4 and 5 provide a list of the equipment used and an overview of the steps performed to prepare the tablet formulation. Similar processes were performed when preparing Batch 1 and Batch 3, which are referenced in Table 2.

[0065] [Table 3]

[0066] [Table 4]

[0067] [Table 5-1] [Table 5-2]

[0068] Photographs of 50% (w / w) and 66.7% (w / w) AG10 HCl coated tablets are shown in Figure 2. The 50% tablets were compressed using an 8 × 17.5 mm capsule-shaped tool, and the 66.7% tablets were compressed using a 7.5 × 15 mm capsule-shaped tool. The physical properties of the two tablets shown are summarized in Table 6.

[0069] [Table 6]

[0070] Measurement of wear degree: As reported in Table 6, the degree of tablet abrasion is determined by the United States Pharmacopeia method. <1216> Accordingly, the weight loss rate of 6.5 g of tablets disintegrated in an abrasion tester (Model EF-2, Electrolab) at 25 rpm for 100 rounds was evaluated. The tablets were dusted, and the weight loss caused by crushing or abrasion was recorded as the weight loss rate. Abrasion of less than 1% was considered acceptable.

[0071] Next, the dissolution profiles of 50% (w / w) and 66.7% (w / w) AG10 HCl-coated tablets were determined. Dissolution experiments were performed by placing the tablet formulations in the 0.1 N HCl solution described in Table 7.

[0072] [Table 7]

[0073] Figure 3 shows the dissolution profiles of 50% (w / w) and 66.7% (w / w) AG10 HCl coated tablets. Dissolution experiments were performed after the tablets were formulated, without any significant incubation time. As seen in Figure 3, dissolution was 100% released within 10 minutes for both tablets.

[0074] Example 3: Tablet formulations with AG10 content exceeding 33.3% showed tablet erosion during the abrasion test. The following example describes an AG10 tablet formulation that failed to exceed a drug filling rate of 33.3% without undergoing tablet erosion during abrasion testing.

[0075] The AG10 formulations were prepared as generally outlined in Figures 4 and 5. The amounts of AG10 and other components are shown in the areas in Table 8.

[0076] [Table 8]

[0077] Each of the above formulations was prepared as a 200 mg tablet and subjected to abrasion testing as described in Example 2. Tablets L018A and L018B, prepared with a 33.0% drug fill density (and compressed to high and medium hardness kP values, respectively), were resistant to disintegration, with only slight erosion (if any) of the tablet edges after abrasion testing. See Figure 6. In comparison, L016 and L017, prepared with a 40% drug fill density and compressed to the maximum achievable hardness, showed significant tablet edge erosion after abrasion testing. See Figure 7.

[0078] The above formulation used standard-grade microcrystalline cellulose, and the resulting tablets, containing more than 33.0% AG10, had abrasion issues that impaired clinical use. In comparison, the formulation of Example 2 used high-grade microcrystalline cellulose, possessed desirable physical properties, and reliably provided tablets that were less prone to disintegration.

[0079] Example 4: Dissolution test under "accelerated stability conditions" demonstrates the stability of a high-concentration AG10 tablet formulation. The following examples describe the preparation of an immediate-release tablet formulation containing 33% AG10 HCl (200 mg) with standard microcrystalline cellulose, and a tablet formulation containing 66.7% AG10 HCl (400 mg) with high-grade microcrystalline cellulose, as well as subsequent dissolution tests.

[0080] The formulations for each tablet are shown in Tables 9 and 10.

[0081] [Table 9] a. The actual amount of AG10 hydrochloride is adjusted based on the potency of the active pharmaceutical ingredient and corresponds to 177.82 mg of AG10 free base. The actual amount of silicified microcrystalline cellulose is based on concomitant reduction so that the core weight remains at 606 mg. b. Prosolv HD 90 d. Solutab type A e. Plasdone S-630 f. Ligamed MF-2-V g. Purified water is used in the film coating process and is removed during the process. h. This represents a 3% weight increase in the tablet core. Opadry White, Colorcon 33G28707 contains hypromellose (European Pharmacopoeia), titanium dioxide (European Pharmacopoeia), and triacetin (European Pharmacopoeia).

[0082] [Table 10] a. The actual amount of AG10 hydrochloride is adjusted based on the potency of the active pharmaceutical ingredient and corresponds to 355.64 mg of AG10 free base. The actual amount of microcrystalline cellulose is based on concomitant reduction so that the core weight remains at 600 mg. b. Ceolus UF-711 or equivalent c. Ac-Di-Sol SD711 or equivalent d. Syloid 244 FP or equivalent e. Hyqual 5712, Ligamed MF-2-K, or equivalent. f. Purified water is used in the film coating process and is removed during the process. g.This represents a 4% weight increase in the tablet core. Opadry QX White, Colorcon 321A180025 contains GMCC type 1 / monoglycerides and diglycerides, polyethylene glycol polyvinyl alcohol graft copolymer, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

[0083] The manufacturing processes for the two tablet formulations are shown in Figures 8 and 9.

[0084] 33% AG10 HCl tablets were bottled and placed under accelerated storage conditions (40°C / 75% relative humidity (RH)). Figure 10 shows that storage under accelerated storage conditions significantly reduced the dissolution rate of the 33% AG10 HCl tablets.

[0085] 66.7% AG10 HCl tablets were bottled and placed under accelerated storage conditions. Figure 11 shows that 400 mg AG10 HCl tablets did not show a decrease in dissolution rate after 6 months of storage.

[0086] Both formulations of AG10 HCl tablets were evaluated for release and stability using the same dissolution method (USP 2 apparatus (paddle), 900 mL 0.1 N HCl, 75 RPM, 37°C). The 66.7% AG10 HCl tablet formulation performed better than the 33% AG10 HCl tablet formulation in terms of dissolution rate after storage, indicating that the 66.7% AG10 HCl tablets have improved storage capacity.

[0087] While the aforementioned inventions have been described in some detail as examples and illustrations to clarify their understanding, those skilled in the art will understand that certain changes and modifications may be implemented within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference to the same extent as if each reference were incorporated individually by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. a. 400 mg of 3-(3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy)-4-fluorobenzoate; and High-grade microcrystalline cellulose in amounts of 1% to 60% by weight, consisting of UF-702, UF-711, KG-802, KG-1000, or a combination thereof. Tablets containing; and b. Optionally, a coating agent A pharmaceutical preparation containing [ingredient name], with a total tablet weight of 470 mg to 1000 mg.

2. The pharmaceutical formulation according to claim 1, wherein the tablet contains 5% to 55% by weight of high-grade microcrystalline cellulose.

3. The pharmaceutical formulation according to claim 1, wherein the tablet contains 10% to 50% by weight of high-grade microcrystalline cellulose.

4. The pharmaceutical formulation according to claim 1, wherein the tablet contains 15% to 45% by weight of high-grade microcrystalline cellulose.

5. The pharmaceutical formulation according to claim 1, wherein the tablet contains 26% by weight of high-grade microcrystalline cellulose.

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the total weight of the tablets is 533 mg to 800 mg.

7. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the total weight of the tablets is 600 mg.

8. The aforementioned tablets are as follows: 400 mg of 3-(3-(3,5-dimethyl-1H-pyrazole-4-yl)propoxy)-4-fluorobenzoate; 153.5 mg of high-grade microcrystalline cellulose; 36 mg of croscarmellose sodium 1.5 mg of silicon dioxide; and 9 mg magnesium stearate A pharmaceutical preparation according to claim 7, including the above.

9. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the pharmaceutical formulation is dissolved by at least 75% after a dissolution test is performed for 10 minutes in a 0.1 N HCl solution at 37 ± 0.5 °C using a device II (paddle) having a paddle speed of 50 rpm.

10. The pharmaceutical preparation according to claim 9, wherein the dissolution test is performed at least three months after the preparation of the pharmaceutical preparation.

11. The pharmaceutical preparation according to claim 9, wherein the dissolution test is performed at least six months after the preparation of the pharmaceutical preparation.

12. The pharmaceutical formulation according to any one of claims 1 to 8, wherein the pharmaceutical formulation is dissolved by at least 75% after a dissolution test is performed for 10 minutes in 900 mL of 0.1 N HCl solution at 37 ± 0.5 °C in a device II (paddle) having a paddle speed of 75 rpm.

13. The pharmaceutical preparation according to claim 12, wherein the dissolution test is performed at least three months after the preparation of the pharmaceutical preparation.

14. The pharmaceutical preparation according to claim 12, wherein the dissolution test is performed at least six months after the preparation of the pharmaceutical preparation.

15. The pharmaceutical preparation according to any one of claims 1 to 14, wherein the coating agent is present in an amount of 4% by weight of the tablet.

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