Formulations of AG10

Abstract

The present disclosure provides a high load tablet formulation of AG10, or a pharmaceutically acceptable salt thereof. In some aspects, provided herein are tablet formulations of AG10 or a pharmaceutically acceptable salt thereof comprising at least 40% by weight or more of AG10 and at least one pharmaceutical excipient selected from the group consisting of one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application Serial No. 62 / 765,154, filed August 17, 2018, pursuant to 35 USC §119(e), the entire contents of which are incorporated herein by reference.

[0002] Claims of rights for inventions resulting from federally supported research and development not applicable Refer to the "Sequence List," table, or computer program list appendix submitted on the CD. not applicable Background of the Invention Abnormal protein interactions and aggregation (whether through protein misfolding or overactivation of signaling pathways) are the root cause of many human degenerative diseases. Therefore, targeting protein interactions (PPIs) has therapeutic implications.

[0003] To date, approved PPI inhibitors are protein-based, not small-molecule, inhibitors. For example, therapeutic monoclonal antibodies (mAbs) are used to treat cancer, autoimmune diseases, infectious diseases, and neurodegenerative diseases. Therapeutic monoclonal antibodies are expensive to produce, require injection, and may trigger an immune response in patients. For these reasons, there remains interest in developing small-molecule inhibitors of PPIs.

[0004] 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. When dissociated from its homotetrameric form, the WT TTR dimer can misfold into amyloid monomers. The formation of amyloid-forming monomers has been observed in conjunction with WT TTR and over 100 different variants. Studies have shown that stabilizing the tetrameric form of TTR can inhibit the misfolding of amyloid monomers and subsequent TTR amyloid formation.

[0005] Recent work has identified 3-(3-(3-,3,5-dimethyl-1H-pyrazol-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 has been disclosed in WO 2014 / 100227. Despite the disclosure of this compound, obtaining an improved pharmaceutical formulation that provides increased stability and consistent pharmacokinetic data remains challenging.

[0006] Therefore, there is a need to produce pharmaceutical formulations suitable for administration to humans or other animals. This disclosure addresses these needs and also provides related advantages. Summary of the Invention

[0007] This disclosure provides a high-load tablet 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 is coated with a coating agent.

[0008] Brief description of the attached figures Figure 1 A process flow diagram for preparing the AG10 formulation in Example 2 is shown.

[0009] Figure 2 An image of the AG10 HCl-coated tablets prepared in Example 2 is shown.

[0010] Figure 3 The dissolution image of the AG10 solid tablets described in Example 2 is shown.

[0011] Figure 4 A process flow diagram for preparing the AG10 formulation described in Example 3 is shown.

[0012] Figure 5 The process flow for preparing the aqueous coated suspension formulation or the AG10 formulation described in Example 3 is shown.

[0013] Figure 6 The images shown illustrate that the tablet edges were not eroded after brittleness testing of L018A (high hardness, left) and L018B (medium hardness, right) (33.0% at AG3).

[0014] Figure 7 Images of major edge corrosion of tablets L016 (left) and L017 (right) after brittleness testing are shown (both formulations have 40% AG10 load and maximum hardness).

[0015] Figure 8 A process flow diagram for the 33% AG10 HCl tablets described in Example 4 is provided.

[0016] Figure 9 A process flow diagram for the 66.7% AG10 HCl tablets described in Example 4 is presented.

[0017] Figure 10 Dissolution profiles of 33.3% AG10 HCl tablets after storage at 40°C / 75% relative humidity are shown. T = 0 (hollow triangle); T = 1 month (hollow rhombus); T = 3 months (solid circle); T = 6 months (solid square).

[0018] Figure 11 Dissolution profiles of 66.7% AG10 HCl tablets after storage at 40°C / 75% relative humidity are shown. T = 0 (hollow triangle); T = 3 months (solid circle); T = 6 months (solid square). Detailed Implementation

[0019] Overview This disclosure is based in part on the finding that formulations containing 40% or more AG10 can be successfully formulated into tablets. These tablets are particularly suitable for administration to human and animal subjects because these amounts meet the stability and pharmacokinetic requirements for oral formulations. Other formulations, such as capsules, do not meet these requirements.

[0020] High-load, immediate-release AG10 tablets can be successfully obtained using advanced microcrystalline cellulose. In contrast, tablets with an AG10 content exceeding 33.3% using standard-grade microcrystalline cellulose showed signs of tablet corrosion after brittleness testing and reduced dissolution after prolonged storage.

[0021] definition Unless otherwise specifically indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, any method or material similar to or equivalent to those described herein may be used to practice this invention. For the purposes of this invention, the following terms are defined.

[0022] As used herein, the terms “a,” “an,” or “the” include not only aspects of a single member but also aspects of more than one member. For example, the singular forms of “a,” “an,” or “the” include plural objects unless the context explicitly specifies otherwise. Thus, for example, reference to “a cell” includes multiple such cells, while reference to “a pharmaceutical agent” includes one or more pharmaceutical agents known to those skilled in the art, and so on.

[0023] As used herein, the term "about" refers to a range of values ​​that includes a specified value and that will be reasonably considered by those skilled in the art to be reasonably similar to the specified value. In some embodiments, the term "about" refers to a standard deviation using measurement methods generally acceptable in the art. In some embodiments, about refers to a range extended to + / - 10% of a specific value. In some embodiments, approximately refers to a specific value.

[0024] The term "tablet" refers to a solid pharmaceutical preparation, with or without coating. The term "tablet" also refers to a tablet having one, two, three, or even more layers, wherein each of the above types of tablets may have or not have one or more coatings. In some embodiments, the tablets of this disclosure may be prepared by rolling or other suitable methods known in the art. The term "tablet" also includes micronized, melt-forming, chewable, effervescent, and orally disintegrating tablets. Tablets comprise AG10 and at least one, and a pharmaceutical excipient selected from one or more fillers, one or more binders, one or more disintegrants, and one or more lubricants. Optionally, a coating agent is also included. The amount of coating agent is not included in the calculation of the weight percentage of the tablet. That is, the weight percentages reported herein are the weight percentages of uncoated tablets.

[0025] The term "salt" refers to the acid or basic salt of the compounds disclosed herein. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium compounds (methyl iodide, iodoethane, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

[0026] Implementation of this disclosure This disclosure specifically provides tablets of AG10 or a pharmaceutically acceptable salt thereof. AG10 is a compound of the following formula: .

[0027] In some implementations, a pharmaceutically acceptable salt of AG10 corresponds to Formula I.

[0028] (I), Where X is a pharmaceutically acceptable anion of a protic acid.

[0029] Many protic acids are suitable for preparing pharmaceutically acceptable salts of Formula I. It can be seen that the pharmaceutically acceptable anion of a protic acid depends on the protic acid used. For example, protic acids that can be used in this disclosure include hydrochloric acid, hydrobromic acid, sulfonic acid, toluenesulfonic acid (p-toluenesulfonic acid), methanesulfonic acid, nitric acid, or acetic acid. Therefore, pharmaceutically acceptable anions of protic acids include chloride ions (Cl... - ), bromide ion (Br - ), sulfonate (HS(O)2O - Toluenesulfonate (TsO)- ), mesylate (MsO) - ), nitrate (NO3) - ) and acetate (CHO3) O - (or a combination thereof).

[0030] In some implementations, the pharmaceutically acceptable anion of the protic acid is the mesylate anion.

[0031] In some implementations, the pharmaceutically acceptable anion of the protic acid is toluenesulfonate.

[0032] In some embodiments, the pharmaceutically acceptable anion of the protic acid is chloride, and the pharmaceutically acceptable salt of formula I is represented by formula (Ia). (Ia).

[0033] Pharmaceutically acceptable salts of Formula I can be produced using many conventional methods in the art. For example, the free acid form of a compound of Formula I can be contacted with a stoichiometric amount of a suitable acid in water, an organic solvent, or a mixture of both. In some embodiments, pharmaceutically acceptable salts of Formula I are prepared in a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. In some embodiments, pharmaceutically acceptable salts of Formula I are crystallized by dissolving a compound of Formula IX in water, adding an appropriate amount of HX to form a mixture, and adding a non-aqueous solvent (e.g., the non-aqueous medium described above). In some embodiments, the appropriate amount of HX is a stoichiometric amount. It should be understood that HX includes hydrogen, and X is a pharmaceutically acceptable anion of a protic acid as defined above.

[0034] The tablet formulations disclosed herein may contain, for example, about 40 to 85 or about 50 to 75% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 50% to 70% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 50% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 66.7% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 75% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 80% by weight AG10 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets contain about 85% by weight AG10 or a pharmaceutically acceptable salt thereof.

[0035] The amount of AG10 or its pharmaceutically acceptable salt in the tablet can be from about 0.1 to about 500 mg, from about 0.1 to about 250 mg, or from about 0.1 to about 100 mg. In some embodiments, the amount of AG10 present in the tablet is about 10, 25, 50, 100, 200, 300, 400, or 500 mg. In some embodiments, the amount of AG10 present in the tablet is about 50, 100, 200, or 400 mg. In some embodiments, the total weight of the tablet (e.g., active ingredient plus excipients - excluding coating) 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.

[0036] The tablet formulations disclosed herein may contain 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 tablets contain one or more excipients selected from advanced microcrystalline fillers, inorganic salt fillers, disintegrants, and lubricants.

[0037] In some embodiments, the tablet formulations of this disclosure comprise one or more fillers. Suitable fillers are described below. In some embodiments, the one or more fillers are present in amounts of about 1% to 60%, 5% to 55%, 10% to 50%, or 15% to 45% by weight. In some embodiments, the one or more fillers are present at about 42.5% by weight. In some embodiments, the one or more fillers are present at about 25.8% by weight. In some embodiments, the one or more fillers are present at about 17.5% by weight.

[0038] In some embodiments, the tablet formulations of this disclosure contain 1-3 fillers. In some embodiments, the tablet formulations of this disclosure contain 1-2 fillers. In some embodiments, the tablet formulations of this disclosure contain two fillers.

[0039] Suitable fillers include, for example, oligosaccharides (e.g., lactose), sugars, starches, modified starches, sugar alcohols (e.g., mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, hydroxypropyl methylcellulose), calcium sulfate, complexes and oxides of aluminum silicate and magnesium, etc. Examples of inorganic salt fillers include phosphates, such as dicalcium hydrogen phosphate dehydrated salts, sulfates, and silica. In some embodiments, one or more fillers comprise cellulose derivatives or alkaline earth metal salts of chlorides, phosphates, sulfates, etc. In some embodiments, one or more fillers comprise cellulose derivatives and inorganic salts. In some embodiments, one or more fillers are microcrystalline cellulose and silica. In some embodiments, one or more fillers are microcrystalline cellulose. In some embodiments, the microcrystalline cellulose is a higher type of microcrystalline cellulose.

[0040] High-grade microcrystalline cellulose is a cellulose-derived product with specific properties that are not the primary characteristics of more standard microcrystalline cellulose formulations. For example, in some embodiments, high-grade microcrystalline cellulose is characterized by a cellulose polymer having a spherical morphology and a porous structure. These properties can be found in CEOLUS TM UF-grade microcrystalline cellulose (e.g., UF-702 and UF-711) and similar products are available. In some embodiments, advanced microcrystalline cellulose is characterized by a cellulose polymer having a needle-like particle shape. These properties are found in CEOLUS. TM It is found in KG-grade microcrystalline cellulose (e.g., KG-802 and KG-1000).

[0041] The high-grade cellulose filler may be present in an amount of about 1 to 60% by weight. In some embodiments, the high-grade microcrystalline cellulose is present in an amount of about 5 to 55% by weight. In some embodiments, the high-grade microcrystalline cellulose is present in an amount of about 10 to 50% by weight. In some embodiments, the 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, the high-grade microcrystalline cellulose is present in an amount of about 17%. In some embodiments, the high-grade microcrystalline cellulose is present in an amount of about 26%. In some embodiments, the high-grade microcrystalline cellulose is present in an amount of about 42%.

[0042] In some embodiments, the tablet formulations of this disclosure comprise one or more binders. Suitable binders are described below. In some embodiments, the amount of one or more binders is from about 0.5% to 15%, from about 0.5% to 10%, or from about 1% to 10% by weight. In some embodiments, the amount of one or more binders is from about 3% to 8% by weight. In some embodiments, the amount of one or more binders is from about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% by weight. In some embodiments, the amount of one or more binders is from about 5% by weight.

[0043] In some embodiments, the tablet formulations of this disclosure comprise 1-3 binders. In some embodiments, the tablet formulations of this disclosure comprise one binder.

[0044] Suitable binders include, for example, povidone, lactose, starch, modified starch, sugar, gum arabic, tragacanth gum, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone, gelatin, sodium alginate, etc. Non-cellulose binders include polymer binders lacking a cellulose backbone and other binders. Examples of non-cellulose binders include povidone, lactose, starch, modified starch, gums, guar gum, pectin, waxes, gelatin, alginate, etc. In some embodiments, the formulation comprises a non-cellulose binder, such as povidone or copovidone. In some embodiments, the non-cellulose binder is copovidone.

[0045] In some embodiments, the tablet formulations of this disclosure comprise one or more disintegrants. Suitable disintegrants are described below. In some embodiments, one or more disintegrants are present in amounts 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 amounts of about 3-8% by weight. In some embodiments, the formulation comprises about 3, 4, 5, 6, 7, or 8% by weight of disintegrant. In some embodiments, the formulation comprises about 5% by weight of disintegrant. In some embodiments, the formulation comprises about 6% by weight of disintegrant.

[0046] In some embodiments, the tablet formulations of this disclosure contain 1-3 disintegrants. In some embodiments, the tablet formulations of this disclosure contain only one disintegrant.

[0047] Suitable disintegrants include, for example, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, and corn starch. In some embodiments, the formulation comprises a disintegrant such as sodium glycolate starch or crospovidone. In some embodiments, the disintegrant is croscarmellose sodium.

[0048] In some embodiments, the tablet formulations of this disclosure comprise one or more lubricants. Suitable lubricants are described below. In some embodiments, the amount of one or more lubricants present is from about 0.1% to 8% by weight, 0.5% to 5% by weight, or 0.5% to 3% by weight. In some embodiments, the amount of one or more lubricants present is from 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, the amount of one or more lubricants present is about 1.5% by weight.

[0049] In some embodiments, the tablet formulations of this disclosure contain 1-3 lubricants. In some embodiments, the tablet formulations of this disclosure contain only one lubricant.

[0050] 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 stearate fumarate. In some embodiments, one or more lubricants are magnesium stearate and / or sodium stearate fumarate.

[0051] Other suitable fillers, binders, disintegrants, lubricants and other excipients that may be used are described in *Handbook of Pharmaceutical Excipients*, 2nd ed., American Lachman, Leon, 1976; *Pharmaceutical Dosage Forms: Tablet Volumes*, Vol. 1, 2nd ed., Lieberman, Herbert A. et al., 1989; *Modern Pharmaceutics*, Banker, Gilbert and Rhodes, Christopher T., 1979; and *Remington's Pharmaceutical Sciences*, 15th ed., 1975, each of which is incorporated herein by reference in its entirety.

[0052] In some implementations, the tablets are coated with a coating agent. Suitable coating agents include ethyl cellulose, polymethyl methacrylate, and those derived from OPADRY. TMCoated products for sale. 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 tablet weight percentage. That is, the weight percentage reported herein is the weight percentage of uncoated tablets.

[0053] In some embodiments, the tablet comprises, by weight, about 40% to 85% of AG10 or a pharmaceutically acceptable salt thereof; and about 5% to 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 formulation includes a coating agent.

[0054] In some embodiments, the tablet comprises, by weight, about 50% to 75% of AG10 or a pharmaceutically acceptable salt thereof; and about 10% to 50% by weight of one or more fillers; about 3% to about 8% by weight of one or more disintegrants; and 0.5% to 3% by weight of one or more lubricants. In some embodiments, the formulation includes a coating agent.

[0055] In some embodiments, the tablet formulation comprises, by weight, about 50% 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 formulation includes a coating agent.

[0056] 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 formulation includes a coating agent.

[0057] In some embodiments, the tablet formulation comprises, by weight, about 75% AG10 or a pharmaceutically acceptable salt thereof; about 17.5% 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 formulation includes a coating agent.

[0058] In some embodiments, in apparatus II (paddle method), at 37 ± 0.5 °C and a paddle speed of approximately 50 rpm, after 10 minutes, the tablets of the present invention are at least 75% dissolved in a 0.1 N HCl solution. In some embodiments, in apparatus II (paddle method), at 37 ± 0.5 °C and a paddle speed of approximately 50 rpm, after 10 minutes, the tablets of the present invention are at least 85% dissolved in a 0.1 N HCl solution. In some embodiments, in apparatus II (paddle method), at 37 ± 0.5 °C and a paddle speed of approximately 50 rpm, after 10 minutes, the tablets of the present invention are at least 95% dissolved in a 0.1 N HCl solution. In some embodiments, the tablets tested are prepared within one week of the dissolution test. In some embodiments, the tablets tested are prepared at least one month prior to the dissolution test. In some embodiments, the tablets tested are prepared at least three months prior to the dissolution test. In some embodiments, the tablets tested are prepared at least six months prior to the dissolution test. In some embodiments, the tablets are incubated at 25°C and 60% relative humidity (room temperature) for one month prior to the dissolution test. In some embodiments, the tablets are incubated at 25°C and 60% relative humidity (room temperature) for two months prior to the dissolution test. In some embodiments, the tablets are incubated at 25°C and 60% relative humidity (room temperature) for three months prior to the dissolution test. In some embodiments, the tablets are incubated at 40°C and 75% relative humidity (room temperature) for one month prior to the dissolution test. In some embodiments, the tablets are incubated at 40°C and 75% relative humidity (room temperature) for three months prior to the dissolution test. In some embodiments, the tablets are incubated at 40°C and 75% relative humidity (room temperature) for six months prior to the dissolution test.

[0059] Example The following embodiments are provided to illustrate, but do not limit, the claimed invention.

[0060] Example 1: Evaluation of capsules and tablets; inconsistent oral pharmacokinetic data provided by capsules. The pharmacokinetic characteristics of AG10 were determined in dogs administered once daily at doses of 20, 60, and 200 mg / kg via tube feeding for 3 days (Study No. 1). Each group consisted of two animals / sex / group. Blood samples were collected from animals on day 1 before administration, and at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration, and on day 3 before administration, and at 0.25, 0.5, 1, 2, 2, 4, 8, 12, 24, 48, and 72 hours after administration. AG10 in plasma samples was determined by LCMS / MS. Overall, the mean Cg of AG10 was [data missing]. max Value and AUC0-24 No gender differences were observed in the values. Therefore, the results for the 20 mg / kg dose group are presented as combined gender values ​​in Table 1 below.

[0061] The pharmacokinetic properties of AG10 were also determined in non-juvenile male and female beagle dogs following oral administration (Study No. 2). The study design included three treatment groups (n = 2 / sex / group). Groups 1 and 2 received 5 mg / kg and 20 mg / kg of AG10 in 0.5% methylcellulose (MC) formulations, respectively. Group 3 animals received 20 mg / kg of AG10 in gelatin capsule form. Blood samples were collected before administration and approximately 2, 4, 6, 8, 12, and 24 hours after administration. AG10 in plasma samples was determined by LC-MS / MS. Plasma exposure (AUC) of AG10 in dogs administered 20 mg / kg of AG10 (a suspension prepared in 0.5% methylcellulose) was recorded. 0-24 Similar to Study 1 (Table 1). Plasma exposure to AG10 was also similar in dogs given the same dose in the form of a 0.5% methylcellulose suspension or gelatin capsules without any excipients.

[0062] Four male beagle dogs were orally administered AG10, each with a 50 mg tablet, a 200 mg tablet, and a 200 mg capsule (number 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. AG10 in plasma samples was determined by LC-MS / MS. The C-values ​​of the dogs administered the 200 mg tablet and 200 mg capsule were determined using an unpaired t-test. max and AUC 0-inf The values ​​showed no significant difference (P < 0.05) (C max and AUC 0-inf The p-values ​​were 0.0788 and 0.0995, respectively.

[0063] Table 1: Comparison of pharmacokinetic characteristics of various formulations of AG10 administered orally to dogs via forced feeding. In canine studies comparing AG10 methylcellulose formulations, the time to reach maximum concentration (Tmax) was 0.44 ± 0.38 hr in Study 1 and 2.5 ± 1 hr in Study 2. The capsules in Study 2, which were not formulated with excipients, showed lower variability compared to the methylcellulose comparison formulation (Tmax = 2 ± 0 hours). In Study 3, even though the maximum exposure of AG10 tablets was comparable to that of capsules, there was greater variability in AG10 absorption among the four animals orally administered capsules containing excipients. For the 50 mg tablets, the time to reach maximum concentration (Tmax) was 0.500 ± 0 hours, and for the 200 mg tablets, Tmax was 1.00 ± 0 hours. For the 200 mg capsules containing excipients, Tmax varied more significantly at 1.38 ± 0.750 hr. Therefore, in head-to-head comparisons, tablets produce more consistent oral absorption of AG10.

[0064] Example 2: High-load immediate-release tablet formulation of AG10 The following examples describe a method for successfully preparing tablets containing a large amount of AG10.

[0065] Three tablets containing different amounts of AG10 were prepared. Table 2 provides information on the relative amounts used in each formulation.

[0066] Table 2: High-load AG10 tablet formulation After compression, the tablets are coated with Opadry QX white film.

[0067] use Figure 1 The diagram provided below illustrates the preparation of tablets. Table 3 below provides exemplary amounts of 66.7% AG10 HCl for preparing tablets (second batch), and Tables 4 and 5 provide a list of the equipment used and an overview of the steps for preparing the tablets. Referring to Table 2, a similar process was performed for the preparation of the first and third batches.

[0068] Table 3: High-load AG10 tablet formulation Table 4: Equipment Used Table 5: Program Summary Figure 2The figures show 50% (w / w) and 66.7% (w / w) AG10 HCl coated tablets. The 50% tablets were pressed using an 8 x 17.5 mm capsule die, while the 66.7% tablets were pressed using a 7.5 x 15 mm capsule die. The physical properties of the two types of tablets shown are summarized in Table 6.

[0069] Table 6: Summary of Physical Properties Measurement of fragility: As shown in the table, according to the USP method <1216> The fragility of tablets was assessed by the percentage of weight loss of a 6.5g NLT tablet, tumbled in a crusher (EF-2 type, Electrolab) at 25 rpm for 100 revolutions. The tablets were dusted, and the weight loss due to breakage or abrasion was recorded as a percentage of weight loss. Fragility less than 1% was considered acceptable.

[0070] Next, the dissolution rates of 50% (w / w) and 66.7 (w / w) AG10 HCl-coated tablets were determined. Dissolution tests were conducted by placing the tablets in the 0.1N HCl solution described in Table 7.

[0071] Table 7: Dissolution parameters Figure 3 Dissolution profiles are shown for tablets coated with 50% (w / w) and 66.7% (w / w) AG10 HCl. Dissolution tests were performed after tablet preparation without a significant incubation time. Figure 3 As observed, both tablets dissolved and achieved 100% release within 10 minutes.

[0072] Example 3: During the fragility test, more than 33.3% of the AG10 tablet formulations showed tablet erosion. The following examples describe AG10 tablets in which the drug loading does not exceed 33.3% if there is no tablet erosion in the fragility test.

[0073] The formulation of AG10 is according to Figure 4 and Figure 5 The preparation was carried out according to an overview. The amounts of AG10 and other components are described in Table 8.

[0074] Table 8: Formulation of the prepared AG10 tablets Each of the above reference formulations was prepared as a 200 mg tablet and subjected to a fragility test according to the method of Example 2. L018A and L018B tablets formulated at a drug load of 33.0% (compressed at high and medium hardness kP values, respectively) exhibited shatter resistance, with only slight edge erosion (if any) observed after the fragility test. See also Figure 6 In contrast, L016 and L017, prepared with a 40% drug loading and compressed at the maximum achievable hardness, exhibited primary tablet edge erosion after brittleness testing. See also Figure 7 .

[0075] The formulations discussed above use standard-grade microcrystalline cellulose, and the resulting tablets with an AG10 content greater than 33.0% exhibit fragility issues, impairing their clinical use. In contrast, the formulation of Example 2 uses advanced microcrystalline cellulose, reliably providing tablets with good physical properties and low fragility.

[0076] Example 4: Dissolution testing under "accelerated stability conditions" demonstrated the stability of high-load AG10 tablets. The following examples describe the preparation and subsequent dissolution tests of immediate-release tablets containing 33% AG10 HCl (200 mg) and standard microcrystalline cellulose, and tablets containing 66.7% AG10 HCl (400 mg) and high-purity microcrystalline cellulose.

[0077] The formulations for each tablet are shown in Tables 9 and 10, respectively.

[0078] Table 9. Quantitative Composition of 33% AG10 HCl Tablets a. The actual content of AG10 hydrochloride was adjusted based on the potency of the active pharmaceutical ingredient, equivalent to 177.82 mg of AG10 free base. The actual amount of silanized microcrystalline cellulose was reduced accordingly, keeping the target core weight at 606 mg.

[0079] b. Prosolv HD 90 C. Pearlitol 100SD d. Solutab Type A e. Plasdone S-630 f. Ligamed MF-2-V g. Pure water is used in the film coating process and is removed during processing. h. This indicates a 3% increase in tablet core weight. Opadry White, Colorcon 33G28707 contains hydroxypropyl methylcellulose (Ph. Europe), titanium dioxide (Ph. Europe), and triacetin (Ph. Europe).

[0080] Table 10. Quantitative Composition of 66.7% AG10 HCl Tablets a. The actual content of AG10 hydrochloride was adjusted based on the potency of the active pharmaceutical ingredient, equivalent to 355.64 mg of AG10 free base. The actual dosage of microcrystalline cellulose was based on a concomitant reduction to maintain the target core weight 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. Pure water is used in the film coating process and is removed during processing. g. This indicates a 4% increase in tablet core weight. Opadry QX White, Colorcon 321A180025 contains GMCC Type 1 / glycerol mono- and diglycerides, polyethylene glycol-polyvinyl alcohol graft copolymer, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide.

[0081] Figure 8 and Figure 9 The manufacturing process of two tablets is shown in the image.

[0082] Bottle 33% AG10 HCl tablets and store them under accelerated storage conditions (40°C / 75% relative humidity (RH)). Figure 10 The results showed that storage under accelerated storage conditions significantly reduced the dissolution rate of 33% AG10 HCl tablets.

[0083] The 66.7% AG10 HCl tablets were also bottled and placed under accelerated storage conditions. Figure 11 The results showed that the 400 mg AG10 HCl tablets did not show a decrease in dissolution after 6 months of storage.

[0084] The release and stability of the two formulations of AG10 HCl tablets were evaluated using the same dissolution method (USP 2 instrument (slurry method), 900 mL 0.1 N HCl, 75 RPM, 37 °C). Regarding the rate of dissolution after storage, the 66.7% AG10 HCl tablet was superior to the 33% AG10 HCl tablet, indicating that the 66.7% AG10 HCl tablet has excellent storage capacity.

[0085] Although the foregoing invention has been described in detail by way of illustration and example for clarity of understanding, those skilled in the art will understand that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by reference in its entirety to the same extent as if it were individually incorporated by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A tablet, characterized in that, The tablet comprises AG10 or a pharmaceutically acceptable salt thereof and at least one pharmaceutical excipient selected from the following: one or more fillers, one or more binders, one or more disintegrants and one or more lubricants, wherein the tablet comprises at least 40% by weight or more AG10 or a pharmaceutically acceptable salt thereof.

2. The tablet as described in claim 1, characterized in that, The tablets contain about 40 to 85% by weight of AG10 or a pharmaceutically acceptable salt thereof.

3. The tablet as described in claim 1, characterized in that, The tablets contain about 50 to 75% by weight of AG10 or a pharmaceutically acceptable salt thereof.

4. The tablet as described in claim 1, characterized in that, The tablets contain approximately 50% by weight of AG10 or a pharmaceutically acceptable salt thereof.

5. The tablet as described in claim 1, characterized in that, The tablet contains approximately 66.7% by weight of AG10 or a pharmaceutically acceptable salt thereof.

6. The tablet as claimed in claim 1, characterized in that, The tablets contain approximately 75% by weight of AG10 or a pharmaceutically acceptable salt thereof.

7. The tablet according to any one of claims 1 to 6, characterized in that, The tablet contains about 1 to 60% by weight of one or more fillers.

8. The tablet as claimed in claim 7, characterized in that, The one or more fillers therein comprise about 5 to 55% of the weight of the tablet.

9. The tablet as claimed in claim 7, characterized in that, The one or more fillers therein comprise about 10 to 50% of the weight of the tablet.

10. The tablet as claimed in claim 7, characterized in that, The one or more fillers therein comprise about 15 to 45% of the weight of the tablet.

11. The tablet according to any one of claims 1 to 10, characterized in that, The tablets contain advanced microcrystalline cellulose as a filler component.

12. The tablet as claimed in claim 11, characterized in that, The advanced microcrystalline cellulose is characterized by being a cellulose polymer with a spherical morphology and a porous structure.

13. The tablet as claimed in claim 12, characterized in that, The advanced microcrystalline cellulose is selected from the group consisting of UF-702 and UF-711.

14. The tablet as claimed in claim 11, characterized in that, The advanced microcrystalline cellulose is characterized by having a cellulose polymer with a needle-like particle shape.

15. The tablet as claimed in claim 14, characterized in that, The advanced microcrystalline cellulose is selected from the group consisting of KG-802 and KG-1000.

16. The tablet according to any one of claims 1 to 10, characterized in that, The one or more fillers are selected from cellulose derivatives or inorganic salts.

17. The tablet according to any one of claims 1 to 10, characterized in that, The one or more fillers are microcrystalline cellulose and silicon dioxide.

18. The tablet according to any one of claims 1 to 17, characterized in that, The tablet contains about 1 to about 15% by weight of one or more disintegrants.

19. The tablet as claimed in claim 18, characterized in that, The one or more disintegrants comprise approximately 3% to 8% of the weight of the tablet.

20. The tablet as claimed in claim 18, characterized in that, The one or more disintegrants comprise approximately 6% of the weight of the tablet.

21. The tablet as claimed in any one of claims 18 to 20, characterized in that, One or more disintegrants are croscarmellose sodium.

22. The tablet according to any one of claims 1 to 21, characterized in that, The tablet contains approximately 0.1% to 8% by weight of lubricant.

23. The tablet as claimed in claim 22, characterized in that, The one or more lubricants comprise approximately 1.5% of the weight of the tablet.

24. The tablet as claimed in claim 22 or 23, characterized in that, One or more of the lubricants are magnesium stearate.

25. The tablet according to any one of claims 1 to 24, characterized in that, At 37°C ± 0.5°C, in apparatus II (paddle method), at a paddle speed of approximately 50 rpm, after 10 minutes, the tablets dissolved at least approximately 75% in a 0.1 N HCl solution.

26. The tablet according to any one of claims 1 to 24, characterized in that, At 37°C ± 0.5°C, in apparatus II (paddle method), at a paddle speed of approximately 50 rpm, after 10 minutes, the tablets dissolved at least approximately 85% in a 0.1 N HCl solution.

27. The tablet according to any one of claims 1 to 24, characterized in that, At 37°C ± 0.5°C, in apparatus II (paddle method), at a paddle speed of approximately 50 rpm, after 10 minutes, the tablets dissolved at least approximately 95% in a 0.1 N HCl solution.

28. The tablet as claimed in any one of claims 25 to 27, characterized in that, The tablets are prepared at least three months prior to the dissolution test.

29. The tablet according to any one of claims 1 to 28, characterized in that, The tablet further comprises a coating agent.

30. The tablet as claimed in claim 29, characterized in that, The coating agent is Opadry QX 321A180025.

31. The tablet according to any one of claims 1 to 30, characterized in that, The AG10 is a pharmaceutically acceptable salt form of formula Ia. (It).

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