Pharmaceutical preparations

Abstract

The pharmacokinetic profile of the SGLT2 inhibitor bexagliflozin can be improved by formulating it as an extended-release tablet. Compared to standard immediate-release dosage forms, these tablets achieve a shorter peak plasma concentration C while maintaining therapeutic plasma concentrations for the desired period. max This can be used, for example, to administer lower doses while still providing the same pharmacological effect.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to International Application PCT / CN2020 / 119816, filed on 5 October 2020, which is incorporated in its entirety by reference for all purposes.

[0002] The present invention provides pharmaceutical formulations of SGLT2 inhibitors useful for treating diabetes mellitus and other conditions, particularly an oral formulation of bexagliflozin having improved pharmacokinetic properties. [Background technology]

[0003] Bexagliflozin (EGT0001442, EGT1442, THR1442, THR0001442) is an SGLT2 (renal Na+ / glucose transporter) inhibitor useful in the treatment and management of various conditions, including diabetes (see Zhang et al. (2011) Pharmacol Res 63(4):284-93; Allegretti et al. (2019) Am J Kidney Dis. 74:328 doi:10.1053 / j.ajkd.2019.03.417; Zhang et al. (2019) Xenobiotica doi:10.1080 / 00498254.2019.1654634). This has been tested in humans in oral solid dosage form (see, e.g., NCT01377844 or NCT01029704) and oral solution form, and has been shown to be well-tolerated and to result in sustained and clinically significant improvements in glycemic control, as well as reductions in weight and blood pressure in diabetic adults (Halvorsen et al. (2019) Diabetes Obes Metab doi:10.1111 / dom.13833, Halvorsen et al. (2019) Diabetes Obes Metab 21:2248 doi:10.1111 / dom.13801). [Overview of the project]

[0004] Studies in human subjects in which bexagliflozin was administered in the form of an oral capsule or oral solution have shown a high peak / trough ratio (C min relative to C max and C 24h relative to C max both) of bexagliflozin plasma concentration and a rapid decline in the alpha phase. The inventors have found that a better pharmacokinetic profile can be achieved by formulating bexagliflozin as a sustained-release tablet. Compared to standard immediate-release dosage forms, these tablets allow for lower-dose administration (lower peak plasma concentration C max ) while providing the same pharmacological effect and can reduce the likelihood of side effects at any given dose. Adverse drug reactions, particularly rare reactions that are difficult to predict (often not detected during pre-approval testing of new drugs but which, if discovered, can lead to restrictions or withdrawal of approved pharmaceuticals), are more likely to occur with pharmaceuticals that require administration at high doses, and it is well known in the art that the likelihood of adverse reactions generally increases with increasing C max . Thus, in a first aspect, the present invention provides a sustained-release tablet of bexagliflozin.

[0005] Particularly preferred tablets of the first aspect release bexagliflozin in vivo to provide a plasma C max that is at least 125,000 times lower per milliliter than the total bexagliflozin content of the tablet in a fasting subject. Thus, for example, a tablet containing 20 mg of bexagliflozin provides a fasting C max of 160 ng / mL or less. Ideally, the plasma C max is at least 135,000 times lower (i.e., 148 ng / mL or less for a 20 mg bexagliflozin-containing tablet) or at least 145,000 times lower (i.e., 138 ng / mL or less for a 20 mg tablet) than the bexagliflozin content.

[0006] According to a second aspect, the present invention comprises 10 mg to 20 mg of bexagliflozin, and in a fasted subject, the in vivo plasma C2 concentration is 160 ng / mL or less. max We provide sustained-release tablets that provide C max The concentration is 133 ng / mL or less. In one embodiment, the tablet contains 10 mg of bexagliflozin, and C max The concentration is 80 ng / mL or less. In another embodiment, the tablet contains 20 mg of bexagliflozin, C max The concentration is 160 ng / mL or less.

[0007] According to a third aspect, the present invention comprises 30 mg to 60 mg of bexagliflozin and provides in vivo plasma C2 with a concentration of less than 400 ng / mL in fasted subjects. max The present invention provides sustained-release tablets that provide plasma C. In one embodiment, the tablet contains 40 mg of bexagliflozin and plasma C. max It is less than 320 ng / mL. In another embodiment, the tablet contains 50 mg of bexagliflozin and plasma C max The level is less than 400 ng / mL.

[0008] In both the first and second embodiments, the preferred tablet contains 20 mg of bexagliflozin and has an AUC of 600-1200 ng·h / mL in fasted subjects. 0-t The following is provided: Similarly, preferred tablets contain 20 mg of bexagliflozin and have an AUC of 675-1275 ng·h / mL in fasted subjects. 0-∞ To provide.

[0009] In both the first and second embodiments, the preferred tablet contains 20 mg of bexagliflozin and 80-150 ng / mL of plasma C in fasted subjects. max To provide.

[0010] In the first, second, and third embodiments, the preferred tablet has a bexagliflozin plasma concentration of 5 ng / mL or more, ideally 10 ng / mL or more, 24 hours after administration (i.e., C 24h ) provides.

[0011] In the first, second, and third embodiments, the preferred tablet is the time to reach the peak plasma concentration of bexagliflozin (i.e., T), which is 2 to 6 hours, ideally 2 to 4.5 hours, in fasted subjects. max ) provides.

[0012] As will be explained in more detail below, the properties defined for a tablet are typically measured after administration of a representative specimen of the batch in which the tablet is the model, and an appropriate mean (e.g., geometric mean) of the results is calculated. With this in mind, a batch of tablets according to the first embodiment releases bexagliflozin in vivo, resulting in a geometric mean plasma C content in fasted subjects that is at least 125,000 times lower per milliliter than the total bexagliflozin content of each tablet. max It may provide the following. Similarly, a batch of tablets according to the second embodiment provides in vivo geometric mean plasma C13 160 ng / mL or less in fasted subjects. max (For example, geometric mean C) max It may provide a geometric mean C of ≤133 ng / mL. For example, a tablet containing 10 mg of bexagliflozin may have a geometric mean C of ≤80 ng / mL. max It provides, or contains 20 mg of bexagliflozin and a geometric mean C of 160 ng / mL or less. max It may provide the following. Similarly, a batch of tablets according to the third embodiment provides less than 400 ng / mL of in vivo geometric mean plasma C in fasted subjects. max It may provide: For example, a tablet containing 40 mg of bexagliflozin and a geometric mean plasma C content of less than 320 ng / mL. max Provides or contains 50 mg bexagliflozin and geometric mean plasma C less than 400 ng / mL max It may provide the following. Furthermore, batches of tablets of the first and second embodiments containing 20 mg of bexagliflozin in fasted subjects (i) a geometric mean AUC of 600-1200 ng·h / mL 0-t , and / or (ii) geometric mean AUC of 675-1275 ng·h / mL 0-∞ , and / or (iii) geometric mean plasma C of 80-150 ng / mL maxThis may provide. Similarly, in the first, second, and third embodiments, the batch of tablets has a geometric mean C of 5 ng / mL or more, ideally 10 ng / mL or more. 24h It can provide.

[0013] In the batches of tablets according to the first, second, and third embodiments, bexagliflozin plasma C max Value and C min The median ratio of the values ​​can be less than 10, for example, 5-10, 6-8, or 7-8. Therefore, the high peak / trough ratio seen in prior art can be avoided. At least 10 ng / mL of C min The median value is preferred. As shown below, these pharmacokinetic parameters represent robust statistical estimates based on measurements from over 800 subjects in various regions of the world using a variety of different sustained-release bexagliflozin tablets.

[0014] The inventors also observed that bexagliflozin is a P-gp substrate and that the absorption of bexagliflozin from the large intestine is minimized. Since P-gp expression increases with distance along the small intestine, absorption is likely to be greater in the duodenum than in the ileum, [ 14 Quantitative mass balance studies using [13C]-bexagliflozin have shown minimal absorption in the colon (Zhang et al. Xenobiotica. 2019 Aug 27:1-11. doi:10.1080 / 00498254.2019.1654634). Due to the potential practical imperfections of using sustained-release tablets while aiming for most drug release to occur highly in the small intestine, the tablets of the present invention include a gastric retention fit that can advantageously help them to be retained in the stomach. Thus, most of the sustained release of bexagliflozin can occur in the stomach, allowing drug absorption to occur at a desired location in the small intestine, thereby providing a favorable pharmacokinetic profile. Despite bexagliflozin being unstable in the prolonged presence of acid and susceptible to acid degradation, tablets with a gastric retention fit have been shown to function well in vivo.

[0015] Various adaptations may be used to help the tablets of the present invention stay in the stomach, including but not limited to: (i) including an effervescent excipient that can provide buoyancy during gas release in gastric acid; (ii) preventing the complete tablet from being expelled from the stomach in a single event by rapid gastric dispersion into multiple granules or pellets; (iii) using a low-density excipient to provide a buoyant or floating tablet; and / or (iv) including a mucosal adhesive in the tablet. These four approaches can be used individually or in combination to provide a tablet that is advantageous for the delivery of bexagliflozin.

[0016] According to a fourth aspect, the present invention provides a sustained-release tablet comprising bexagliflozin and a mucosal adhesive. Ideally, the tablet has a density lower than that of gastric contents. It can also be effervescent (especially when in contact with gastric acid) and / or disperse into a plurality of granules or pellets when in contact with gastric acid.

[0017] According to a fifth aspect, the present invention provides a solid oral dosage form, typically a sustained-release tablet, comprising bexagliflozin, which, in an in vitro dissolution test in simulated gastric juice (see below), releases 17% or less of the bexagliflozin after 1 hour and 80% or more after 8 hours. In one embodiment, this releases 20-45% (including both ends) of the bexagliflozin after 3 hours and / or 45-75% (including both ends) of the bexagliflozin after 5 hours. This tablet may be from a manufacturing batch of tablets that meet the formal dissolution pass / fail criteria discussed below.

[0018] According to a sixth aspect, the present invention provides a solid oral dosage form, typically a sustained-release tablet, comprising bexagliflozin, having an f² value > 50 when compared to a reference tablet in an in vitro dissolution test in simulated gastric juice (see below), where f² is proportional to the decimal logarithm of 1 plus the mean squared error:

number

[0019] In the formula, n is the number of time points at which elution is measured, and R i is the dissolution rate of the reference tablet at time i, and T i This represents the dissolution rate of the solid oral dosage form at the i-th time point.

[0020] The reference tablet is a sustained-release tablet containing bexagliflozin, which, in an in vitro dissolution test in simulated gastric juice, releases 17% or less of its bexagliflozin in 1 hour, 80% or more in 8 hours, optionally releasing 20-45% (including both ends) of its bexagliflozin in 3 hours, and / or 45-75% (including both ends) of its bexagliflozin in 5 hours. Three preferred reference tablets are disclosed below in more detail as reference tablets (a) to (c), with tablet (c) being preferred. The value of n is preferably at least 3, for example 4-8.

[0021] According to a seventh aspect, the present invention relates to a batch of bexagliflozin sustained-release tablets, in which, when administered to a cohort of healthy, fasting subjects, a first representative sample set of tablets from the batch is, in some cases, C max The first mean logarithm and AUC 0-t It provides the first mean logarithm, and a second representative sample of tablets from the batch, in another case, C max The second mean logarithm and AUC 0-t This produces the second mean logarithm of C max The difference between the first and second mean logarithms and AUC 0-t The batch is provided such that the difference between the first and second mean logarithms both exhibit a 90% confidence interval with endpoints ranging from -0.22314 to +0.22314. Further details regarding the evaluation of these parameters are described in the "Bioequivalence" section below, e.g., the use of randomized crossover trials in a suitable test population. Ideally, each tablet in the batch contains 5 mg, 10 mg, or 20 mg of bexagliflozin.

[0022] According to the eighth aspect, the present invention relates to a batch of bexagliflozin sustained-release tablets, in which, when administered to a cohort of healthy subjects, each subject is provided, in one case, with one tablet from a first representative tablet sample set in a fasted state, and in another case, with one tablet from a second representative tablet sample set in a fed state (e.g., 30 minutes after a standard high-fat, high-calorie meal, as described in the "Bioequivalence" section below and the references therein), ln(C max ) and ln(AUC 0-t ) average difference (C in feeding state max The logarithm and AUC 0-t From the logarithm of C in a fasting state max The logarithm and AUC 0-t The results (generated by subtracting the logarithm of ) both provide a batch that shows a 90% confidence interval with endpoints between -0.22314 and +0.58779. Ideally, each tablet in the batch contains 5 mg, 10 mg, or 20 mg of bexagliflozin.

[0023] According to the ninth aspect, the present invention relates to a batch of bexagliflozin sustained-release tablets, in which, when administered to a cohort of fasted healthy subjects, each provides, in some cases, one tablet from a first representative tablet sample set without any prior administration of parenteral GLP-1 receptor agonist, and in other cases, one tablet from a second representative tablet sample set 30 minutes after an approved dose of parenteral GLP-1 receptor agonist, ln(C max ) and ln(AUC 0-t ) mean difference (C of the second sample set max The logarithm and AUC 0-t From the logarithm of C in the first sample set max The logarithm and AUC 0-t The batch is provided such that both (generated by subtracting the logarithm of ) show a 90% confidence interval with an upper limit of 0.69315. Ideally, each tablet in the batch contains 5 mg, 10 mg, or 20 mg of bexagliflozin.

[0024] According to a tenth aspect, the present invention relates to a batch of bexagliflozin sustained-release tablets, in which, when administered to a cohort of healthy subjects, each subject is provided with, in some cases, one tablet from a first representative tablet sample set in a fasted state, and in other cases, one tablet from a second representative tablet sample set in a fed state (e.g., 30 minutes after a standard high-fat, high-calorie meal, as described in the "Bioequivalence" section below), and in a fed state max From the values, T is in a fasting state. max The batch is provided in which the difference generated by subtracting the values ​​is less than or equal to 3.5 hours, resulting in a median. The median difference is the difference when 50% of the subjects have a value above the median and 50% of the subjects have a value below the median. For example, in an ordered list of differences, for an odd number of subjects (e.g., 2n+1 subjects), the median is the difference for the subjects at the midpoint of the list (n+1 subject), and for an even number of subjects (e.g., 2n subjects), the median is the arithmetic mean of the differences for two adjacent subjects at the midpoint (n and n+1 subjects). Ideally, each tablet in the batch contains 5 mg, 10 mg, or 20 mg of bexagliflozin.

[0025] According to the eleventh aspect, the present invention comprises bexagliflozin and provides a first plasma C to a fasted subject. max , the first AUC 0-t , and the first T max Provides a second plasma C in subjects with a feeding status. max , second AUC 0-t , and the second T max A solid oral dosage form, typically a sustained-release tablet, is provided, (i) a second C max to the first C max The ratio obtained by dividing by is 0.8 to 1.8, and (ii) the second AUC 0-t to the first AUC 0-t The ratio obtained by dividing by is 0.8 to 1.8, or (iii) the second T max to the first T max The present invention provides a solid oral dosage form in which the ratio obtained by dividing by is 0.8 to 3.0.

[0026] As described below, the properties defined for such tablets are typically measured after administering a representative sample of the batch for which the tablet is an example. Thus, a batch of tablets of the eleventh aspect provides a first geometric mean plasma C max , a first geometric mean AUC 0-t , and a first T max median value, and provides a second geometric mean plasma C max , a second geometric mean AUC 0-t , and a second T max median value in a fed subject, and (i) the ratio of the second geometric mean C max divided by the first geometric mean C max is 0.8 to 1.8, (ii) the ratio of the second geometric mean AUC 0-t divided by the first geometric mean AUC 0-t is 0.8 to 1.8, or (iii) the ratio of the second T max median value divided by the first T max median value is 0.8 to 3.0.

[0027] According to the twelfth aspect, the present invention provides a first plasma C max , a first AUC 0-t , and a first T max in a subject who has not previously been administered a parenteral GLP-1 receptor agonist and contains bexagliflozin, and a second plasma C max , a second AUC 0-t , and a second T max in a subject who has previously been administered a parenteral GLP-1 receptor agonist, and is a solid oral dosage form, typically a sustained-release tablet, and (i) the ratio of the second plasma C max divided by the first plasma C max is 0.8 to 2.0, (ii) the ratio of the second AUC 0-t divided by the first AUC 0-t is 0.8 to 2.0, or (iii) the ratio of the second T max divided by the first T max is 0.8 to 3.0.

[0028] As described below, the characteristics defined for such tablets are typically measured after administration of a representative specimen of the batch for which the tablet is an example. Thus, the batch of tablets of the twelfth aspect provides the first geometric mean plasma C max , the first geometric mean AUC 0-t , and the first T max median value, and the second geometric mean plasma C max , the second geometric mean AUC 0-t and the second T max median value in a subject previously administered a parenteral GLP-1 receptor agonist, where (i) the ratio of the second geometric mean plasma C max to the first geometric mean C max is 0.8 to 2.0, (ii) the ratio of the second geometric mean AUC 0-t to the first geometric mean AUC 0-t is 0.8 to 2.0, or (iii) the ratio of the second T max median value to the first T max median value is 0.8 to 3.0.

[0029] The present invention also provides a method for treating a patient, as discussed in more detail below.

Brief Description of the Drawings

[0030] [Figure 1] Figure 1 shows the geometric mean plasma concentration (ng / mL) of bexagliflozin in fasted subjects as a function of time (h) after administration. Filled circles (●) represent data for the 20 mg capsule formulation, and the other symbols represent data for the 15 mg tablets XR5 (▼), XR8 (△), or XR11 (○).

[0031] [Figure 2] Figure 2 shows the geometric mean plasma concentration (ng / mL) of bexagliflozin in fasted subjects who ingested tablets of 10 mg (●), 15 mg (○), or 30 mg (▼).

[0032] [Figure 3] Figure 3 shows the percentage (vertical axis) of bexagliflozin released after 1 hour (◆), 3 hours (■), 5 hours (▲), or 8 hours (×) in the in vitro dissolution test. The tablets were stored at 25°C (Figure 3A) or 30°C (Figure 3B) for up to 60 months (horizontal axis). The graph shows the measured mean values ​​as a regression line. [Modes for carrying out the invention]

[0033] The present invention provides a sustained-release tablet formulation that offers improved pharmacokinetic properties of bexagliflozin compared to capsule formulations.

[0034] Bexagliflozin Bexagliflozin is a C-arylglucoside SGLT2 inhibitor, and its formula is (I): [ka] It holds.

[0035] Its IUPAC name is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol. Its CAS registry number is 1118567-05-7.

[0036] The tablets of the present invention typically contain bexagliflozin in the form of a crystalline solid (see, for example, WO2011 / 153953). In some embodiments, bexagliflozin may exist in the form of an ester (mono, di, tri, or tetra), but typically bexagliflozin is used as the tetraol of formula (I) as shown above. Furthermore, in some embodiments, bexagliflozin may exist in the form of a cocrystal, for example, as a cocrystal with proline, such as "THR1474" (bexagliflozin:proline in a molar ratio of 1:2) disclosed in WO2010 / 022313. These forms of bexagliflozin may optionally exist as solvates in the tablets of the present invention. The present invention encompasses all such forms of bexagliflozin.

[0037] The amount of bexagliflozin in the tablets of the present invention is generally in the range of 1 mg to 100 mg, preferably in the range of 5 mg to 50 mg (for example, 10 to 20 mg in a second embodiment of the present invention). Tablets containing 5 mg, 10 mg, or 20 mg are particularly preferred. These values ​​are expressed with respect to the tetraol of formula (I). Sustained-release tablets of these strengths (and especially 20 mg) provide good therapeutic effects.

[0038] References to the specific content of bexagliflozin in tablets are understood in the usual context of pharmaceutical formulations. Therefore, the content is, for example, as stated in the USP General Chapter. <905> This can be measured in accordance with the European Pharmacopoeia 2.9.40 Method for Testing Formulation Uniformity, or the Japanese Pharmacopoeia 6.02 Method for Testing Formulation Uniformity. If the tablets are approved for medical use in a particular region, the relevant approvals, marketing authorizations, prescription information, product characteristics summaries, product information, patient literature, etc., will specifically mention the amount of bexagliflozin, for example, tablet dosages of strength 5 mg, 10 mg, 20 mg, 40 mg, or 50 mg.

[0039] The tablets of the present invention may contain impurities and / or degradation products related to bexagliflozin. In such cases, these must be present in an amount of 1.0% or less of the total mass of bexagliflozin in the tablet, and any specific impurities or degradation products must be present in an amount of 0.20% or less of the total mass of bexagliflozin.

[0040] general The terms “comprising,” “encompasses,” “including,” and “consisting” are used. For example, a composition “comprising” X may consist solely of X, or it may include additional elements, such as X + Y.

[0041] The term "approximately" in relation to the numerical value x is optional and can mean, for example, x ± 10%.

[0042] The term "substantially" does not exclude "completely"; for example, a composition that "substantially does not contain" Y does not have to contain Y completely. The term "substantially" may be omitted when defining the present invention as needed.

[0043] The term "between" two values ​​includes those two values; for example, the range of 10 mg to 20 mg specifically includes 10, 15, and 20 mg.

[0044] Estimated pharmacokinetic parameters for non-compartmental analysis are defined herein as those most frequently used in the art and are summarized below.

[0045] "T max " is the time at which the observed peak plasma concentration was recorded, and when presented for a population, it is given as the median of the population unless otherwise specified.

[0046] "C max " is the highest plasma concentration observed.

[0047] "C min " is the lowest plasma concentration observed, typically obtained as the value before repeated doses in a regularly scheduled dosing regimen. For example, in a daily dose, C min This is often recorded 24 hours after the previous dose.

[0048] AUC is the area under the curve of plasma concentration as a function of time, and is constructed by the linear trapezoidal law, which states that AUC is given by multiplying the sum of the arithmetic mean of concentrations at two adjacent sampling points by the time difference between those sampling points: (C(ti) + C(ti+1))(ti+1-ti) / 2.

[0049] AUC 0-t This represents the AUC from time 0 (e.g., at the time of ingestion) to the final quantifiable concentration.

[0050] AUC 0-∞ " represents the AUC from time 0 to infinity and is generated by extrapolating a simple (single-phase) exponential decay: AUC 0-∞ =AUC 0-t +C last / k el , where C last This is the final concentration that can be quantified, and k el This is the terminal phase disappearance rate constant.

[0051] "t 1 / 2 This is the terminal phase half-life, also called the elimination half-life. If the empirically determined terminal phase elimination dynamics are not temporally first, t 1 / 2 It is not possible to define T. 1 / 2 =-ln(2) / k el Approximately 0.693 / k el .

[0052] The terms "d(0.1)", "d(0.5)", and "d(0.9)" represent the threshold diameters of particles that fall within the smallest 10%, 50%, and 90% of the total volume of all particles. Therefore, at d(0.9), 90% of the sample volume will consist of particles with a diameter smaller than d(0.9).

[0053] As used herein, "logarithm" by default refers to the natural logarithm, which is often written as ln(x) as a function of argument x, and to avoid misunderstanding, x = e ln(x) Let's assume that when the base of the logarithm is 10, the logarithm is called a decimal logarithm and is expressed as a function of argument y. 10 It is written as (y), and to avoid misunderstanding, y=10 log10(y) Let's assume that.

[0054] In this specification, “solid oral dosage form” can be any solid (or semi-solid) dosage form that can be administered orally. This can take the form of a tablet, solid pill, capsule, caplet, encapsulated gel or encapsulated liquid, or a combination thereof or a solidified form which may be present in layers or subcomponents such as beads, droplets or particles of various shapes and different properties, embedded in a matrix or contained within a capsule or caplet.

[0055] The “batch” size of tablets can range from 100 tablets to a complete manufacturing batch (for example, all tablets made from the same initial amount of material and undergoing the same series of manufacturing operations, or the total amount of tablets pooled for testing or distribution purposes after undergoing similar manufacturing operations). The definition of “manufacturing batch” includes, as provided in 21 USC 201.3, “a specific amount of drug or other material produced in the same manufacturing cycle according to a single manufacturing order, intended to have uniform characteristics and quality within specified limits.”

[0056] When applied to a batch unit or sample, the term “representative” means a unit or sample that is free from manufacturing defects, is drawn substantially randomly from the batch, and is not pre-selected for any particular characteristic such as weight, density, hardness, or coating hue.

[0057] The phrase "substantially random" means that all units in a batch are selected completely randomly so that they have equal selection probabilities, or by a process aimed at achieving a practically balanced representation of the batch being sampled. For example, representative units may be taken at regular intervals during manufacturing or coating to avoid sampling imbalances, such as overestimating units with slightly different characteristics produced from the first or last run. Such units are said to have been taken substantially randomly from the batch.

[0058] As used herein, “sample set” refers to a collection of units or samples that can be analyzed individually or collectively to estimate the characteristics of an entire batch or population. When used in connection with in vitro or in vivo testing of tablet characteristics, a sample set refers to a collection of individually tested samples from which the characteristics of an entire batch of tablets are estimated.

[0059] The characteristics defined for any particular unit (e.g., a tablet) should be understood as the characteristics of a representative unit taken from a manufacturing batch, and its members typically derive or exhibit the characteristics referenced in appropriate tests consuming multiple units from the manufacturing batch. Therefore, when we say that a unit produces a particular pharmacokinetic parameter, it will be understood that this parameter is typically measured after administering a representative sample from the manufacturing batch for which the unit is a model, and an appropriate statistical characterization of the result is calculated. (Examples of parameters based on plasma bexagliflozin concentration (e.g., C max T) is typically characterized as a geometric mean, but max These are typically characterized by the median of the population. Furthermore, if a pharmacokinetic parameter is defined as having a specific range of values, it should be understood that administration of a representative sample from a manufacturing batch, whose unit is the model example, will produce a characterized parameter (e.g., geometric mean or median) that falls within the indicated range of values ​​in a well-structured experimental cohort.

[0060] For example, a statistical measure in which a tablet falls within a specific range of values ​​(e.g., geometric mean C) max When it is said that this results in the production of a representative sample from a manufacturing batch in which the tablet is the model, the model is a statistical measure (e.g., geometric mean C) that falls within the indicated range of values ​​in a properly constructed cohort. max ) results in.

[0061] A “properly constructed cohort” typically refers to a set of subjects consisting of healthy individuals of both sexes with a sample size that provides adequate power to estimate the desired pharmacokinetic parameter. A sample size that provides adequate power can be calculated as described below. In routine practice, for example, to demonstrate bioequivalence for regulatory purposes, 12 or more subjects from each sex are often recruited, and if the sex balance is not maintained, a total of 24 subjects are recruited. Participants in this type of study are typically required to limit alcohol consumption and avoid consuming foods known to significantly affect drug metabolism. For example, although not a regulatory requirement, for the purpose of determining whether a sample set represents the tablets of the present invention, the experimental cohort should consist of individuals close to the median of the entire healthy young adult population, and it should be understood that the cohort should not predominantly include individuals who are overweight or underweight, extremely lean or obese, elderly, or have unusual dietary habits or consumption of drugs, herbal preparations, or supplements that could interfere with the measurements.

[0062] The "sample size that provides adequate power" for estimating pharmacokinetic parameters is, for example, the number of individuals in a cohort required to achieve a certain degree of differentiation between groups subjected to two experimental conditions, such as consuming tablets from one supplier or tablets from another. Methods for calculating statistical power are well known in the art. In its simplest form, statistical power describes the probability that a study will yield a statistically significant result if an expected difference actually exists between two populations. Power calculation is often positioned as determining the minimum sample size to detect a true difference between groups (casting), and involves a specified probability of failure due to randomness. For example, 90% power means that statistically significant results will be obtained in 9 out of 10 studies, but in 1 out of 10 studies, significance will not be achieved despite a difference being present. Thus, the probability of a false negative is 100% minus power. Typical power values ​​when testing pharmacokinetic parameters are 90% or higher, and for clarity, "adequate power" is defined as 95% or higher in this specification. To calculate statistical power, it is necessary to input the variability of the obtained measurements, usually expressed as the standard deviation, and the difference detected (the difference between measurements from two groups detected). If there is significant uncertainty in the standard deviation of the population measurements, this can be determined empirically. When used in the setting of non-inferiority determination, the calculation of statistical power is used to estimate the sample size required to confirm that the difference between two groups is less than a certain amount. For example, a bioequivalence study is a two-sided non-inferiority test aimed at demonstrating that the difference between two formulations falls within a certain boundary.

[0063] Where dietary conditions such as fasting or feeding are specified, the fasting condition is achieved by refraining from consuming food or beverages other than water for at least 10 hours prior to tablet intake, and the feeding condition is achieved by each subject by consuming a standard high-fat, high-calorie diet as provided by regulatory guidance (e.g., FDA Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs - General Considerations, March 2014), with the tablet taken 30 minutes after the start of dietary intake. Further information on how these specific dietary conditions are achieved is provided in the "Bioequivalence" section below.

[0064] Sustained-release tablets Bexagliflozin is administered to humans in several dosage forms. In a radiolabeled tracer mass balance study, 50 mg of bexagliflozin delivered as an aqueous solution to healthy male volunteers resulted in a C2 concentration of 692 ng / mL. max AUC of 2523 ng·h / mL 0-t , and AUC of 2604 ng·h / mL 0-∞ It was found that this occurs, T max It is 0.5 hours, and t 1 / 2 The time interval was 5.6 hours (Zhang et al. (2019), op.cit.). Dose-normalized C max The concentration was 13.84 ng / mL per 1 mg of bexagliflozin.

[0065] Oral administration of bexagliflozin capsules is well tolerated in healthy and diabetic subjects at single and repeated doses up to 100 mg. The capsules provide relatively rapid in vivo release of bexagliflozin, but subsequent plasma concentrations show a high peak / trough ratio. Capsules containing 6.7, 16.7, and 34 mg of bexagliflozin have plasma concentrations of 12.6, 11.3, and 11.5 ng / mL·mg, respectively.-1 mg -1 Dose-normalized C after ingestion of bexagliflozin in a fasted state max This results in T max The median times were 1, 2, and 1 hour, respectively. Based on these values, for example, a capsule containing bexagliflozin 20 mg would have a response time of approximately 1 to 2 hours after administration (i.e., approximately 1 to 2 hours T). max In subjects in a fasted state resulting from ) a C26-252 ng / mL max This shows that the absorption rate is fastest in oral solutions, which is the smallest T max and maximum dose normalized C max This indicates that the capsule containing 34 mg has a C content greater than 10 ng / mL. 24h This occurred. Plasma concentrations show a rapid decrease during the alpha phase (i.e., the distribution phase of a standard two-compartment model).

[0066] Compared to immediate-release capsules, the inventors have found that formulating bexagliflozin as a sustained-release tablet improves the pharmacokinetic profile of bexagliflozin. These tablets, in the case of a 20 mg tablet, have a pharmacokinetic profile of approximately 10 ng / mL. 24h While maintaining a lower C max (For example, a concentration of 8 ng / mL or less per 1 mg of bexagliflozin can be provided.) max A decrease in [the substance] reduces the risk of side effects, but a plasma concentration of 10 ng / mL or higher 24 hours after administration (i.e., C) is not achieved. 24h In dosage forms that can provide this, nearly maximum urinary glucose excretion is observed, thus maintaining the efficacy of the drug.

[0067] Therefore, a first aspect of the present invention provides a sustained-release tablet of bexagliflozin.

[0068] Sustained-release tablets (also called extended-release or sustained-release tablets) release their contents in vivo over a long period after ingestion. Ideally, release should begin immediately after ingestion (for example, as soon as the tablet enters the stomach) and should not be delayed. Therefore, since enteric coatings give a delayed-release profile, tablets of the present invention generally do not have enteric coatings.

[0069] The tablets of the present invention need to provide a unimodal plasma concentration of bexagliflozin as a function of time (in most subjects). Therefore, after administration of one tablet to a subject, the subsequent plasma concentration of bexagliflozin should show only one peak (see, for example, Figures 1 and 2).

[0070] The tablets of the present invention can substantially exhibit zero-order release of bexagliflozin in vitro.

[0071] The plasma concentration of bexagliflozin is C max After reaching this point, it can decrease in a biphasic manner.

[0072] As described above, capsules containing 20 mg of bexagliflozin show a plasma C level of approximately 226-252 ng / mL in fasted subjects. max This indicates that C per milliliter of plasma max This is 80,000 to 90,000 times lower than the total bexagliflozin content of the capsule. However, in the preferred tablets of the present invention, C in fasted subjects max The C content must be at least 125,000 times lower than the bexagliflozin content of the tablet. Therefore, a 20 mg tablet must have a C content of 160 ng / mL or higher. max Provides C relative to the bexagliflozin content. max The ratio is even higher than 125,000 times, for example, 135,000 times or 145,000 times or more.

[0073] Therefore, the present invention particularly relates to in vivo geometric mean plasma C60 at a concentration of 8 ng / mL or less per 1 mg of bexagliflozin in the tablet (ideally, 6 ng / mL or less per 1 mg of bexagliflozin) in healthy fasted subjects (e.g., a cohort of 6 or more fasted subjects weighing over 60 kg). max The present invention provides sustained-release tablets that provide [a specific function / effect]. In one embodiment, the tablet contains 10 mg of bexagliflozin and has a C content of 80 ng / mL or less. max In another embodiment, the tablet contains 20 mg of bexagliflozin and has a C content of 160 ng / mL or less. max To provide.

[0074] The tablets of the present invention contain 160 ng / mL or less of C max If providing C max The C2 concentration is preferably 150 ng / mL or less, and ideally 80-150 ng / mL (especially for a 20 mg bexagliflozin dose). A preferred 20 mg tablet has a C2 concentration of 85-145 ng / mL. max More preferably 95-140 ng / mL C max To provide.

[0075] The sustained-release tablets of the present invention contain 3 ng / mL or more of bexagliflozin plasma C in fasted subjects. 24h It is necessary to provide the following: As mentioned above, plasma C is nearly the maximum urinary glucose excretion of 10 ng / mL or more. 24h As observed, therefore, the preferred tablets of the present invention contain plasma C10 ng / mL or more, for example, in the range of 10 to 25 ng / mL. 24h This can provide: In one embodiment, the tablet contains 10 mg of bexagliflozin and has a C content of 3 ng / mL or higher. 24h In another embodiment, the tablet contains 20 mg of bexagliflozin and contains 6 ng / mL or more of C. 24h To provide.

[0076] As described above, the capsule formulation of besagliflozin showed a plasma T1 level of approximately 1 hour in fasted subjects. maxThis shows. In contrast, the preferred tablets of the present invention are typically fasted for 2 to 6 hours in fasted subjects. max Therefore, the tablets of the present invention can provide a T of bexagliflozin compared to immediate-release capsules. max It can be delayed.

[0077] The preferred tablets of the present invention exhibit a plasma AUC of 15-60 ng·h / mL per 1 mg of besagliflozin in the tablet in fasted subjects. 0-t The present invention provides: In one embodiment, the tablet contains 10 mg of bexagliflozin and has an AUC of 150-600 ng·h / mL, for example, 350-450 ng·h / mL. 0-t In another embodiment, the tablet contains 20 mg of bexagliflozin and has an AUC of 600-1200 ng·h / mL, for example, 650-1150 ng·h / mL. 0-t To provide.

[0078] The preferred tablets of the present invention exhibit a plasma AUC of 17.5 to 65 ng·h / mL per 1 mg of bexagliflozin in the tablet in fasted subjects. 0-∞ The present invention provides: In one embodiment, the tablet contains 10 mg of bexagliflozin and has an AUC of 410-510 ng·h / mL. 0-∞ In another embodiment, the tablet contains 20 mg of bexagliflozin and has an AUC of 675-1275 ng·h / mL, for example, 750-1200 ng·h / mL. 0-∞ To provide.

[0079] The preferred tablets of the present invention are effective in fasting subjects for 7 to 14 hours, for example, 8 to 13 hours. 1 / 2z (Provides terminal phase disappearance half-life)

[0080] C max , T max t 1 / 2z , C 24h AUC 0-t , and AUC 0-∞These are standard pharmacokinetic parameters. They can be estimated manually or using modeling software well-known in the art, such as the Phoenix WinNonlin package using a non-compartment model. The general basis for calculating these quantities is well known (see, for example, Rowland & Tozer (2019) Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications ISBN 978-1496385048, or Jambekar & Breen (2012) Basic Pharmacokinetics ISBN 978-0853699804). Typically, parameters are evaluated as the mean (e.g., geometric mean) within a group of at least 12 (usually 24-36) healthy adults. Parameters should be measured according to standards and practices accepted by pharmaceutical regulatory bodies such as the FDA, EMEA, MHLW, or WHO. The values ​​may be based on measurements taken at appropriate intervals after the tablet has been taken, for example, every hour, or at increasing sparse sampling intervals, for example, 1, 3, 5, 7, 9, 11, 13, 15, 20, and 24 hours after ingestion.

[0081] The pharmacokinetic parameters described above were defined for plasma in fasted human subjects, i.e., subjects fasted for at least 10 hours overnight. These parameters for bexagliflozin differ between fasted and fed subjects, and typically, when the tablet is taken after a meal (e.g., 30 minutes after the start of a meal), C max , C 24h AUC 0-t , and AUC 0-∞All of these will be higher. The fasting subjects for which the parameters defined herein need to be evaluated and measured are healthy, fasting adult Caucasian subjects (males and females) weighing 60–100 kg, e.g., about 75 kg. The same behavior may be observed in other subjects (such as Asian subjects or patients with lower body weight), but the population for which the parameters are evaluated must meet these criteria. A cohort study of at least six subjects is typical.

[0082] Desired C max , T max , C 24h AUC 0-t , and / or AUC 0-∞Sustained-release tablets with specific properties should be prepared in conjunction with general knowledge regarding the preparation of sustained-release tablets, and refer to the following guidance, for example, Chapter 32 of Collett & Moreton (2007) in Pharmaceuticals: The Science of Dosage Form Design (3rd edition), Chapter by Lordi (1986) in Theory and Practice of Industrial Pharmacy (3rd edition), Timmins et al. (2014) Hydrophilic Matrix Tablets for Oral Controlled Release ISBN 978-1493915187, Sushma et al. (2014) Matrix Tablets: An Approach Towards Sustained Release Drug Delivery ISBN 978-3659579110, Rasul et al. (2011) Sustained Release Tablets ISBN 978-3844323719, and Eyjolfsson (2014) Design and Manufacture of Pharmaceutical Tablets. It can be prepared according to the guidance described in ISBN 978-0128021828. Patel (2013) Extended Release Tablet of Antidiabetic Drug: Development, Optimization and Evaluation, ISBN 978-3659448140 describes how extended-release tablets of glipizide were developed using hydroxyethylcellulose and hydroxypropylcellulose.

[0083] Thus, the principle of manufacturing sustained-release tablets is well known in the art. Compared with immediate-release capsules of any specific dose, the use of sustained-release tablet technology allows for the C of bexagliflozin to be released according to the desired pharmacokinetic profile of the present invention. max This reduces the amount of [unclear value]. The degree of reduction can be controlled by modifying the properties of the sustained-release tablet in accordance with known design principles.

[0084] There are three main methods for achieving sustained release from tablets: (i) by using a monolithic matrix in which drug particles are dispersed in either a soluble or insoluble matrix; (ii) by a reservoir or membrane control system; or (iii) by an osmotic pump system. Tablets based on a soluble matrix contain a compressed mixture of bexagliflozin and a water-swellable hydrophilic polymer, and upon entering the gastrointestinal tract, the tablet begins to dissolve and releases bexagliflozin over a long period of time. Tablets based on an insoluble matrix contain a mixture of bexagliflozin and a water-insoluble substance such as wax, fat, or polymer, into which water can diffuse to dissolve the bexagliflozin and enable its release. The pathway for water diffusion may be part of the tablet when it is swallowed, or it may appear after ingestion as channeling agents leach from the tablet. Tablets based on a reservoir system contain a membrane in which bexagliflozin needs to diffuse, and this diffusion is made possible by hydration of the membrane. The membrane is generally made from polymers that remain intact during the release period, such as acrylic copolymers, ethylcellulose, shellac, and zein. The osmotic pump system is similar to a reservoir system, but hydrostatic pressure is generated by the hydration of the tablet core, which forces the dissolved bexagliflozin through the pores in the semipermeable coating of the core. Details of release control agents suitable for use in these tablets are provided below.

[0085] These general approaches are well known, and those skilled in the art of tablet formulation can use any of these approaches to manufacture and test tablets and adapt them according to the desired pharmacokinetic properties of the tablets. The properties of the tablets can be modified depending on the characteristics of the formulation approach used. For example, in soluble matrices, the release can be controlled by selecting the chemical, physical properties, and amount of the water-swellable hydrophilic polymer. In water-insoluble (e.g., wax) matrices, the release can be controlled by selecting the amount of water-insoluble substance as well as the properties and amount of the channeling agent. In insoluble polymer matrices, the pore structure of the matrix is ​​an important parameter, and harder, less porous matrices generally result in slower release. In reservoir systems, the choice of membrane, in particular the choice and amount of membrane plasticizer, is important, but the addition of water-soluble components to the membrane can also be used to increase the release rate. In osmotic pump systems, the rate at which water can enter the core and the rate at which bexagliflozin can exit the pores of the coating govern the release properties of the tablet. Therefore, the components and design principles for controlling the release characteristics of tablets while providing physically stable tablets are well known, and those skilled in the art of tablet formulations can use any of these approaches to prepare and test tablets (both in vitro and in vivo) to ensure that the release characteristics are such that the desired C is achieved for any particular amount of bexagliflozin. max , T max , C 24h AUC 0-t , and AUC 0-∞ We can provide products that grant [a certain characteristic].

[0086] A preferred tablet of the present invention comprises bexagliflozin dispersed in a water-insoluble (e.g., wax) matrix (e.g., based on glyceryl dibehenate, as discussed below).

[0087] In addition to using these techniques to provide sustained release from tablets, it is also desirable to further refine the in vivo pharmacokinetic behavior by adapting the tablets for gastric retention (described later), increasing the rate of sustained release occurring in the duodenum, and thereby delaying the progression of bexagliflozin through the small intestine.

[0088] C in humans max , T max , C 24h AUC 0-t , and / or AUC 0-∞ Prior to in vivo trials to determine the optimal outcome, it may be useful to subject the tablets to in vitro dissolution testing to make some preliminary predictions and facilitate design modifications. These in vitro trials are used in regulatory settings to ensure that the tablets can reliably and safely deliver the required therapeutic dose of drug into the bloodstream and involve applying formal dissolution pass / fail tests to tablets sampled from manufacturing batches intended for delivery to human patients. Such formal pass / fail tests ensure that the desired amount of bexagliflozin can be delivered in vivo over the desired time interval.

[0089] Accordingly, the present invention provides a solid oral dosage form (most typically a sustained-release tablet) containing bexagliflozin that releases 17% or less of bexagliflozin after 1 hour and 80% or more after 8 hours in an in vitro dissolution test in simulated gastric juice (see below). Thus, at least 83% of the bexagliflozin was retained in the dosage form after 1 hour of the in vitro dissolution test, but at least 80% was released after 8 hours of the test (this includes embodiments in which 100% was already released at 8 hours). The amount of bexagliflozin released from this tablet after 1 hour in the dissolution test is less than that released using an immediate-release capsule containing the same amount of bexagliflozin. In one embodiment, this dosage form releases 20-45% of its bexagliflozin (including both ends) after 3 hours and 45-75% of its bexagliflozin (including both ends) after 5 hours.

[0090] In embodiments of the present invention in which a dosage form (such as a sustained-release tablet) releases 20-45% of its bexagliflozin after 3 hours in an in vitro dissolution test, the dosage form can be prepared so that 23-43% of the bexagliflozin is released after 3 hours.

[0091] In embodiments of the present invention in which a dosage form (such as a sustained-release tablet) releases 45-75% of its bexagliflozin after 5 hours in an in vitro dissolution test, the dosage form can be prepared to (a) release 45-72% of its bexagliflozin after 5 hours, (b) release 50-70% of its bexagliflozin after 5 hours, (c) release 49-69% of its bexagliflozin after 5 hours, or (d) release 48-68% of its bexagliflozin after 5 hours. More generally, the dosage form may release x-y% of its bexagliflozin after 5 hours, where x is selected from 45, 47, 48, 49, or 50, and y is selected from 68, 69, 70, 72, or 75.

[0092] In one embodiment, a sustained-release tablet may, in an in vitro dissolution test, (1) release 23-43% of its bexagliflozin after 3 hours, and (2) release 45-72%, 50-70%, 49-69%, or 48-68% of its bexagliflozin after 5 hours. Therefore, these percentages may be used as references for 3 hours and 5 hours in the in vitro dissolution tests disclosed herein.

[0093] Since determining these release characteristics is inherently destructive, these parameters do not need to be determined directly for the specific tablet in question, but rather for tablets produced using the same ingredients and the same manufacturing process. Therefore, a manufacturing batch of tablets can be produced by a specific process, and an in vitro dissolution test is performed on a representative sample set of tablets from that manufacturing batch. If the results of this test satisfy the above requirements, the tablets produced by the manufacturing process in question are the tablets of the present invention. Thus, the present invention also provides tablets from any such manufacturing batch.

[0094] The in vitro dissolution tests used in these decisions are one of several standard practices in the relevant field, particularly for sustained-release tablets. For example, USP <711> For dissolution or refer to European Pharmacopoeia 2.9.3, further details are provided below.

[0095] Studies of specific types of tablet formulations have revealed the in vitro properties of tablets (e.g., rate or degree of drug release) and the associated in vivo response (e.g., C max or AUC 0-t This makes it possible to provide IVIVC (in vitro-in vivo correlation) that explains the relationship between ) and ). This type of model facilitates the rational development, evaluation, and modification of the sustained-release dosage form tablets of the present invention.

[0096] Ideally, sustained-release preparations should not be dependent on dietary conditions; however, if such influence is unavoidable (for example, if the sustained-release mechanism depends on the mechanism of gastric contents release, as in some embodiments of the present invention), it is desirable that the outcome of prior food intake be predictable and limited so as not to present the patient with any risk of adverse side effects or insufficient therapeutic effect. These criteria can be met by the tablets of the present invention.

[0097] It is known that various drugs affect gastrointestinal motility, either as a side effect or as part of their therapeutic mechanism. Among the drugs that affect gastric emptying and are frequently delivered co-administered with oral antidiabetic drugs are glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 receptor agonists can suppress gastric emptying and mimic the state of eating, thereby increasing exposure to bexagliflozin if delivered before bexagliflozin administration. Currently, most GLP-1 receptor agonists are delivered by subcutaneous injection, but semaglutide preparations for oral delivery have recently been approved, and more such agonist formulations or synthetic agonists may be approved in the future. As with the state of eating, it is desirable that the outcomes of GLP-1 receptor agonist administration be predictable and limited. These criteria are met by the tablets of the present invention.

[0098] gastric retention Desired C max , T max , C 24h AUC 0-t , and / or AUC0-∞ Sustained-release tablets with specific properties can be prepared by following the guidance above, in conjunction with general knowledge regarding the preparation of sustained-release tablets. A further way to modify the tablet to achieve the desired parameters is to incorporate into the tablet a gastric retention fit, in particular one or more of the four fits discussed below. The overall goal of the gastric retention discussed herein is to delay the progression of bexagliflozin through the small intestine, thereby promoting that the majority of the sustained release of bexagliflozin occurs in the stomach or upper small intestine (see Hou et al. (2003) Crit Rev Ther Drug Carrier Syst 20:459-97). Compared to immediate-release capsules, all of these fits are therapeutically useful. 24h While still providing in vivo plasma C max It reduces T max AUC 0-t , and AUC 0-∞ It is indicated that it should be kept within the desired range.

[0099] A first approach to achieving the desired in vivo pharmacokinetic behavior is to include effervescent excipients, particularly excipients that effervesce upon contact with gastric acid, such as carbonates, bicarbonates, or sodium bicarbonate, in the tablet. When a tablet effervesce, it tends to float due to the release of gas, thus delaying its progression to the pyloric sphincter at the bottom of the stomach (see, e.g., Wei et al. (2001) Drug Dev Ind Pharm 27:469-74, Ray & Prusty (2010) Int J Appl Pharmaceutics 2:12-16). A tablet matrix containing bicarbonate offers the additional benefit of protecting bexagliflozin from acid degradation. By including effervescent excipients, as shown in the examples, C max This decreases, thereby contributing to the desired pharmacokinetic profile.

[0100] A second approach to achieving desired in vivo pharmacokinetic behavior is to construct the tablet so that, upon contact with gastric contents, it disperses into numerous granules or pellets, thereby providing sustained release. Generally, the stomach takes longer to expel multiple small granules / pellets than one large tablet. A similar approach is disclosed by Aburahma & Hamza Yel (2011) Pharm Dev Technol 16(4):316-30, in which sustained-release beads containing rapidly disintegrating components are compressed.

[0101] A third approach to achieving the desired in vivo pharmacokinetic behavior is to use a low-density excipient, thereby providing a buoyant or floating tablet. By using an appropriate amount of low-density excipient, it is possible to provide a tablet with an overall density lower than that of gastric contents, thereby allowing the tablet to float in the stomach and thus delay its passage through the pyloric sphincter without requiring effervescence (e.g., Srikanth Meka et al. (2014) Acta Pharm 64:485-494). As shown in the examples, this approach is C max It provides a useful reduction. Gastric contents are approximately 1.004-1.010 g / cm³. 3 Since it has a density of [a certain value], the tablet needs to have a lower density so that it can ideally float.

[0102] Buoyancy and the length of time the tablet maintains buoyancy during disintegration can be evaluated in vitro in simulated gastric fluid maintained at 37°C. In some embodiments, the tablet of the present invention can maintain buoyancy (i.e., remain on the surface) until it has released 90% of its bexagliflozin. In some embodiments, the tablet of the present invention can maintain buoyancy for 5 hours or more, for example, 8 hours or more. In practice, the tablet can be studied using the same method as described below for in vitro dissolution testing, for example, in an apparatus (simulated gastric fluid) containing 900 mL of 0.1N HCl at 37±0.5°C. The density of the tablet can be determined by a substitution method using analytical grade benzene as the substitution medium.

[0103] A fourth approach to achieving desired in vivo pharmacokinetic behavior is to include a mucosal adhesion excipient in the tablet. Mucosal adhesions allow the tablet to interact with mucosal surfaces of the gastrointestinal tract, such as the stomach wall, thereby slowing tablet progression. This approach is discussed, for example, in Jha & Nanda (2013) Asian J Biomed Pharm Sci 3:44-49. Various mucosal adhesion excipients suitable for inclusion in tablets are known in the art, and these are often hydrophilic polymers. Generally, good mucosal adhesions have strong hydrogen bonding groups (-OH, -COOH), strong anionic charge, sufficient flexibility to penetrate the extended glycan network of the cellular glycocalyx, suitable surface tension properties for wetting mucus / mucosal tissue surfaces, and / or high molecular weight (see Yadav et al. (2010) J Chem Pharm Res 2:418-32). Examples of mucosal adhesion excipients are listed below. Several mucosal adhesives are known to provide sustained-release properties to tablets (e.g., HPMC, polyethylene oxide), and therefore can effectively perform both roles in the tablets of the present invention. The useful amount of mucosal adhesive in the tablets of the present invention may be 10 to 25% by weight of the total tablet weight.

[0104] Accordingly, a fourth aspect of the present invention provides a sustained-release tablet comprising bexagliflozin and a mucosal adhesive. The mucosal adhesive is included in the tablet in an amount that delays in vivo progression through the stomach and / or duodenum compared to an equivalent tablet having the same composition except in the absence of the mucosal adhesive. Preferred mucosal adhesives to be included in the tablets of the present invention are nonionic polyethylene oxide polymers having an average molecular weight of 800,000 or more, for example, 900,000 to 5,000,000. These hydrophilic polymer powders are available in pharmacopoeia grade from Dow Chemical under the trade name POLYOX®, with molecular weights in the range of 100,000 to 7,000,000. They can play both roles in the tablets of the present invention, as they are known to provide both mucosal adhesive properties and sustained-release properties. Preferred amounts of mucosal adhesives are discussed above.

[0105] By using the four approaches described above individually, it is possible to provide sustained-release tablets for bexagliflozin delivery exhibiting the desired pharmacokinetic parameters. In particular, each approach, compared to an immediate-release formulation, max This can reduce the desired C for any specific amount of bexagliflozin in a tablet. The degree of reduction can be controlled to a specific extent, particularly by increasing the specific fit, to achieve the desired C max This can provide: For example, by increasing the amount of effervescent excipient or increasing the number of individual granules / pellets, gastric retention increases up to a certain point, and C accordingly. max This decreases. Similarly, increased buoyancy increases gastric retention, but there are practical limitations on how much buoyancy can be increased. Finally, increasing the level of mucosal adhesive or using a stronger mucosal adhesive increases gastric retention, but again, there are practical limitations on the tablet's ability to handle mucosal adhesive content. However, generally speaking, those skilled in the art of tablet formulations will be able to utilize these approaches to manufacture and test tablets and adapt them according to desired pharmacokinetic properties.

[0106] The four approaches can be used individually, but they can also be combined to your advantage.

[0107] The inventors believe that the first approach is itself C max These tablets can reduce the desired level, but there is significant variability between patients (especially T). maxWe found that this may be the case. While we do not wish to be bound by theory, this behavior may occur in some patients when the tablet leaves the stomach earlier than desired, after which it is no longer subject to the acid-driven effervescence disintegration force, thus reducing drug release and therefore bioavailability. To mitigate this problem, the first and second approaches can be combined, for example, by compressing multiple effervescent granules into a single tablet, so that the individual effervescent granules are released as the tablet disperses in the stomach.

[0108] The second approach is technically difficult to implement consistently, C max While it reduces [the [condition]], the effect is not very significant (for example, not as significant as the first approach). Furthermore, because the granules may have a relatively short commercial shelf life, the second approach is undesirable, either on its own or in combination with any of the other approaches.

[0109] When multiple approaches are used to improve pharmacokinetics, one option is to combine the third and fourth approaches to provide a low-density tablet containing a mucosal adhesive. As shown in the examples, this combination of approaches provides a tablet having properties favorable for the delivery of bexagliflozin in humans. Accordingly, the present invention provides a sustained-release tablet comprising bexagliflozin and a mucosal adhesive having a density lower than the density of human gastric acid. Further details of preferred mucosal adhesives and their content, as well as preferred densities, are discussed above.

[0110] Gastric retention can be measured by including a radionuclide in the formulation and directly recording the percentage of the formulation that remains in the stomach as a function of time after administration using a suitable scintillation camera. While this approach has relatively high accuracy, it has two main drawbacks: (i) the radionuclide itself is not typically found in the product, and therefore in the formulation, its composition deviates from the intended product form; and (ii) conducting such experiments is difficult and expensive, and participants are exposed to the additional risk of radioactivity. Therefore, instead, gastric retention can be inferred from other properties of the formulation, for example, the amount of gastric retention produced by the formulation. max and T produced by the immediate-release formulation max By comparison with, or in a fasting state, T max and T in the feeding state max This can be determined by comparison with [ 14 Studies using [C]-bexagliflozin have shown minimal absorption in the colon, with the majority of absorption occurring in the small intestine. The effect of dietary status is consistent with this explanation. For example, bexagliflozin capsules of strength 6.7-34 mg showed a 1-2 hour thaw in a fasted state. max This occurred, but in a fasted state, it lasted 5 hours, which can be explained if the release of gastric contents is necessary for the maximum absorption rate. The U20 formulation of bexagliflozin sustained-release tablets (see below) lasted 3.5 hours in a fasted state. max And in the feeding state, 5 hours T max This is consistent with the view that they result in longer retention in the stomach than sustained-release formulations.

[0111] Tablet ingredients As described above, the tablets of the present invention, in addition to bexagliflozin, generally or optionally include one or more release control agents (such as components for forming a matrix or membrane), one or more matrix or membrane modifiers (such as channeling agents or wicking agents), one or more solubilizers, one or more flow promoters, lubricants, and / or flow aids, one or more disintegrants, one or more fillers, one or more binders, one or more density modifiers and / or foaming components, one or more colorants, one or more flavoring agents, one or more antioxidants, and / or one or more mucosal adhesives. Such components generally exist as a mixture within the tablet, but may also exist in different proportions in layers or distinct geometric structures such as particles or spheres of a certain composition embedded in something else, or in sheets or blocks of materials of different bulk compositions.

[0112] It is common to manufacture tablets having a core of a certain composition surrounded by a coating or another outer layer. The tablets of the present invention typically include a coating.

[0113] Examples of release-controlled agents for forming the matrix include, but are not limited to, water-swellable hydrophilic polymers (hydroxypropylcellulose or hydroxymethylcellulose, sodium carboxymethylcellulose, alginates, alginic acid, gelatin, xanthan gum (with or without locust bean gum), Carbopol, polyethylene oxide, galactomannose, etc.), waxes (hydrogenated vegetable oil, microcrystalline wax, carnauba wax, etc.), and insoluble polymers (ethylcellulose, etc.). These components can constitute 15-40% by weight of the tablet.

[0114] A particularly useful release control agent for forming the tablet matrix of the present invention is glyceryl dibehenate, because it has a favorably lower density than gastric juice and is resistant to gastric lipase. Glyceryl dibehenate is known for its use as a sustained-release agent (e.g., described in Opota et al. (2013) Int J Pharm Tech Res 5:622-8). Preferred tablets contain 30-35% by weight of glyceryl dibehenate. The term "glyceryl dibehenate" is the current preferred pharmaceutically acceptable description for commercially available mixtures of glyceryl esters (including mono, di, and tribehenate esters), which are mainly in the form of diesters. There are two positional isomers of glyceryl monobehenate and two positional isomers of glyceryl dibehenate. Previously, the term "glyceryl behenate" was used to represent commercial mixtures of esters, but this term has the disadvantage of being inaccurate, as it suggests that the composition is mainly in the form of monobehenate. Commercial preparations of glyceryl dibehenate contain 40–60% by weight of the diester in the mixture. References to "glyceryl dibehenate" herein should be understood to refer to products containing mixtures of glyceryl esters of behenic acid, and not to the amount of glyceryl dibehenate ester contained therein.

[0115] Commercial preparations of glyceryl dibehenate may be formulated to improve performance in pharmaceutical manufacturing processes, for example, to improve mixing or flow properties, and the inventors have found that micronized or pulverized formulations (such as Compritol888ATO®) can have preferred properties for preparing the tablets of the present invention.

[0116] Examples of release control agents for membrane formation include, but are not limited to, ethylcellulose, acrylic polymers (e.g., Eudragit RL&RS®), shellac, and zein. These can be combined with plasticizers such as dibutyl phthalate, diethyl phthalate, dibutyl sebesate, and citrate esters. The plasticizer is generally included in about 10–25% by weight of the membrane polymer, sufficient to completely bond the membrane and form a film, without making the membrane too elastic, plastic, flexible, or permeable.

[0117] Examples of matrix modifiers include, but are not limited to, sugars, polyols, and soluble salts. These can alter the diffusion properties of the matrix and the rate and degree of its hydration, and thus alter the release of bexagliflozin. Channeling agents include sodium chloride, sugars, and polyols (such as lactose), which can constitute 10-30% by weight of the tablet.

[0118] Examples of solubilizers include, but are not limited to, surfactants (including ionic and nonionic surfactants), such as sodium lauryl sulfate, cetyltrimethylammonium bromide, polysorbates (e.g., polysorbate 20 or 80), poloxamers (poloxamer 188 or 207), and macrogol. Preferred tablets contain poloxamer, which is ideally micro-prilled, for example (EP-A-1661558). An average poloxamer particle size of 10-200 μm is useful. The most preferred poloxamer is micro-prilled poloxamer 188. The preferred amount of poloxamer 188 in the tablets of the present invention is 10-12% by weight. Higher levels of poloxamer may result in faster release from the tablet.

[0119] In some embodiments, for the purpose of providing tablets having extended stability and good bioavailability (and optionally, being bioequivalent to the reference tablets disclosed herein), a surfactant can be combined with amorphous bexagliflozin in the manner disclosed in WO2018 / 167589. Useful surfactants for such embodiments are available under the trade names SEPITRAP® 80 and Dubcare® GPE810. SEPITRAP® 80 is a microencapsulated form of polysorbate 80 in powder form, in which polysorbate 80 is adsorbed onto a porous magnesium aluminometasilicate carrier. Dubcare® GPE810 is a mixture of PEG-8 caprylic / capric acid glycerides.

[0120] Examples of lubricants, flow promoters, and flow aids include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl dibehenate, sodium stearyl fumarate, colloidal silicon dioxide, and talc. The amount of lubricant in a tablet can generally be 1 to 5% by weight. Preferred tablets of the present invention contain magnesium stearate and / or colloidal silicon dioxide (e.g., amorphous anhydrous form). Preferred tablets contain 1.5 to 2.5% by weight of magnesium stearate and / or 1.0 to 1.5% by weight of colloidal silicon dioxide.

[0121] Examples of disintegrants include, but are not limited to, starch, cellulose, cross-linked PVP, sodium starch glycolate, and croscarmellose sodium.

[0122] Examples of fillers (also known as bulking agents or diluents) include, but are not limited to, starch, maltodextrin, polyols (such as lactose), and cellulose. Preferred tablets of the present invention contain lactose and / or microcrystalline cellulose (e.g., Avicel product line; see Doelker et al. (1995) Drug Dev Ind Pharmacy 21:643-61). Lactose can be used in anhydrous or hydrated form (such as monohydrate) and is typically prepared by spray drying, fluidized bed granulation, or roller drying. Preferred microcrystalline cellulose has a particle size of about 150-200 μm. Preferred tablets contain 11-13% by weight of lactose and / or 18-20% by weight of microcrystalline cellulose. Spray-dried lactose monohydrate is preferred.

[0123] Examples of binders include, but are not limited to, cross-linked PVP, HPMC, microcrystalline cellulose, sucrose, and starch.

[0124] Examples of effervescent ingredients include, but are not limited to, carbonates or bicarbonates (sodium bicarbonate), such as sodium bicarbonate.

[0125] Examples of antioxidants include, but are not limited to, butylated hydroxyanisole, butylated hydroxytoluene, sodium metabisulfite, propyl gallate, and cysteine. Preferred tablets contain butylated hydroxytoluene as an antioxidant.

[0126] Examples of mucosal adhesives include, but are not limited to, carbopol (polymer of acrylic acid crosslinked with polyalkenyl ether or divinyl glycol), crosslinked carboxypolymethylene, carboxymethylcellulose (such as sodium carboxymethylcellulose), hydroxyethylcellulose, hydroxypropylmethylcellulose, polycarbophil, tragacanth gum, poly(acrylic acid / divinylbenzene), alginates (such as sodium alginate), karaya gum, and polyoxyethylene (also known as polyethylene oxide or polyethylene glycol). As stated above, the useful amount of mucosal adhesive in the tablets of the present invention may be 10 to 25% by weight of the total tablet. Preferred mucosal adhesive components included in the tablets of the present invention are, in particular, nonionic polyethylene oxide polymers having an average molecular weight (e.g., number average) of at least 800,000 (based on rheological measurements). Preferred tablets contain 16 to 20% by weight of polyethylene oxide.

[0127] Uncoated tablets may also be used, but it is more common to provide coated tablets, in which case conventional non-enteric coatings may be used. The coating may be white or colored, for example, blue. Suitable coatings include, but are not limited to, polymer film coatings, such as those containing polyvinyl alcohol, e.g., "Opadry II" (trademark) (containing partially hydrolyzed PVA, titanium dioxide, macrogol 3350, and talc, and optionally containing a coloring agent such as indigo carmine or iron oxide yellow or FD&C yellow #6). The amount of coating is generally 2.5–3.5% of the core weight.

[0128] Some components can play multiple roles in tableting; for example, glyceryl dibehenate can be used as a release control agent in the tablet matrix, or as a gastric retention excipient (depending on its density), or as a lubricant; polyethylene oxide can be used as a release control agent or as a mucosal adhesion agent. Thus, one component can play multiple roles within a single tablet, but components are often included for a single purpose, so their amount and location (in the tablet and / or during the manufacturing process) are selected accordingly.

[0129] The tablets of the present invention generally have a hardness in the range of 20 to 100 N, and more typically have a hardness of 20 to 60 N, 30 to 40 N, or 60 to 90 N. Hardness is measured according to USP standards. <1217> It can be conveniently evaluated using a Dr. Schleuniger Pharmatron tester, which operates according to the instructions and drives the anvil to compress the tablet at a constant speed until the tablet breaks.

[0130] The tablets of the present invention typically have a degree of abrasion of 1% by weight or less. The degree of abrasion is defined as USP <1216> It can be evaluated according to this.

[0131] The tablets of the present invention generally have a moisture content of 5% by weight or less. The moisture content is as specified in the USP <921> It can be evaluated according to this.

[0132] The tablets of the present invention can be conveniently prepared by direct compression (followed by coating as needed).

[0133] Preferred tablets Preferred tablets of the present invention comprise bexagliflozin, glyceryl dibehenate, polyethylene oxide, lactose (anhydrous or preferably monohydrate), poloxamer 188 (preferably in microparticle form), microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate, and optionally also have a coating containing polyvinyl alcohol.

[0134] An example of such a tablet has the following composition per tablet: 30-60 mg bexagliflozin, 100-140 mg dibehenate glyceryl, 50-75 mg polyethylene oxide, 40-50 mg lactose, 40-45 mg poloxamer 188, 60-80 mg microcrystalline cellulose, 4-5 mg colloidal silicon dioxide, and 6-9 mg magnesium stearate, and optionally also has a coating of 10-12 mg containing polyvinyl alcohol.

[0135] Three preferred tablets of the present invention comprise one of the following cores, and the details of the excipients are well known and can be found in the Handbook of Pharmaceutical Excipients (eds. Sheskey, Cook & Cable; 8th edition, 2016). [Table 1]

[0136] The core preferably has a hardness of 40-60N or 60-90N and a wear rate of 1% by weight or less.

[0137] The present invention also provides a tablet comprising one of these three cores coated with a polymer film coating containing polyvinyl alcohol, titanium dioxide, and macrogol 3350. The amount of coating may be 3% of the weight of the core.

[0138] In these preferred tablets, poloxamer 188 must be micronized, lactose may be anhydrous but preferably monohydrate, and optional coatings may include polyvinyl alcohol, titanium dioxide, macrogol 3350, talc, Brilliant Blue FCF, and indigo carmine such as Opadry II Blue product.

[0139] The present invention also relates to logarithmically transformed C max and logarithmically transformed AUC 0-tThe 90% confidence interval of is, when raised to a power, the geometric mean C of the values ​​obtained in the same cohort by a reference tablet having one of the following compositions (see also tablets U5, U10, and U20 below). max and geometric mean AUC 0-t The geometric mean C falls perfectly within the range of 80.00 to 125.00%. max and geometric mean AUC 0-t The present invention provides oral dosage forms (particularly solid oral dosage forms such as tablets) that occur in a cohort of healthy subjects: (a) a core consisting of a mixture of 5 mg bexagliflozin, 65 mg nonionic polyethylene oxide having an average molecular weight of approximately 900,000, 120 mg dibehenate glyceryl powder, 45 mg spray-dried lactose monohydrate, 42 mg microparticle poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium stearate, and PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF, and indigo carmine (Opadry A tablet having a film coating consisting of a mixture of 10.77 mg of II (trademark) Blue 85F99153, etc., wherein the core is formed by compression using a 14.8 × 6.5 mm caplet-shaped tablet punch having a tablet hardness of 40 to 60 N. (b) A tablet having a core consisting of a mixture of 10 mg bexagliflozin, 65 mg nonionic polyethylene oxide having an average molecular weight of approximately 900,000, 120 mg glyceryl dibehenate powder, 45 mg spray-dried lactose monohydrate, 42 mg microparticle poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium stearate, and a film coating consisting of a mixture of 10.92 mg of PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF, and indigo carmine (such as Opadry II® Blue 85F99153), wherein the core has a tablet hardness of 40-60 N and is formed by compression using a 14.8 × 6.5 mm caplet-shaped tablet punch. (C) A tablet having a core consisting of a mixture of 20 mg bexagliflozin, 65 mg nonionic polyethylene oxide having an average molecular weight of approximately 900,000, 120 mg dibehenate glyceryl powder, 45 mg spray-dried lactose monohydrate, 42 mg microparticle poloxamer 188, 70 mg microcrystalline cellulose, 4.5 mg amorphous anhydrous colloidal silicon dioxide, and 7.5 mg magnesium stearate, and a film coating consisting of a mixture of 11.22 mg of PVA, titanium dioxide, macrogol 3350, talc, brilliant blue FCF, and indigo carmine (such as Opadry II® Blue 85F99153), wherein the core has a tablet hardness of 40-60 N and is formed by compression using a 14.8 × 6.5 mm caplet-shaped tablet punch.

[0140] These reference tablets (a), (b), and (c) can be manufactured as follows: (i) blend bexagliflozin, colloidal silicon dioxide, and 80% of MCC, then sifting the mixture; (ii) add the remaining MCC to obtain mixture "A"; (iii) sift polyethylene oxide, dibehenyl glycerate, and lactose to obtain mixture "B"; (iv) blend mixtures "A" and "B" together; (v) add sifted magnesium stearate, then blend further; (vi) compress the material into a tablet core using, for example, a 14.8 × 6.5 mm caplet punch and a suitable die; and (vii) remove dust; and (viii) coat using, for example, a 12% or 18% w / w suspension of coating material to achieve a coating that results in an increase of about 3% in tablet mass. The bexagliflozin preparations used to manufacture these reference tablets must have a solid crystalline form as disclosed in WO2011 / 153953. A preferred embodiment of such a preparation has a particle size distribution having d(0.9) ≤ 700 μm.

[0141] Logarithmically transformed C max Value and AUC 0-tDetails for evaluating whether the 90% confidence interval of the value falls within the range of 80.00–125.00% of the value achieved with the reference tablet, including the use of randomized crossover studies in a suitable trial population, are provided in the following sections.

[0142] bioequivalence Accordingly, the present invention provides oral dosage forms that are bioequivalent to the reference tablets (a) to (c). The oral dosage forms contain the same molar amount of bexagliflozin as the associated reference tablets, i.e., the same amount as 5 mg, 10 mg, or 20 mg of bexagliflozin of formula (I).

[0143] In the field of bioavailability and bioequivalence, methods for determining whether any particular tablet meets the regulatory requirements for equivalent bioavailability and pharmacokinetic bioequivalence are well known. Niazi (2014) Handbook of Bioequivalence Testing, 2 ndEdition, ISBN 978-1482226379; FDA Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, December 2013; FDA Guidance for Industry: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs - General Considerations, March 2014; FDA Guidance for Industry: Bioanalytical Method Validation, May 2018; Guideline On The Investigation Of Bioequivalence, EMA January 2010(CPMP / EWP / QWP / 1401 / 98 Rev.1 / Corr **); and Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms, EMA November 2014(EMA / CPMP / EWP / 280 / 96 Corr1).

[0144] Many individual-dependent factors can affect drug concentrations in plasma. Therefore, regardless of whether the drug is administered under fasting or feeding conditions, it is common practice to consider the subject's body weight, the degree of impairment of their liver and / or kidney function, concomitant medications, diet, alcohol or tobacco consumption, and the influence of sex, race, genetics, and culture. Consequently, drug concentrations can vary significantly from person to person, even under optimally controlled conditions. The specifications of sustained-release formulations are most accurately derived by referring to properties that can be measured in vitro, such as solubility as a function of time (see other parts of this specification). When referring to properties measured in vivo, it is appropriate to adjust or normalize the effect for the expected behavior in a well-characterized prototype subject.

[0145] However, from a practical standpoint, even the specifications of the original subject cannot capture all inter-individual variability, and for this reason, comparisons between formulations are typically made by administering each formulation being compared (e.g., a reference formulation on one day, a comparison formulation on another, and vice versa) to the same individual. Since a considerable period of time (at least 10 half-lives of the drug since the previous formulation) is usually acceptable, there is little possibility that a previous administration of one formulation will affect measurements taken after administration of a subsequent formulation. Because considerable inter-individual variability is almost always present, comparisons are usually made in groups of 12 or more individuals. Formulations are said to be bioequivalent if certain criteria are met for comparing pharmacokinetic measurements between subjects who have received each of the two formulations.

[0146] In principle, there are many ways to define bioequivalence between formulations, but the widely accepted criterion for regulatory purposes used herein is that two formulations can be considered bioequivalent for a particular pharmacokinetic parameter if the lower limit of the 90% confidence interval of the logarithm of the geometric mean of the parameters of the test formulation, when raised to a power, is greater than or equal to 80.00% of the geometric mean of the same parameter of the reference formulation, and the upper limit of the 90% confidence interval of the logarithm of the geometric mean of the parameters of the test formulation, when raised to a power, is less than or equal to 125.00% of the geometric mean of the parameters of the reference formulation. Typical parameters that need to be found to satisfy this test are the highest observed drug concentration (C) max ), the area under the curve (AUC) of the concentration as a function of time from the start of administration to the last accurately measurable value. 0-t ), and the area under the curve (AUC) of the concentration as a function of time extrapolated to infinite time from the start of administration. 0-∞ ) Most physiological variables, including drug plasma concentrations, typically exhibit a log-normal distribution in repeated sampling of the same individual and sampling from different individuals within a population; therefore, geometric mean and logarithms are used in these calculations.

[0147] Therefore, the present invention relates to a sustained-release tablet containing bexagliflozin, comprising one of the reference tablets (a) to (c) and C max and AUC 0-t The present invention provides sustained-release tablets that are bioequivalent.

[0148] To ensure statistical power, C max Value and AUC 0-t Studies measuring the value are conducted in groups of multiple subjects, for example, a group of at least 12 (usually 24-36) healthy human adults.

[0149] To establish bioequivalence, two-period, two-sequence, two-treatment, single-dose, crossover study designs, single-dose parallel study designs, or repeated study designs may be used. The preferred design is a two-period, two-sequence, two-treatment, single-dose, crossover study using healthy subjects. Each subject should receive each treatment (experimental drug and reference drug) in a randomized order. The most accurate, sensitive, and reproducible method for measuring drug concentrations in plasma should be used. For bexagliflozin, the preferred method is validated high-performance or ultra-high-performance liquid chromatography separation with analyte detection by tandem mass spectrometry. For bexagliflozin sustained-release tablets, both fasting and feeding bioequivalence studies should be performed. In each case, the highest dose strength formulation should be tested. Multiple-dose (e.g., steady-state) studies are not recommended.

[0150] To establish bioequivalence, a minimum of 12 subjects with evaluable data is generally required. In studies conducted under fasting conditions, a minimum of 10 hours of fasting is required before administration, and water should be withheld from 1 hour before administration until 1 hour after administration. No food should be provided for at least 4 hours after administration. The investigational drug may be administered with 240 mL of water.

[0151] Studies conducted on the dietary state of consumption require a minimum of 10 hours of fasting before a standard 800-1000 kcal high-fat, high-calorie meal containing approximately 150, 250, and 500-600 kcal of protein, carbohydrates, and fat, respectively (see, for example, FDA Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (2013) and Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA / CPMP / EWP / 280 / 96 Corr1) Section 5.1.4.1). The meal should be consumed in less than 30 minutes, and the drug should be administered 30 minutes after the start of the meal. No additional food should be provided for at least 4 hours.

[0152] Testing in any dietary state generally requires collecting venous blood samples at appropriate intervals, totaling 12 to 18 samples, encompassing at least three terminal phase elimination half-lives of the drug. max To provide the expected T max High-density sampling in the vicinity is recommended.

[0153] C max Value and AUC 0-t In determining the values, each tablet tested is inevitably consumed, and there are variations from test to test. Therefore, even if the tablets are identical in all respects and the same subjects are used, the pharmacokinetic parameters will differ from those of the set of subjects to which a representative sample set of tablets from the manufacturing batch was administered. max And the mean of the AUC value is determined. The mean is constructed geometrically, not arithmetically. C in this and below max Taking this as an example, in a cohort of 6 subjects, the geometric mean C max The six Cs of the target are max It is calculated as the sixth root of the product of the value. C maxThe same result is obtained by raising the arithmetic mean of the logarithms of the values ​​to a power. C for each object max The logarithmic value of C max The distribution of the logarithms of the individual values ​​is collectively constructed.

[0154] To compare the second production batch with the first production batch, the measurement process can be repeated using the same subjects but with tablets from the second production batch (in actual practice, the order of administration is typically randomly selected for each subject, so some subjects may receive tablets from the second production batch first, while others may receive tablets from the first production batch first). For each subject, the C of tablets from the second production batch max From the logarithm of the C of tablets from the first manufacturing batch max The difference is calculated by subtracting the logarithm of the first tablet. The power of this difference is the C of the first tablet. max The second tablet C max This is the ratio, and if the difference is zero, it is 1(e 0 =1). Following the usual statistical method for analyzing the difference between two sets of values ​​(analysis of variance), the endpoint of the 90% confidence interval for the difference in logarithms is determined. For the two distributions to be considered biologically equivalent, the endpoint of the 90% confidence interval for the difference in logarithms must fall between -0.22314 and +0.22314. When these values ​​are raised to powers, they become 80.00% and 125.00% respectively (for example, e -0.22314 (=0.8000).

[0155] To minimize variability between measurements, it is considered advantageous to administer tablets from each manufacturing batch to each subject. However, if different subject cohorts are used to evaluate tablets from two manufacturing batches, a similar approach can be used, in which the mean log difference is calculated for the two cohorts and a 90% confidence interval for the log difference is constructed.

[0156] This type of test can be applied to determine whether the tablet in question is a tablet as defined herein. A batch of tablets manufactured by an unknown manufacturing process can be determined by the methodology described above to be C max and AUC 0-t Compared to a batch of tablets of the present invention as defined by referring to C max and AUC 0-t If the 90% confidence interval endpoint of the logarithmic difference between the values ​​of the two batches for both falls between -0.22314 and +0.22314, then the batch of tablets manufactured by an unknown process is associated with C max and AUC 0-t It is a tablet that meets the requirements.

[0157] As a consequence of the above, the target cohort was administered two doses of the tablets of the present invention from the same manufacturing batch, and the cohort was C max and AUC 0-t If defined by referring to C max and AUC 0-t For both, the 90% confidence interval endpoint for the logarithmic difference between the values ​​of the first and second doses falls within the range of -0.22314 to +0.22314.

[0158] This means that, using two representative sample sets from the same batch, in a cohort of healthy subjects, the endpoint of the 90% confidence interval for the difference between the logarithmic sets falls within the range of -0.22314 to +0.22314. max Logarithms and AUC 0-t This can be more formally expressed as stating that a mean difference occurs between sets of logarithms. The difference from the previous paragraph is that the order of trials from the two sample sets may be randomly assigned among the subjects of the cohort, for example, as recommended in regulatory guidance documents for bioequivalence trials.

[0159] In vitro dissolution test Test methods for sustained-release solid oral dosage forms are well known in the art, and the types of apparatus and methods of use for immediate-release and sustained-release solid oral dosage forms are specified in the USP. <711> Includes.

[0160] Testing of bexagliflozin sustained-release tablets is performed in a USP apparatus 1 (e.g., a basket apparatus with a nominal volume of 1 liter), filled with 900 mL of 0.1 N HCl (i.e., simulated gastric juice), and stirred at a speed of 50 rpm at a temperature maintained at 37 ± 0.5 °C. Individual tablets are placed in the apparatus, and sampling is performed by taking 10 mL of liquid without replacement at specified time intervals (e.g., 1, 3, 5, and 8 hours). At each time point, the concentration of bexagliflozin in the liquid sample is determined (e.g., by a validated HPLC method), thereby allowing for the calculation of the amount released from the tablet. If such a method involves filtering the liquid taken before HPLC analysis, it may be useful to separate the first fraction of the liquid (e.g., 3.5 mL of the 10 mL sample) and then analyze the subsequent fraction (e.g., the remaining 6.5 mL of the 10 mL sample) to avoid variations caused by possible interactions between bexagliflozin and the filter (e.g., PVDF material).

[0161] The test can proceed in up to three stages, referred to as levels. In the first stage (Level 1 test), six tablets are analyzed. Success is recorded if the individual values ​​do not fall outside the indicated ranges and the individual values ​​do not fall below the indicated amount at the final test. If these criteria are not met, an additional six tablets are analyzed (Level 2 test). Success is recorded if the average value of all 12 units falls within the indicated ranges (i.e., 1, 3, 5, and 8 hours) and does not fall below the indicated value at the final test, and none of them fall outside the indicated ranges by more than 10% of the labeled amount (i.e., 2 mg for a 20 mg tablet), and none of them fall below the indicated amount by more than 10% of the labeled amount at the final test. If the Level 2 criteria are not met, a Level 3 test must be performed. An additional 12 tablets are tested. The average value of all 24 tablets must fall within the indicated ranges and must not fall below the indicated amount at the final test. Of the 24 units, two or fewer fell outside the range indicated as exceeding 10% of the labeled content, and two or fewer of the 24 units were below the amount indicated as exceeding 10% at the time of final testing. None of the units fell outside the range indicated as exceeding 20% ​​of the labeled content (i.e., 4 mg for a 20 mg tablet) at the time of final testing, nor were they below the amount indicated as exceeding 20% ​​of the labeled content.

[0162] A manufacturing batch of bexagliflozin sustained-release tablets is considered to have passed a formal dissolution test if it meets the acceptance criteria for at least one of the three test levels. A representative unit of a manufacturing batch is specified in the USP <711> The candidate must meet the criteria defined in Pass / Fail Judgment Table 2. In practice, the exam ends upon success. No additional exams are permitted, such as restarting the exam at Level 1 if the candidate fails at Level 3.

[0163] Accordingly, the present invention provides sustained-release tablets comprising bexagliflozin, derived from a manufacturing batch having a test or manufacturing composition or method that falls within formally acceptable ranges for process, testing, or variation of components of the U5, U10, U20, or U40 formulations (see below). Of these four formulations, U20 is most preferred for use in the treatment of diabetes.

[0164] The present invention also provides sustained-release tablets containing bexagliflozin, derived from a manufacturing batch having the composition of a U5, U10, U20, or U40 formulation (see below).

[0165] Similarly, the present invention provides a solid oral dosage form (particularly a tablet such as a sustained-release tablet) comprising bexagliflozin, having an f² value greater than 50 when compared to one of the reference tablets (a), (b), or (c) defined above in an in vitro dissolution test in simulated gastric juice, where f² is the decimal logarithmic inverse square root transformation of the sum of squared errors.

number

[0166] The present invention provides a sustained-release tablet containing bexagliflozin, which, in an in vitro dissolution test in simulated gastric juice, releases 17% or less of the bexagliflozin after 1 hour and 80% or more after 8 hours. Preferably, the tablet releases 20-45% of the bexagliflozin after 3 hours and / or 45-75% of the bexagliflozin after 5 hours. As described above, within the range of 45-75% after 5 hours, the tablet can release (a) 45-72% of the bexagliflozin, (b) 50-70% of the bexagliflozin, (c) 49-69% of the bexagliflozin, or (d) 48-68% of the bexagliflozin. Furthermore, after 3 hours, the tablets can release 23-43% of bexagliflozin within a range of 20-45%.

[0167] The present invention also provides a solid oral dosage form, typically a sustained-release tablet, comprising bexagliflozin, which passes a formal dissolution pass / fail test in simulated gastric fluid (see above) with standard criteria of releasing 17% or less of the bexagliflozin dose after 1 hour and 80% or more of the bexagliflozin after 8 hours. Preferably, the standard criteria for the dissolution pass / fail test require that 20-45% (e.g., 23-43%) of the bexagliflozin is released after 3 hours and / or 45-75% (e.g., 45-72%, 50-70%, 49-69%, or 48-68%) of the bexagliflozin is released after 5 hours. In the formal dissolution pass / fail test, these dosage forms must meet the USP standards. <711> Pass at least one of the three formal levels of the examination protocol defined in Pass / Fail Judgment Table 2.

[0168] Treatment method The tablets of the present invention may be used to treat diabetes and its symptoms, particularly type 2 diabetes. More specifically, the tablets of the present invention may be used as dietary and exercise aids to improve blood glucose control in adults with type 2 diabetes.

[0169] The present invention provides a method for treating a subject suffering from diabetes or its symptoms. The method includes administering to the subject a tablet of the present invention, generally including repeated administration (e.g., once a day) indefinitely or until a desired treatment result is obtained. A dose of 5 mg, 10 mg, 20 mg, or 40 mg of bexagliflozin once a day is typical.

[0170] Similarly, the present invention provides a tablet of the present invention for use in such a treatment method.

[0171] The present invention also provides the use of bexagliflozin and at least one pharmaceutically acceptable excipient in the manufacture of a medicament for treating diabetes, wherein the medicament is the tablet of the present invention as described above. The pharmaceutically acceptable excipient can be selected as discussed herein to provide a sustained-release tablet of the present invention.

[0172] As described above, one tablet of the present invention preferably contains 5 mg, 10 mg, 20 mg, or 40 mg of bexagliflozin. Accordingly, the methods and uses of the present invention generally include administering to the subject once a day 5 mg, 10 mg, 20 mg, or 40 mg (or an integer multiple thereof) of bexagliflozin, e.g., 5 mg, 10 mg, 20 mg, or 40 mg.

[0173] These treatment methods and uses can be performed on diabetic patients who are also receiving type 2 diabetes medications such as GLP-1 receptor agonists (e.g., exenatide, lixisenatide, dulaglutide, liraglutide, albiglutide, or semaglutide). As discussed elsewhere herein, the tablets of the present invention can be safely administered to such subjects without requiring a change in the prescription pattern.

[0174] Existing GLP-1 receptor agonists include exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, and semaglutide (reviewed by Gentilella et al., (2019) Diabetes Metab Res Rev 35:e3070 doi:10.1002 / dmrr.3070). The first two are analogs of exendin-4, peptides isolated from the saliva of the Gila monster, which facilitate predation by causing severe hypoglycemia in bitten prey. The latter four are analogs of human GLP-1 with modifications that extend the plasma half-life. The approved dosages for these agonists are as follows: exenatide is delivered by subcutaneous injection of 5 μg or 10 μg twice daily, or by weekly injection of a sustained-release depot preparation; lixisenatide is delivered by subcutaneous injection of 20 μg once daily; for maintenance therapy, liraglutide is delivered by subcutaneous injection of 1.2 or 1.8 mg once daily; the others are delivered by weekly subcutaneous injection, with albiglutide at a dose of 30 or 50 mg, dulaglutide at a dose of 0.75 or 1.5 mg, and semaglutide at a dose of 0.5 or 1.0 mg. [Examples]

[0175] Example 1 - Effervescent Tablets Effervescent tablets containing 10 mg, 15 mg, or 20 mg of bexagliflozin were developed. Initial tablets were formed by direct compression and consisted of hydroxypropyl methylcellulose (HPMC; low and medium viscosity), lactose monohydrate, sodium bicarbonate, and magnesium stearate. Each of these excipients was initially shown to be compatible with bexagliflozin during stability studies (e.g., decomposition was observed when citrate monohydrate was tested as an effervescent agent). Bexagliflozin and lactose monohydrate (diluent) were mixed, sieved, and then HPMC, sodium bicarbonate, and silicon dioxide were added to a blender. Finally, magnesium stearate was added as a lubricant to form tablets.

[0176] We initially proposed two targeted release profiles that release more than 80% of bexagliflozin in either 12 or 18 hours, as evaluated by an in vitro dissolution test of the tablets in 900 mL of 0.1 N HCl (USP instrument 2, 50 rpm, 37 ± 0.5 °C, with sinker). The tablet composition is as follows: [Table 2]

[0177] Tablets containing a mixture of HPMCs showed a 68% release rate after 10 hours and an 82% release rate after 14 hours. In contrast, tablets containing a single HPMC compound showed a 62% release rate after 10 hours, a 75% release rate after 12 hours, and an 89% release rate after 16 hours.

[0178] Two further batches were prepared. [Table 3]

[0179] These two tablets had similar release profiles (75%) up to 12 hours, but subsequent release was slightly faster with the HPMC mixture (91% vs. 87% at 18 hours).

[0180] Further various tablets were prepared, and the final tablet composition was selected as follows. [Table 4]

[0181] We initially tested different formulations of 20 mg tablets. [Table 5]

[0182] These tablets had a slower-than-desired release profile (less than 75% after 12 hours in both cases), so modifications were made. The final tablet compositions for the 15 mg and 20 mg tablets were selected as follows: [Table 6]

[0183] Data from various further in vitro studies have shown that a low viscosity HPMC (19 - 24% methoxyl, 7 - 12% hydroxypropyl, apparent viscosity of 2% aqueous solution at 20°C of about 3000 mPa·s) can be used as the sole release - controlling polymer material while giving the desired release profile. By using 1% magnesium stearate, tackiness was avoided. Therefore, the final batch for clinical studies was prepared with the following composition (mass in mg) and release profile. [Table 7]

[0184] These three tablets were made by mixing lactose monohydrate and bexagliflozin, then adding HPMC, sodium bicarbonate, and silicon dioxide, and finally adding magnesium stearate. The mixture was tableted by direct compression with a 7 - mm punch. The tablets were stable for 1 month at 40°C and 75% relative humidity.

[0185] These three sustained - release (XR) tablets, together with 20 - mg immediate - release (IR) tablets, were tested in human clinical trials to evaluate pharmacokinetics and pharmacodynamics. The tablets were administered once daily for 5 days under fasting conditions (days 1 and 2) or fed conditions (day 3). The mean PK parameters ± SD obtained from the fasting - condition test are as follows. [Table 8]

[0186] Thus, compared with the 20 - mg immediate - release tablets, the C of the 20 - mg sustained - release tablets maxIt showed a longer half-life of approximately 40%, but apparent bioavailability decreased by approximately 30%. Absorption and clearance were consistent across the three sustained-release doses. max Furthermore, the AUC value increased with increasing dose.

[0187] In the 20mg IR formulation, a lower C max and longer T max As shown by the extension, food reduced the amount of bexagliflozin and delayed its absorption. Food reduced the absorption rate of the 20 mg IR formulation but had little effect on overall bioavailability.

[0188] In the 10mg XR formulation, the average T max Aside from a shortening of the time interval, food appeared to have little effect on the PK profile. However, by examining the PK parameters, T max The median was found to be the same under both feeding and fasting conditions.

[0189] For the 15 mg and 20 mg XR formulations, food is T for both dose levels. max It lowered the average C max and AUC 0-∞ The results were similar under both feeding and fasting conditions. These observations indicate that food may accelerate the absorption of bexagliflozin after administration of 15 mg and 20 mg of the XR formulation, but it did not increase the magnitude of bexagliflozin absorption.

[0190] Regarding pharmacodynamics, all tablets were associated with significantly dose-dependent diabetes in healthy subjects. Glucose excretion occurred more slowly with the XR formulation compared to the IR formulation, but total daily glucose excretion was comparable. In general, urinary glucose excretion was highest for all tablets during the first 12 hours after administration and on day 2 under both fasting and feeding conditions. Since excretion under feeding conditions was within the range observed during fasting, food appeared to have minimal impact on 24-hour glucose excretion for all tablets.

[0191] These XR formulations are C of besagliflozin max We succeeded in reducing T, but bioavailability and pharmacokinetics were more volatile than desired. In particular, T max The variability was unacceptably high, likely due to the tablets not being able to remain in the stomach. Early expulsion from the stomach may explain the sporadicly lower bioavailability, partly due to the absence of the destructive stress resulting from acid-induced foaming. Therefore, we developed further XR formulations to mitigate this variability.

[0192] Example 2 - Pellet-Releasing Capsule Capsules that disperse into many small pellets or granules in the stomach would reduce the chances of the total dose of bexagliflozin being emptied from the stomach in a single event. Therefore, we proposed two approaches that rely on capsules that release multiple bexagliflozin pellets: the first releases low-density pellets that float in gastric acid, and the second releases coated pellets.

[0193] Five formulations were prepared using floating pellets ("floater" capsules) and evaluated in the same manner as before by in vitro dissolution tests in 0.1N HCl. The contents of these capsules (mg per capsule) and the percentage of bexagliflozin released after 12 hours are as follows. [Table 9]

[0194] Twenty-one formulations using coated pellets were tested, each consisting of seven pellets with three different coatings. The composition and dissolution percentage at 12 hours are as follows. [Table 10] [Table 11] [Table 12] Based on in vitro dissolution testing, the formulations were selected as follows: [Table 13]

[0195] To produce pellets, bexagliflozin, glyceryl dibehenate (retardant and flotation agent), ethyl acrylate / methyl methacrylate copolymer (Eudragit RS PO; matrix material), microcrystalline cellulose (MCC; filler), and polyvinylpolypyrrolidone (binder and disintegrant) were mixed, and then water was added to obtain moist granules. Moist pellets were obtained by extrusion and spheroidization, and then dried to obtain floating pellets, which were then filled into capsules.

[0196] To produce coated granules, bexagliflozin, microcrystalline cellulose (excipient), poloxamer 188 (solubilizer), and polyvinylpolypyrrolidone (binding and disintegrating agent) were mixed, and then water was added to obtain wet granules. Wet pellets were obtained by extrusion and spheroidization, and these were dried. Next, talc (lubricant), TEC (plasticizer), and water were mixed to obtain a suspension, which was then mixed with two Eudragit copolymer components (sustained-release coating) to form a coating composition. This was used to coat the dried pellets, and the coated pellets were filled into capsules.

[0197] Accelerated stability studies showed that the compositions were stable for 8 weeks at 40°C and 75% RH, but the dissolution profile was significantly altered (slower in coated pellets and faster in floaters). Therefore, while these formulations successfully altered the pharmacokinetic profile of bexagliflozin, their shelf life is not optimal for commercial purposes.

[0198] Example 3 - Floating Tablets Tablets suspended in the stomach contents delay their movement from the stomach, thus avoiding rapid premature expulsion from the stomach, as described in Example 1 above.

[0199] Two prototype formulations with the following composition (mg per tablet) were prepared. [Table 14]

[0200] These tablets were compressed to a hardness of 40N or 50N and then subjected to in vitro dissolution tests in the same manner as in Examples 1 and 2. The percentage of bexagliflozin released at 8 and 12 hours was as follows: [Table 15]

[0201] Based on these results, the final tablet formulation was selected as follows. [Table 16]

[0202] These tablets are manufactured by combining (a) bexagliflozin, MCC, glyceryl dibehenate, and PEO, and (b) silicon dioxide and magnesium stearate, and then combining (a) and (b) for direct compression to form tablets.

[0203] Accelerated stability studies showed that the tablets were stable for 8 weeks at 40°C and 75% relative humidity, with minimal differences in dissolution profiles.

[0204] Example 4 - Tablets with faster sustained release While maintaining a similar tablet composition and direct compression manufacturing technique, further work was carried out to obtain faster release from the mucosal adhesive tablet of Example 3 (aiming for complete release in 4-6 hours). Therefore, the tablet composition was modified, and investigations resulted in two additional formulations. [Table 17]

[0205] These tablets were manufactured in the same manner as in Example 3. That is, all components except the lubricant and flow promoter were combined, then mixed with the combined lubricant / flow promoter, and compressed into tablets by direct compression to a hardness of 30N.

[0206] The 8-hour dissolution profile of the tablet is as follows: [Table 18]

[0207] The tablets remained stable for at least 8 weeks at 40°C and 75% RH. After this storage, the dissolution profile of tablet J showed only negligible differences, while the release profile of tablet K was slightly faster. Furthermore, both tablets became slightly harder after storage.

[0208] Therefore, earlier release was successfully achieved compared to Example 3.

[0209] Example 5 - Lactose-free sustained-release tablets Tablet J in Example 4 contains lactose. Since this is an animal-derived material, alternative fillers were tested in order to ensure that the tablets have a similar release profile. In particular, mannitol, sorbitol, xylitol, and maltodextrin were tested as substitutes (45 mg each).

[0210] All four of these components were initially shown to be compatible with bexagliflozin.

[0211] By using mannitol instead of lactose, tablets with similar release behavior were obtained, and both formulations released over 90% in vitro within 5 hours. When higher tablet hardness (45-55N) was tested, the suspend time was shortened and dissolution was slightly faster.

[0212] Maltodextrin, sorbitol, and xylitol showed slightly faster release profiles than lactose and mannitol, likely due to their higher elution rates.

[0213] Overall, it was possible to achieve equivalent solubility behavior by replacing lactose with an alternative excipient.

[0214] Example 6 - Sustained-release tablets for clinical trials Five floating, mucosal-adhering tablets, including the final formulation from Example 3 and tablets J and K from Example 4, were prepared for clinical trials. Their compositions and properties were as follows. [Table 19]

[0215] Generally, these were prepared by combining (a) a mixture of bexagliflozin and MCC, (b) a mixture of lubricants and flow promoters, and (c) a mixture of the remaining components. The mixture was then compressed to the desired hardness using a rotary compressor equipped with a 14 × 6 mm caplet-shaped punch. The abrasion rate was less than 1% w / w.

[0216] Some stickiness was observed with formulation N, so the amount of magnesium stearate was increased to 4.5 mg, which resolved the problem. Then, formulation O was obtained by further increasing the amount of silicon dioxide.

[0217] Formulations L, M, and O were found to possess the best overall properties in terms of dissolution and stability. To further study the effect of dissolution time, these three tablets were selected. Tablet L transitioned to 80% to 90% release after 10-12 hours of sample, tablet M occurred after 8-10 hours, and tablet O after 5-6 hours. Therefore, to reflect their dissolution profiles, these tablets were named XR11, XR8, and XR5, and proceeded to clinical trials.

[0218] Example 7 - Alternative dosage of tablets for clinical trials Based on the XR5 results of Example 6 (Tablet O), further floating mucosal-adhering tablets were prepared in the same manner, except that they contained 10 mg or 30 mg of bexagliflozin. Furthermore, these tablets had a film coating made using OpdaryII White. The final tablets had the following composition (mg per tablet): [Table 20]

[0219] Coated tablets were cured at 50°C for up to 24 hours to study the effect on hardness. Since the tablet's dissolution-release profile and hardness were not affected by curing, this treatment was not used in further research.

[0220] The accelerated stability study did not show any effect on the dissolution properties of the tablets.

[0221] The release of bexagliflozin in the in vitro dissolution test (conducted in the same manner as above) was as follows: [Table 21]

[0222] Because the stability and release profiles of these tablets were consistent with the intended properties, they were advanced to human clinical trials along with the XR5, XR8, and XR11 tablets of Example 6.

[0223] Example 8 - Particle Size Distribution The effect of the particle size distribution of crystalline bexagliflozin on tablet dissolution was evaluated in in vitro dissolution tests using five types of XR tablets containing a total dose of 20 mg or 30 mg of bexagliflozin. Various particle size distributions were tested using d(0.9) values ​​ranging from approximately 10 μm to approximately 700 μm, such as 220 μm or 325 μm (i.e., a particle size distribution in which 90% of the cumulative volume of crystalline bexagliflozin particles have a diameter of 10 μm to 700 μm). No significant variation in the tablet dissolution profile was observed with these different d(0.9) values, therefore, the particle size distribution of crystalline bexagliflozin is not considered an important parameter of tablet dissolution.

[0224] Example 9 - Clinical Trial To evaluate the pharmacokinetics of these floating tablets at multiple doses, a two-part, open-label Phase 1 study was conducted in healthy male subjects. Part 1 evaluated the PK profiles of XR5, XR8, or XR11 tablets (Example 6). Part 2 evaluated three dose intensities (10 mg, 15 mg, and 30 mg) of tablets with a 5-hour release profile (Example 7). Secondary objectives were to evaluate the safety and tolerability of bexagliflozin and to assess the effect of food on PK parameters.

[0225] Part 1 used a crossover design. Twenty participants were administered either three 15 mg tablets or a 20 mg capsule (size 2 white opaque gelatin capsule containing 20 mg bexagliflozin and silicified microcrystalline cellulose). There were four administration periods with no washouts between them. The first administration period consisted of two days of once-daily administration in a fasted state, followed by one day of administration in a fed state. The second to fourth administration periods consisted of one day of administration in a fasted state, followed by one day of administration in a fed state. Participants were randomized to receive one of the four formulations in one of 24 possible permutations for the four-period crossover study, with a single constraint that the first administration period included five doses of each formulation.

[0226] In Part 2, a parallel design was used with 30 participants. The tablets were administered once daily for two days in a fasted state and for one day in a fed state.

[0227] To ensure swallowing without chewing, subjects were given tablets (or capsules) with approximately 200 mL of water while standing. Administration while fasting was performed after a minimum of 10 hours of overnight fasting. In the case of administration while fasting, breakfast was provided one hour after administration. In the case of administration while feeding, it was performed 30 minutes after the start of a standard meal. Plasma concentrations of bexagliflozin were determined from K2EDTA-anticoagulated total venous blood samples using a validated HPLC-MS / MS method (see below).

[0228] Figure 1 shows the geometric mean plasma concentration of bexagliflozin in fasted subjects in Part 1 of the study. The capsule formulation showed high C max This indicates that, however, using XR5, XR8, or XR11 tablets successfully reduces this, and in fasted subjects, all three XR tablets reduce T for 3 hours. max This represents the median and provides an extended absorption period (compared to 1 hour with capsules). Considering their lower doses (15 mg vs. 20 mg), the normalized C of the tablets... max It decreased to less than 5 ng / mL / mg compared to 10.2 ng / mL / mg. The degree is low, but C max It also decreased during feeding. XR11 showed the greatest decrease. max After reaching a certain level, plasma concentrations decreased in a biphasic manner in both the tablet and capsule formulations. Overall, the specific pharmacokinetic parameters were as follows: [Table 22]

[0229] Figure 2 shows the geometric mean plasma concentrations of bexagliflozin in fasted subjects in Part 2 of the study. All three doses (10, 15, and 30 mg) showed an extended absorption period, and all doses showed a 3-hour T in fasted subjects. maxIt was the median. C max After reaching [a certain point], plasma concentrations decreased in a biphasic manner for all three tablets. Exposure (AUC) 0-24h and C max The pharmacokinetic parameters generally appeared to increase in a dose-proportional manner within the range of 10–30 mg, but clearance and distribution were dose-independent. Overall, the specific pharmacokinetic parameters were as follows: [Table 23]

[0230] In summary, pharmacokinetic studies showed that administration of XR11, XR8, and XR5 tablets resulted in longer absorption compared to capsule formulations. Mean exposure was higher after administration of 20 mg capsule formulations than after administration of 15 mg XR formulations, regardless of the dietary state. Among the XR formulations, XR5 resulted in the greatest exposure. Administration of XR formulations in a fed state compared to administration in a fasted state resulted in a higher AUC. 0-24 and C max Exposure increased from 27% to 49% and from 71% to 97%, respectively. Administration of 10, 15, and 30 mg of the XR5 formulation increased exposure in a dose-proportional manner.

[0231] Methods for analyzing human plasma samples As described above, the bexagliflozin concentration in human plasma samples was determined using validated HPLC-MS / MS methods. An example of a preferred method is provided below.

[0232] The internal standard "IS" has six hexose carbons 13 The internal standard was bexagliflozin substituted with 1C. Other internal standards such as tolbutamide can be used, but isotope-labeled internal standards are preferred.

[0233] Each implementation includes "blank + IS" and "blank + drug" samples to monitor the contribution from IS to the analyte or vice versa. Methanol is the solvent for all standards and reconstitutions. The matrix is ​​human plasma anticoagulated with K2EDTA.

[0234] The analytical procedure is as follows: Thaw the standard, QC, blank matrix, and study sample (if applicable), vortex for approximately 3 minutes, and then pipette; add 100 μL of blank plasma to the blank, blank + IS, blank + drug, test sample, and calibration standard, the spike blank + drug containing 5 μL of 16000 ng / mL bexagliflozin spike solution, and the spike test sample containing 5 μL of 80 ng / mL spike solution; add 5 μL of each concentration of spike solution to the calibration standard; Q Add 100 μL of the appropriate concentration and number of QC samples to the C tube; if applicable, add 100 μL of each test sample to the appropriate tube; if applicable, add 5 μL of MeOH to the blank, blank + IS, QC, and study sample tubes; add 50 μL of IS to the test material, blank + IS, calibration standard, and QC (and study sample, if applicable) tubes; add 50 μL of MeOH to the blank and blank + drug tubes; vortex at high speed for approximately 2 minutes.

[0235] The protein precipitation extraction procedure is as follows: Add 500 μL of acetonitrile (ACN) to all tubes; vortex the tubes at high speed for approximately 3 minutes, then centrifuge at 3000 rpm for 10 minutes; transfer the supernatant to 16 × 100 mm labeled tubes; evaporate to dryness in a 40°C bath under a nitrogen stream for approximately 10 minutes; reconstitute all samples in each tube with 200 μL of MeOH and vortex at high speed for approximately 1 minute; transfer to autosampler vials for LC-MS / MS analysis; centrifuge the vials at 3000 rpm for approximately 5 minutes.

[0236] The equipment used included a vacuum degasser, DGU14A, Shimadzu Corp.; a solvent delivery system, LC-10ADvp, SCL-10Avp, Shimadzu Corp.; an autoinjector, HTCPAL, CTC Analytics; a 35°C column heater, TS-130, Phenomenex™; and a mass spectrometer, Triple Quadrupole MS (API4000), Sciex. [Table 24] [Table 25] [Table 26]

[0237] Example 10 - Additional Tablet Strength To complement Example 9, 3 mg and 90 mg tablets of bexagliflozin were prepared. The 3 mg tablets were similar to those in Example 9, but the excipients were removed from the 90 mg tablets, causing them to lose their buoyancy properties. Placebo tablets were also prepared to observe buoyancy properties. Mucosal adhesives were retained in all tablets. The new tablets had the following composition: [Table 27]

[0238] It was found that the absence of MCC in tablet S affected its compressibility, leading to severe stacking. Therefore, additional 90 mg tablets were prepared containing either 25 mg or 50 mg of MCC, or a combination of 20 mg lactose and 25 mg of MCC. Furthermore, lubricants and flow enhancers were co-sieved with bexagliflozin to reduce stacking. Based on the observed dissolution and buoyancy profiles, the following tablets were prepared for clinical use. [Table 28]

[0239] These were prepared, as before, by (a) mixing bexagliflozin and MCC with (b) polyethylene oxide, poloxamer, lactose, and glyceryl dibehenate by co-sieving, followed by (c) adding a mixture of magnesium stearate and silicon dioxide. This material was compressed to the desired hardness using a 14 × 6 mm caplet-shaped punch, and then coated into tablets.

[0240] The release of bexagliflozin from these tablets is as described above in the USP <711> The results were evaluated by an in vitro elution test (USP instrument 1, packed with 900 mL of 0.1N HCl, stirred at 50 rpm and 37°C, sampling without replacement). The following table shows the chromatographic conditions suitable for detecting bexagliflozin in 0.1N HCl. A 10 mL sample from instrument 1 was passed through a 10 μm PVDF filter, and 50 μL was injected into the chromatography column. [Table 29]

[0241] The results of these in vitro dissolution tests are as follows: [Table 30]

[0242] The specific pharmacokinetic parameters of T10 and T30 tablets in clinical trials in patients in both feeding and fasting states are as follows: [Table 31]

[0243] Example 11 - Further mucosal adhesive clinical tablets Based on the above examples, tablets were prepared for clinical trials as follows. [Table 32]

[0244] The tablets were prepared as follows: (i) Using a vibrating sieve machine equipped with #20 sieves, 80% of the bexagliflozin, colloidal silicon dioxide, and MCC were co-sieved; (ii) The sieved materials were blended in a container tumbler at 14 rpm (U5) or 18 rpm (U10 and U20) for 6 minutes; optionally, (iii) this material together with the remaining MCC was sieved at 1000 rpm through a conical screen mill equipped with an 813 μm screen to obtain mixture "A"; (iv) Equipped with #20 sieves Using a vibrating sieve, polyethylene oxide, glyceryl dibehenate, and lactose are sieved to obtain mixture "B"; (v) Mixtures "A" and "B" are blended in a container tumbler at 14 rpm; (vi) Magnesium stearate sieved through a #30 sieve is added and blended in a container tumbler at 14 rpm; (vii) Using a 14.8 × 6.5 mm beveled caplet-shaped punch and appropriate dies, using a set of 10 punches and a force feeder at 20-50 rpm (viii) compress the material into tablet cores using a Korsch XL100 press equipped with a feeder and a turret at 55-70 rpm, or a T-300 press equipped with 32 punch sets and a minimal force feeder; (viii) remove dust; (ix) coat with an 18% w / w suspension of the coating material in a 600 mm (U5) or 800 mm (U10 and U20) pan.

[0245] The release of bexagliflozin in the in vitro dissolution test was as follows, measured using USP apparatus 1 with 900 mL of 0.1N HCl, maintained at 37±0.5°C and stirred at 50 rpm. [Table 33]

[0246] We confirmed the stability of the tablets. For clinical applications requiring a 20 mg dose of bexagliflozin, we selected the U20 tablets.

[0247] Further batches of tablets were prepared in a similar manner with minor modifications. For example, step (vii) was modified to use a Killian T-200 press with 19 heads. Additionally, the concentration of the coating material in step (ix) was reduced from 18% to 12%. Tablets formulated by these modified processes possessed the desired properties.

[0248] A reference batch of U20 tablets was prepared, and in vitro dissolution tests of tablet samples showed the release of 7%, 27%, 50%, and 86% bexagliflozin at 1, 3, 5, and 8 hours, respectively. Nine further production batches were tested (all tested at 1, 5, and 8 hours, and five also tested at 3 hours), and the f2 values ​​ranged from 54 to 94 compared to the reference tablet.

[0249] Example 12 - Stability Test U20 tablets are stored for up to 5 years at either 25°C / 60% relative humidity or 30°C / 75% relative humidity, and their dissolution is controlled by USP. <711> Accordingly, the study involved in vitro dissolution tests in simulated gastric fluid at various time points (3, 6, 9, 12, 18, 24, 36, 48, and 60 months).

[0250] Figure 3 shows the average percentage of bexagliflozin release from six representative stored tablets tested at 1, 3, 5, and 8 hours in simulated gastric fluid. Under both storage conditions and over the full 5-year period, the percentage released in the dissolution test was well below 17% at 1 hour, well within the range of 20–45% (further 23–43%) at 3 hours, well within the range of 45–75% (further 48–68%) at 5 hours, and well above 80% at 8 hours.

[0251] For samples stored at 25°C, the linear regression showed a very slight positive slope for the mean percentage released at 1 and 8 hours, and a very slight negative slope for the mean percentage released at 3 and 5 hours. For samples stored at 30°C, the linear regression showed a very slight positive slope for the mean percentage released at 8 hours, and a very slight negative slope for the mean percentage released at 1, 3, and 5 hours. However, under both storage conditions, the upper and lower limits of the 95% confidence interval were greater than and less than 0 for all four dissolution time points, respectively, indicating that the slopes were not significantly different from 0. Furthermore, the small magnitude of the change over time is consistent with the interpretation that the tablet release profile does not change significantly with storage up to 5 years.

[0252] Example 13 - Efficacy of the U20 formulation in a randomized controlled trial To support late-stage clinical development, seven batches of U20 tablets were prepared, including five batches of approximately 800,000 tablets each. The trials involved 200 to 1700 participants each and were conducted as follows: [Table 34]

[0253] Clinical pharmacological studies and food efficacy studies using Example 14-U20 Further in vivo characterization of the U20 formulation was provided in the course of five clinical pharmacology studies investigating the effects of prior food intake on the pharmacokinetics of bexagliflozin delivered by the formulation and the effects of co-administration of other drugs on its pharmacokinetics. Only the results from the latter group of studies (i.e., the control group) in which no additional drugs were co-administered are provided in the following edit.

[0254] After administration, the U20 tablet was administered following a fasting period of at least 10 hours overnight, during which no food or nutrition was given for 4 hours. The tablet was taken with 240 mL of water, but no water was given 1 hour before or 1 hour after administration. Co-administration of additional medications was not permitted.

[0255] The geometric mean of the given number (n) is as follows: [Table 35]

[0256] These data illustrate the generally expected variability of pharmacokinetic parameters arising from in vivo analysis of formulations in the experimental cohort. The data also highlight the importance of conducting trials in a crossover design, where each individual serves as their own control. Dose-normalized C max The mean value was 5.7 ng / mL·mg of bexagliflozin, dose-normalized C for immediate-release capsules administered in a fasted state. max The corresponding values ​​for capsules containing 6.7, 16.7, and 34 mg of bexagliflozin were 12.6, 11.3, and 11.5 ng / mL·mg of bexagliflozin, respectively. Dose-normalized C for a 50 mg oral solution dose administered in a fasted state. max The AUC of a 50 mg oral solution containing 13.8 ng / mL·mg of bexagliflozin was 2523 ng·h / mL. 0-t This corresponds to a dose strength of 20 mg at 1009 ng·h / mL. Therefore, the U20 formulation has a dose-normalized AUC compared to the rapidly absorbed oral solution. 0-t While slightly reducing, significantly lower dose-normalized C max To provide.

[0257] The effect of prior food consumption has been fairly consistent across multiple studies. In specialized food effects studies with randomized sequencing of subjects, the geometric mean C after ingestion in a feeding state was... max The blood glucose level was 175.7 ng / mL compared to 133.7 ng / mL in a fasted state, or the geometric mean C during fasting. max It was 131.4% of AUC. 0-t and AUC 0-∞ Although it also increased with feeding, the percentages were small, at 13.9% and 11.1%, respectively. maxThe median time was 3.5 hours after administration in a fasted state and 5 hours after administration in a fed state. Other studies comparing pharmacokinetics after administration under different dietary conditions showed that the T value was lower in a fasted state. max The median is typically 3 hours, and T in the feeding state. max The median response time was typically 5 hours. Therefore, the relatively mild effect of prior consumption of high-fat, high-calorie meals and the fact that pharmacokinetic parameters measured after administration do not fluctuate significantly regardless of the dietary state are advantages of the formulation of the present invention.

[0258] In several clinical pharmacology studies, subjects were administered the drug while eating, following a protocol in which they fasted for at least 10 hours and then consumed a high-calorie, high-fat meal within 30 minutes. Subjects ingested the U20 tablet 30 minutes after the start of the meal and did not consume any additional food for at least 4 hours thereafter. Results from several studies of this type are shown in the following table, provided as geometric mean values. [Table 36]

[0259] In a clinical pharmacological study of drug interactions, the effect of the GLP-1 receptor agonist exenatide on the pharmacokinetics of bexagliflozin was investigated in a randomized crossover study. Since GLP-1 receptor agonists are known to delay gastric emptying, and the bexagliflozin dosage form has a gastric retention mechanism, it was considered important to address the potential impact of this delay on bexagliflozin delivery (see, e.g., Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms (EMA / CPMP / EWP / 280 / 96 Corr1) section 5.1.4.2). In this study, participants were assigned to receive either bexagliflozin alone initially, or combination therapy with bexagliflozin and exenatide initially. Each group alternated between the two treatment periods in a crossover design (2 periods, 2 treatments) separated by a 7-day washout period. AUC of bexagliflozin administered 30 minutes after delivery of 10 μg of exenatide by subcutaneous injection. 0-t AUC 0-∞ , and C max Systemic exposure, as measured by [method / tool], increased by approximately 48%, 38%, and 25%, respectively, compared to administration of bexagliflozin alone. AUC of bexagliflozin and exenatide compared to bexagliflozin alone. 0-t AUC 0-∞ , and C maxThe geometric least squares mean ratios [90% confidence interval] were 147.50% [130.23%, 167.07%], 137.56% [122.28%, 154.75%], and 125.27% [104.45%, 150.24%], respectively. The confidence interval endpoints were outside the 80–125% range, indicating that the interaction results in a change in exposure when bexagliflozin is administered after exenatide, but the effect of exenatide on the pharmacokinetics of bexagliflozin is not significant enough to threaten patient safety or recommend a change in prescribing pattern. Within-subject variability when comparing bexagliflozin and exenatide with bexagliflozin alone was AUC, the primary PK parameter. 0-t and AUC 0-∞ For C, the figure is less than 22%. max The rate was approximately 32%. When bexagliflozin was administered 30 minutes after exenatide injection, absorption was delayed, and T max The median time was 5.00 hours after administration, compared to 2.00 hours after administration of bexagliflozin alone.

[0260] Example 15 - Population Pharmacokinetic Modeling Sparse sampling of plasma drug concentrations from large, diverse populations, combined with pharmacokinetic modeling (population PK modeling), is a tool for investigating the potential influence (covariates) on drug pharmacokinetics. Samples for the bexagliflozin population PK analysis were obtained from healthy volunteers or diabetic patients enrolled in studies evaluating pharmacokinetics, diabetic patients participating in a sparse sampling program to obtain samples from multicenter international clinical trials, patients with moderate hepatic impairment, and hypertensive patients participating in an open-label induction period (the period during which all subjects received bexagliflozin). Participants were recruited from North America, Europe, and East Asia. The analysis database included 884 subjects with 6247 concentration records. The analysis included participants exposed to T3, T10, T30, and T90 formulations, as well as U5, U10, and U20 formulations. Most subjects were exposed to the U20 formulation. Participants who consented to participate in the sparse sampling program provided three blood samples taken at various time intervals after administration, typically 6–8 weeks after the start of administration. Study data included administration history (intensity, date and time of administration), plasma concentrations and corresponding sample collection dates and times, demographic descriptors, laboratory values, and records of concomitant medications. The model initially included terms related to dietary status, age, weight, body mass index (BMI), body surface area, albumin, alanine transaminase, aspartate transaminase, bilirubin, creatinine clearance, dose, sex, race, disease status, nationality, and concomitant medications.

[0261] The data were well fitted by combining the transit compartment model for the absorption phase with the typical central and peripheral two-compartment model for the elimination phase. Inter-individual variability for absorption rate constant, clearance, and central compartment volume was assumed to follow a log-normal distribution, although the actual distribution had a larger fat tail. Overall, the final PPK model explains the observed data very well. Body weight, creatinine clearance, dietary status, and Asian race were significant in the PPK model. Heavier patients were found to have lower exposures, while decreased creatinine clearance was associated with higher exposures. Dietary status was C max It was found that this reduces AUC and C min The results were similar to those observed after ingestion in a fasted state. Population PK estimates for food effects were contrary to those of definitive food effect studies, and by-study analysis of population PK study data indicated that food effect study data appear to deviate from the population-wide data. Asians had higher C max And it was related to clearance.

[0262] A group PK simulation of a reference group composed of healthy Caucasians showed a C of 7.67. min C for max The ratio and the median 24-hour AUC at steady state of 1023 ng·h / mL compared to the C of 112 ng / mL max Median and 14 ng / mL C min The median was obtained. In the simulation of the diabetic Caucasian population, a median approximately 10% lower was obtained, C min C for max The ratio was 7.66. C of the latter group min The first and third quartiles were 10.6 and 20.2 ng / mL, respectively, which were above the target concentration of 10 ng / mL (in vitro IC). 50 (Approximately 10 times) C min ≥10 ng / mL and C <10 min C for maxThe ratio was a design goal of the sustained-release formulation development program.

[0263] Example 16 - Clinically acceptable solid dosage forms The inventors have provided a tablet composition and a method of manufacture that ensure the sustained-release formulation of the present invention behaves consistently in accordance with rigorous and well-established standards of in vitro dissolution testing. However, not all aspects of the in vivo behavior of a formulation can be captured by in vitro testing. When different formulations are designed to impart similar properties to the formulation through different compositions of materials or different principles for achieving sustained release, formal bioequivalence testing can confirm that the in vivo properties are similar. Such testing ensures that the rate and degree of absorption are not significantly or unfavorably altered by the new composition.

[0264] The gastric retention tablets of the U5, U10, and U20 formulations have been tested in large-scale randomized controlled trials in human patients with diabetes and have been found to provide statistically significant therapeutic effects. To ensure that further formulations provide similar therapeutic benefits and to be clinically acceptable, each batch of tablets designated for human consumption must undergo formal dissolution pass / fail testing (i.e., USP) through the three levels of process described above. <711> It must pass the test (as documented in Pass / Fail Judgment Table 2), using a test method based on USP apparatus 1, in which 900 mL of 0.1N HCl is initially filled and maintained at 37±0.5℃ with a stirring speed of 50 rpm, and less than 17% of bexagliflozin is released within 1 hour, 23% to 43% of bexagliflozin is released within 3 hours, 45% to 75% of bexagliflozin is released within 5 hours, and more than 80% of bexagliflozin is released within 8 hours.

[0265] When making significant changes to a formulation, in addition to passing these formal dissolution test standards, the tablets must meet at least C max and AUC 0-t The parameters need to be shown to be clinically acceptable in vivo bioequivalence to a reference batch of tablets.

[0266] A formulation is clinically acceptable if (i) it has been shown to be clinically effective in treating a disease or condition, is manufactured in a pre-specified manner, is well controlled by adhering to acceptable ranges of components and manufacturing processes that pass formal dissolution acceptance tests, and is (ii) deviates from the original manufacturing range of components and / or manufacturing processes, but passes formal dissolution acceptance tests and is further shown to be bioequivalent to the original formulation. The present invention encompasses all such clinically acceptable oral solid dosage forms.

[0267] The following criteria (from the FDA's March 2014 Guidance for Industry: CMC Postapproval Manufacturing Changes To Be Documented in Annual Reports, Appendix B) indicate the extent of changes to formulations that do not require bioequivalence documentation under normal circumstances. Furthermore, other specific changes may be permitted, as provided in Appendix A of the guidance. 1. Any changes made to conform to the official outline of a designated U20 formulation, except for relaxation of pass / fail criteria or deletion of the test. 2. Complete or partial removal of any ingredient intended to affect only the color, flavor, or aroma of the formulation without altering any other approved specifications. 3. Changes to non-release control excipients, expressed as a percentage (w / w) of the total formulation approved in the initial application, that are below the following percentage ranges: filler (lactose monohydrate, MCC) ±5%, lubricant (magnesium stearate) ±0.25%, flow enhancer (colloidal silicon dioxide) ±0.1%, and film coat (Opadry II Blue) ±1%. 4. Changing the supplier of excipients, provided that the technical grade and specifications of the excipients remain the same. 5. Changes to release-controlled excipients (polyethylene oxide, poloxamer 188, glyceryl dibehenate) must be 5% or less of the total release-controlled excipients (w / w) in U20. After the change, the total weight and specifications of the dosage form must be maintained the same as U20.

[0268] The present invention is described above for illustrative purposes only, and it should be understood that modifications may be made within the scope and spirit of the invention.

Claims

1. (a) 3 to 60 mg of bexagliflozin; (b) 100-140 mg of glyceryl dibehenate; (c) 50-75 mg of polyethylene oxide having an average molecular weight of 900,000; (d) 40-50 mg of lactose monohydrate; (e) 40-45 mg of poloxamer 188; (f) 60-80 mg of microcrystalline cellulose; (g) 4-5 mg of colloidal silicon dioxide; and (h) 6-9 mg of magnesium stearate Tablets containing [this ingredient].

2. The tablet contains 8 ng / mL or less of plasma bexagliflozin C per 1 mg of bexagliflozin in a fasted subject with a body weight of more than 60 kg. ｍａｘ A tablet according to claim 1, which provides the following:

3. The tablet according to claim 1, wherein the tablet comprises (i) 10 mg of bexagliflozin and C max is 80 ng / mL or less, (ii) 20 mg of bexagliflozin and C max is 160 ng / mL or less, or (iii) 40 mg of bexagliflozin and C max is 320 ng / mL or less.

4. The tablet according to claim 1, which releases bexagliflozin in vivo to provide a Tmax of 2 to 6 hours in a fasted human subject.

5. The tablet according to claim 1, comprising 20 mg of bexagliflozin, providing an AUC 0-t of 600 to 1200 ng·h / mL in fasted human subjects.

6. The tablet according to claim 1, comprising 20 mg of bexagliflozin, providing an AUC 0-∞ of 675 to 1275 ng·h / mL in fasted human subjects.

7. The tablet according to claim 1, comprising 20 mg of bexagliflozin, which provides a plasma Cmax of 80 to 150 ng / mL in fasted human subjects.

8. The tablet according to claim 1, which provides a bexagliflozin plasma concentration in which the ratio of the median C max to the median C min is less than 10.

9. A tablet according to claim 1, comprising 20 mg of bexagliflozin, wherein in an in vitro dissolution test performed using a United States Pharmacopeia (USP) apparatus 1 at 50 rpm, 37 ± 0.5°C, with 900 mL of 0.1 N HCl, it releases 17% or less of the bexagliflozin after 1 hour.

10. A tablet according to claim 1, comprising 20 mg of bexagliflozin, wherein in an in vitro dissolution test performed using a United States Pharmacopeia (USP) apparatus 1 at 50 rpm, 37 ± 0.5°C, with 900 mL of 0.1 N HCl, 20-45% of the bexagliflozin is released after 3 hours.

11. A tablet according to claim 1, comprising 20 mg of bexagliflozin, wherein in an in vitro dissolution test performed using a United States Pharmacopeia (USP) apparatus 1 at 50 rpm, 37 ± 0.5°C, with 900 mL of 0.1 N HCl, 45-75% of the bexagliflozin is released after 5 hours.

12. A tablet according to claim 1, comprising 20 mg of bexagliflozin, wherein in an in vitro dissolution test performed using a United States Pharmacopeia (USP) apparatus 1 at 50 rpm, 37 ± 0.5°C, with 900 mL of 0.1 N HCl, it releases 80% or more of the bexagliflozin after 8 hours.

13. The tablet according to any one of claims 1 to 12, wherein the bexagliflozin is in the form of a crystalline solid.

14. A tablet according to any one of claims 1 to 13, having a coating surrounding the core.

15. (a) 20 mg of bexagliflozin; (b) 65 mg of polyethylene oxide having an average molecular weight of 900,000; (c) 120 mg of glyceryl dibehenate; (d) 45 mg lactose monohydrate; (e) 42 mg of poloxamer 188; (f) 70 mg of microcrystalline cellulose; (g) 4.5 mg of colloidal silicon dioxide; and (h) 7.5 mg magnesium stearate Tablets containing [this ingredient].

16. Use of the tablet according to any one of claims 1 to 15 for the manufacture of a pharmaceutical product for treating diabetes or its symptoms.

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