Veterinary pharmaceutical preparation

Abstract

In the specification of the present application, an oral immediate-release formulation of bexagliflozin for administration to a companion animal is provided.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to International Patent Application No. PCT / CN2022 / 093377, filed on May 17, 2022, which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present invention provides a pharmaceutical preparation of bexagliflozin useful for the treatment of diabetes, hypertension, renal failure, or heart failure in companion animals. An oral formulation of bexagliflozin that is convenient for administration, readily accepted by cats and dogs, and has improved pharmacokinetic properties is described.

Background Art

[0003] Bexagliflozin is a C - aryl glucoside inhibitor of human sodium - glucose cotransporter 2 (SGLT2), a renal re - uptake transporter in the kidney responsible for the recovery of most of the glucose removed from plasma in the fluid filtered by the renal glomerulus. In recent years, inhibitors of SGLT2 (and to some extent, the related SGLT1 transporter) have been found to have beneficial effects in humans with respect to the treatment of diabetes, kidney disease, and congestive heart failure.

[0004] Among the potential uses of SGLT inhibitors for companion animal diseases, one of the most relevant opportunities for the present invention is the improvement of diabetes management in felines. Currently, there are no approved oral hypoglycemic drugs for managing feline diabetes. The standard treatment for feline diabetes requires twice-daily injections of insulin that are titrated up to efficacy. Cats have a significant inter-individual variability in insulin sensitivity and must be closely monitored to avoid fatal or neurologically devastating hypoglycemia. Insulin administration can help manage diabetes and delay disease progression, but it can be difficult to provide the appropriate dose and timing of insulin. For example, insulin administration is recommended to be timed around meals, but consistent timing of meals and insulin can be difficult for cat owners to achieve.

[0005] Accordingly, one need in the art is for more effective methods and compositions for managing feline diabetes and prediabetes. Bexagliflozin has promising properties for this indication. Inhibition of SGLT2 by bexagliflozin results in significant and saturable glucosuria in mice, rats, cats, dogs, rabbits, monkeys, and humans.

[0006] Bexagliflozin has been studied in diabetic mice, rats, cats, and humans. In each case, this compound has been found to lower blood glucose levels and improve long-term measures of glycemic control such as HbA 1c , or fructosamine in cats. Experiments using diabetic rodent genetic models have shown that bexagliflozin can result in a decrease in blood glucose levels and a partial alleviation of the disease even in the presence of pre-existing glucosuria. Thus, the presence of glucosuria does not preclude the application of bexagliflozin for the treatment of diabetes.

[0007] Bexagliflozin has also been found to have a favorable effect on fluid retention caused by the antidiabetic agent pioglitazone, a thiazolidinedione (U.S. Patent Application Publication No. 20190343853A1). This effect is presumably at least partly due to the natriuresis induced by bexagliflozin, which can be a result of osmotic diuresis, as well as a disruption of sodium balance due to blockade of sodium cotransport from the fluid filtered in the kidney. Through its effect on the kidney, bexagliflozin can have a beneficial effect on chronic kidney disease and heart failure in dogs and cats.

[0008] In cats, the action of bexagliflozin is unusually potent and qualitatively superior to that observed in other organisms. Bexagliflozin results in clinical remission of the disease in a high proportion of diabetic cats, which in turn results in serum fructosamine concentrations that fall within the normal range for healthy cats (U.S. Patent Application No. 16818026). Despite the high efficacy of bexagliflozin in cats, no clinically significant signs or objective measurements of hypoglycemia have been observed to date. The combination of high efficacy and low risk makes bexagliflozin an excellent option for the treatment of diabetes in felines. Of particular interest and utility is the observation that bexagliflozin as monotherapy has been shown to restore fructosamine levels within the normal range in the test laboratory in the majority of cats in a field study where the drug was administered to cats by their owners in an unsupervised (at-home) setting (U.S. Patent Application No. 16818026).

[0009] Bexagliflozin (also known as EGT0001442, EGT1442, THR1442, THR0001442) has been found to be useful for the treatment and management of various conditions including human 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). It has been shown to be well - tolerated in humans, providing a sustained and clinically significant improvement in glycemic control, as well as a reduction in body weight and blood pressure in adult diabetics (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).

[0010] Bexagliflozin has also been reported to be useful as an adjunct to insulin for the management of feline diabetes, resulting in an improvement in glycemic control and a reduction in insulin dosage (Benedict et al. (2022) Can J Vet Res 86:52 - 58).

[0011] Bexagliflozin has been found to reduce the rate of decline in glomerular filtration rate in humans, thereby preventing the progression of kidney disease, and also yields a hazard ratio of 0.774 for the reduction of major adverse cardiovascular events, indicating a lower likelihood of cardiovascular risk.

[0012] The delivery of bexagliflozin to cats in need of diabetes treatment can be achieved by oral administration. Desired characteristics for oral administration include ease of dispensing, stability under normal storage conditions, promotion of absorption of the drug being delivered, and ready acceptance by the animal being treated. For the last of these characteristics, the administration of oral dosage forms to cats presents particular challenges since it is well known that cats have difficulty administering conventional solid dosage forms. As a result, drugs for cats are often formulated as oral liquids.

[0013] For chronic diseases such as diabetes, the importance of a compatible dosage form is magnified as cats will engage in avoidance behaviors such as hiding, fleeing, or exhibiting aggressive responses when dosing is initiated in association with the perception that they are at immediate risk of exposure to an undesirable product. Thus, acceptability of the formulation is a very important design element for drugs intended for daily administration.

[0014] An administration system that places few requirements on the caregiver is preferred. For example, preparation requirements such as reconstitution of a solution or providing accurate measurement for delivery by a dropper or syringe dispenser are less attractive than an administration system that enables delivery in a single pre-determined unit to achieve the treatment objective. This is often achieved in human diseases by providing administration in a single tablet that delivers the therapeutic agent in a convenient once-daily dosing regimen. However, this has often been difficult to achieve in delivery to cats. SUMMARY OF THE INVENTION

[0015] In some aspects, provided herein are formulations comprising bexagliflozin for administration to companion animals. In some embodiments, the formulation is a tablet, capsule, softgel, or liquid formulation. In some embodiments, the formulation is a tablet.

[0016] In some embodiments, an immediate-release tablet formulation comprising bexagliflozin for administration to a companion animal is provided herein.

[0017] In some embodiments, the immediate-release formulation releases at least 70% of the bexagliflozin after 10 minutes in an in vitro dissolution test. In some embodiments, the immediate-release formulation releases at least 85% of the bexagliflozin after 30 minutes in 0.1 N HCl solution at 37 ± 0.5 °C in USP (United States Pharmacopeia) Apparatus 2 (paddle apparatus) at a paddle speed of about 75 rpm. In some embodiments, the immediate-release formulation releases > 41.2% of the bexagliflozin dose after 5 minutes and ≧ 80% of the bexagliflozin after 30 minutes. In some embodiments, the immediate-release formulation releases 5.4 - 78.4% of the bexagliflozin after 10 minutes and / or 80.1 - 86.2% of the bexagliflozin after 15 minutes in an in vitro dissolution test.

[0018] In some embodiments, the formulations of the present disclosure include a flavoring agent. In some embodiments, the flavoring agent includes tuna, salmon, cream, beef, peanuts, mint, chicken liver powder, poultry extract, avian hydrolyzed liver, butter, or bacon flavor. In some embodiments, the flavoring agent includes the flavor of meat or liver. In some embodiments, the flavoring agent includes hydrolyzed liver of chicken.

[0019] In some embodiments, the tablet formulations of the present disclosure may include at least one component selected from one or more fillers, one or more glidants, one or more lubricants, and one or more binders, or other components.

[0020] In some embodiments, the companion animal is a cat. In some embodiments, the companion animal is a dog.

[0021] In some embodiments, when tested by dissolving in USP Apparatus 2 (paddle) containing 500 ml of 0.1 N HCl with stirring at 37°C ± 0.5°C and 75 rpm, tablets are provided herein that yield an f2 value of ≧50 as compared to the reference tablets of the formulations in Table 35 and contain 15 mg of bexagliflozin.

[0022] In some embodiments, tablets are provided herein having a composition of 10 - 20 mg of bexagliflozin, 17.5 - 27.5 mg of lactose monohydrate, 20.5 - 30.5 mg of microcrystalline cellulose, 7.5 - 11 mg of flavoring agent, 3 - 5 mg of pregelatinized starch, 1.5 - 2.5 mg of colloidal silicon dioxide, and 0.75 - 1.25 mg of magnesium stearate per tablet.

[0023] In some embodiments, when tested by dissolving in USP Apparatus 2 (paddle) containing 500 ml of 0.1 N HCl with stirring at 37°C ± 0.5°C and 75 rpm, tablets are provided herein that yield an f2 value of ≧50 as compared to the reference tablets of the formulations in Table 38 and contain 15 mg of bexagliflozin.

[0024] In some embodiments, provided herein is a method for treating a companion animal suffering from a disease or syndrome sensitive to treatment with an SGLT2 inhibitor, the method comprising administering to the companion animal any of the formulations described herein. In some embodiments, the companion animal is diagnosed with diabetes or prediabetes. In some embodiments, the companion animal is diagnosed with type 1 diabetes. In some embodiments, the companion animal is diagnosed with type 2 diabetes. In some embodiments, the companion animal is diagnosed with hypertension. In some embodiments, the companion animal is diagnosed with renal insufficiency. In some embodiments, the companion animal is diagnosed with heart failure.

[0025] In some embodiments, provided herein is a liquid formulation containing bexagliflozin at 30 mg / mL, ethanol at 125 - 175 mg / mL, glycerin at 250 - 300 mg / mL, PEG - 400 at 125 - 175 mg / mL, polysorbate 80 at 25 - 75 mg / mL, one or more optional flavoring agents at 1 - 15 mg / mL, and the balance being an aqueous buffer having a pH of 6.0 - 8.0.

[0026] In some embodiments, a formulation containing bexagliflozin as described herein, when tested with 3 mg / kg of bexagliflozin after delivery to a properly constituted cohort of healthy, fasted adult cats, gives a mean plasma bexagliflozin AUC of greater than 1000 ng·h / mL per mg / kg of bexagliflozin. 0-24 In some embodiments, this formulation is a tablet formulation.

[0027] In some embodiments, a formulation containing bexagliflozin as described herein, when tested with 3 mg / kg of bexagliflozin after delivery to a properly constituted cohort of healthy, fasted adult cats, gives a mean plasma bexagliflozin C of greater than 300 ng / mL per mg / kg of bexagliflozin. max In some embodiments, this formulation is a tablet formulation.

[0028] In some embodiments, provided herein is a batch of bexagliflozin veterinary tablets containing 15 mg of bexagliflozin which, when administered to a properly constituted cohort of healthy, fasted subjects, gives, for a first representative set of tablets from the batch, a first mean logarithm of C max and a first mean logarithm of AUC 0-t and for a second representative sample of tablets from the batch, in a different case, a second mean logarithm of C max and a second mean logarithm of AUC 0-t and the difference between the first mean logarithm and the second mean logarithm of C max and the difference between the first mean logarithm and the second mean logarithm of AUC 0-tThe difference between the logarithm of the first average and the logarithm of the second average both show 90% confidence intervals, and their endpoints are between -0.51083 and +0.51083.

[0029] In some embodiments, a batch of venglustat veterinary tablets containing 15 mg of venglustat is provided herein, which, when administered to a properly constituted cohort of healthy fasting subjects, in some cases, a first representative sample set of tablets from the batch results in a first average logarithm of C max and the first average logarithm of AUC 0-t and in some different cases, a second representative sample of tablets from the batch results in a second average logarithm of C max and the second average logarithm of AUC 0-t and the difference between the first average logarithm and the second average logarithm of C max and the difference between the first average logarithm and the second average logarithm of AUC 0-t both show 90% confidence intervals, and their endpoints are between -0.28768 and +0.28768.

[0030] In some embodiments, a batch of venglustat veterinary tablets containing 15 mg of venglustat is provided herein, which, when administered to a properly constituted cohort of healthy fasting subjects, in some cases, a first representative sample set of tablets from the batch results in a first average logarithm of C max and the first average logarithm of AUC 0-t and in some different cases, a second representative sample of tablets from the batch results in a second average logarithm of C max and the second average logarithm of AUC 0-t and the difference between the first average logarithm and the second average logarithm of C max and the difference between the first average logarithm and the second average logarithm of AUC 0-t both show 90% confidence intervals, and their endpoints are between -0.22314 and +0.22314.

[0031] In some embodiments, batches of venglustat veterinary tablets containing 15 mg of venglustat are provided herein, which, when administered to a properly constituted cohort of healthy, fasted subjects, result in a representative sample set of tablets from the batch having a first mean logarithm of C max and a first mean logarithm of AUC 0-t and a representative sample of tablets from a reference batch of 15 mg venglustat veterinary tablets having a second mean logarithm of C max and a second mean logarithm of AUC 0-t and the difference between the first mean logarithm and the second mean logarithm of C max and the difference between the first mean logarithm and the second mean logarithm of AUC 0-t both exhibit 90% confidence intervals with endpoints between -0.51083 and +0.51083.

[0032] In some embodiments, batches of venglustat veterinary tablets containing 15 mg of venglustat are provided herein, which, when administered to a properly constituted cohort of healthy, fasted subjects, result in a representative sample set of tablets from the batch having a first mean logarithm of C max and a first mean logarithm of AUC 0-t and a representative sample of tablets from a reference batch of 15 mg venglustat veterinary tablets having a second mean logarithm of C max and a second mean logarithm of AUC 0-t and the difference between the first mean logarithm and the second mean logarithm of C max and the difference between the first mean logarithm and the second mean logarithm of AUC 0-t both exhibit 90% confidence intervals with endpoints between -0.28768 and +0.28768.

[0033] In some embodiments, batches of venglustat veterinary tablets containing 15 mg of venglustat are provided herein, which, when administered to a properly constituted cohort of healthy, fasted subjects, result in a representative sample set of tablets from the batch having a first mean logarithm of C maxThe logarithm of the first average and the AUC 0-t yield the logarithm of the first average, and a representative sample of tablets from a reference batch of 15 mg bexagliflozin veterinary tablets is C max The logarithm of the second average and the AUC 0-t yield the logarithm of the second average, and C max The difference between the logarithm of the first average and the logarithm of the second average, and the AUC 0-t The difference between the logarithm of the first average and the logarithm of the second average both show a 90% confidence interval, and its endpoint is between -0.22314 and +0.22314.

[0034] A kit comprising the formulations and instructions for use described herein. In some embodiments, the kit also comprises another therapeutic agent.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0048] I. General The present disclosure provides an oral formulation for administering bexagliflozin to companion animals. Companion animals, particularly feline animals, can be difficult to administer pharmaceuticals. The formulations disclosed herein not only provide desirable stability and pharmacological properties, but also have a very low administration refusal rate.

[0049] II. Definitions As used herein, the term "administering" means delivering by oral, buccal, nasal, rectal, vaginal or dermal routes, or by other topical contact, or by intravenous, intraperitoneal, intramuscular, intralesional, or subcutaneous routes, or by implantation into a sustained release device or formulation such as a pump, gel, reservoir, or erodible substance. Administration can be effected by any route including parenteral and transmucosal (e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, intracisternal, and intracranial. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0050] As used herein, "anti - diabetic agent" refers to a composition comprising a pharmaceutical, drug, or agent commonly used for the management of diabetes in animals. Generally, it is accepted that oral medications for the treatment of type 2 diabetes in humans have little utility for the management of diabetes in felines. To date, no oral medications for the management of diabetes in felines have been approved by regulatory authorities in the United States, the European Union, or Japan.

[0051] As used herein, the phrase "appropriately constituted cohort" refers to a set of test subjects typically consisting of healthy individuals of both genders at a sample size that provides adequate statistical power for estimating the desired pharmacokinetic parameters. The sample size that provides adequate statistical power can be calculated as described below. In common practice, for example, for demonstrating bioequivalence for regulatory purposes, 12 or more subjects of each gender are often employed, or a total sample size of 24 subjects is employed if there is no gender balance. Although not a regulatory requirement, it is of course desirable that for the purpose of determining whether the test substance is a composition of the present invention, the experimental cohort should be composed of individuals close to the midpoint of a healthy population of young adults as a whole, so that, for example, the cohort does not contain individuals with predominance of high or low body weight, or unusually lean or obese body states, or elderly individuals with diseases or conditions that could essentially affect the absorption, distribution, metabolism or excretion of bexagliflozin.

[0052] As used herein, the term "AUC" means an estimated value of the area under the curve of the plasma concentration of an analyte as a function of time. AUC is calculated by the linear trapezoidal method, which means that the AUC between two time points is taken as the average of the concentrations at the two time points, multiplied by the time between these points.

[0053] As used herein, "AUC 0-24 " means the AUC from the time of administration to 24 hours after administration.

[0054] As used herein, "AUC 0-∞ " means the AUC from time 0 to infinity when generated by extrapolation of a simple (monophasic) exponential decay. AUC 0-∞ = AUC 0-t + C last / k el where C last is the last quantifiable concentration expressed in concentration units of AUC, and kel is the terminal-phase elimination rate constant expressed as the reciprocal of the time unit (typically, hour) in which the AUC is expressed.

[0055] As used herein, the term "AUC" 0-t means the AUC from the time of administration to the last measurable time point where quantification is possible.

[0056] As used herein, the term "batch" describes a collection of individual dosage forms, such as oral solid dosage forms or unit liquid dosage forms, which can range in size from 100 units to a complete manufacturing run (e.g., all units made from the same initial quantity of material and subjected to the same series of manufacturing operations, or any total quantity of units that are subjected to similar manufacturing operations and pooled for testing or distribution purposes). The definition of "manufacturing batch" includes that provided by Title 21, Section 201.3 of the USC, namely, "a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture".

[0057] As used herein, "bexagliflozin" refers to (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol having the following chemical structure. [Chemical Structure]

[0058] As used herein, the terms "cat" and "feline," when used as adjectives, are used interchangeably and mean an animal of the family Felidae or related thereto, and in particular, an animal maintained as a pet or companion animal, typically belonging to the genus Felis, of the species silvestris catus or catus, and includes members of that family of cats often referred to as domestic cats or house cats.

[0059] As used herein, the term "cat," when used as a noun, refers to an animal of the family Felidae.

[0060] As used herein, the term "CL / F" means the apparent clearance obtained by dividing the clearance CL by the bioavailability F. CL / F is the measured clearance, while CL is an estimate except when the bioavailability is 100%.

[0061] As used herein, the term "C max " means the maximum observed plasma concentration of the analyte.

[0062] As used herein, the term "C min " means the lowest observed plasma concentration, typically obtained as the value before repeated dosing in a regularly scheduled dosing regimen. For example, in the case of daily dosing, C min is often recorded 24 hours after the previous dose.

[0063] The terms "d(0.1)", "d(0.5)", and "d(0.9)" describe the threshold diameters of the particles that fall within the smallest 10%, 50%, and 90% of the total volume of all particles. Thus, at d(0.9), 90% of the volume of the sample can be found in particles with diameters smaller than d(0.9).

[0064] As used herein, the term "treatment failure", when applied to the circumstances surrounding the administration of a formulation, indicates that the fraction of the formulation delivered to the animal was less than 50% of the amount attempted to be delivered.

[0065] As used herein, the term "treatment refusal", when applied to the circumstances surrounding the administration of a formulation, indicates that the animal to which delivery of the formulation was attempted escaped from or resisted treatment by, for example, running away, struggling, scratching, biting, or attempting to wound the person administering the formulation, or exhibited signs of distress after administration such as blowing bubbles, excessive salivation, or vomiting.

[0066] As used herein, the term "fasting", when applied to the circumstances surrounding the collection of a test specimen, indicates that the animal from which the specimen was collected was not given food for an extended period of time, typically for 8 hours or more, or overnight if the specimen was collected in the morning. Samples taken during fasting are useful for measuring formulations that have performance characteristics affected by feeding.

[0067] As used herein, the term "feeding", when applied to the circumstances surrounding the collection of a test specimen, indicates that the animal from which the specimen was collected was allowed to consume a standard diet within a short interval (30 minutes or less) of dosing. Comparison of pharmacokinetics and pharmacodynamics after fasting and after feeding can indicate whether dosing instructions must specify a particular feeding state.

[0068] As used herein, "k" el " means the first-order rate constant for the disappearance of a substance from plasma during the terminal phase of concentration decline. During this phase, when the kinetics are first-order, the concentration of the substance c(t) as a function of time is described by dc(t) / dt = -k el · c(t). When the kinetics are not first-order, k el cannot be defined.

[0069] As used herein, the term "logarithm" refers to the natural logarithm, unless otherwise specified, which is often described as ln(x) as a function of the argument x, where, to avoid ambiguity, x = e ln(x) is. When the base of the logarithm is 10, the logarithm is called the common logarithm and is also described as log 10 (y) as a function of the argument y, where, to avoid ambiguity, y = 10 log10(y) is.

[0070] As used herein, "managing diabetes" or "diabetes management" refers to the process by which the owner or other person responsible for the care of the animal addresses the disease by specific measures intended to alleviate or cure the disease or to alleviate symptoms or alter the perceived health of the animal by various means. Such means may include changes in the animal's diet, including the provision of a special or prescription diet, or other changes in the type or amount of food provided, or the promotion or provision of activities that result in increased exercise or metabolic energy consumption, or the provision of herbal preparations, nutritional supplements or pharmaceuticals.

[0071] As used herein, the term "palatability agent" refers to an excipient added to a formulation to enhance the palatability of the formulation for a companion animal. Palatability agents are flavoring agents that are tailored to the medicament and the target animal species. Some palatability agents are species-specific, while others may include flavors or combinations of flavors that are attractive to multiple species. Palatability agents often take into account human perception, for example because a composition with the smell of rotten meat may be attractive to dogs, but humans tend not to give their pets products with odors they find unpleasant and have been shown to recoil.

[0072] As used herein, "plasma concentration" refers to the concentration of an analyte obtained by measurement of the liquid phase of whole blood, typically venous blood, separated from the cellular components of the blood by a method that prevents the blood from clotting.

[0073] As used herein, the term "representative," when applied to a unit or sample of a batch, is not preselected for any particular property such as coating weight, density, hardness, or hue, and means a unit or sample that is free of manufacturing defects and is drawn substantially at random from the batch.

[0074] As used herein, the phrase "sample set" refers to a collection of units or samples that can be analyzed individually or collectively to estimate the properties of a batch or population as a whole. When used in connection with in vitro or in vivo testing for tablet properties, the sample set refers to a collection that is tested individually and from which the properties of the entire batch of tablets are estimated.

[0075] The properties defined for any particular unit (e.g., a tablet, or a defined volume of liquid) should be understood to be the properties of a representative unit drawn from the manufacturing batch, and its constituents confer or exhibit the properties that are referenced in a suitable test that typically consumes multiple units from the manufacturing batch. Thus, when a unit is said to yield a particular pharmacokinetic parameter, it is understood that this parameter will typically be measured after administration of a representative test article of the manufacturing batch for which that unit is exemplary, and that a proper statistical characterization of the results will be calculated.

[0076] For oral solid dosage forms, the sampling unit is typically an individual dose, while for liquids, the sampling unit is often a bottle or similar reservoir containing the oral liquid. A specified volume is withdrawn or delivered from the reservoir for testing, and the test is intended to confirm that the independently selected reservoirs contain contents of similar potency, palatability, and composition. In some embodiments, the reservoir is a single-use (single-dose) delivery system, in which case the sampling unit is that single-use article.

[0077] When the pharmacokinetic parameters are defined to have values within a specific range, it should be understood that the administration of a representative test article of a manufacturing batch such that the unit is exemplary will result in a characterized parameter (e.g., mean or median value) that falls within the described range of values in a properly constituted experimental cohort.

[0078] For example, when it is said that a tablet yields a statistical measure (e.g., mean C max ) that falls within a certain range of values, it should be understood that the administration of a representative test article of a manufacturing batch such that the tablet is exemplary will result in a statistical measure (e.g., mean C max ) that falls within the described range of values in a properly constituted cohort.

[0079] Similarly, when a liquid formulation yields a statistical measure that falls within a specific range of values, it should be understood that the delivery of a test volume from a representative reservoir selected from a manufacturing batch will result in a statistical measure (e.g., mean C max ) that falls within the described range of values in a properly constituted cohort.

[0080] As used herein, the phrase "number of samples providing adequate power" for estimating pharmacokinetic parameters is, for example, the number of individuals within a cohort necessary to achieve a particular degree of discrimination between groups subjected to two experimental conditions, where the groups have ingested a pharmaceutical from one source or another. Methods for calculating power are well known in the art. In its simplest form, power describes the probability of obtaining a statistically significant result in a test where a predicted difference actually exists between two populations. The calculation of power is often a calculation as the determination of the minimum number of samples to detect a true difference between groups that has a particular likelihood of failure due to randomness. For example, 90% power means that a statistically significant result will appear in 9 out of 10 tests, but in 1 out of 10, significance will not be achieved even though a difference exists. Thus, subtracting the power from 100% gives the probability of a false negative. Typical values of power in testing pharmacokinetic parameters are 90% or greater, and for clarity, "adequate power" is defined herein as 95% or greater.

[0081] To perform the calculation of power, the variation in the measurements obtained, typically expressed as the standard deviation, and the difference to be detected (the difference in the values of the measurements from the two groups to be detected) must be input. If there is substantial uncertainty about the standard deviation of the measurements in a population, it can be determined empirically. When used in the setting of a non-inferiority determination, the calculation of power is used to estimate the number of samples necessary to confirm that the difference between two groups is less than a particular amount. For example, a bioequivalence study is a two-sided non-inferiority test aimed at showing that the difference between two samples falls within a particular boundary.

[0082] When a dietary state, such as fasting or fed, is specified, the fasting state should be achieved for each subject by food withdrawal for at least eight hours prior to ingestion of the formulation, and the fed state should be achieved for each subject by ingestion of a standard diet normally provided for the nutrition of the subject, and the delivery of the formulation is within 30 minutes after ingestion of the diet.

[0083] As used herein, "serum concentration" refers to the concentration of an analyte measured in the liquid phase of whole blood, typically venous blood, where coagulation is permitted. Serum consists essentially of plasma depleted of coagulation factors and concentrated in the content of platelet granules.

[0084] As used herein, the term "solid oral dosage form" means any solid (or semi-solid) dosage form that can be administered orally. This may include tablets, solid pills, capsules, caplets, hard or soft encapsulated gels, or capsules containing encapsulated liquids in the form of soft gels, or may be present in the form of layered or sub-components such as beads, droplets, or particles of various shapes, and may take the form of combinations or aggregates such as those of different properties embedded in a matrix or contained in a capsule or caplet.

[0085] As used herein, the phrase "substantially at random" when referring to the sampling of production units from a batch containing a large number of units means either that the sampling is completely random such that all units within the batch have an equal probability of being selected, or that the batch being sampled is selected by a process aimed at achieving a practically balanced representative batch. For example, representative units can be drawn at regular intervals during production to avoid sampling imbalances where units with slightly different properties, such as those produced at the start or end of production, are over-represented. Such units are said to be drawn substantially at random from the batch.

[0086] As used herein, the term "t 1 / 2 " means the half-life in the terminal phase and is also referred to as the elimination half-life. If the empirically determined elimination kinetics in the terminal phase are not first-order with respect to time, t 1 / 2 cannot be determined. t 1 / 2 = -ln(2) / k el ≈ 0.693 / k el .

[0087] As used herein, the term "T" max " means the observation time of C max .

[0088] As used herein, the term "V z / F" means the apparent volume of distribution, which is the volume of distribution V z divided by the bioavailability F.

[0089] The characteristics specified for any particular unit (e.g., tablet) should be understood to be the characteristics of a representative unit drawn from the manufacturing batch, and its constituents confer or exhibit the reference characteristics in a suitable test typically consuming multiple units from the manufacturing batch. Thus, when a unit is said to yield a particular pharmacokinetic parameter, this parameter will typically be measured after administration of a representative test article of the manufacturing batch for which the unit is exemplary, and appropriate statistical characterization of the results will be calculated. Parameters based on the concentration of bexagliflozin in plasma (e.g., C max and AUC) are typically characterized as geometric means, while T max is typically characterized by the population median. Further, when a pharmacokinetic parameter is specified to have a certain range of values, administration of a representative test article of the manufacturing batch for which the unit is exemplary will result in a characterized parameter (e.g., geometric mean or median) that falls within the stated range of values in a properly constituted experimental cohort.

[0090] For example, when a tablet is said to yield a statistical measure (e.g., geometric mean C max ) within a certain range of values, administration of a representative test article of the manufacturing batch for which the tablet is exemplary will result in a statistical measure (e.g., geometric mean C max ) that falls within the stated range of values in a properly constituted cohort.

[0091] III. Embodiments Oral formulations of bexagliflozin for administration to companion animals are provided herein. In some embodiments, the formulation is a tablet, capsule, softgel, or liquid formulation. Further details regarding possible components of these formulations are provided in Subsections A - E below.

[0092] In some aspects, the formulations described herein are characterized by an in vitro dissolution test and release at least 70% of the bexagliflozin in a solution of 0.1 N HCl at 37 ± 0.5 °C in Apparatus 2 (paddle apparatus) at a paddle speed of about 75 rpm after 10 minutes and at least 85% of the bexagliflozin after 30 minutes.

[0093] In some embodiments, the invention also provides an oral dosage form that produces a geometric mean C max and geometric mean AUC 0-t in a cohort of healthy feline subjects, and for this oral dosage form, the 90% confidence intervals of the log-transformed C max and log-transformed AUC 0-t are completely within the range of 80.00 - 125.00% of the geometric mean C max and geometric mean AUC 0-t produced by the reference formulation in the same cohort upon exponentiation.

[0094] In some embodiments, the invention also provides a solid oral dosage form that produces a geometric mean C max and geometric mean AUC 0-t in a cohort of healthy subjects, and for this solid oral dosage form, the 90% confidence intervals of the log-transformed C max and log-transformed AUC 0-t are completely within the range of 80.00 - 125.00% of the geometric mean C max and geometric mean AUC 0-t produced by a reference formulation having one of the following compositions in the same cohort upon exponentiation: (a) A tablet comprising a mixture of 15 mg of bexagliflozin, for example, spray-dried Foremost NF, 135 mg of lactose monohydrate which is lactose hydrate, for example, 154.5 mg of microcrystalline cellulose such as Heweten 102, 37.5 mg of a suitable flavoring agent such as FlavorPAL™ X1212.1, 24 mg of pregelatinized starch such as Colorcon Starch 1500 (Starch 1500®), 6 mg of amorphous anhydrous colloidal silicon dioxide such as Aerosil 200 Pharma, and 3 mg of magnesium stearate such as Hyqual®, wherein the core has a tablet hardness of 5 - 10 kp and is formed by compression using a 10 mm pentagonal tablet punch. (b) A tablet comprising a mixture of 15 mg of bexagliflozin, for example, spray-dried Foremost NF, 22.5 mg of lactose monohydrate which is lactose hydrate, for example, 25.5 mg of microcrystalline cellulose such as Heweten 102, 6 mg of a suitable flavoring agent such as FlavorPAL™ X1212.1, 4 mg of pregelatinized starch such as Colorcon Starch 1500 (Starch 1500®), 2 mg of amorphous anhydrous colloidal silicon dioxide such as Aerosil 200 Pharma, and 1 mg of magnesium stearate such as Hyqual®, wherein the core has a tablet hardness of 5 - 10 kp and is formed by compression using a 5 - 6 mm round tablet punch.

[0095] Accordingly, the present invention provides an oral dosage form that is biologically equivalent to the reference tablet. The oral dosage form will contain the same amount of bexagliflozin as the relevant reference tablet.

[0096] The present invention also provides a reference oral solvent dosage form. The reference oral liquid dosage form contains the same amount of bexagliflozin as the reference tablet in a 0.5 mL liquid, and produces the same exposure amount as the reference tablet after delivery of the 0.5 mL liquid, which is measured as AUC, and has the following composition per mL: 30 mg of bexagliflozin, 150 μL of ethanol, 250 μL of glycerol, 150 μL of PEG-400, 50 μL of polysorbate 80, 2 - 5 μL of flavoring agent, and phosphate buffered saline up to a volume of 1 mL (approximately 365 μL). The phosphate buffered saline contains 137 mM of NaCl, 2.7 mM of KCl, 8 mM of Na2HPO4, and 2 mM of KH2PO4.

[0097] In the technology of bioavailability and bioequivalence, methods for determining whether any given dosage unit meets the regulatory requirements for equivalent bioavailability and pharmacokinetic bioequivalence are well known. For example, Niazi (2014) Handbook of Bioequivalence Testing, 2 nd Edition, ISBN 978 - 1482226379, FDA Guidance for Industry #35 Bioequivalence Guidance (November, 2006), FDA Guidance for Industry Bioequivalence: Blood Level Bioequivalence Study, (December 2016), FDA Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs - General Considerations (March 2014), and Guideline on the Investigation of Bioequivalence, EMA January 2010 (CPMP / EWP / QWP / 1401 / 98 Rev.1 / Corr ** ) may be referred to.

[0098] An important element of any bioequivalence study is the assay used to determine the plasma concentration of the target analyte, and generally, it is necessary to ensure that the methods followed and the data obtained conform to the regulatory quality expectations, in accordance with the recommendations of the FDA Guidance for Industry: Bioanalytical Method Validation (May 2018).

[0099] Many factors that vary from one member of a species to another can affect the concentration of a drug in plasma. Therefore, it is common to take into account the mass of the subject, whether the drug is administered in a fasting state or in a fed state, the subject's diet and dosing regimen, as well as the subject's signalment. Thus, drug concentrations can vary substantially from subject to subject, even under optimally controlled conditions. To control inter-subject variability as much as possible, the formulations to be compared are often administered to young, healthy adult subjects in a fasting state, provided with a standard diet and housing conditions. When referring to in vivo measured properties, it is appropriate to adjust or normalize the effect on the expected behavior in a well-characterized prototype subject.

[0100] However, from a practical perspective, even the specifications of a prototype subject cannot capture all of the variability between individuals, and for this reason, comparisons between formulations are typically performed by administering each of the formulations to be compared, e.g., the reference formulation on one day and the test formulation on another day, to the same individual, and vice versa. Usually, a substantial period of time is allowed to elapse (at least the drug's half-life from the preceding formulation) so that the previous administration of one formulation has little potential to affect the measurements made after the administration of the subsequent formulation. Because substantial inter-individual variability almost always exists, comparisons are usually made on groups of typically 12 or more individuals. Two formulations are said to be bioequivalent if the comparison of the pharmacokinetic measurements between subjects administered each of the two formulations meets certain criteria.

[0101] In principle, as discussed in FDA Guidance for Industry #35, Bioequivalence Guidance (November 2008), there are many ways to determine biological equivalence between formulations, but the most common is based on blood level equivalence. According to this standard, two preparations are considered biologically equivalent for a particular pharmacokinetic parameter if the lower limit of the 90% confidence interval for the logarithm of the geometric mean of a particular pharmacokinetic parameter of the test preparation results in a value at least as high as a portion of the geometric mean of the same parameter of the reference preparation, usually 80.00% or more, upon exponentiation, and if the upper limit of the 90% confidence interval for the logarithm of the geometric mean of the parameter of the test preparation results in a value no higher than another value of the geometric mean of the parameter of the reference preparation, usually 125.00% or less, upon exponentiation. Typical parameters that must be found to satisfy this test are the observed maximum drug concentration (C max ), the area under the curve of concentration as a function of time from the start of dosing to the last accurately measurable value (AUC 0-t ), and the area under the curve of concentration as a function of time from the start of dosing extrapolated to infinite time (AUC 0-∞ ). Geometric means and logarithms are used in these calculations because most physiological variables, including drug plasma concentrations, typically exhibit a lognormal distribution for repeated sampling within the same individual and sampling from different individuals within a population.

[0102] Accordingly, in one aspect, the present invention provides a tablet comprising bexagliflozin, which is biologically equivalent to either of the above reference tablets (a) or (b) in terms of C max and AUC 0-t .

[0103] To ensure assay sensitivity, the tests for measuring C max values and AUC 0-t values will be conducted in a group of multiple subjects, such as at least 12 (and usually 24 - 36) healthy adults.

[0104] To establish biological equivalence, a two-period, two-sequence, two-treatment, single-dose, crossover trial design, single-dose parallel trial design, or repeated trial design can be used. The preferred design is a two-period, two-sequence, two-treatment, single-dose, crossover trial using healthy subjects. Each test subject should receive each treatment (test drug and reference drug) in a random order. The most accurate, sensitive, and reproducible method for measuring drug concentration in plasma should be used. For bexagliflozin, the preferred method is a validated high-performance or ultra-high-speed liquid chromatography (HPLC or UPLC) separation involving detection of the analyte by tandem mass spectrometry.

[0105] To support the determination of biological equivalence, at least 12 subjects with evaluable data are usually required. For a test conducted in a fasting dietary state, a minimum of 8 hours of fasting before dosing is required, and water should be withheld from 1 hour before dosing until 1 hour after dosing. Food should not be given for at least 4 hours after dosing.

[0106] Venous blood samples should be collected at appropriate intervals, usually consisting of a total of 12 to 18 samples and covering at least three terminal-phase elimination half-lives of the drug. To provide the most accurate C max to provide the expected T max Peripheral high-density sampling is recommended.

[0107] C max values and AUC 0-t values, due to the fact that each tablet tested is necessarily consumed, and because tablets are identical in all respects and there will be variability from one test to the next even when using the same subjects, pharmacokinetic parameters are determined with respect to the mean of the C max values and AUC values of a representative set of tablets selected substantially at random from the manufacturing batch for the set of subjects administered. The mean is geometrically rather than arithmetically constituted. This and the following as an example of Cmax To obtain it, for six target cohorts, the geometric mean C max is calculated as the sixth root of the product of six C max values for the subject. The same result will be obtained if the arithmetic mean of the logarithms of the C max values is exponentiated. The logarithmic values of C for each subject will collectively create the individual logarithmic distributions of the C max values. max

[0108] To compare the second production batch with the first production batch, for the same subjects, the measurement process can be repeated using tablets from the second production batch. (In practice, the order of administration will typically be randomly selected for each subject, such that some will receive tablets from the second production batch first and some will receive tablets from the first production batch first.) For each subject, the logarithm of C max for the tablets from the first production batch is subtracted from the logarithm of C max for the tablets from the second production batch to calculate the difference. The exponent of this difference is the ratio of C max for the second tablets to C max for the first tablets, and is 1 if the difference is zero (e 0 = 1). Following the usual statistical method (analysis of variance) for analyzing the difference between two sets of values, the endpoints of the 90% confidence interval for the difference in logarithms are determined. For two distributions considered to be bioequivalent, the endpoints of the 90% confidence interval for the difference in logarithms must fall between appropriately pre-specified values, for example, -0.22314 and +0.22314. When these values are exponentiated, they give 80.00% and 125.00% respectively (e -0.22314 = 0.8000). Other endpoint values determined by the regulatory authority may be appropriate, for example, -0.28768 to +0.28768 corresponding to 75.00% to 133.33%, or -0.51083 and +0.51083 corresponding to 60.00% and 166.67%.

[0109] It is considered advantageous to administer tablets from each manufacturing batch to each subject to minimize the variation between measured values. However, when using different subject cohorts to evaluate tablets from two manufacturing batches, a similar approach can be used where the difference in the mean values in logarithms for the two cohorts is calculated and a 90% confidence interval is constructed for that logarithmic difference.

[0110] Applying this type of test can establish whether the tablets in question are the tablets defined herein. A batch of tablets produced by an unknown manufacturing process, when compared to a batch of tablets of the present invention defined with reference to C max and AUC 0-t and, when both C max and AUC 0-t are considered, if the endpoints of the 90% confidence interval for the difference in logarithms of the values for the two batches are between the pre-specified values, then the batch of tablets produced by the unknown process is a tablet that meets the relevant C max and AUC 0-t requirements.

[0111] The above inference is that if a subject in a certain cohort is administered tablets of the present invention from the same manufacturing batch twice and C max and AUC 0-t are defined by reference, then the endpoints of the 90% confidence interval for the difference in logarithms between the values of the first administration and the values of the second administration for both C max and AUC 0-t will fall between the pre-specified values.

[0112] Thus, two representative sample sets from the same batch, in a cohort of healthy subjects, the logarithm of C max and AUC 0-tIt results in a difference in the mean value between sets in terms of logarithms, and more formally, it can be expressed as showing that the endpoints of the 90% confidence interval for the difference between these sets of logarithms fall between pre-specified values. The distinction from the previous paragraph is that, for example, as recommended in the regulatory guidance document for bioequivalence testing, the sequence of the tests from two sample sets can be randomly assigned among the subjects of the cohort.

[0113] Methods for the dissolution test of solid oral dosage forms are well-known in the art and include USP (United States Pharmacopeia) <711>, which specifies the types of apparatus and their methods of use.

[0114] The test of bexagliflozin veterinary tablets is carried out in a USP Apparatus 2 (paddle apparatus, for example with a nominal capacity of 1 liter) without a sinker, filled with 500 mL of 0.1 N HCl (i.e., simulated gastric fluid), stirred at a speed of 75 rpm while maintaining the temperature at 37 ± 0.5 °C. Individual tablets are placed in the apparatus, and sampling is performed at specified times (e.g., 5, 10, 15, 20, 25, 30, 45, and 60 minutes, followed by an additional 15 minutes of stirring at 250 rpm) by taking out 1 mL of liquid without replacement. At each time point, the concentration of bexagliflozin in the liquid sample is determined (e.g., by a validated HPLC method), enabling the calculation of the amount released from the tablets. These conditions comply with the recommendations of the FDA Guidance for Industry Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances (August 2018), and the use of an angular velocity of 75 rpm is justified by the need to avoid corning (i.e., IV. Standard Dissolution Testing Conditions).

[0115] The test can be carried out in a maximum of three stages as described in USP General chapter <711>, Dissolution, Acceptance Table 1. For the Vexagliflozin veterinary tablets, let the quantity Q be the amount of the dissolved active ingredient, which is 80%. To avoid doubt, Q being 80% means that 12 mg of Vexagliflozin is dissolved in the simulated gastric fluid. In stage 1, six tablets are analyzed. If each unit is Q + 5% (85%) or more, it is recorded as a success. If this criterion is not met, in stage 2, an additional six tablets are analyzed. It is recorded as a success in the following cases: (i) when the average of 12 units (from stages 1 and 2) is Q or more, and (ii) when there are no units less than Q - 15% (65%). If the criteria for stage 2 are not met, it is necessary to conduct the stage 3 test. In stage 3, an additional 12 tablets are tested, and the cumulative data of the 24 tested tablets needs to meet the following conditions: (i) the average of all 24 tablets must be Q (80%) or more, (ii) no more than 2 of the 24 tablets are less than Q - 15% (65%), and (iii) there are no tablets less than Q - 25% (55%).

[0116] The manufacturing batch of Vexagliflozin veterinary tablets is said to have passed the official dissolution approval test when at least one of the success criteria in the three test stages is met. As defined in Acceptance Table 1 of USP <711>, representative units of the manufacturing batch will meet these criteria. In practice, the test ends when success is achieved. No additional tests, such as repeating the test starting anew in stage 1 if the test fails in stage 3, should be carried out.

[0117] Therefore, the present invention provides tablets containing Vexagliflozin, and the tablets are from a manufacturing batch having a composition or method of testing or manufacturing that falls within the official acceptable range regarding variations in the process, test, or components of the above tablets (a) or (b).

[0118] Similarly, the present invention provides a solid oral dosage form (particularly a tablet, e.g., a flavored veterinary tablet) containing bexagliflozin and having an f2 value > 50 when compared to one of the reference tablets (a) or (b) as defined above in an in vitro dissolution test in simulated gastric fluid, where f2 is the reciprocal square root transformation of the common logarithm of the sum of the squared errors, and in the formula, n is the number of time points at which dissolution is measured, R i is the dissolution rate of the reference tablet at the i-th time point, and T i is the dissolution rate of the test solid oral preparation at the i-th time point.

[0119] The present invention also provides a solid oral dosage form, typically a veterinary tablet, containing bexagliflozin and passing a formal dissolution approval test (the above reference) according to the criteria of releasing > 41.2% of the bexagliflozin dose after 5 minutes and ≧ 80% of bexagliflozin after 30 minutes in simulated gastric fluid. The criteria for the dissolution pass test preferably require that 65.4 - 78.4% of bexagliflozin is released after 10 minutes and / or 80.1 - 86.2% of bexagliflozin is released after 15 minutes. In the formal dissolution pass test, these dosage forms pass at least one level of the formal 3 - level test protocol defined in Acceptance Table 2 of USP <711>.

[0120] A. Flavoring agents It is well known that companion animals, particularly felines, can be difficult to administer pharmaceuticals to. Flavoring agents are excipients added to a formulation to enhance the palatability of the formulation for companion animals, thereby improving the success rate of administration.

[0121] The flavoring agent of the present disclosure includes flavors that are attractive to companion animals, such as sweet flavoring agents or meat flavoring agents. Sweet flavoring agents are typically used for companion animals of dogs or other non-feline animals because felines cannot perceive sweet flavors.

[0122] In one embodiment, the flavoring agent includes tuna, salmon, cream, beef, peanuts, dog mint, chicken liver powder, poultry extract, hydrolyzed liver of avian, butter, or bacon flavoring. In another embodiment, the flavoring agent includes chicken liver flavoring. In another embodiment, the flavoring agent includes hydrolyzed liver of chicken. In another embodiment, the flavoring agent includes hydrolyzed liver of avian. In another embodiment, the flavoring agent includes peanut butter flavoring.

[0123] The formulations described herein are suitable for administration to cats, dogs, and other companion animals. The formulations can be successfully administered with very few administration rejection reactions. For example, in some embodiments, the formulation can be delivered daily with less than 1 administration rejection reaction per 30 administration events. In some embodiments, the formulation can be delivered daily with less than 1 administration rejection reaction per 100 administration events. In some embodiments, the formulation can be delivered daily with less than 1 administration rejection reaction per 300 administration events.

[0124] B. Tablet formulation components The tablet formulation of the present disclosure can include at least one component selected from one or more fillers, one or more glidants, one or more lubricants, and one or more binders, or other components.

[0125] In some embodiments, the tablet formulation of the present disclosure includes about 1-25% by weight, 4-20% by weight, 4-8% by weight, 2-6% by weight, 8-16% by weight, or 17-23% by weight of bexagliflozin. In some embodiments, the tablet formulation of the present disclosure includes about 20% by weight of bexagliflozin. In some embodiments, the tablet formulation of the present disclosure includes about 4% by weight of bexagliflozin.

[0126] In some embodiments, the tablet formulations of the present disclosure also include flavoring agents. In some embodiments, the tablet formulations of the present disclosure include from about 1 to 30 wt%, 2 to 25 wt%, 5 to 15 wt%, or 7 to 10 wt% of a flavoring agent. In some embodiments, the tablet formulations of the present disclosure include about 7.9 wt% of a flavoring agent. In some embodiments, the tablet formulations of the present disclosure include about 10 wt% of a flavoring agent. Suitable flavoring agents are further described in the section above.

[0127] In some embodiments, the tablet formulations of the present disclosure include one or more fillers. Suitable fillers are described below. In some embodiments, one or more fillers are present in an amount of from about 1 to 70 wt%, 5 to 65 wt%, 20 to 60 wt%, 30 to 50 wt%, or 31 to 45 wt%. In some embodiments, one or more fillers are present in an amount of about 34 wt%. In some embodiments, one or more fillers are present in an amount of about 41 wt%.

[0128] In some embodiments, the tablet formulations of the present disclosure include from one to three fillers. In some embodiments, the tablet formulations of the present disclosure include from one to two fillers. In some embodiments, the tablet formulations of the present disclosure include two fillers.

[0129] Suitable fillers include, for example, sugar alcohols (e.g., mannitol, sorbitol, xylitol, lactitol), inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, silicified microcrystalline cellulose, cellulose, hypromellose), calcium sulfate, magnesium aluminum silicate complexes, and oxides. In some embodiments, one or more fillers include a cellulose derivative. In some embodiments, one or more fillers are microcrystalline cellulose.

[0130] In some embodiments, the tablet formulations of the present disclosure include one or more glidants. Suitable glidants are described below. In some embodiments, the one or more glidants are present in an amount of about 0.5 to 8 wt%, 1 to 4 wt%, or 1.5 to 3 wt%. In some embodiments, the one or more glidants are present in an amount of about 2.6 wt%. In some embodiments, the one or more glidants are present in an amount of about 1.6 wt%. In some embodiments, the one or more glidants are present in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 wt%. In some embodiments, the one or more glidants are present in an amount of about 5 wt%.

[0131] A glidant is a substance that increases the flowability of a powder useful during tablet forming processes. Suitable glidants include, for example, colloidal silicon dioxide, ascorbyl palmitate, calcium palmitate, talc, magnesium carbonate, and the like. In some embodiments, the one or more glidants include colloidal silicon dioxide.

[0132] In some embodiments, the tablet formulations of the present disclosure include one or more lubricants. Suitable lubricants are described below. In some embodiments, the one or more lubricants are present in an amount of about 0.1 to 8 wt%, 0.1 to 4 wt%, 0.5 to 2 wt%, 0.6 to 1.3 wt%. In some embodiments, the one or more lubricants are present in an amount of about 0.5, 0.75, 1, 1.5, 2, 3, 4, or 5 wt%. In some embodiments, the one or more lubricants are present in an amount of about 1.3 wt%. In some embodiments, the one or more lubricants are present in an amount of about 0.8 wt%.

[0133] In some embodiments, the tablet formulations of the present disclosure include one to three lubricants. In some embodiments, the tablet formulations of the present disclosure include one lubricant.

[0134] Suitable lubricants include, for example, magnesium stearate, stearic acid, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol, and sodium stearyl fumarate. In some embodiments, the one or more lubricants are magnesium stearate.

[0135] In some embodiments, the tablet formulations of the present disclosure include one or more binders. Suitable binders are described below. In some embodiments, the one or more binders are present in an amount of about 30-50, 32-45, 35-45, or 42% by weight. In some embodiments, the one or more binders are present in an amount of about 42% by weight.

[0136] In some embodiments, the tablet formulations of the present disclosure include one to three binders. In some embodiments, the tablet formulations of the present disclosure include one binder. In some embodiments, the tablet formulations of the present disclosure include two binders. In some embodiments, the ratio of the first binder to the second binder is about 36:6.

[0137] Suitable binders include, for example, povidone, lactose, starch, modified starch, pregelatinized starch, saccharides, gum acacia, gum tragacanth, guar gum, pectin, wax binders, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, copovidone (copovidone), gelatin, sodium alginate, and the like. Non-cellulose binders include polymer binders and other binders lacking a cellulose backbone. Examples of non-cellulose binders include povidone, lactose, starch, modified starch, gum, guar gum, pectin, wax, gelatin, alginate, and the like. In some embodiments, the formulation contains non-cellulose binders such as lactose monohydrate and pregelatinized starch.

[0138] In some embodiments, the first binder constitutes 29.6% to 36% by weight of the tablet formulation. In some embodiments, the filler constitutes 33.6% to 41% by weight of the tablet formulation. In some embodiments, the second binder constitutes 5.3 to 6.4% by weight of the tablet formulation. In some embodiments, the flavoring agent constitutes 7.9% and 10.0% by weight of the tablet formulation. In some embodiments, the glidant constitutes 1 to 3% by weight of the tablet formulation. In some embodiments, the lubricant constitutes 0.5 to 1.3% by weight of the tablet formulation. In some embodiments, bexagliflozin constitutes 2 to 6% by weight of the tablet formulation.

[0139] In some embodiments, lactose monohydrate constitutes 29.6% to 36% by weight of the tablet formulation. In some embodiments, microcrystalline cellular constitutes 33.6% to 42% by weight of the tablet formulation. In some embodiments, pregelatinized starch constitutes 5.3 to 6.4% by weight of the tablet formulation. In some embodiments, the flavoring agent constitutes 7.9% and 10.0% by weight of the tablet formulation. In some embodiments, silicon dioxide constitutes 1 to 3% by weight of the tablet formulation. In some embodiments, magnesium stearate constitutes 0.5 to 1.3% by weight of the tablet formulation. In some embodiments, bexagliflozin constitutes 2 to 6% by weight of the tablet formulation.

[0140] In some embodiments, the tablet formulation described herein contains 15 mg of bexagliflozin. In some embodiments, the tablet formulation described herein contains 10 mg of bexagliflozin. In some embodiments, the tablet formulation described herein contains 5 mg of bexagliflozin.

[0141] In some embodiments, the tablet formulation described herein comprises 15 mg of bexagliflozin, 110.0 - 160 mg of lactose monohydrate, 117.0 - 185.4 mg of microcrystalline cellulose, 30 - 44.2 mg of flavoring agent, 19.2 - 54 mg of pregelatinized starch, 6 - 13.5 mg of colloidal silicon dioxide, and 3.0 - 3.5 mg of magnesium stearate.

[0142] In some embodiments, the tablet formulation is as described in Table 34. In some embodiments, the tablet formulation is as described in Table 37.

[0143] C. Capsule formulation components The capsule formulations of the present disclosure typically contain a dry powder or small pellets. In some embodiments, the capsule formulations of the present disclosure contain only bexagliflozin or are mixed with one or more excipients.

[0144] Additional excipients in the capsule formulation include excipients that can improve desirable biological properties such as increased adsorption. In some embodiments, the capsule formulations of the present disclosure contain microcrystalline cellulose. When mixed with one or more excipients, bexagliflozin can constitute 1 - 99% by weight of the total mixture. In some embodiments, bexagliflozin constitutes 5% (w / w) of the mixture.

[0145] The capsules of the present disclosure are generally hard gelatin capsules, but various materials for making the capsules are known in the art and are encompassed by the present disclosure.

[0146] D. Soft gel formulation components The soft gel formulations of the present disclosure may contain at least one component selected from one or more solubilizing agents, one or more surfactants, and one or more high molecular weight solubility enhancers.

[0147] In some embodiments, the soft gel formulation of the present disclosure comprises about 1 to 25 wt%, 2 to 20 wt%, 3 to 10 wt%, 2 to 6 wt%, or 10 to 20 wt% of bexagliflozin. In some embodiments, the soft gel formulation of the present disclosure comprises about 3 wt% of bexagliflozin.

[0148] In some embodiments, the soft gel formulation of the present disclosure also comprises a flavoring agent. In some embodiments, the soft gel formulation of the present disclosure comprises about 1 to 30 wt%, 2 to 25 wt%, 4 to 10 wt%, 2 to 6 wt%, or 7 to 10 wt% of a flavoring agent. In some embodiments, the soft gel formulation of the present disclosure comprises about 4 wt% of a flavoring agent. Suitable flavoring agents are further described in the previous section.

[0149] In some embodiments, the soft gel formulation of the present disclosure comprises one or more solubilizers. Suitable solubilizers are described below. In some embodiments, one or more solubilizers are present in an amount of about 10 to 70, 20 to 65, 40 to 60, or 45 to 50 wt%. In some embodiments, one or more solubilizers are present in an amount of about 47 wt%.

[0150] Suitable solubilizers include, for example, diethylene glycol ethyl ether (DEGEE), Labrasol, Gelucire 44 / 14, Labrafil M2130CS, Labrafil M2125CS, Gelucire 50 / 13, and the like. In some embodiments, one or more solubilizers are diethylene glycol ethyl ether.

[0151] In some embodiments, the soft gel formulation of the present disclosure comprises one or more surfactants. Suitable surfactants are described below. In some embodiments, one or more surfactants are present in an amount of about 10 to 60, 25 to 50, 30 to 40, or 35 to 45 wt%. In some embodiments, one or more surfactants are present in an amount of about 35 wt%.

[0152] Suitable surfactants include, for example, D-α-tocopherol polyethylene glycol succinate, polyoxyl 40 hydrogenated castor oil, macrogol-40-glycol hydroxystearate, macrogol glycerol ricinoleate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 100.

[0153] In some embodiments, the soft gel formulation of the present disclosure includes one or more high molecular weight solubility enhancers. Suitable high molecular weight solubility enhancers are described below. In some embodiments, one or more binders are present in an amount of about 2 to 20 wt%, 5 to 15 wt%, 8 to 12 wt%. In some embodiments, one or more surfactants are present in an amount of about 10 wt%.

[0154] Suitable high molecular weight solubility enhancers include, for example, polyvinylpyrrolidone (povidone or PVP). In one embodiment, the high molecular weight solubility enhancer is selected from the group consisting of PVP K12, PVP K17, PVP K30, PVP K60, and PVP K90. In some embodiments, the high molecular weight solubility enhancer is PVP K90.

[0155] In some embodiments, the soft gel formulation is as described in Table 8. In some embodiments, the soft gel formulation is as described in Table 9.

[0156] The soft gel component of the present disclosure is typically a gelatin-based composition that includes a mixture of gelatin, a plasticizer (e.g., glycerin), and optionally water or a colorant.

[0157] E. Liquid formulation components The liquid formulations of the present disclosure are generally in their liquid form at room temperature and contain a component that dissolves bexagliflozin. Generally, the liquid formulations can be prepared using an ethanol-glycerin mixture that further contains additional components. The liquid formulations can also be prepared using a diethylene glycol ethyl ether (DEGEE)-PEG-400 mixture.

[0158] Buffers can also be optionally included in the liquid formulations to maintain the desired pH. Suitable buffers include, for example, PBS buffer, citrate buffer, fumarate buffer, or combinations thereof. Typically, the amount of buffer is an amount sufficient to achieve and maintain the desired pH or to make up the desired amount.

[0159] In some embodiments, the liquid formulations of the present disclosure contain diethylene glycol ethyl ether (DEGEE), PEG-400, bexagliflozin, and a buffer. The amount of bexagliflozin in these solutions can vary. Exemplary amounts are from 1 to 50 mg. In some embodiments, the liquid formulation contains 3 mg, 10 mg, or 30 mg of bexagliflozin. In some embodiments, the concentration of bexagliflozin in the liquid formulation is about 100 mM. In some embodiments, the ratio of DEGEE to PEG-400 is from 4:1 to 1:4. In some embodiments, the ratio of DEGEE to PEG-400 is from 2:3 to 3:2. In some embodiments, the ratio of DEGEE to PEG-400 is from 1:2 to 2:1. In some embodiments, the ratio of DEGEE to PEG-400 is 3:2. In some embodiments, the buffer is a fumarate buffer at pH 6.5. In some embodiments, the liquid formulation is as described in Table 4.

[0160] In some embodiments, the liquid formulations of the present disclosure include ethanol, glycerin, bexagliflozin, a buffer, and optionally additional components. The amount of bexagliflozin in these solutions can vary. Exemplary amounts are from 1 to 50 mg. In some embodiments, the liquid formulation includes 3 mg, 10 mg, or 30 mg of bexagliflozin. In some embodiments, the ratio of ethanol to glycerin is from 4:1 to 1:4. In some embodiments, the ratio of ethanol to glycerin is from 5:3 to 3:5. In some embodiments, the ratio of ethanol to glycerin is from 4:3 to 3:4. In some embodiments, the ratio of ethanol to glycerin is from 1:2 to 2:1. In some embodiments, the ratio of ethanol to glycerin is 3:4. In some embodiments, the ratio of ethanol to glycerin is 1:2. In some embodiments, the ratio of ethanol to glycerin is 3:5. In some embodiments, the buffer is PBS at pH 7.4, or citrate buffer at pH 6.5, or fumarate buffer at pH 6.5. Additional components in these formulations include one or more of propylene glycol, PEG-400, polysorbate 80, sucralose, sorbitol, 2-pyrrolidone.

[0161] In some embodiments, the liquid formulations of the present disclosure also include a flavoring agent. Typically, the amount of flavoring agent added to the liquid formulation is an amount sufficient to reduce administration refusal from companion animals. The flavoring agent for the liquid formulation is provided in solid form and can be dissolved in the liquid formulation or pre-dissolved in a concentrated stock solution and added to the liquid formulation. Suitable flavoring agents are further described in the previous section. In some embodiments, the flavoring agent includes flavors of cream, tuna, salmon, or bacon.

[0162] In some embodiments, the liquid formulation of the present disclosure contains about 0.01 to 5% by volume of a flavoring agent. In some embodiments, the liquid formulation of the present disclosure contains about 0.1 to 15, 0.1 to 5 mg / mL, 1 to 3, 4 to 9, or 10 to 5 mg / mL of a flavoring agent. In some embodiments, the liquid formulation of the present disclosure contains about 1 to 15 mg / mL of a flavoring agent.

[0163] In some embodiments, the liquid formulation further contains a preservative. In some embodiments, the preservative is butylated hydroxyanisole, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, sorbic acid, potassium sorbate, propionic acid, etc. In some embodiments, the liquid formulation further contains butylated hydroxyanisole.

[0164] In some embodiments, the liquid formulation is as described in Tables 2, 3, or 6. In some embodiments, the liquid formulation is as described in Tables 16 or 23.

[0165] In some embodiments, the liquid formulation contains bexagliflozin, ethanol, glycerin, PEG-4000, polysorbate, and phosphate buffered saline (PBS), pH 7.4.

[0166] In some embodiments, provided herein is a liquid formulation containing bexagliflozin at 20 to 40 mg / mL, ethanol at 125 to 175 mg / mL, glycerin at 250 to 300 mg / mL, PEG-400 at 125 to 175 mg / mL, polysorbate 80 at 25 to 75 mg / mL, one or more optional flavoring agents at 1 to 15 mg / mL, and the balance being an aqueous buffer having a pH of 6.0 to 8.0.

[0167] In some embodiments, provided herein is a liquid formulation comprising bexagliflozin at 30 mg / mL, ethanol at 125 - 175 mg / mL, glycerin at 250 - 300 mg / mL, PEG - 400 at 125 - 175 mg / mL, polysorbate 80 at 25 - 75 mg / mL, one or more optional flavoring agents at 1 - 15 mg / mL, and the balance being an aqueous buffer having a pH of 6.0 - 8.0.

[0168] In some embodiments, the liquid formulation comprises bexagliflozin at 30 mg / mL, ethanol at 150 mg / mL, glycerin at 250 - 300 mg / mL, PEG - 400 at 150 mg / mL, polysorbate 80 at 50 mg / mL, one or more optional flavoring agents at 1 - 15 mg / mL, and the balance being phosphate buffered saline at pH 7.4.

[0169] F. Method of Use The present disclosure further provides methods of using the formulations of bexagliflozin described herein for the prevention and treatment of diseases. In one embodiment, the present disclosure provides a method of treating a disease or condition affected by inhibiting SGLT2, the method comprising administering to a subject in need of treatment a formulation described herein. Diseases affected by inhibiting SGLT2 include, but are not limited to, type 1 and type 2 diabetes, hyperglycemia, renal insufficiency, diabetic complications (retinopathy, nephropathy, neuropathy, ulcers, microvascular and macrovascular disorders, gout, and diabetic foot disease), insulin resistance, metabolic syndrome (syndrome X), hyperinsulinemia, hypertension, hyperuricemia, heart failure, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, cancer, and related diseases, and the method includes administering a formulation described herein. In another embodiment, the present invention provides a method of using a formulation described herein for the preparation of a medicament for treating type 1 and type 2 diabetes, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, cancer, and related diseases. In other embodiments, the present invention provides a method of treating type 1 diabetes, type 2 diabetes, hyperglycemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edema, dyslipidemia, chronic heart failure, atherosclerosis, and cancer.

[0170] In other embodiments, the present disclosure provides a method of treating diabetes, the method comprising administering to a subject in need of treatment a formulation described herein. The diabetes can be any suitable form of diabetes, including but not limited to type 1 diabetes, type 2 diabetes, and diabetic complications. In some embodiments, the diabetes is type 1 diabetes. In some other embodiments, the diabetes is type 2 diabetes.

[0171] The present disclosure also contemplates the use of the formulations in combination with other therapeutic agents, particularly agents used to treat the above-described diseases and conditions such as, for example, anti-diabetic agents, lipid-lowering agents / lipid-regulating agents, agents for treating diabetic complications, anti-obesity agents, antihypertensive agents, uric acid-lowering agents, and agents for treating chronic heart failure, atherosclerosis or related disorders. One of ordinary skill in the art will understand that the other therapeutic agents discussed below may have multiple therapeutic uses and that a listing of agents in one particular category should not be construed as limiting in any way the usefulness of such agents in combination therapy with the compounds of the present invention.

[0172] Examples of antidiabetic agents suitable for use in combination with the formulations described herein include insulin and insulin mimetics, sulfonylureas (acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, glipizide, glimepiride, glypidide, gliclazide, glyclopyramide, tolazamide, tolcyclamide, tolbutamide, etc.), insulin secretagogues (JTT-608, glibuzole, etc.), biguanides (metformin, buformin, phenformin, etc.), combinations of sulfonylureas / biguanides (glyburide / metformin, etc.), meglitinides (repaglinide, nateglinide, mitiglinide, etc.), thiazolidinediones (rosiglitazone, pioglitazone, isaglitazone, netoglitazone, riboglitazone, balaglitazone, daruglitazone, CLX-0921, etc.), combinations of thiazolidinediones / biguanides (pioglitazone / metformin, etc.), oxadiazolidinediones (YM440, etc.), peroxisome proliferator-activated receptor (PPAR) gamma agonists (farglitazar, metaglidasen, MBX-2044, GI262570, GW1929, GW7845, etc.), PPAR-alpha / gamma dual agonists (muraglitazar, naveglitazar, tesaglitazar, peliglitazar, JTT-501, GW-409544, GW-501516, etc.), PPAR-alpha / gamma / delta pan agonists (e.g., PLX204, GlaxoSmithKline 625019, GlaxoSmithKline 677954, etc.), retinoid-x receptor (RXR) agonists (ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754, bexarotene, etc.), alpha-glucosidase inhibitors (e.g., acarbose, miglitol, etc.), stimulators of insulin receptor tyrosine kinase (e.g., TER-17411,L-783281, KRX-613, etc.), tripeptidyl peptidase II inhibitors (such as UCL-1397), dipeptidyl peptidase IV inhibitors (sitagliptin, vildagliptin, denagliptin, saxagliptin, alogliptin, dutogliptin, NVP-DPP728, P93 / 01, P32 / 98, FE99901, TS-021, TSL-225, GRC8200, compounds described in U.S. Patent Nos. 6,869,947, 6,727,261, 6,710,040, 6,432,969, 6,172,081, and 6,011,155, etc.), glucokinase activators (ARRY-403, piragliatin (RO4389620), RO0281675, MK-0941, TTP355, GKA50, GKA60, GKM-001, PSN010, PSN-GK1, compounds described in Sarabu, R., et al., Expert Opinion on Therapeutic Patents, Vol. 21, No. 1, 2011, pp. 13-33, etc.), protein tyrosine phosphatase-1B inhibitors (KR61639, IDD-3, PTP-3848, PTP-112, OC-86839, PNU-177496, compounds described in Vats, R.K., et al., Current Science, Vol. 88, No. 2, 25 January 2005, pp. 241-249, etc.), glycogen phosphorylase inhibitors (such as NN-4201, CP-368296), glucose-6-phosphatase inhibitors, fructose 1,6-bisphosphatase inhibitors (such as CS-917, MB05032), pyruvate dehydrogenase inhibitors (such as AZD-7545), imidazoline derivatives (such as BL11282), inhibitors of gluconeogenesis in the liver (such as FR-225659), D-chiro-inositol, glycogen synthase kinase-3 inhibitors (compounds described in Vats, R.K., et al., Current Science, Vol. 88, No. 2, 25 January 2005, pp. 241-249, etc.), 11 beta-hydroxysteroid dehydrogenase type 1 inhibitors (such as carbenoxolone, INCB13739), glucagon receptor antagonists (BAY-27-9955,NN-2501, NNC-92-1687, etc.), glucagon-like peptide-1 (GLP-1), GLP-1 receptor agonists (exenatide, liraglutide, semaglutide, dulaglutide, CJC-1131, AVE-0100, AZM-134, LY-315902, GlaxoSmithKline 716155, etc.), or combinations of GLP-1 receptor agonists with other peptide hormone agonists or antagonists such as, for example, the dual GLP-1-GIP agonist tirzepatide or the GLP-1 agonist-GIP antagonist AMG133, amylin, amylin analogs and agonists (such as pramlintide), fatty acid binding protein (aP2) inhibitors (compounds described in U.S. Patent Nos. 6,984,645, 6,919,323, 6,670,380, 6,649,622, 6,548,529, etc.), beta-3 adrenergic receptor agonists (solabegron, CL-316243, L-771047, FR-149175, etc.), and other insulin sensitizers (reglixane, ONO-5816, MBX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929, AR-H049020, GW-501516, etc.).

[0173] Examples of agents for treating diabetic complications suitable for use in combination with the formulations described herein include aldose reductase inhibitors (e.g., epalrestat, imirestat, torestat, minalrestat, ponalrestat, zopolrestat, fidarestat, ascorbyl gamolenate, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, risarestat, zenarestat, methosorbinil, AL-1567, M-16209, TAT, AD-5467, AS-3201, NZ-314, SG-210, JTT-811, lindolrestat, sorbinil, etc.), inhibitors of advanced glycation end product (AGE) formation (pyridoxamine, OPB-9195, ALT-946, ALT-711, pimagedine, etc.), AGE degrading agents (ALT-711, etc.), sulodexide, 5-hydroxy-1-methylhydantoin, insulin-like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analogs, epidermal growth factor, nerve growth factor, uridine, protein kinase C inhibitors (ruboxistaurin, midostaurin, etc.), sodium channel antagonists (mexiletine, oxcarbazepine, etc.), nuclear factor-κB (NF-κB) inhibitors (dexlipotam, etc.), lipid peroxidase inhibitors (e.g., tirilazad mesylate, etc.), N-acetylated-alpha-linked acidic dipeptidase inhibitors (GPI-5232, GPI-5693, etc.), and carnitine derivatives (carnitine, levacecamine, levocarnitine, ST-261, etc.).

[0174] Examples of urate-lowering drugs suitable for use in combination with the formulations described herein include uric acid synthesis inhibitors (such as allopurinol, oxypurinol, etc.), uricosuric agents (such as probenecid, sulfinpyrazone, benzbromarone, etc.), and urinary alkalinizers (such as sodium bicarbonate, potassium citrate, sodium citrate, etc.).

[0175] Examples of lipid-lowering agents / lipid-regulating agents suitable for use in combination with the formulations described herein include hydroxymethylglutaryl coenzyme A reductase inhibitors (acitemate, atorvastatin, bervastatin, carvastatin, cerivastatin, cholesterol, crilvastatin, darvastatin, fluvastatin, glenvastatin, lovastatin, mevastatin, nisvastatin, pitavastatin, pravastatin, ritonavir, rosuvastatin, saquinavir, simvastatin, visastatin, SC-45355, SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BMS-180431, BMY-21950, U.S. Patent Nos. 5,753,675, 5,691,322, 5,506,219, 4,686,237, 4,647,576, 4,613,610, 4,499,compounds described in No. 289, etc.), fibrin acid derivatives (e.g., gemfibrozil, fenofibrate, bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, nicofibrate, pirifibrate, ronifibrate, simfibrate, teofibrate, AHL-157, etc.), PPAR-alpha agonists (such as GlaxoSmithKline 590735, etc.), PPAR-delta agonists (such as GlaxoSmithKline 501516, etc.), acyl-coenzyme A: cholesterol acyltransferase inhibitors (avasimibe, eflucimibe, eldacimibe, lecimibide, NTE-122, MCC-147, PD-132301-2, C1-1011, DUP-129, U-73482, U-76807, TS-962, RP-70676, P-06139, CP-113818, RP-73163, FR-129169, FY-038, EAB-309, KY-455, LS-3115, FR-145237, T-2591, J-104127, R-755, FCE-27677, FCE-28654, YIC-C8-434, CI-976, RP-64477, F-1394, CS-505, CL-283546, YM-17E, 447C88, YM-750, E-5324, KW-3033, HL-004, etc.), probucol, thyroid hormone receptor agonists (liothyronine, levothyroxine, KB-2611, GC-1, etc.), cholesterol absorption inhibitors (ezetimibe, SCH48461, etc.), lipoprotein-related phospholipase A2 inhibitors (rilapladib, darapladib, etc.), microsomal triglyceride transfer protein inhibitors (CP-346086, BMS-201038, U.S. Patent Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983, 5,962,440, 6,197,798, 6,617,325, 6,compounds described in Japanese Patent No. 821,967 and U.S. Patent No. 6,878,707, etc.), low-density lipoprotein receptor activators (LY295427, MD-700, etc.), lipoxygenase inhibitors (compounds described in International Publication No. WO97 / 12615, International Publication No. WO97 / 12613, International Publication No. WO96 / 38144, etc.), carnitine palmitoyl-transferase inhibitors (etomoxir, etc.), squalene synthase inhibitors (YM-53601, TAK-475, SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856, compounds described in U.S. Patent Nos. 5,712,396, 4,924,024, 4,871,721, etc.), nicotinic acid derivatives (acipimox, nicotinic acid, ricotinamide, nicomol, nisertrol, nicorandil, etc.), bile acid sequestrants (e.g., cholestyramine, colestipol, colestilan, colesevelam, GT-102-279, etc.), sodium / bile acid cotransporter inhibitors (264W94, S-8921, SD-5613, etc.), and cholesterol ester transfer protein inhibitors (e.g., torcetrapib, JTT-705, PNU-107368E, SC-795, CP-529414, etc.).,

[0176] Examples of anti-obesity drugs suitable for use in combination with the formulations described herein include serotonin-norepinephrine reuptake inhibitors (such as sibutramine, milnacipran, mirtazapine, venlafaxine, duloxetine, desvenlafaxine, etc.), norepinephrine-dopamine reuptake inhibitors (such as radafaxine, bupropion, amineptine, etc.), serotonin-norepinephrine-dopamine reuptake inhibitors (such as tesofensine, etc.), selective serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, etc.), selective norepinephrine reuptake inhibitors (such as reboxetine, atomoxetine, etc.), norepinephrine-releasing stimulants (such as, for example, loliipram, YM-992, etc.), anorectic drugs (such as amphetamine, methamphetamine, dextroamphetamine, phentermine, benzphetamine, fenproporex, fenmetrazine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phenylpropanolamine, etc.), dopamine agonists (such as, for example, ER-230, doprexin, bromocriptine mesylate, etc.), H3-histamine antagonists (such as impentamine, thioperamide, ciproxifan, clobenpropit, GT-2331, GT-2394, A-331440, etc.), 5-HT2c receptor agonists (such as 1-(m-chlorophenyl)piperazine (m-CPP), mirtazapine, APD-356 (lorcaserin), SCA-136 (bavsicerin), ORG-12962, ORG-37684, ORG-36262, ORG-8484, Ro-60-175, Ro-60-0332, VER-3323, VER-5593, VER-5384, VER-8775, LY-448100, WAY-161503, WAY-470, WAY-163909, MK-212, BVT.933, YM-348, IL-639, IK-264, ATH-88651, ATHX-105, etc. (such as, for example, Nilsson BM, J. Med. Chem.(see 2006, 49: 4023-4034), beta-3 adrenergic receptor agonists (L-796568, CGP12177, BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-331648, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, GW-2696, etc.), cholecystokinin agonists (SR-146131, SSR-125180, BP-3.200, A-71623, A-71378, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, GW-5823, etc.), combinations of antidepressants / acetylcholinesterase inhibitors (venlafaxine / rivastigmine, sertraline / galantamine, etc.), lipase inhibitors (e.g., orlistat, ATL-962, etc.), antiepileptic drugs (topiramate, zonisamide, etc.), leptin, leptin analogs and leptin receptor agonists (LY-355101, etc.), neuropeptide Y (NPY) receptor antagonists and modulators (SR-120819-A, PD-160170, NGD-95-1, BIBP-3226, 1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814, etc.), ciliary neurotrophic factor (e.g., Axokine, etc.), thyroid hormone receptor-beta agonists (KB-141, GC-1, GC-24, GB98 / 284425, etc.), cannabinoid CB1 receptor antagonists (rimonabant, SR147778, SLV319, etc. (e.g., Antel J et al., J. Med. Chem.(see, e.g., Handlon AL and Zhou H, J. Med. Chem. 2006, 49:4008-4016), melanin-concentrating hormone receptor antagonists (such as GlaxoSmithKline 803430X, GlaxoSmithKline 856464, SNAP-7941, T-226296, etc. (see, e.g., Handlon AL and Zhou H, J. Med. Chem. 2006, 49:4017-4022)), melanocortin-4 receptor agonists (including PT-15, Ro27-3225, THIQ, NBI55886, NBI56297, NBI56453, NBI58702, NBI58704, MB243, etc. (see, e.g., Nargund RP et al., J. Med. Chem. 2006, 49:4035-4043)), selective muscarinic receptor M1 antagonists (such as telenzepine, pirenzepine, etc.), opioid receptor antagonists (e.g., naltrexone, methylnaltrexone, nalmeffene, naloxone, alvimopan, norbinaltorphimine, nalorphine, etc.), and combinations thereof.

[0177] Examples of antihypertensive agents and agents for treating chronic heart failure, atherosclerosis or related diseases, which are suitable for use in combination with the formulations described herein, include bimoclomol, angiotensin-converting enzyme inhibitors (captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, etc.), neutral endopeptidase inhibitors (thiorphan, omapatrilat, MDL-100240, fasidotril, sampatrilat, GW-660511, mixanpril, SA-7060, E-4030, SLV-306, ecadotril, etc.), angiotensin II receptor antagonists (candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomil, telmisartan, valsartan, tasosartan, enoltasosartan, etc.), endothelin-converting enzyme inhibitors (CGS35066, CGS26303, CGS-31447, SM-19712, etc.), endothelin receptor antagonists (tracleer, sitaxsentan, ambrisentan, L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, BMS-193884, darusentan, TBC-3711, bosentan, tezosentan, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enlasentan, BMS-207940, etc.), diuretics (hydrochlorothiazide, bendroflumethiazide, trichlormethiazide, indapamide, metolazone, furosemide, bumetanide, torsemide, chlorthalidone, metolazone, cyclopenthiazide, hydroflumethiazide, tripamide, mefruside, benzylhydrochlorothiazide, penflutizide, methyclothiazide, azosemide, ethacrynic acid, torsemide, pyritanide, meclan, potassium canrenoate, spironolactone, triamterene, aminophylline, cycletanine, LLU-alpha, PNU-80873A, isosorbide,D-mannitol, D-sorbitol, fructose, glycerin, acetazolamide, methazolamide, FR-179544, OPC-31260, lixivaptan, conivaptan, etc.), calcium channel antagonists (amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipen, nimodipine, verapamil, S-verapamil, aranidipine, efonidipine, barnidipine, benidipine, manidipine, cilnidipine, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, pranidipine, lercanidipine, isradipine, elgodipine, azelnidipine, lacidipine, batandipine, remirdipine, diltiazem, clentiazem, fasudil, bepridil, gallopamil, etc.), vasodilatory antihypertensive drugs (indapamide, todorazine, hydralazine, cadralazine, budralazine, etc.), beta blockers (acebutolol, bisoprolol, esmolol, propanolol, atenolol, labetalol, carvedilol, metoprolol, etc.), sympathetic nerve blockers (amosulalol, terazosin, bunazosin, prazosin, doxazosin, propanolol, atenolol, metoprolol, carvedilol, nipradilol, seriprolol, nebivolol, betaxolol, pindolol, tertatolol, bevantolol, timolol, carteolol, bisoprolol, bopindolol, nipradilol, penbutolol, acebutolol, chilosolol, nadolol, urapidil, indralamine, etc.), alpha-2-adrenergic receptor agonists (clonidine, methyldopa, CHF-1035, guanabenz acetate, guanfacine, moxonidine, rofexidine, talipexole, etc.), centrally acting antihypertensive drugs (reserpine, etc.), platelet aggregation inhibitors (warfarin, dicumarol, phenprocoumon, acenocoumarol, anisindione, phenindione, ximelagatran, etc.), and antiplatelet drugs (aspirin, clopidogrel, ticlopidine, dipyridamole, cilostazol, ethyl icosapentate, sarpogrelate, dilazep, trapidil, beraprost, etc.).

[0178] The formulations described herein are also useful for the treatment of glucose disorders. In some embodiments, the invention provides a method of lowering blood glucose in a subject in need thereof, the method comprising administering to the subject a formulation described herein. In other embodiments, the invention provides a method of lowering the serum concentration of fructosamine in a subject in need thereof, the method comprising administering to the subject a formulation described herein. In still other embodiments, the invention provides a method of increasing urinary glucose excretion in a subject in need thereof, the method comprising administering to the subject a formulation described herein.

[0179] The treatments of the present disclosure can be administered prophylactically to prevent or delay the onset or progression of a disease or condition, such as hyperglycemia, or therapeutically to achieve a desired effect, such as a desired concentration of serum glucose, over a sustained period.

[0180] All publications and patent applications cited herein are hereby incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Any conflict between any reference cited herein and the teachings of this specification should be resolved in favor of the teachings of this specification. Similarly, any conflict between the definition of a word or phrase recognized in the art and the definition provided herein should be resolved in favor of the definition provided herein. The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, but it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made without departing from the spirit or scope of the appended claims. The invention is illustrated in more detail by specific examples.

Examples

[0181] The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various minor parameters that may be changed or modified to produce substantially the same results.

[0182] Compositions of bexagliflozin for oral administration in veterinary use were prepared as solutions, soft gels, capsules, and tablets. Candidate veterinary formulations were evaluated according to multiple criteria including pharmacokinetics, pharmacodynamics, palatability, and stability. Pharmacokinetics Produced by Veterinary Formulations

[0183] Overview Table 1 presents the C max and AUC 0-t exposures for bexagliflozin after administration to experimental cats using various formulations at different doses. The exposures are normalized to the dose in mg of bexagliflozin per kg of body weight, such that C max is given in ng / mL per mg / kg of dose, and AUC 0-t is given in ng·h / mL per mg / kg of dose. The dose-normalized values in Table 1 provide an assessment of the effectiveness of the formulations in delivering bexagliflozin to the plasma of cats orally administered at the indicated doses.

[0184] The pharmacokinetic parameters determined in the experiments presented in Table 1 were mainly evaluated after administration in the fasting state. For two tablet formulations, tests were also conducted in the fed state for comparison. In one example, the effect of providing intermittent food as a reward with an administration of 10 tablets per cat was investigated.

[0185] Table 1 shows that within a given formulation, the normalized values of AUC are generally not dose-dependent and are consistent with linear pharmacokinetics. Greater variability is observed for C max whereas AUC is more consistent.

[0186] The first capsule formulation consisting of capsules containing bexagliflozin, microcrystalline cellulose, and magnesium stearate resulted in an exposure of less than 1000 ng·h / mL per mg / kg dose in terms of AUC 0-t whereas all liquid formulations containing diethylene glycol monoethyl ether resulted in an exposure exceeding 1000 ng·h / mL per mg / kg dose in terms of AUC 0-t . The tablet formulation was similar to the DEGEE liquid formulation but produced somewhat less exposure. The exposure in soft gels was equivalent to that in capsules, with a normalized AUC 0-t of less than 1000 ng·h / mL per mg / kg dose (Table 1).

Table 1

[0187] The following examples demonstrate the effect of formulations on pharmacokinetics.

[0188] Pharmacokinetics Produced by Capsule Formulations Capsules were evaluated using a cohort of four experimental cats administered the test substance at multiple doses. The test substance was prepared in size 4 gelatin capsules and orally administered to animals fasted for 12 hours. The capsules were loaded with 5% bexagliflozin (w / w) in microcrystalline cellulose for doses of 0.1, 0.3, and 1.0 mg / kg, and bexagliflozin alone for doses of 3.0 and 10.0 mg / kg. The cats were allowed free access to food 2 hours after dosing.

[0189] A blood sample was collected from the peripheral vein of the extremities at a scheduled time point. A 0.1 - 0.3 mL sample was collected into a 1.5 mL tube containing dipotassium EDTA as an anticoagulant. The sample was immediately mixed by gently inverting the tube about 8 times. Immediately after mixing, the tube was placed on crushed ice and kept cooled until centrifugation. The sample was centrifuged within 1 hour after collection. After centrifugation, the tube was returned to the crushed ice, and the supernatant was transferred to a microcentrifuge tube and frozen. The tube was stored frozen in a -20°C freezer at the test facility before shipping for analysis. The concentration of bexagliflozin in plasma was measured by LC-MS / MS method. Separation was performed using an Agilent 1200 equipped with a Thermo Betasil C18, 50×2.1 mm, 5 μm packed column, or a Phenomenex Gemini C18, 50×4.5 mm, 5 μm packed column. Analyte detection was performed using an ABI 4000 or an AB Sciex QTRAP 5500 mass spectrometer.

[0190] The plasma concentration profile as a function of time is shown in Figure 1. Bexagliflozin was rapidly absorbed at T max between 0.6 and 1.2 hours. The volume of distribution was relatively large, in the range of 5.5 - 11.9 L / kg, and there was no dose-dependent trend. The elimination half-life was in the range of 2.9 - 5.9 hours, and there was no dose-dependent trend. Most of the variability in the half-life was due to variability in the volume of distribution, and the clearance was relatively constant at 1.46 ± 0.24 L / h / kg. AUC 0-24 was proportional to the dose over the entire dosing range, and a slope of 762 ng·h / mL per mg / kg dose was obtained by linear regression with an intercept of 0 ng·h / mL at 0 mg / kg (Figure 2). C max was dose-linear up to 3 mg / kg, but was below the prediction by linear regression at 10 mg / kg.

[0191] Pharmacokinetics Produced by the Liquid Preparation Multiple liquid formulations for the delivery of bexagliflozin to cats were prepared and tested in various ways, including by determining the pharmacokinetics induced after administration to healthy cats, as described below.

[0192] In one example, three compositions were selected for investigation (Table 2).

Table 2

[0193] In another example, a formulation containing diethylene glycol ethyl ether (DEGEE) was prepared for comparison with formulation F02A. The compositions of these two formulations are shown in Table 3.

Table 3

[0194] Four experimental cats were orally administered a liquid formulation containing 30 mg / mL of bexagliflozin dissolved in the aqueous solution shown in Table 3. The dose was 0.1 mL / kg to achieve a dose of 3 mg / kg. Blood was collected from the distal limb veins at the time point before administration and at 0.5, 1, 2, 4, 8, and 24 hours after administration.

[0195] Figure 3 shows the plasma concentration of bexagliflozin as a function of time after administration. The decline in plasma concentration in the initial (distribution) phase was similar for the two liquid formulations, while in the terminal (elimination) phase, the composition containing DEGEE showed a slower decline rate after administration (Figure 3). This abnormal effect suggests a distribution to different compartments after administration in the DEGEE formulation, which is most likely in the proximal compartment of the upper gastrointestinal tract or its components, based on the known properties of DEGEE as a penetration enhancer.

[0196] Figure 3 also shows the plasma concentration of bexagliflozin administered in capsules at the same dose (3 mg / kg). C maxwas lower, but otherwise the concentration profiles were closely parallel to those seen with the F02A formulation (glycerin / ethanol / PEG-400). C max The fact that it is lower indicates that the efficiency of initial absorption is poor, which may reflect the small volume of liquid and the relatively low solubility of bexagliflozin in an aqueous medium at 37°C (approximately 0.5 mg / mL).

[0197] In further experiments using liquid formulations, groups of 8 or 9 cats were administered fixed doses of 1.5 mg of bexagliflozin on days 0 - 3, 5 mg on days 4 - 7, and 15 mg on days 8 - 11 for 4 consecutive days as 0.5 mL of the formulation shown in Table 4. In the sodium form, it was prepared with fumaric acid buffer.

[0198] Blood was collected at the pre - dosing time point and at 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing. Blood was obtained directly via venipuncture using appropriately sized needles and syringes. Approximately 0.5 mL of blood was collected and immediately placed into a cooled tube containing K2EDTA as an anticoagulant. The blood tube was inverted several times to ensure mixing of the blood and the anticoagulant. The blood samples were centrifuged at a force of 1100 - 1300×g for 10 minutes. Once separated, the plasma was transferred to a set of two labeled cryovials and frozen at ≤ - 70°C. After completion of the in - life test, one set of samples was shipped on dry ice to the bioanalytical facility for analysis.

[0199] For analysis, 100 μL of calibration standards, QC samples, test samples, and blanks were pipetted into a 2.4 mL 96-well plate using a pipette or automated liquid handler. The reagent blank was 100 μL of water. 50.0 μL of methanol:water (50:50 v / v) was added to the wells containing the blanks using a pipette or automated liquid handler, and 50.0 μL of internal standard solution was added to all other wells. 700 μL of methyl-tert-butyl ether was added to each well using a pipette or automated liquid handler. The well contents were mixed by aspiration and injection 25 times with an automated liquid handler. The plate was sealed and centrifuged at a minimum of 1640×g for approximately 5 minutes. 500 μL was transferred from the organic layer to a clean 2-mL 96-well plate using an automated liquid handler. The wells were then evaporated to dryness at 40 °C under a nitrogen stream. The dried samples were reconstituted by adding 150 μL of acetonitrile:water (30:70) using a pipette or automated liquid handler. The plate was sealed, vortexed for 1 minute, and stored under cooling conditions for analysis.

[0200] The concentration of bexagliflozin in plasma was measured by LC-MS / MS. Thermo Aquasil C 18 Separation was performed using a Shimadzu Prominence 20 series HPLC equipped with a 50×2.1 mm, 3 μm packed column. Elution was with a homogeneous solvent of 10 mM ammonium acetate (62%) and acetonitrile (38%), and the typical retention time was 0.85 minutes. Analyte detection was performed in electrospray ionization positive ion mode using a Sciex API 4500 mass spectrometer at a spray voltage value of 4000 V. The internal standard was bexagliflozin uniformly labeled with C in the glucose moiety, and detection was based on transitions of 482.2→167.1 for the analyte and 488.2→169.1 for the standard. 13

[0201] Based on the body weight of the cats, the doses were set at 0.3, 1.0, and 3.0 mg / kg on average for three doses. The plasma concentration of bexagliflozin as a function of time is shown in Figure 4.

Table 4

Table 5

[0202] A number of additional liquid formulations were prepared as described in Table 6 and tested in four cats each. Formulation P produced a different profile compared to the others, while the others were closely similar (Figure 5). The lower the proportion of DEGEE used, the less effect on pharmacokinetics was observed. The highest absorption (C max ) was produced by Formulation W, resulting in the highest AUC (Table 7). The next highest C max values were produced by Formulations M and V, and the lowest C max and AUC values were produced by Formulation P (Table 7).

Table 6

Table 7

[0203] Pharmacokinetics produced by soft gel formulations To further characterize the potential usefulness of DEGEE as an excipient, a flavored soft gel delivery system was explored. The composition was a flavored encapsulated liquid preparation prepared with two solvent compositions and two flavoring agents (salmon and tuna flavors). Tables 8 and 9 show the composition of the soft gels prepared.

Table 8

Table 9

[0204] Four experimental cats were each administered one soft gel from each of the two preparations described above. Plasma was collected at the time point before administration and at 0.5, 1, 2, 4, 8, and 24 hours after administration and analyzed by HPLC MS / MS method. Figure 6 shows that the two formulations produced nearly identical plasma concentrations after exceeding 2 hours. C max produced by the soft gel formulation D was max greater than 458 ng / mL and was 747 ng / mL, and also the AUC 0-t (AUC 0-24 ) value reflected this difference, with an AUC 0-t of 1752 ng·h / mL produced by formulation D and 1430 ng·h / mL produced by formulation B (Table 10). The doses in mg / kg units were nearly identical, being 1.78 for the administration of formulation D and 1.79 for the administration of formulation B.

Table 10

[0205] Pharmacokinetics Produced by Tablet Formulations A dose range-finding study was conducted using tablets prepared using polyacrylic resin slurry processing. For the evaluation of pharmacodynamics, canned food was fed to the animals to promote a constant daily urine volume and the collection of appropriate urine samples. Water was freely available.

[0206] All animals were administered the test substance at each dose. At the 2.5 mg dose, it was delivered as half of one 5 mg tablet cut with a pill cutter. At the 5 mg dose, it was delivered as one 5 mg tablet per cat, at the 10 mg dose, it was delivered as one 10 mg tablet per cat, and at the 30 mg dose, it was delivered as two 15 mg tablets per cat. For the pharmacokinetic study, the test substance was administered after blood collection at the time point before administration (0 hours). For the pharmacodynamic study, the test substance was administered daily at 9:00 - 9:30 for four consecutive days, and urine excreted by the animals in the latest three days (after administration and before the next administration) was collected.

[0207] To reduce the impact of daily fluctuations in urinary excretion, collection was carried out over three days. The per-tablet content of bexagliflozin in 5 mg tablets was significantly lower than expected (3.9 mg, 78% of the target content). In referring to the dose, for convenience, the nominal dose is used in this report, but the calculation of the dose-response relationship in mg / kg units was based on the measured bexagliflozin content.

[0208] Blood samples were collected from the peripheral veins of the extremities at the scheduled time points. Samples of 0.1 - 0.3 mL were collected into 1.5 mL tubes containing dipotassium EDTA as an anticoagulant. The samples were immediately mixed gently by inverting the tubes about 8 times to confirm that the blood at the bottom of the tube was thoroughly mixed. Immediately after mixing, the tubes were placed on crushed ice and kept cooled until centrifugation. The samples were centrifuged within 1 hour of collection to recover the plasma. The tubes were centrifuged at 4 °C for 5 minutes using a centrifuge set at 5,000 rpm. After centrifugation, the tubes were returned to the crushed ice, and the supernatant was transferred to a microcentrifuge tube and frozen. The tubes were stored frozen at -20 °C in a freezer at the test facility before shipping for analysis.

[0209] The concentration of bexagliflozin in plasma was measured by LC-MS / MS method. Thermo Betasil C 18 50×2.1 mm, 5 μm column, or Phenomenex Gemini C 18 Separation was carried out using an Agilent 1200 equipped with a 50×4.5 mm, 5 μm column. Analyte detection was performed using an ABI 4000 or AB Sciex QTRAP 5500 mass spectrometer.

[0210] The plasma concentration of bexagliflozin as a function of time is shown in Figure 7. A dose-dependent increase in exposure was observed, although there were some differences in the profile as the dose increased. The contribution of the distribution phase was most prominent at the lowest dose level, which may suggest a saturable compartment or a saturable metabolic pathway. Dose-normalized C maxIt was slightly variable and showed no significant trend with increasing dose. On the other hand, the dose-normalized AUC was higher at the highest dose (Table 11).

Table 11

[0211] Under high temperature and high humidity conditions, the resin slurry formulation accumulated impurities that were products of the cleavage of cyclopropyl ether (Figure 13). It was hypothesized that the ion exchange resin might be involved in the formation of the impurities.

[0212] To evaluate this, three candidate alternative formulations were prepared: A-Na incorporating a neutralization step prepared in the same manner as the acidic resin slurry formulation but with the protons of the resin replaced by sodium ions, DB-A-H prepared by a dry mixture of the resin and other excipients (and leaving the resin in the hydrogen ion form), and DB which was a dry mixture of the active ingredient and other excipients excluding the ion exchange resin. The relative pharmacokinetics after single-dose administration to six cats were determined.

[0213] Figure 8 shows that the plasma concentration as a function of time was broadly similar among the alternative formulations. Table 12 summarizes the estimated pharmacokinetic parameters. Formulations A-Na and DB-A-H yielded slightly lower C max and AUC than the acidic resin slurry formulation, while formulation DB yielded greater exposure in both measurements. The results of tablet delivery in the fasting or fed state are shown in Figure 9.

Table 12

[0214] To evaluate the pharmacokinetic results of the food reward provided to fasting cats after each dosing session, in two studies, fasting cats were administered ten tablets of the DB formulation in four sessions of two or three tablets per session. In the first study, cats were not given a food reward but were returned to their cages after administration. In the second study, after each session, cats were given a food reward (approximately 5 g of standard diet). All cats consumed all of the reward.

[0215] Table 13 compares the results of the pharmacokinetic parameters of the ten-dose administration regardless of the presence or absence of a food reward. C max The C value and the AUC value were divided by 10 to enable the evaluation of the linearity of pharmacokinetics. As shown in Table 13, the exposure of bexagliflozin in terms of AUC appears to have high dose linearity and the effect of the food reward is not substantial. The dose-normalized C max resulting from ten tablets is approximately 30% lower than the C max resulting from a single tablet (Table 13).

Table 13

[0216] Similar pharmacokinetics could be obtained with smaller tablets. A comparison of the plasma concentration profiles resulting from 10 mm pentagonal tablets (the composition of Table 35) and 5.5 mm round tablets (the composition of Table 38) is shown in Figure 10. Pharmacodynamics resulting from veterinary formulations

[0217] Pharmacodynamics resulting from capsule formulations The pharmacodynamics of inhibitors of renal glucose reabsorption can be easily monitored by measuring urinary glucose excretion (UGE). Sodium-coupled glucose transporters SGLT1 and SGLT2 are expressed in the second and first segments (straight and convoluted proximal tubules) of the proximal tubule of the kidney, respectively. There is no substantial source or sink of glucose downstream of the renal proximal tubule, and thus, the degree to which renal reabsorption is impaired by the inhibition of these transporters is measured by the net urinary glucose excretion.

[0218] As described above, four experimental cats were each administered venglustat either as a mixture with microcrystalline cellulose or as pure venglustat, in each case in gelatin capsules. Venglustat induced significant glucosuria in healthy cats. At 3 mg / kg, the total urinary glucose excreted over 24 hours was 4.78 g (Table 14). Glucosuria was dose-dependent, and the ED 50 was 0.56 mg / kg and appeared to be maximal with a test substance of 3 mg / kg. Glucosuria after administration of the test substance in the fasting state was higher than that after administration in the fed state (lower part of Table 14). A graphical representation of these results can be seen in Figure 12.

Table 14

[0219] Pharmacodynamics produced by the liquid formulation The pharmacodynamics produced by the liquid formulation of venglustat were also evaluated. Cats were fed daily with whiskas canned cat food (ocean fish), and venglustat was delivered orally daily in various formulations derived from F16D as shown in Table 15.

Table 15

[0220] Cats were administered F16D-V0 (0.1 mL / kg) for two days (vehicle control), and urine samples were collected on the second day for glucose excretion analysis. Similarly, from the first day to the fourth day, cats were administered F16D-V1 (0.1 mL / kg) at a dose of 0.1 mg / kg daily, and urine samples were collected from the second day to the fourth day for glucose excretion analysis. From the fifth day to the eighth day, cats were administered F16D-V2 (0.1 mL / kg) at a dose of 0.3 mg / kg daily, and urine samples were collected from the sixth day to the eighth day for glucose excretion analysis. From the ninth day to the twelfth day, cats were administered F16D-V3 (0.1 mL / kg) at a dose of 1 mg / kg daily, and urine samples were collected from the tenth day to the twelfth day for glucose excretion analysis. From the thirteenth day to the sixteenth day, cats were administered F16D (0.1 mL / kg) at a dose of 3 mg / kg daily, and urine samples were collected from the fourteenth day to the sixteenth day for glucose excretion analysis.

[0221] Urine samples were analyzed using a Hitachi 7600-010 automated biochemical analyzer. Urinary glucose and creatinine concentrations were measured. No data correction was made for possible species and / or analyte source differences in sensitivity and / or measurement response.

[0222] The results are shown in Figure 11. The maximum glucose excretion per day was 7854 mg, and the maximum half (ED 50 ) was predicted to be 0.383 mg / kg / day.

[0223] Pharmacodynamics produced by tablet formulations The pharmacodynamics elicited by bexagliflozin to be delivered by tablets were also evaluated. A single dose of bexagliflozin tablets was administered to each of four healthy cats. The tablets were manufactured with a consistent size and shape and with a characteristic odor comparable to that of a dry hood for cats.

[0224] Vexagliflozin, when administered as a tablet for veterinary use, induced significant glucosuria in healthy cats. Glucosuria, as indicated by urinary glucose excretion and the glucose-to-creatinine ratio, showed logistic behavior with UGE of 0.505 mg / kg (corrected for analysis), as shown in Figure 12. These dose-response curves did not reproduce the previously observed decrease in glucosuria at a dose of 3 mg / kg for capsule administration (Figure 12). 50 showed logistic behavior with UGE of 0.505 mg / kg (corrected for analysis). These dose-response curves did not reproduce the previously observed decrease in glucosuria at a dose of 3 mg / kg for capsule administration (Figure 12).

[0225] Palatability of veterinary formulations Whether an oral drug can be favorably delivered to an animal depends on the acceptability of the dosage form. Many drugs have what humans consider an unpleasant taste and are delivered to humans via the oral route in capsules or film-coated tablets that block direct contact of the active ingredient with the taste receptors in the oral cavity. Animals can be difficult to administer oral solid dosage forms, and cats are particularly resistant. As a result, the preferred dosage form for cats tends to be an oral liquid that can be administered deep into the mouth using a dropper or syringe, and in most cases, induces reflex swallowing that allows most of the dose to be delivered. However, it is difficult to mask the perception of an undesirable taste.

[0226] The perception of taste varies by species and within species. In hypercarnivores (animals that consume more than 70% meat in their diet), loss of taste receptors for sugar is common (Jiang et al., 2012 Proc Natl Acad Sci USA 109:4956 doi:10.1073 / pnas.1118360109). In particular, cats are known to lack the perception of sweetness and have accumulated inactivating mutations in the gene encoding the receptor for sweet substances (Li et al. 2006 J Nutr 136:1932S doi:10.1093 / jn / 136.7.1932S). Variations in taste perception make it important to establish the acceptability of candidate oral formulations through palatability testing in the target species.

[0227] The palatability test of bexagliflozin veterinary products was conducted on oral liquid and oral tablet dosage forms as described in the following examples.

[0228] Palatability of Liquid Preparations A palatability test was conducted to evaluate the acceptability of some candidate liquid preparations. In this test, short-haired domestic cats, 402 - 932 days old at the start of dosing, were used. Physiologically, the cats were healthy and their body weights ranged from 2.5 to 7.1 kg.

[0229] Twenty-five cats (7 castrated males and 18 females) were acclimated to the test conditions for 7 days. At the end of the acclimation period, 24 cats (7 castrated males and 17 females) were considered eligible and entered the dosing period.

[0230] Each cat was acclimated to the acceptability test procedure on days -3 to -1 before the start of the acceptability test using commercially available treats. Pet liquid treats were given to each cat on days -3 to -1.

[0231] A total volume of 0.5 mL was given to each cat, and then the test substance or treat was orally administered according to the following general procedure. The dosing technician ensured that the mouth was free of food or other substances. The cat's head was tilted backward with the nose upward. The dosing syringe was placed at the back of the mouth, and all the substance was gently administered.

[0232] The acceptability of the test substance was scored as follows. 3: All substances were ingested willingly. 2: The substance was ingested with minimal restraint. A short break may be required during dosing. 1: The substance was ingested, but with considerable restraint and, in some cases, multiple dosing efforts. 0: The full dose could not be administered, and the cats became uncontrollable, with excessive salivation, retching, and disappearance of the administered substance, regardless of its presence or absence.

[0233] Acceptance was defined as score 2 or 3.

[0234] Table 16 shows the composition of the formulation. The components were bexagliflozin (10 mg / mL), butylated hydroxyanisole (BHA), diethylene glycol ethyl ether (DEGEE), polyethylene glycol, molecular weight 400 (PEG-400), glycerin, bacon flavor, and sodium citrate buffer (100 mM) at pH 6.5.

Table 16

[0235] The scores regarding administration are shown in Table 17. Many cats were scored 3, which means that the administration was well accepted. However, the immediate reactions to the intake of the test substance formulation included excessive salivation and / or blowing bubbles from the mouth, retching, and narrowing of the eyes. Furthermore, in all formulations, there was at least one vomiting episode, except for formulations H and J, where score 1 was the highest number.

Table 17

[0236] Formulations G and K had a 100% acceptance rate (Table 18). Among the remaining formulations, the acceptability was ranked as follows: F > L > H. Formulation J was not considered acceptable with an acceptance rate of 69%.

Table 18

[0237] In another palatability test, short-haired domestic cats, 163 to 970 days old at the start of dosing, were used. Physiologically, the cats were healthy and weighed in the range of 2.8 to 4.1 kg. Twenty-six cats (7 males and 19 females) were acclimated to the test conditions for 7 days. At the end of the acclimation period, 24 cats (7 males and 17 females) were considered eligible and entered the dosing period.

[0238] Each cat was acclimated to the palatability test procedure on days -3 to -1 before the start of the acceptance test using commercially available treats. Pet liquid treats were given to each cat on days -3 to -1. A total volume of 0.5 mL was given to each cat.

[0239] The substance or treat was administered orally according to the following general procedure. The dosing technician ensured that the mouth was free of food or other substances. The cat's head was tilted backward with the nose upward. The dosing syringe was positioned at the back of the mouth and all of the substance was administered gently.

[0240] The acceptability of the test substance was scored as follows. 3: All of the substance was ingested willingly. 2: The substance was ingested with minimal restraint. A short break may be required during dosing. 1: The substance was ingested, but with considerable restraint and, in some cases, multiple dosing efforts. 0: The full dose could not be administered and the cat became overly unmanageable, regardless of excessive salivation, retching, and disappearance of the substance during dosing. Acceptance was defined as a score of 2 or 3.

[0241] Table 19 shows the composition of the formulation. The components were bexagliflozin (10 mg / mL), propylene glycol (PG), polyethylene glycol, molecular weight 400 (PEG-400), polyoxyethylene (20) sorbitan monooleate (PS80), diethylene glycol ethyl ether (DEGEE), isosorbide dimethyl ether (IDE), propylene glycol monolaurate (PG-12), 2-pyrrolidinone, and citrate buffer (100 mM) at pH 6.5. [Table 19]

[0242] The scores regarding administration are shown in Table 20. Vomiting after administration was seen sporadically. Each formulation, except formulation AH with low tolerance, vomited once after administration. [Table 20]

[0243] Formulations AJ, AK, AM, and Q were considered acceptable, all having an acceptance rate exceeding 70%. Formulations AL and AH were not considered acceptable with acceptance rates of 50% and 31% respectively. Formulation AK, consisting of 50% PEG-400, 15% propylene glycol, and 5% diethylene glycol ethyl ether, was most easily accepted and produced the least amount of hypersalivation (Table 21). [Table 21]

[0244] An oral liquid containing bexagliflozin was also evaluated in an experiment involving 28 mature short-haired domestic cats, 19 to 33 months old and weighing 2.40 to 6.90 kg, which were offered as candidates for the test. All cats were judged to be in good general health as confirmed by physical examination and daily overall health observations. Each cat was from the facility's resident colony and was permanently identified by a unique tattoo number on the left pinna. Demographic information on the registered cats is shown in Table 22.

Table 22

[0245] Cats were eligible for inclusion if they were mature (over 6 months old), judged healthy based on physical examination and daily overall health observations, and had a temperament suitable for the experimental procedure. Females could not be pregnant or lactating. Candidates could also be excluded if they proved particularly resistant to oral administration during the placebo training sessions. Candidates were acclimatized to the test conditions for seven days prior to the first treatment. During the acclimatization phase, care, diet, and water were the same as the conditions during the treatment phase. During the acclimatization period, general health observations were made once a day.

[0246] Also, during this period, three flavored oral formulations were administered for several days to acclimatize the cats to oral administration. All candidates received the same training formulation on a given day.

[0247] Individual doses of the bexagliflozin liquid formulation were prepared for each registered cat based on the assignment of each cat to a group and the intended standard dose of 0.5 mL. All 24 cats were treated once a day for 4 consecutive days (days 0 to 3) with the formulation assigned to the cat. The composition of the oral liquid is shown in Table 23.

Table 23

[0248] Acceptability was based on the binary scoring scheme shown in Table 24.

Table 24

[0249] The acceptance scores for each formulation are shown in Table 25. The total acceptance scores over the entire test period were summarized as a proportion and also presented as a percentage (Table 26).

Table 25

Table 26

[0250] Formulations A, B, D, and E were acceptable to less than 50% of the cats treated with the investigational drug over the course of the trial. Formulations C and F were acceptable to 50% and 62.5%, respectively, of the cats treated with these formulations.

[0251] Additional tests were conducted to evaluate the acceptability of a number of candidate excipient compositions. In this test, only the vehicle was evaluated.

[0252] Twenty-four mature shorthair domestic cats were acclimated to the test conditions for three days. The candidate cats were determined to be in good general health as confirmed by past health records and daily overall health observations.

[0253] Each cat was from the facility's resident colony and was permanently identified with a unique tattoo number in the left pinna. Demographic information for the registered cats is shown in Table 27.

Table 27

[0254] Table 28 shows the vehicle composition. The components were propylene glycol, polyethylene glycol, molecular weight 400 (PEG-400), polyoxyethylene sorbitan monooleate (polysorbate 80), sucralose, diethylene glycol ethyl ether (DEGEE), 2-pyrrolidinone, and a citrate buffer (100 mM) at pH 6.5.

Table 28

[0255] Acceptability was based on a binary scoring scheme as previously shown in Table 24.

[0256] The acceptance scores for each vehicle are shown in Table 29. The sum of the acceptance scores over the entire test period was summarized as a proportion and also expressed as a percentage (Table 30).

Table 29

Table 30

[0257] Formulations M, O, Q, and S were acceptable to more than 75% of the cats treated with their respective test substances over the course of the trial. Formulations S and O were acceptable to 100% and 93.75%, respectively, of the treated cats.

[0258] Palatability of Tablet Formulations To evaluate the palatability of the veterinary tablets of bexagliflozin, 10 cats were acclimated to the test conditions for 7 days, during which physical examinations, body weight measurements, training and scoring of the acceptability test, and daily clinical observations were performed.

[0259] At the end of the acclimation period, 8 cats were selected to enter the dosing phase based on signalment characteristics, health, training scores of the acceptability test, and suitability for the test procedure.

[0260] Acceptability was scored as follows during both the training period and the test period. 3: All substances were ingested from the dish 2: All substances were ingested from the hand 1: Only part of the substance was ingested 0: No substance was ingested

[0261] Each cat was acclimated to the acceptability test procedure on days -3 to -1 before the start of the acceptability test using commercially available treats as follows. Pet treats were given to each cat at 11:30 (±30 minutes) after a short fasting period of at least 2.5 hours according to the following general procedure. The cat (while in the cat's cage) was administered by being given the substance or treat from a clean, empty food dish. If the cat removed the substance or treat from the dish and did not ingest it, it was returned to the dish. The allotted time for ingesting the substance or treat was 3 minutes, and if it was not ingested within the allotted time, it was given by hand wearing gloves. If the cat did not ingest the substance or treat 5 minutes after the total offering time (bowl and hand), the test was terminated.

[0262] The acceptance rates of the test substance and the control substance (milbemectin oxime / praziquantel tablets) were 75% and 41% respectively (Table 31). Therefore, this test substance was considered acceptable.

Table 31

[0263] In the target animal safety test, the 15 mg veterinary tablets of bexagliflozin in the composition shown in Table 35 were orally administered to cats bred for research for 182 days. The dosing was adjusted to ensure that the minimum dose was either 5, 15, or 25 mg / kg / day. For male animals in the cohort with ≥25 mg / kg / day, in the dosing session delivering a maximum of 4 tablets per session, approximately 9 tablets per day were administered, with a 15-minute rest period between sessions. No major difficulties were encountered and all animals completed the test.

[0264] In the field evaluation test, the 15 mg veterinary tablets of bexagliflozin were orally administered to dogs of different breeds over various lengths of time. The 15 mg veterinary tablets of bexagliflozin in the composition shown in Table 35 were well tolerated and no dosing failures were reported.

[0265] In one case, it was reported by a pet owner who kept both cats and dogs in the family that the dog chewed open a container containing tablets intended for the treatment of the cat and ingested all the tablets. No obvious harmful effects were observed. The 15 mg veterinary tablets of bexagliflozin in the composition shown in Table 35 were considered attractive to at least one dog.

[0266] Stability of veterinary preparations Stability of liquid preparations To understand the solvation power of various excipient mixtures and the stability of the solutions obtained after long-term incubation at room temperature, the preparations presented in were evaluated. Preparation T-PG was found to form crystals after 72 hours of incubation, while preparations F02A and F02B formed clear solutions that were stable to long-term incubation at room temperature (Table 32). The viscosity of F02A was lower than that of F02B (Table 32).

Table 32

[0267] The sample was stored at -20 °C for 24 hours, then thawed at room temperature for 1 hour, and then stored at 50 °C for 24 hours. This cooling / heating cycle was repeated for a total of three cycles. Viscosity was measured at the end of cycle 3. The liquid formulation T-PG did not function well in this test (Table 33).

Table 33

[0268] Stability of tablet formulations The stability of tablet formulations was also investigated. The acidic resin slurry tablet formulations showed excellent palatability and good bioavailability, but were found to accumulate impurities in stability tests including long-term exposure to storage conditions of 40 °C and 75% relative humidity. A linear increase in impurities resulting from the cleavage of the cyclopropyl ether of bexagliflozin was observed (Figure 13).

[0269] Since the impurities were suspected to be due to the presence of the acidic resin, several formulations were prepared in which the resin was changed, the resin was mixed with the excipient in a different way, or the resin was omitted.

[0270] The resin-free dry mixture tablets with the composition provided in Table 35 were selected for further characterization. The tablets were pressed and bottled in 30-tablet or 90-tablet high-density polyethylene bottles with child-resistant closures. Representative samples that were bottled were incubated at 25 ± 2 °C and 60 ± 5% relative humidity for 36 months. Impurities resulting from the cleavage of the cyclopropyl ether were present at 0.06%, 0.14%, and 0.07% in the tablets packaged in 30-tablet bottles and at 0.05%, 0.14%, and 0.07% in the tablets packaged in 90-tablet bottles. In this analysis, the tablets in 30-tablet bottles were 98.5%, 99.6%, and 99.8%, and the tablets in 90-tablet bottles were 99.6%, 99.7%, and 100.2%. The dry mixture tablets were concluded to have excellent stability characteristics.

[0271] Preparation of veterinary formulations Preparation of Liquid Formulations The preparation of the formulations varied depending on the type. Liquid formulations were generally prepared at the experimental site. Some formulations were prepared elsewhere and delivered to the site. The volume of the prepared liquid agent was typically 10 mL.

[0272] Preparation of Soft Gel Formulations A soft gel formulation containing water-soluble vitamin E (D-α-tocopheryl polyethylene glycol succinate) was prepared as follows. A stainless steel container was charged with D-α-tocopheryl polyethylene glycol succinate, NF (420.0 g). D-α-tocopheryl polyethylene glycol succinate was heated until completely melted, and the temperature was kept not exceeding 65 °C. The stainless steel container was charged with diethylene glycol ethyl ether (574.5 g). Under constant mixing, diethylene glycol ethyl ether was heated to 45 - 55 °C, and the melted D-α-tocopheryl polyethylene glycol was added. Vexagliflozin (37.5 g) was slowly added and mixed until completely dissolved. Then, while maintaining constant mixing and a temperature of 45 - 55 °C, 120.0 g of povidone, USP (K value 90) was added and mixed until the composition became homogeneous (10 - 15 minutes). The temperature was lowered to 40 - 50 °C, and while maintaining constant mixing, 48 g of flavoring agent was added and mixing was continued until the materials became uniform (5 - 10 minutes). Then, the composition was degassed for more than 5 minutes, nitrogen was introduced, and it was sealed.

[0273] A soft gel formulation containing polyoxyl castor oil was prepared as follows. A stainless steel container was filled with polyoxyl 40 hydrogenated castor oil, NF (420.0 g) and heated until the material was completely melted, maintaining the temperature below 45°C. The stainless steel container was filled with diethylene glycol ethyl ether (574.5 g) and heated to 45 - 55°C while mixing. While maintaining constant mixing, the melted polyoxyl 40 hydrogenated castor oil was added, followed by the slow addition of vexagliflozin (37.5 g), and the composition was further mixed until the vexagliflozin was completely dissolved. Next, 120.0 g of povidone, USP (K value 90) was slowly added and the composition was mixed until homogeneous (15 - 30 minutes). The temperature was lowered to 40 - 50°C and while continuing mixing, 48.0 g of flavoring agent was added and mixing was continued until the material was uniform (5 - 10 minutes), then degassed for 5 minutes or more, nitrogen was introduced, and it was sealed.

[0274] Preparation of Tablet Formulation The first resin - based tablet formulation was prepared by forming a slurry of vexagliflozin and polyacrillex resin, removing excess water from the slurry by centrifugation, drying the centrifuged solid in a fluid - bed dryer, and pulverizing the product to produce a powder such that a mixture for tablet forming could be produced in combination with additional excipients.

[0275] The composition per tablet produced by resin slurry processing is provided in Table 34. [Table 34]

[0276] The composition of a 1 kg batch of 15 mg vexagliflozin veterinary tablets produced by dry - mixture processing is provided in Table 35. [Table 35]

[0277] The production of a 1 kg tablet batch was carried out as follows. Step 1 Bexagliflozin and 100 of about 160 g of lactose monohydrate were sieved through a #30 mesh hand-held sieve. Step 2 Colloidal silicon dioxide and flavoring agent were tumble blended in a suitable polyethylene bag for 2 minutes. Step 3 Microcrystalline cellulose, half of the pregelatinized starch, and the remaining lactose monohydrate were sieved through a #30 mesh sieve. Step 4 Steps 3 and 1 were added to a 4-quart V-blender shell in the following order: (a) Half of the product of Step 3 (b) The product of Step 1 (c) Half of the product of Step 3 Step 5 The remaining half of the pregelatinized starch and magnesium stearate were tumble blended in a polyethylene bag of appropriate size for 1 minute and then manually sieved through a #30 sieve using a polypropylene hand scraper. Step 6 The sieved material from Step 5 was added to a 4-quart V-blender and mixed at 25 RPM for 2 minutes. Step 7 The mixture was discharged into a polyethylene bag of suitable size.

[0278] The manufacturing process for a 75 kg tablet batch is as follows. Step 1 The following were added to a 10-cubic-foot V-blender in the listed order: (a) Microcrystalline cellulose, 15.45 kg (b) Lactose monohydrate, 13.5 kg. Step 2 This component was mixed in the V-blender at 20 (19 - 21) RPM for 3 minutes. Step 3 The following were added to the same V-blender in the listed order: (a) Bexagliflozin, 3.0 kg (b) Pregelatinized starch, 4.8 kg (c) Colloidal silicon dioxide, 1.2 kg (d) Microcrystalline cellulose, 15.45 kg (e) Lactose monohydrate, 6.75 kg Step 4 The contents of the V-blender were mixed at 20 (19 - 21) RPM for 10 minutes without an I-bar. Step 5 The mixture was discharged into a container double-lined with a PE bag. Step 6 The mixture was milled at a mill speed of 1200 rpm using a Quadro Comil equipped with a sieve of 2A018R01530 or 2C018R01530 (equivalent to 457 microns, 40 mesh) and a round impeller. The milled substance was collected in a container double-lined with a PE bag. Step 7 The following components were milled at a mill speed of 1200 rpm using a Quadro Comil equipped with a sieve of 2A018R01530 or 2C018R01530 (equivalent to 457 microns, 40 mesh) and a round impeller. (a) Flavoring agent, 7.5 kg (b) Lactose monohydrate, 6.75 kg Step 8 The milled material was collected in a container double-lined with a PE bag. Step 9 The V-blender of Step 5 was filled with the following: (a) The milled mixture of Step 7 (b) The milled flavoring agent / lactose monohydrate of Step 7 Step 10 The contents of the V-blender were mixed at 20 (19 - 21) RPM for 13 minutes. Step 11 Magnesium stearate (0.6 kg) was sieved through a #30 mesh hand-held sieve and collected in a container double-lined with a PE bag. Step 12 The sieved magnesium stearate was added to the V-blender of Step 9. Step 13 The contents of the V-blender were mixed at 20 (19 - 21) RPM for 4 minutes. Step 14 The mixture was discharged into a product container of known tare weight double-lined with a PE bag. To produce tablets from the above, the tablet press was set to an operating limit of tablet weight of 375 mg ± 3%, an acceptance limit of 375 mg ± 5%, a hardness of 7 kp (range 5 - 10 kp), a thickness of 5.1 mm (± 3 mm), and a wear rate of 1% or less. Compression was carried out at 20 - 40 rpm, with a pre-compression thickness of 2.60 mm and a main compression thickness of 1.78 mm, a pre-penetration of the upper punch of 3.5 mm, a main penetration of 3.5 mm, a cam size of 4 - 11 mm, and a filling depth of 8.64 mm.

[0279] The preparation of smaller tablets containing 15 mg of bexagliflozin was also evaluated. These included both round tablets and pentagonal tablets.

[0280] Three batches of tablets were prepared using a 7 mm pentagonal molding die. The formulation composition is shown in Table 36, and the tablet characteristics are shown in Table 37.

Table 36

[0281] Table 37 shows that the mixing uniformity of the tablets (RSD < 3%) and the weight deviation of the tablets (< 5%) met the product requirements.

Table 37

[0282] Table 38 shows the composition of batches of 5 mm round tablets and 5.5 mm round tablets that resulted in the results shown in Table 39 and Figure 10, respectively.

[0283] Table 39 shows the characteristics of 5 mm round tablets. These tablets met the shipping specifications. The close similarity in the pharmacokinetic profiles shown in Figure 10 indicates that within the dry mixture formulation, lactose monohydrate can constitute 29.6% - 36% of the formulation, microcrystalline cellulose can vary between 33.6% - 41% of the formulation, pregelatinized starch can be between 5.3% - 6.4% of the total amount, and the flavoring agent can vary between 7.9% - 10.0%, without significantly affecting the in vivo properties imparted by the formulation. For these excipients, the acceptable approximate range is 80% - 100% of the relative proportions seen in 10 mm tablets. Silicon dioxide, a glidant present in relatively small amounts per tablet, and magnesium stearate, a lubricant, can vary over a somewhat larger relative range without significantly affecting pharmacokinetics. The proportions of silicon dioxide and magnesium stearate are higher as the tablets become smaller, being 2.6% instead of 1.6% for silicon dioxide and 1.3% instead of 0.8% for magnesium stearate.

Table 38

Table 39

[0284] Dissolution test of veterinary oral solid dosage forms Dissolution test of veterinary tablets The dissolution test of oral solid dosage forms can be carried out by many methods known to those skilled in the art. Various standard-type devices and different aqueous solutions that simulate to various degrees the conditions likely to be encountered within the gastrointestinal tract can be used. Table 40 shows the chromatographic conditions suitable for the detection of bexagliflozin in the liquid aspirated from the dissolution test chamber, and Table 41 shows an example of the veterinary tablet test conditions that can be used to establish the release rate of bexagliflozin into the test medium.

Table 40

Table 41

[0285] Table 42 shows the composition of various experimental batches of the 15 mg bexagliflozin veterinary tablets to be used in the dissolution test. Each batch contained 15 mg of bexagliflozin, and each tablet weighed 375 mg. The amount of lactose monohydrate varied between 110.0 mg (formulation F5) and 161.0 mg (formulations F1, F3, F7, F9). The amount of microcrystalline cellulose varied between 117.0 mg (F13) and 185.4 (F11), while the amount of pregelatinized starch varied between 2.4 mg (F12) and 54 mg (F13), the amount of colloidal silicon dioxide varied between 0.6 mg (F12) and 13.5 mg (F13), the amount of magnesium stearate varied between 3.0 mg (F1, F6, F7 - F11, F13) and 22.5 mg (F14), and the amount of palatant varied between 30 mg (F9, F10) and 44.2 mg (F3).

Table 42

[0286] The following three formulations were found to be different from the reference formulation (F6) according to the f2 < 50 criterion: F14, F16, and F17. Furthermore, F15 was at the borderline (f2 = 50). Equivalent dissolution according to the f2 criterion can be achieved with tablets containing 110.0 mg - 161.0 mg of lactose monohydrate, 117.0 - 185.4 mg of microcrystalline cellulose, 19.2 - 54.0 mg of pregelatinized starch, ~mg of colloidal silicon dioxide, 3.0 - 3.5 mg of magnesium stearate, and 30 - 44.2 mg of palatant (Tables 42 and 43).

Table 43

Claims

1. A tablet formulation comprising bexagliflozin for administration to a companion animal, wherein, in an in vitro dissolution test, the tablet formulation releases at least 85% of its bexagliflozin after 30 minutes in a solution of 0.1 N HCl at 37 ± 0.5 °C in a USP (United States Pharmacopeia) Apparatus 2 (apparatus 2) (paddle apparatus) at a paddle speed of approximately 75 rpm.

2. A tablet formulation according to claim 1, further comprising a stimulant.

3. The tablet formulation according to claim 2, wherein the flavoring agent comprises a flavoring agent of tuna, salmon, cream, beef, peanuts, catnip, chicken liver powder, poultry extract, hydrolyzed chicken liver, butter, or bacon.

4. The tablet formulation according to claim 2, wherein the flavoring agent comprises a meat or liver flavoring agent.

5. The tablet formulation according to claim 2, wherein the palatable agent comprises hydrolyzed liver.

6. The tablet formulation according to claim 2, wherein the palatine agent comprises hydrolyzed liver of a bird (avian).

7. A tablet formulation according to any one of claims 1 to 6, further comprising one or more fillers, one or more flow promoters, one or more lubricants, and one or more binders.

8. A tablet formulation according to any one of claims 1 to 6, comprising approximately 4 to 20% by weight of bexagliflozin.

9. A tablet formulation according to claim 8, comprising approximately 20% by weight of bexagliflozin.

10. A tablet formulation according to claim 8, comprising approximately 4% by weight of bexagliflozin.

11. A tablet formulation according to claim 8, comprising approximately 15 mg of bexagliflozin.

12. A tablet formulation according to any one of claims 2 to 6, comprising approximately 2 to 25% by weight of a palatability agent.

13. A tablet formulation according to claim 12, comprising approximately 5 to 15% by weight of a palatability agent.

14. A tablet formulation according to claim 12, comprising approximately 7.9% by weight of a palatability agent.

15. A tablet formulation according to claim 12, comprising approximately 10% by weight of a palatability agent.

16. A tablet formulation according to claim 7, comprising one or more fillers in an amount of approximately 20 to 60% by weight.

17. The tablet formulation according to claim 12, wherein the one or more fillers constitute about 30 to 50% by weight of the tablet formulation.

18. The tablet formulation according to claim 12, wherein the one or more fillers constitute about 34 to 45% by weight of the tablet formulation.

19. The tablet formulation according to claim 12, wherein the one or more fillers constitute about 34% by weight of the tablet formulation.

20. The tablet formulation according to claim 12, wherein the one or more fillers constitute about 41% by weight of the tablet formulation.

21. The tablet formulation according to claim 7, wherein the one or more fillers are microcrystalline cellulose.

22. A tablet formulation according to claim 7, comprising one or more flow promoters in an amount of approximately 0.5 to approximately 8% by weight.

23. The tablet formulation according to claim 22, wherein the one or more flow promoters constitute about 1 to 4% by weight of the tablet formulation.

24. The tablet formulation according to claim 22, wherein the one or more flow promoters constitute about 2.6% by weight of the tablet formulation.

25. The tablet formulation according to claim 22, wherein the one or more flow promoters constitute about 1.6% by weight of the tablet formulation.

26. The tablet formulation according to claim 22, wherein the one or more flow promoters are colloidal silicon dioxide.

27. A tablet formulation according to claim 7, comprising approximately 0.1 to 4% by weight of a lubricant.

28. The tablet formulation according to claim 27, wherein the one or more lubricants constitute about 1.3% by weight of the tablet formulation.

29. The tablet formulation according to claim 27, wherein the one or more lubricants constitute about 0.8% by weight of the tablet formulation.

30. The tablet formulation according to claim 27, wherein the one or more lubricants are magnesium stearate.

31. A tablet formulation according to claim 7, comprising one or more binders in an amount of approximately 30 to approximately 50% by weight.

32. The tablet formulation according to claim 31, wherein the one or more binders constitute about 35 to 45% by weight of the tablet formulation.

33. The tablet formulation according to claim 31, wherein the one or more binders constitute about 35% by weight of the tablet formulation.

34. The tablet formulation according to claim 31, wherein the one or more binders constitute about 42% by weight of the tablet formulation.

35. The tablet formulation according to claim 31, wherein the ratio of the first binder to the second binder is approximately 5.5:

1.

36. The tablet formulation according to claim 31, wherein the one or more binders are lactose monohydrate and pregelatinized starch.

37. The tablet formulation according to claim 7, wherein the tablet contains 15 mg of bexagliflozin, 110.0 to 160 mg of lactose monohydrate, 117.0 to 185.4 mg of microcrystalline cellulose, 30 to 44.2 mg of a palatability agent, 19.2 to 54 mg of pregelatinized starch, 6 to 13.5 mg of colloidal silicon dioxide, and 3.0 to 3.5 mg of magnesium stearate.

38. The tablet formulation according to any one of claims 1 to 6, wherein the companion animal is a cat.

39. The tablet formulation according to any one of claims 1 to 6, wherein the companion animal is a dog.

40. The tablet formulation according to any one of claims 1 to 6, wherein the tablet formulation can be delivered daily with fewer than one refusal of administration per 30 administration events.

41. The tablet formulation according to any one of claims 1 to 6, wherein the tablet formulation can be delivered daily with fewer than one administration refusal per 100 administration events.

42. The tablet formulation according to any one of claims 1 to 6, wherein the tablet formulation can be delivered daily with fewer than one administration refusal per 300 administration events.

43. A formulation containing bexagliflozin, when tested with 3 mg / kg bexagliflozin after delivery to a properly constructed cohort of fasted healthy adult cats, showed an average AUC of plasma bexagliflozin exceeding 1000 ng·h / mL per 1 mg / kg bexagliflozin. ０－２４ A preparation that provides [something].

44. A formulation containing bexagliflozin, when tested with 3 mg / kg of bexagliflozin after delivery to a well-structured cohort of fasted, healthy adult cats, showed an average plasma bexagliflozin level greater than 300 ng / mL per 1 mg / kg of bexagliflozin. ｍａｘ A preparation that provides [something].

45. The formulation releases bexagliflozin in vivo, and the T2 test in fasted cats takes 0.1 to 2 hours. ｍａｘ A formulation according to any one of claims 1 to 6, which provides

46. The formulation according to any one of claims 1 to 6, wherein the tablet has a hardness of 5 to 10 kp and / or abrasion of ≤1% by weight.

47. When tested by dissolving 15 mg of bexagliflozin in 500 ml of 0.1 N HCl in a USP (United States Pharmacopeia) Apparatus 2 (apparatus 2) (paddle) containing 37°C ± 0.5°C and stirred at 75 rpm, the formulation showed a value of ≥ 50 f compared to the reference tablet of the formulation in Table 35. ２ A tablet that produces a value.

48. Each tablet contains 10-20 mg of bexagliflozin, 17.5-27.5 mg of lactose monohydrate, 20.5-30.5 mg of microcrystalline cellulose, 7.5-11 mg of a palatability agent, 3-5 mg of pregelatinized starch, 1.5-2.5 mg of colloidal silicon dioxide, and 0.75-1.25 mg of magnesium stearate.

49. When tested by dissolving a 15 mg bexagliflozin-containing formulation in 500 ml of 0.1 N HCl in a USP (United States Pharmacopeia) Apparatus 2 (apparatus 2) (paddle) at 37°C ± 0.5°C and 75 rpm, it showed a f value of ≥ 50 compared to the reference tablet of the formulation in Table 38. ２ A tablet that produces a value.

50. A method for treating a non-human animal suffering from a disease or syndrome that is susceptible to treatment with an SGLT2 inhibitor, comprising the step of administering a formulation according to any one of claims 1 to 6 to the non-human animal.

51. A liquid formulation containing 30 mg / mL of bexagliflozin, 125-175 mg / mL of ethanol, 250-300 mg / mL of glycerin, 125-175 mg / mL of PEG-400, 25-75 mg / mL of polysorbate 80, and 1-15 mg / mL of one or more optional flavor enhancers, with the remainder being an aqueous buffer solution having a pH of 6.0-8.

0.

52. A batch of venglustat veterinary tablets containing 15 mg of venglustat per tablet, which, when administered to a properly constituted cohort of healthy fasted subjects, in some cases, a first representative sample set of tablets from said batch results in a first mean logarithm of C ｍａｘ and a first mean logarithm of AUC ０－ｔ and in some different cases, a second representative sample of tablets from said batch results in a second mean logarithm of C ｍａｘ and a second mean logarithm of AUC ０ －ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both show a 90% confidence interval, and its endpoint is between -0.51083 and +0.51083. 【Request Item 53】 A batch of bexagliflozin veterinary tablets, each containing 15 mg of bexagliflozin, when administered to a well-structured cohort of healthy, fasting subjects, a first representative sample set of tablets from the batch, in some cases, C ｍａｘ The first mean logarithm and AUC ０－ｔ The first mean logarithm is obtained, and a second representative sample of tablets from the batch is, in some different cases, C ｍａｘ The second mean logarithm and AUC ０－ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both shows a 90% confidence interval, and its endpoint is between -0.28768 and +0.28768. 【Request Item 54】 A batch of bexagliflozin veterinary tablets, each containing 15 mg of bexagliflozin, when administered to a well-structured cohort of healthy, fasting subjects, a first representative sample set of tablets from the batch, in some cases, C ｍａｘ The first mean logarithm and AUC ０－ｔ The first mean logarithm is obtained, and a second representative sample of tablets from the batch is, in some different cases, C ｍａｘ The second mean logarithm and AUC ０－ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both show a 90% confidence interval, and its endpoint is between -0.22314 and +0.22314. 【Request Item 55】 A batch of bexagliflozin veterinary tablets, each containing 15 mg of bexagliflozin, when administered to a well-structured cohort of healthy, fasting subjects, shows that a representative sample set of tablets from the batch is C ｍａｘ The first mean logarithm and AUC ０－ｔ The first mean logarithm is obtained, and a representative sample of tablets from a reference batch of 15 mg bexagliflozin veterinary tablets is C ｍａｘ The second mean logarithm and AUC ０－ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both show a 90% confidence interval, and its endpoint is between -0.51083 and +0.51083. 【Request Item 56】 A batch of bexagliflozin veterinary tablets, each containing 15 mg of bexagliflozin, when administered to a well-structured cohort of healthy, fasting subjects, shows that a representative sample set of tablets from the batch is C ｍａｘ The first mean logarithm and AUC ０－ｔ The first mean logarithm is obtained, and a representative sample of tablets from a reference batch of 15 mg bexagliflozin veterinary tablets is C ｍａｘ The second mean logarithm and AUC ０－ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both shows a 90% confidence interval, and its endpoint is between -0.28768 and +0.28768. 【Request Item 57】 A batch of bexagliflozin veterinary tablets, each containing 15 mg of bexagliflozin, when administered to a well-structured cohort of healthy, fasting subjects, shows that a representative sample set of tablets from the batch is C ｍａｘ The first mean logarithm and AUC ０－ｔ The first mean logarithm is obtained, and a representative sample of tablets from a reference batch of 15 mg bexagliflozin veterinary tablets is C ｍａｘ The second mean logarithm and AUC ０－ｔ This yields the second mean logarithm of C ｍａｘ The difference between the logarithm of the first mean and the logarithm of the second mean, and AUC ０－ｔ A batch in which the difference between the logarithm of the first mean and the logarithm of the second mean both show a 90% confidence interval, and its endpoint is between -0.22314 and +0.22314.

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