An oral liquid pharmaceutical composition of ertugliflozin

Abstract

An oral liquid liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of a compound of Formula (I) or a salt thereof, b) a poloxamer, and c) a solvent.

Description

25867FFAN ORAL LIQUID PHARMACEUTICAL COMPOSITION OF ERTUGLIFLOZINBACKGROUND

[0001] Ertugliflozin (MK-8835) is a potent sodium glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 is responsible for the reabsorption of filtered glucose from the kidney back to the blood stream. By its inhibitory mechanism, Ertugliflozin can effectively promote glucose excretion in urine and thus prevent accumulation in blood stream.

[0002] US Patent No. 8,080,580 discloses ertugliflozin. Also disclosed are formulations with aqueous solvents such as polyethylene glycol. Specifically disclosed is a formulation comprising ertugliflozin, PEG 400 and hydroxypropyl beta cyclodextrin (HPBCD). Poloxamer used as a surfactant is not disclosed.

[0003] Stelglatro® tablets, which contain ertugliflozin L-pyroglutamic acid (ertugliflozin L- PGA) as an active ingredient, are approved and marked for lowering the blood glucose levels in human adults with type 2 diabetes mellitus. Kovacich et al. Pharmacy &Therapeutics, December 2018, Volume 43, No. 12, pp 736-742.

[0004] W02020026273A1 discloses crystalline forms of ertugliflozin (IS, 2S, 3S, 4R, 5S)-5- (4-chl oro-3 -(4-ethoxybenzyl) phenyl)-l -(hydroxymethy l)-6,8-dioxabicyclo [3.2.1] octane- 2,3,4-triol free base and process for the preparation thereof. Also disclosed are amorphous, solid dispersions of ertugliflozin L-PGA (IS, 2S, 3S, 4R, 5S)-5-(4-chloro-3-(4-ethoxybenzyl) phenyl)- 1- (hydroxymethyl)-6,8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol L-pyroglutamic acid and process the preparation thereof. The solid dispersion comprises at least one pharmaceutically acceptable excipient selected from a list including polyethylene glycol and poloxamer.25867FF

[0005] US20230140631A1 discloses SGLT2 inhibitors or pharmaceutically acceptable forms thereof for use in the treatment and / or prevention of a metabolic disorder in a feline animal where the metabolic disorder is selected from the group consisting of ketoacidosis, prediabetes, diabetes mellitus type 1 or type 2, insulin resistance, obesity, hyperglycemia, impaired glucose tolerance, hyperinsulinemia, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, hepatic lipidosis, atherosclerosis, inflammation of the pancreas, neuropathy and / or Syndrome X (metabolic syndrome) and / or loss of pancreatic beta cell function and / or where the remission of the metabolic disorder is achieved and / or maintained.

[0006] WO2016077126A1 discloses certain SGLT-2 inhibitors, such as ertugliflozin or a cocrystal or a pharmaceutically acceptable salt thereof, for treating and / or preventing metabolic disorders, such as type 1 or type 2 diabetes mellitus or pre-diabetes, in patients with renal impairment or chronic kidney disease (CKD). A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Poloxamer is not disclosed.

[0007] WO2017155841A1 discloses the use of certain SGLT-2 inhibitors, such as ertugliflozin or a pharmaceutically acceptable salt or a co-crystal thereof, for treating, reducing the risk of and / or preventing heart failure, myocardial infarction, cardiovascular disease, or cardiovascular death in animals without type 2 or type 1 diabetes mellitus, or in animals with pre-diabetes, or in animals with type 2 or type 1 diabetes mellitus or pre-diabetes. A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Poloxamer is not disclosed.

[0008] WO2021165177 discloses SGLT-2 inhibitors including Ertugliflozin or pharmaceutically acceptable forms thereof for use in a method of prevention and / or treatment of one or more cardiac diseases in feline animals. The SGLT-2 inhibitors may be prepared as25867FF pharmaceutical compositions. They may be prepared as solid or as liquid formulations for oral administration, preferably in liquid form for oral administration. Poloxamer is not disclosed. WO2021105152 discloses the use of SGLT-2 Inhibitors (e.g., ertugliflozin) for the drying-off of non-human mammals, preferably ruminant. The SGLT-2 inhibitors may be prepared as solid or as liquid formulations, preferably for parenteral administration, preferably in liquid form. The liquid formulations may be, e.g., solutions, syrups or suspensions. Poloxamer is not disclosed.

[0009] WO2021092341 discloses a method for the treatment of heart failure in a companion animal, comprising administering to the companion animal a compound that inhibits a sodiumdependent glucose transporter (SGLT) or prodrug thereof. The compound is administered as an oral liquid dosage form. Poloxamer is not disclosed.

[0010] WO2015110402 discloses a method of treatment and / or prevention of a metabolic disorder in a canine animal comprising administering to the canine animal a composition comprising one or more SGLT-2 inhibitors (e.g., ertugliflozin) or pharmaceutically acceptable forms thereof. Also disclosed is that the one or more SGLT2 inhibitors may effectively be administered to a canine animal orally, e.g., in liquid form. Liquid formulations may be, e.g., solutions, syrups or suspensions. Poloxamer is not disclosed.

[0011] W02015091313 discloses a method of treatment and / or prevention of a metabolic disorder in a feline animal comprising administering to the feline animal a composition comprising one or more SGLT-2 inhibitors (e.g., ertugliflozin) or pharmaceutically acceptable forms thereof. Also disclosed is that the one or more SGLT2 inhibitors may effectively be administered to a feline animal orally, e.g., in liquid form. Liquid formulations may be, e.g., solutions, syrups or suspensions. Poloxamer is not disclosed.

[0012] WO2014161836 discloses an SGLT2 inhibitor (e.g., ertugliflozin) or a pharmaceutically acceptable form thereof for use in the treatment and / or prevention of a metabolic disorder of an equine animal. A further advantage of the present invention is that the SGLT2 inhibitor may effectively be administered to an equine animal orally, e.g., in liquid form. Liquid formulations may be, e.g., solutions, syrups or suspensions (cf. description). Poloxamer is not disclosed.

[0013] WO2018055496 discloses a crystalline form of Ertugliflozin and that this crystalline form may be used in a pharmaceutical composition comprising at least one or more pharmaceutically acceptable excipients including polyethylene glycol. Poloxamer is not disclosed.

[0014] WO2017032799 disclosed a liquid pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the at least one SGLT-2 inhibitor comprises l-cyano-2-(4-cyclopropyl-benzyl)-4-(-D-glucopyranos-l-yl)-benzene. The25867FF liquid pharmaceutical composition is suitable for direct administration to a subject, preferably an animal, (e.g., a horse, cat or dog. The composition additionally comprises one or more solubilizing agents, (e.g., Lutrol F 68 (Poloxamer 188), PEG 300). Ertugliflozin is not disclosed. There is a need for a stable liquid ertugliflozin pharmaceutical composition that is acceptable for oral administration to feline animals.SUMMARY OF THE INVENTION

[0015] An embodiment of the invention is an oral liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of a compound of Formula (I)Formula (I) or a salt thereof, b) a poloxamer, and c) a solvent.DESCRIPTION OF THE FIGURES

[0016] Figures 1 A and IB demonstrate the amount of solubilizer needed to achieve full dissolution of required dose of ertugliflozin.

[0017] Figure 2 shows a chromatographic overlay of the 6-month stability results from the no flavor PEG formulation and the no flavor Pl 88 formulation.

[0018] Figure 3 shows the urinary glucose levels.

[0019] Figure 4 shows the blood plasma concentrations of ertugliflozin.25867FFDETAILED DESCRIPTION

[0020] The subject invention is an oral composition of ertugliflozin for the treatment of type-2 diabetes in cats in which the ertugliflozin is sufficiently stable for the expected shelve life of 1 to 3 years for the product.

[0021] A successful formulation of ertugliflozin must comprise excipients that can adequately carry the active ingredient, maintain it stability throughout the life of the product, and be conveniently administered and accepted by the animal.

[0022] The ertugliflozin oral composition can be flavored with flavors to enhance its acceptance with the patients. Examples of flavor are malt, honey, vanillin, sucralose or mixtures thereof. Poloxamers provide a protective effect to ertugliflozin in the presence of a flavor.

[0023] The ertugliflozin oral composition can be administered once daily at 0.1 mL / Kg by use of an oral syringe for ease of dosing. The target dose is 0.3 mg / Kg (or 3 mg / mL). Alternatively, the target dose is 0.1 mg / Kg (1 mg / mL). In a further alternative, the target dose is between about 0.05 mg / Kg (mg / mL) to about 0.25 mg / Kg (mg / mL). In yet a further alternative, the target dose is between about 0.5 mg / Kg (mg / mL) to about 0.25 mg / Kg (mg / mL). Since the aqueous solubility of Ertugliflozin is 0.76 mg / mL, either dose requires solubilization by an enabling excipient.

[0024] Ertugliflozin may be administered in doses of 0.01-5 mg / kg per day or 0.01-4 mg / kg or 0.01-3 mg / kg or 0.01-2 mg / kg or 0.01-1.5 mg / kg or 0.01-1 mg / kg or 0.01-0.75 mg / kg or 0.01-0.5 mg / kg or 0.01-0.4 mg / kg or 0.01-0.4 mg / kg per day; or 0.1 to 3.0 mg / kg per day, preferably from 0.2 to 2.0 mg / kg per day, more preferably from 0.1 to 1 mg / kg per day. In another preferred embodiment the dose is 0.02-0.5 mg / kg per day, more preferably 0.03-0.4 mg / kg per day, e.g., 0.03-0.3 mg / kg per day.

[0025] The administration of the dose of ertugliflozin may be at frequency greater than once a day. For example, the ertugliflozin dose may be administered once every 3 days or once every 7 days or once every 10 days.

[0026] When longer durations between the administration of the doses of ertugliflozin are used, the doses may be 1-10 mg / kg.

[0027] Additionally, the ertugliflozin oral solution can be presented in a multi-dose bottle. The multi-dose bottle which may require the use of preservatives. Such a bottle may be a PIBA bottle as described below.

[0028] Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide)) flanked by two hydrophilic chains of25867FF polyoxyethylene (poly(ethylene oxide)). For example, Poloxamer 188 (polyethylene glycol)- Z> / ocA poly(propylene glycolj- xA-poly / ethylene glycol)) has the following structure:

[0029] See Chen et al. AAPS Open (2022) 8:5 doi.org / 10.1186 / s41120-022-00055-4. Other examples of poloxamers are Poloxamer 124 and 407.

[0030] All values and concentrations presented herein are subject to inherent variations acceptable in biological science within an error of ±10%. The term "about" also refers to this acceptable variation.

[0031] A feline animal is a member of the Felidae family (i.e., a felid). It may thus belong either to the subfamily felinae or the subfamily pantherinae. The term feline animal encompasses the term cat, e.g., a domestic cat. The term domestic cat encompasses the terms Felis catus and Felis silvestris catus.

[0032] Clinical signs of diabetes mellitus observed with feline animals include polydipsia, polyuria, weight loss, and / or polyphagia. Pathognomonic for diabetes mellitus in cats is a plantigrade stance (weakness in hind legs, hocks touch the ground when the cat walks). This is caused by a diabetic neuropathy. Further particularly relevant clinical signs of diabetes mellitus in feline animals within the context of the present invention are hyperglycaemia and glucosuria. Hyperglycaemia in a feline animal (e.g., a cat) is defined as plasma glucose values above normal values (3.9 - 8.3 mmol / 1 or 70 - 150 mg / dl), e.g., 8 mmol / 1 or more or 150 mg / dl or more plasma glucose. Glucosuria in a feline animal (e.g., a cat) is defined as glucose levels in urine above normal values (0 - 2 mmol / L, or 36 mg / dl). The renal threshold is reached with blood glucose concentrations of approximately 11 - 17 mmol / 1 or 200 to 300 mg / dl. The diagnosis of diabetes mellitus in feline animals may alternatively be based on three criteria, e.g., as follows: (l)Fasting blood glucose concentration measurements> 250 mg / dl; (2) Glucosuria as defined above; and (3) One or more of the following: polyuria, polydipsia, polyphagia, weight loss despite good appetite, or ketonuria (without signs of severe ketoacidosis). See W02015091313, page 21, lines 8-27.

[0033] Oral syringe is a syringe designed for oral administration of medicines.

[0034] A PIBA bottle is a bottle with a press in bottle adaptor which allows oral syringes to draw the exact amount needed while reducing the risk of spill, evaporation, and contamination. A preservative is a substance or a chemical that is added to products such as food products, beverages, pharmaceutical drugs, paints, biological samples, cosmetics, wood, and many other25867FF products to prevent decomposition by microbial growth or by undesirable chemical changes. Examples are methylparaben and propylparaben.

[0035] A buffer solution is an aqueous solution consisting of a mixture of a weak acid and its conjugate base, or vice versa. The pH of the buffered solution is resistant to change when a small amount of strong acid or base is added to the solution. Examples of a buffer are citric acid and sodium citrate. Other examples of buffers are citric acid / disodium phosphate, and acetic acid / sodium acetate.

[0036] In another embodiment of the invention, the compound of Formula (I) is ertugliflozin L- pyroglutamic acid.

[0037] In another embodiment of the invention, the solvent is water.

[0038] In an alternative embodiment of the invention, the solvent is ethanol, water, a water miscible solvent or mixtures thereof.

[0039] In another embodiment of the invention, the poloxamer is Poloxamer 188.

[0040] In another embodiment of the invention, the poloxamer is Poloxamer 124.

[0041] In another embodiment of the invention, the poloxamer is Poloxamer 407.

[0042] In another embodiment of the invention, the composition further comprises a buffer, a preservative, a flavor or mixtures thereof.

[0043] In another embodiment of the invention, the preservative is methylparaben, propylparaben or mixtures thereof.

[0044] In another embodiment of the invention, the buffer is citric acid and a citrate salt.

[0045] In another embodiment of the invention, the buffer is citric acid and disodium phosphate.

[0046] In another embodiment of the invention, the buffer is acetic acid and sodium acetate.

[0047] In another embodiment of the invention, the flavor is malt, honey, vanillin, sucralose or mixtures thereof.

[0048] In another embodiment of the invention, the amount of the compound of Formula (I) in the composition is between about 0.01 and about 1% (w / v) or is between about 0.05 and about 0.5 % (w / v) or is between about 0.1 and about 0.15% (w / v) or is between about 0.3 and about 0.4%(w / v).

[0049] In another embodiment of the invention, the amount of poloxamer in the composition is between about 0.1% (w / v) and about 10% (w / v) or about 0.2% (w / v) and about 5% (w / v) or is between about 0.5% (w / v) and about 2.0 % (w / v) or is between about 0.8% (w / v) and about 1.3%(w / v).25867FF

[0050] In another embodiment of the invention, the composition has a pH of between about 3.0 and about 5.0 or between about 3.5 and about 4.5 or between about 3.5 and about 4.0.

[0051] An alternative embodiment of the invention is a method of treating type 2 diabetes in an animal comprising administering to the animal the above liquid pharmaceutical compositions.

[0052] In another embodiment of the invention, the animal is a feline.

[0053] In another embodiment of the invention, the animal is a companion animal.

[0054] In another embodiment of the invention, the animal is a dog.

[0055] In an embodiment of the invention, the oral liquid pharmaceutical composition is administered with food.

[0056] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered without food.

[0057] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered to an animal in the fasted state.

[0058] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered to an animal in the fed state.

[0059] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered to an animal irrespective of the fed or fasted state of the animal.

[0060] In another embodiment of the invention, the administration is via oral syringe.

[0061] In another embodiment of the invention, the formulation is contained in a PIBA bottle.

[0062] In another embodiment of the invention, the liquid pharmaceutical composition is administered once per day or once every three days or once every seven days or once every ten days.

[0063] In another embodiment of the invention, the dose of the compound of Formula (I) is between about 0.01 and about 1.0 mg / Kg of animal body weight, or between about 0.05 to 0.5 mg / kg of animal body weight, or preferably about 0.1 to 0.3 mg / Kg of animal body weight.

[0064] In an alternative embodiment of the invention, the oral liquid pharmaceutical composition comprises ertugliflozin, polyethylene glycol and a solvent.

[0065] In another embodiment of the invention, the polyethylene glycol is polyethylene glycol 400.

[0066] In another embodiment of the invention, the amount of polyethylene glycol in the composition is between about 1% (w / v) and about 30% (w / v) or about 5% (w / v) and about 25% (w / v) or is between about 10% (w / v) and about 25 % (w / v) or is between about 15% (w / v) and about 20%(w / v).25867FF

[0067] In an alternative embodiment of the invention, the oral liquid pharmaceutical composition further comprises a viscosity modifying agent. In an embodiment, the viscosity modifying agent is carbomer, povidone, xanthan gum, and cellulose derivatives such as hydroxypropyl methyl cellulose, (HPMC) and hydroxy propyl cellulose (HPC).

[0068] In an embodiment of the invention the solvent is water, water and water miscible liquid or water miscible liquid.

[0069] A water miscible liquid (also referred to as a cosolvent) can be, but is not limited to, ethanol, isopropanol, benzyl alcohol, glycol ethers (e.g., including, but limited to, diethylene glycol monoethylether (DGME, Transcutol®), butyl diglycol, dipropylene glycol n-butyl ether, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and the like), liquid polyethylene glycols (PEGs) (for example, PEG 400), propylene glycol, carbonates (e.g., propylene carbonate), cyclic ethers (e.g., as tetrahydrofuran and dioxane), 2- pyrrolidone, N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylformamide, acetamide dimethylacetamide, dimethyl sulfoxide, glycerol or a mixture thereof.

[0070] In one embodiment of the invention, the water miscible liquid can be a polar protic solvent including, but not limited to, an alcohol such as ethanol, isopropanol or a glycol or glycol ether.

[0071] In one embodiment of the invention, the water miscible liquid can be a polar aprotic solvent such as N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, dimethyl sulfoxide or propylene carbonate.

[0072] In an embodiment, the pharmaceutical composition is substantially free of a water miscible liquid (co-solvent).EXAMPLESExample 1 Solubility Screen

[0073] The aqueous solubility of ertugliflozin is 0.76mg / mL. Since the target concentration of ertugliflozin in the drug product is 3mg / mL, an effective solubilizer was needed. Several solubilizers were evaluated, summarized in the table below. All the solubilizers tested, other than Glycerin, can effectively dissolve ertugliflozin at the recommended levels in the table below. However, only Pol oxamer 188 and PEG 400 were deemed good candidates for further development work due to their lack of safety concern and acceptable palatability to the cats.25867FFTable 1

[0074] A justification study was conducted to determine the appropriate amount of solubilizer needed to achieve full dissolution of required dose of ertugliflozin. In an embodiment of the oral liquid pharmaceutical composition, a target concentration of 3 mg / mL (0.3% w / v) ertugliflozin will be solubilized by approximately 0.8% w / v Pol oxamer 188, or by approximately 15% w / v PEG 400. See Figures 1 A and IB.Example 2 - Formulation Table 2 discloses a typical formulation of the invention.25867FFTable 2*Note: 0.389% Ertugliflozin L-PGA is equivalent to 0.3% Ertugliflozin based on potency factor of 0.772**Note: 0.130% Ertugliflozin L-PGA is equivalent to 0.1% Ertugliflozin based on potency factor of 0.772

[0075] The processes to make the 0.389 or 0.130% Ertugliflozin L-PGA formulations are described below.Process to prepare 0.1% w / v Ertugliflozin solution (g / lOOmL)

[0076] An excipient solution was prepared by adding 90g of water into a beaker. 1.0 g of Pol oxamer 188, 0.26 g of citric acid monohydrate, 0.22 g of sodium citrate dihydrate, 0.05 g of vanillin, 0.24 g of sucralose, 0.1 g of methylparaben and 0.01 g of propylparaben were charged into the beaker and mixed until a clear excipient solution was obtained. 0.13 g of Ertugliflozin L- PGA was added to separate lOOmL flask. The excipient solution was added to the flask and mixed until a clear solution was obtained. The solution was then brought to a final volume of lOOmL with water.Process to prepare 0.3% w / v Ertugliflozin solution (g / lOOmL)

[0077] The same procedure used for the 0.1% w / v ertugliflozin solution was used to prepare the 0.3% w / v ertugliflozin solution.Table 325867FFExample 3 Stability studies

[0078] Determination of the ertugliflozin assay in the stability studies was conducted in accordance the conditions described in Table 4.25867FFPrototype formulations stability with different flavors

[0079] Prototype formulations containing different flavors in each of the two solubilizers were placed in 40°C / 75% relative humidity (RH) to evaluate their stability. It was observed that impurity peaks of the PEG 400 flavored formulations grew faster than the Pol oxamer 188 formulations.Table 5 - Six-month stability study

[0080] Flavor Stability Data - Poloxamer 188 vs. PEG 400, 6M Stability at 40°C / 75%RH Long term stability studies were conducted to evaluate the stability of ertugliflozin in flavored formulations contain Poloxamer 188 (Pl 88) or Polyethylene glycol 400 (PEG 400) as a surfactant. The formulations contained 2% P 188 or 30 % PEG 400, 0.2% methylparaben, 0.02% propylparaben, 0.24% citric acid anhydrous, 0.22% sodium citrate dihydrate, plus the individual flavors listed in the table below. The studies performed at accelerated aging conditions of 40°C and 75% relative humidity (RH).Table 525867FF

[0081] Figure 2 shows a chromatographic overlay of the 6-month stability results from the No Flavor PEG formulation and the No Flavor Pl 88 formulation. The three main EFD peaks are labeled alongside two unknown degradant peaks, marked A (retention time 1.28 min) and B (retention time 1.83 min). The PEG formulation shows increased degradation compared to the Pl 88 formulation.

[0082] The flavored formulations with PEG 400 also displayed more degradation of ertugliflozin across all flavors and at all time points up to six months than the flavored formulations with P188. Longer Term Stability Studies

[0083] Several long-term stability studies were conducted to demonstrate the stability of ertugliflozin formulations with Pol oxamer 188 as a surfactant. Ertugliflozin concentrations of 0.1% and 0.3% w / v were evaluated at both normal conditions (30°C and 65% relative humidity (RH)) and accelerated conditions (40°C / 75%RH). Table 6 - 12 Month Stability Data for 0.1% Ertugliflozin Formulation (See Table 3) at 30°C / 65%RH,25867FFTable 7 - 12 Month Stability Data for 0.1% Ertugliflozin Formulation (See Table 3) at 40°C / 75%RH25867FFTable 8 - Three-month Stability Data for 0.3% Ertugliflozin Formulation (See Table 3) at 30°C / 65%RH25867FFTable 9 - 12 month Stability Data for 0.3% Ertugliflozin Formulation (See Table 3) at 40°C / 75%RH25867FFExample 4 - pH study

[0084] Ertugliflozin L-PGA has a pH of 2 in aqueous medium. Therefore, the final drug product was pH adjusted to approximately 3.8 with the use of buffer system. Stability studies at accelerated conditions of 40°C / 75%RH indicate good stability of the drug products at the 2 intended doses (0.389 and 0.130 w / v %) for up to 9 months. This is the equivalent of 18 months of stability at ambient conditions. Stability of the drug product at other pH values, included pH 5, 6, and 7 were also evaluated. However, the drug product quickly changed color and degraded at higher pH values. The final drug product specification for pH is targeted for pH 3.8+ / - 0.5. Stability studies are conducted to determine stability at pH 3.3 and 4.3. pH Justification Study

[0085] Formulation 17 to 21 were created to study the stability of the final formulation under different pH values. The final formulation is buffered to pH 3.8 due to the acidic nature of the drug substance and palatability improvement. Upon accelerated stability, formulations 17 to 19 showed color change and degradation within 1 month. While formulations 20 and 21 showed good stability past 1 month. Although their stability will continue to be monitored, their stability so far supports the final drug product pH specification of 3.8+ / -0.5.25867FFTable 1 la - 1 Month Stability Data for 0.1% Ertugliflozin Formulation at pH 5, stored at 40°C / 75%RH (Formulation 18 in table 10)Table 11 b - 1 Month Stability Data for 0.1% Ertugliflozin Formulation at pH 6, stored at 40°C / 75%RH (Formulation 19 in table 10)Table 11 c - 1 Month Stability Data for 0.3% Ertugliflozin Formulation at pH 7, stored at 40°C / 75%RH (Formulation 17 in table 10)Example 5 - Pharmacokinetic and Pharmacodynamic (PK / PD) Study

[0086] A study was performed to assess the pharmacokinetics and pharmacodynamics of ertugliflozin, administered at a dose of 0.03, 0.1, 0.3 or 1 mg / kg for 4 consecutive days in fed25867FF healthy male cats to determine the level of glucosuria associated with each dose. Ertugliflozin was administered at the indicated doses as a flavored liquid solution in a volume of 0.1 mL / kg. See Table 12 below. Cats were presented with food 30 min prior to each dose after an overnight fast. Blood was drawn prior to dosing, and at 0.5, 1, 2, 4, 8, and 24h after the initial dose, and prior to dosing, and at 0.5, 1, 2, 4, 8, 24, 32, 48, 56, and 72h after the final dose. Urine was collected from each cat 24h prior to the initial dose, throughout the entire dosing period and for 72h after the last dose, and aliquoted in 24h samples for the measurement of glucose and creatitnine. Table 12 Formulations used in PK / PD Study

[0087] Figure 3 shows the urinary glucose levels. Figure 4 shows the blood plasma concentrations of ertugliflozin. The results of the study demonstrated that glucosuria was similar in cats dosed with 0.1, 0.3, and 1 mg / kg ertugliflozin and that exposure to drug was dose related. The minimal dose of ertugliflozin which produced near maximal glucosuria in this study was 0.1 mg / kg.

Claims

25867FFCLAIMS1. An oral liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of a compound of Formula (I)Formula (I) or a salt thereof, b) a poloxamer, and c) a solvent.

2. The liquid pharmaceutical composition of claim 1, wherein the compound of Formula (I) is ertugliflozin L-pyroglutamic acid.

3. The liquid pharmaceutical composition of anyone of claims 1-2, wherein the solvent is water.

4. The liquid pharmaceutical composition of anyone of claims 1-3, wherein the poloxamer surfactant is poloxamer 188.

5. The liquid pharmaceutical composition of anyone of claims 1-4, wherein composition further comprises a buffer, a preservative, a flavor or mixtures thereof.

6. The liquid pharmaceutical composition of 5, wherein the preservative is methylparaben, propylparaben or mixtures thereof.25867FF7. The liquid pharmaceutical composition of claim 5, wherein the buffer is citric acid and a citrate salt.

8. The liquid pharmaceutical composition of claim 5, wherein the flavor is malt, honey, vanillin, sucralose or mixtures thereof.

9. The liquid pharmaceutical composition of any one of claims 1-8, wherein the amount of the compound of Formula (I) in the composition is between about 0.01 and about 1% (w / v) or is between about 0.05 and about 0.5 % (w / v) or is between about 0.1 and about 0.15% (w / v) or is between about 0.3 and about 0.4%(w / v).

10. The liquid pharmaceutical composition of any one of claims 1-9, wherein the amount of surfactant in the composition is between about 0.1% (w / v) and about 30% (w / v) or is between about 0.8% (w / v) and about 2.0 % (w / v) or is between about 15% (w / v) and about 25%(w / v).

11. The liquid pharmaceutical composition of any one of claims 1-10, wherein the composition has a pH of between 3.0 and 4.5.

12. A method of treating type 2 diabetes in an animal comprising administering to the animal an effective amount of the liquid pharmaceutical composition of anyone of claims 1-11.

13. The method of claim 12, wherein the animal is a feline.

14. The method of anyone of claims 11-13, wherein the administration is via oral syringe.

15. The method of anyone of claims 11-14, wherein the liquid pharmaceutical composition is administered once per day.

16. The method of anyone of claims 11-15, wherein the dose of the compound of Formula (I) is between about 0.01 and about 1.0 mg / Kg of animal body weight, or between about 0.05 to 0.5 mg / kg of animal body weight, or preferably about 0.1 to 0.3 mg / Kg of animal body weight.

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