An oral liquid pharmaceutical composition of ertugliflozin

Abstract

An oral liquid pharmaceutical composition comprising a) a pharmaceutically effective amount of a compound of Formula (I) or a salt thereof, b) a polyethylene glycol (PEG), and c) a solvent wherein in the pH of the oral liquid pharmaceutical composition is between about 3.0 to about

Description

AN 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).

[0003] Stelglatro® tablets, which contain ertugliflozin L-pyroglutamic acid (ertugliflozin L- PGA) as an active ingredient, are approved and marketed 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-di oxabicyclo [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.

[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.

[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.

[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 aspharmaceutical compositions. They may be prepared as solid or as liquid formulations for oral administration, preferably in liquid form for oral administration.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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.

[0013] 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).

[0014] 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.

[0015] 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. The liquid pharmaceutical composition is suitable for direct administration to a subject, preferably ananimal, (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.

[0016] There is a need for a stable liquid ertugliflozin pharmaceutical composition that is acceptable for oral administration to feline animals.SUMMARY OF THE INVENTION

[0017] 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 polyethylene glycol, and c) a solvent, wherein in the pH of the oral liquid pharmaceutical composition is between about 3.0 to about 5.0.DESCRIPTION OF THE FIGURES

[0018] Figures 1 A and IB demonstrate the amount of solubilizer needed to achieve full dissolution of required dose of ertugliflozin.

[0019] Figure 2 shows a chromatographic overlay of the 6-month stability results from the no flavor PEG formulation and the no flavor poloxamer Pl 88 formulation.

[0020] Figure 3 shows the urinary glucose levels of cats administered the ertugliflozin PEG 400 formulation.

[0021] Figure 4 shows the blood plasma concentrations of ertugliflozin of cats administered the ertugliflozin PEG 400 formulation.DETAILED DESCRIPTION

[0022] The subject invention is an oral composition of ertugliflozin for the treatment of diabetes mellitus in animals in which the ertugliflozin is sufficiently stable for the expected shelf life of 1 to 3 years for the product.

[0023] A successful formulation of ertugliflozin must comprise excipients that can adequately carry the active ingredient, maintain chemical and physical stability throughout the life of the product, and be conveniently administered and accepted by the animal.

[0024] Ertugliflozin is a compound of Formula I or a salt thereof.

[0025] In one embodiment of the invention, the compound of Formula (I) is ertugliflozin L- pyroglutamic acid (L-PGA).

[0026] In an 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).

[0027] The ertugliflozin oral composition can be administered once daily at 0.1 mL / Kg preferably by use of an oral syringe for ease of dosing. The target dose is 0.3 mg / Kg. Alternatively, the target dose is 0.1 mg / Kg.

[0028] In a further alternative, the target dose is between about 0.05 mg / Kg to about 0.25 mg / Kg. In yet a further alternative, the target dose is between about 0.5 mg / Kg to about 0.25 mg / Kg. Since the aqueous solubility of Ertugliflozin as Ertugliflozin L-PGA is 0.76 mg / mL, either dose requires solubilization by an enabling excipient.

[0029] The composition according to the invention may include a polyethylene glycol as enabling agent. Polyethylene glycol (PEG) is a polyether derived from petroleum and is known for its many medicinal application. The structure of PEG is H-(O-CH2-CH2)n_OH.

[0030] Polyethylene glycol 400 (PEG 400), a low-molecular-weight grade of polyethylene glycol, is a clear, colorless, viscous liquid that is used in pharmaceutical formulations.

[0031] The polyethylene glycol surfactant has a molecular weight in the range of about 200 to 600. Preferably, the polyethylene glycol surfactant is polyethylene glycol 400 (PEG 400).

[0032] In an embodiment of the invention, the amount of polyethylene glycol in the composition is between about 1% (w / v) and about 50% (w / v) or is between about 1% (w / v) and about 30% (w / v) or is between 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)) or is between about 20% (w / v) and about 40% (w / v) or is between about 25% (w / v) and about 35% (w / v) or is between about 40% (w / v) and about 50% (w / v).

[0033] 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.

[0034] 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 other products to prevent decomposition by microbial growth or by undesirable chemical changes. Examples are methylparaben and propylparaben.

[0035] In an embodiment of the invention, the composition further comprises a preservative.

[0036] In an embodiment of the invention, the preservative is methylparaben, propylparaben or mixtures thereof.

[0037] In an embodiment of the invention, the preservative is benzoic acid or a salt thereof.

[0038] In an embodiment of the invention, the preservative is benzoic acid.

[0039] In an embodiment of the invention, the preservative is sodium benzoate.

[0040] In an alternative embodiment, the composition is preservative free.

[0041] The composition of the invention includes a solvent.

[0042] In one embodiment of the invention, the solvent is water.

[0043] In an alternative embodiment of the invention, the solvent is ethanol, water, a water miscible solvent or mixtures thereof. In an embodiment of the invention the solvent is water, water and water miscible liquid or water miscible liquid.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] In an embodiment, the pharmaceutical composition is substantially free of a water miscible liquid (co-solvent).

[0048] In an embodiment of the invention, the oral liquid pharmaceutical composition comprises ertugliflozin, polyethylene glycol and a solvent.

[0049] In another embodiment of the invention, the composition further comprises a flavor.

[0050] In another embodiment of the invention, the flavor is malt, honey, vanillin, sucralose, or mixtures thereof.

[0051] Long term stability of the oral liquid pharmaceutical formulation is dependent upon achieving and maintaining the correct pH range. Stability of the flavoring in the formulation is influenced by pH. Color stability of the formulation is also influenced by the pH. Finally, resistance to microbial contamination is affected by pH. This is particularly important if the formulation is in a multiuse container.

[0052] It has been found that it is beneficial that 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 or between about 3.6 and about 3.8 or between about 4.3 and about 4.5.

[0053] It has been found to be beneficial that the composition comprises a buffer.

[0054] 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 / monosodium phosphate, citric acid / disodium phosphate, monosodium phosphate / phosphoric acid and acetic acid / sodium acetate.

[0055] In another embodiment of the invention, the buffer is citric acid and a citrate salt.

[0056] In another embodiment, the ratio of the citric acid to the citrate salt is between about 1 : 1 to about 4: 1 or between about 1.5: 1 to about 3.5: 1 or between about 0.25:0.20 to about 0.35:0.10 or about 0.26:022 or about 0.33:0.11.

[0057] In another embodiment of the invention, the buffer is citric acid and monosodium phosphate.

[0058] In another embodiment of the invention, the buffer is acetic acid and sodium acetate.

[0059] In an 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).

[0060] 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 polyethylene glycol,c) a flavor and d) a solvent.

[0061] 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 polyethylene glycol c) a buffer, and d) a solvent.

[0062] 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 polyethylene glycol c) a buffer, d) a flavor and e) a solvent.

[0063] 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 polyethylene glycol surfactant c) a buffer,d) a flavor and e) a solvent.

[0064] 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 polyethylene glycol c) a buffer, d) a flavor e) a solvent, and f) a preservative, wherein the buffer is citric acid and sodium citrate, the flavor is vanillin, sucralose or mixtures thereof and the solvent is water, and wherein the pH of the oral liquid pharmaceutical composition is between about 3.0 to about 5.0.

[0065] 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 surfactant, and c) a solvent, wherein in the pH of the oral liquid pharmaceutical composition is between about 3.0 to about 5.0.

[0066] 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 polyethylene glycol surfactant, and c) a solvent,wherein in the pH of the oral liquid pharmaceutical composition is between about 3.0 to about 5.0.

[0067] An embodiment of the invention is a method of treating type 2 diabetes in an animal comprising administering to the animal the above liquid oral pharmaceutical compositions.

[0068] In an embodiment of the invention, the animal is a companion animal.

[0069] In another embodiment of the invention, the animal is a feline animal.

[0070] 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.

[0071] 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 hyperglycemia and glucosuria. Hyperglycemia 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.

[0072] In another embodiment of the invention, the animal is a dog.

[0073] In an embodiment of the invention, the oral liquid pharmaceutical composition is administered with food.

[0074] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered without food.

[0075] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered to an animal in the fasted state.

[0076] In another embodiment of the invention, the oral liquid pharmaceutical composition is administered to an animal in the fed state.

[0077] 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.

[0078] In another embodiment of the invention, the administration is via oral syringe.

[0079] Oral syringe is a syringe designed for oral administration of medicines.

[0080] In another embodiment of the invention, the formulation is contained in a PIBA bottle.

[0081] 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.

[0082] Ertugliflozin in the composition according to the invention may be administered in doses of 0.01-5 mg / kg bodyweight 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.

[0083] 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.

[0084] 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.

[0085] The administration of the dose of ertugliflozin may be at frequency less 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.

[0086] When longer durations between the administration of the doses of ertugliflozin are used, the doses may be 1-10 mg / kg.EXAMPLESExample 1 Solubility Screen

[0087] The aqueous solubility of ertugliflozin L-PGA is 0.76mg / mL. An ability to solubilize a concentration of ertugliflozin in the drug product of at least 3mg / mL, was determined for an effective solubilizer to be selected. The concentration was selected to meet the maximum foreseeable dose in combination with the smallest foreseeable dose volume. 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.Table 1

[0088] A justification study was conducted to determine the appropriate amount of solubilizer needed to achieve full dissolution of required dose of ertugliflozin L-PGA. 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 Poloxamer 188, or by approximately 15% w / v PEG 400. See Figures 1 A and IB.Example 2 Ertugliflozin Formulation with PEG 400

[0089] Table 2 discloses a 0.10 %w / v ertugliflozin in PEG 400 formulation.Table 2

[0090] A IL sample of the ertugliflozin PEG 400 formulation was prepared. 500mL of purified water was charged into a compounding vessel. 300g of polyethylene glycol 400 was charged into the compounding vessel and mixed until homogenous. 1g methylparaben and lOOmg propylparaben were added into to the compounding vessel then mixed until dissolved.

[0091] 500mg vanillin, 2.4g sucralose, 2.6g citric acid monohydrate, and 2.2g sodium citrate dihydrate were also added into to the compounding vessel and mix until dissolved. Finally, 1.3g ertugliflozin-L-PGA was charged into the compounding vessel and mixed until dissolved. If needed to perform pH adjustment with hydrochloric acid or sodium hydroxide to a target pH of 3.7. Purified water was added q.s. to the batch and mixed until a homogenous final bulk drug product was obtained.

[0092] A 0.3 % w / v ertugliflozin in PEG 400 formulation is disclosed in Table 3.Table 3

[0093] The 0.3 % w / v ertugliflozin formulation was prepared as described above for 0.1 % w / v ertugliflozin formulation.Example 3 Stability studies

[0094] Determination of the ertugliflozin assay in the stability studies was conducted in accordance the conditions described in Table 4.Prototype formulations stability with different flavors.

[0095] Prototype formulations containing different flavors in each of the two solubilizers were placed in 40°C / 75% relative humidity (RH) to evaluate their stability.Table 5 - Six-month stability study

[0096] Flavor Stability Data - Poloxamer 188 vs. PEG 400, 6M Stability at 40°C / 75%RH.

[0097] 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). The formulations contained 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 5

[0098] 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).Longer Term Stability Studies

[0099] Several long-term stability studies were conducted to demonstrate the stability of ertugliflozin formulations with PEG400. 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 - 6 Month stability of ertugliflozin PEG 400 formulationExample 5 - Pharmacokinetic and Pharmacodynamic (PK / PD) Study of the ertugliflozin PEG 400 formulation

[0100] A study was performed to assess the pharmacokinetics and pharmacodynamics of the ertugliflozin formulation with PEG 400 as described in Example 2, Tables 2 and 3, administered at a dose of 0.03, 0.1, 0.3 or 1 mg / kg for 4 consecutive days in healthy male cats in a fasted or fed state 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. Cats were fasted overnight prior to the first dose and were presented with food 30 min prior to eachdose after an overnight fast for the next 3 consecutive doses. 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 (4th) 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 creatinine.

[0101] 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.Example 6 - Comparative Large-Scale production of ertugliflozin poloxamer formulation

[0102] An ertugliflozin poloxamer formulation was manufactured at 300L scale. 300g of methylparaben and 30g of propylparaben were dissolved into 150L of purified water at 60°C. After dissolution of methylparaben and propylparaben, 720g of sucralose, 150g of vanillin, 780g of citric acid monohydrate, and 660g of sodium citrate were added to the solution and dissolved at 60°C. 3kg of poloxamer 188 and 120L of purified water then added to the solution and mixed until dissolved and homogeneous. The solution was then cooled to less than 40°C. After cooling, 394.0g of ertugliflozin L-pyroglutamic acid was added to the solution and dissolved. Finally, the solution was q.s. with purified water to 300L.

[0103] 100L of the resulting 300L batch was transferred through a 10pm stainless steel filter into a holding vessel after manufacture. The solution was then held at ambient conditions for approximately 30 days. After 30 days, a crystalline material was identified at the bottom of the vessel. The vessel was drained of liquid and the resulting crystals were isolated with a spatula. Crystalline material was then dried by blowing overlayed nitrogen on the crystals at ambient temperature for approximately 24 hours. The crystals were then further rinsed with water to remove any excipients remaining in the process and dried for further characterization. These crystals were identified ertugliflozin sesquihydrate.

[0104] These results indicate that ertugliflozin L-pyroglutamic acid is not stable in the poloxamer formulation at concentrations higher than 0.1%. Rather it tends to precipitate out as ertugliflozin sesquihydrate. As a liquid solution formulation was desired, these results were not acceptable.Example 7 Large scale production of ertugliflozin PEG formulation

[0105] An ertugliflozin in PEG 400 formulation was manufactured at 300L scale. 150L of purified water was first added to a stainless steel vessel with overhead propeller stirrer and homogenizer with a constant agitator speed of 200RPM and a homogenizer speed of 1000RPM throughout the batch. Next, 90kg of PEG 400 was added and mixed for 10 minutes to ensure homogeneity. 300g of methylparaben and 30g of propylparaben were then dissolved into the batch over 30 minutes of mixing. After dissolution of methylparaben and propylparaben, 720g of sucralose, 150g of vanillin, 780g of citric acid monohydrate, and 660g of sodium citrate were added to the solution and dissolved in 15 minutes. 394.0g of ertugliflozin L-pyroglutamic acid was then added to the solution and dissolved over 30 minutes. The solution was pH adjusted to 3.7 with hydrochloric acid, diluted and mixed for 30 minutes. Finally, the batch was q.s. with purified water to 300L. 20L of the resulting 300L batch was transferred through a 10pm stainless steel filter into a holding vessel after manufacture. The solution was then held at ambient conditions for approximately 30 days. After 30 days, a sample was withdrawn for analytical testing of assay and appearance and showed no significant differences to the solution prior to holding. Most important, no ertugliflozin precipitated from the formulation.Example 8 - Solubility study of ertugliflozin sesquihydrate

[0106] Solubility of Ertugliflozin Sesquihydrate was assessed in the co-solvents Ethanol, Glycerol, PEG400, Propylene Glycol. Solubility was assessed by mixing lOOmg of bulk crystals in 5mL of cosolvent or cosolvent / water mixture overnight at 300 RPM on a stir plate. Solubilities up to a maximum of approximately 20mg / mL were assessed. Samples were then filtered and tested for solubility concentration via UPLC. Results are in the table below:Table 7

[0107] An additional study was conducted to evaluate the ability for Polysorbate 80 andPol oxamer 188 to dissolve 0.4% Ertugliflozin Sesquihydrate. Studies were conducted by adding bulk crystals into solvent and mixing overnight at 300 RPM on a stir plate. Full dissolution was assessed visually the next day. Polysorbate solutions were not able to fully dissolve the ertugliflozin sesquihydrate below 1% polysorbate 80. Poloxamer 188 was not able to solubilize 0.4% Ertugliflozin Sesquihydrate at Poloxamer 188 concentrations up to 5%.Table 8aTable 8bExample 9 - The Effect of pH on Color Change of Ertugliflozin / PEG Formulations

[0108] Solutions of Ertugliflozin oral solution were manufactured according to the formulation in Table 9 below:Table 9

[0109] The pH of the solutions was modified to pH 3.3, 3.7, and 4.5 with addition of hydrochloric acid or sodium hydroxide. Samples were then placed into glass containers at 60°C and tested for color after 2 and 6 weeks.

[0110] Color of solutions are measured via a LICO Colorimeter. The equipment measures the color difference between two solutions:AL* - is a measure of the lightness and darkness between two samples (+ = lighter, - = darker)Aa* - is a measure of the redness versus greenness between two samples (+ = redder, - = greener)Ab* - is a measure of the yellowness versus blueness between two samples (+ = yellower, - = bluer)AE is calculated based on the following calculation:[OHl] The comparison was made with a colorless solution of water. The human eye can detect a AE of greater than 1.Results of the study are shown below:Table 10

[0112] Results show reduced color change over shelf life with reduced pH.

[0113] Example 10 Ertugliflozin / PEG 400 Formulation with benzoic acid preservative

[0114] Table 11Stability study

[0115] Long-term stability studies were conducted to demonstrate the stability of the above benzoic acid containing ertugliflozin formulations with PEG400. Ertugliflozin concentrations of5 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).

[0116] 0.1% Ertugliflozin - 40 °C / 75% RH - Ertugliflozin formulation with Benzoic AcidTable 12Table 12

[0117] 0.3% Ertugliflozin - 40 °C / 75% RH - Ertugliflozin formulation with BenzoicAcidTable 135

[0118] Antimocrobial Effectiveness testing

[0119] The ertugliflozin PEG400 formulation containing benzoic acid was evaluated for inhibition of growth of microorganisms according to US Pharmacopoeia 51 and EP European Pharmacopoeia, Chapter 5.1.3. The standard is given below

[0120] USP <51> and Ph. Eur. 5.1.3 requirement for antimicrobial effective10 Table 14

[0121] The ertugliflozin PEG400 formulation containing sodium benzoate was compared to ertugliflozin PEG400 formulation containing a mixture of methylparaben and propylparaben. Table 15O.l° / o ERTU P. Aeruginosa E. Coli S. Aureus C. Albicans A. Brasiliensis

[0122]

Claims

CLAIMS:

1. 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 polyethylene glycol (PEG), and c) a solvent wherein in the pH of the oral liquid pharmaceutical composition is between about 3.0 to about 5.0.

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 polyethylene glycol (PEG) surfactant is polyethylene glycol (PEG) 400.

5. The liquid pharmaceutical composition of anyone of claims 1-4, wherein composition further comprises a flavor.

6. The liquid pharmaceutical composition of anyone of claims 1-5, wherein composition further comprises a buffer.

7. The liquid pharmaceutical composition of anyone of claims 1-6, wherein composition further comprises a preservative.

8. The liquid pharmaceutical composition of 7, wherein the preservative is methylparaben, propylparaben or mixtures thereof.

9. The liquid pharmaceutical composition of 7, wherein the preservative is benzoic acid or a salt thereof.

10. The liquid pharmaceutical composition of any one of claims 6-9, wherein the buffer is citric acid and a citrate salt.

11. The liquid pharmaceutical composition of claim 10, wherein the ratio of the citric acid to the citrate salt is between about 1 : 1 to about 4: 1, preferably between about 0.25:0.20 to about 0.35:0.10.

12. The liquid pharmaceutical composition of anyone of claims 5-11, wherein the flavor is malt, honey, vanillin, sucralose or mixtures thereof.

13. The liquid pharmaceutical composition of any one of claims 1-12, 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).

14. The liquid pharmaceutical composition of any one of claims 1-13, 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).

15. The liquid pharmaceutical composition of any one of claims 1-14, wherein the composition has a pH of between about 3.6 to about 3.8 or between about 4.3 to about 4.

516. A method of treating diabetes mellitus in an animal comprising administering to the animal an effective amount of the liquid pharmaceutical composition of anyone of claims 1-15.

17. The method of claim 16, wherein the animal is a feline animal.

18. The method of anyone of claims 16-17, wherein the administration is via oral syringe.

19. The method of anyone of claims 16-18, wherein the liquid pharmaceutical composition is administered once per day.

20. The method of anyone of claims 16-19, 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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