Stable RUC-4 formulation

Abstract

The present disclosure relates to solid and liquid formulations of RUC-4 that are stable under a range of storage conditions.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 150,168, filed February 17, 2021, the contents of which are incorporated by reference herein in their entirety. [Background technology]

[0002] RUC-4 is an inhibitor of the platelet αIIbβ3 receptor and is described in U.S. Patent No. 9,303,044, which is incorporated herein by reference. In this disclosure, RUC-4 is referred to as compound (1). There is a need for solid and liquid formulations of RUC-4 that are stable under a range of storage conditions. Summary of the Invention

[0003] In one aspect, the present specification provides a compound (1): [ka] and acetic acid. In some embodiments, the molar ratio of compound (1) to acetic acid is about 1:2. In some embodiments, the composition comprises an additional acid or acids. In some embodiments, the composition further comprises additional excipients or additives to adjust properties such as osmolality and stability. In some embodiments, the composition is a chemically and physically stable solution.

[0004] In another aspect, provided herein is a composition comprising Compound (1) in the form of an acetic acid addition salt. In certain embodiments, the molar ratio of Compound (1) to acetic acid ranges from about 1:0.5 to about 1:3. In certain embodiments, the composition is a lyophilized solid.

[0005] In another aspect, provided herein is a method of making a lyophilized composition, comprising preparing a solution comprising Compound (1) and acetic acid, filtering the solution, freezing the solution, and removing water from the frozen solution by sublimation at low pressure. In certain embodiments, the solution comprises an additional acid or acids. In certain embodiments, the solution further comprises additional excipients or additives that adjust properties such as osmolality and stability.

[0006] In another aspect, provided herein is a method of making a solution of Compound (1) for administration by injection, comprising contacting Compound (1), or a pharma- ceutically acceptable salt thereof, or a lyophilized composition described herein, with a pharma- ceutically acceptable solvent in a vial, syringe, or autoinjector. [Brief description of the drawings]

[0007] [Figure 1] Illustrated are the levels of des-glycine degradation products observed in the formulations of Table 4 as prepared (initial), after 1 month of storage at 5° C., and after 3 months of storage at 5° C. [Diagram 2] 4 shows the levels of des-glycine degradation products observed in the formulations of Table 4 upon preparation (initial) and after 1, 2, or 3 months of storage at 25° C. / 60% RH. [Diagram 3] 4 shows the levels of des-glycine degradation products observed in the formulations of Table 4 upon preparation (initial) and after 1, 2, or 3 months of storage at 40° C. / 75% RH. [Figure 4] Shown are the total impurity levels observed in the formulations in Table 4 upon preparation (initial) and after 1, 2, or 3 months of storage at 5°C. [Diagram 5] Shown are the total impurity levels observed in the formulations in Table 4 upon preparation (initial) and after 1, 2, or 3 months of storage at 25°C. [Figure 6] Shown are the total impurity levels observed in the formulations in Table 4 upon preparation (initial) and after 1, 2, or 3 months of storage at 40°C. [Figure 7] Shown are the levels of des-glycine degradation products observed in formulations as prepared (initial) and after 3 weeks and 1, 2, 3, or 6 months of storage at 5°C. [Figure 8] Shown are the levels of des-glycine degradation products observed in formulations as prepared (initial) and after 3 weeks and 1, 2, or 3 months of storage at 25° C. / 60% RH. [Figure 9] Shown are the total impurity levels observed in the formulations as prepared (initial) and after 3 weeks and 1, 2, 3, or 6 months of storage at 5°C. [Figure 10] Shown are the total impurity levels observed in the formulations as prepared (initial) and after 3 weeks and 1, 2, or 3 months of storage at 25° C. / 60% RH. [Figure 11] 1 shows the stability report for Formulation 1 after 6 months of storage at 2-8° C. [Figure 12] 1 shows the stability report for Formulation 1 after 6 months of storage at 25° C. / 60% RH. [Figure 13] Lyophilization stability data at 25° C. / 60% RH and 5° C. are shown. Formulation: 110 mg of compound (1), 1:1.1 molar ratio of compound (1) to acetic acid, and 2 mL of sterile water for injection (SWFI) in a 5 mL vial. Samples were frozen at −45° C., dried at 100-150 mTorr at −25° C. for 39 hours, and then dried at ambient temperature for an additional 5 hours. [Figure 14] Lyophilization stability data at 40° C. / 75% RH is shown. Formulation: 110 mg of compound (1), 1:1.1 molar ratio of compound (1) to acetic acid, and 2 mL of SWFI in a 5 mL vial. Samples were frozen at −45° C., dried at 100-150 mTorr at −25° C. for 39 hours, then dried at ambient temperature for an additional 5 hours. [Figure 15]Lyophilization stability data at 25° C. / 60% RH and 5° C. are shown. Formulation: 110 mg of compound (1), 1:1.1 molar ratio of compound (1) to acetic acid, 47.2 mg of sucrose, and 2 mL of SWFI in a 5 mL vial. Samples were frozen at -45° C., dried at 100-150 mTorr at -25° C. for 39 hours, then dried at ambient temperature for an additional 5 hours. [Figure 16] Lyophilization stability data at 40° C. / 75% RH is shown. Formulation: 110 mg of compound (1), 1:1.1 molar ratio of compound (1) to acetic acid, 47.2 mg of sucrose, and 2 mL of SWFI in a 5 mL vial. Samples were frozen at -45° C., dried at 100-150 mTorr at -25° C. for 39 hours, then dried at ambient temperature for an additional 5 hours. [Figure 17] Exemplary excipients for use in the lyophilized formulations are provided, including bulking agents, buffers, solubilizers, and mixtures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present disclosure is based in part on the discovery of compound (1) that is surprisingly highly soluble in acetic acid. In particular, solutions of greater than 300 mg / mL are obtained.

[0009] The present disclosure relates to compound (1): [ka] and acetic acid.

[0010] In certain embodiments, the composition includes an additional acid, which may act as a solubilizer, pH adjuster, or stabilizer, hi certain embodiments, the additional acid is one or more of a pharma- ceutically acceptable organic acid and / or a pharma-ceutically acceptable inorganic acid.

[0011] In certain embodiments, provided herein are compositions comprising Compound (1), acetic acid, and hydrochloric acid, in which the molar ratio of Compound (1) to acetic acid is about 1:2.4, about 1:2.2, about 1:2, about 1:1.9, about 1:1.8, about 1:1.6, about 1:1.4, about 1:1.2, about 1:1, about 1:0.8, about 1:0.6, or about 1:0.4.

[0012] In certain embodiments, provided herein are compositions comprising Compound (1), acetic acid, hydrochloric acid, and citric acid, in certain embodiments, the molar ratio of Compound (1) to acetic acid is about 1:2.4, about 1:2.2, about 1:2, about 1:1.9, about 1:1.8, about 1:1.6, about 1:1.4, about 1:1.2, about 1:1, about 1:0.8, about 1:0.6, or about 1:0.4.

[0013] In certain embodiments, the composition is a solution comprising water. In certain embodiments, the pH is about 4.0-6.0, inclusive. In certain embodiments, the solution has a pH of about 4.25-6.0, inclusive. In certain embodiments, the pH is about 4.0-5.0, inclusive. In certain embodiments, the pH is about 4.25-4.75, inclusive. In certain embodiments, the pH is about 4.5-5.5, inclusive. In certain embodiments, the pH is about 4.75-5.25, inclusive. In certain embodiments, the pH is about 4.5-5.0, inclusive.

[0014] In certain embodiments, the composition is a solution and the total chloride ion concentration in the composition is ≦35 mM. In certain particular embodiments, the total chloride ion concentration is about 5-35 mM, about 10-30 mM, about 15-25 mM, about 20-35 mM, or about 25-35 mM. In certain embodiments, the solution comprises an additional pharma- ceutically acceptable solvent. In certain embodiments, the composition is a solution in a solvent that comprises water and another pharma-ceutically acceptable solvent.

[0015] In certain embodiments, the composition is a solution of Compound (1) and acetic acid in water, further comprising an additional acid that is not hydrochloric acid. In certain embodiments, the concentration of the additional acid is ≦35 mM. In certain particular embodiments, the concentration of the additional acid is about 5-35 mM, about 10-30 mM, about 15-25 mM, about 20-35 mM, or about 25-35 mM.

[0016] In certain embodiments, the composition is a solution comprising water having an osmolality of ≧200 mmol / L. In certain specific embodiments, the osmolality is about 200-250 mmol / L, about 250-300 mmol / L, about 300-350 mmol / L, or about 350-400 mmol / L. In certain embodiments, the composition further comprises one or more osmotic agents, including, but not limited to, salts and polyols (including, for example, sugars).

[0017] In certain embodiments, the composition is a solution comprising about 1-500 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 1-400 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 1-300 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 1-200 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 1-100 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 1-50 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 5-25 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 10-25 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 10-20 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 10-20 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 12-20 mg / mL of compound (1). In certain embodiments, the composition is a solution comprising about 15-20 mg / mL of compound (1). In certain embodiments, the composition comprises about 12-18 mg / mL of Compound (1). In certain embodiments, the composition comprises about 15-18 mg / mL of Compound (1).

[0018] In certain embodiments, the composition comprises 1-20 mg / mL acetic acid. In certain embodiments, the composition comprises 1-15 mg / mL acetic acid. In certain embodiments, the composition comprises 1-10 mg / mL acetic acid. In certain embodiments, the composition comprises 3-8 mg / mL acetic acid. In certain embodiments, the composition comprises 3-7 mg / mL acetic acid. In certain embodiments, the composition comprises 3-6 mg / mL acetic acid. In certain embodiments, the composition comprises 4-8 mg / mL acetic acid. In certain embodiments, the composition comprises 4-7 mg / mL acetic acid. In certain embodiments, the composition comprises 4-6 mg / mL acetic acid. In certain embodiments, the composition comprises 5-8 mg / mL acetic acid. In certain embodiments, the composition comprises 5-7 mg / mL acetic acid. In certain embodiments, the composition comprises 5-6 mg / mL acetic acid. In certain embodiments, the composition comprises 10-20 mg / mL acetic acid. In certain embodiments, the composition comprises 10-15 mg / mL acetic acid. In certain embodiments, the composition comprises 15-20 mg / mL acetic acid. In certain embodiments, the composition comprises about 1 mg / mL acetic acid. In certain embodiments, the composition comprises about 2 mg / mL acetic acid. In certain embodiments, the composition comprises about 3 mg / mL acetic acid. In certain embodiments, the composition comprises about 4 mg / mL acetic acid. In certain embodiments, the composition comprises about 5 mg / mL acetic acid. In certain embodiments, the composition comprises about 6 mg / mL acetic acid. In certain embodiments, the composition comprises about 7 mg / mL acetic acid. In certain embodiments, the composition comprises about 8 mg / mL acetic acid. In certain embodiments, the composition comprises about 9 mg / mL acetic acid. In certain embodiments, the composition comprises about 10 mg / mL acetic acid. In certain embodiments, the composition comprises about 11 mg / mL acetic acid. In certain embodiments, the composition comprises about 12 mg / mL acetic acid. In certain embodiments, the composition comprises about 13 mg / mL acetic acid. In certain embodiments, the composition comprises about 14 mg / mL acetic acid. In certain embodiments, the composition comprises about 15 mg / mL acetic acid. In certain embodiments, the composition comprises about 16 mg / mL acetic acid. In certain embodiments, the composition comprises about 17 mg / mL acetic acid. In certain embodiments, the composition comprises about 18 mg / mL acetic acid.In certain embodiments, the composition comprises about 19 mg / mL acetic acid. In certain embodiments, the composition comprises about 20 mg / mL acetic acid.

[0019] In certain embodiments, the composition comprises 1-10 mg / mL citric acid. In certain embodiments, the composition comprises 3-8 mg / mL citric acid. In certain embodiments, the composition comprises 5-8 mg / mL citric acid. In certain embodiments, the composition comprises 3-5 mg / mL citric acid. In certain particular embodiments, the composition comprises 0-3 mg / mL citric acid. In certain embodiments, the composition comprises 1-3 mg / mL citric acid. In certain embodiments, the composition comprises 1-2 mg / mL citric acid. In certain embodiments, the composition comprises about 2 mg / mL citric acid. In certain embodiments, the composition comprises about 1.35 mg / mL citric acid. In certain embodiments, the composition comprises about 1 mg / mL citric acid.

[0020] In some embodiments, the composition further comprises a polyol. In some embodiments, the polyol is glycerin, i.e., glycerol. In some embodiments, the polyol is propylene glycol. In some embodiments, the composition comprises about 1-50 mg / mL of polyol. In some embodiments, the composition comprises about 10-30 mg / mL of polyol. In some embodiments, the composition comprises about 10-20 mg / mL of polyol. In some embodiments, the composition comprises about 12-18 mg / mL of polyol.

[0021] In certain embodiments, the polyol is a sugar. In certain particular embodiments, the sugar is sucrose. In certain particular embodiments, the sugar is mannitol. In certain particular embodiments, the sugar is trehalose.

[0022] In certain embodiments, the composition further comprises one or more additional agents, such as a buffering agent, a tonicity agent, a stabilizing agent, or a solubilizing agent.

[0023] The effect of various formulation components on stability is shown in Tables 1-2. Figures 1-10 show specific or total impurity levels.

[0024] [Table 1]

[0025] [Table 2]

[0026] In certain embodiments, the compositions described herein comprise Compound (2): [ka] or a salt thereof. In certain embodiments, compound (2) is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

[0027] In certain embodiments, the compositions described herein comprise Compound (3): [ka] or a salt thereof. In certain embodiments, compound (3) is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

[0028] In certain particular embodiments, provided herein are compositions comprising the following ingredients per milliliter of water:

[0029] (1) Formulation 1 (pH 5.0 ± 0.1) [Table 3] (2) Formulation 2 (pH 4.75 ± 0.1) [Table 4] (3) Formulation 3 (pH 4.75 ± 0.1) [Table 5] (4) Formulation 4 (pH 5.0 ± 0.1) [Table 6] (5) Formulation 5 (pH 4.75 ± 0.1) [Table 7] (6) Formulation 6 (pH 4.5 ± 0.1) [Table 8] (7) Formulation 7 (pH 4.25 ± 0.1) [Table 9]

[0030] In certain embodiments, the compositions described herein are stable at 25° C. / 60% relative humidity (RH) for at least 1 month. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 3 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 6 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 6-18 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 6-12 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 12-24 months.

[0031] In certain embodiments, the compositions described herein are stable at 5° C. for at least 1 year. In certain embodiments, the compositions described herein are stable at 5° C. for at least 2 years. In certain embodiments, the compositions described herein are stable at 5° C. for at least 3 years. In certain embodiments, the compositions described herein are stable at 5° C. for at least 4 years. In certain embodiments, the compositions described herein are stable at 5° C. for at least 5 years.

[0032] In some embodiments, the liquid compositions (e.g., solutions) described herein are formulated for injection. In some embodiments, the injection is intramuscular. In some embodiments, the injection is subcutaneous, for example, into the arms, legs, thighs, back, buttocks, and abdomen. In some embodiments, the injection is by pre-filled syringe, pen, or auto-injector. In some embodiments, the injection is self-administered by auto-injector.

[0033] In certain embodiments, the injection volume is 2 mL or less. In certain embodiments, the injection volume is 1 mL or less, for example, about 0.9 mL, about 0.8 mL, about 0.7 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL, about 0.3 mL, about 0.2 mL, or about 0.1 mL.

[0034] In another aspect, the present specification provides a compound (1): [ka] in the form of a salt of acetic acid. In certain embodiments, the molar ratio of compound (1) to acetic acid ranges from about 1:0.2 to about 1:2.5. In certain embodiments, the molar ratio of compound (1) to acetic acid ranges from about 1:0.2 to about 1:3.5. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:0.25. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:0.5. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:1. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:2. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:2.5. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:3. In certain embodiments, the molar ratio of compound (1) to acetic acid is about 1:3.5.

[0035] In certain embodiments, the composition further comprises a polyol. In certain embodiments, the polyol is a sugar. In certain embodiments, the sugar is a non-reducing sugar. In certain embodiments, the non-reducing sugar is sucrose. In certain particular embodiments, the sugar is sucrose, trehalose, or mannitol. In certain embodiments, the molar ratio of compound (1) to sugar ranges from about 2:1 to about 1:2. In certain embodiments, the molar ratio ranges from about 2:1 to about 1:1. In certain embodiments, the molar ratio ranges from about 1.5:1 to about 1:1.

[0036] In some embodiments, the composition is a solution in water. In some embodiments, the solution is intended for lyophilization. In some embodiments, the solution is a reconstituted lyophilizate, the lyophilizate being as described herein. In some embodiments, the reconstituted lyophilizate further comprises sodium chloride.

[0037] In certain embodiments, the composition is a solid lyophilizate.

[0038] Other excipients are known in the art. Such excipients include bulking agents, buffers, tonicity modifiers, antimicrobial agents, and solubilizers. Representative excipients that may be used in lyophilized formulations are shown in Figure 17. See also A. Baheti, et al. J. Excipients and Food Chem. 1(1) 2010.

[0039] In certain embodiments, the composition is a spray-dried solid. In certain embodiments, the composition is a finely divided solid.

[0040] In certain embodiments, the compositions described herein contain less than 25% by weight of compound (4): [ka] or a salt thereof.

[0041] In certain embodiments, the composition comprises less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, or less than about 0.5% by weight of Compound (4), or a salt thereof. In any of the preceding embodiments, the composition comprises a detectable amount of Compound (4) or a salt thereof.

[0042] In certain embodiments, the compositions are stable at 25° C. / 60% RH for at least 1 month. In certain embodiments, the compositions are stable at 25° C. / 60% RH for at least 3 months. In certain embodiments, the compositions are stable at 25° C. / 60% RH for at least 6 months. In certain embodiments, the compositions are stable at 25° C. / 60% RH for at least 6-18 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 6-12 months. In certain embodiments, the compositions described herein are stable at 25° C. / 60% RH for at least 12-24 months.

[0043] In certain embodiments, the composition is stable at 5° C. for at least 1 year. In certain embodiments, the composition is stable at 5° C. for at least 2 years. In certain embodiments, the composition is stable at 5° C. for at least 3 years. In certain embodiments, the composition is stable at 5° C. for at least 4 years. In certain embodiments, the composition is stable at 5° C. for at least 5 years.

[0044] In another aspect, provided herein is a method of making a lyophilized composition (i.e., a lyophilizate) described herein, comprising preparing a solution comprising Compound (1) and acetic acid; filtering the solution; freezing the solution; and removing water from the frozen solution by sublimation at low pressure. In certain embodiments, the solution further comprises additional components, such as one or more inorganic and / or organic acids, buffers, polyols (e.g., sugars), or preservatives. In certain embodiments, the solution comprises Compound (1), acetic acid, and a non-reducing sugar. In certain embodiments, the non-reducing sugar is sucrose. In certain embodiments, the solution is frozen at a temperature between -10°C and -78°C.

[0045] In another aspect, provided herein is a method of making a solution of Compound (1) for administration by injection, comprising contacting Compound (1), or a pharma- ceutically acceptable salt thereof, or a lyophilized composition (i.e., lyophilisate) described herein, with a pharma- ceutically acceptable solvent in a suitable container, e.g., a vial, a syringe, or an autoinjector. In certain embodiments, the syringe is a single-chamber syringe. In certain embodiments, the syringe is a dual-chamber syringe. An example of a suitable dual-chamber syringe is the Companion® safety syringe manufactured by Credence MedSystems.

[0046] In certain embodiments, Compound (1), or a pharma- ceutically acceptable salt thereof, or a lyophilized composition is present in a syringe prior to contact with the solvent. In certain embodiments, the pharma- ceutically acceptable solvent comprises sterile water for injection, saline, or other suitable diluent for the constitution of the lyophilizate. In certain embodiments, the pharma- ceutically acceptable solvent further comprises a pharma- ceutically acceptable acid.

[0047] definition "Pharmaceutically acceptable" means something that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, including something that is acceptable for veterinary and human pharmaceutical use.

[0048] The term "pharmaceutically acceptable salts" refers to those salts that are suitable for use in contact with human and non-human animal tissues without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or methanesulfonic acid, or by other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-phenylpropionate salts, such as phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. + (C 1-4 Alkyl)4 -Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0049] A solid formulation of Compound (1) described herein is characterized as being "stable" if it undergoes less degradation than an unformulated solid form of Compound (1), or a salt thereof, under the same conditions, including, for example, time, temperature, and relative humidity (RH). A liquid formulation of Compound (1) described herein is characterized as being "stable" if it undergoes less degradation than an unformulated liquid preparation (e.g., a solution or suspension) of Compound (1), or a salt thereof, under the same conditions, including, for example, time, temperature, and relative humidity. EXAMPLES

[0050] Equipment and materials RUC-4 (compound (1)) was supplied by CeleCor Therapeutics. All commercially available chemicals and materials were obtained from commercial vendors and used as received without further purification. Water suitable for HPLC analysis was Barnstead NanoPure or equivalent. Methanol was Fisher Optima® or equivalent. Isopropanol was Fisher HLPC Grade or equivalent. Acetonitrile was Fisher Optima® or equivalent. Trifluoroacetic acid (TFA) was Fisher Optima® or equivalent. HPLC analyses reported herein utilized an HPLC system with UV detection and equipped with a thermostated column oven, a thermostated autosampler, and a quaternary or binary pump.

[0051] [Table 10]

[0052] Example 1. Formulation stability test The formulation solutions described in Table 3 below were prepared and divided into three equal portions and stored overnight (approximately 18 hours) at -20°C, 5°C, and 20°C, respectively. The formulations were observed and characterized as reported in Table 3 immediately at room temperature, immediately after removing the 5°C formulation from the refrigerator, and after thawing the -20°C formulation. Clear solutions of Compound (1) were obtained at a concentration of ≦17.5 mg / mL at pH 4.75. Physical instability at lower pH (4.75-5.00) was improved by formulating at lower drug concentrations (<17.5 mg / mL), thereby preserving chemical (e.g., less Ds-Gly formation) and physical (e.g., less crystal formation) stability properties.

[0053] [Table 11]

[0054] Example 2. Formulation stability test The formulation solutions described in Table 4 were prepared and stored at -20°C, 5°C, and room temperature and monitored for long term (6 months and in some cases longer) stability. The formulations were observed for physical and chemical stability.

[0055] [Table 12-1] [Table 12-2]

[0056] Example 3. Preparation of lyophilized formulations The first step is to determine the amount of RUC-4 (at 100% purity), acetic acid, sucrose, and sterile WFI (water for injection) needed for the batch size. These calculations are based on preparing a RUC-4 concentration of 55 mg / mL for a given batch size. A portion of the sterile WFI is weighed into a container with a mixer. The required amount of acetic acid is then added and the mixture is mixed for 5 minutes. Sucrose is added to the acetic acid solution and mixed to dissolve. The RUC-4 is then added and mixed until completely dissolved. The remaining amount of sterile WFI is added and the solution is mixed to complete the solution preparation process.

[0057] The final drug solution is filtered through a Millipak-20, 0.22-micron Durapore® membrane filter. After successful filter integrity testing, the filtered solution is aseptically filled into 5 mL clear glass USP Type 1 vials (fill of 2.06 g + / - 0.04 g per vial) to yield 110 mg of RUC-4 per vial.

[0058] Fill weight checks are performed every 20 minutes. The vials are then placed on trays and loaded into the freeze dryer. Freeze drying involves the following steps: (i) The solution is frozen on a shelf maintained at -45°C for 8 hours.

[0059] (ii) After the freezing and holding step, the shelves are warmed to a temperature of -30°C and ice sublimation (primary drying) is carried out at a chamber pressure of approximately 100 mTorr for 24 hours.

[0060] (iii) The shelf is then warmed to a temperature of -25°C and ice sublimation (primary drying) is carried out for an additional 24 hours at a chamber pressure of approximately 100 mTorr.

[0061] (iv) At the end of primary drying, the shelves are warmed to +25°C and secondary drying is carried out for 11 hours at a chamber pressure of approximately 100 mTorr to remove absorbed water and achieve a residual water content of approximately 1%.

[0062] (v) Purge the chamber with dry nitrogen.

[0063] (vi) The vials were stoppered and crimped.

[0064] (vii) The vials are stored at −5° C. until visual inspection is completed.

[0065] (viii) Store the finished product vials at −20° C. until use.

[0066] The above mentioned process parameters may vary depending on the size of the batch and the capacity of the freeze dryer. Storage conditions may also vary as required.

[0067] The order of addition of the excipients mentioned above is important since RUC-4 dissolves rapidly when added to acetic acid. After sterile filtration of the RUC-4 solution, the physical integrity of the filter is tested to ensure that its integrity was not compromised during filtration. This step is essential to ensure the microbial purity of the solution and the final lyophilized product. The lyophilization process is robust since the selected primary and secondary temperatures along with the duration of primary and secondary drying have been shown to be conservative based on results from several development batches. The selected lyophilization parameters should also ensure low moisture content in the final product.

[0068] [Table 13]

[0069] Embodiment 1. Compound (1): [ka] and acetic acid.

[0070] 2. The composition of embodiment 1, wherein the molar ratio of compound (1) to acetic acid is about 1:3.5.

[0071] 3. The composition of any one of the preceding embodiments, wherein the composition is a solution in water having a pH of about 4.0 to 6.0, inclusive.

[0072] 4. The composition of embodiment 3, wherein the pH is about 4.0 to 5.5, inclusive.

[0073] 5. The composition of embodiment 3, wherein the pH is about 4.25 to 5.25, inclusive.

[0074] 6. The composition of embodiment 3, wherein the pH is about 4.25 to 4.75, inclusive.

[0075] 7. The composition of embodiment 3, wherein the pH is about 4.75 to 5.25, inclusive.

[0076] 8. The composition of any one of the preceding embodiments, further comprising an additional acid or acids.

[0077] 9. The composition of embodiment 8, wherein the additional acid or acids are one or more of a pharma- ceutically acceptable organic acid and a pharma- ceutically acceptable inorganic acid.

[0078] 10. The composition of embodiment 9, wherein the pharma- ceutically acceptable inorganic acid is hydrochloric acid.

[0079] 11. The composition of embodiment 9, wherein the pharma- ceutically acceptable organic acid is citric acid.

[0080] 12. The composition of embodiment 10, wherein the total chloride ion concentration is ≦35 mM.

[0081] 13. The composition of any one of the preceding embodiments, wherein the composition is a solution in water having an osmolality of ≧200 mmol / L.

[0082] 14. The composition of any one of the preceding embodiments, comprising about 1-100 mg / mL of compound (1).

[0083] 15. The composition of embodiment 14, comprising about 5 to 25 mg / mL of compound (1).

[0084] 16. The composition of embodiment 14, comprising about 10 to 25 mg / mL of compound (1).

[0085] 17. The composition of embodiment 14, comprising about 10 to 20 mg / mL of compound (1).

[0086] 18. The composition of embodiment 14, comprising about 12 to 20 mg / mL of compound (1).

[0087] 19. The composition of embodiment 14, comprising about 15 to 20 mg / mL of compound (1).

[0088] 20. The composition of embodiment 14, comprising about 12 to 18 mg / mL of compound (1).

[0089] 21. The composition of embodiment 14, comprising about 15 to 18 mg / mL of compound (1).

[0090] 22. The composition of any one of the preceding embodiments, comprising about 3-15 mg / mL acetic acid.

[0091] 23. The composition of embodiment 22, comprising about 3-8 mg / mL acetic acid.

[0092] 24. The composition of embodiment 22, comprising about 3-7 mg / mL acetic acid.

[0093] 25. The composition of embodiment 22, comprising about 3-6 mg / mL acetic acid.

[0094] 26. The composition of embodiment 22, comprising about 4-8 mg / mL acetic acid.

[0095] 27. The composition of embodiment 22, comprising about 4-7 mg / mL acetic acid.

[0096] 28. The composition of embodiment 22, comprising about 4-6 mg / mL acetic acid.

[0097] 29. The composition of embodiment 22, comprising about 5-8 mg / mL acetic acid.

[0098] 30. The composition of embodiment 22, comprising about 5-7 mg / mL acetic acid.

[0099] 31. The composition of embodiment 22, comprising about 5-6 mg / mL acetic acid.

[0100] 32. The composition of embodiment 22, comprising about 10-15 mg / mL acetic acid.

[0101] 33. The composition of any one of the preceding embodiments, further comprising a polyol.

[0102] 34. The composition of embodiment 33, wherein the polyol is glycerin (i.e., glycerol).

[0103] 35. The composition of any one of embodiments 33-34, comprising about 1-50 mg / mL of polyol.

[0104] 36. The composition of embodiment 35, comprising about 10-30 mg / mL of polyol.

[0105] 37. The composition of embodiment 35, comprising about 10-20 mg / mL of polyol.

[0106] 38. The composition of embodiment 35, comprising 12-18 mg / mL of polyol.

[0107] 39. The composition of any one of the preceding embodiments, further comprising about 1-10 mg / mL citric acid.

[0108] 40. The composition of embodiment 39, comprising about 3-8 mg / mL citric acid.

[0109] 41. The composition of embodiment 39, comprising about 5-8 mg / mL citric acid.

[0110] 42. The composition of embodiment 39, comprising about 3-5 mg / mL citric acid.

[0111] 43. The composition of embodiment 39, comprising about 0-3 mg / mL citric acid.

[0112] 44. The composition of embodiment 39, comprising about 1-3 mg / mL citric acid.

[0113] 45. The composition of embodiment 39, comprising about 1-2 mg / mL citric acid.

[0114] 46. ​​The composition of embodiment 39, comprising about 2 mg / mL citric acid.

[0115] 47. The composition of embodiment 39, comprising about 1.35 mg / mL citric acid.

[0116] 48. The composition of embodiment 39, comprising about 1 mg / mL citric acid.

[0117] 49. Compound (2): [ka] or a salt thereof.

[0118] 50. The composition of embodiment 49, wherein compound (2) or a salt thereof is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

[0119] 51. Compound (3): [ka] or a salt thereof.

[0120] 52. The composition of embodiment 51, wherein compound (3) is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

[0121] 53. Each milliliter of water contains: [Table 14] 2. The composition of embodiment 1, wherein the composition has a pH of 5.0±0.1.

[0122] 54. Each milliliter of water contains: [Table 15] 2. The composition of embodiment 1, wherein the composition has a pH of 4.75±0.1.

[0123] 55. Each milliliter of water contains: [Table 16] 2. The composition of embodiment 1, wherein the composition has a pH of 4.75±0.1.

[0124] 56. Each milliliter of water contains: [Table 17] 2. The composition of embodiment 1, wherein the composition has a pH of 5.0±0.1.

[0125] 57. Each milliliter of water contains: [Table 18] 2. The composition of embodiment 1, wherein the composition has a pH of 4.75±0.1.

[0126] 58. Each milliliter of water contains: [Table 19] 2. The composition of embodiment 1, wherein the composition has a pH of 4.5±0.1.

[0127] 59. Each milliliter of water contains: [Table 20] 2. The composition of embodiment 1, wherein the composition has a pH of 4.25±0.1.

[0128] 60. The composition of any one of the preceding embodiments, wherein the composition is stable at 25° C. / 60% RH for at least 1 month.

[0129] 61. The composition of any one of the preceding embodiments, wherein the composition is stable at 25° C. / 60% RH for at least 3 months.

[0130] 62. The composition of any one of the preceding embodiments, wherein the composition is stable at 25° C. / 60% RH for at least 6 months.

[0131] 63. The composition of any one of the preceding embodiments, wherein the composition is stable at 25° C. / 60% RH for at least 12-18 months.

[0132] 64. The composition of any one of the preceding embodiments, wherein the composition is stable at 5° C. for at least 1 year.

[0133] 65. The composition of any one of the preceding embodiments, wherein the composition is stable at 5° C. for at least 2 years.

[0134] 66. The composition of any one of the preceding embodiments, wherein the composition is stable at 5° C. for at least 3 years.

[0135] 67. The composition of any one of the preceding embodiments, wherein the composition is stable at 5° C. for at least 4 years.

[0136] 68. The composition of any one of the preceding embodiments, wherein the composition is stable at 5° C. for at least 5 years.

[0137] 69. Compound (1): [ka] in the form of a salt of acetic acid.

[0138] 70. The composition of embodiment 69, wherein the molar ratio of compound (1) to acetic acid ranges from about 1:0.5 to about 1:35.

[0139] 71. The composition of embodiment 70, wherein the molar ratio of compound (1) to acetic acid is about 1:1.

[0140] 72. The composition of any one of embodiments 69-71, further comprising a sugar.

[0141] 73. The composition of embodiment 72, wherein the sugar is a non-reducing sugar.

[0142] 74. The composition of embodiment 73, wherein the non-reducing sugar is sucrose.

[0143] 75. The composition of any one of embodiments 72-74, wherein the molar ratio of compound (1) to said sugar ranges from about 2:1 to about 1:2.

[0144] 76. The composition of embodiment 75, wherein the molar ratio ranges from about 2:1 to about 1:1.

[0145] 77. The composition of embodiment 76, wherein the molar ratio ranges from about 1.5:1 to about 1:1.

[0146] 78. The composition of any one of embodiments 69 to 77, wherein the composition is a solution in water.

[0147] 79. The composition of embodiment 78, wherein the solution is intended for lyophilization.

[0148] 80. The composition of any one of embodiments 69-77, wherein the composition is a solid lyophilizate.

[0149] Less than 81.5% by weight of compound (4): [ka] or a salt thereof.

[0150] 82. The composition of embodiment 81, comprising less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of compound (4).

[0151] 83. The composition of any one of embodiments 80-82, wherein the composition is stable at 25° C. / 60% RH for at least 1 month.

[0152] 84. The composition of any one of embodiments 80-82, wherein the composition is stable at 25 °C / 60% RH for at least 3 months.

[0153] 85. The composition of any one of embodiments 80-82, wherein the composition is stable at 25 °C / 60% RH for at least 6 months.

[0154] 86. The composition of any one of embodiments 80-82, wherein the composition is stable at 25 °C / 60% RH for at least 6-12 months.

[0155] 87. The composition of any one of embodiments 80-82, wherein the composition is stable at 25° C. / 60% RH for at least 12-24 months.

[0156] 88. The composition of any one of embodiments 80-82, wherein the composition is stable at 5° C. for at least one year.

[0157] 89. The composition of any one of embodiments 80-82, wherein the composition is stable at 5° C. for at least 2 years.

[0158] 90. The composition of any one of embodiments 80-82, wherein the composition is stable at 5° C. for at least 3 years.

[0159] 91. The composition of any one of embodiments 80-82, wherein the composition is stable at 5° C. for at least 4 years.

[0160] 92. The composition of any one of embodiments 80-82, wherein the composition is stable at 5° C. for at least 5 years.

[0161] 93. The composition of embodiment 78, wherein the solution is a reconstituted lyophilizate.

[0162] 94. The composition of embodiment 93, comprising about 5 to 50 mg / mL of compound (1).

[0163] 95. The composition described in embodiment 93, wherein the lyophilisate is a composition described in any one of embodiments 33 to 43.

[0164] 96. The composition of embodiment 93, further comprising sodium chloride.

[0165] 97. A method for making a freeze-dried composition according to any one of embodiments 80 to 92, comprising: Providing a solution comprising compound (1) and acetic acid; filtering the solution; freezing the solution; and removing water from said frozen solution by sublimation at low pressure. The method comprising:

[0166] 98. A method for preparing a solution of compound (1) for administration by injection, comprising contacting compound (1), or a pharma- ceutically acceptable salt thereof, or a lyophilizate according to any one of embodiments 80 to 92, with a pharma- ceutically acceptable solvent in a syringe.

[0167] 99. The method of embodiment 98, wherein the syringe is a single-chamber syringe.

[0168] 100. The method of embodiment 98, wherein the syringe is a dual-chamber syringe.

[0169] 101. The method of embodiment 98, wherein the syringe is an autoinjector.

[0170] 102. The method according to any one of embodiments 98-101, wherein compound (1), or a pharma- ceutically acceptable salt thereof, or a lyophilisate thereof, is present in the syringe prior to contact with the solvent.

[0171] 103. The method of any one of embodiments 98-102, wherein the pharma- ceutically acceptable solvent comprises water or saline.

[0172] 104. The method of embodiment 103, wherein the pharma- ceutically acceptable solvent further comprises a pharma- ceutically acceptable acid.

Claims

1. Compound (1): 【Chemistry 1】 and acetic acid.

2. The composition of claim 1, wherein the composition is a solution in water.

3. The composition described in claim 2, wherein the solution is a reconstituted lyophilizate.

4. Compound (1): 【Chemistry 2】 in the form of a salt of acetic acid.

5. The composition of claim 4, wherein the composition is a solution in water.

6. The composition described in claim 5, wherein the solution is a reconstituted lyophilizate.

7. The composition of claim 4, wherein the composition is a solid lyophilizate.

8. The composition according to any one of claims 1 to 6, wherein the molar ratio of compound (1) to acetic acid is from about 1:0.5 to about 1:3.

5.

9. 7. The composition of any one of claims 1 to 6, wherein the composition is a solution in water having a pH of about 4.0 to 6.0 (inclusive); about 4.0 to 5.5 (inclusive); about 4.25 to 5.25 (inclusive); about 4.25 to 4.75 (inclusive); or about 4.75 to 5.25 (inclusive).

10. 8. The composition of any one of claims 1 to 7, further comprising an additional acid or acids, wherein the additional acid or acids is one or more of hydrochloric acid and citric acid.

11. 11. The composition of claim 10, wherein the total chloride ion concentration is ≦35 mM.

12. The composition according to any one of claims 1 to 6, wherein the composition is a solution in water having an osmolality of ≧200 mmol / L.

13. The composition of any one of claims 1 to 6, comprising about 1 to 100 mg / mL, about 5 to 25 mg / mL, about 10 to 25 mg / mL, about 10 to 20 mg / mL, about 12 to 20 mg / mL, about 15 to 20 mg / mL, about 12 to 18 mg / mL, or about 15 to 18 mg / mL of compound (1).

14. 7. The composition of any one of claims 1 to 6, comprising about 3-15 mg / mL, about 3-8 mg / mL, about 3-7 mg / mL, about 3-6 mg / mL, about 4-8 mg / mL, about 4-7 mg / mL, about 4-6 mg / mL, about 5-8 mg / mL, about 5-7 mg / mL, about 5-6 mg / mL, about 10-15 mg / mL, or about 1-5 mg / mL of acetic acid.

15. The composition of any one of claims 1 to 6, further comprising about 1 to 50 mg / mL, about 10 to 30 mg / mL, about 10 to 20 mg / mL, or about 12 to 18 mg / mL of polyol.

16. The composition of claim 15, wherein the polyol is glycerin.

17. 7. The composition of any one of claims 1 to 6, further comprising about 1-10 mg / mL, about 3-8 mg / mL, about 5-8 mg / mL, about 3-5 mg / mL, about 0-3 mg / mL, about 1-3 mg / mL, about 1-2 mg / mL, about 2 mg / mL, about 1.35 mg / mL, or about 1 mg / mL of citric acid.

18. Compound (2): 【Chemistry 3】 or a salt thereof, optionally wherein compound (2) or a salt thereof is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

19. Compound (3): 【Chemistry 4】 or a salt thereof, optionally wherein compound (3) is present in an amount that is less than about 10% by weight, less than about 8% by weight, less than about 6% by weight, less than about 4% by weight, less than about 2% by weight, or less than about 1% by weight of the composition.

20. Each milliliter of water contains: 【Table 1】 wherein the composition has a pH of 5.0±0.1; 【Table 2】 wherein the composition has a pH of 4.75±0.1; 【Table 3】 wherein the composition has a pH of 4.75±0.1; 【Table 4】 wherein the composition has a pH of 5.0±0.1; 【Table 5】 wherein the composition has a pH of 4.75±0.1; 【Table 6】 wherein the composition has a pH of 4.5±0.1; 【Table 7】 wherein the composition has a pH of 4.25±0.1; 【Table 8】 wherein the composition has a pH of 5.0±0.1; 【Table 9】 wherein the composition has a pH of 5.0±0.1; 【Table 10】 wherein the composition has a pH of 5.0±0.1; 【Table 11】 wherein the composition has a pH of 4.5±0.1; 【Table 12】 wherein the composition has a pH of 4.75±0.1; 【Table 13】 wherein the composition has a pH of 5.0±0.1; 【Table 14】 wherein the composition has a pH of 5.0±0.1; 【Table 15】 wherein the composition has a pH of 5.0±0.1; 【Table 16】 wherein the composition has a pH of 5.0±0.1; or 【Table 17】 and the composition has a pH of 5.0±0.

1. The composition according to any one of claims 1 to 6.

21. 8. The composition of any one of claims 1 to 7, wherein the composition is stable at 25°C / 60% RH for at least 1 month, stable at least 3 months at 25°C / 60% RH, stable at least 6 months at 25°C / 60% RH, stable at least 12-18 months at 25°C / 60% RH, stable at least 1 year at 5°C, stable at least 2 years at 5°C, stable at least 3 years at 5°C, stable at least 4 years at 5°C, or stable at least 5 years at 5°C.

22. 8. The composition of any one of claims 1 to 7, further comprising a sugar, wherein the molar ratio of compound (1) to the sugar ranges from about 2:1 to about 1:2, from about 2:1 to about 1:1, or from about 1.5:1 to about 1:

1.

23. 23. The composition of claim 22, wherein the non-reducing sugar is sucrose.

24. Less than 5% by weight of compound (4): 【Chemistry 5】 or a salt thereof, optionally wherein the composition comprises less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight, or less than about 0.5% by weight of compound (4).

25. 8. A method of making the freeze-dried composition of claim 7, comprising: providing a solution comprising compound (1) and acetic acid; filtering said solution; freezing the solution; and removing water from said frozen solution by sublimation at low pressure. The method comprising:

26. 11. A method of making a solution of Compound (1) for administration by injection, comprising contacting Compound (1), or a pharma- ceutically acceptable salt thereof, or the lyophilizate of claim 7, with a pharma- ceutically acceptable solvent in a syringe, optionally wherein the syringe is a single-chamber syringe, a dual-chamber syringe, or an auto-injector.

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