Freeze-dried metolazone formulations for non-digestive administration

Abstract

The present invention relates to novel compositions of metobuperazone lyophilisate and pharmaceutically acceptable diluents useful for reconstitution of metobuperazone lyophilisate to provide a clear solution suitable for non-digestive tract administration. The present invention also relates to a novel composition of the prelyophilized metobuperazone and to the use of the reconstituted prelyophilized metobuperazone.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical compositions and their medical uses. It also relates to the manufacture of pharmaceutical compositions. The active ingredient in question is metoprazine. This invention is advantageous because it provides a stable metoprazine formulation suitable for non-gastrointestinal administration (parenteral administration), of which only metoprazine tablets have been commercially available until now. The effect of this invention is that it can effectively treat patients with metoprazine-responsive disease who are unconscious or have swallowing difficulties. Background Technology

[0002] Metoprazor is a well-known active ingredient and is commercially available in 2.5 mg, 5 mg, and 10 mg tablets. Its chemical name is 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolin sulfonamide (Formula I, hereinafter). It is sparingly soluble in water (2.4 mg / mL) at 25°C. 10 -5 g / mL), and is sparingly soluble in ethanol (9 g / mL) at 25°C. 10 -3 g / mL).

[0003] I

[0004] Metoprazor is a quinazoline diuretic used to reduce swelling and fluid retention caused by congestive heart failure or chronic kidney disease. Metoprazor is used to relieve salt and water retention, known as edema. It is also used to treat congestive heart failure and hypertension.

[0005] There is no commercially available injectable form of metoprazine, primarily due to its extremely low solubility and instability in solution (e.g., its degradation in solution, making long-term storage difficult, if not impossible). Because there is no available injectable form of metoprazine, there is an unmet medical need for patients for whom oral administration or titration of metoprazine or its metoprazine dose is critical to achieving maximum efficacy or in whom rapid onset of action is required.

[0006] U.S. Patent No. 5,124,152 describes non-digestive formulations of metoprazine comprising an aqueous solution containing 0.1-8 mg / mL metoprazine, 5-15% w / v 95% ethanol, 0-3% v / v benzyl alcohol, and a co-solvent selected from 30-65 w / v propylene glycol, 25-50% v / v polyethylene glycol 300, or 25-50% v / v polyethylene glycol 400. It has been found that the use of any of these co-solvents leads to degradation products during storage. Therefore, these formulations lack long-term stability.

[0007] The liquid metoprazine formulation mentioned in U.S. Patent No. 5,124,152 is proposed as an alternative to a lyophilized solid prepared from sodium hydroxide and the sodium salt of metoprazine, which provides a pH of approximately 11 upon reconstitution with water. This is too high for administration to patients.

[0008] U.S. Patent Nos. 5,633,240, 5,684,009, and 5,814,623 propose liquid metoprazine formulations for non-gastrointestinal administration, which use aqueous buffer systems with a pH of 10.5–12.5, making them unsuitable for patient administration. Furthermore, these solutions have been found to lack long-term stability.

[0009] U.S. Patent No. 6,048,874 describes a method for preparing a metoprazan composition, comprising: a) providing a solvent comprising propylene glycol, polyethylene glycol, polypropylene glycol, or glycerin; b) adding metoprazan to the solvent; and c) heating the mixture of solvent and metoprazan. This method provides a metoprazan concentration of 9 mg / mL, which is above the apparent equilibrium solubility. These formulations are expected to lack long-term stability.

[0010] In U.S. Patent Nos. 7,923,447 and 9,427,398, dimethylacetamide was proposed as a solvent in non-gastrointestinal metoprazine formulations. However, this solvent is considered a developmental toxin (see OECD SIDS N,N-dimethylacetamide DMAC, 2001).

[0011] U.S. Patent Publication No. 2018 / 0296556 describes a non-aqueous homogeneous metoprazine solution comprising a dissolved lipophilic agent and an amphiphilic liquid polymeric solvent. The formulation is substantially free of non-polymeric organic solvents, water, and undissolved particles, and the dissolved lipophilic agent has a concentration of at least about 0.5 mg / mL. Furthermore, the solution remains stable and substantially free of undissolved particles for at least 40 days when stored at room temperature (25°C). However, this system does not provide the long-term stability required in the drug supply chain.

[0012] In view of the above, there remains a need in the art for metolazine formulations that can be administered outside the digestive tract and have sufficient long-term storage stability for use in the pharmaceutical supply chain.

[0013] The object of this invention is to solve at least one or more of the problems mentioned above. In particular, this invention aims to provide metoprazine formulations with long-term storage stability. Summary of the Invention

[0014] In one aspect, a novel metoprazine lyophilized composition comprising metoprazine and a building agent is described.

[0015] On the other hand, a novel pre-lyophilized composition is described, comprising metoprazine, filler, solvent, and water.

[0016] On the other hand, novel pharmaceutically acceptable diluents (diluents) suitable for reconstructing metoprazine lyophilized compositions are described.

[0017] On the other hand, a novel intravenous metoprazine kit is described, which comprises a lyophilized metoprazine composition and a pharmaceutically acceptable diluent.

[0018] On the other hand, a method for reconstructing metoprazine solution suitable for non-gastrointestinal administration is described.

[0019] On the other hand, a novel, ready-to-use reconstituted metoprazine solution and its uses are described.

[0020] On the other hand, a metoprazan lyophilized kit is described, comprising:

[0021] a. A first container comprising: a lyophilized metoprazine composition in the form of a lyophilized powder, said lyophilized metoprazine composition comprising:

[0022] i. Methoradzon; and,

[0023] b. A second container containing: a pharmaceutically acceptable diluent,

[0024] The diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of about 5.0-8.0 for non-gastrointestinal administration.

[0025] In one embodiment, the lyophilized metoprazine composition in powder form comprises a filler. Preferably, the filler is selected from mannitol, lactose, dextrose, sucrose, and hydroxypropyl- - Cyclodextrin; more preferably, the filler is or contains mannitol.

[0026] In one embodiment, the pharmaceutically acceptable diluent comprises one or more selected from water, solubilizers, and buffers.

[0027] In one implementation, the pharmaceutically acceptable diluent comprises water.

[0028] In one embodiment, the pharmaceutically acceptable diluent contains a solubilizer.

[0029] In one implementation, the pharmaceutically acceptable diluent contains a buffer.

[0030] In one embodiment, the volume of the diluent is 5-20 mL.

[0031] In one embodiment, the metotrazol lyophilized composition contains 0.2-1.75 mg of tert-butanol.

[0032] In one embodiment, the metoprazine lyophilized kit further includes a connector for holding the first and second containers together.

[0033] In one embodiment, the diluent (i.e., a pharmaceutically acceptable diluent) further comprises 2-4% w / v macrogol-15-hydroxystearate.

[0034] In one embodiment, the metotrazoline lyophilized composition comprises:

[0035] i. 2.5-20 mg metoprazine; and,

[0036] ii. 2.5-1000 mg mannitol; and,

[0037] The diluent comprises:

[0038] i. 25-45% w / v polyethylene glycol 400;

[0039] ii. TRIS buffer or phosphate buffer; and,

[0040] iii. The rest is water;

[0041] The pH of the diluent is 7-8.

[0042] Preferably, the metotrazoline lyophilized composition comprises:

[0043] i. 2.5-10 mg metoprazine; and,

[0044] ii. 25-500 mg mannitol; and,

[0045] The diluent comprises:

[0046] i. 30-40% w / v polyethylene glycol 400;

[0047] ii. TRIS buffer or phosphate buffer; and,

[0048] iii. The rest is water;

[0049] The pH of the diluent is 7.5.

[0050] In another aspect, a process for reconstructing metoprazine lyophilized compositions is described, the process comprising:

[0051] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0052] Contact the metoprazine lyophilized composition with a pharmaceutically acceptable diluent; and,

[0053] Mix the resulting solution until it becomes clear;

[0054] The resulting clear solution is suitable for non-gastrointestinal administration, and the diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of about 5.0-8.0 for non-gastrointestinal administration.

[0055] Ideally, a clear solution should be obtained in less than 5 minutes.

[0056] On the other hand, a clear, reconstituted metoprazor solution is described for natriuretic and / or diuretic therapy in patients in need, the treatment comprising:

[0057] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0058] The metoprazine lyophilized composition is contacted with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of approximately 5.0-8.0 for non-gastrointestinal administration.

[0059] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0060] Administer a therapeutically effective amount of clear, reconstituted metoprazine solution to patients requiring natriuretic and / or diuretic therapy.

[0061] On the other hand, a clear, reconstituted metoprazan solution is described for furosemide-tolerant treatment in patients in need, the treatment comprising:

[0062] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0063] The metoprazine lyophilized composition is contacted with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of approximately 5.0-8.0 for non-gastrointestinal administration.

[0064] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0065] Administer a therapeutically effective amount of clear, reconstituted metoprazan solution to patients requiring furosemide-tolerant treatment.

[0066] On the other hand, a liquid metoprazine pre-lyophilized composition is described, comprising:

[0067] a. Metola Dzong;

[0068] b. Filler;

[0069] c. alcohols; and,

[0070] d. Water;

[0071] The liquid metoprazine pre-lyophilized composition is lyophilized into a lyophilized powder after being lyophilized.

[0072] Preferred alcohol is tert-butanol.

[0073] In one embodiment, the filler is selected from mannitol, lactose, dextrose, sucrose, and hydroxypropyl- -Cyclodextrin.

[0074] In one embodiment, the metotrazine pre-lyophilized composition comprises:

[0075] a. 0.1-2 mg / ml metoprazor;

[0076] b. 1-50 mg / mL mannitol;

[0077] c. 30-70% v / v tert-butanol; and,

[0078] d. The rest is water.

[0079] In one embodiment, the metotrazine pre-lyophilized composition comprises:

[0080] a. 0.1-1.5 mg / ml metoprazor;

[0081] b. 2.5-60 mg / mL mannitol;

[0082] c. 30-70 vol% tert-butanol; and,

[0083] d. The rest is water.

[0084] For example, any embodiment of the metolazoline pre-lyophilized composition contains

[0085] a. 0.1-1 mg / ml metoprazor;

[0086] b. 5-10 mg / mL mannitol;

[0087] c. 40-60 vol% tert-butanol; and,

[0088] d. The rest is water.

[0089] For example, any of the metoprazan pre-lyophilized compositions further comprises 1-15 mg / mL polyethylene glycol-15-hydroxystearate.

[0090] On the other hand, a metoprazan lyophilized composition is described, comprising:

[0091] a. Methoradzong; and,

[0092] b. Filler;

[0093] The metotrazoline lyophilized composition is in the form of a lyophilized powder.

[0094] Preferably, the metoprazine lyophilized composition can be obtained by lyophilization from the liquid metoprazine pre-lyophilized composition as defined above.

[0095] More preferably, the metotrazoline lyophilized composition contains 0.2-1.75 mg of tert-butanol.

[0096] These and other aspects will become clear in the following detailed description, which has been achieved by the inventors through the discovery of novel metoprazine lyophilized compositions. Attached Figure Description

[0097] Figure 1 The content of tert-butanol (TBA) (mg / vial) is shown based on the mannitol concentration (mg / mL).

[0098] Figure 2 The level (%) of impurity B is shown versus the concentration (mg / mL) of mannitol.

[0099] Figure 3 The level (%) of impurity B is shown versus the residual TBA concentration (mg / vial).

[0100] Figure 4 The solubility of metoprazine (mg / mL) is shown as the TBA fraction (%) in the solvent. Detailed Implementation

[0101] This document describes exemplary aspects of the invention. Although the following detailed description contains numerous details for illustrative purposes, those skilled in the art will understand that variations and modifications to these details are within the scope of the invention. Therefore, the following aspects of the invention are set forth without losing the generality of the claimed invention and without imposing limitations on it.

[0102] Metotrazoline lyophilized composition

[0103] One aspect of the present invention relates to a novel lyophilized metoprazine composition comprising:

[0104] a. Methoradzong; and,

[0105] b. Filler;

[0106] The metotrazoline lyophilized composition is in the form of a lyophilized powder.

[0107] In some respects, the storage stability of metoprazine lyophilized powder, measured at 40°C and / or 75% relative humidity, is at least 3 months. Storage stability is achieved if all known and unknown impurities are less than 0.5% w / w. Another example is less than 0.2% w / w.

[0108] In some cases, the metotrazine lyophilized powder is reconstituted in a diluent to form a clear solution in less than about 5 minutes. Other examples include less than about 4, 3, and / or 2 minutes.

[0109] In some cases, approximately 2.5–20 mg of metoprazine is present in the lyophilized product. Other examples of the amount of metoprazine present include approximately 2.5–10 mg. Further examples include approximately 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 to / and approximately 20 mg.

[0110] In some respects, metoprazan is micronized. Examples of micronized metoprazan include D90, which is less than 10 micrometers. D90 means that 90% of the samples have a particle diameter of <10 micrometers. Particle size is measured using a Malvern mastersizer.

[0111] In some aspects, the filler is selected from mannitol, lactose, dextrose, sucrose, and cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin). Examples of filler amounts present in the lyophilized composition include about 2.5-1000 mg, about 25-500 mg, about 25-150 mg, about 50-150 mg, about 2.5-60 mg, about 25-55 mg, and about 35-45 mg. Other examples include approximately 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 to / and about 1000 mg.

[0112] In some respects, the lyophilized composition contains less than about 3500 ppm of tert-butanol. Other examples include less than about 3000, 2500 to / and about 2000 ppm.

[0113] In some respects, the lyophilized composition contains 0.2-1.75 mg of tert-butanol. Other examples include 0.2-1.6, 0.2-1.5, 0.2-1.4, 0.2-1.3, 0.2-1.2, 0.2-1.1, 0.2-1.0, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.2-0.6 to / and 0.2-0.5 mg of tert-butanol.

[0114] In some respects, the amount of filler present (e.g., mannitol) is sufficient to ensure that the residual tert-butanol (TBA) level (the amount of TBA remaining after lyophilization) is less than about 1.75 mg / vial. Other examples of residual TBA remaining after lyophilization include less than about 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 to / and about 0.2 mg / vial.

[0115] On the other hand, the lyophilized composition comprises:

[0116] a. Approximately 2.5-20 mg of metoprazine; and,

[0117] b. Approximately 2.5-1000 mg of filler, said filler being selected from mannitol, lactose, dextrose, sucrose and hydroxypropyl-□-cyclodextrin.

[0118] On the other hand, the lyophilized composition comprises:

[0119] a. Approximately 2.5-10 mg of metoprazine; and,

[0120] b. Approximately 2.5-500 mg of mannitol.

[0121] On the other hand, the lyophilized composition comprises:

[0122] a. Approximately 2.5-10 mg of metoprazine; and,

[0123] b. Approximately 2.5-50 mg of mannitol.

[0124] On the other hand, the lyophilized composition comprises:

[0125] a. Approximately 2.5-10 mg of metoprazine; and,

[0126] b. Approximately 5-15 mg of mannitol.

[0127] On the other hand, the lyophilized composition comprises:

[0128] a. Approximately 2.5-10 mg of metoprazine; and,

[0129] b. Approximately 2.5-10 mg of mannitol.

[0130] On the other hand, the lyophilized composition comprises:

[0131] a. Approximately 5 mg of metoprazine; and,

[0132] b. Approximately 25-55 mg of mannitol.

[0133] On the other hand, the lyophilized composition comprises:

[0134] a. Approximately 5 mg of metoprazine; and,

[0135] b. Approximately 50 mg of mannitol.

[0136] On the other hand, the lyophilized composition comprises:

[0137] a. Approximately 5 mg of metoprazine; and,

[0138] b. Approximately 100 mg of mannitol.

[0139] On the other hand, the lyophilized composition comprises:

[0140] a. Approximately 5 mg of metoprazine; and,

[0141] b. Approximately 150 mg of mannitol.

[0142] On the other hand, the lyophilized composition comprises:

[0143] a. Approximately 10 mg of metoprazine; and,

[0144] b. Approximately 50-150 mg of mannitol.

[0145] On the other hand, the lyophilized composition comprises:

[0146] a. Approximately 10 mg of metoprazine; and,

[0147] b. Approximately 50 mg of mannitol.

[0148] On the other hand, the lyophilized composition comprises:

[0149] a. Approximately 10 mg of metoprazine; and,

[0150] b. Approximately 100 mg of mannitol.

[0151] On the other hand, the lyophilized composition comprises:

[0152] a. Approximately 10 mg of metoprazine; and,

[0153] b. Approximately 150 mg of mannitol.

[0154] In another aspect, the present invention relates to lyophilized compositions, wherein the compositions are contained in a container.

[0155] Examples of containers include vials (e.g., clear or colored (e.g., amber)) (e.g., glass or plastic) and multi-chamber syringe presentations, in which the lyophilized material and the diluent are part of the same syringe (but in different chambers).

[0156] In another aspect, the present invention relates to lyophilized compositions wherein the container is an amber-colored vial.

[0157] In another aspect, the present invention relates to lyophilized compositions, wherein the container is a syringe.

[0158] Pre-lyophilized composition

[0159] In another aspect, the present invention relates to a liquid metoprazine pre-lyophilized composition comprising:

[0160] a. Metola Dzong;

[0161] b. Filler;

[0162] c. alcohols; and,

[0163] d. Water;

[0164] The liquid metoprazine pre-lyophilized composition is lyophilized into a lyophilized powder after being lyophilized.

[0165] In some respects, the water (e.g., in the pre-lyophilized composition and in the diluent) is typically water suitable for injection (water for injection or WFI). In some respects, if WFI is not used (e.g., in the diluent described herein), the water is typically treated (e.g., sterilized) in a manner that makes the water (or the resulting composition) suitable for injection.

[0166] As described herein, alcohol and water are removed during lyophilization to leave the lyophilized product or freeze-dried powder. The lyophilized product is stable (as described herein) and can be reconstituted in a diluent to provide a clear solution suitable for intravenous administration of metoprazine.

[0167] In some aspects, the amount of metoprazine present in the metoprazine pre-lyophilized compositions is about 0.1-2 mg / mL, about 0.1-1.5 mg / mL, and about 0.1-1 mg / mL. Other examples include about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 to / and about 2 mg / mL.

[0168] In some respects, the filler is selected from mannitol, lactose, dextrose, sucrose, and cyclodextrin (e.g., hydroxypropyl-β-cyclodextrin). Examples of filler amounts present in the lyophilized composition include about 2.5-500 mg, about 25-150 mg, about 50-150 mg, about 2.5-60 mg, about 25-55 mg, and about 35-45 mg. Other examples include approximately 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 to / and approximately 150 mg.

[0169] In some aspects, the alcohol in the metotrazol pre-lyophilized composition is tert-butanol (TBA). Examples of the amount of TBA present include about 30-70% v / v (volume / volume or by volume), about 30-70% v / v, and about 40-60% v / v. Other examples include about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 to / and about 70% v / v.

[0170] In another aspect, the present invention relates to a liquid metoprazine pre-lyophilized composition comprising:

[0171] a. Metola Dzong;

[0172] b. Selected from mannitol, lactose, dextrose, sucrose, and hydroxypropyl- - Cyclodextrin as a filler;

[0173] c. tert-butanol; and,

[0174] d. Water.

[0175] In another aspect, the present invention relates to a liquid metoprazine pre-lyophilized composition comprising:

[0176] a. Metola Dzong;

[0177] b. Mannitol;

[0178] c. tert-butanol; and,

[0179] d. Water.

[0180] On the other hand, the pre-lyophilized composition comprises:

[0181] a. Approximately 0.1-2 mg / ml of metoprazine;

[0182] b. Approximately 1-50 mg / mL mannitol;

[0183] c. Approximately 30-70% v / v tert-butanol; and,

[0184] d. The rest is water.

[0185] On the other hand, the pre-lyophilized composition comprises:

[0186] a. Approximately 0.1-1.5 mg / ml metoprazine;

[0187] b. Approximately 2.5-60 mg / mL mannitol;

[0188] c. Approximately 30-70 vol% tert-butanol; and,

[0189] d. The rest is water.

[0190] On the other hand, the pre-lyophilized composition comprises:

[0191] a. Approximately 0.1-1 mg / ml metoprazine;

[0192] b. Approximately 5-10 mg / mL mannitol;

[0193] c. Approximately 40-60 vol% tert-butanol; and,

[0194] d. The rest is water.

[0195] On the other hand, the pre-lyophilized composition comprises:

[0196] a. Approximately 0.1-1 mg / ml metoprazine;

[0197] b. Approximately 5-10 mg / mL mannitol;

[0198] c. Approximately 50% by volume tert-butanol; and,

[0199] d. The rest is water.

[0200] On the other hand, the pre-lyophilized composition comprises:

[0201] a. Approximately 1 mg / ml of metoprazor;

[0202] b. Approximately 5 mg / mL mannitol;

[0203] c. Approximately 50% by volume tert-butanol; and,

[0204] d. The rest is water.

[0205] On the other hand, the pre-lyophilized composition comprises:

[0206] a. Approximately 1 mg / ml of metoprazor;

[0207] b. Approximately 10 mg / mL mannitol;

[0208] c. Approximately 50% by volume tert-butanol; and,

[0209] d. The rest is water.

[0210] On the other hand, the pre-lyophilized composition comprises:

[0211] a. Approximately 0.5 mg / ml metoprazine;

[0212] b. Approximately 5 mg / mL mannitol;

[0213] c. Approximately 50% by volume tert-butanol; and,

[0214] d. The rest is water.

[0215] On the other hand, the pre-lyophilized composition comprises:

[0216] a. Approximately 0.5 mg / ml metoprazine;

[0217] b. Approximately 10 mg / mL mannitol;

[0218] c. Approximately 50% by volume tert-butanol; and,

[0219] d. The rest is water.

[0220] In some cases, the ratio (volume:volume) of tert-butanol (TBA) to water is at most about 60% TBA and at least about 40% water. Other examples of TBA:water ratios include 50:50 and 35:65.

[0221] On the other hand, the pre-lyophilized composition further comprises:

[0222] Nonionic solubilizer.

[0223] In some respects, the nonionic solubilizer is polyethylene glycol-15-hydroxystearate.

[0224] Polyethylene glycol-15-hydroxystearate is also known as polyethylene glycol 660 12-hydroxystearate and polyoxyethylated 12-hydroxystearate, and is traded under the name Kolliphor. HS 15.

[0225] Examples of amounts of polyethylene glycol-15-hydroxystearate present in the pre-lyophilized composition include about 1-15 mg / mL, about 1-10 mg / mL, and about 1-4 mg / mL. Other examples include about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 to / and about 15 mg / mL.

[0226] On the other hand, the pre-lyophilized composition further comprises:

[0227] Approximately 1-15 mg / mL of polyethylene glycol-15-hydroxystearate.

[0228] In some aspects, the present invention relates to a method for preparing a metoprazine lyophilized composition, comprising the step of lyophilizing the metoprazine pre-lyophilized composition described herein to form the lyophilized composition described herein.

[0229] In some respects, dimethylacetamide (DMAC) is absent from metoprazine pre-lyophilized compositions, metoprazine lyophilized compositions, and / or final pharmaceutical products (after reconstitution of the metoprazine lyophilized composition).

[0230] In another aspect, the present invention provides a metoprazine lyophilized composition which can be obtained by lyophilization of a liquid metoprazine pre-lyophilized composition according to any embodiment of the present invention.

[0231] In some respects, the obtained metoprazan lyophilized compositions contain 0.2-1.75, 0.2-1.6, 0.2-1.5, 0.2-1.4, 0.2-1.3, 0.2-1.2, 0.2-1.1, 0.2-1.0, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.2-0.6 to / and 0.2-0.5 mg of tert-butanol.

[0232] Pharmaceutically acceptable diluent

[0233] In another aspect, the present invention relates to a pharmaceutically acceptable diluent comprising:

[0234] a. Solubilizer;

[0235] b. Buffer; and,

[0236] c. Water;

[0237] The pH of the diluted solution is approximately 6-8.

[0238] In some cases, a diluent is prepared by first preparing a buffer (e.g., a TRIS buffer or a phosphate buffer) and adjusting the pH (e.g., by adding an acid or base) to the desired pH (e.g., pH 7.5). A solubilizer is then mixed into the buffer.

[0239] In some cases, the diluent is filtered and sterilized once it is formed. For example, the diluent can be aseptically filtered through a 0.2-micron filter and filled into a container (e.g., a glass vial). The container can then be sterilized at 121°C for 30 minutes.

[0240] In some respects, the pH of the diluent is approximately 6, 6.5, 7, 7.5 to / and 8.0.

[0241] In some cases, the solubilizer is polyethylene glycol 400 (PEG-400). Examples of amounts of PEG-400 include about 5-70% w / v (weight to volume), about 10-50% w / v, about 25-45% w / v, and about 30-40% w / v. Other examples of amounts of polyethylene glycol 400 include about 5, 10, 15, 120, 25, 30, 35, 40, 45, 50, 55, 60, 65, and / or 70% w / v.

[0242] In some respects, the buffer is a TRIS (tris(hydroxymethyl)aminomethane) or phosphate buffer. Examples of buffer amounts include about 0.1-100 mM (millimoles). Other examples of buffer amounts present include about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 to / and 100 mM.

[0243] On the other hand, the diluent comprises:

[0244] a. Approximately 10-40% w / v of polyethylene glycol 400;

[0245] b. TRIS buffer or phosphate buffer; and,

[0246] c. The rest is water;

[0247] The pH of the diluted solution is approximately 7-8.

[0248] On the other hand, the diluent comprises:

[0249] a. Approximately 25-45% w / v of polyethylene glycol 400;

[0250] b. TRIS buffer or phosphate buffer; and,

[0251] c. The rest is water;

[0252] The pH of the diluted solution is approximately 7-8.

[0253] On the other hand, the diluent comprises:

[0254] a. Approximately 30-40% w / v of polyethylene glycol 400;

[0255] b. TRIS buffer or phosphate buffer; and,

[0256] c. The rest is water;

[0257] The pH of the diluted solution is approximately 7.5.

[0258] On the other hand, the diluent comprises:

[0259] a. Approximately 40% w / v of polyethylene glycol 400;

[0260] b. TRIS buffer; and,

[0261] c. The rest is water;

[0262] The pH of the diluted solution is approximately 7.5.

[0263] On the other hand, the diluent comprises:

[0264] a. 40% w / v polyethylene glycol 400;

[0265] b. Phosphate buffers; and,

[0266] c. The rest is water;

[0267] The pH of the diluted solution is approximately 7.5.

[0268] In some respects, the weight ratio (weight:weight) of the solubilizer to the drug is about 25-2000. Other examples include a PEG-400:metoprazine weight ratio of about 25-2000. These weight ratios can be before reconstitution (e.g., the ratio is for the solubilized (e.g., PEG-400) to metoprazine in the lyophilized composition) or after reconstitution.

[0269] On the other hand, the diluent further comprises:

[0270] Nonionic solubilizer.

[0271] In some respects, the nonionic solubilizer in the diluent is polyethylene glycol-15-hydroxystearate. Examples of amounts of polyethylene glycol-15-hydroxystearate present in the diluent include about 1-5% w / v (weight:volume) and about 2-4% w / v. Other examples include about 1, 1.5, 2, 2.5, 3, 3.5, to / and about 4% w / v.

[0272] On the other hand, the diluent further comprises:

[0273] Approximately 1-5% w / v of polyethylene glycol-15-hydroxystearate.

[0274] On the other hand, the diluent further comprises:

[0275] Approximately 2-4% w / v of polyethylene glycol-15-hydroxystearate.

[0276] Intravenous metoprazan reagent kit

[0277] In another aspect, the present invention relates to an intravenous nemetazone kit comprising:

[0278] a. A first container comprising: the metoprazine lyophilized composition described herein; and...

[0279] b. A second container containing: the pharmaceutically acceptable diluent as described herein.

[0280] The diluent is suitable for recombinating the lyophilized composition into a metoprazine solution with a pH of about 5.0-8.0 suitable for non-gastrointestinal administration.

[0281] In another aspect, the present invention relates to a kit for intravenous metoprazine lyophilized products, comprising:

[0282] a. A first container comprising: a lyophilized metoprazine composition in the form of a lyophilized powder, said lyophilized metoprazine composition comprising:

[0283] i. Methoradzon; and,

[0284] b. A second container containing: a pharmaceutically acceptable diluent,

[0285] The diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of about 5.0-8.0 for non-gastrointestinal administration.

[0286] In another aspect, the lyophilized metoprazine composition in the lyophilized powder form of the kit includes a filler. In another aspect, the filler is selected from mannitol, lactose, dextrose, sucrose, and hydroxypropyl-β-cyclodextrin. Preferably, the filler is mannitol.

[0287] In another aspect, a pharmaceutically acceptable diluent for the kit contains water. In another aspect, a pharmaceutically acceptable diluent for the kit contains a solubilizer. In another aspect, a pharmaceutically acceptable diluent for the kit contains a buffer.

[0288] On the other hand, the kit further includes a connector for holding the first and second containers. The connector serves as an aid in the reconfiguration of the IV product. In some aspects, the connector is permanently attached to the first and second containers (e.g., the containers are directly attached to each other or attached via spacers). In other aspects, the connector can be attached to the containers when product reconfiguration is required (e.g., placing the containers into a holder).

[0289] In another aspect, the present invention relates to a metoprazine lyophilized reagent kit comprising:

[0290] a. A first container comprising: a lyophilized metoprazine composition in the form of a lyophilized powder, said lyophilized metoprazine composition comprising:

[0291] i. Methoradzon; and,

[0292] ii. filler; and,

[0293] b. A second container comprising: a pharmaceutically acceptable diluent, said diluent comprising:

[0294] i. Solubilizer;

[0295] ii. buffer; and,

[0296] iii. Water;

[0297] The diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of about 5.0-8.0 for non-gastrointestinal administration.

[0298] In some respects, examples of pharmaceutical products with pH remodeling include approximately 5.0, 5.5, 6, 6.5, 7, 7.5 to / and 8.0.

[0299] On the other hand, the diluent further comprises:

[0300] Nonionic solubilizer.

[0301] In some aspects, the nonionic solubilizer in the diluent is polyethylene glycol-15-hydroxystearate. Examples of the amount of polyethylene glycol-15-hydroxystearate present in the diluent include about 1-5% w / v (weight:volume) and about 2-4% w / v. Other examples include about 1, 1.5, 2, 2.5, 3, 3.5, to / and about 4% w / v.

[0302] On the other hand, the diluent further comprises:

[0303] Approximately 1-5% w / v of polyethylene glycol-15-hydroxystearate.

[0304] On the other hand, the diluent further comprises:

[0305] Approximately 2-4% w / v of polyethylene glycol-15-hydroxystearate.

[0306] In some aspects, the metotrazol lyophilized compositions contain less than about 10,000 ppm, 5,000 ppm, or 3,500 ppm of tert-butanol. Other examples include less than about 3,000, 2,500, and / or about 2,000 ppm.

[0307] In some respects, the metoprazan lyophilized composition contains 0.2-1.75 mg of tert-butanol. Other examples include 0.2-1.6, 0.2-1.5, 0.2-1.4, 0.2-1.3, 0.2-1.2, 0.2-1.1, 0.2-1.0, 0.2-0.9, 0.2-0.8, 0.2-0.7, 0.2-0.6 to / and 0.2-0.5 mg of tert-butanol.

[0308] On the other hand, in the Metotrazine lyophilized reagent kit:

[0309] The metotrazoline lyophilized composition comprises:

[0310] i. Approximately 2.5-20 mg of metoprazine; and,

[0311] ii. Approximately 2.5-1000 mg of mannitol; and,

[0312] The diluent comprises:

[0313] i. Approximately 25-45% w / v of polyethylene glycol 400;

[0314] ii. TRIS buffer or phosphate buffer; and,

[0315] iii. The rest is water;

[0316] The pH of the diluted solution is approximately 7-8.

[0317] On the other hand, in the Metotrazine lyophilized reagent kit:

[0318] The metotrazoline lyophilized composition comprises:

[0319] i. Approximately 2.5-10 mg of metoprazine; and,

[0320] ii. Approximately 25-500 mg of mannitol;

[0321] The diluent comprises:

[0322] i. Approximately 30-40% w / v of polyethylene glycol 400;

[0323] ii. TRIS buffer or phosphate buffer; and,

[0324] iii. The rest is water;

[0325] The pH of the diluted solution is approximately 7.5.

[0326] On the other hand, in the Metotrazine lyophilized reagent kit:

[0327] The metotrazoline lyophilized composition comprises:

[0328] i. Approximately 5 mg of metoprazine; and,

[0329] ii. Approximately 50-150 mg of mannitol;

[0330] The diluent comprises:

[0331] i. Approximately 40% w / v of polyethylene glycol 400;

[0332] ii. TRIS buffer; and,

[0333] iii. The rest is water;

[0334] The pH of the diluted solution is approximately 7.5.

[0335] On the other hand, in the Metotrazine lyophilized reagent kit:

[0336] The metotrazoline lyophilized composition comprises:

[0337] i. Approximately 5 mg of metoprazine; and,

[0338] ii. Approximately 50 mg of mannitol;

[0339] The diluent comprises:

[0340] i. Approximately 40% w / v of polyethylene glycol 400;

[0341] ii. TRIS buffer; and,

[0342] iii. The rest is water;

[0343] The pH of the diluted solution is approximately 7.5.

[0344] On the other hand, in the Metotrazine lyophilized reagent kit:

[0345] The metotrazoline lyophilized composition comprises:

[0346] i. Approximately 5 mg of metoprazine; and,

[0347] ii. Approximately 100 mg of mannitol;

[0348] The diluent comprises:

[0349] i. Approximately 40% w / v of polyethylene glycol 400;

[0350] ii. TRIS buffer; and,

[0351] iii. The rest is water;

[0352] The pH of the diluted solution is approximately 7.5.

[0353] On the other hand, in the Metotrazine lyophilized reagent kit:

[0354] The metotrazoline lyophilized composition comprises:

[0355] i. Approximately 5 mg of metoprazine; and,

[0356] ii. Approximately 150 mg of mannitol;

[0357] The diluent comprises:

[0358] i. Approximately 40% w / v of polyethylene glycol 400;

[0359] ii. TRIS buffer; and,

[0360] iii. The rest is water;

[0361] The pH of the diluted solution is approximately 7.5.

[0362] On the other hand, in the Metotrazine lyophilized reagent kit:

[0363] The metotrazoline lyophilized composition comprises:

[0364] i. Approximately 10 mg of metoprazine; and,

[0365] ii. Approximately 50-150 mg of mannitol;

[0366] The diluent comprises:

[0367] i. Approximately 40% w / v of polyethylene glycol 400;

[0368] ii. TRIS buffer; and,

[0369] iii. The rest is water;

[0370] The pH of the diluted solution is approximately 7.5.

[0371] On the other hand, in the Metotrazine lyophilized reagent kit:

[0372] The metotrazoline lyophilized composition comprises:

[0373] i. Approximately 10 mg of metoprazine; and,

[0374] ii. Approximately 50 mg of mannitol;

[0375] The diluent comprises:

[0376] i. Approximately 40% w / v of polyethylene glycol 400;

[0377] ii. TRIS buffer; and,

[0378] iii. The rest is water;

[0379] The pH of the diluted solution is approximately 7.5.

[0380] On the other hand, in the Metotrazine lyophilized reagent kit:

[0381] The metotrazoline lyophilized composition comprises:

[0382] i. Approximately 10 mg of metoprazine; and,

[0383] ii. Approximately 100 mg of mannitol;

[0384] The diluent comprises:

[0385] i. Approximately 40% w / v of polyethylene glycol 400;

[0386] ii. TRIS buffer; and,

[0387] iii. The rest is water;

[0388] The pH of the diluted solution is approximately 7.5.

[0389] On the other hand, in the Metotrazine lyophilized reagent kit:

[0390] The metotrazoline lyophilized composition comprises:

[0391] i. Approximately 10 mg of metoprazine; and,

[0392] ii. Approximately 150 mg of mannitol;

[0393] The diluent comprises:

[0394] i. Approximately 40% w / v of polyethylene glycol 400;

[0395] ii. TRIS buffer; and,

[0396] iii. The rest is water;

[0397] The pH of the diluted solution is approximately 7.5.

[0398] On the other hand, in the Metotrazine lyophilized reagent kit:

[0399] The metotrazoline lyophilized composition comprises:

[0400] i. Approximately 5 mg of metoprazine; and,

[0401] ii. Approximately 50-150 mg of mannitol;

[0402] The diluent comprises:

[0403] i. Approximately 40% w / v of polyethylene glycol 400;

[0404] ii. Phosphate buffers; and,

[0405] iii. The rest is water;

[0406] The pH of the diluted solution is approximately 7.5.

[0407] On the other hand, in the Metotrazine lyophilized reagent kit:

[0408] The metotrazoline lyophilized composition comprises:

[0409] i. Approximately 5 mg of metoprazine; and,

[0410] ii. Approximately 50 mg of mannitol;

[0411] The diluent comprises:

[0412] i. Approximately 40% w / v of polyethylene glycol 400;

[0413] ii. Phosphate buffers; and,

[0414] iii. The rest is water;

[0415] The pH of the diluted solution is approximately 7.5.

[0416] On the other hand, in the Metotrazine lyophilized reagent kit:

[0417] The metotrazoline lyophilized composition comprises:

[0418] i. Approximately 5 mg of metoprazine; and,

[0419] ii. Approximately 100 mg of mannitol;

[0420] The diluent comprises:

[0421] i. Approximately 40% w / v of polyethylene glycol 400;

[0422] ii. Phosphate buffers; and,

[0423] iii. The rest is water;

[0424] The pH of the diluted solution is approximately 7.5.

[0425] On the other hand, in the Metotrazine lyophilized reagent kit:

[0426] The metotrazoline lyophilized composition comprises:

[0427] i. Approximately 5 mg of metoprazine; and,

[0428] ii. Approximately 150 mg of mannitol;

[0429] The diluent comprises:

[0430] i. Approximately 40% w / v of polyethylene glycol 400;

[0431] ii. Phosphate buffers; and,

[0432] iii. The rest is water;

[0433] The pH of the diluted solution is approximately 7.5.

[0434] On the other hand, in the Metotrazine lyophilized reagent kit:

[0435] The metotrazoline lyophilized composition comprises:

[0436] i. Approximately 10 mg of metoprazine; and,

[0437] ii. Approximately 50-150 mg of mannitol;

[0438] The diluent comprises:

[0439] i. Approximately 40% w / v of polyethylene glycol 400;

[0440] ii. Phosphate buffers; and,

[0441] iii. The rest is water;

[0442] The pH of the diluted solution is approximately 7.5.

[0443] On the other hand, in the Metotrazine lyophilized reagent kit:

[0444] The metotrazoline lyophilized composition comprises:

[0445] i. Approximately 10 mg of metoprazine; and,

[0446] ii. Approximately 50 mg of mannitol;

[0447] The diluent comprises:

[0448] i. Approximately 40% w / v of polyethylene glycol 400;

[0449] ii. Phosphate buffers; and,

[0450] iii. The rest is water;

[0451] The pH of the diluted solution is approximately 7.5.

[0452] On the other hand, in the Metotrazine lyophilized reagent kit:

[0453] The metotrazoline lyophilized composition comprises:

[0454] i. Approximately 10 mg of metoprazine; and,

[0455] ii. Approximately 100 mg of mannitol;

[0456] The diluent comprises:

[0457] i. Approximately 40% w / v of polyethylene glycol 400;

[0458] ii. Phosphate buffers; and,

[0459] iii. The rest is water;

[0460] The pH of the diluted solution is approximately 7.5.

[0461] On the other hand, in the Metotrazine lyophilized reagent kit:

[0462] The metotrazoline lyophilized composition comprises:

[0463] i. Approximately 10 mg of metoprazine; and,

[0464] ii. Approximately 150 mg of mannitol;

[0465] The diluent comprises:

[0466] i. Approximately 40% w / v of polyethylene glycol 400;

[0467] ii. Phosphate buffers; and,

[0468] iii. The rest is water;

[0469] The pH of the diluted solution is approximately 7.5.

[0470] In some cases, the volume of the diluent is about 5-20 mL, about 5-10 mL, and about 10-20 mL. Other examples of the volume of the diluent include about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 to / and about 15 mL.

[0471] In some respects, the ratio (volume:weight) of the diluent to metoprazine in the kit is approximately 1-20.

[0472] Reconstructed metoprazine solution

[0473] In another aspect, the present invention relates to a process for reconstructing metoprazine lyophilized compositions, the process comprising:

[0474] Contact the metoprazine lyophilized composition described herein with the pharmaceutically acceptable diluent described herein; and,

[0475] Mix the resulting solution until it becomes clear;

[0476] The resulting clear solution is suitable for administration outside the digestive tract.

[0477] In another aspect, the present invention relates to a process for reconstructing metoprazine lyophilized compositions, the process comprising:

[0478] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0479] Contact the metoprazine lyophilized composition with a pharmaceutically acceptable diluent; and,

[0480] Mix the resulting solution until it becomes clear;

[0481] The resulting clear solution is suitable for non-digestive tract administration, and

[0482] The diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of about 5.0-8.0 for non-gastrointestinal administration.

[0483] On the other hand, in the remodeling process, a clear solution is obtained in less than about 5 minutes. "Clear" means free of visible particulate matter. Other examples of times to obtain a clear solution include less than about 4, 3, and / or 2 minutes.

[0484] In some respects, the ratio (volume:weight) of the diluent to metoprazine in the reconstituted metoprazine solution is approximately 1-20.

[0485] Ready-to-use and applications of reconstituted metoprazine solution

[0486] In another aspect, the present invention relates to a ready-to-use injectable metolarine formulation for non-gastrointestinal administration, which is obtained by mixing the metolarine lyophilized composition described herein with a pharmaceutically acceptable diluent described herein, wherein the resulting ready-to-use injectable metolarine formulation has a pH of about 5-8.

[0487] For example, ready-to-use injectable metoprazine formulations for non-gastrointestinal administration are obtained by mixing the following substances:

[0488] Metoprazine lyophilized composition comprising:

[0489] i. Approximately 2.5-20 mg of metoprazine; and,

[0490] ii. Approximately 2.5-1000 mg of mannitol; and,

[0491] With approximately 5-15 mL of diluent, said diluent contains

[0492] i. Approximately 25-45% w / v of polyethylene glycol 400;

[0493] ii. TRIS buffer or phosphate buffer; and,

[0494] iii. The rest is water;

[0495] The pH of the diluted solution is approximately 7-8.

[0496] In another example, the diluent in the ready-to-use formulation further comprises:

[0497] Approximately 2-4% w / v of polyethylene glycol-15-hydroxystearate.

[0498] In another aspect, the present invention relates to a method for treating patients requiring natriuretic and / or diuretic therapy, comprising:

[0499] Contact the metoprazine lyophilized composition described herein with the pharmaceutically acceptable diluent described herein; and,

[0500] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0501] Administer a therapeutically effective dose of reconstituted metoprazine to patients requiring natriuretic and / or diuretic therapy.

[0502] In another aspect, the present invention relates to a method for treating patients with furosemide tolerance, comprising:

[0503] Contact the metoprazine lyophilized composition described herein with the pharmaceutically acceptable diluent described herein;

[0504] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0505] Administer a therapeutically effective amount of clear, reconstituted metoprazan solution to patients requiring furosemide-tolerant treatment.

[0506] In another aspect, the present invention relates to a clear, reconstituted metoprazor solution for natriuretic and / or diuretic therapy in patients in need, said therapy comprising:

[0507] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0508] The metoprazine lyophilized composition is contacted with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of approximately 5.0-8.0 for non-gastrointestinal administration.

[0509] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0510] Administer a therapeutically effective amount of clear, reconstituted metoprazine solution to patients requiring natriuretic and / or diuretic therapy.

[0511] In another aspect, the present invention relates to a clear, reconstituted metoprazan solution for furosemide-tolerant treatment in patients in need, said treatment comprising:

[0512] Provides a lyophilized composition of metoprazine in the form of a lyophilized powder.

[0513] The metoprazine lyophilized composition is contacted with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituted the lyophilized composition into a pharmaceutical product with a pH of approximately 5.0-8.0 for non-gastrointestinal administration.

[0514] Mix the resulting solutions until a clear, reconstituted metotrazine solution is obtained;

[0515] Administer a therapeutically effective amount of clear, reconstituted metoprazan solution to patients requiring furosemide-tolerant treatment.

[0516] On the other hand, a therapeutically effective dose of reconstituted metoprazine contains approximately 2.5–20 mg of metoprazine. Other examples of therapeutically effective doses of metoprazine include approximately 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 to / and approximately 20 mg.

[0517] On the other hand, patients requiring natriuretic and / or diuretic therapy suffer from congestive heart failure or kidney disease.

[0518] On the other hand, the patient suffers from loop diuretic resistance.

[0519] On the other hand, the patient had furosemide tolerance.

[0520] On the other hand, the patient suffers from hypertension.

[0521] The invention may be implemented in other specific forms without departing from the spirit or essential attributes of the invention. The invention encompasses all combinations of the aspects of the invention described herein. It should be understood that any and all embodiments of the invention may be combined with any other one or more embodiments to describe further embodiments. It should also be understood that each individual element of an embodiment is intended to be considered independently as its own. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

[0522] definition

[0523] Unless otherwise stated, the instances provided in the definitions herein are not exclusive. They include, but are not limited to, the listed instances.

[0524] When describing elements or aspects of this disclosure, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more of the stated elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and mean that additional elements besides those listed may be present.

[0525] When used in a list of two or more items, the term "and / or" means that any of the listed items can be used alone or in combination with any one or more of the listed items. For example, the expression "A and / or B" is intended to mean either or both of A and B, that is, A alone, B alone, or a combination of A and B. The expression "A, B and / or C" is intended to mean A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B and C.

[0526] This includes approximately + / - 10% of the value.

[0527] The terms “subject” and “patient” are used interchangeably and refer to all members of the animal kingdom (e.g., humans).

[0528] "Mammals" and "patients" encompass warm-blooded mammals (e.g., humans and domesticated animals) that are typically under medical care. Examples include felines, canines, equines, bovines, non-human primates, and humans, as well as humans only.

[0529] Freeze-dried products are products that have been freeze-dried (products made by freeze-drying).

[0530] Lyophilization, or freeze-drying, is a low-temperature dehydration process that involves freezing the solution, reducing the pressure, and removing ice through sublimation.

[0531] Other features of the invention will become clear during the following description of exemplary embodiments, which are given to illustrate the invention and are not intended to limit it.

[0532] Example

[0533] Kolliphor HS 15 is a yellowish-white paste at room temperature (25°C), which becomes liquid at approximately 30°C. It dissolves in water, ethanol, and 2-propanol to form clear solutions. Its solubility in water decreases with increasing temperature. It is insoluble in liquid paraffin. Its pharmacopoeia name is polyethylene glycol 660 12-hydroxystearate or polyethylene glycol-15-hydroxystearate.

[0534] Freeze-drying is a process that can produce products with extremely small particle sizes and can promote the rapid dissolution of metoprazine. Therefore, assuming a 2-vial / container system, one container will contain freeze-dried metoprazine, and the second container will contain a diluent that has been aseptically filtered and terminally sterilized.

[0535] API polymorphs

[0536] Metoprazine USP is obtained from a quality source. Metoprazine (API) is reported to be polymorphic. Type I metoprazine is always manufactured and supplied by the supplier. The form of the API can affect its solubility. In the context of the formulations described herein, the form of the API may not make a significant difference, as the final API is dissolved in a suitable reagent before lyophilization.

[0537] API granularity distribution [PSD]

[0538] The dissolution rate will depend on the PSD of the API; therefore, it has been observed that the smaller the PSD, the faster the dissolution rate. Thus, having a micronized API is advantageous. For example, a D90 of less than 10 micrometers (90% of samples have a particle diameter <10 mm) can be used, as measured by a Malvern Mastersizer.

[0539] Before commencing solvent-based lyophilization experiments, a detailed assessment of the solubility of metoprazine in water + TBA (tert-butanol) was conducted to determine the optimal TBA:water ratio.

[0540] Table 1: tert-butanol-water solubility test

[0541]

[0542] Based on these experiments, it appears that a TBA:water ratio of at least 30:70 will provide a clear solution of Methorazo.

[0543] Example 1: Composition: #01

[0544]

[0545] Target strength 10mg / vial

[0546] The following procedure is used in Example 1:

[0547] a. HPBCD (hydroxypropyl-) was added under continuous stirring. - Cyclodextrin (filler) dissolved in WFI

[0548] b. Add metoprazine to the vortex to form a clear solution.

[0549] c. Add filler mannitol

[0550] d. Filter the solution through a 0.22-micron filter.

[0551] e. Fill the solution into a USP Type I clear glass vial, and

[0552] f. Freeze-dry the solution according to the following parameters.

[0553] HPBCD is.

[0554] freeze-drying parameters

[0555]

[0556] A nice cake-like substance is formed, which can be reconstituted with a suitable diluent (e.g., water for injection with a suitable pH of 5.5 to 8). It has been determined that the diluent may optionally contain a surfactant to provide a clear solution.

[0557] Example 2: Composition #02

[0558]

[0559] *The TBA density used for calculation is 0.775 g / mL. Total TBA is 30% v / v.

[0560] Detailed manufacturing process:

[0561] Step-1: Transfer the required amount of drug substance into a suitable SS316 vessel.

[0562] Step 2: Add the required amount of solvent (TBA) to step 1 and mix using a top-mounted stirrer at 500-800 rpm until a clear solution is observed. If a clear solution is not observed with TBA, add 35% of the batch quantity of WFI and mix until a clear solution is observed.

[0563] Step 3: Once a clear solution is obtained, add up to 90% of the batch amount of WFI and mix using a top stirrer at 500-800 rpm to obtain a clear solution.

[0564] Step 4: Add the batch amount of mannitol and mix with a top-mounted stirrer at 500-800 rpm to obtain a clear solution. Once a clear solution is obtained, make up the final volume with WFI.

[0565] Step 5: Using an SS pressure vessel filled with nitrogen, the solution from step 4 was filtered through a 0.22 μm PVDF filter. The filtered bulk solution was then purged with nitrogen for 1 hour.

[0566] Step 6: Fill the required volume of filtered solution into a 50 mL or suitable glass vial and partially seal it with an uncoated rubber stopper with a single vent.

[0567] Step 7: Load the filled vials into the freeze dryer and start the freeze drying cycle according to the provided parameters.

[0568] Step 8: Once the freeze-drying cycle is complete, the vacuum is partially released with nitrogen and the vial is plugged.

[0569] Step 9: After unloading, seal the vial with an aluminum seal featuring a plastic flip-off cap. Store the vial in a carton box at room temperature (25°C) for future experiments.

[0570] freeze-drying parameters

[0571]

[0572] No collapse was observed in any of the lyophilized vials. White cakes or powder were observed. No vial breakage was observed at the end of the lyophilization cycle. The lyophilized cakes were reconstituted with a suitable dilution of PEG 400 containing 30% w / v in phosphate buffer at pH 7.5. Reconstitution occurred in less than 3 minutes.

[0573] Example 3: Composition #06 (freeze-drying time reduced from 92 hours to 72 hours)

[0574]

[0575] *The TBA density used for calculation is 0.775 g / mL. Total TBA is 30% v / v.

[0576] freeze-drying parameters

[0577]

[0578] The total cycle time was reduced from 96 hours in the previous test to approximately 72 hours. Observations were similar to those in composition test 2. No collapse was observed in any of the lyophilized vials. White cakes or powder were observed. No vial breakage was observed at the end of the lyophilization cycle.

[0579] Reconstruction with 30% PEG 400 and 70% phosphate buffer (pH 7.4): The reconstruction vehicle was prepared by mixing 30% PEG 400 with phosphate buffer (pH 7.4). 10 mL of the reconstruction vehicle was added to a lyophilized product vial using a 10 mL plastic syringe. The vial was vortexed for approximately 1 minute. No clear solution was observed. Another 10 mL of the reconstruction vehicle was added to the vial using a 10 mL plastic syringe, and the vial was vortexed for approximately 1–2 minutes. A clear solution was observed. The vial was kept at room temperature for 24 hours for observation. A clear solution without any precipitation was observed. It was observed that 15–20 mL of dilution provided faster reconstruction. Further optimization of the dilution was performed because dilutions smaller than 15 mL would be beneficial.

[0580] The diluent is used to reconstitute the lyophilized cake in two vials of the kit and can be prepared by dissolving the buffer in water and adjusting the pH to between 5 and 8. If desired, a suitable surfactant or solubilizer can be added to the solution to obtain the diluent system, which can then be filtered (e.g., through a 0.22-micron filter) and then filled into containers (e.g., vials) for terminal sterilization.

[0581] Table 2 illustrates some of the studies conducted on diluents with different solubilizers and cosolvents.

[0582] Table 2: Dilution optimization study of composition #06

[0583]

[0584]

[0585] Based on these experiments, it is clear that PEG, Kolliphor HS 15, and ethanol can be part of an effective diluent system in a 2-vial kit.

[0586] Example 4: Composition #07

[0587]

[0588] *The TBA density used for calculation is 0.775 g / mL. Total TBA is 30% v / v.

[0589] Observation results:

[0590] Based on the results of Example 3, the same lyophilization parameters were used in Example 4. The total cycle time was approximately 72 hours. The observations were the same as in Test #006. No collapse was observed in any of the lyophilized vials. White cakes were observed in several vials, and fluffy powder was observed in several others.

[0591] The stability of this batch of samples was studied under accelerated conditions of 40°C / 75%RH, intermediate conditions of 30°C / 65%RH, and room temperature of 25°C / 60%RH. Upon withdrawal, the samples were analyzed by HPLC using a modified USP method (USP29-NF24) with the following modifications: GL Science, Inertsil ODS 3V, 150 A 4.6 mm and 5 μm column was used, with ACN:MeOH:buffer (10:30:60) v / v as the mobile phase, MeOH:H2O (50:50) v / v as the diluent, and 10 μL as the injection volume. Metoprazine sample and reference solution were also used. The observation results for this batch are recorded in the table below.

[0592] Stability of Composition #07

[0593]

[0594] Stability of Composition #07 - Continued

[0595]

[0596] ND: Not detected

[0597] Freeze-dried metotrazones exhibit excellent stability under all conditions, thus providing a shelf life of at least 24 months based on satisfactory accelerated stability conditions.

[0598] Example 5: Composition: #10

[0599]

[0600] Removed during freeze-drying.

[0601] The density of TBA used for calculation is 0.775 g / mL.

[0602] The manufacturing process remained the same as for earlier batches, preparing reconstituted diluents or batches and filtering them through a 0.2-micron filter, with or without exposure to an autoclave to examine the performance of different diluents prepared in phosphate buffer or TRIS buffer. The table below provides diluent evaluation.

[0603] Evaluation of Composition #10: 10 mL dilution

[0604]

[0605] Evaluation of Composition #10: 10 mL dilution - Continued

[0606]

[0607] It was observed that, in most cases, clear solutions of metolazoline were obtained after reconstruction with diluents containing PEG alone or in combination with Kolliphor HS 15.

[0608] It should be noted that a composition containing 50 mg / mL mannitol results in almost 500 mg mannitol per vial. This amount of mannitol may cause some hazy solution during reconstitution, which is generally to be avoided.

[0609] Example 6: Composition #019

[0610]

[0611] Removed during freeze-drying.

[0612] The density of TBA used for calculation is 0.775 g / mL.

[0613] The manufacturing process is the same as in the previous embodiments.

[0614] freeze-drying parameters

[0615]

[0616] To investigate the remodeling time, the following dilution was prepared at pH 7.5, with a target volume of 10 mL.

[0617] Table 3: Composition of PEG in the diluent of phosphate buffer

[0618]

[0619] The density of polyethylene glycol-400 is 1.13 g / mL.

[0620] The batch was manufactured and filled into 10 mL vials, which were then plugged and sealed. After sealing, the vials were autoclaved at 121°C for 15 minutes.

[0621] Table 4: Diluent composition of PEG in TRIS buffer

[0622]

[0623] The batch was manufactured and filled into 10 mL vials, which were then plugged and sealed. After sealing, the vials were autoclaved at 121°C for 15 minutes.

[0624] Table 5: Reconstitution with 10 mL dilution at pH 7.5

[0625]

[0626] Further experiments with mannitol were conducted. The following experiments illustrate the effects of 5 mg / mL and 15 mg / mL mannitol.

[0627] Example 7: Composition: #20

[0628]

[0629] Removed during freeze-drying.

[0630] The density of TBA used for calculation is 0.775 g / mL.

[0631] Example 8: Composition: #21

[0632]

[0633] Removed during freeze-drying.

[0634] The density of TBA used for calculation is 0.775 g / mL.

[0635] Example 9: Composition: #16

[0636]

[0637] Removed during freeze-drying.

[0638] The density of TBA used for calculation is 0.775 g / mL.

[0639] Examples 7-9 were lyophilized using the parameters of Example 6, and reconstruction and clarity were tested using the diluents from Table 5, resulting in a clear solution within 120 seconds.

[0640] Example 10: Composition: #24

[0641]

[0642] Removed during freeze-drying.

[0643] The density of TBA used for calculation is 0.775 g / mL.

[0644] Example 11: Composition #26

[0645]

[0646] Removed during freeze-drying.

[0647] The density of TBA used for calculation is 0.775 g / mL.

[0648] Examples 10-11 were freeze-dried using the parameters of Example 6, and the reconstruction was tested as described below.

[0649]

[0650] Example 12: Effect of mannitol concentration

[0651] Three batches of mannitol with different levels were prepared, and the quality and performance properties of the drug products were tested.

[0652]

[0653] Water for injection will be removed during freeze-drying.

[0654] The density of TBA used for calculation is 0.775 g / mL.

[0655] program:

[0656] 1. Use a weighing balance to dispense batch quantities of metolazoline and all raw materials. Thaw the TBA before dispensing.

[0657] 2. Collect a slightly excess of water for injection (WFI) of the total batch size in a clean SS316L jacketed container and keep at room temperature.

[0658] 3. To approximately 20% v / v of water for injection (WFI) of total batch size, add 100% w / v of the batch amount of tert-butanol (TBA) based on density by weight, and mix thoroughly to obtain a homogeneous mixture.

[0659] 4. Add metoprazan to solutions TBA and WFI and dissolve by stirring at 500-800 RPM until a clear solution is obtained using a top stirrer.

[0660] 5. Add mannitol to the solution from step 4 and dissolve it using a top-mounted stirrer. Once a clear solution is observed, bring the volume to 100% v / v using WFI.

[0661] 6. Use nitrogen gas to filter the solution using a 0.22 μm polyethersulfone (PES) or other suitable filter membrane with a filtration kit.

[0662] 7. Fill the target volume of filtered solution into a 10 mL USP Type I glass vial and partially seal the vial with a 20 mm Lyo rubber stopper.

[0663] 8. The partially sealed vials are placed into a freeze dryer and the product is freeze-dried in a nitrogen atmosphere using the freeze-drying process described above.

[0664] The residual TBA content of batches with different mannitol concentrations was determined and listed below and plotted on [the chart / plot]. Figure 1 middle.

[0665]

[0666] Observation results: such as Figure 1As shown, higher mannitol concentrations correlated with higher levels of residual TBA observed in the vials. Based on ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), 1700 ppm or 1.75 mg / vial is the limit for residual TBA. The test results above indicate that, depending on the mannitol concentration, the residual TBA levels range from 0.2 mg to 0.5 mg / vial, which are well within the target limits according to ICH.

[0667] Impurity B: The main acid- and base-catalyzed hydrolytic degradation product of metolazine is a metolazine benzamide analog, 2-amino-4-chloro-5-aminosulfonyl-N-(o-tolyl)benzamide (impurity-B). It was determined that 1 week at 60°C provides the same level as 3 months (3M) at 40°C / 75% RH (relative humidity). Therefore, 1 week at 60°C was used as an alternative condition to determine the impurity level in the test product.

[0668] The contents of impurity B in batches prepared with different mannitol concentrations after one week at 60°C are shown in the table below and plotted on the graph. Figure 2 and Figure 3 middle.

[0669]

[0670] Observation results:

[0671] a. The above results (see also) Figure 2 The results show that the formation of impurity B in the formulation is directly proportional to the mannitol concentration. The slope of this relationship is 0.2062. (10%) or 0.18558 to 0.22682. This slope can be used to select the optimal mannitol concentration for the formulation.

[0672] b. The above results (see also) Figure 3 The results show that the formation of impurity B in the formulation is directly proportional to the residual TBA concentration. The slope of this relationship is 3.2108 ( (10%) or 2.88972 to 3.53188. This slope can be used to select the optimal residual TBA concentration for the formulation.

[0673] Example 13: Effect of TBA / Water Ratio

[0674] The saturated solubility studies of metoprazine were conducted at different water:tert-butanol ratios ranging from 20-40% TBA to 80-60% water. The studies were performed in triplicate. The saturated solubility data indicated that a minimum of 30% TBA was required to dissolve 1 mg / mL of metoprazine.

[0675]

[0676] Observation results:

[0677] a. TBA needs to be combined with water to dissolve metotrazine.

[0678] b. A solvent with a ratio of 30:70 to 40:60 (TBA:water) can dissolve Metoprazine at 1 mg / mL.

[0679] c. The solubility of metoprazine increases with increasing TBA content (see [reference needed]). Figure 4 The results showed that the solubility of metoprazine was directly proportional to the TBA fraction in the solvent. The slope of this relationship was 0.0913. (10%) or 0.08217 to 0.10043. This slope can be used to select the optimal TBA concentration to dissolve metoprazine for the formulation.

[0680] Example 14: Effect of diluent

[0681] A diluent selection study was conducted to determine the optimal diluent combination for metoprazine. The following components were evaluated in conjunction with a phosphate buffer to examine the solubility of metoprazine and observe the clarity of the solution.

[0682] Procedure for Examples III-1 to III-5: An excess of the drug substance with a PSD (particle size distribution) of 10 micrometers (60 mg) was added to a 20 mL dilution mixture specified in Examples III-1 to III-5, resulting in a theoretical concentration of 3 mg / mL. After the addition of the drug, these samples were sonicated at room temperature for up to 4 hours. Clarity of solution and quantitative solubility were observed.

[0683]

[0684] Observation results: Metotrazine can be dissolved in any of the following mixtures at an appropriately selected concentration.

[0685] a. PEG-400 + phosphate buffer, pH 7.5;

[0686] b. PEG-400 + TRIS buffer, pH 7.5;

[0687] c. PEG-400 + Kolliphor HS-15 + phosphate buffer pH 7.5;

[0688] d. PEG-400 + Kolliphor HS-15 + TRIS buffer pH 7.5; and,

[0689] e. TBA and water.

[0690] The order of quantitative solubility is as follows:

[0691] a. TBA and water>

[0692] b. PEG-400 + Kolliphor HS-15 + TRIS buffer pH 7.5 >

[0693] c. PEG-400 + Kolliphor HS-15 + phosphate buffer pH 7.5 >

[0694] d. PEG-400 + phosphate buffer pH 7.5 >

[0695] e. PEG-400 + TRIS buffer pH 7.5.

[0696] Observations on solubility: Using 40% PEG in all tested buffers, metoprazine API with a particle size D90 < 10 μm showed a solubility > 1.2 mg / mL. This provides a baseline solubility for type I crystalline APIs. However, after lyophilization, the drug is expected to be lyophilized to the submicron level (amorphous, crystalline, or a combination of both), resulting in a significant improvement in API solubility.

[0697] The solubility of lyophilized metoprazine was determined by the following: Lyophilized powder was removed from a vial and added to 5 mL of diluent (PEG-400 (40%) + phosphate buffer, pH 7.5). Three (3) vials of lyophilized metoprazine powder (equivalent to 15 mg of metoprazine powder at a total weight of 90 mg) were completely dissolved in 5 mL of diluent. This resulted in a minimum solubility of 3 mg / mL for metoprazine. More vials could be added to 5 mL of diluent, potentially achieving a solubility of 20 mg of metoprazine in 5 mL of diluent, resulting in a solubility of 4 mg / mL for metoprazine. This represents a 400% increase in solubility of metoprazine (1.8 mg / mL for unlyophilized compared to 4 mg / mL for lyophilized).

[0698]

[0699] Lyophilized metoprolol + mannitol powder, per 30mg vial, contains 5mg metoprolol.

[0700] The PEG-400 to drug ratio (weight / weight) in the table below is part of this invention.

[0701] Table A

[0702]

[0703] Table B

[0704]

[0705] Table C

[0706]

[0707] Table D

[0708]

[0709] Table E

[0710]

[0711] Example 15: The effect of minimum PEG 400 in the diluent

[0712] The volume of the diluent and the percentage of PEG are important for obtaining a clear solution for reconstituted metoprazine. The clarity of the solution containing 40% PEG-400 is shown above. The following studies were conducted to determine the minimum PEG-400 concentration required to achieve a clear solution when combined with a phosphate buffer at pH 7.5.

[0713] Lyophilized batches of metoprazine containing varying percentages of PEG 400 (e.g., 10%–15%) were prepared using a phosphate buffer at pH 7.5. These dilutions were used for reconstitution studies and the following observations were obtained.

[0714]

[0715] Observations: PEG 400 at concentrations of 10% w / v or higher, alone or in combination with phosphate buffer or any solvent mixture (as listed in Example-3), can be used to reconstitute lyophilized injectable metoprazine.

[0716] The drug-to-diluent drug ratio (weight / volume) in the table below is part of this invention.

[0717] Table A

[0718]

[0719] Table B

[0720]

[0721] Table C

[0722]

[0723] Table D

[0724]

[0725] Surprisingly, it was found that metolazoline can be efficiently freeze-dried using an aqueous or hydroalcoholic system, which can be further reconstituted with a suitable diluent containing buffers and solubilizers.

[0726] For patients with impaired renal function who are expected to use metoprazine, it is important to minimize the volume of fluid administered. Using the metoprazine composition described above, lyophilized metoprazine can be reconstituted with 10-20 mL or even less than 10 mL of reconstituted fluid (diluent). The reconstituted fluid can be given directly to patients in need, and if necessary, can be diluted with different infusion solvents before administration.

[0727] All references listed in this article are incorporated into this article in their entirety through citation.

[0728] In light of the foregoing teachings, many modifications and variations of the present invention are possible. Therefore, it should be understood that the invention can be practiced in ways other than those specifically described herein, within the scope of the appended claims.

Claims

1. A methotrexate lyophile kit comprising: a. a first container comprising: a methotrexate lyophile composition in lyophilized powder form, the methotrexate lyophile composition comprising: i. methotrexate; and, b. a second container comprising: a pharmaceutically acceptable diluent, wherein the diluent is suitable for reconstituting the lyophile composition into a pharmaceutical product having a pH of about 5.0-8.0 for parenteral administration.

2. The methotrexate lyophile kit of claim 1, wherein the methotrexate lyophile composition in lyophilized powder form comprises a filler.

3. The kit of metoclopramide lyophile according to claim 2, wherein the filler is selected from mannitol, lactose, dextrose, sucrose and hydroxypropyl- - cyclodextrin; preferably, wherein the filler is mannitol.​ 4. The methotrexate lyophile kit of any one of the preceding claims, wherein the pharmaceutically acceptable diluent comprises water.

5. The methotrexate lyophile kit of any one of the preceding claims, wherein the pharmaceutically acceptable diluent comprises a solubilizer.

6. The methotrexate lyophile kit of any one of the preceding claims, wherein the pharmaceutically acceptable diluent comprises a buffer.

7. The methotrexate lyophile kit of any one of the preceding claims, wherein the diluent has a volume of 5-20 mL.

8. The methotrexate lyophile kit of any one of the preceding claims, wherein the methotrexate lyophile composition contains 0.2-1.75 mg of tert-butyl alcohol.

9. The methotrexate lyophile kit of any one of the preceding claims, further comprising a linker for holding the first and second containers.

10. The methotrexate lyophile kit of any one of the preceding claims, wherein the diluent further comprises: 2-4% w / v polyethylene glycol-15-hydroxystearate.

11. The methotrexate lyophile kit of any one of the preceding claims, wherein the methotrexate lyophile composition comprises: i. 2.5-20 mg methotrexate; and, ii. 2.5-1000 mg mannitol; and, the diluent comprises: i. 25-45% w / v polyethylene glycol 400; ii. a TRIS buffer or a phosphate buffer; and, iii. the remainder is water; wherein the diluent has a pH of 7-8.

12. The methotrexate lyophile kit of claim 11, wherein the methotrexate lyophile composition comprises: i. 2.5-10 mg methotrexate; and, ii. 25-500 mg mannitol; and, the diluent comprises: i. 30-40% w / v polyethylene glycol 400; ii. a TRIS buffer or a phosphate buffer; and, iii. the remainder is water; wherein the diluent has a pH of 7.

5.

13. A process for reconstituting a methotrexate lyophile composition, the process comprising: providing a methotrexate lyophile composition in lyophilized powder form comprising methotrexate, contacting the methotrexate lyophile composition with a pharmaceutically acceptable diluent; and, mixing the resulting solution until clear; wherein the resulting clear solution is suitable for parenteral administration, and wherein the diluent is suitable for reconstituting the lyophilized composition into a pharmaceutical product having a pH of about 5.0-8.0 for parenteral administration.

14. The process of claim 13, wherein a clear solution is obtained in less than 5 minutes.

15. A clear reconstituted metolazone solution for natriuretic and / or diuretic treatment of a patient in need thereof, the treatment comprising: providing a metolazone lyophilized composition in the form of a lyophilized powder comprising metolazone, contacting the metolazone lyophilized composition with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituting the lyophilized composition into a pharmaceutical product having a pH of about 5.0-8.0 for parenteral administration mixing the resulting solution until a clear reconstituted metolazone solution is obtained; administering a therapeutically effective amount of the clear reconstituted metolazone solution to a patient in need of natriuretic and / or diuretic treatment.

16. A clear reconstituted metolazone solution for furosemide resistant treatment of a patient in need thereof, the treatment comprising: providing a metolazone lyophilized composition in the form of a lyophilized powder comprising metolazone, contacting the metolazone lyophilized composition with a pharmaceutically acceptable diluent; wherein the diluent is suitable for reconstituting the lyophilized composition into a pharmaceutical product having a pH of about 5.0-8.0 for parenteral administration mixing the resulting solution until a clear reconstituted metolazone solution is obtained; administering a therapeutically effective amount of the clear reconstituted metolazone solution to a patient in need of furosemide resistant treatment.

17. A liquid metolazone pre-lyophilized composition comprising: a. metolazone; b. a bulking agent; c. an alcohol; and, d. water; wherein the liquid metolazone pre-lyophilized composition forms a lyophilized powder upon being subjected to lyophilization.

18. The metolazone pre-lyophilized composition of claim 17, wherein the alcohol is tert-butyl alcohol.

19. The metolazone pre-lyophilisate composition according to claim 17 or 18, wherein the filler is selected from mannitol, lactose, dextrose, sucrose and hydroxypropyl- - cyclodextrin.​ 20. The metolazone pre-lyophilized composition of claim 17, 18, or 19, comprising: a. 0.1-2 mg / ml metolazone; b. 1-50 mg / mL mannitol; c. 30-70% v / v tert-butyl alcohol; and, d. the remainder water.

21. The metolazone pre-lyophilized composition of claim 17, 18, or 19, comprising: a. 0.1-1.5 mg / ml metolazone; b. 2.5-60 mg / mL mannitol; c. 30-70% v / v tert-butyl alcohol; and, d. the remainder water.

22. The metolazone pre-lyophilized composition of claim 20 or 21, comprising: a. 0.1-1 mg / ml metolazone; b. 5-10 mg / mL mannitol; c. 40-60% v / v tert-butyl alcohol; and, d. the remainder water.

23. The metolazone pre-lyophilized composition of any of the preceding claims 17-22, further comprising: 1-15 mg / mL polyethylene glycol-15-hydroxystearate.

24. A metolazone lyophilized composition comprising: a. metoclopramide; and b. a bulking agent; wherein the metoclopramide lyophile composition is in the form of a lyophilized powder.

25. The metoclopramide lyophile composition according to claim 24, obtainable by lyophilization from the liquid metoclopramide pre-lyophile composition according to any one of claims 19-23.

26. The metoclopramide lyophile composition according to claim 25, wherein the metoclopramide lyophile composition contains 0.2-1.75 mg of tert-butyl alcohol.

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