Liquid, storage-stable, directly injectable pantoprazole formulations, uses and manufacture thereof

Abstract

The present invention provides a concentrated, storage-stable, liquid composition of pantoprazole or a pharmaceutically acceptable salt thereof. The present invention further provides uses of the composition, as well as a packaging container comprising the composition. In particular, the present invention relates to a stable pantoprazole sodium formulation with controlled room temperature as storage condition, in the form of a ready-to-use liquid solution or in the form of a dilution ready-to-use formulation for dilution with an infusion solution, methods of its preparation and uses.

Description

Technical Field

[0001] This invention relates to a concentrated liquid composition comprising the proton pump inhibitor pantoprazole. The composition exhibits extended storage stability and is suitable for direct injection. Upon dilution with a suitable diluent, a solution with physiologically compatible pH and osmolality is obtained. Accessibility for caregivers and patients is significantly improved, increasing patient comfort. This invention is beneficial to the fields of pharmaceutical preparation and its applications.

[0002] Injectable formulations of stable, concentrated liquids with controlled room temperature as storage conditions are provided. The compositions are stable, ready-to-use liquid solutions and / or readily dilute with infusion solutions. Furthermore, the present invention provides methods for their preparation and uses, as well as packaging containers comprising the compositions. Background Technology

[0003] Benzimidazole-based proton pump inhibitors (PPIs) share a common structural element: the benzimidazole ring. Some examples of benzimidazole PPI compounds are pantoprazole, omeprazole, lansoprazole, rabeprazole, and esomeprazole. Pantoprazole sodium sesquihydrate is a substituted benzimidazole, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole sodium, a compound that inhibits gastric acid secretion, with the following chemical structure:

[0004]

[0005] The main challenges associated with PPI injection formulations are hydrolysis and thermal instability, requiring freeze-dried / lyophilized formulations.

[0006] Pantoprazole sodium is commercially available in injectable formulations as sterile lyophilized / freeze-dried powder or cakes, and is sold in 40 mg / vial (equivalent to 45.1 mg of pantoprazole sodium). Pantoprazole sodium powder for injection is labeled for administration as an infusion (4 mg / mL for gastroesophageal reflux disease (GERD) or pathological hypersecretion) or as a 15-minute infusion (0.4 mg / mL, 0.8 mg / mL, or 1.3 mg / mL for GERD or pathological hypersecretion). The 2-minute infusion requires a reconstitution step with 0.9% sodium chloride injection, and the 15-minute infusion requires a second dilution with either 5% dextran injection or 0.9% sodium chloride injection.

[0007] U.S. Patent No. 6,780,881 discloses a lyophilized pantoprazole formulation, which can be obtained by lyophilizing pantoprazole, ethylenediaminetetraacetic acid and / or suitable salts thereof, and an aqueous solution of sodium hydroxide and / or sodium carbonate.

[0008] Existing techniques for preparing pantoprazole sodium for injection (e.g., 40 mg / vial) involve lyophilization, which requires reconstitution before intravenous injection or infusion. Furthermore, lyophilization methods for preparing lyophilized powders or cakes are expensive and complex. Existing reconstitution processes for lyophilized pantoprazole sodium formulations require several lengthy and complex preparation steps, including reconstitution of each vial and subsequent dilution into infusion bags. Additionally, the reconstituted formulation exhibits limited stability.

[0009] In addition, the freeze-drying process requires complex and time-consuming steps to obtain sterile freeze-dried products, which increases the commercial cost of the products.

[0010] In the United States, commercially available frozen, ready-to-use single-dose bags of pantoprazole sodium in 50 or 100 mL of 0.9% sodium chloride are available for intravenous infusion. However, this product has limitations. It is specifically designed for intravenous infusion. Additionally, the product must be stored, transported, and handled below -20°C (-4°F) and is fragile in its frozen state. The bags must be thawed at room temperature (20°C to 25°C or 68°F to 77°F) or refrigerated (2°C to 8°C or 36°F to 46°F) before use. This process requires advance planning and is time-consuming, resulting in extended waiting times for patients, which is undesirable when timely administration is critical to patient care. Furthermore, after thawing, the solution is only stable for 21 days under refrigeration.

[0011] Therefore, there is a need in the art to simplify the reconstitution process of lyophilized formulations of pantoprazole, particularly pantoprazole sodium, to make them suitable for use over extended periods. Furthermore, there is a need in the art to address the costs and / or complexities associated with the lyophilization process.

[0012] Alternative solutions are needed in the art. The object of this invention is to provide a long-term stable pantoprazole composition that can be administered directly by injection or infusion without reconstitution of the lyophilized product or thawing, allowing for rapid administration and ease of use. In particular, there is a need for long-term stable, ready-to-use intravenous formulations designed for bolus injection. Such compositions would allow patients to receive treatment at home without hospitalization, for example, through self-administration using pre-filled syringes or pens. Summary of the Invention

[0013] The present invention provides ready-to-use and / or ready-to-dilute compositions comprising a pharmaceutically acceptable salt of pantoprazole, a solvent system comprising one or more organic solvents, and a stabilizer.

[0014] This invention provides a storage-stable, directly injectable formulation (ready-to-use). This formulation is ready to use after dilution with an infusion solution, without the need to prepare a premixed solution containing a weight-molar osmolality adjuster or pH adjuster.

[0015] In a first aspect, the present invention provides a concentrated, storage-stable, non-aqueous composition of pantoprazole, comprising:

[0016] Pharmaceutically acceptable salts (APIs) of pantoprazole in doses of 20-80 mg, expressed in pantoprazole amounts.

[0017] The amount of polyethylene glycol used to dissolve the API.

[0018] Optional stabilizer, preferably an alkali metal hydroxide, more preferably sodium hydroxide.

[0019] The composition is contained in a volume equal to or less than 1.0 ml.

[0020] The inventors have surprisingly discovered that pantoprazole liquid compositions comprising polyethylene glycol and a stabilizer (preferably an alkali metal hydroxide) provide formulations with improved stability that can be stored at a controlled room temperature of 20°–25°C (68°–77°F).

[0021] Preferably, the volume of the concentrated, storage-stable, non-aqueous composition is equal to or less than 0.5 mL. More preferably, the volume is 0.5 mL.

[0022] Preferably, the concentrated, storage-stable, non-aqueous composition has a storage stability of at least 1 year as measured at 25°C and 60% relative humidity, wherein the composition contains equal to or less than 4.0% w / w total impurities, as determined by HPLC.

[0023] Preferably, the concentrated, storage-stable, non-aqueous composition contains impurity C equal to or less than 2.5% w / w, as determined by HPLC.

[0024] Preferably, the pantoprazole salt of the concentrated, storage-stable, non-aqueous composition is a pantoprazole sodium salt, more preferably a pantoprazole sodium sesquihydrate salt.

[0025] Preferably, the concentrated, storage-stable, non-aqueous composition comprises 40 mg of a pharmaceutically acceptable salt (API) of pantoprazole, contained in a volume of 0.5 ml.

[0026] Preferably, the amount of stabilizer in the concentrated, storage-stable, non-aqueous pantoprazole composition is 0.01 to 1.50 mg / mL, more preferably 0.03 to 1.20 mg / mL, even more preferably 0.05 to 0.50 mg / mL, and most preferably 0.1 to 0.3 mg / mL.

[0027] Preferably, the amount of stabilizer in the concentrated, storage-stable non-aqueous composition is 0.05 to 0.50 mg / mL, more preferably 0.1 to 0.3 mg / mL.

[0028] More preferably, the composition contains 0.1 to 1.50 mg / mL sodium hydroxide, even more preferably 0.2 to 1.40 mg / mL sodium hydroxide, even more preferably 0.3 to 1.30 mg / mL, and even more preferably 0.5 to 1.2 mg / mL; most preferably 0.2 mg / mL.

[0029] Preferably, the polyethylene glycol in the pharmaceutically acceptable form of the concentrated, storage-stable, non-aqueous composition for pantoprazole has an average molecular weight of less than 500, and more preferably, the polyethylene glycol is PEG 300 (average Mw 300).

[0030] Preferably, the dissolved oxygen content in the pharmaceutically acceptable form of the concentrated, storage-stable, non-aqueous pantoprazole composition is less than 10 ppm, more preferably less than 5 ppm, and most preferably about 2 ppm.

[0031] Preferably, the water content in the composition of a pharmaceutically acceptable form of concentrated, storage-stable, non-aqueous pantoprazole is equal to or less than 4.0% w / v.

[0032] In another aspect, according to one embodiment of the invention, a concentrated, storage-stable, non-aqueous composition of a pharmaceutically acceptable salt of pantoprazole is used to treat a patient suffering from a gastrointestinal disorder, wherein the patient is given 1 ml or less of the composition intravenously without prior dilution.

[0033] In another aspect, the present invention provides a method for treating a patient suffering from a gastrointestinal disease, comprising the step of administering, by bolus (ready-to-use) a composition of a concentrated, storage-stable, non-aqueous pantoprazole salt according to an embodiment of the present invention.

[0034] In another aspect, the present invention relates to a method for treating a patient suffering from a gastrointestinal disease, comprising the steps of: diluting a composition of a concentrated, storage-stable, non-aqueous, pharmaceutically acceptable salt of pantoprazole according to an embodiment of the present invention to 0.4-4.0 mg / ml of a pharmaceutically acceptable salt of pantoprazole, denoted as pantoprazole, with a suitable aqueous diluent; thereafter administering the obtained diluted composition to the patient by infusion (dilution-ready type).

[0035] Preferably, the weight molar osmotic pressure concentration of the obtained diluted composition is 200-1000 mOsmol / kg.

[0036] Preferably, the pH of the obtained diluted composition is 8.2-10.5, and most preferably 8.5-10.0.

[0037] More preferably, the diluted composition obtained by diluting the concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention has a weight molar osmotic pressure concentration of 200-1000 mOsmol / kg and a pH of 8.2-10.5.

[0038] Most preferably, the diluted composition obtained by diluting the concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention has a weight molar osmolality of 220-600 mOsmol / kg and a pH of 8.5-10.0.

[0039] Preferably, in the method according to an embodiment of the present invention, the diluent is selected from water for injection, 0.9% sodium chloride solution (NaCl), or 5% dextrose solution.

[0040] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate (expressed as pantoprazole) in 1 mL or less of polyethylene glycol is diluted with 10 mL of water for injection to obtain an aqueous solution of 4-8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmotic pressure concentration of 200-300 mOsmol / kg and a pH of 9.5-10.2.

[0041] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate (expressed as pantoprazole) in polyethylene glycol is first diluted with 10 mL of water for injection, and then further diluted with 0.9% sodium chloride and 5% dextrose solution to a total volume of 100 mL, thereby obtaining an aqueous solution of 0.4-0.8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmotic pressure concentration of 200-600 mOsmol / kg and a pH of 8.5-10.0.

[0042] In another aspect, the present invention provides a packaging container comprising one or more unit doses of a concentrated, storage-stable, non-aqueous, pharmaceutically acceptable salt composition of pantoprazole according to an embodiment of the present invention.

[0043] Preferably, the packaging container according to an embodiment of the invention is covered by a topspace having an oxygen content of less than 10%, preferably less than 5%, and even more preferably less than 2%. The oxygen content of the topspace is measured using a fiber optic oxygen transmitter (PreSens, Microx 4). The measurement is performed as follows: the vial is punctured with a fiber optic syringe needle, and the oxygen level in the topspace is measured as a percentage (%).

[0044] Preferably, the packaging container is a glass vial, syringe, or pen.

[0045] In another aspect, the present invention provides a prefilled syringe comprising a concentrated, storage-stable, non-aqueous composition according to an embodiment of the invention.

[0046] In a final aspect, the present invention provides a method for manufacturing a concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention, comprising the following steps:

[0047] - Provides polyethylene glycol with an oxygen content of less than 2 ppm.

[0048] - Heat the polyethylene glycol to a temperature between 45°C and 55°C.

[0049] - A certain amount of stabilizer is dissolved in warm polyethylene glycol, preferably an alkali metal hydroxide, more preferably sodium hydroxide.

[0050] - Cool the mixture obtained in the previous step to below 25°C.

[0051] - Add a pharmaceutically acceptable salt of pantoprazole to the cooled liquid mixture to obtain a pantoprazole solution of 40-80 mg / mL.

[0052] Preferably, the 40-80 mg / mL pantoprazole solution is divided into 1 ml or smaller portions, and each portion is filled into a packaging container, preferably into a dehydrogenated transparent glass vial, syringe or pen. Detailed Implementation

[0053] At the outset of this detailed description, it is understood that the following description illustrates only specific forms of the invention. However, such specific forms are merely exemplary embodiments and are not intended to imply any limitation on the scope of the invention. Therefore, this description should be understood as exemplary embodiments and teachings of the invention, and not as limiting.

[0054] It should also be understood that the terminology used herein is for the purpose of describing a particular implementation only and is not intended to limit the scope of this disclosure.

[0055] When a range of values ​​is provided, it should be understood that, unless the context explicitly specifies otherwise, every intermediate value between the upper and lower limits of the range (to one-tenth of the lower limit unit), as well as any other value or intermediate value within the range, is encompassed within the method. The upper and lower limits of these smaller ranges may be independently included within the smaller range and are also encompassed within the method, subject to any specific exclusion limits within the range. Where the range includes one or two limits, the range excluding any one or both of the included limits is also included in the method.

[0056] This document presents certain ranges where numerical values ​​are preceded by the term "about". The term "about" is used herein to provide textual support for the exact number that follows it, as well as numbers that are close to or approximate the number following the term. In determining whether a number is close to or approximates a specifically listed number, an unlisted number that is close to or approximates a number that provides a substantial equivalent to the specifically listed number in its presented context. In embodiments, "about" may mean within one or more standard deviations, or within ±30%, 25%, 20%, 15%, 10%, or 5% of the stated value.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, preferred methods and materials are described.

[0058] For the purposes of this invention, the following terms are defined as follows: the articles “a” and “an” are used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, “an element” means one or more elements.

[0059] As used herein, the terms “comprises” or “comprising” are generally used in the sense of inclusion, that is, allowing the presence of one or more features or components.

[0060] The term "excipient" is used to describe an inert substance added to a pharmaceutical composition to make the active ingredient easier to administer. This can include a range of substances such as surfactants, tensioning agents, pH adjusters, buffers, preservatives, mediators, vegetable oils, and polyethylene glycol.

[0061] The terms "formulation" or "composition" refer to a pharmaceutical formulation of pantoprazole described herein with a pharmaceutically acceptable carrier and / or excipient. The terms "formulation" or "composition" are used interchangeably.

[0062] As used herein, the term “pantoprazole” means “pantoprazole” or its pharmaceutically acceptable salt, or its pharmaceutically acceptable stereoisomer, or its pharmaceutically acceptable solvate, or its pharmaceutically acceptable hydrate, or its pharmaceutically acceptable anhydrous form, or its pharmaceutically acceptable polymorph, or its pharmaceutically acceptable prodrug, and other similar forms suitable for pharmaceutical use.

[0063] The term "pharmaceutically acceptable carrier" refers to a substance that serves as a carrier, medium, adjuvant, or solvent in a drug formulation without causing significant irritation to the body or interfering with the drug's biological activity. The terms "medium," "solvent," and "solvent system" refer to the same components and are used interchangeably.

[0064] The term "subject" includes mammals (especially humans) and other animals, such as domesticated animals (e.g., household pets, including cats and dogs) and non-domesticated animals (e.g., wild animals). Each embodiment is provided to explain the invention, not to limit it. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the compounds and methods described herein without departing from the scope or spirit of the invention. For example, features shown or described as part of one embodiment may be applied to another embodiment to produce yet another embodiment. Therefore, the invention is intended to include such modifications and variations and their equivalents.

[0065] Other objects, features, and aspects of the invention are disclosed or will be apparent from the following detailed description. Those skilled in the art will understand that this discussion is merely a description of exemplary embodiments and should not be construed as limiting the broader aspects of the invention.

[0066] The phrase "ready-to-use" refers to any form of pantoprazole that can be administered directly to the patient without additional processing or dilution. The phrase "dilution ready-to-use" refers to a formulation that can be directly combined with a diluent such as dextran solution, saline solution, or any other infusion medium and then administered to the patient.

[0067] This invention provides compositions for stabilizing ready-to-use and / or diluted ready-to-use formulations, said compositions comprising a proton pump inhibitor (PPI), a solvent system, and a pH adjuster as a stabilizer. In some embodiments, the formulation exhibits stability when stored under controlled room temperature conditions. In embodiments, the formulation is a liquid, injectable formulation. Furthermore, controlled room temperature refers to conditions within a temperature range of 20°C to 25°C.

[0068] In the embodiments, any PPI may be used in the composition, formulation, and / or method described herein. Examples of PPIs include, but are not limited to, pantoprazole, omeprazole, lansoprazole, rabeprazole, and esomeprazole. In some embodiments, the PPI is pantoprazole.

[0069] In another embodiment, the present invention provides a composition comprising pantoprazole or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. In another embodiment, the composition further comprises a solvent system and an excipient. In yet another embodiment, the composition comprises a non-aqueous solvent system and a pH adjuster as a stabilizer.

[0070] In a further embodiment, the composition comprises pantoprazole or a pharmaceutically acceptable salt or stereoisomer thereof, a solvent system comprising one or more organic solvents, a pH adjuster as a stabilizer, and a pharmaceutically acceptable carrier or excipient. Examples of excipients include, but are not limited to, surfactants, isotonic agents, pH adjusters, buffers, preservatives, vegetable oils, and any combination thereof.

[0071] In some embodiments, the composition comprises pantoprazole sodium in the range of about 4% (w / v) to about 8% (w / v).

[0072] In another embodiment, pantoprazole is dissolved in a solvent system to a concentration greater than about 40 mg / mL and up to about 80 mg / mL, providing an injection volume of less than 1 mL. In another embodiment, the concentration of pantoprazole is about 80 mg / mL, delivering 40 mg in an injection volume of 0.5 mL. The lower solvent injection volume minimizes the risks associated with the hyperosmolarity of organic solvent-based injections, thus allowing for the possibility of ready-to-use (direct intravenous injection).

[0073] In some embodiments, the solvent system comprises a non-aqueous solvent. The non-aqueous solvent comprises one or more organic solvents selected from glycols, glycerols, alcohols, and amides. Examples of glycols include, but are not limited to, polyethylene glycol, propylene glycol, and combinations thereof. In another embodiment, the concentration of the organic solvent ranges from about 20% (v / v) to about 100% (v / v). In some embodiments, the concentration of the organic solvent is from about 40% (v / v) to about 100% (v / v).

[0074] In some embodiments, the glycol is propylene glycol. In further embodiments, the concentration of propylene glycol ranges from about 20% (v / v) to about 100% (v / v). In some embodiments, the concentration of propylene glycol is from about 40% (v / v) to about 100% (v / v).

[0075] In some embodiments, the glycol is polyethylene glycol (PEG). Examples of PEG include, but are not limited to, PEG-200 (average molecular weight 200 Da), PEG-300 (average molecular weight 300 Da), PEG-400 (average molecular weight 400 Da), PEG-600 (average molecular weight 600 Da), PEG-800 (average molecular weight 800 Da), etc. In some embodiments, the PEG is PEG-300 (average molecular weight 300 Da) and / or PEG-400 (average molecular weight 400 Da). In some embodiments, the concentration of PEG can range from about 20% (v / v) to about 100% (v / v). In embodiments, the composition comprises a combination of PEGs with different molecular weights. In some embodiments, the formulations of the present invention comprise a combination of PEG-300 and PEG-400. In some cases, the concentration of PEG-400 ranges from about 60% (v / v) to about 100% (v / v). In further cases, the concentration range of PEG-300 is from about 60% (v / v) to about 100% (v / v).

[0076] Examples of alcohols include, but are not limited to, ethanol, tert-butanol, etc. In some embodiments, the alcohol is ethanol. In further embodiments, the concentration of ethanol ranges from about 20% (v / v) to about 100% (v / v).

[0077] Examples of amides include, but are not limited to, dimethylformamide (DMF), dimethylacetamide (DMA), etc. In some embodiments, the amide is DMA. In some embodiments, the concentration of the amide solvent may range from about 10% (v / v) to about 40% (v / v). In some embodiments, the organic solvent is selected from ethanol, propylene glycol, polyethylene glycol-400, polyethylene glycol-300, N,N-dimethylacetamide, and combinations thereof.

[0078] In the embodiments, the stabilizer is a pH adjuster selected from, but not limited to, sodium hydroxide, potassium hydroxide, arginine, tromethorphan, meglumine, sodium citrate, sodium carbonate, sodium acetate, sodium bicarbonate, potassium bicarbonate, and any combination thereof. In a further embodiment, the stabilizer is present in an amount ranging from 0.01% w / v to 5% w / v, and preferably in an amount ranging from 0.01% w / v to 2% w / v.

[0079] In the embodiments, the pH adjuster is soluble in polyethylene glycol (PEG), and preferably, the pH adjuster is soluble in polyethylene glycol 300 (PEG 300).

[0080] In this embodiment, the solvent is PEG, and the stabilizer is sodium hydroxide. Preferably, the solvent is PEG 300.

[0081] In the embodiments, the formulation is a ready-to-use and / or dilute-to-use formulation, comprising polyethylene glycol and sodium hydroxide as a stabilizer. More preferably, the formulation is a ready-to-use and / or dilute-to-use formulation, comprising polyethylene glycol 300 and sodium hydroxide.

[0082] In some embodiments, the formulation is a ready-to-use and / or diluted ready-to-use formulation comprising PPI, PEG 300, and sodium hydroxide; wherein the PPI is dissolved in a solvent system at a concentration greater than about 40 mg / mL and up to about 80 mg / mL, providing an injection volume of less than one mL. In another embodiment, the PPI concentration is about 80 mg / mL, delivering 40 mg in a 0.5 mL injection volume.

[0083] In a further embodiment, the formulation is a ready-to-use and / or diluted ready-to-use formulation comprising pantoprazole, PEG 300, and sodium hydroxide; wherein the pantoprazole is dissolved in a solvent system to a concentration greater than about 40 mg / mL and up to about 80 mg / mL, providing an injection volume of less than one mL. In another embodiment, the PPI concentration is about 80 mg / mL, delivering 40 mg in a 0.5 mL injection volume.

[0084] In the embodiments, the concentration of sodium hydroxide ranges from about 0.01 mg / mL to about 40 mg / mL, from about 0.002 mg / mL to about 10 mg / mL, or from about 0.1 mg / mL to about 6 mg / mL; most preferably about 0.2 mg / mL.

[0085] In another embodiment, the composition is a stable injectable formulation comprising pantoprazole or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which is readily dilute with an infusion solution without the need to prepare a premixed solution.

[0086] Furthermore, the present invention provides a method for preparing compositions comprising a PPI or a pharmaceutically acceptable salt thereof for use in ready-to-use and / or dilution of ready-to-use formulations. In embodiments, the method comprises mixing a PPI or a pharmaceutically acceptable salt thereof or a stereoisomer thereof with a solvent system, a stabilizer, and a pharmaceutically acceptable carrier or excipient to obtain a clear solution. The method further comprises filtering the solution and filling the filtered solution into a container. In some embodiments, the PPI or a pharmaceutically acceptable salt or stereoisomer thereof, the solvent system, the stabilizer, and the pharmaceutically acceptable carrier or excipient are the same as defined in any of the foregoing embodiments. In embodiments, the container refers to a closed system such as an ampoule, vial, pre-filled syringe, and other suitable container.

[0087] In some embodiments of this method, the PPI is pantoprazole, the solvent is PEG 300, and the stabilizer is sodium hydroxide.

[0088] In yet another embodiment, the present invention provides a method for treating or preventing a condition or disorder in a subject of need by administering an effective amount of the ready-to-use and / or diluted ready-to-use formulation of the present invention. In some embodiments, a condition or disorder refers to a disease condition for which the use of a proton pump is beneficial. Examples of such disorders include, but are not limited to, conditions or disorders selected from a history of gastric ulcer, gastroesophageal reflux disease (GERD) and erosive esophagitis (EE), and Zollinger-Ellison (ZE) syndrome in adults.

[0089] In a further aspect, the present invention provides a concentrated, storage-stable, non-aqueous composition of pantoprazole, comprising:

[0090] Pharmaceutically acceptable salts (APIs) of pantoprazole in doses of 20-80 mg, expressed in pantoprazole amounts.

[0091] The amount of polyethylene glycol used to dissolve the API.

[0092] Optional stabilizer, preferably an alkali metal hydroxide, more preferably sodium hydroxide.

[0093] The composition is contained in a volume equal to or less than 1.0 ml.

[0094] Preferably, the amount of API contained in 1 ml or less is 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mg of pantoprazole; which is in the form of a pharmaceutically acceptable salt (API) of pantoprazole.

[0095] In a preferred embodiment, the volume of the composition according to the invention is equal to or less than 0.5 ml. This is a suitable volume for injection. Preferably, the composition is contained in 0.5 mL. Preferably, the injection volume is 0.5 mL. In an alternative embodiment, the volume of the composition according to an embodiment of the invention is 0.25 mL.

[0096] In another preferred embodiment, the concentrated, storage-stable, non-aqueous composition according to embodiments of the invention has a storage stability of at least 6 months, more preferably at least 12 months, even more preferably at least 18 months, and most preferably at least 24 months, measured at 25°C and 60% relative humidity, wherein the composition contains equal to or less than 4.0% w / w total impurities, as determined by HPLC. More preferably, the level of total impurities is less than 3.5% w / w, even more preferably less than 3.0% w / w, and most preferably less than 2.5% w / w.

[0097] In a preferred embodiment, the concentrated, storage-stable, non-aqueous composition of the present invention contains an impurity C of 2.5% w / w or less, as determined by HPLC. More preferably, the level of impurity C is less than 2.2% w / w; even more preferably less than 2.0% w / w; and most preferably less than 1.5% w / w.

[0098] Pantoprazole and related substances are discussed in Ph.Eur. and USP Monograph for Pantoprazole, Sodium Sesquihydrate, Organic Impurities Test 2.

[0099] In a preferred embodiment, the pharmaceutically acceptable pantoprazole salt is a sodium salt. More preferably, the pharmaceutically acceptable pantoprazole salt is pantoprazole sodium sesquihydrate.

[0100] In a preferred embodiment, the concentrated, storage-stable, non-aqueous pantoprazole composition according to embodiments of the present invention contains 40 mg of the pharmaceutically acceptable pantoprazole salt in a volume of 0.5 ml, expressed in the amount of pantoprazole.

[0101] In the embodiments, the stabilizer is a pH adjuster selected from strong bases, such as alkali metal compounds, such as alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, and cesium hydroxide; or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate, calcium hydroxide, and magnesium hydroxide; or strongly basic substances, such as arginine. Preferably, the stabilizer is an alkali metal hydroxide; more preferably, the stabilizer is sodium hydroxide.

[0102] In another embodiment, the amount of stabilizer is 0.01 to 1.50 mg / mL, preferably 0.03 to 1.20 mg / mL, more preferably 0.05 to 0.50 mg / mL, and most preferably 0.1 to 0.3 mg / mL.

[0103] In a preferred embodiment, the amount of sodium hydroxide is 0.05 to 0.50 mg / mL, preferably 0.1 to 0.3 mg / mL. Typically, it is about 0.2 mg / mL.

[0104] Most preferably, the composition according to an embodiment of the invention comprises 0.1 to 1.50 mg / mL sodium hydroxide, even more preferably 0.2 to 1.40 mg / mL sodium hydroxide, even more preferably 0.3 to 1.30 mg / mL, and even more preferably 0.4 to 1.2 mg / mL; most preferably 0.2 mg / mL.

[0105] In a preferred embodiment, the concentrated, storage-stable, non-aqueous pantoprazole composition comprises:

[0106] 40 mg pantoprazole, in the form of pantoprazole sodium sesquihydrate salt (API).

[0107] The amount of polyethylene glycol used to dissolve the API.

[0108] Sodium hydroxide, used as a stabilizer, is preferably present in an amount of 0.01 to 1.5 mg / mL, more preferably 0.03 to 1.0 mg / mL, even more preferably 0.05 to 0.50 mg / mL, and most preferably 0.1 to 0.3 mg / mL.

[0109] The composition is contained in a volume of 0.5 mL.

[0110] In a preferred embodiment, the concentrated, storage-stable, non-aqueous pantoprazole composition comprises:

[0111] 40 mg pantoprazole, in the form of pantoprazole sodium sesquihydrate salt (API).

[0112] The amount of polyethylene glycol used to dissolve the API.

[0113] Sodium hydroxide, used as a stabilizer, is present in an amount of 0.1 to 0.3 mg / mL.

[0114] The composition is contained in a volume of 0.5 mL.

[0115] The most preferred solvent is polyethylene glycol, which is the only solvent present.

[0116] In a preferred embodiment, the concentrated, storage-stable, non-aqueous pantoprazole composition comprises:

[0117] 40 mg pantoprazole, in the form of pantoprazole sodium sesquihydrate salt (API).

[0118] The amount of polyethylene glycol used to dissolve the API.

[0119] Sodium hydroxide, used as a stabilizer, is present in an amount of 0.1 to 0.3 mg / mL.

[0120] The composition is contained in a volume equal to 0.5 mL.

[0121] Furthermore, the composition has storage stability of at least 1 year as measured at 25°C and 60% relative humidity, wherein the composition contains equal to or less than 4.0% w / w total impurities and / or less than 2.5% w / w impurity C, as determined by HPLC.

[0122] In a preferred embodiment, the polyethylene glycol contained in the composition according to the invention has an average molecular weight of less than 500, more preferably less than 300, and alternatively less than 200 or 100. Most preferably, the non-aqueous solvent is PEG 300 (average Mw 300).

[0123] Preferably, the polyethylene glycol excipient used in the preparation of the formulation in this invention is prevented from oxidation by covering it with an inert gas (e.g., nitrogen or argon).

[0124] In a preferred embodiment, the polyethylene glycol excipient used in this invention has an ethylene glycol (EG) and diethylene glycol (DEG) content of less than or equal to 0.1 w / v. More preferably, the liquid composition according to an embodiment of the invention has an EG and DEG content of less than or equal to 0.1 w / v. See FDA Guidance (May 2023), Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol solution, and other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol. USP General Chapter 469 Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances provides a gas chromatographic assay procedure for impurity analysis of EG / DEG.

[0125] In a preferred embodiment, the concentrated, storage-stable, liquid pantoprazole composition according to embodiments of the present invention has a dissolved oxygen content of less than 10 ppm. More preferably, the dissolved oxygen content is less than 5 ppm, and even more preferably less than 2 ppm. The dissolved oxygen content can be reduced by bubbling the composition with nitrogen. The dissolved oxygen content is measured using a fiber optic oxygen transmitter (PreSens, Microx 4). The fiber optic syringe needle is inserted into the solution to be measured and the measurement of the dissolved oxygen level begins. The reading is recorded in ppm.

[0126] In a preferred embodiment, the concentrated, storage-stable, liquid pantoprazole composition according to embodiments of the invention preferably has a water content of less than 4.0% w / v. More preferably, the water content is less than 3.0% w / v; even more preferably less than 2.0% w / v; and most preferably less than 1.8% w / v. The water content is maintained at a low level by selecting raw materials with low water content, especially polyethylene glycol. Moisture content is maintained at a low level during the preparation and filling processes. Advantageously, the storage containers are pre-rinsed and dried. The water content can be determined using the Karl Fisher moisture determination method, known to those skilled in the art.

[0127] In a preferred embodiment, a concentrated, storage-stable, liquid pantoprazole composition according to embodiments of the invention is provided for intravenous administration. This specifically refers to physiologically acceptable compositions, for example, in terms of osmolality and pH. pH measurements are performed between 23°C and 25°C. As a substantially non-aqueous product, pH is measured by mixing 0.5 mL of the sample with 10 mL of carbon dioxide-free water and 30 μL of a saturated potassium chloride (KCl) solution (PEG USP monograph).

[0128] Preferably, the pH of the composition is between 9.0 and 11.5, including the endpoint; more preferably between 9.2 and 10.5; even more preferably between 9.6 and 10.2; and most preferably between 9.7 and 9.9.

[0129] In a preferred embodiment, the composition does not contain a metal scavenger. Preferably, the composition does not contain Na-EDTA.

[0130] In a further aspect, the present invention provides the use of the compositions according to embodiments of the present invention. The present invention also provides a method for processing the compositions according to embodiments of the present invention.

[0131] In an embodiment, the present invention provides a concentrated, storage-stable, non-aqueous pharmaceutically acceptable salt composition of pantoprazole according to an embodiment of the present invention for treating a patient suffering from a gastrointestinal disorder, wherein 1 ml or less of the composition is administered intravenously to the patient without prior dilution.

[0132] In a further aspect, the present invention provides a method for treating patients suffering from gastrointestinal disorders, comprising the step of administering by bolus injection a concentrated, storage-stable, non-aqueous composition of a pharmaceutically acceptable salt of pantoprazole according to an embodiment of the invention. This is advantageous because it provides a ready-to-use medication. It offers time savings for hospital staff as no preparation steps are required. Dilution errors are eliminated.

[0133] In another aspect, the present invention relates to a method for treating a patient suffering from a gastrointestinal disease, comprising the steps of: diluting a composition of a concentrated, storage-stable, non-aqueous, pharmaceutically acceptable salt of pantoprazole according to an embodiment of the present invention to 0.4-4.0 mg / ml of a pharmaceutically acceptable salt of pantoprazole, denoted as pantoprazole, with a suitable aqueous diluent; thereafter administering the obtained diluted composition to the patient by infusion (dilution-ready type).

[0134] In a preferred embodiment, after dilution, the final product has a concentration of 0.4, 0.8, 1.3, or 4 mg pantoprazole equivalents / ml. A suitable diluent can be used to obtain the dilution.

[0135] Suitable diluents for use in this method are selected from water for injection (WFI; 0.9% NaCl aqueous solution, 5% dextrose solution).

[0136] In a preferred embodiment, the final product has a weight molar osmotic pressure concentration of 250-1000 mOsmol / kg.

[0137] In a preferred embodiment, the final product has a pH of 9.0 to 10.5, preferably 9.6 to 10.2, and even more preferably 9.7 to 9.9.

[0138] More preferably, the diluted composition obtained by diluting the concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention has a weight molar osmotic pressure concentration of 200-1000 mOsmol / kg and a pH of 8.2-10.5.

[0139] Most preferably, the diluted composition obtained by diluting the concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention has a weight molar osmolality of 220-600 mOsmol / kg and a pH of 8.5-10.0.

[0140] Specifically, the present invention provides a method for treating a patient suffering from a gastrointestinal disease, comprising the following steps: diluting a composition of a concentrated, storage-stable, non-aqueous pantoprazole salt according to an embodiment of the present invention to 0.4-4.0 mg / ml of a pharmaceutically acceptable salt of pantoprazole, denoted as pantoprazole, with a suitable aqueous diluent; thereafter administering the obtained diluted composition to the patient by infusion (dilution-ready type).

[0141] In this procedure, the ready-to-use composition is diluted to a preferred concentration. Under conditions suitable for liquid administration, there is no reconstitution time to obtain a solid composition, such as a lyophilized powder or a frozen infusion bag. In contrast, the ready-to-use diluted product according to embodiments of the invention provides increased comfort for hospital staff.

[0142] In a preferred embodiment, the final product, obtained by dilution of the composition according to an embodiment of the invention, is administered to the patient and has a weight molar osmolality of 200-1000 mOsmol / kg.

[0143] In a preferred embodiment, the final product having a pH of 8.2 to 10.5, or even more preferably 8.5 to 10.0, is administered to the patient.

[0144] Suitable diluents for use in this method are selected from water for injection (WFI; 0.9% NaCl aqueous solution, 5% dextrose solution).

[0145] Preferably, when diluted in water for injection to obtain a pantoprazole concentration of 4 mg / mL, the resulting diluted formulation has a weight molality osmolality between 150 and 600 mOsmol / kg, inclusive. More preferably, the resulting diluted product has a weight molality osmolality of 200-260 mOsmol / kg, and most preferably 220-250 mOsmol / kg.

[0146] Preferably, when diluted in 0.9% sodium chloride to obtain a pantoprazole concentration of 4 mg / mL, the resulting diluted formulation has a weight molality osmolality between 200 and 1000 mOsmol / kg, including the endpoints. More preferably, the resulting diluted product has a weight molality osmolality of -200 to 800 mOsmol / kg. Even more preferably, -220 to 750 mOsmol / kg, and most preferably, 220 to 650 mOsmol / kg.

[0147] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate (expressed as pantoprazole) in 1 mL or less of polyethylene glycol is diluted to a total volume of 100 mL of 0.9% NaCl to obtain an aqueous solution of 4-8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmotic pressure concentration of 200-600 mOsmol / kg and a pH of 8.4-10.0; most preferably 8.9-9.5.

[0148] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate in polyethylene glycol is first diluted with 10 mL of 0.9% NaCl or dextrose solution, and then further diluted with 0.9% sodium chloride or 5% dextrose solution to a total volume of 100 mL, thereby obtaining an aqueous solution of 0.4-0.8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmolality of 200-400 mOsmol / kg and a pH of 8.4-10.5.

[0149] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate in polyethylene glycol is first diluted with 10 mL of 0.9% sodium chloride solution, and then further diluted with 0.9% sodium chloride solution to a total volume of 100 mL, thereby obtaining an aqueous solution of 0.4-0.8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmotic pressure concentration of 200-400 mOsmol / kg and a pH of 8.4-10.5.

[0150] Preferably, in the method according to an embodiment of the invention, 40-80 mg of pantoprazole sodium sesquihydrate (expressed as pantoprazole) in 1.0 mL of polyethylene glycol solution is diluted in 100 mL of an infusion bag containing 0.9% sodium chloride or 5% dextrose to obtain an aqueous solution of 0.4-0.8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmolar concentration of 200-650 mOsmol / kg and a pH of 8.4-10.5.

[0151] In another aspect, the present invention provides a method for manufacturing a concentrated, storage-stable, liquid pantoprazole composition according to an embodiment of the present invention, comprising the following steps:

[0152] i) Optionally, purge the polyethylene glycol solution with nitrogen until the dissolved oxygen content is less than 2 ppm.

[0153] ii) Optionally, heat the polyethylene glycol solution from step i) to 45°C-55°C.

[0154] iii) A stabilizer is dissolved in polyethylene glycol, preferably an alkali metal hydroxide, more preferably sodium hydroxide, and even more preferably sodium hydroxide sesquihydrate.

[0155] iv) Optionally, cool the solution from step iii) to no more than 25°C.

[0156] v) Add 20-80 mg of a pharmaceutically acceptable salt (API) of pantoprazole, expressed as an amount of pantoprazole, to the cooled solution.

[0157] vi) Optionally, make up the volume of the solution from step v to the desired final volume using polyethylene glycol.

[0158] vii) Optionally, the solution from step vi is aseptically filtered.

[0159] Alternatively, the present invention provides a method for manufacturing a concentrated, storage-stable, non-aqueous pantoprazole composition according to an embodiment of the invention, comprising the following steps:

[0160] - Provides polyethylene glycol with an oxygen content of less than 2 ppm.

[0161] - Heat the polyethylene glycol to a temperature between 45°C and 55°C.

[0162] - A certain amount of stabilizer is dissolved in warm polyethylene glycol, preferably an alkali metal hydroxide, more preferably sodium hydroxide.

[0163] - Cool the mixture obtained in the previous step to below 25°C.

[0164] - Add a pharmaceutically acceptable salt of pantoprazole to the cooled liquid mixture to obtain a pantoprazole solution of 40-80 mg / mL.

[0165] Preferably, the 40-80 mg / mL pantoprazole solution is divided into 1 mL or smaller portions, and each portion is filled into a packaging container, preferably into a dehydrogenated transparent glass vial, syringe or pen.

[0166] In a further aspect, the present invention provides a packaging container comprising one or more unit doses of a concentrated, storage-stable, non-aqueous composition of a pharmaceutically acceptable salt of pantoprazole according to an embodiment of the present invention.

[0167] Preferably, the headspace of the packaging container covering the concentrated, storage-stable, liquid pantoprazole composition has an oxygen content of less than 10%; more preferably less than 7%, even more preferably less than 5%, and most preferably less than 2%. The headspace oxygen content can be obtained by purging the packaging container with nitrogen during the filling operation. The headspace oxygen content is measured using a fiber optic oxygen transmitter (PreSens, Microx 4). The measurement is performed as follows: the vial is punctured with a fiber optic syringe needle, and the headspace oxygen level is measured as a percentage (%).

[0168] In a preferred embodiment, the packaging container is a multi-dose packaging container.

[0169] Preferably, the multi-dose packaging container is a glass vial, syringe, or pen. More preferably, the (multi-dose) packaging container for containing the composition according to an embodiment of the invention is provided with an inert atmosphere, such as nitrogen or argon.

[0170] In a final aspect, the present invention provides a pre-filled syringe comprising a concentrated, storage-stable, liquid pantoprazole composition according to an embodiment of the invention.

[0171] The present disclosure has now been generally described and will be more readily understood by referring to the following embodiments, which are only for illustrating certain aspects and implementations of the present disclosure and are not intended to limit the present disclosure in any way.

[0172] Example

[0173] Although the invention is further illustrated by the examples, it is not limited to the following examples as long as the spirit of the invention is not followed. The values ​​of various manufacturing conditions and evaluation results in the following examples refer to preferred values ​​of the upper or lower limits in the embodiments of the invention, and the preferred range may be a range defined by the combination of the above upper or lower limits and the values ​​of the following examples or the values ​​of the examples.

[0174] Examples 1 to 4

[0175] Table 1 shows a comparative description of the different formulations of the compositions of Examples 1-4. All examples contained pantoprazole dissolved in a non-aqueous solvent system. Examples 3 and 4 further contained a pH adjuster as a stabilizer. The stability of the formulations was evaluated based on stability data obtained under accelerated, intermediate, and long-term stability conditions as shown in Tables 2, 3, and 4, respectively. Therefore, the stability of the compositions was evaluated based on the percentage amount (% w / w) of the relevant substances. Among the different types of impurities analyzed for stability testing, the most significant impurity was impurity C, and data for impurity C were analyzed in addition to the total impurity content under different conditions.

[0176] Compared to the other formulations of Examples 1 and 2 without sodium hydroxide, Example 3 containing sodium hydroxide showed a better stability profile, especially with respect to impurity-C levels. Example 3 containing sodium hydroxide and the organic solvent PEG300 showed a better stability profile than Example 1 without sodium hydroxide, especially for impurity-C levels. Example 3 containing sodium hydroxide as a stabilizer and PEG 300 as a solvent system showed a better stability profile than Example 4, especially for impurity-C levels, which contained the same sodium hydroxide as a pH adjuster but used propylene glycol instead of PEG 300 as the solvent system.

[0177] α-Tocopherol was also tested as a stabilizer, but it precipitated when diluted with 0.9% sodium chloride solution.

[0178] The results suggest that PEG, preferably PEG 300, with sodium hydroxide provides a formulation with improved stability, which can be stored at a controlled room temperature of 20°–25°C (68°–77°F).

[0179] Table 1: Compositions

[0180]

[0181] QS: Sufficient quantity

[0182] API: Pantoprazole sodium sesquihydrate

[0183] The relevant substance (% w / w) results for the compositions provided in Table 1 are summarized in Table 2.

[0184] Table 2: Accelerated stability (40°C / 75%RH)

[0185]

[0186] M: Month

[0187] ND: Not detected

[0188] Table 3: Mid-term stability (30°C / 65%RH)

[0189]

[0190] Table 3: Interim stability (30°C / 65%RH) – Continued

[0191]

[0192] ND: Not detected

[0193] M: Month

[0194] Table 4: Long-term stability (25°C / 60%RH)

[0195]

[0196] Table 4: Long-term stability (25°C / 60%RH) – Continued

[0197]

[0198] ND: Not detected

[0199] M: Month

[0200] Examples 5 to 8: NaOH amount

[0201] Other compositions were prepared and are summarized in Table 5.

[0202] Given the use of a relatively high amount of sodium hydroxide, Example 8 was prepared using heating. The inventors found that this had a positive effect on the water content.

[0203] Based on the development work carried out, the following optimized manufacturing process was obtained.

[0204] Manufacturing process:

[0205] Step 1: Distribute active and inactive ingredients

[0206] Step 2: Collect the required amount of polyethylene glycol (PEG) in a mixing container.

[0207] Step 3: Purge the PEG with nitrogen to obtain the desired dissolved oxygen (DO) level, less than 2 ppm.

[0208] Step 4: When using sodium hydroxide, heat the PEG to 45°C-55°C and add the weighed sodium hydroxide to the mixing container, stirring until a clear solution is formed.

[0209] Step 5: Then cool the PEG solution to no more than 25°C and add the weighed amount of pantoprazole, preferably pantoprazole sodium sesquihydrate, and stir until a clear solution is obtained.

[0210] Step 6. Make up the volume to 100% with polyethylene glycol and stir to obtain a homogeneous solution.

[0211] Step 7: The solution is aseptically filtered through a 0.22-micron PVDF filter to obtain a sterile filtrate.

[0212] Step 8: Aseptically fill the filtered bulk solution into a dehydrogenated clear glass vial, then plug and seal it.

[0213] For the compositions summarized in Table 5, the PEG used was PEG300.

[0214] All embodiments contain less than 2 ppm of oxygen and less than 3% oxygen in the headspace.

[0215] Table 5: Pantoprazole Compositions with and without Stabilizers

[0216]

[0217] QS: Sufficient quantity

[0218] API: Pantoprazole sodium sesquihydrate

[0219] Heating is used during manufacturing.

[0220] Samples were stored under different conditions, and assay contents, sample characteristics (pH, wt. molality, water content), and impurity levels were determined at regular time intervals. Results obtained under storage conditions of 25°C and 60% relative humidity are provided in Table 6. Regarding impurities, the most important impurity, C, is reported together with the total impurities.

[0221] in conclusion:

[0222] The results showed that pantoprazole in PEG with sodium hydroxide provided formulations with improved stability, especially for impurity C levels. These solutions could be stored for extended periods at a controlled room temperature of 20°–25°C (68°–77°F).

[0223] Actual results show a shelf life of at least 6 months at room temperature. Extrapolation suggests a shelf life of at least 2 years under these storage conditions. This is commercially relevant and enables the use of the product throughout the supply chain, from large-scale manufacturer to patient, including storage and distribution.

[0224] Based on storage conditions of 40°C, Example 8 shows that prolonged exposure of the final product to elevated temperatures should be avoided to ensure an extended shelf life.

[0225]

[0226]

[0227]

[0228] Examples 9 to 11: Weight molality of osmotic pressure

[0229] The following formulations were prepared as described in Table 8 below. Furthermore, the weight molality osmolality of each formulation was measured at four recommended different dilution concentrations using the freezing point depression method. The results are shown in Table 9 below. Diluents were prepared using water for injection, 0.9% sodium chloride solution (NaCl), or 5% preferably a sugar solution.

[0230] Table 8: Compositions

[0231]

[0232] API: Pantoprazole sodium sesquihydrate

[0233] QS: Sufficient quantity

[0234] As can be seen from Table 9 below, in Example 9, the formulations, without freezing at concentrations of 4 mg / mL and 0.8 mg / mL, exhibited very high theoretically calculated molality osmolality values. In Example 10, the composition showed a significant reduction in molality osmolality values. However, the molality osmolality values ​​of Example 10 still exceeded the tolerable molality osmolality range for the 4 mg / mL dilution. In Examples 11 and 5, the compositions showed molality osmolality values ​​below the recommended upper limit of 1000 mOsm / kg for small-volume injections (≤100 mL) for intravenous administration at all dilution concentrations. Furthermore, as can be seen from Examples 5, 6, 7, and 8, the molality osmolality values ​​were well below 1000 mOsm / kg and close to the molality osmolality of reconstituted solutions of Protonix iv, a US Reference Listed Drug (RLD).

[0235]

[0236] Example 12: More preferred compositions (diluted, undiluted)

[0237] Table 10: Preferred Compositions

[0238]

[0239] WFI: Water for injection

[0240] API: Pantoprazole sodium sesquihydrate

[0241] Density PEG 300: 1.127 g / mL

[0242] QS: Sufficient quantity

[0243] pH was tested according to a procedure equivalent to that recommended by the USP for pH measurement of PEG (0.5 mL sample + 10 mL water + 30 μL saturated potassium chloride solution).

[0244] Example 13: Use of the composition in clinical practice - undiluted

[0245] The inventors have discovered that the compositions according to the invention, wherein a highly concentrated pantoprazole composition (40-80 mg / mL) is contained in a non-aqueous polyethylene glycol solvent, can be administered directly intravenously to patients, provided that the volume is kept below 1 mL, preferably corresponding to 0.5 mL. This overcomes the prejudice that pantoprazole-based PEG solutions require dilution before use in human patients.

[0246] Patients with gastrointestinal disorders requiring proton pump inhibition are prescribed pantoprazole IV. The composition according to the invention is administered intravenously to the patient by direct injection of 0.5 ml of pantoprazole stable at 40-80 mg / mL in PEG solution.

[0247] The products of this invention have the advantage of being directly accessible to caregivers and patients. Pre-diluting of the lyophilized composition is unnecessary. Treatment can be administered without thawing frozen infusion bags.

[0248] Example 14: Use of the composition in clinical practice - Dilution

[0249] Alternatively, 0.5 ml of pantoprazole at a stable concentration of 40-80 mg / mL in PEG solution is introduced into the infusion bag. For example, a syringe filled with 0.5 ml of the composition is injected into the infusion bag. A preferred dilution factor is ×10 to ×100.

[0250] As can be seen from the examples, the selection of a suitable diluent provides a physiologically acceptable formulation (weight mol osmolality, pH) without the need for separate addition of weight mol osmolality adjusters or pH adjusters.

[0251] The advantage of this treatment method is its compatibility with existing procedures for administering pantoprazole via infusion. Using the composition according to embodiments of the invention is advantageous because it is readily available as a liquid, thus avoiding concerns about particle size when diluting lyophilized compositions.

[0252] Example 15: Preferred Compositions (Diluted, Undiluted)

[0253] Table 11 provides compositional details for an optimized formulation of pantoprazole sodium injection 40 mg / 0.5 mL (heating required).

[0254] Table 11: Preferred Undiluted Compositions

[0255]

[0256] qs: sufficient quantity

[0257] Example 16: Overview of pH and wt. molality of diluted solutions obtained from the concentrated formulation with 0.2 mg / mL NaOH in Table 11.

[0258] Example 16.a. Water for injection (4 mg / mL; dilution concentration only)

[0259] Table 12

[0260]

[0261] Example 16. b 0.9% NaCl (4 mg / mL)

[0262] Table 13

[0263]

[0264] Example 16. c 0.9% NaCl (0.4 mg / mL)

[0265] Table 14

[0266]

[0267] Example 16. d-dextrose (4 mg / mL)

[0268] Table 15

[0269]

[0270] Example 16. e-dextrose (0.4 mg / mL)

[0271] Table 16

[0272]

[0273] Example 17: Weight molality and pH value observed after dilution of the formulation according to Table 11

[0274] Table 17: Weight molality, osmotic concentration, and pH value of the obtained diluents

[0275]

Claims

1. A concentrated, storage-stable, non-aqueous pantoprazole composition comprising: Pharmaceutically acceptable salts (APIs) of pantoprazole in doses of 20-80 mg, expressed in pantoprazole amounts. The amount of polyethylene glycol used to dissolve the API. Optional stabilizer, preferably an alkali metal hydroxide, more preferably sodium hydroxide. The composition is contained in a volume equal to or less than 1.0 ml.

2. The concentrated, storage-stable, non-aqueous pantoprazole composition according to claim 1, wherein the volume is equal to or less than 0.5 ml.

3. The concentrated, storage-stable, non-aqueous pantoprazole composition according to claim 1 or 2, having a storage stability of at least 1 year as measured at 25°C and 60% relative humidity, wherein the composition contains equal to or less than 4.0% w / w total impurities, as determined by HPLC.

4. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 3, wherein the composition contains impurity C equal to or less than 2.5% w / w, as determined by HPLC.

5. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of the pantoprazole salt is pantoprazole sodium sesquihydrate.

6. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 5, wherein 40 mg of a pharmaceutically acceptable salt (API) of said pantoprazole, expressed in the amount of pantoprazole, is contained in a volume of 0.5 ml.

7. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 6, wherein the concentration of the stabilizer is 0.01 to 1.50 mg / mL, preferably 0.03 to 1.20 mg / mL, even more preferably 0.05 to 0.50 mg / mL, and most preferably 0.1 to 0.3 mg / mL.

8. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 7, wherein the stabilizer is sodium hydroxide at a concentration of 0.05 to 0.50 mg / mL; preferably 0.1 to 0.3 mg / mL.

9. The concentrated, storage-stable, non-aqueous pantoprazole according to any one of claims 1 to 8, wherein the polyethylene glycol has an average molecular weight of less than 500, preferably PEG300 (average Mw 300).

10. The concentrated, storage-stable, non-aqueous pantoprazole according to any one of claims 1 to 9, wherein the dissolved oxygen content is less than 10 ppm, preferably less than 5 ppm, and most preferably about 2 ppm.

11. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 10, wherein the water content is equal to or less than 4.0% w / v.

12. The concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 11, for the treatment of patients with gastrointestinal disorders, wherein 1 ml or less of the composition is administered intravenously to the patient without prior dilution.

13. A treatment method for patients suffering from gastrointestinal diseases, comprising the step of administering, by bolus injection (ready-to-use), the concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 11 without prior dilution.

14. A treatment method for a patient suffering from a gastrointestinal disease, comprising diluting a concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 11 to a pharmaceutically acceptable salt of pantoprazole, denoted as pantoprazole, to 0.4-4.0 mg / ml using a suitable aqueous diluent; thereafter administering the resulting diluted composition to the patient by infusion (dilution-ready type).

15. The treatment method according to claim 14, wherein the weight molar osmotic pressure concentration of the obtained diluted composition is 200-1000 mOsmol / kg.

16. The treatment method according to claim 14 or 15, wherein the pH of the obtained diluted composition is 9.0-10.5, preferably 9.6-10.2, and even more preferably 9.7-9.

9.

17. The treatment method according to any one of claims 14 to 16, wherein the diluent is selected from water for injection, 0.9% sodium chloride solution (NaCl), or 5% dextrose solution.

18. The treatment method according to any one of claims 14 to 17, wherein 40-80 mg of pantoprazole sodium sesquihydrate in 1 mL or less of polyethylene glycol is diluted with 10 mL of water for injection to obtain an aqueous solution of 4-8 mg / mL pantoprazole sodium sesquihydrate having a weight molality of 200-350 mOsmol / kg and a pH of 9.6-10.

2.

19. The treatment method according to any one of claims 14 to 17, wherein 40-80 mg of pantoprazole sodium sesquihydrate, expressed as pantoprazole, in a volume of 1 mL or less of polyethylene glycol solution is first diluted with 10 mL of water for injection, and then further diluted to a total volume of 100 mL of 0.9% sodium chloride or 5% dextrose, thereby obtaining an aqueous solution of 0.4-0.8 mg / mL pantoprazole sodium sesquihydrate having a weight molar osmolality of 200-400 mOsmol / kg and a pH of 9.6-10.

2.

20. A packaging container containing one or more unit doses of a concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 12.

21. The packaging container of claim 20, wherein the concentrated, storage-stable, non-aqueous pantoprazole composition is covered by a headspace having an oxygen content of less than 10%, preferably less than 5%, and even more preferably less than 2%.

22. The packaging container according to claim 20 or 21, wherein the packaging container is a glass vial, syringe, or pen.

23. A pre-filled syringe comprising a concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 12.

24. A method for manufacturing a concentrated, storage-stable, non-aqueous pantoprazole composition according to any one of claims 1 to 12, comprising the following steps: - Provides polyethylene glycol with an oxygen content of less than 2 ppm, - Heat the polyethylene glycol to a temperature between 45°C and 55°C. - A certain amount of stabilizer is dissolved in warm polyethylene glycol, preferably an alkali metal hydroxide, more preferably sodium hydroxide. - Cool the mixture obtained in the previous step to below 25°C. - Add a pharmaceutically acceptable salt of pantoprazole to the cooled liquid mixture to obtain a 40-80 mg / mL pantoprazole solution.

25. The manufacturing method according to claim 24, wherein the 40-80 mg / mL pantoprazole solution is aliquoted into 1 mL or smaller portions and each portion is filled into a packaging container, preferably into a dehydrogenated transparent glass vial, syringe or pen.

Images