WO2025041069A1

WO2025041069A1 - Stabilized pharmaceutical compositions of proton pump inhibitors

Info

Publication number: WO2025041069A1
Application number: PCT/IB2024/058162
Authority: WO
Inventors: Reena Patel; Dinesh Patel; Sachin Patel; Shashikant KURANI; Milind Sathe; Surjyanarayan Mandal
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-08-23
Filing date: 2024-08-22
Publication date: 2025-02-27
Anticipated expiration: 2026-02-23

Abstract

The present invention relates to clear stable ready to use (RTU) aqueous injectable compositions of proton pump inhibitor compounds, in particular pantoprazole and rabeprazole and salts thereof and to processes to prepare such compositions. The compositions comprise proton pump inhibitor compounds, L-arginine, at least one antioxidant and at least one chelating agent.

Description

STABILIZED PHARMACEUTICAL COMPOSITIONS OF PROTON PUMP INHIBITORS Field of the Invention The present invention provides clear stable ready to use injectable compositions of Proton pump inhibitors. The invention also provides process for preparation of said injectable compositions. The compositions are ready to use compositions. Background of the Invention Proton pump inhibitors (PPIs) belong to benzimidazole class of compounds and used to treat gastric acidity and ulcer. Omeprazole, lansoprazole, rabeprazole and pantoprazole are some of PPIs that are used for the treatment of treatment of heartburn and acid-related disorders PPIs are available in the form of tablets, capsules or delayed release tablets, powder for injection. Ready to use injections which don’t need reconstitution before use are not available till date. The reason being, PPIs are sensitive to light, humidity, temperature, pH and are prone to acid degradation, to destruction by hydrolysis and are highly unstable and very susceptible to external environment and to fast decay and disintegration. Therefore, PPI’s are formulated as lyophilized powders or cakes, which are to be reconstituted before use. Number of available documents teach solid dosage forms such as granules, enteric coated pellets, multilayered and taste masked tablets, disintegrating capsules of PPIs. PPI particles in solid dosage forms such as tablets, lyophilized powders are often surrounded by protective excipients ie by inert or alkaline substances. The alkaline substances are added to granules of PPIs while preparing lyophilized powder. Accordingly, the solid forms comprising PPIs after dissolving in water are required to be consumed immediately. Delay in consumption results in degradation of the PPI active. PPIs are highly unstable in organic and aqueous vehicles. Reconstituted PPI solutions also have short life. Therefore to formulate liquid ready to use clear stable injectable compositions is a great challenge. WO2002041919 discloses lyophilized preparations of pantoprazole. The preparation is required to be reconstituted with physiological saline before use. EP0649,655 discloses reconstitution of the lyophilized preparation of benzimidazole with sterile distilled water.. AU674015B2 discloses a lyophilized product of an alkaline aqueous solution a lyophilized product of an alkaline aqueous solution of 2-[(2-pyridyl)methylsulfinyl]-benzimidazole compound(omeprazole). WO2004/063152 discloses a liquid formulation of lansoprazole for parenteral administration containing one or more of an oil, a solvent, a surfactant or another excipient. WO/2002/015908 discloses an injectable formulation of a benzimidazole compound that contains 1 equivalent of a strong alkaline per mole of the compound and is substantially free from a nonaqueous solvent. WO2006082490 describes an injectable formulation comprising a benzimidazole compound; L-arginine; and, optionally one or more pharmaceutically acceptable excipients, wherein the molar ratio of benzimidazole and L-arginine is greater than about 1:20 and less than 1:80 when there is no alkali present. The injections of PPIs available in the market namely, PROTONIX I.V, NEXIUM I.V. , PREVACID I.V. are either lyophilized powders or freeze dried cakes and contain strong alkali Sodium hydroxide to ensure pH is above 9 upto 11 to render the solution stable. The injections are to be reconstituted just before use. Non-availability of ready to use solutions of PPIs is a great problem that needs immediate resolution. Preparing a solution of powder for injection is costly affair and adds to cost of health services besides polluting environment. In view of the problems and limitations of presently available proton pump inhibitors (PPIs) powder for injection, there is urgent need to provide clear stable ready to use aqueous injectable compositions which are economical, that can save time of health workers and that can resolve emergency situations which require immediate health services. There is need to provide the process to prepare clear stable ready to use aqueous injectable compositions of pantoprazole and Rabeprazole as these are not available. Objects of the invention The object of the invention is to provide clear stable, ready to use aqueous compositions of proton pump inhibitors (PPIs), in particular pantoprazole and rabeprazole. Another object is to provide a process for preparing ready to use aqueous compositions of proton pump inhibitors (PPIs), in particular pantoprazole and rabeprazole. Yet another object of the invention is to provide a method of treating gastric ulcers by administration of ready to use clear stable injectable compositions of proton pump inhibitors. Summary of the Invention The present invention solves the problems of prior art. The inventors found that a stable ready to use injectable composition can be prepared by using at least one antioxidant, at least one chelating agent and L-arginine in a particular amount with respect to the proton pump inhibitor (PPI) compound along with other optional excipients. The composition is prepared directly in liquid form and does not require the steps of lyophilization and reconstitution. The composition is a ready to use composition and was found stable for a longer time. The invention eliminates the need of lyophilization operations. Elimination of lyophilization simplifies the process of preparation and thus reduces the cost. The present invention eliminates need to maintain additional inventory of solvents. It also does away with skill to withdraw solvents and make up volume and helps in emergency situations. The present invention provides an aqueous ready to use, composition comprising a proton pump inhibitor (PPI), L-arginine, an antioxidant, and a chelating agent. The proton pump inhibitor is selected from Pantoprazole and Rabeprazole or sodium salt thereof. In one embodiment, the proton pump inhibitor is Pantoprazole. In another embodiment the proton pump inhibitor is sodium salt of Pantoprazole. In yet another embodiment, the proton pump inhibitor is Rabeprazole. In still another embodiment the proton pump inhibitor is sodium salt of Rabeprazole. In one embodiment the composition comprises proton pump inhibitor in an amount of 4 mg/ml. the composition comprises L-arginine in an amount between 60-75 mg/ml, antioxidant in an amount from 2-8.5 mg/ml, and chelating agent in an amount between 0.1-2 mg/ml. In an embodiment, the ratio of L-arginine to proton pump inhibitor is from 15:1 to 18.75:1. In another embodiment, the ratio of chelating agent to proton pump inhibitor is from 0.025:1 to 0.5:1. In yet another embodiment, the ratio of antioxidant to proton pump inhibitor is from 0.5:1 to 2.13:1. In second embodiment, the composition comprises proton pump inhibitor in an amount of 0.4 mg/ml. the composition comprises L-arginine in an amount between 2-3 mg/ml, antioxidant in an amount from 0.3-0.4mg/ml, and chelating agent in an amount between 0.1-0.2 mg/ml. In an embodiment, the ratio of L-arginine to proton pump inhibitor is from 5:1 to 7.5:1. In another embodiment, the ratio of chelating agent to proton pump inhibitor is from 0.25:1 to 0.5:1. In yet another embodiment, the ratio of antioxidant to proton pump inhibitor is from 0.75:1 to 1:1. The antioxidant is selected from ascorbic acid, monothioglycerol, sodium sulfite, sodium bisulfite, gentisic acid, gentisic acid ethanolamine, sodium metabisulfite, butylated hydroxytoluene, tocopherols and sodium thioglycolate or a combination thereof. In one embodiment, the antioxidant is sodium sulfite. In another embodiment, the antioxidant is sodium thioglycolate. In yet another embodiment, the antioxidant is a combination of sodium sulfite and sodium thioglycolate. The chelating agent is selected from sodium EDTA, disodium EDTA, edetate calcium disodium; and EDTA acetic acid salt. In one embodiment, the chelating agent is disodium EDTA. The composition optionally comprises alkaline substances or basic substances selected from meglumine or hydroxides or carbonates of sodium and potassium. In one embodiment, the alkaline substance is meglumine. In one another embodiment the composition comprises meglumine in an amount of 15mg/ml. In an embodiment, the composition comprises Pantoprazole in an amount of 4mg/ml, L-arginine in an amount of 70mg/ml, antioxidant in an amount of 6mg/ml and chelating agent in an amount of 0.10 mg/ml. In one particular embodiment, the antioxidant is sodium sulfite and chelating agent is disodium EDTA. The composition may also comprise a solvent selected from TRIS, normal saline (NS), and Dextrose 5% in water. In one particular embodiment, the solvent used is TRIS. In another embodiment the solvent used is normal saline (NS). In yet another embodiment the solvent is water. The composition also comprises one or more pharmaceutically acceptable excipients. In one particular embodiment the pharmaceutically acceptable excipient is tonicity modifying agent. In one embodiment, the tonicity modifying agent is normal saline (NS). The composition provided in the present invention is required to be stored in amber colour glass or an opaque plastic container. The composition remained stable for at least 6 months. Detailed Description of the Invention The present invention provides clear stable aqueous ready to use compositions of a proton pump inhibitor (PPI) compound. The PPI compound is selected from Pantoprazole or Rabeprazole or its free base or acid or alkali salt or acid salt, hydrate, ester, amide, enantiomer, isomer, tautomer, polymorph, derivative or a prodrug. The composition comprises at least one chelating agent, L- arginine and at least one antioxidant. The composition further comprises one or more pharmaceutically acceptable excipients. The term "injectable composition" refers to composition which is intended to be administered by injection route or parenteral route. Unlike prior art marketed compositions the compositions of present invention need not be reconstituted. These compositions are in the form of clear stable ready to use aqueous injectable compositions. The term "pharmaceutically acceptable excipient" as used herein may include one or more of solvents, co-solvents, buffers or pH adjusting agents, antimicrobial or antibacterial preservatives, tonicity modifying agents or tonicity contributors, and alkalizing substances. The “benzimidazole compound” compound herein is a proton-pump inhibitor (herein after also referred as PPI) preferably Pantoprazole or salt thereof and Rabeprazole or salt thereof. The salt herein is preferably a sodium salt. The quantity of PPI salt such as Pantoprazole sodium or Rabeprazole Sodium used is in an amount which is equivalent to Pantoprazole or Rabeprazole 4mg/ml or 0.4mg/ml, respectively. Ratios with other ingredients of the composition are calculated using quantity of PPI as 4mg or 0.4mg. Related Substances are structurally related to a drug substance. These substances may be identified or unidentified degradation products or impurities arising from a manufacturing process or during storage of a material. The term alkaline substances or basic substances refer to substances like meglumine or hydroxides or carbonates of sodium, potassium and are optional ingredients. As discussed above, the proton pump inhibitors are sensitive to light, humidity, and temperature. The PPI substances are prone to acid degradation and destruction by hydrolysis. Therefore, PPI substances are highly unstable and are formulated as lyophilized powders or cakes. Such lyophilized powders are required to be reconstituted before use. It was surprisingly observed that when L-arginine, a chelating agent and an antioxidant are incorporated with proton pump inhibitor in specific amounts, a stable ready to use aqueous composition is obtained. The composition is found stable for at least 6 months. The present invention provides an aqueous injectable composition comprising a proton pump inhibitor, at least one antioxidant, at least one chelating agent, and L-arginine. The composition optionally comprises one or more pharmaceutically acceptable excipients. The ready to use clear stable aqueous injectable compositions of the present invention may be used in the form of intravenous injection, intramuscular injection, subcutaneous injection or may be further diluted with suitable diluents to form a drip infusion as per physicians advise. In one embodiment, the composition comprises proton pump inhibitor in an amount of 4mg/ml. In second embodiment, the composition comprises proton pump inhibitor in an amount of 0.4 mg/ml. The proton pump inhibitor used in the present invention is selected from pantoprazole or Rabeprazole or sodium salt thereof. L-Arginine is incorporated in the composition in defined proportion to PPI substance. The term 'L-arginine' as used herein refers to L-arginine preferably, although it includes its salts. In the compositions comprising PPI in an amount of 4mg/ml, the amount of L-arginine is from 60- 75mg/ml. In one embodiment, the amount of L-arginine is 60mg/ml. In another embodiment, the amount of L-arginine is 70 mg/ml. In yet another embodiment, the amount of L-arginine is 75mg/ml. Presence of L-Arginine in specific proportion to PPIs is of critical importance. In one embodiment, the ratio of L-arginine: PPI in the composition is from 15:1 to 18.75:1. In the compositions comprising PPI in an amount of 0.4mg/ml, the amount of L-arginine is from 2-3 mg/ml. In one embodiment, the amount of L-arginine is 2 mg/ml. In another embodiment, the amount of L-arginine is 3mg/ml. In such compositions, the ratio of L-arginine: PPI is from 5:1 to 7.5:1. The composition comprises at least one antioxidant. It was observed that use of more than one antioxidant further improves the stability of the injectable composition of the present invention. The antioxidants namely ascorbic acid, Monothioglycerol, sodium sulfite, sodium bisulfite, gentisic acid, gentisic acid ethanolamine, sodium metabisulfite, butylated hydroxytoluene, tocopherols and sodium thioglycolate are suitable to prepare ready to use stable compositions of the present invention. In one embodiment, the antioxidant used is sodium sulfite. In another embodiment, the antioxidant used is sodium thioglycolate. In still another embodiment, more than one antioxidant is used. In one embodiment, combination of sodium sulfite and sodium thioglycolate provides stable solution. In the compositions comprising PPI in an amount of 4mg/ml, the amount of antioxidant used is from 2-8.5 mg/ml. In one embodiment, the amount of antioxidant used is 2mg/ml. In another embodiment, the amount of antioxidant used is 8.5 mg/ml. In one particular embodiment, the composition comprises sodium sulfite in an amount of 2mg/ml. In another particular embodiment, the composition comprises a combination of sodium sulfite and sodium thioglycolate in an amount of 8.5 mg/ml. The ratio of antioxidant to PPI is from 0.5:1 to 2.13:1. In the compositions comprising PPI in an amount of 0.4mg/ml, the amount of antioxidant used is from 0.3-0.4 mg/ml. In one embodiment, the amount of antioxidant used is 0.3 mg/ml. In another embodiment, the amount of antioxidant used is 0.4 mg/ml. In one particular embodiment, the composition comprises sodium sulfite in an amount of 0.3 mg/ml. In another particular embodiment, the composition sodium sulfite as an antioxidant. The ratio of antioxidant to PPI is from 0.75:1 to 1:1. The composition comprises chelating agents. It was observed that use of more than one chelating agents further improves the stability of the injectable composition of the present invention. Chelating agents such as sodium EDTA, disodium EDTA, edetate calcium Disodium, EDTA acetic acid salt, are used to prepare clear aqueous ready to use stable injectable compositions of the present invention. In the compositions comprising PPI in an amount of 4mg/ml, the amount of chelating agent used is from 0.1-2 mg/ml. In one embodiment, the amount of chelating agent used is 1mg/ml. In another embodiment, the amount of chelating agent used is 2 mg/ml. In one particular embodiment, the composition comprises disodium EDTA as a chelating agent. The ratio of chelating agent to PPI is from 0.025:1 to 0.5:1. In the compositions comprising PPI in an amount of 0.4mg/ml, the amount of chelating agent used is from 0.1-0.2 mg/ml. In one embodiment, the amount of chelating agent used is 0.1 mg/ml. In another embodiment, the amount of chelating agent used is 0.2 mg/ml. In one particular embodiment, the composition comprises disodium EDTA as a chelating agent. The ratio of chelating agent to PPI is from 0.25:1 to 0.5:1. The composition optionally comprises one or more pharmaceutically acceptable excipients selected from alkalizing substances, solvents, surfactants, cosolvents, buffers or pH adjusting agents, Antimicrobial or antibacterial preservatives, tonicity modifying agents or tonicity contributors. Alkalizing substances that may be used are meglumine, alkaline hydroxides, alkaline salts such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, Aluminium magnesium calcium antacid salt. These alkaline substances were used as essential element in prior art for stabilizing PPIs in solid dosage forms as these alkalizing substances form protective layer around PPI which is not possible in liquid or solution as solution has dynamic interface where molecules of different ingredients of composition are in continuous motion thereby exposing each other. In one particular embodiment, the composition comprises meglumine in an amount of 15mg/ml. One or more Antibacterial or antimicrobial preservatives, selected from phenylmercuric nitrate, thimersal, benzalkonium chloride, benzethonium chloride, Propyl paraben, Methyl Paraben, metacresol, phenol, butyl paraben, benzyl alcohol, cresol and chlorobutanol are useful to prepare clear stable ready to use compositions of the present invention. Water is preferred solvent. One may use TRIS, normal saline (NS), Dextrose 5% in water as solvent/cosolvent. If more than one solvent is used, one of them is cosolvent. One may incorporate one or more tonicity imparting agents or tonicity contributors including sodium chloride, potassium chloride, dextrose, mannitol, sorbitol and lactose to prepare clear stable ready to use compositions of the present invention. Buffers are ingredients or excipients which maintain suitable pH that stabilizes Pantoprazole or Rabeprazole in aqueous solution. It is advisable to keep the pH in the desirable range of 9-12, desirable range being 10-11.5. Buffers including one or more of tartrate, phosphate, acetate, citrate, benzoate and bicarbonate may be used. Buffering agents may also be selected from, but not limited to Potassium Phosphate salts like mono or di Potassium Phosphate salt, Sodium Acetate, Sodium Citrate, Sodium Phosphate salts like monosodium phosphate salt or disodium phosphate salt or Disodium Citrate, Trisodium Citrate, tris-(hydroxymethyl)-aminomethane, Tris base-65, Tris acetate, Tris HCl -65, boric acid, Maleic acid, Sodium Carbonate, Sodium Bicarbonate, Citric Acid, Benzene Sulfonic Acid, Monoethanolamine, Sodium Succcinate, Disodium Succcinate, Sodium Tartrate, phosphate buffers, citric acid, acetic acid, phosphoric acid, succinic acid with suitable salts and alike or malic acid, potassium citrate, lactic acid, gluconic acid, tartaric acid, fumaric acid or any combination thereof. It was surprisingly noticed that addition of external buffer may not be required if the process taught by the present invention is followed. The composition provided in the present invention is stored in an amber colour glass or an opaque plastic container. The present invention also provides a process to prepare ready to use clear stable aqueous injectable compositions. Manufacturing Procedure: Weigh all ingredients. Purge nitrogen continuously and maintain 2°C to 8°C during entire manufacturing process. 1. Take water for injection (herein after referred as WFI)or Tris Buffer and cool to 2°C to 8°C under nitrogen purging to obtain cooled water (or Tris Buffer) to obtain cooled solution. 2. Add chelating agent to part of cooled solution obtained in step 1 in suitable container to dissolve completely to obtain chelating agent solution. A mild stirring may also be performed. 3. Add an antioxidant to chelating agent solution obtained in step 2 and dissolve completely, to obtain antioxidant solution. If more than one antioxidant is used, add another antioxidant and stir well to dissolve. The pH of solution should be preferably between 9.0-12.0. This is antioxidant solution. 4. Add L-Arginine under mild stirring to antioxidant solution obtained in step 3 and dissolve completely to obtain amino acid solution. 5. Finally add PPI or salt thereof into the amino acid solution obtained in step 4 and stir well to dissolve to obtain PPI solution. 6. Make up the volume of PPI solution obtained in step 5 with WFI/Tris buffer maintained at 2°C to 8°C to obtain volume adjusted solution. 7. Check the pH of the volume adjusted solution obtained in step 6 to obtain pH tested solution or unfiltered solution. It should be between 9 -12, more desirable range being 9- 11.5. 8. Analyze the pH tested solution or unfiltered solution for complete characterization. 9. The pH tested solution or unfiltered solution obtained in step 7 is then filtered through 0.22 micron filter to obtain filtered clear ready to use aqueous injectable composition of PPI, Pantoprazole or Rabeprazole. 10. Subject unfiltered and filtered solutions obtained in Step 7 and Step 9 to stability testing protocol at 20C-80C and or 250C/60%RH and or 400C/75% RH. Alternatively, one may follow the procedure as described below: 1. Take Water for Injection (WFI) (or Tris Buffer), cool to 2°C-8°C under nitrogen purging during the entire manufacturing process to obtain cooled water (or Tris Buffer). 2. Add chelating agent to part of cooled water (or Tris Buffer) obtained in step 1 in suitable container and under mild stirring dissolve completely to obtain chelating agent solution. 3. Add L – Arginine to chelating agent solution obtained in step 2 under mild stirring to dissolve completely to obtain amino acid solution. 4. Add an antioxidant into amino acid solution obtained in step 3 and stir well to dissolve. If more than one antioxidant is used, add another antioxidant and stir well to dissolve. The pH of solution should be preferably between 9.0-12.0. This is antioxidant solution. 5. Add PPI or salt thereof into the antioxidant solution obtained in step 4 and stir to dissolve completely to obtain PPI solution. 6. Make up the volume with cooled WFI (or Tris Buffer) maintained at 2°C to 8°C and check the pH of the solution (Limit- 10 to 11). This is pH tested solution or unfiltered solution. 7. Analyze the pH tested solution or unfiltered solution for complete characterization. 8. Filter the unfiltered solution obtained in step 6 through 0.22 micron filter to obtain filtered clear ready to use aqueous injectable composition of PPI, Pantoprazole. 9. Subject filtered solutions obtained in Step 6 and Step 8 to stability testing protocol such as 250C/60%RH, 400C/75% RH. Normally pH within the range of 9.0 to 12 is achieved after making up the volume and it remains within the range of 9 to 12, preferably 9 to 11.5. Therefore, pH adjustment with 0.1N NaOH may not be required. If required pH adjustment may be done with 0.1N NaOH. Unfiltered solutions are filtered into suitable plain or amber glass or plastic container and sealed hermetically in sterile area. Plain containers if used, are to be stored in light resistant cartons. Compositions of the present invention when filled and sealed into amber glass containers USP Type I and or Type II are found to be better stable. The above and other objects, features and advantages of the present invention are now described in detail with reference to certain exemplary embodiments illustrated in the example section but are not limitative of the present invention. While the invention will be described in conjunction with exemplary embodiments, it will be understood that present description is not intended to limit the invention to those exemplary embodiments. On the contrary, the invention is intended to cover not only the exemplary embodiments, but also various alternatives, modifications, equivalents and other embodiments, which may be included within the spirit and scope of the invention as defined by the appended claims. Thus, composition wherein an additional active ingredient is present along with PPI and proportions or ratios of various ingredients are as described in detailed description taught by present invention, would fall within the purview of the claims of present invention. Invention sets the limits of proportions of Chelating agent to Benzimidazole or PPI, antioxidant to PPI and L-Arginine to PPI by illustrating use of one and more than one Chelating agent/s, antioxidant/s. Therefore, independent of number of chelating agents, antioxidants used, if their ratio falls within the ambit of ratios claimed in this patent application, such composition would fall within the ambit claims of this patent application. Compositions of present invention when used for administration by parenteral route or by any other route would be within the ambit of the claims of present invention. EXAMPLES Example 1: Ready to use compositions of Pantoprazole. Quantities are expressed per ml and batch sizes of 1 Liter were manufactured. Ingredient K K1 L L1 L

Example 2: Manufacturing Procedure for Compositions in Example 1: Continuous nitrogen purging and temperature between 2°C to 8°C is maintained during the entire manufacturing process. For composition of Example 1 WFI is used. For Example 9 Tris buffer is used. 1. WFI or Tris Buffer is cooled to 2°C-8°C under nitrogen purging to obtain cooled water (or Tris Buffer). 2. Disodium Edetate is added and dissolved completely under mild stirring into part of cooled water (or Tris Buffer) obtained or prepared in step 1 in suitable container to obtain chelating agent solution. 3. L – arginine is added under mild stirring to chelating agent solution obtained in step 2 and dissolved completely to obtain amino acid solution. 4. Sodium Sulfite is added to amino acid solution obtained in step 3 and stirred well to dissolve completely. Required quantity of Sodium Thioglycolate is added to amino acid solution in which Sodium Sulfite is dissolved to obtain antioxidant solution. Checked the pH of solution It was within the Limit: 9.0-12.0. 5. Pantoprazole Sodium is added to the antioxidant solution obtained in step 4 and stirred to dissolve completely to obtain PPI solution. 6. PPI solution is made up with water for injection (WFI) (or Tris Buffer). The pH of the solution is checked to obtain pH tested solution or unfiltered solution. pH was within the limit 9 to 12. 7. The pH tested solution or unfiltered solution resulting in step 6 is analyzed for complete characterization. 8. The unfiltered solution obtained in step 6 is filtered through 0.22 micron filter to obtain filtered clear ready to use aqueous injectable composition of Pantoprazole. 9. The unfiltered and filtered solutions obtained in Step 6 and Step 8 is subjected to stability testing protocol at 250C/60%RH, 400C/ 75% RH. 7. The sample of the solution is analyzed for complete characterization. Example 3: Stability results of compositions K and L of Example 1 at 1 Month in at 40⁰C /75 % RH and 2⁰C-8⁰C. K L K L

colourless colourless colourless colourless colourless pH (9-12) 9.63 9.56 9.63 9.56 Relate

, ty-D+F – NMT 1.5%, Impurity-B NMT 0.2%, Any Single Impurity NMT 0.2%, Total Impurity NMT 2.0% and Compositions K and L comply with the specifications at the end of 1 month. NMT = not more than. Example 4: 1 liter Clear stable ready to use compositions of Rabeprazole G (mg/ml) H (mg/ml) H1 (mg/ml) H2 (mg/ml)

Example 5: Stability of compositions G and H of Example 4 at 40 C /75 % RH and 20C-80C at 1 Month. 400C/75%RH 20C-80C

Related substances specification is “Any maximum single impurity Not more than (NMT) 0.5% and Total Impurity NMT 2.0%” and compositions G and H comply with this specification. Example 6: Stability of compositions G and H of Example 4 and compositions K and L of example 1 at 250C/60 % RH at 1 Month. 250C/60%RH 250C/60%RH G H K L s Related substan

p y g p y e than (NMT) 0.5% and Total Impurity NMT 2.0%” and compositions G and H comply with this specification. Example 7: Analysis of Pantoprazole compositions was performed according to In-House method as described below to estimate Assay and related substances. [NOTE—Protect solutions containing pantoprazole sodium from light.] Buffer: 6.8 g/L of Potassium dihydrogen phosphate in water, add 1.0 g of 1- Hexane sulphonic acid adjusted with sodium hydroxide to a pH of 7.3 Mobile phase: Prepare a mixture of Buffer and Acetonitrile (50:50) Diluent: Mobile phase. Standard solution: Weigh about 22.0 mg of Pantoprazole Sodium WS in 100 ml of diluent. Sample solution: Weigh 2.5 g of sample under analysis in 50 mL volumetric flask and make up the volume with diluent. Mode: LC Detector: UV 290 nm, Column: 4.6-mm × 25-cm; 5-μm packing L1, Column: Ambient, Flow rate: 1.5 mL/min, Injection volume: 10 μL, Run time 10.0 minutes. Suitability requirements: Relative standard deviation: NMT 2.0%, Standard solution Analysis: Samples: Standard solution and Sample solution Calculate percentage of pantoprazole sodium equivalent to Pantoprazole in the portion of Pantoprazole Sodium taken: Result = (rU/rS)×(CS/CU)×0.9456 × Potency rU = peak response from the Sample solution, rS = peak response from the Standard solution, CS = concentration of Pantoprazole Sodium WS in the Standard solution (mg/mL), CU = concentration of Pantoprazole Sodium in the Sample solution (mg/mL) Related substances: ( By HPLC ) Prepare a solution containing equal volumes of acetonitrile and 0.001M sodium hydroxide (solution A). Test solution: Shake a quantity of the injection containing of 40 mg of pantoprazole sodium in 50 mL of solution A, dilute with sufficient solution A to produce 100 mL and filter. Standard solution: Weigh 20 mg of Pantoprazole sodium in 100 mL volumetric flask make up to volume with diluent. Take 1.0 ml of this solution to 100 mL with diluent. Solution (1): Shake a quantity of the injection containing of 40 mg of pantoprazole sodium in 50 mL of solution A, dilute with sufficient solution A to produce 100 mL and filter. Solution (2): Weigh 20 mg of Pantoprazole sodium in 100 mL volumetric flask make up to volume with diluent. Take 1.0 ml of this solution to 100 mL with diluent. (3) 0.05% w/v of pantoprazole for system suitability EPCRS in solution A. Placebo preparation: Shake a quantity of the injection placebo equivalent to 40 mg of pantoprazole sodium in 50 mL of solution A, dilute with sufficient solution A to produce 100 mL and filter. CHROMATOGRAPHIC CONDITIONS (a) Use a stainless steel column (12.5 mm x 4 mm) packed with octadecylsilyl silica gel for chromatography (5 micron) (Hypersil ODS is suitable). b) Use gradient elution and the mobile phase described below. Time (min) Mobile phase A (%) Mobile phase B (%)

3-33 90-60 10-40 33-48 60-15 40-85 (c) Use a fl

0°C. (e) Use an autosampler temperature of 5°C. (I) Use a detection wavelength of 290 nm. (g) Inject 20 µL of each solution. MOBILE PHASE: Mobile phase A: 0.01M dipotassium hydrogen phosphate trihydrate, adjusted to pH 7.0 with a 20% vlv solution of orthophosphoric acid. Mobile phase B: 1 volume water and 99 volumes of acetonitrile. Procedure: Analysis: When the chromatograms are recorded under the prescribed conditions the retention times relative to pantoprazole (retention time about 22 minutes) are: impurity C, about 0.6; impurity A, about 0.9; impurity D + F, about 1.1; impurity E, about 1.3 and impurity B, about 1.4. SYSTEM SUITABILITY: The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity D + F and pantoprazole is greater than 3.0. LIMITS Identify any peak in the chromatogram obtained with solution (I) due to impurity C using the chromatogram obtained with solution (3) and multiply the area of this peak by a correction factor of 0.6. In the chromatogram obtained with solution (1): the area of any peak due to impurities D + F (combined peak area) is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%); the area of any peak due' to impurity A is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5% of each); the area of any other secondary peak is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.2%); the sum of the areas of any secondary peaks is not greater man 4 times the area of the principal peak in the chromatogram obtained with solution (2) (2.0%). Samples: Standard solution, Placebo and Sample solution Calculate percentage of each impurity in the portion of Pantoprazole Sodium taken: Result = (r U/r S) × (C S/C U) × (F) × 100 r U = peak response of each impurity from the Sample solution. r S = peak response of pantoprazole sodium from the Standard solution. C S = concentration of Pantoprazole Sodium RS in the Standard solution (mg/mL). C U = concentration of Pantoprazole Sodium in the Sample solution (mg/mL). F = Correction factor Example 8: Analysis of Rabeprazole compositions was performed according to IP 2022, Page no 3439 – 3440, volume 3. Example 9: Compositions G, H, G1, H1 with different ratios of chelating agent, L-arginine, antioxidant with respect to p. Batch size 1 Litre. Ingredients expressed as quantity/ml. Procedure to prepare is as in Example 2. Ingredients G (mg/ml) H(mg/ml) G1(mg/ml) H1(mg/ml) e

Example 10: 6M stability of compositions G and H of Example 9 at 2⁰C -8⁰C and at 25⁰C/ 60%RH. G H G H Composition 25⁰C/60% RH 25⁰C/60% RH 2⁰C -8⁰C 2⁰C -8⁰C s s Exampl

e : ea y to use compostons o aeprazoe. atc szes o ter. Ingredients (mg/ml) _{E F} E1 F1 r

Example 12: Stability data of compositions E and F of Example 11 at 6Months at 2⁰C -8⁰C and at 25⁰C/60%RH E F E F Composition 25⁰C/60 % RH 25⁰C/60 % RH 2⁰C -8⁰C 2⁰C -8⁰C ss Related su

p y g p y n (NMT) 0.5% and Total Impurity NMT 2.0%” and compositions G and H comply with the specifications of finished product. Example 13: Ready to use Compositions I and J Batch size 100ml Name of Ingredients I (mg/ml) J(mg/ml) Manufacturin

1. For batch size of 100 ml, taken 150 ml WFI and cooled to 2°C to 8°C under nitrogen purging to prepare cooled water. 2. Collected 50 ml quantity of cooled water prepared in step 1 in separate vessel of (200 ml) sufficient volume or capacity and remaining was retained in the first vessel of Step 1. 3. Added disodium EDTA and sodium sulfite into cooled water collected in separate vessel in step 2, under mild stirring to dissolve completely to prepare antioxidant solution. Dissolution of disodium EDTA and sodium sulfite can as well be performed by sequential addition of disodium EDTA and dissolving it completely followed by addition of sodium sulfite and dissolving it completely or by adding and dissolving sodium sulfite first followed by adding and dissolving Disodium EDTA to prepare antioxidant solution. 4. Added L – Arginine to antioxidant solution obtained in step 3 under mild stirring to dissolve completely to obtain amino acid solution. 5. Added Pantoprazole Sodium into the amino acid solution obtained in step 4 and stirred to dissolve completely to obtain Pantoprazole solution. 6. Made up the volume of Pantoprazole solution obtained in step 5 with cooled water from first Vessel as mentioned in step 2 and checked the pH of the solution (Limit- 9.0 to 11.5). This is pH tested solution or unfiltered solution. 7. Analyzed the pH tested solution obtained in step 6 for description, Assay, RS and pH. 8. Filtered the unfiltered solution obtained in step 6 through 0.45-0.22 micron capsule prefilter-filter assembly into suitable amber glass container and sealed hermetically to obtain filtered clear ready to use aqueous injectable composition of PPI, Pantoprazole. 9. Subjected unfiltered and filtered solutions obtained in Step 6 and Step 8 to stability testing at 250C/60%RH, 400C/75% RH. Example 14: Stability of compositions I in Example 13. Assay and Impurities Data of Assay (Limit- 93%- 105%) Stability Conditions Time Periods

Data of Related substances T_est ²⁵0C/60%RH 400C/75% RH y

_{Any Single Impurity- NMT 0.2%} ^{0.096% 0.173%} SOASP- NMT 2.0% 0.527% 1.232% NMT ater than 4 times t

%) Example 15: RTU compositions having 0.4 mg/ml of Pantoprazole and procedure to prepare. Quantity expressed as mg/ml Ingredient mg/ml I II III IV _IIIR qs= Quan from 5:1 to 7.5:1.

Continuous nitrogen purging and 2°C to 8°C is maintained during entire manufacturing process. 1. Taken 600 ml of WFI and cooled to 2°C to 8°C under nitrogen purging. Prepared 0.9% w/v saline by adding 90 mg/ml of NaCl. This is saline solution. 2. In a separate glass beaker of 200 ml, taken 150 ml of the saline solution obtained in Step no. 1, added Di-Sodium Edetate followed by Sodium Sulfite and L- Arginine under mild stirring to dissolve completely to obtain amino acid solution. 3. Finally added the Pantoprazole Sodium to amino acid solution obtained in step 2. and then made up 200 ml with the saline solution obtained in Step 1 to obtain Pantoprazole solution with 0.4mg/ml concentration. 4. Checked the pH of the solution, (Limit- 9.0 to 10.50). If required; one may adjust with 0.1 N NaOH solution. This is pH checked solution. 5. Analyzed the pH checked solution for complete characterization. 6. Optionally it is sterilized by suitable means and filled into suitable containers such as amber glass or plastic containers having suitable volume. Batch size of optimized batch Trial 10R was 1 Liter and hence quantities were taken accordingly while producing that batch. Example 16: Testing results of Optimized composition IIIR. Test 250C / 60 % RH 400C / 75 % RH Cl r li htl SOASP = Su es the area of the

principle peak in the chromatogram obtained with solution (2) (2.0%). Example 17: Compositions depicted in Example 15 when prepared with 0.2mg/ml of Disodium Edetate as per procedure given in Example 15 are also stable for 1 month at 250C/60%RH. When 0.2mg of disodium Edetate is incorporated, the ratio of chelating agent to PPI is 0.5:1 Batch size 500ml. Ingredient I

Sodium Sulfite 0.30 mg

Example 18: C

, ility of composition PAN23-20 Pantoprazole 4mg/ml. Batch size 1 liter. Name of Ingredients PAN23-20

Initial 6 0 0 0 0 Test Specification M.25C±2C 6M.40C±2C /60%±5% RH /75%±5 % RH

Continuous nitrogen purging and 2°C to 8°C maintained during entire manufacturing process. 1. Taken 1.2 liters of WFI and cooled to 2°C to 8°C temperature under nitrogen purging to prepare cooled water. 2. Transfer 400 ml of cooled water obtained in step 1 into separate container and retained 800 ml in original container of step 1. 3. Added Disodium EDTA and sodium sulfite under mild stirring into 800ml cooled water present in original container in step 1 to dissolve completely, to prepare antioxidant solution. 4. Added L – Arginine under mild stirring to antioxidant solution obtained in step 3, and dissolved completely to obtain amino acid solution. 5. Added Pantoprazole Sodium into antioxidant solution obtained in step 4 to obtain PPI solution and stirred to dissolve completely. 6. Made up the volume of PPI solution obtained in step 5 with cooled WFI from step 2, to 1 liter to obtain unfiltered composition. 7. Checked the pH of unfiltered composition obtained in step 6 (Limit- 9.0 to 11.5). 8. Analyzed the developed injection for Assay, RS, pH and appearance or description. 9. Filtered the unfiltered solution obtained in step 6 through 0.22 micron filter to obtain filtered clear ready to use aqueous injectable composition of Pantoprazole. Filled and sealed the filtered composition in USP Type 1 amber coloured glass container. 10. Subjected filtered solutions obtained in Step 6 and Step 9 to stability testing protocol such as 250C/60%RH, 400C/ 75% RH. Comparative Examples: Comparative examples provide compositions having one of the essential ingredients is missing or wherein at least one ratio of L-arginine: PPI or chelating agent: PPI or antioxidant: PPI is beyond the claimed ratios of the present invention. As explained below, the comparative compositions were found unstable. Ratios are calculated by comparing quantity of essential ingredient with 4mg/ml and 0.4mg/ml of proton pump inhibitor (Pantoprazole/Rabeprazole). mg/ml, mg/mL and mg/Ml mean one and the same thing i.e. milligrams per milliliter. Comparative Example 1: (Compositions having 4mg/ml of PPI): Compositions N, N1, O, O1, N2 and N3 do not contain at least one essential ingredient as shown in the table below. Compositions N, N1, N2 and N3 do not contain L-Arginine. Composition O and O1do not have chelating agent and antioxidant respectively. Ingredient (mg/ml) _N N1 O O1 N2 N3 5 5

Claimed ratios: L-arginine: PPI 15:1 to 18.75:1, chelating agent/s: PPI 0.025:1 to 0.5:1 and antioxidant: PPI 0.5:1 to 2.13:1 Compositions N, N1, N2 and N3 have Chelating agent: PPI and Antioxidant: PPI ratios that fall within claimed range but it is devoid of L-Arginine. Composition O: ratios of Antioxidant: PPI and L-Arginine: PPI fall within the claimed range but it is devoid of chelating agent. Composition O1: Ratio of L-Arginine: PPI and of Chelating agent: PPI is within the required range but is devoid of an antioxidant. Comparative Example 2: Stability results of Compositions N, O and N1, O1 and N2 and N3 of Comparative Example 1 at 1 Month at 40⁰C /75 % RH and 2⁰C-8⁰C. Composition N, N1 -N3 and O and O1 N, N1-N3 and O and O1 Test 40⁰C /75 % RH 2⁰C -8⁰C All comp scription” or “Appearan

ce , n cat ng t at t ese were unsta e. ence were not ana yze urt er as they were visibly unstable. Comparative Example 3: Compositions with ratios of L-Arginine: PPI; Antioxidant: PPI and Chelating agent to PPI beyond the ratios of present invention Ingredient mg/ml R1 R2 ^R3

Chelating agent: PPI Present 0.75 0.0125 0.75 invention (0.025:1 to 0.5:1) Ratios

r or higher than those claimed ratios. All above compositions were unstable and turned yellow in one month at 20C-80C and 40⁰C/75%RH. They failed in the test of “Description” or “Appearance” and hence further analysis was not required and not done. It proves that in order to be clear stable compositions of the invention, ratios of all three essential elements i.e. Ratio of L-arginine: PPI should be from 15:1 to 18.75:1, the ratio of chelating agent/s: PPI should be from 0.025:1 to 0.5:1 and ratio of antioxidant: PPI should be from 0.5:1 to 2.13:1. Comparative Example 4: Compositions having 0.4mg/ml of PPI: The ratio of L-arginine: PPI is from 5:1 to 7.5:1. ratio of antioxidant: PPI is from 0.75:1 to 1:1. The ratio of chelating agent/s: PPI is from 0.25:1 to 0.5:1. Compositions of Trial -1, Trial-2 and Trial-3 do not contain at least one essential element required to stabilize RTU. In composition of Trial-4 ratio of Antioxidant: PPI is lower than the claimed ratio. In composition Trial-5, ratio of L-arginine: PPI is lower than the claimed ratio. Ingredient mg/ml Trial-1 Trial-2 Trial-3 Trial-4 Trial 5

Antioxidant: PPI Present invention (0.5:1 to 0.75 1 - 0.25 0.75 Compa

, Trial-7 is devoid of L-Arginine. Composition of Trial-15 has lower ratio of Chelating agent: PPI although ratios of Antioxidant: PPI and L-Arginine: PPI were in desired range. Composition of Trial-16 has lower ratio of Antioxidant: PPI and composition of Trial-17 had higher ratio of L-Arginine: PPI. Ingredient mg/ml Trial-6 Trial-7 Trial-15 Trial-16 Trial 17

Comparative Example 6: All 0.4mg/ml compositions described above i.e. Trial-1, Trial-2, Trial-3, Trial-4, Trial-5, Trial-6, Trial-7, Trial-15, Trial-16, Trial-17 at 40⁰C /75 % RH and 2⁰C- 80C developed yellow colour at the end of 1 month indicating that these were unstable. They failed in the initial test of “Appearance or description”. Therefore, further analysis was not performed. Trial-1 to Trial-7, Trial- Trial-1 to Trial-7, Composition 15 to Trial 17 Trial-15 to Trial 17 Comparati PI ratio higher than claimed

a ge. Ingredient mg/ml Trial-20

chelating agent/s: PPI 075

Comparative Example 8: Composition of PPI 4mg/ml with chelating agent: PPI ratio higher than claimed range. Ingredient mg/ml H1

ame ra os

Claims

We Claim: 1. An aqueous ready to use, composition comprising a proton pump inhibitor (PPI), L- arginine, an antioxidant, and a chelating agent; wherein the proton pump inhibitor is selected from Pantoprazole and Rabeprazol or sodium salt thereof; wherein the proton pump inhibitor is present in an amount 4 mg/ml.

2. The composition as claimed in claim 1, wherein the ratio of L-arginine to proton pump inhibitor is from 15:1 to 18.75:1.

3. The composition as claimed in claim1, wherein the ratio of chelating agent to proton pump inhibitor is from 0.025:1 to 0.5:1.

4. The composition as claimed in claim 1, wherein the ratio of antioxidant to proton pump inhibitor is from 0.5:1 to 2.13:1. 5. The composition as claimed in claim 1 wherein the composition comprises L-arginine in an amount between 60-75 mg/ml, antioxidant in an amount from 2-8.

5 mg/ml, and chelating agent in an amount between 0.1-2 mg/ml.

6. An aqueous ready to use, composition comprising a proton pump inhibitor (PPI), L- arginine, an antioxidant, and a chelating agent; wherein the proton pump inhibitor is selected from Pantoprazole and Rabeprazol or sodium salt thereof; wherein the proton pump inhibitor is present in an amount 0.4 mg/ml.

7. The composition as claimed in claim 6, wherein the composition comprises L-arginine in an amount between 2-3mg/ml, antioxidant in an amount from 0.3-0.4mg/ml, and chelating agent in an amount between 0.1-0.2 mg/ml.

8. The composition as claimed in claim 6, wherein the ratio of L-arginine to proton pump inhibitor is from 5:1 to 7.5:1.

9. The composition as claimed in claim1 or claim 6, wherein the ratio of chelating agent to proton pump inhibitor is from 0.25:1 to 0.5:1.

10. The composition as claimed in claim 6, wherein the ratio of antioxidant to proton pump inhibitor is from 0.75:1 to 1:1.

11. The composition as claimed in claim 1 or claim 6, wherein the antioxidant is selected from ascorbic acid, monothioglycerol, sodium sulfite, sodium bisulfite, gentisic acid, gentisic acid ethanolamine, sodium metabisulfite, butylated hydroxytoluene, tocopherols and sodium thioglycolate or a combination thereof.

12. The composition as claimed in claim 1 or claim 6, wherein the antioxidant is selected from sodium sulfite and sodium thioglycolate or a combination thereof.

13. The composition as claimed in claim 1 or claim 6, wherein the chelating agent is selected from Sodium EDTA, Disodium EDTA, Edetate Calcium Disodium; and EDTA Acetic acid salt .

14. The composition as claimed in claim 1 or claim 6, wherein the chelating agent is Disodium EDTA.

15. The composition as claimed in claim 1 or claim 6, wherein the composition optionally comprises alkaline substances or basic substances selected from meglumine or hydroxides or carbonates of sodium and potassium.

16. The composition as claimed in claim 15, wherein the composition comprises meglumine in an amount of 15mg/ml.

17. The composition as claimed in claim 1, wherein the composition comprises pantoprazole in an amount of 4mg/ml, L-arginine in an amount of 70mg/ml , antioxidant in an amount of 6mg/ml and chelating agent 0.10 mg/ml.

18. The composition as claimed in claim 17, wherein the antioxidant is sodium sulfite and chelating agent is Disodium EDTA.

19. The composition as claimed in any preceding claim, wherein the composition comprises a solvent selected from TRIS, normal saline (NS), and Dextrose 5% in water.

20. The composition as claimed in any preceding claim, wherein the composition is stored in amber colour glass or an opaque plastic container.

21. The composition as claimed in any preceding claim, wherein the composition comprises one or more pharmaceutically acceptable excipients.