BE1021311B1 - METHOD FOR MAKING A POWDERED PROTON PUMP INHIBITOR COMPOSITION, MENTIONED COMPOSITION AND USE - Google Patents

Abstract

The present invention relates to a method of making a powdered proton pump inhibitor composition for injection or infusion after reconstitution. The method is characterized by protecting the proton pump inhibitor from oxidation. The invention also relates to a composition obtainable by the method. The resulting composition is characterized by an improved stability. The invention provides a vial comprising a powdered proton pump inhibitor composition according to an embodiment of the invention. The obtained preparations are advantageously used as medicament.

Description

Method for making a powdered proton pump inhibitor composition, said composition and use

TECHNICAL DOMAIN

The invention relates to a method for making powdered pharmaceutical compositions. More specifically, the invention relates to a method for making a powdered proton pump inhibitor composition that is suitable for injection after reconstitution. Proton pump inhibitors include the following molecules: lansoprazole, rabeprazole, esomeprazole, pantoprazole or a pharmacologically acceptable salt of one of these molecules.

BACKGROUND ART

A problem with the known methods for producing powdered proton pump inhibitors is that chemical degradation of the proton pump inhibitor occurs during the process.

There is a need for improved stability.

It is an object of the present invention to find a solution to at least some of the aforementioned problems.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides a method for making a powdered proton pump inhibitor composition for injection or infusion after reconstitution, which composition comprises the following components: - 86.0-99.9 weight percent proton pump inhibitor; - 0-13% by weight of a chelating agent; - 0.1-1.0 weight percent of a base; wherein the weight percentage of each component is expressed relative to the total weight of the composition, said method comprising the following steps: 1) preparing a proton pump inhibitor solution: a) provided with a solvent with a temperature below 25 ° C; b) optionally adding the chelating agent to the solvent; c) adding the base to the mixture; d) adding the proton pump inhibitor to the mixture; e) bubbling the mixture with an inert gas until the solution comprises less than 5 ppm oxygen; and 2) freeze-drying the solution.

This method is advantageous because the active ingredient is protected against oxidation.

In a second aspect, the invention provides a powdered proton pump inhibitor composition obtainable according to a method of the invention.

A composition prepared according to the method comprises a reduced number of impurities due to oxidation of the active ingredient.

In a third aspect, the invention provides a vial comprising a powdered proton pump inhibitor according to the second aspect of the invention.

This form of packaging is ready for use. Administration of a physiologically acceptable solvent such as water for injection is sufficient to obtain a preparation for administration. The water can be administered to the vial, the powder dissolves, and provides a solution suitable for injection.

The invention further provides a composition for injection or infusion comprising a composition according to an embodiment of the invention and a physiologically acceptable solvent.

The invention also provides a composition according to an embodiment of the invention for use as a medicament.

This is an advantage for use in the treatment of reflux, stomach ulcer, dyspepsia, Zollinger-Ellison syndrome or a Helicobacter pylori infection.

DETAILED DESCRIPTION

Unless defined otherwise, all terms used in the description of the invention, including technical and scientific terms, have the meaning as generally understood by those skilled in the art of the invention. For a better assessment of the description of the invention, the following terms are explicitly explained. "A", "de" and "het" in this document refer to both the singular and the plural unless the context clearly assumes otherwise. For example, "a vial" means one or more than one vial.

When "about" or "round" is used in this document for a measurable quantity, a parameter, a duration or moment, and the like, variations are meant of +/- 20% or less, preferably +/- 10% or less, more preferably +/- 5% or less, even more preferably +/- 1% or less, and even more preferably +/- 0.1% or less than and of the quoted value, insofar as such variations of are applicable in the described invention. However, it must be understood here that the value of the quantity at which the term "about" or "round" is used is itself specifically disclosed.

The terms "include", "comprising", "consist of", "consisting of", "provided with", "contain", "containing", "include", "including", "contents", "contents" are synonyms and are inclusive or open terms indicating the presence of what follows, and which do not preclude or preclude the presence of other components, features, elements, members, steps, known from or described in the prior art.

The citation of numerical intervals by the end points includes all integers, fractions and / or real numbers between the end points, including these end points.

A proton pump is a protein complex that extends through a cell membrane. A proton pump pumps protons through the cell membrane so that a higher concentration of protons is built up on one side than the other side of the cell membrane. This creates a low pH value on one side of the cell membrane. There are many proton pumps in the stomach wall that take care of the acidic environment in the stomach.

Proton pump inhibitors are molecules that show an affinity with at least a part of a proton pump and thereby inhibit the functioning of the proton pump. This can cause the pH of the stomach contents to rise, which is advisable in the treatment of reflux, stomach ulcer, dyspepsia, Zollinger-Ellison syndrome or a Helicobacter pylori infection.

In a first aspect, the invention provides a method for making a powdered proton pump inhibitor composition.

In a preferred embodiment, the proton pump inhibitor is lansoprazole or rabeprazole, more preferably omeprazole and most preferably esomeprazole or pantoprazole or a pharmacologically acceptable salt of one of these molecules. Preferably the salts are sodium salts, potassium salts, strontium salts or magnesium salts, whether or not comprising hydrate water.

Esomeprazole (formula I) is the S enantiomer of omeprazole. Esomeprazole has (S) -5-methoxy-2 - [(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl] -3H-benzoimidazole as IUPAC and has 119141-88-7 as CAS number.

Formula I

The most common salts are esomeprazole sodium; CAS 161796-78-7, magnesium esomeprazole; CAS 161973-10-0, magnesium esomeprazole trihydrate; CAS 217087-09-7 and Strontium esomeprazole; 934714-36-0.

Pantoprazole (formula II) is a racemic mixture and has (RS) -6- (Difluoromethoxy) -2 - [(3,4-dimethoxypyridin-2-yl) methylsulfinyl] -1H-benzo [c /] imidazole as IUPAC name and has 102625-70 as CAS number.

Formula II

The most common salts are pantoprazole sodium; CAS 138786-67-1, pantoprazole sodium sesquihydrate; CAS 164579-32-2, magnesium pantoprazole and magnesium pantoprazole dihydrate.

In a preferred embodiment, the powdered composition comprises an amount of proton inhibitor between 86.0 and 99.9 weight percent proton inhibitor, more preferably between 90 and 97 weight percent and most preferably between 95 and 96 weight percent.

In a preferred embodiment, the powdered composition comprises an amount of chelating agent between 0 and 13% by weight, more preferably between 1 and 10% by weight and even more preferably between 2 and 5% by weight, and most preferably between 3 and 4% by weight.

The chelating agent is a molecule that ensures that metal ions that are present in the powder as contaminants are complexed and cannot interact with the proton pump inhibitors in this way. This prevents the formation of proton pump inhibitor-metal ion complexes that may be insoluble or possibly catalyze the metal ion chemical reactions. The metal ions may be present in the ingredients of the composition from contamination during the synthesis of these ingredients, or the metal ions may be present in the container or plug in which the composition is located. Preferably, the chelating agent is selected from the list of ethylenediamine, methylamine, porphine, heme groups, ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate, dimercaprol, diethylenetriaminepentaacetic acid, nitrilotriacetic acid or a crown ether. Preferably the invention uses ethylenediaminetetraacetic acid (EDTA) or disodium ethylenediaminetetraacetate as a chelating agent.

In a preferred embodiment, the powdered composition comprises an amount of base between 0.1 and 1.0 weight percent. The addition of base benefits the reconstitution of the powder into an injectable liquid. After all, the solubility of many proton pump inhibitors is much higher in the alkaline medium than in the acidic or neutral medium. It is recommended that a powdered composition dissolve rapidly after adding an amount of water for injection so that no undissolved powder particles are injected into the patient. Preferably, the base is selected from the list of sodium hydroxide, magnesium hydroxide, aluminum hydroxide, calcium hydroxide, lithium hydroxide, potassium hydroxide, zinc hydroxide and diethanolamine. Sodium hydroxide is used as a favorite in the invention.

The method for making a powdered proton pump inhibitor composition comprises the steps of: 1) preparing a proton inhibitor solution; 2) freeze-drying the solution, whereby a powdered composition is obtained.

Step 1) comprises the following steps: a) provided with a solvent with a temperature below 25 ° C; b) adding the chelating agent to the solvent or a mixture obtained in step c), d) or e); c) adding the base to the solvent or a mixture obtained in step b), d) or e); d) adding the proton pump inhibitor to the solvent or a mixture obtained in step b), c) or e); e) bubbling the solvent or a mixture obtained in steps a), b), c) and / or d) with an inert gas until the solution comprises less than 5 ppm oxygen gas.

The order in which these steps are followed can vary and some steps can be carried out several times.

In a preferred embodiment, the solvent in step a) is water or an aqueous solution. The temperature of the solvent is kept below 25 ° C. This has the advantage that the proton pump inhibitors are protected against thermal decomposition at elevated temperature.

In a preferred embodiment, mixtures or the solvent are bubbled with an inert gas, preferably nitrogen gas. Oxygen gas in the mixture or solvent is removed by bubbling and the oxygen content is brought below 5 ppm, preferably below 2 ppm, even more preferably below 1 ppm and most preferably below 0.5 ppm. A low oxygen content benefits the chemical stability of the proton pump inhibitor. Oxidative stress can chemically degrade the proton pump inhibitor. Protection against oxidation has the advantage that fewer impurities are present in a solution for injection or infusion.

In a preferred embodiment, the base in step c) is added as an aqueous solution until the pH of the solution exceeds 11. Preferably the pH value of the solution is between 11.0 and 11.5; more preferably between 11.1 and 11.4 and most preferably between 11.2 and 11.3. This pH setting ensures rapid dissolution of the proton pump inhibitor when dissolving the powder in a physiologically acceptable solvent, such as water for injections. This shortens the time required to prepare a preparation for injection or infusion. By adding a physiologically acceptable solvent, the pH is adjusted to a pH suitable for administration by injection or infusion.

In a preferred embodiment, the freeze-drying solution is filtered. A sterile solution can be obtained in this way. Preferably the solution is filtered through at least one, preferably at least two filters. Preferably, a filter with a filter opening of 0.2 micron or smaller is used. In a further preferred embodiment, the filter is made from polyvinylidene fluoride (PVDF). The filter is preferably a polyvinylidene fluoride membrane.

In a preferred embodiment, the filters and filter installation are sterilized, preferably at 123 ° C for at least 20 minutes.

In a preferred embodiment, after filtration, the solution is distributed over vials, preferably vials in dark colored glass such as brown glass. This is advantageous to protect the powder against degradation by light.

In a preferred embodiment, freeze-drying proceeds according to the following procedure: freezing of the solution in the vials, preferably at a temperature below 0 ° C, more preferably below -15 ° C, even more preferably below -30 ° C, and most preferably lower than -45 ° C, a first drying at a temperature lower than + 10 ° C, more preferably lower than 5 ° C and a pressure lower than 80 Pa or 800 pbar, more preferably lower than 60 Pa or 600 pbar, most preferably lower than 10 Pa or 100 pbar, a second drying at a temperature lower than 70 ° C, preferably lower than 60 ° C, even more preferably lower than 50 ° C and most preferably lower than 40 ° C and a pressure lower than 8 Pa or 80 pbar, preferably lower than 6 Pa or 60 pbar and most preferably lower than 1 Pa or 10 pbar.

A maximum temperature of 70 ° C and most preferably 40 ° C during the freeze-drying process ensures a minimal decomposition of the proton pump inhibitor due to thermal stress.

In a preferred embodiment, freeze drying lasts no longer than 50 hours, more preferably no longer than 40 hours.

In a preferred embodiment of the invention, the proton pump inhibitor solution is shielded from light. Preferably, the illuminance reaching the solution is no more than 250 lux, more preferably no more than 100 lux, even more preferably no more than 50 lux, most preferably no more than 10 lux and most preferably no more than 1 lux.

In a second aspect, the invention provides a powdered proton pump inhibitor composition obtainable according to a previously described embodiment of the invention.

In a third aspect, the invention provides a vial comprising a powdered proton pump inhibitor according to the second aspect of the invention.

In a preferred embodiment, the vial is made from type I glass. Ph. Eur 3.2.1 In another preferred embodiment the vial is provided with a bromobutyl rubber stopper. The plug can be closed by a metal casing, preferably by an aluminum casing.

In a further aspect, the invention provides a composition for injection or infusion comprising a composition according to an embodiment of the invention and a physiologically acceptable solvent. A physiologically acceptable solvent is, for example, water for injections or 0.9% sodium chloride. A solution for infusion can be prepared by dissolving the contents of a vial containing, for example, 40 mg esomeprazole in a maximum of 100 ml of 0.9% sodium chloride for intravenous use.

In a further aspect, the invention provides a use of a composition according to an embodiment of the invention, as a medicament.

Preferably, a composition comprises 20 or 40 mg esomeprazole. In another preference, a composition comprises 20 or 40 mg of pantoprazole.

In the following, the invention is described a.d.h.v. non-limiting examples illustrating the invention, and which are not intended or may be interpreted to limit the scope of the invention. EXAMPLE 1: Composition Esomeprazole

In a first example, a powder for solution for injection and intravenous infusion was prepared with composition according to Table 1. The water was removed by freeze-drying and a composition as shown in Table 2 was obtained. Nitrogen may be present in the headspace of the vial. (1): equivalent to 40 mg Esomeprazole

Table 1: For freeze drying

Table 2: After freeze drying

EXAMPLE 2: Composition of pantoprazole

In a second example, a powder for solution for injection and intravenous infusion was prepared with the composition according to Table 3. The water was removed by freeze-drying and a composition as shown in Table 4 was obtained. Nitrogen may be present in the headspace of the vial.

Table 3: Before freeze drying

Table 4: After freeze drying

(1): Equivalent to 40 mg pantoprazole. (2): Used as sodium hydroxide 0.1M. (3): Water for injection was removed by freeze-drying process. EXAMPLE 3: Degradation study for esomeprazole

An esomeprazole solution was subjected to various conditions that may cause dissolution of the active ingredient. The products formed were analyzed according to a method known in the European Pharmacopoeia. The impurities listed in the table below are referred to as in monographs 0942 and 2372 for omeprazole and for esomeprazole magnesium trihydrate respectively. The procedure is known as the Ph Eur impurities assay method. The results are shown in Table 5. The interpretation is summarized in Table 6.

Esomeprazole sodium was subjected to the following conditions: 1 liter of esomeprazole sodium solution 21.25 mg / ml (equivalent to 20 mg / ml esomeprazole) was prepared using water for injection. Portions of the solution were subjected to:

-oxidation: in a 100 ml volumetric bottle, 1.0 ml of a 30% hydrogen peroxide solution was added and mixed with 99 ml of solution. The mixture was stored in the dark for 24 hours at 25 ° C light: 100 ml of solution was placed in a volumetric bottle and exposed to UV light of 254 nm for 7 days at 25 ° C. heat: 100 ml of the solution was placed in a volumetric bottle and exposed to a temperature of 100 ° C - 105 ° C for 4 hours. -pH 3.0: the pH of 100 ml of the solution was adjusted to 3.0 using HCl 0.1 M. The acidified solution was stored in the dark for 24 hours at 25 ° C. -pH 7.0: the pH of 100 ml of the solution was adjusted to 7.0 using HCl 0.1 M. The acidified solution was stored in the dark for 24 hours at 25 ° C. -pH 9.0: the pH of 100 ml of the solution was adjusted to 9.0 using HCl 0.1 M. The acidified solution was stored in the dark for 24 hours at 25 ° C. -pH 11.5: 100 ml of the solution was stored in the dark for 24 hours at 25 ° C.

Chromatograms of the different solutions were recorded. By means of a blank solution consisting of the mobile phase, and recording of a chromatogram, the peaks related to the mobile phase could be rejected.

Table 5: Composition of an esomeprazole solution after exposure to different stress conditions

*: Sodium esomeprazole is not soluble at this pH.

Table 6: Conclusions

EXAMPLE 4: Degradation study for pantoprazole

A pantoprazole solution was subjected to various conditions that may cause dissolution of the active ingredient, according to the procedure described for esomeprazole in Example 3. The products formed were analyzed according to a method known in the pharmacopoeia 2296. The impurities listed in the table below are known in this pharmacopoeia. The procedure is known as the Ph Eur impurities assay method. The results are shown in Table 7. The interpretation was summarized in Table 8.

Table 7: Exposure of a pantoprazole composition to different stress conditions

(1): Due to the high number of impurities due to oxidation, it was not possible to determine this concentration. EXAMPLE 5: Solubility esomeprazole

For solubility measurement, for each pH value, 2125 mg of sodium esomeprazole was added to 100 ml of water that was stirred. Solubility was checked visually during preparation and after 3 days at 25 ° C. The results are shown in Table 8.

Table 8: Solubility at different pH

The above results show that by adjusting the pH of the solution for lyophilization one can influence the solubility of the powder upon reconstitution. Preferably the pH is at least 11. EXAMPLE 6: Solubility pantoprazole

To measure solubility, 2259 mg of sodium pantoprazole sesquihydrate was added to 100 ml of water that was stirred for each pH value. Solubility was checked visually during preparation and after 3 days at 25 ° C. The results are shown in Table 9.

Table 9: Pantoprazole solubility at different pH

EXAMPLE 7: Method according to a preferred form of the invention An example of a method according to the invention:

Step 1: ingredients were weighed against the amount of proton pump inhibitor, here sodium esomeprazole weighed from chelating agent, here EDTA,

Step 2: sterilization of plugs, filters and machines

All parts that will come into contact with the solution or the freeze-dried product have been steam sterilized,

Step 3: composition of the solution 80% of the estimated amount of water was placed in a container at a temperature between 18 ° C and 22 ° C; with stirring, the amount of EDTA was added and stirred until dissolved; while stirring, nitrogen gas filtered through a 0.2 µm filter was bubbled through the solution until a maximum of 0.5 ppm oxygen gas was present in the solution; pH of this solution was measured and adjusted with 0.1 M sodium hydroxide to pH between 11.0 and 11.2; check whether oxygen gas was below 0.5 ppm, if not nitrogen gas was bubbled back through the solution; the amount of sodium esomeprazole was added during stirring and stirred until this amount was completely dissolved; check whether oxygen gas was below 0.5 ppm, if not nitrogen gas was bubbled back through the solution; pH of this solution was measured and adjusted with 0.1 M sodium hydroxide to pH between 11.2 and 11.4; replenishing the solution with water that has previously been bubbled with nitrogen gas so that the amount of oxygen gas in this water was below 0.5 ppm; homogenization of the solution by stirring; check whether oxygen gas was below 0.5 ppm, if not nitrogen gas was bubbled back through the solution;

Step 4: cleaning and sterilizing the vials,

Step 5: sterilize the solution by filtration,

Step 6: filling of solution in vials and freeze-drying,

Step 7: taking out the vials,

Step 8: inspection,

Step 9: printing cardboard boxes,

Step 10: labeling and packaging.

It is believed that the present invention is not limited to the embodiments described above and that some modifications or changes can be added to the described examples without re-evaluating the appended claims. For example, the present invention has been described with reference to esomeprazole, but it should be understood that the invention can be applied to, for example, lansoprazole or rabeprazole.

Claims (16)

CONCLUSIONS A method for making a powdered proton pump inhibitor composition for injection or infusion after reconstitution, the composition comprising the following components: - 86.0-99.9 weight percent proton pump inhibitor; - 0-13% by weight of a chelating agent; - 0.1-1.0 weight percent of a base; wherein the weight percentage of each component is expressed relative to the total weight of the composition, said method comprising the following steps: 3) preparing a proton pump inhibitor solution: f) provided with a solvent with a temperature below 25 ° C; g) optionally adding the chelating agent to the solvent; h) adding the base to the mixture; i) adding the proton pump inhibitor to the mixture; j) bubbling the mixture with an inert gas until the solution comprises less than 5 ppm oxygen; and 4) freeze-drying the solution. Method according to claim 1, characterized in that the solution is filtered. Method according to at least one of the preceding claims, characterized in that step 2) is carried out with an illuminance on the solution lower than 250 lux. Method according to at least one of the preceding claims, characterized in that the temperature during freeze drying is not higher than 40 oc. The method according to at least one of the preceding claims, characterized in that the proton pump inhibitor is omeprazole. The method according to at least one of the preceding claims, characterized in that the proton pump inhibitor is esomeprazole. The method according to at least one of the preceding claims, characterized in that the proton pump inhibitor is pantoprazole. Process according to at least one of the preceding claims, characterized in that the solvent comprises water. Method according to at least one of the preceding claims, characterized in that the pH of the solution is above 11.0. Method according to at least one of the preceding claims, characterized in that the base is sodium hydroxide. A method according to at least one of the preceding claims, characterized in that the inert gas is nitrogen gas. Process according to at least one of the preceding claims, characterized in that the chelating agent is ethylenediaminetetraacetic acid or a pharmacologically acceptable salt thereof. A powdered proton pump inhibitor composition obtainable by a method according to at least one of claims 1-12. A vial comprising a powdered proton pump inhibitor composition according to claim 13. A composition for injection or infusion comprising a composition according to claim 13 and a physiologically acceptable solvent. A composition according to claim 13 or 15 for use as a medicament.