WO2009001163A1

WO2009001163A1 - Lyophilized preparations of pantoprazole sodium for injection

Info

Publication number: WO2009001163A1
Application number: PCT/IB2007/003338
Authority: WO
Inventors: Sergio Lloret Perez; Begoña Duarte Lopez
Original assignee: Combino Pharm, S.L.
Priority date: 2006-06-01
Filing date: 2007-06-01
Publication date: 2008-12-31
Also published as: AR061155A1

Abstract

The invention relates, in general, to new lyophilized preparations of pantoprazole sodium for injection that include other ingredients (e.g., dibasic sodium phosphate and/or sodium citrate), and to a process for their preparation. The invention further includes pantoprazole sodium for injection obtained by reconstitution of the lyophilized products described herein.

Description

LYOPHILIZED PREPARATIONS OF PANTOPRAZOLE SODIUM FOR INJECTION

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application No.60/809,791, filed June 1 , 2006, which application is expressly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the invention

2. Discussion of the related art

Pantoprazole, 5-difluoromethoxy-2[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-l//- benzimidazole, is a benzimidazole compound that inhibits gastric acid secretion. Pantoprazole sodium has been approved by the FDA for parenteral administration under the name Protonix IV* and for oral administration under the name Protonix^® for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GEHD), for maintenance of healing of erosive esophagitis and for treatment of pathological hypersecretory conditions, including, for example, Zollinger-Ellison syndrome. Pantoprazole is a chiral compound, and the term pantoprazole also includes the pure enantiomers of pantoprazole and their mixtures in any mixing ratio. Pantoprazole also refers to all solvates, and in particular to hydrates, of 5-difluoromethoxy-2[(3,4-dimethoxy- 2-pyridinyl)methylsulfinyl]-lH-benzimidazole and salts thereof, preferably pantoprazole sodium sesquihydrate. In past years, pantoprazole sodium for injection was commercially available in the

United States under the tradename Protonix LV. as a freeze-dried powder in a clear glass vial fitted with a rubber stopper and crimp seal containing only pantoprazole sodium. However, as disclosed in Physicians' Desk Reference entry available in 2003 for Protonix LV. product in the United States (see page 12, chapter Dosage and Administration), this preparation presented an important drawback, i.e., a precipitate was formed when the reconstituted drug was mixed with I. V. solutions, and hence an in-line filter should be used for intravenous administration, which make the administration of Protonix I.V troublesome.

USP (United States Pharmacopoeia) 24 as well as European Pharmacopoeia (EP) S.4 describe physical tests performed for the purpose of enumerating subvisible extraneous particles within specific size ranges and also define that the particulate matters limit for small-volume injections is of 6,000 subvisible particles per vial, the particles having a size equal to or greater than lOμm.

Aimed to reduce the number of particles after reconstitution, and thus to eliminate the requirement of an in-line filter, U.S. Patent No. 6,780,881 describes that by freeze drying of an aqueous solution of pantoprazole, ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate to regulate the pH of the solution, a lyophilisate is obtained having significantly lower number of subvisible particles after reconstitution with a solvent compared to lyophilisates of the state of the art

Presently, Protonix IV^® (pantoprazole sodium for injection) is commercially available in the United States as a freeze-dried powder in a clear glass vial fitted with a rubber stopper and crimp seal containing pantoprazole sodium, edetate disodium and sodium hydroxide to adjust pH.

The stability of pantoprazole sodium in aqueous solution is pH-depεndent. The rate of degradation of pantoprazole sodium increases with decreasing pH. In this regard, the reconstituted solution of Protonix I.V. for injection should be in the pH range 9.0 to 10.5.

For that reason, the presently marketed lyophilized preparation of pantoprazole sodium for injection presents an important drawback, i.e., the edetate disodium used to reduce the number of particles presents acid properties, and hence increases the rate of degradation of pantoprazole sodium. With this problem in mind, both the preparation of the lyophilisate of pantoprazole sodium for injection and the reconstituted solution necessarily require the presence of sodium hydroxide to adjust the pH as to avoid the degradation of pantoprazole sodium, which makes the preparation cumbersome.

In view of the foregoing, there is therefore the need for an alternative lyophilized preparation of pantoprazole sodium for injection that avoids the drawbacks of prior art, i.e., shows a reduced number of particles after reconstitution, and thus does not require of an in-line filter for intravenous administration, and that does not need of additional substances to adjust the pH.

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.

The invention provides new lyophilized preparations of pantoprazole sodium for injection that includes other ingredients (e.g., dibasic sodium phosphate and/or sodium citrate), and to a process for their preparation. The invention further includes pantoprazole sodium for injection obtained by reconstitution of the lyophilized products described herein. Dibasic sodium phosphate and/or sodium citrate are believed to be acting as both sequestering agent and buffering agent, which resists changes in pH. Thus, the lyophilized preparation shows a reduced number of particles after reconstitution, and thus does not require of an in-line filter for intravenous administration, and does not need of additional substances to adjust the pH.

Accordingly, one aspect of the invention relates to a new, rapidly soluble, lyophilized preparation for injection that includes: i. approximately 21.1 mg to approximately 63.4 mg of pantoprazole sodium which is equivalent to approximately 20 mg to approximately 60 mg of pantoprazole which is equivalent to approximately 22.6 mg to approximately 67.7 mg of pantoprazole sodium sesquihydrate; and ii. approximately 15.0 mg to approximately 45.0 mg of dibasic sodium phosphate. In another aspect, the invention relates to a new, rapidly soluble, lyophilized preparation for injection that includes: i. approximately 21.1 mg to approximately 63.4 mg of pantoprazole sodium which is equivalent to approximately 20 mg to approximately 60 mg of pantoprazole which is equivalent to approximately 22.6 mg to approximately 67.7 mg of pantoprazole sodium sesquihydrate; and ii. approximately 17.3 mg to approximately 51.8 mg of sodium citrate.

Preferably, the above-described lyophilized preparation for injection comprises approximately 42.3 mg of pantoprazole sodium which is equivalent to approximately 40 mg of pantoprazole which is equivalent to 45.1 mg of pantoprazole sodium sesquihydrate.

Preferably, the above-described lyophilized preparation for injection comprises approximately 34.5 mg of sodium citrate.

In another aspect, the invention relates to a process for preparing the above- described lyophilized preparations for injection. In another aspect, the invention provides pantoprazole sodium injections obtainable by reconstitution of the lyophilized products described herein.

In another aspect, and unlike the commercially available Protonix IV^®, which contains edetate disodium and requires that the pH of the product be adjusted with sodium hydroxide, the lyophilized products according to the invention do not require a processing step in order to adj ust the pH.

In view of the foregoing, one embodiment of the invention encompasses a new, rapidly soluble, lyophilized preparation for injection that includes: i. approximately 42.3 mg of pantoprazole sodium which is equivalent to approximately 40 mg of pantoprazole which is equivalent to approximately 45.1 mg of pantoprazole sodium sesquihydrate; and ii. approximately 30.0 mg of dibasic sodium phosphate.

Another embodiment of the invention provides a process for preparing the above- described lyophilized preparation for injection that includes the following steps: i. bubbling nitrogen gas through approximately 3 mL of water to decrease the oxygen content of said water, to obtain deoxygenated water; ii. adding pantoprazole sodium sesquihydrate to an approximately 90% volume of deoxygenated water of step i. while nitrogen is bubbled through solution, to obtain a solution; iii. - adding dibasic sodium phosphate to the solution of step step ii. while nitrogen is bubbled through solution, to obtain a solution; iv. adjusting the volume of the solution obtained in step iii. by adding approximately 10% volume of deoxygenated water of step L; v. filtering the solution obtained in step iv. through a 0.22 μm polyvinylidene difluoride (PVDF) membrane filter,

Vt. filling the solution obtained in step v. into a vial; vii. lyophilizing the solution in order to obtain an off-white lyophilized product; and viii. closing the vial under nitrogen atmosphere. A further embodiment of the invention provides a new, rapidly soluble, lyophilized preparation for injection that includes: i. approximately 42.3 mg of pantoprazole sodium which is equivalent to approximately 40 mg of pantoprazole which is equivalent to approximately 45.1 mg of pantoprazole sodium sesquihydrate; and ii. approximately 34.S mg of sodium citrate.

In another aspect, reconstitution upon dissolution in a pharmaceutically acceptable solvent of the above-described lyophilized preparation for injection, leads to a preparation showing an appropriate number of subvisible particles per vial compared to the limits established in USP 24 and EP S.4, the particles having a size equal to or greater than 10 μm, wherein the number of particles is determined according to EP 5.4 by light obscuration particle test count.

Suitable pharmaceutically acceptable solvent used in reconstitution of the above- described lyophilized preparation for injection include solvents such as water for injection, physiological saline, aqueous solution of 5% glucose, and distilled water. Preferably, the pharmaceutically acceptable solvent is water for injection.

The above-described reconstituted lyophilized preparation for injection typically has less than 2,000 subvisible particles per vial, the particles having a size equal to or greater than 10 μm, wherein the number of particles is determined according to EP 5.4 by light obscuration particle test count.

The above-described lyophilized preparation of pantoprazole sodium for injection has advantageous properties, i.e., shows a reduced number of particles after reconstitution, and thus does not require of an in-line filter for intravenous administration, and does not need of additional substances to adjust the pH.

Yet another embodiment of the invention provides a process for preparing the above-described lyophilized preparation for injection that includes the following steps: i. bubbling nitrogen gas through approximately 3 mL of water to decrease the oxygen content of said water, to obtain deoxygenated water; ii. adding pantoprazole sodium sesquihydrate to an approximately 90% volume of deoxygenated water of step i. while nitrogen is bubbled through solution, to obtain a solution; iii. adding sodium citrate to the solution of step step ii. while nitrogen is bubbled through solution, to obtain a solution; iv. adjusting the volume of the solution obtained in step iii. by adding approximately 10% volume of deoxygenated water of step i.; v. filtering the solution obtained in step iv. through a 0.22 μm PVDF membrane filter, vi. filling the solution obtained in step v. into a vial; vii. lyophilizing the solution in order to obtain an off-white lyophilized product; and viii. closing the vial under nitrogen atmosphere.

Another embodiment of the invention provides the above-described pantoprazole sodium injections via reconstitution of the lyophilized products described above with a quantity of a pharmaceutically acceptable solvent (e.g., water for injection, physiological saline, aqueous solution of 5% glucose, or distilled water) prior to injection.

A further embodiment of the invention includes the use of the lyophilized products and sodium pantoprazole injection according to the invention for the treatment and s prevention of those diseases {e.g., short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), for maintenance of healing of erosive esophagitis and for the treatment of pathological hypersecretory conditions, including, for example, Zollinger-EUison syndrome) that are regarded as treatable or avoidable by the use of pyridine-2-yImethyIsulfinyI-lH-benzimidazoles. 0 It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents. 5 Specific Examples

The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.

EXAMPLE 1: Preparation of an Injectable Formulation of Pantoprazole Sodium

Table 1 illustrates a lyophilized preparation of pantoprazole sodium for injection with the following constituents:

Table 1

The lyophilized preparation of pantoprazole sodium for injection of Table 1 was prepared as follows: A nitrogen sparge was connected for at least 1 S minutes to a total volume of 3 mL of water in order to decrease the oxygen content in the water. The nitrogen purge was continued while mixing and maintained throughout the entire process. Pantoprazole sodium sesquihydrate was added to approximately 90% of the total volume of the degassed water and dissolved. Once the pantoprazole sodium sesquihydrate was totally dissolved, dibasic sodium phosphate was added to the solution and dissolved to yield a clear solution. The solution was increased to its final volume of 3 mL by the addition of approximately 10% of the total volume of the degassed water. The solution was then filtered through a 0.22 μm PVDF membrane filter and filled into a vial under nitrogen atmosphere.

The vial was half driven with a rubber stopper and was lyophilized (i.e., freeze-dried) by a conventional method to yield an off white powder that was ready for reconstitution. At the end of the lyophilization process, the vial was closed under nitrogen atmosphere. A reconstituted solution of the lyophilized product has a pH range of 9.0 to 10.S.

EXAMPLE 2; Preparation of an Injectable Formulation of Pantoprazole Sodium

Table 2 illustrates another lyophilized preparation of pantoprazole sodium for injection with the following constituents:

Table 2

The lyophilized preparation of pantoprazole sodium for injection of Table 2 was prepared as follows: A nitrogen sparge was connected for at least 1 S minutes to a total volume of 3 mL of water in order to decrease the oxygen content in the water. The nitrogen purge was continued while mixing and maintained throughout the entire process. Pantoprazole sodium sesquihydrate was added to approximately 90% of the total volume of the degassed water and dissolved. Once the pantoprazole sodium sesquihydrate was totally dissolved, sodium citrate was added to the solution and dissolved to yield a clear solution. The solution was increased to its final volume of 3 mL by the addition of approximately 10% of the total volume of the degassed water. The solution was then filtered through a 0.22 μm PVDF membrane filter and filled into a vial under nitrogen atmosphere.

The vial was half driven with a rubber stoppers and was lyophilized {i.e., freeze-dried) by a conventional method to yield an off white powder that was ready for reconstitution. At s the end of the lyophilization process, the vial was closed under nitrogen atmosphere. A reconstituted solution of the lyophilized product has a pH range of 9.0 to 10.S.

A reconstituted solution of the lyophilized preparation of pantoprazole sodium for injection of Table 2 typically has less than 2000 subvisible particles per vial, the particles having a size equal to or greater than 10 μm, wherein the number of particles is determined0 according to EP 5.4 by light obscuration particle test count.

Although the invention has been described and illustrated with certain degree of particularity, it is to be understood that the present disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.5

Claims

What is claimed is:

1. A lyophilized preparation for injection comprising: i. between approximately 21 mg and approximately 64 mg of pantoprazole sodium; and ii. between approximately 17 mg and approximately 52 mg of sodium citrate.

2. The preparation of claim 1, wherein said preparation comprises between approximately 42 mg and approximately 43 mg of pantoprazole sodium.

3. The preparation of claim 1, wherein said preparation comprises approximately 42.3 mg of pantoprazole sodium.

4. The preparation of any of claims 1-3, wherein said preparation comprises between approximately 34 and approximately 35 mg of sodium citrate.

5. The preparation of any of claims 1 -3, wherein said preparation comprises approximately 34.5 mg of sodium citrate.

6. A process for preparing a lyophilized preparation for injection comprising: i. obtaining a solution by adding between approximately 22 mg and approximately 68 mg of pantoprazole sodium sesquihydrate in deoxygenated water; ii. adding between approximately 17.0 mg and approximately 52.0 mg of sodium citrate to said solution;

Hi. optionally adjusting the volume of said solution by adding additional deoxygenated water; iv. filtering said solution through a membrane filter; v. filling said solution into a vial; and vi. lyophilizing said solution to obtain an off-white lyophilized product.

7. The process of claim 6, wherein said step of obtaining a solution by adding between approximately 22 mg and approximately 68 mg of pantoprazole sodium sesquihydrate in deoxygenated water comprises between approximately 1.5 mL and approximately 4.5 inL of deoxygenated water.

8. The process of claim 7, wherein said deoxygenated water comprises approximately 3 mL of deoxygenated water.

9. The process of claim 6, wherein said step of obtaining a solution by adding between approximately 22 mg and approximately 68 mg of pantoprazole sodium sesquihydrate in

S deoxygenated water comprises between approximately 45 mg and 46 mg of pantoprazole sodium sesquihydrate.

10. The process of claim 9, wherein pantoprazole sodium sesquihydrate comprises approximately 45.1 mg of pantoprazole sodium sesquihydrate

1 1. The process of claim 6, wherein said step of adding between approximately 17.0 mg0 and approximately 52.0 mg of sodium citrate to said solution comprises adding between approximately 34 and approximately 35 mg of sodium citrate.

12. The process of claim 11, wherein said sodium citrate comprises approximately 34.5 mg of sodium citrate.

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