WO2006082490A1

WO2006082490A1 - Injectable formulations of benzimidazole compounds

Info

Publication number: WO2006082490A1
Application number: PCT/IB2006/000167
Authority: WO
Inventors: Ashish Sehgal; Pallerla Bhaskar; Jyoti Srivastava; Vinod Kumar Arora
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2005-02-02
Filing date: 2006-01-31
Publication date: 2006-08-10
Also published as: CN1813729A

Abstract

The present invention relates to an injectable pharmaceutical formulation of a benzimidazole compound. Also provided are processes of making and methods of using these pharmaceutical formulations.

Description

INJECTABLE FORMULATIONS OF BENZIMID AZOLE COMPOUNDS

Field of the Invention

Background of the Invention

Benzimidazole compounds are extensively used in the treatment of gastric acidity and ulcer. Injectable formulations would be preferred in case of patients who cannot take oral formulations and when an immediate response is desired. Japanese Patent Application No. 59,167,587 discloses an injectable formulation of omeprazole sodium in a lyophilized form to be dissolved in water for injection, wherein the formulation contains a mixture of polyethylene glycol 400 and sodium dihydrogen orthophosphate.

WO 04/63152 discloses a liquid formulation of lansoprazole for parenteral administration containing one or more of an oil, a solvent, a surfactant or another excipient.

WO 02/41919 discloses a freeze-dried preparation of pantoprazole containing ethylenediamine tetraacetic acid (EDTA), sodium hydroxide and/or sodium carbonate.

Chinese Patent Application No. 1,385,214 discloses omeprazole sodium powder for injection containing 0.9 % to 15 % (w/w) of inorganic salt, such as sodium chloride, sodium bicarbonate, sodium dihydrogen orthophosphate and calcium chloride or an organic salt, such as sodium or calcium lactate. The injection also contains 0.01 %-0.1 % disodium methylene diaminetetraacetate.

Japanese Patent Application No. 2,138,213 discloses an injectable solution of lansoprazole in a freeze-dried form containing an excess of alkaline (NaOH) and at least one of ethanol, propylene glycol and polyethylene glycol.

European Patent Application No. 649,655 discloses a stable pharmaceutical composition of a benzimidazole compound containing a water-soluble carboxylic acid amide (such as nicotinamide). The composition in spray-dried or lyophilized form is dissolved in sterile distilled water before use.

WO 94/02141 discloses an injection solution comprising a 2-[(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt thereof having antiulcer activity and an aqueous solvent devoid of nonaqueous solvent, wherein the pH of the injection solution is not less than 9.5 and not more than 11.5. The injection may contain mannitol, glycine, sorbitol, inositol and mixtures thereof.

WO 02/15908 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. The formulation may include N-methyl glucamine and a saccharide, such as mannitol, and may be freeze-dried.

It was observed that mere adjustment of the solution pH with an alkaline base as suggested by the prior art was not sufficient to solubilize, and therefore stabilize, the benzimidazole compounds. Surprisingly we observed that benzimidazole compounds can be sufficiently stabilized using L-arginine alone. This reduces the need to use extra excipients in the formulation thereby decreasing the processing time and the cost of production. Such formulations are economical and preferred for a commercial scale production.

Summary of the Invention In one general aspect there is provided an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;

wherein Rl is hydrogen, methoxy or difluoromethoxy; R2 is hydrogen, methyl or methoxy; R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy; and, R4 is hydrogen, methyl or methoxy;

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.

Embodiments of the present invention may include one or more of the following features. For example, the benzimidazole compound may be one or more of lansoprazole, omeprazole, rabeprazole, and pantoprazole.

The optional pharmaceutically acceptable excipients may be one or more of antibacterial preservatives, antioxidants, buffers and tonicity contributors

In another general aspect there is provided an injectable pharmaceutical formulation comprising: ... a benzimidazole compound of formula I;

L-arginine; one or more of alkaline substances; and, optionally one or more pharmaceutically acceptable excipients, wherein the molar ratio of benzimidazole and L-arginine is greater than about 1 :2 and less than about 1 :5. - A -

Embodiments of the present invention may include one or more of the following features. For example, the benzimidazole compound may include one or more of lansoprazole, omeprazole, rabeprazole and pantoprazole. The molar ratio of benzimidazole and L-arginine is about 1:70 or the molar ratio of benzimidazole and L- arginine is about 1 :3.

The alkaline substance may be one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine.

The pharmaceutically acceptable excipients may include one or more of antibacterial preservatives, antioxidants, buffers and tonicity contributors.

In another general aspect there is provided a process for the preparation of an injectable pharmaceutical formulation. The process includes the steps of: a) adding a benzimidazole compound of formula I, L-arginine, and optionally one or more alkaline substances and one or more pharmaceutically acceptable excipients to aqueous solution; and, b) lyophilizing the aqueous solution of step a) to obtain the injection formulation.

In another general aspect there is provided a method of treating gastric ulcers. The method includes administering to a patient in need thereof an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;

L-arginine; one or more of alkaline substances; and, optionally one or more pharmaceutically acceptable excipients, wherein the molar ratio of benzimidazole and L-arginine is greater than about 1 :2 and less than about 1:5.

Detailed Description of the Invention

The present invention provides for an injectable pharmaceutical formulation. The formulation includes: a benzimidazole compound of formula I;

wherein Rl is hydrogen, methoxy or difluoromethoxy; R2 is hydrogen, methyl or methoxy; R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy; and, R4 is hydrogen, methyl or methoxy; 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. The term "injection" refers to sterile formulations intended for parenteral use and after reconstitution should be essentially free from particles that can be observed upon visual inspection. The injectable pharmaceutical formulation may be as a solid in a lyophilized, freeze-dried or spray dried form. This solid may be reconstituted in an aqueous solvent before use. The aqueous solvent may be sterile water for injection, physiological saline, aqueous solution of 5 % glucose or mixtures thereof.

The term "pharmaceutically acceptable excipient" as used herein may include one or more of antibacterial preservatives, antioxidants, buffers and tonicity contributors.

The injectable pharmaceutical formulation may be used in the form of a drip infusion, intravenous injection, intramuscular injection or subcutaneous injection. When given as a drip infusion the pharmaceutical formulation may not contain antibacterial preservatives.

The benzimidazole compound may include one or more compounds of formula I;

wherein Rl is hydrogen, methoxy or difluoromethoxy; R2 is hydrogen, methyl or methoxy; R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy; and, R4 is hydrogen, methyl or methoxy. The compounds formed may be well known and very effective medicinal compounds widely used in the treatment of gastric disorders. For example, the compound may be lansoprazole, omeprazole, rabeprazole and pantoprazole.

The term 'L-arginine' as used herein refers to L-arginine or salts thereof. The molar ratio of the benzimidazole compound to the L-arginine may be greater than 1 :2 when used in combination with an alkaline substance. The ratio may also be greater than 1 :2 and less than 1 :5, or it may be 1:3. Particularly, the ratio may be greater than 1 :20 when L-arginine is used alone, or the ratio may greater than 1 :20 and less than 1:80. For example, the ratio may be 1 :70.

The alkaline substances may include one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine. The injectable pharmaceutical formulation may optionally include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more of antibacterial preservatives, including from one or more of phenylmercuric nitrate, thimersal, benzalkonium chloride, benzethonium chloride, phenol, cresol and chlorobutanol; antioxidants including one or more of ascorbic acid, sodium sulfite, sodium bisulfite and sodium metabisulfite; buffers including one or more of acetate, citrate, tartarate, phosphate, benzoate and bicarbonate; and tonicity contributors including one or more of sodium chloride, potassium chloride, dextrose, mannitol, sorbitol and lactose.

Also provided are processes for the preparation of the injectable pharmaceutical formulation. The process includes lyophilizing or freeze-drying an aqueous solution, preferably an alkaline aqueous solution, which includes a benzimidazole compound having antiulcer activity and L-arginine. The aqueous solution may also optionally include one or more pharmaceutically acceptable excipients. An exemplary procedure comprises freezing the aqueous solution at -40°C to -25°C and, with the internal negative pressure of the freeze-drier being maintained at about 0.1 Torr or less, increasing the plate temperature at a rate of about 1°C to 5°C/hour to an ultimate temperature of about 25⁰C to 4O⁰C.

The following non- limiting examples further illustrate injection formulations of benzimidazole compounds and process of making thereof.

Example 1A-1B

* Does not remain in the formulation.

Process of preparation: Example 1 A: a) The lansoprazole and L-arginine were dissolved in water to obtain a solution; b) The solution of step (a) was asceptically filtered and filled in to presterilized vials; and, c) The filtered solution of step (b) was lyophilized. Example 1 B: a) The lansoprazole, L-arginine and sodium hydroxide were dissolved in water to obtain a solution; b) The solution of step (a) was asceptically filtered and filled in to presterilized vials; and, c) The filtered solution of step (b) was lyophilized.

Examples 2A - 2F

For comparative evaluation, a series of formulations (given in the table below) were prepared with varying molar ratios of L-arginine with respect to lansoprazole and also with one or more alkaline substances/solubilizers.

Process of preparation: a) The lansoprazole and other ingredients were dissolved in water to obtain a solution; b) The solution of step (a) was asceptically filtered and filled in to presterilized vials; and, c) The filtered solution of step (b) was lyophilized.

It was observed that in the case of formulations (example 2A) comprising lansoprazole and L-arginine in a molar ratio of 1 : 1 along with sodium hydroxide, lansoprazole was found to be insoluble; albeit the pH of the formulations ranged between 9.5 and 11.0. Similarly, in case of formulations (comparative example 2B) containing L- arginine alone, lansoprazole was found to be insoluble when the molar ratio of lansoprazole and L-arginine was 1 :20. Further, lansoprazole was found to be insoluble in case of formulations (Examples 2C-2F) without L-arginine.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

We claim:

1. An injectable pharmaceutical formulation comprising a benzimidazole compound of formula I;

wherein Rl is hydrogen, methoxy or difiuoromethoxy; R2 is hydrogen, methyl or methoxy; R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy; and, R4 is hydrogen, methyl or methoxy;

2. The pharmaceutical formulation according to claim 1, wherein the benzimidazole compound comprises one or more of lansoprazole, omeprazole, rabeprazole and pantoprazole.

3. The pharmaceutical formulation according to claim 1, wherein the optional pharmaceutically acceptable excipients comprise one or more of antibacterial preservatives, antioxidants, buffers and tonicity contributors

4. An injectable pharmaceutical formulation comprising a benzimidazole compound of formula I;

wherein Rl is hydrogen, methoxy or difluoromethoxy; R2 is hydrogen, methyl or methoxy; R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy; and, R4 is hydrogen, methyl or methoxy; L-arginine; one or more of alkaline substances; and, optionally one or more pharmaceutically acceptable excipients, wherein the molar ratio of benzimidazole and L-arginine is greater than about 1 :2 and less than about 1:5.

5. The pharmaceutical formulation according to claim 4, wherein the benzimidazole compound comprises one or more of lansoprazole, omeprazole, rabeprazole and pantoprazole.

6. The pharmaceutical formulation according to claim 1, wherein the molar ratio of benzimidazole and L-arginine is about 1 :70.

7. The pharmaceutical formulation according to claim 4, wherein the molar ratio of benzimidazole and L-arginine is about 1 :3.

8. The pharmaceutical formulation according to claim 4, wherein the alkaline substance comprises one or more of sodium hydroxide, potassium hydroxide, sodium carbonate and meglumine.

9. The pharmaceutical formulation according to claim 4, wherein the optional pharmaceutically acceptable excipients comprises one or more of antibacterial preservatives, antioxidants, buffers and tonicity contributors.

10. A process for the preparation of an injectable pharmaceutical formulation, the process comprising the steps of: a) adding a benzimidazole compound of formula I, L-arginine, and optionally one or more alkaline substances and one or more pharmaceutically acceptable excipients to aqueous solution; and, b) lyophilizing the aqueous solution of step a) to obtain the injection formulation.

11. A method of treating gastric ulcers, the method comprising administering to a patient in need thereof an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;

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.

12. A method of treating gastric ulcers, the method comprising administering to a patient in need thereof an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;