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WO2006082490A1 - Injectable formulations of benzimidazole compounds - Google Patents

Injectable formulations of benzimidazole compounds Download PDF

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Publication number
WO2006082490A1
WO2006082490A1 PCT/IB2006/000167 IB2006000167W WO2006082490A1 WO 2006082490 A1 WO2006082490 A1 WO 2006082490A1 IB 2006000167 W IB2006000167 W IB 2006000167W WO 2006082490 A1 WO2006082490 A1 WO 2006082490A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
arginine
hydrogen
pharmaceutical formulation
benzimidazole
Prior art date
Application number
PCT/IB2006/000167
Other languages
French (fr)
Inventor
Ashish Sehgal
Pallerla Bhaskar
Jyoti Srivastava
Vinod Kumar Arora
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2006082490A1 publication Critical patent/WO2006082490A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • 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.
  • 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.
  • EDTA ethylenediamine tetraacetic acid
  • Ciprazole 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.
  • 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).
  • 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.
  • an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • 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
  • an injectable pharmaceutical formulation comprising: ... a benzimidazole compound of formula I;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • Embodiments of the present invention may include one or more of the following features.
  • 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.
  • a process for the preparation of an injectable pharmaceutical formulation 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.
  • a method of treating gastric ulcers includes administering to a patient in need thereof an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • a method of treating gastric ulcers includes administering to a patient in need thereof an injectable pharmaceutical formulation comprising: a benzimidazole compound of formula I;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • the present invention provides for an injectable pharmaceutical formulation.
  • the formulation includes: a benzimidazole compound of formula I;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • 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.
  • pharmaceutically acceptable excipient 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;
  • Rl is hydrogen, methoxy or difluoromethoxy
  • R2 is hydrogen, methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 25 0 C to 4O 0 C.
  • 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.
  • step (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.

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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
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.
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;
Figure imgf000003_0001
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;
Figure imgf000004_0001
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. - 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;
Figure imgf000005_0001
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.
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;
Figure imgf000006_0001
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.
Detailed Description of the Invention
The present invention provides for an injectable pharmaceutical formulation. The formulation includes: a benzimidazole compound of formula I;
Figure imgf000007_0001
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;
Figure imgf000008_0001
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
Figure imgf000009_0001
* 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.
Figure imgf000010_0001
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;
Figure imgf000012_0001
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;
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.
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;
Figure imgf000013_0001
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;
Figure imgf000014_0001
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.
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;
Figure imgf000015_0001
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.
PCT/IB2006/000167 2005-02-02 2006-01-31 Injectable formulations of benzimidazole compounds WO2006082490A1 (en)

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CN113101273A (en) * 2021-03-31 2021-07-13 海南锦瑞制药有限公司 Omeprazole sodium for injection
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