FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A stable Lyophilized composition"

2. APPLICANT
(a) NAME: JAIN, MOHAN
(b) NATIONALITY: Indian National
(c) ADDRESS: B/83, Dattani Towers, Kora Kendra Compound,
S.V. Road, Borivali (West), Mumbai - 400 092, Maharashtra, India
3,PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner
in which it is to be performed.

Technical Field:
The present, invention relates to a stable composition of acid sensitive benzimidazole derivative, such as Rabeprazole particularly in the form of lyophilized dry powder for injection. More particularly the present invention relates to lyophilized injection comprising Rabeprazole or its stereoisomers or its salts or derivatives thereof, suitably processed by incorporating tonicity agent, buffer and pH adjustifier.
Background and Prior art:
The most effective suppressors of gastric acid secretion are gastric H+, K.+ ATPasc (proton pump) inhibitors. They are the most effective drugs used in antiulcer therapy and have found worldwide popularity over past decades.
Currently there are several different proton pump inhibitors available for clinical use. Proton pump inhibitors are ""prodrugs", requiring activation in an acid environment. These agents enter the parietal cells from the blood and because of their weak basic-nature, accumulate in the acidic secretary canaliculi of the parietal cell, where they are activated by a proton-catalyzed process that results in the formation of a thiophilic sulfonamide or sulfenic acid. This activated form reacts by covalent binding with the sulphydril group of cystines from the extra cellular domain of the H+„ K+ -ATPase. Binding to cystine 813, in particular, is essential for inhibition of acid production, which is irreversible for that pump molecule.
Proton pump inhibitors have profound effects on acid production. When proton pump inhibitors are given in a sufficient dose, the daily production of acid can be diminished by more than 95 %.
Proton pump inhibitors are unstable at low pH. The oral dosage forms ("delayed release") are supplied as enteric-coated granules encapsulated in a gelatin shell or as enteric-coated
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tablets. The granules dissolve only at an alkaline pH. thus preventing degradation of the drugs by acid in the esophagus and stomach.
Proton pump inhibitors (PPI) are rapidly absorbed, highly protein bound and extensively metabolized in the liver by the cytochrome P450 system (particularly CYP2C19 and CYP3A4). Their sulfated metabolites are excreted in the urine or feces.
All of these PPIs have a common mechanism of action involving chemical rearrangement to a reactive sulfonamide that inhibits the ability of H+, K+ -ATPase (the proton pump) to participate in gastric acid formation. As a result of structural and functional similarities, the PPIs share many pharmacokinetic features (eg. Similar rates of adsorption, maximum plasma concentration and total drug adsorption). All PPIs are extensively metabolized in the liver via CYP2C19 and 3A4 and they all exhibit polymorphic metabolism in humans.
In addition to P450 mediated metabolism, Rabeprazole is also converted nonenzymatically to its thioether analog. Considering the relatively higher lipoplilic character of this product and its relatively longer half life in vivo compared with its parent, it was also concluded in this study.
The potency and specificity of these PPIs as inhibitors of the four principle P450 enzymes (CYP2C9, 2CI9, 3A4 and 2D6) present in human labour microsomes (HLM) which are involved in the metabolism of most drugs and also might be influenced by PPIs.
Rabeprazole has significantly less drug interactions than other PPIs because of its non¬enzyme catalyzed degradation which forms thioether product.
Various PPTs such as Omeprazole, Pantaprazole. Lansoprazole are recognized by those skilled in art as therapeutic agent but Rabeprazole is only effective in relief of cancer-therapy. Rabeprazole with its most rapid activation rate get protonated and changes into activated sulfonamide at parietal cell secretary surface. It has highest Pka value i.e. 5.1
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among all PPPs, causes 100% proton pump inhibition within 5 minutes and has most rapid anti secretary activity which sustains over 24hrs. It has also significantly less drug interaction than other PPI's. Our results showed that this thioether product by itself exhibited inhibitory potency to all the four principle P450 enzymes.
Their plasma half lives are about 1 to 2 hours, but duration of their actions is much longer. Chronic renal failure and liver cirrhosis do not appear to lead to drug accumulation with once-a-day dosing of the drugs.
The requirement for enteric coating poses a challenge to the routine use of oral proton Pump inhibitors in critically ill patients or in patients unable to swallow adequately. Intravenous H2-receptor antagonists have been preferred in patients with contraindications to oral ingestion, but this picture will change with the advent of intravenous preparations of proton pump inhibitors.
Rabeprazole is substituted pyridyl methyl sulfinyl benzimidazole, proton pump inhibitor (PPI) and hence has similar structure and mechanism of action as that of other benzimidazoles like Omeprazole, Lansoparzole, Pantaprazole, etc.
Rabeprazole is a weak base with the pKa value 5.1. Stability of Rabeprazole in aqueous solution is pH dependent and rate of degradation increases with decreasing pH Rabeprazole undergoes acid catalyzed rearrangement to form protonated tetra cyclic sulfonamide which forms covalent disulfide bond with accessible thio group of cystine residues on the targeted receptor protein inhibiting the activity of the acid secreting hydrogen-potassium proton pump.
Rabeprazole is acid labile and hence the tablets are enteric coated. Further an oral liquid dosage form of Rabeprazole requires the addition of an alkaline ingredient with sufficient acid neutralizing capacity to facilitate the drug's safe passage through the stomach.
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The pyridine derivatives and proton pump inhibitors are commercially available and are prepared by the process reported in US5035899 and US5045552. The reported processes in these patents are for preparation of oral dosage form and bulk product.
Rabeprazole sodium is commercially available as ACIPHEX by Eisai Inc., Teaneck. N.I. ACIPHEX is commercially available as a delayed release, once a day, enteric coated tablet containing 20 mg Rabeprazole sodium. The tablets can be administered one to about four times a day.
Rabeprazole with its most rapid activation rate gets protonated and changes into active sulfonamide at the parietal cell secretary surface. Rabeprazole with pKa value of 5.1 (highest among PPIs) causes 100 % proton pump inhibition within 5 minutes and has most rapid anti-secretary activity, which is sustained over 24 hours. Rabeprazole is indicated in dose of 20 mg once daily for symptomatic relief and healing of erosive esophagitis.
Rabeprazole is currently available in the oral dosage forms such as tablets, troches, suspensions, solutions, capsules and the like. Further Rabeprazole is also administered by rectal, transdermal and the like routes with effective dosage of active ingredient.
Oral dosage forms of Rabeprazole are disclosed in US5035899, International patent application no. W09712580 and International patent application no. WO9725030.
International patent application No. WO9601624 discloses multiple unit tablets which contain active ingredient, an acid labile H+ K+ ATPase inhibitor or alkaline salt thereof.
Rectal composition of Rabeprazole is described in EP0645140.
Japanese Patent (unexamined) Publication no. JP167587/1984 describes the process for preparation of injection of Omeprazole. The process comprises dissolving sodium salt of Omeprazole in sterilized water, filtering and lyophilizing the solution to give lyophilized
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product. This lyophilized product is dissolved in a mixture of polyethylene glycol 400 for injection, sodium dihydrogen phosphate and sterilized water.
Lansoprazole lyophilized injection is prepared by dissolving lyophilized product of Lansoprazole in a mixture of acid and at least one of ethanol, propylene glycol and polyethylene glycol as described in Japanese (unexamined) patent no. JP138213/1990.
Freeze dried injectable formulation of Pantoprazole is described in International Patent application WO0241919. Lyophilization of the aqueous solutions of Pantoprazole. ethylenediamine tetra acetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate are disclosed.
Freeze dried formulations for Omeprazole and Lansoprazole, as described in International Patent application WO9402141, comprise the benzimidazole compounds or their salts to which are added an aqueous solvent wherein the pH is not less than 9.5 and not more than 11.2.
US6780882 and US6699885 disclose use of buffering agent for various dosage forms of benzimidazole like oral, nasogastric, and stomach tube wherein the buffering agent is used in an amount sufficient to increase gastric fluid pH of the stomach to a pi) that inhibits acid degradation of the proton pump inhibiting agent in the gastric fluid so as to provide a measurable serum concentration upon pharmacokinetic testing.
However, there is evidence of color change where PPI's are formulated for parenteral delivery as disclosed in WO 99/18959 wherein Glycin NaOH buffer has been tried to overcome the colour formation but the attempts were not successful completely. Similarly UK patent application GB 2404856 discloses lyophilized Rabeprazole formulation, the stability data up to 6 months, the pH of the injection was found at average of 9.4 ± 0.3 & also found the assay degradation at 30°C /65 % RH after one month.
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Hence in the present invention the various buffering agents are studied. It is a completely novel attempt and no literature for parenteral dosage available other than glycin sodium buffer.
Dysphagia is the inability or difficulty in swallowing. The act of swallowing occurs in three stages and requires the integrated action of the respiratory center and motor functions of multiple cranial nerves, and the co-ordination of the autonomic system within the esophagus. Although the main function of swallowing is the propulsion of food from the mouth into the stomach, swallowing also serves a protective reflex for the upper respiratory tract by removing particles trapped in the nasopharynx and oropharynx, returning materials refluxed from the stomach into the pharynx. The absence of an adequate swallowing reflex greatly increases the chance of pulmonary- aspiration.
In the past, patients suffering from dysphagia had to undergo dietary changes or thermal stimulation treatment to regain adequate swallowing reflexes. Thermal stimulation involves immersing a mirror or probe in ice or a cold substance. The tonsillar fossa is stimulated with the mirror or probe and the patient closes his mouth and attempts to swallow. While these traditional methods are usually effective for treating dysphagia, they often require that the patient endure weeks or months of therapy.
There is a need to develop stabilized formulation for treating and / or preventing dysphagia and other esophageal disorders in a patient in need thereof comprising administering a therapeutically effective amount of atleast one proton pump inhibitor. Further the stabilized formulation is also effective as a part of H. Pylori eradication regimen and also in Zollinger-Ellison syndrome.
Various PPls, such as Omeprazole. Pantaprazole and Lansoprazole are recognized by those skilled in the art as therapeutic agents but Rabeprazole is most effective in the relief of Cancer therapy. Rabeprazole is generally more effective in injection form, in unit dosage form, which provides immediate release of the active ingredients.
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Amongst PPIs, Rabeprazole is the only effective therapeutic agent in cancer therapy, preferably in the injection form.
The various attempts for developing Rabeprazole injectable formulations failed due to lack of stability and occurrence of colour change within a relatively short period. Therefore, all attempts made to stabilize Rabeprazole injection were unsuccessful.
Objectives of the invention:
It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide useful alternative.
An object of the present invention is to provide a stabilized dry powder composition in the form of a lyophilized injection comprising Rabeprazole or its stereoisomers or its salts along with pharmaceutically acceptable excipients.
Summary of the invention:
The present invention relates to a stable lyophilized dry powder composition suitable for IV injection comprising anti-ulcer active benzimidazole or their stereoisomers, salts and derivatives thereof along with pharmaceutically acceptable excipients such as Tonicity agent, buffer, pH adjustifier and water for injection.
The anti-ulcer benzimidazole is Rabeprazole.
The Tonicity agent is selected from sodium chloride, mannitol, sucrose, lactose, dextrose, and the like. The concentration of the Dextrose in the formulation is 5 % by weight of the total composition. The concentration of Mannitol in the formulation is 1:0.01 to 1:10 weight by weight of the total composition. The concentration of Sucrose in the formulation is 5 % by weight of the total composition.
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The buffer is selected from phosphate, borate, Tris, diethanolamine, and the like. The pH adjustifier is aqueous solution of sodium hydroxide. The pH of the formulation is 11.4 ± 0.3
A process for preparation of the stable lyophilized composition comprises charging sufficient amount of water for injection; adding Tonicity agent to the water for injection; stirring the mixture at 15° C-25° C to obtain clear bulk solution; dissolving specified amount of buffer in water for injection to obtain buffer solution; adding the buffer solution to the bulk solution; stirring the bulk solution at 15° C-25° C, adding aqueous solution sodium hydroxide to the bulk solution to adjust the pH at 11.4 ± 0.3, adding active benzimidazole or their stereoisomers, salts and derivatives thereof to the bulk solution with stirring; checking the pH of said bulk solution; adding aqueous solution of sodium hydroxide if required to adjust said pH; making up the final volume with water for injection; sterilizing the bulk solution by passing through 0.22 micron bacteria retentive filter and lyophilizing the sterilized filtrate in suitable container.
The process for preparing stable lyophilized composition may be used to prepare a stable lyophilized composition of any benzimidazole or their salts, stereoisomer, or derivatives thereof.
The stable lyophilized composition prepared by the process.
The stable lyophilized composition is used in treating and / or preventing dysphagia; 11. Pylori and in treating Cancer such as gastrointestinal cancer, such as gastric cancer, duodenal cancer, esophageal cancer and the like.
Detailed description:
The present invention discloses the pharmaceutical composition in lyophilized form which comprises an excipient combined with a therapeutically effective cytotoxic amount of PPIs or pharmaceutically acceptable (water soluble) salt in an adequate amount of
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diluent. More specifically, the present invention provides stabilized lyophilized composition of Rabeprazole.
The term 'Rabeprazole' is used in the entire specification and claims in a broad sense to include not only Rabeprazole per se, but also its pharmaceutically available salts, derivatives, stereoisomer, thereof.
The various attempts of developing Rabeprazole injection formulations failed due to unstability and colour change within a relatively short period. All attempts made thereof to stabilize Rabeprazole injection have not been successful.
The present invention provides stable injection composition comprising an active ingredient, Rabeprazole with the buffering agent also acts as a stabilizer which is reconstitutable. The present composition has a distinctive advantage over the conventional formulation with respect to stability over an extended storage period even at zone III and zone IV countries which come under 30°C /35% RH and 30°C/75% RM environmental condition. The stabilizer used in the form of buffering agent is highly effective to keep the product stable & hence consequent therapeutic activity of drug.
The term buffer when used refers to ability of a system particularly an aqueous solution to resist the change of pH on adding acid or alkaline or on dilution with solvent. Buffered solution undergoes small changes of pH on addition of acid or base, in the presence of the weak acid and a salt of weak acid, or a weak base and a salt of a weak base eg. Acetic acid and sodium acetate, ammonia and ammonium chloride, monobasic potassium phosphate and dibasic potassium phosphate.
The experimental results have shown that the injection form of Rabeprazole can be stabilized by adding buffering agent thus avoiding the necessity of adding stabilizing agent or novel complexing agent e.g. Cyclodextrin derivative which involves substantially extra processing steps.
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A stable lyophilized composition suitable for IV injection comprising an anti-ulcer compound, benzimidazole, preferably Rabeprazole along with pharmaceutically acceptable excipients such as tonicity agent, buffer and water for injection.
The concentration of active compound, Rabeprazole used in the present formulation is 20mg/ml.
The tonicity agents are selected from sodium chloride, mannitol, Sucrose, Lactose.
dextrose, etc.
The tonicity agent is sodium chloride and the amount used in the formulation is 0.9 % by
weight of the total composition.
The tonicity agent is lactose and the amount used in the formulation is 0.3 % by weight of
the total composition.
The tonicity agent is Dextrose and the amount used in the formulation is 5 % by weight
of the total composition.
The tonicity agent is Mannitol and the amount used in the formulation is 1:0.01 to 1:10
weight by weight of the active composition.
The tonicity agent is Sucrose and the amount used in the formulation is 5 % by weight of
the total composition.
The solution for reconstitution is water for injection or saline solution.
The buffering agent is selected from the phosphate, borate, Tris buffer. Diethanolamine. Carbonate etc.
The concentration of buffer used in the present invention is quantity sufficient to adjust the pH of the solution at 11.4 ± 0.3.
The buffering agent added is Borate and the pH of the solution is adjusted further with sodium hydroxide to get pH 11.4 ± 0.3.
The buffering agent added is Phosphate and the pH of the solution is adjusted further with sodium hydroxide to get pH 11.4 ± 0.3.
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The buffering agent is Carbonate and the pH of the solution is adjusted further with
sodium hydroxide to get pH 11.4 ± 0.3.
The buffering agent is Tris buffer and the pH of the solution is adjusted further with
sodium hydroxide to get pH 11.4 ± 0.3.
The buffering agent is Diethanol amine and the pH of the solution is adjusted further with
sodium hydroxide to get pH 11.4 ± 0.3.
According to the present invention, a process for preparation of stabilized composition
comprises dissolving the Rabeprazole in water for injection to prepare Rabeprazole
solution; dissolving Tonicity agent, Buffering agent in water for injection to prepare
solution; adding Rabeprazole solution in the above solution of Tonicity agent, buffering
agent, pH adjustfier stirring the above solution until a clear and transparent solution is
obtained; sterilizing the above solution by filtration technique; filling the above sterilized
solution in individual container and lyophilizing to obtain stabilized formulation.
According to the present invention, the lyophilized composition is reconstituted by dissolving a therapeutic quantity of active compound in a sufficient amount of aqueous solution which also comprises a buffering agent that maintains the pH of the solution at 11.4 ±0.3.
The ratio used of active to buffer is in the range of 1:0.1 to 1:5. The solution is then lyophilized in a sealable container. The container is sealed such that the exchange of air below the inside of the sealable container and the internal environment of the container is not possible
According to the present invention, reconstituted solutions for IV administration can be prepared by initially dissolving an amount of a desired lyophilized compound in a sufficient amount of a sterile aqueous solution to completely dissolve the lyophilized compound. Such initially dissolved solutions contain the original buffer system substantially undetected and maintain a pH at 11.4 ± 0.3.
The present Lyophillization technique is a robust and simple manufacturing process to produce stable composition of Rabeprazole with consistent quality.
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This invention relates to a method of stabilizing Rabeprazole composition which is transportable and storable for extended period in vial as well as after reconstitution in a suitable diluent at room temperature in ZONE III and ZONE IV regions. Zone III & zone IV countries come under 30°C /35% RH & 30°C/75% RH environmental condition. The temperature/ Humidity condition of zone III & zone IV are comparatively untolerable than that of zone I & zone II with respect to stability of the product. The invented composition is found stable in this storage condition & no adverse effect on final packing as well as the product even during transportation.
The present Rabeprazole composition can be effectively stabilized by addition of buffering agents with the pH maintained at 11.4 ± 0.3.
The present invention also provides method of stabilization of benzimidazole compound both in the course of preparing lyophilized samples for reconstitution and in reconstituted formulation suitable for IV.
Prior to the present invention, the utility of buffering agent as a colour stabilizer for solution of the compound of the invention was not successful in the art. either for lyophilization or for preparing solutions for IV administration.
Various patents like US6780882 and US6699885 are available on use of buffering agent in oral solid dosage form but not for lyophilized injection. The parenteral delivery as disclosed in WO 99/18959 wherein Glycin NaOH buffer has been used to overcome the colour formation, but the attempts were not successful completely. The colour development is reduced but not completely controlled.
The present invention provides a stable lyophilized injection which is completely devoid of colour development. However the buffering agent claimed as a stabilizer in present invention is optimized to protect the formulation from degradation and color development.
In order to deliver the compound of the present invention intravenously it may be reconstituted in sterile solution suitable for IV administration, such as sterile water for the
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injection. Such a solution typically has a pH of between about 4 and about 5. When the residual buffer system is dissolved in the solution suitable for IV administration, for e.g. 25 to 50 fold dilution of 2 ml of 20mg/ml initial solution of anti-ulcerative compound the pH of resulting solution is maintained between pH 9 to 12 in which the anti-ulcerative compound is more stable. Thus according to the present invention additional superior buffer can be added or included in the final solution to be intravenously administered. The concentration of buffer in the final solution for intravenous administration should be between about 1mM and about 10mM. The pH of the resulting solution should be alkaline, preferably at 11.4 ± 0.3.
Once a day dose of intravenous proton pump inhibitors (dose same as oral dose) may be sufficient to achieve the desired degree of hypochlorhydria.
The entire process disclosed herein to prepare stable lyophilized injection may be used to prepare stable lyophilized injection of any benzimidazoles or their salts, or their stereoisomers, or their derivatives.
The proton pump inhibitor is preferably Rabeprazole. a stereoisomer thereof, and / or a phamnaceutically acceptable salt thereof in other embodiments, at least one proton pump inhibitors (e.g. Rabeprazole, a stereoisomer thereof, and / or a pharmaceulically acceptable salt thereof) is administered.
The present invention provides stabilized composition for treating and / or preventing dysphagia in a patient in need thereof comprising administering a therapeutically effective amount of at least one proton pump inhibitor. The present invention further provides stable lyophilized injection for treating and / or preventing H. Pylori or treating cancer by administering a therapeutically effective amount of at least one proton pump inhibitor and optionally, at least one antibacterial compound. The proton pump inhibitor is preferably Rabeprazole. The present invention yet further provides a composition comprising at least one proton pump inhibitor like Rabeprazole, administered in conjunction (i.e. separately or in the form of a composition) with at least one proton pump inhibitor other than Rabeprazole and optionally at least one antibacterial
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compound. The present stabilized composition is used in cancer therapy, preferably in the injection form. The cancer can be any cancer in the art, but it is generally a gastrointestinal cancer, such as gastric cancer, duodenal cancer, esophageal cancer and the like.
The present invention yet further provides methods for treating and / or preventing dysphagia in a patient in need thereof comprising dilating the patient's esophagus (eg. Lower esophagus) and subsequently administering a therapeutically effective amount of at least one proton.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be falling within the scope of the invention.
The following example is for the purpose of illustration of the invention only and is not intended in any way to limit the scope of the invention.
Example 1

Sr. No. Ingredient Qty
1 Rabeprazole sodium Equivalent to Rabeprazole 20 mg/ml
2 Tonicity agent (Mannitol) 35 mg/ml
Buffering agent (Triss buffer) 10 mg/ml
4 Sodium hydroxide (0.1 M NaOH) q.s. to adjust pH 11.4 ±0.3.
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A process for preparation of Rabeprazole lyophilized injection composition comprises
following steps :
Step 1 : The specified amount of water for injection was taken.
Step 2: The specified amount of bulking agent was dissolved in water for injection. Step
1 and stirred at 15°C-25°C.
Step 4: The specified amount of buffer was dissolved in water for injection.
Step 5: Buffer solution of step 4 was added in Step 1 and stirred at 15° C-25° C.
Step 6: The pH of the above solution was adjusted at 11.4 ± 0.3 with sodium hydroxide
solution.
Step 7: Therapeutic amount of the drug substance Rabeprazole was taken and dissolved
in the above solution.
Step 8: The pH was checked and the volume was made up.
Step 9: The above bulk solution was sterilized by passing it through 0.22 micron bacteria
retentive filter.
Step 10: Sterilized filtrate was filled into the individual sterile container and the container
was partially closed with sterile rubber closure under aseptic conditions.
Step 11: The above individual containers were transferred to the lyophiliser and loaded
into the Lyophilization chamber under aseptic conditions.
Step 12: The solution was frozen by placing in the cooled shelves.
Step 13: The vacuum was applied and the shelves were heated in order to evaporate the
water from containers from frozen state.
Step 14: These partially closed containers were closed completely.
Example 2

Sr. No. Ingredient Qty
1 Rabeprazole sodium Equivalent to Rabeprazole 20mg/ml
2 Tonicity agent (Mannitol) 35 mg/ml
3 Buffering agent (Citric Acid) 10 mg/ml
4 Sodium hydroxide(0.1 M NaOH) q.s. to adjust pH 11.4 ± 0.3.
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A process for preparation of Rabeprazole lyophilized injection composition comprises following steps:
Step 1 : The specified amount of water for injection was taken.
Step 2: The specified amount of bulking agent was dissolved in water for injection. Step
1 and stirred at 15° C-25°C.
Step 4: The specified amount of buffer was dissolved in water for injection.
Step 5: Buffer solution of step 4 was added in Step 1 and stirred at 15° C-25° C.
Step 6: The pH of the above solution was adjusted at 11.4 ± 0.3 with sodium hydroxide
solution.
Step 7: Therapeutic amount of the drug substance Rabeprazole was taken and dissolved
in the above solution.
Step 8: The pH was checked and the volume was made up.
Step 9: The above bulk solution was sterilized by passing it through 0.22 micron bacteria
retentive filter.
Step 10: Sterilized filtrate was filled into the individual sterile container and the container
was partially closed with sterile rubber closure under aseptic conditions.
Step 11: The above individual containers were transferred to the lyophiliser and loaded
into the Lyophilization chamber under aseptic conditions.
Step 12: The solution was frozen by placing in the cooled shelves.
Step 13: The vacuum was applied and the shelves were heated in order to evaporate the
water from containers from frozen state.
Step 14: These partially closed containers were closed completely.
Example 3

Sr. No. Ingredient Qty
1 Rabeprazole sodium Equivalent to Rabeprazole 20mg/ml
2 Tonicity agent (Mannitol) 35 mg/ml
3 Buffering agent (Na2HP04) 10 mg/ml
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4 Sodium hydroxide(0.1 MNaOH) q.s. to adjust pH 11.4 ± 0.3.
A process for preparation of Rabeprazole lyophilized injection composition comprises
following steps:
Step 1 : The specified amount of water for injection was taken.
Step 2: The specified amount of Tonicity agent was dissolved in water for injection. Step
1 and stirred at 15° C-25° C.
Step 4: The specified amount of buffer was dissolved in water for injection.
Step 5: Buffer solution of step 4 was added in Step 1 and stirred at 15° C-25° C.
Step 6: The pH of the above solution was adjusted at 11.4 ± 0.3 with sodium hydroxide
solution.
Step 7: Therapeutic amount of the drug substance Rabeprazole was taken and dissolved
in the above solution.
Step 8: The pH was checked and the volume was made up.
Step 9: The above bulk solution was sterilized by passing it through 0.22 micron bacteria
retentive filter.
Step 10: Sterilized filtrate was filled into the individual sterile container and the container
was partially closed with sterile rubber closure under aseptic conditions.
Step 11: The above individual containers were transferred to the lyophiliser and loaded
into the Lyophilization chamber under aseptic conditions.
Step 12: The solution was frozen by placing in the cooled shelves.
Step 13: The vacuum was applied and the shelves were heated in order to evaporate the
water from containers from frozen state.
Step 14: These partially closed containers were closed completely.
Example 4

Sr. No. Ingredient Qty
1 Rabeprazole sodium Equivalent to Rabeprazole 20mg/ml
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2 Tonicity agent (Mannitol) 35 mg/ml
3 Buffering agent (Carbonate) 10 mg/ml
4 Sodium hydroxide(0.1 M NaOH) q.s. to adjust pH 11.4 ± 0.3.
A process for preparation of Rabeprazole lyophilized injection composition comprises
following steps:
Step 1 : The specified amount of water for injection was taken.
Step 2: The specified amount of Tonicity agent was dissolved in water for injection. Step
1 and stirred at 15° C-25° C.
Step 4: The specified amount of buffer was dissolved in water for injection.
Step 5: Buffer solution of step 4 was added in Step 1 and stirred at 15° C-25° C.
Step 6: The pH of the above solution was adjusted at 11.4 ± 0.3 with sodium hydroxide
solution.
Step 7: Therapeutic amount of the drug substance Rabeprazole was taken and dissolved
in the above solution.
Step 8: The pH was checked and the volume was made up.
Step 9: The above bulk solution was sterilized by passing it through 0.22 micron bacteria
retentive filter.
Step 10: Sterilized filtrate was filled into the individual sterile container and the container
was partially closed with sterile rubber closure under aseptic conditions.
Step 11: The above individual containers were transferred to the lyophiliser and loaded
into the Lyophilization chamber under aseptic conditions.
Step 12: The solution was frozen by placing in the cooled shelves.
Step 13: The vacuum was applied and the shelves were heated in order to evaporate the
water from containers from frozen state.
Step 14: These partially closed containers were closed completely.
The chemical and physical stability of active compound of the present invention was earned out for the strength 20 mg /ml of Rabeprazole in water for injection by adding buffer and dilute sodium hydroxide to adjust the pH at 11.4 ± 0.3 and at room
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temperature, 5° C and -20° C. Chemical stability was monitored by evaluating the residual potency and impurity level over 48 hours by HPLC. Physical stability vvas evaluated by measuring the rate of colour formation at 405 nm and by visual observation. The chemical and physical stability of therapeutically active compound is found to be maintained at pH 11.4 ± 0.3 with Carbonate buffer. Thus the order of pH 11.4>11 .0>10.5 found to maintain with respect to Carbonate, Triss....and phosphate. The same stability was observed at room temperature.
At pll 11.4 ± 0.3.solution of therapeutically active compound was found stable.
Preliminary buffer system
It is desirable that the pH of the solution of the therapeutically active compound of the invention in normal saline remains in the range near about pH above 11 to provide for an acceptable use period in clinical setting. Phosphate, borate, triss buffer and carbonate buffer were tested. Best results were obtained with carbonate buffer.
Effect of storage condition:
The effect of exposure to light and temperature was evaluated as a function of time for different types of reconstitution solutions like sterile water for injection, 0.9 % saline solution containing active compound with or without buffer by monitoring absorbance at 400, 500, 600 nm. It was found that increasing storage temperature caused an increase in undesirable colour development in solution without buffer. It was found that buffer decreases the colour development and ultimately increases the stability of the product.
This composition has been subjected to stability study and has been found to be safe and effective. This would offer considerable advantage to the patient in the form of more stable, effective, safe and less complicative and satisfy the need of Physicians as well as patient for a stable injection composition.
STABILITY DATA Composition: Each vial contains
Rabeprazole Sodium 20mg
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6 Months Stability Data for one of the composition

Conditions Period & Physical Observation Assay (% w/v) pH %

Rabeprazole Sodium
Moisture
Releasing Limits White lyophilized powder, which on reconstitution with 4 ml WF1 gives clear solution. 18.0mg to 22.0 mg (90% to 110%) 11.4 + 0.3 NMT
15%
Initial White lyophilized powder, which on reconstitution with 4 ml WFI gives clear solution 100.9% 11.40 11.72 %
40°C/AH 1M Same as Initial 98.92 % 11.31 1 1.8 %

3M Same as Initial 97.9 % 11.25 11.1 %

6M Same as Initial 97.5 % 11.17 10.8%
30°C/AH 1M Same as Initial 100.1 % 11.39 11.4 %

3M Same as Initial 99.96 % 11.34 11.3 %

6M Same as Initial 99.52 % 11.26 10.7%
2°C - 8°C 1M Same as Initial 100.7% 11.40 11.7%

3M Same as Initial 100.24% 11.39 1 1.6 %

6M Same as Initial 99.89 % 11.39 1 1.6 %
Other compositions working successfully according to the present invention.
The manufacturing process is found to be satisfactory with respect to content of active ingredient, physical parameters and chemical parameters till the end of accelerated studies. The product in final packing is found stable at accelerated temperature. Hence the present invention of manufacturing process for stable composition of Rabeprazole with the effectiveness of buffer found to be cost effective and environmentally friendly process under recommended conditions. The data indicated suitability of buffer in optimized pH range and concentration to make effective stable product.
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I claim:
1. A stable lyophilized dry powder composition of Rabeprazole for intravenous (IV) injection characterized by using stabilizing agent such as buffer selected from phosphate, borate, Triss, Diethanolamine, Carbonate, and the like; comprising 20 mg of Rabeprazole, along with pharmaceutically acceptable exipients such as tonicity agent, and pH adjustifier.
2. The composition as claimed in claim 1, wherein said tonicity agent is 0.9 % sodium chloride, 1:0.01 to 1:10 weight by weight mannitol. 5% sucrose. 5%lactose, 5%dextrose. or the like.
3. The composition as claimed in claim 1, wherein said pH adjustifier is aqueous solution of sodium hydroxide.
4. The composition as claimed in claims 1 to 3, wherein the pH of said composition is at 11.4 ± 0.3.
5. A process for preparation of the stable lyophilized composition comprising charging sufficient amount of water for injection; adding tonicity agent to said water for injection; stirring said mixture at 15° C-25° C to obtain clear bulk solution; dissolving specified amount of buffer in water for injection to obtain buffer solution; adding said buffer solution to said bulk solution; stirring said bulk solution at 15° C-25° C, adding aqueous solution sodium hydroxide to said bulk solution to adjust the pH at 11.4 ± 0.3, adding active benzimidazole or their stereoisomers, salts and derivatives thereof to said bulk solution with stirring; checking the pH of said bulk solution; adding aqueous solution of sodium hydroxide if required to adjust said pH; making up the final volume with water for injection; sterilizing said bulk solution by passing through 0.22 micron bacteria retentive filter and lyophilizing said sterilized filtrate in suitable container.
6. The stable lyophilized composition prepared by the process as claimed in claim 5.
7. The composition as claimed in claim 1 to 4, wherein said composition is used in treating and / or preventing dysphagia; H. Pylori and in treating Cancer such as
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gastrointestinal cancer, gastric cancer, duodenal cancer, esophageal cancer and the like. 8. A stable Lyophilized composition and process for preparation thereof as substantially described herein with reference to foregoing examples 1 to 3.
Dated this the 21st day of March 2005

Mr. Mohan Jain Applicant
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