Technical Field of the Invention
The present invention relates to stable aqueous formulations of ranitidine, particularly an aqueous formulation of ranitidine for oral administration.
Background of the invention
Ranitidine is a well-known histamine H2-receptor antagonist. Chemically, it is, N [2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl -N'-methyl-2-nitro-1,1 -ethenediamine and is used as a hydrochloride salt in the treatment of gastric and duodenal ulcers and hypersecretory conditions. Various oral and parenteral formulations of ranitidine are known in prior art. British patent GB 1565966 discloses an aqueous based formulation for intravenous use and an oral syrup formulation both of which contain hydrochloric acid sufficient to achieve a pH of 5.0. Such formulations containing ranitidine and/or its physiologically acceptable salts are therapeutically effective but suffer from the disadvantage of having a relatively short shelf life due to the breakdown of ranitidine at such low pH.
United States patent No. US 5,068,249 (the '249 patent) discloses the use of ethanol to prepare stable aqueous formulations of ranitidine. The '249 patent covers the marketed formulation of ranitidine syrup sold under the brand name Zantac® by GlaxoSmithKline. The syrup contains ranitidine hydrochloride, ethanol (7.5%), butyl paraben/propyl paraben preservative system, monobasic potassium phosphate, sodium phosphate, hydroxypropyl methylcellulose, sorbitol, saccharin sodium, sodium chloride and purified water.
Ethanol is a flammable solvent and calls for extreme care while handling in the laboratory. Ethanol consumption in some select population is not desirable. It would therefore be desirable to formulate a stable aqueous formulation of ranitidine which does not necessarily contain ethanol and provides an acceptable shelf life and provides intended dose of ranitidine free of its degradation products.
United States Patent No. US 4,585,790 (the 790 patent) discloses ranitidine syrup formulation which is free of ethanol. The syrup has a pH of 6.5 to 7.5. The aqueous ranitidine formulation is claimed to be stable when compared to formulation at a lower pH.
The claimed pH range is disclosed as critical to stability. The said pH has been achieved by means of suitable buffer salts i.e. potassium dihydrogen orthophosphate and disodium hydrogen orthophosphate or citric acid and disodium hydrogen orthophosphate. The patent, at the same time, also discloses the use of parabens as preservatives in the formulation. However, the aqueous formulations as disclosed have the problem of microbial growth in spite of using select preservatives.
We hereby disclose an aqueous formulation of ranitidine for oral administration, which does not require the presence of ethanol and is yet stable with stability complying with US pharmacopoeal requirements.
Summary of the Invention
In one aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben from about 0.4mg/mL to about 1mg/ml_ and propyl paraben from about 0.05mg/mL to about 0.1mg/mL of the formulation.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system, wherein the formulation has pH in the range of 6.5-7.5.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system and is free of ethanol.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system, wherein the formulation has pH in the range of 6.5-7.5 and is free of ethanol.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system and one or more of buffers, and other conventional excipients wherein the formulation has pH in the range of 6.5-7.5.
In another aspect, it relates to an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system and one or more of buffers, and other conventional excipients wherein the formulation has pH in the range of 6.5-7.5 and is free of ethanol.
In another aspect, it relates to a method of treating a human subject in need of therapy with a ranitidine responsive medical condition, the method comprises administering to the human subject an aqueous formulation of ranitidine comprising of methyl paraben and propyl paraben preservative system.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
Ethanol as a solvent is associated with health and laboratory hazards. Ranitidine aqueous formulation, which is free of ethanol, is already known from 790 patent. The patent further discloses use of parabens as a part of the preservative system in the formulation. Nevertheless, the patent does not disclose any particular combination of parabens effective in stabilizing the aqueous formulation. It has been, however, unexpectedly found that a specific combination of preservatives i.e. methyl paraben and propyl paraben preservative system when used in the preparation of aqueous ranitidine formulation provides a formulation which is more stable towards microbial growth than aqueous formulations prepared with butyl paraben and propyl paraben preservative system.
As disclosed in '249 patent the aqueous formulations of ranitidine with ethanol provide enhanced stability in presence of paraben preservatives compared to aqueous
formulations of ranitidine free of ethanol as those disclosed in 790 patent. Our studies with formulation of 790 patent reveal that there is considerable microbial growth when butyl paraben and propyl paraben preservative system is used. However, we have surprisingly found that by substituting butyl paraben with methyl paraben in butyl paraben/propyl paraben preservative system, the aqueous formulation of ranitidine shows enhanced stability which is comparable to that of a formulation containing ethanol.
The aqueous formulation containing methyl paraben and propyl paraben preservative system complies with United States Pharmacopoeia that provides for tests for the estimation of the number of viable aerobic microorganisms present and for freedom from designated microbial species in pharmaceutical articles of all kinds, from raw materials to the finished forms. The concentration of methyl paraben may be from about 0.4mg/mL to about 1mg/mL while that of propyl paraben may be from about 0.05mg/mL to about 0.1mg/mL. The ratio of methyl paraben to propyl paraben may vary from about 7: 1 to about 10:1.
Ranitidine as used herein may be free base or a pharmaceutically acceptable salt. Particularly suitable is the hydrochloride salt. The concentration of ranitidine in the aqueous formulation, expressed as a free base, may be in the range of 2-40 mg/mL, particularly in the range of 2-20 mg/mL and more particularly 15 mg/mL.
The aqueous formulations of ranitidine may have pH within the range of 6.5 to 7.5, particularly 6.8 to 7.4 and more particularly 6.9 to 7.1. The required pH of the formulation is achieved by the use of suitable buffer salts or alkali metal hydroxides and mineral acids.
Besides the methyl paraben/propyl paraben preservative system, the aqueous formulation of ranitidine may contain buffers, viscosity enhancing agents, sweeteners and an aqueous vehicle. The formulation may also contain a suitable flavor e.g. peppermint flavor.
Buffers may be selected from, potassium hydrogen orthophosphate, citric acid and disodium hydrogen orthophosphate and combinations thereof.
Viscosity enhancing agents may be selected from sorbitol; glycerol; sucrose; cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl methylcellulose and hydroxyethyl cellulose; gums such as xanthan gum, gellan gum; alginates; chitosans; polyvinyl alcohol; carboxyvinyl polymers and the like.
Sweeteners may be selected from one or more of saccharin sodium, sodium cyclarnate, sorbitol and sucrose and the like.
The aqueous vehicle may be deionised water, purified water or distilled water. Optionally though, ethanol may be added in amounts of 2 to 10% w/v to further enhance the stability provided by methyl paraben and propyl paraben preservative system.
The aqueous formulation of ranitidine may be prepared by conventional methods known to the skilled in the art. In one embodiment, the aqueous formulation of ranitidine is prepared by dissolving ranitidine hydrochloride in an aqueous solution comprising of sweetener(s), flavor(s), buffer(s) and preservative(s). The resulting aqueous solution is then added to an aqueous solution of viscosity enhancing agent in purified water followed by filtration. Additionally, to overcome the objectionable sulphur like smell of ranitidine, activated charcoal may be added during the preparation or after the preparation is complete. Activated charcoal may be conveniently removed by filtration aids for e.g. by filtration through a 15 micron prefilter.
The following example(s) are illustrative of the invention, and are not intended to be construed as limiting the invention.
Comparative Example 1: Formulation with butyl paraben/propyl paraben and free of ethanol.
(Table Removed)
Procedure:
1. Butyl paraben and propyl paraben were dissolved in a part of pre-heated purified
water
2. Disodium hydrogen orthophosphate and potassium dihydrogen orthophosphate
were dissolved in part of purified water.
3. The bulk of step-2 was added to the bulk of step-1 and stirred.
4. To the bulk of step-3 was added saccharin sodium, sodium chloride and sorbitol
solution.
5. Ranitidine HCI was dissolved in the bulk of step-4.
6. Hydroxypropyl methylcellulose was added to a part of purified water under vigorous
stirring to obtain a clear solution.
7. The bulk of step-5 was added to the bulk of Step-6 under continuous stirring and
added flavor.
8. The remaining purified water was added to make up the volume.
9. The bulk of step-8 was filtered.
Comparative Example 2: Formulation with butyl paraben/propyl paraben and ethanol.
(Table Removed)
were dissolved in part of purified water, and added saccharin sodium, sodium chloride and sorbitol solution.
3. The bulk of step-1 was added to the bulk of step-2 and stirred.
4. Ranitidine HCI was dissolved in the bulk of step-3.
5. Hydroxypropyl methylcellulose was added to a part of purified water under vigorous
stirring to obtain a clear solution.
6. The bulk of step-5 was added to the bulk of step-4 under continuous stirring and
added flavor.
7. The remaining purified water was added to make up the volume.
8. The bulk of step-7 was filtered.

Example A: Formulation with methyl paraben/propyl paraben and free of ethanol
(Table Removed)
1. Methyl paraben and propyl paraben were dissolved in part of pre-heated purified
water.
2. Disodium hydrogen orthophosphate and potassium dihydrogen orthophosphate
were dissolved in part of purified water.
3. Ranitidine HCI was dissolved in the bulk of step-2.
4. Activated charcoal was added to the bulk of step-3 and stirred for 2 hours followed
by filtration through 15 micron prefilter.
5. The bulk of step-1 was added to the bulk of step-4.
6. Saccharin sodium, sodium chloride and sorbitol solution were dissolved in the bulk
of step-5.
7. Hydroxypropyl methylcellulose was added to a part of purified water under vigorous
stirring to obtain a clear solution.
8. The bulk of step-7 was added to the bulk of Step-6 under continuous stirring and
added flavor.
9. Hydrochloric acid or sodium hydroxide solution was added to adjust the pH to 6.5 to
7.5.
10. The remaining purified water was added to make up the volume.
11. The bulk of step-10 was filtered.
Example B: Formulation with methyl paraben/propyi paraben and free of ethanol
(Table Removed)
1. Methyl paraben and propyl paraben were dissolved in part of pre-heated purified
water.
2. Disodium hydrogen orthophosphate and potassium dihydrogen orthophosphate
were dissolved in part of purified water.
3. Ranitidine HCI was dissolved in the bulk of step-2.
4. Activated charcoal was added to the bulk of step-3 and stirred for 2 hours followed
by filtration through 15 micron prefilter.
5. The bulk of step-1 was added to the bulk of step-4.
6. Saccharin sodium, sodium chloride and sorbitol solution were dissolved in the bulk
of step-5.
7. Hydroxypropyl methylcellulose was added to a part of purified water under vigorous
stirring to obtain a clear solution.
8. The bulk of step-7 was added to the bulk of Step-6 under continuous stirring and
added flavor.
9. The remaining purified water was added to make up the volume.
10. The bulk of step-9 was filtered.
The microbial limit tests were performed for the formulations of comparative examples 1 and 2 and examples A and B by following the "Plate method" as per General Chapter <61>, "Microbial Limit Tests," USP 27-NF 22. (US Pharmacopoeal Convention, Rockville, MD, 2004), pp. 2152-2157. The results are given in the Table 1 below:
Table 1: - Microbial test results of formulations of comparative examples 1 and 2 and examples A and B.
(Table Removed)

WE CLAIM:
1. An aqueous formulation of ranitidine comprising of methyl paraben and propyl
paraben preservative system.
2. The formulation according to claim 1, wherein the formulation has pH in the
range of 6.5 to 7.5.
3. The formulation according to claim 1, wherein the formulation comprises of
methyl paraben from about 0.4mg/ml_ to about 1mg/mL and propyl paraben from
about 0.05mg/mL to about 0.1 mg/mL of the formulation.
4. The formulation according to claim 1, wherein ranitidine is present the range of
2-40 mg/mL expressed as a free base.
5. The formulation according to claim 1, wherein the formulation further comprises
one or more of buffers, viscosity enhancing agents, sweeteners and an aqueous
vehicle.
6. The formulation according to claim 5, wherein buffer(s) are selected from
potassium hydrogen orthophosphate, citric acid, sodium citrate, disodium
hydrogen orthophosphate and combinations thereof.
7. The formulation according to claim 5, wherein viscosity enhancing agents are
selected from sorbitol, glycerol, sucrose, carboxymethyl cellulose, hydroxypropyl
methylcellulose, hydroxyethyl cellulose, xanthan gum, gellan gum, alginates,
chitosans, polyvinyl alcohol and carboxyvinyl polymers.
8. The formulation according to claim 5, wherein the sweeteners are selected from
saccharin sodium, sodium cyclamate, sorbitol and sucrose.
9. The formulation according to claim 5, wherein the aqueous vehicle is selected
from deionised water, purified water and distilled water.
10. The formulation according to claim 9, wherein the aqueous vehicle further
contains 2-10% ethanol w/v.
11. An aqueous formulation of ranitidine comprising ranitidine hydrochloride, methyl
paraben, propyl paraben, buffer, viscosity enhancing agent, sweetener and
water and has pH of 6.5-7.5.
12. A method of treating a human subject in need of therapy with a ranitidine
responsive medical condition, the method comprises administering to the human
subject an aqueous formulation of ranitidine comprising of methyl paraben and
propyl paraben preservative system.