Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Aluminum – calcium or magnesium element – or compound containing
Reexamination Certificate
2000-09-07
2002-04-09
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Aluminum, calcium or magnesium element, or compound containing
C424S468000
Reexamination Certificate
active
06368638
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a novel process of making liquid antacid calcium carbonate containing compositions for neutralizing stomach acid (and calcium source or calcium nutritional supplement) in humans and other animals.
BACKGROUND OF THE INVENTION
Liquid pharmaceutical compositions for delivery of an antacid are generally of the suspension form. They constitute a finely divided antacid active, in solid form which is suspended in a liquid medium. These compositions generally are alkaline, with typical pH values in the range of 7.5 to 8.7.
One problem faced by such liquid compositions is that the pH may drift either below or over the 7.5 to 8.7 pH limits due to equilibrium not being established within 24 hours between the carbonate salt and its environment. This results in such things as color changes if a pH sensitive dye is used, possible microbial growth, and acceleration of base catalyzed degradations.
One method which has been used to stabilize such a suspension is described in U.S. Pat. No 5,498,426, Wilson et al., which includes an alkali metal phosphate salt, and alkali metal bicarbonate salt in addition to the alkaline earth carbonate salt.
Another group of patents to Beyerle et al., U.S. Pat. No. 5,631,026 and U.S. Pat. No. 5,455,050 include with the calcium carbonate a magnesium carbonate and/or magnesium trisilcate as well as a carboxylic acid pH adjusting agent.
U.S. Pat. No. 5,002,777 discloses a concentrated suspension of calcium carbonate in a liquid carrier contained in a capsule, in which the liquid carrier is PEG 400.
The problem faced by the pH drift has not been successfully solved for liquid antacid compositions which are magnesium or aluminum free. The present invention is the recognition of this problem and a solution to such whereby a pleasant liquid antacid formulation is achieved which is pH stable.
SUMMARY OF THE INVENTION
The present invention is to a process of making an aluminum and magnesium free liquid antacid formulation which is stable at a pH from about 7.5 to about 8.7. The liquid antacid formulation is also free from antimicrobial contamination during the stable shelf life of the product.
The aluminum and magnesium free antacid formulation is a calcium carbonate aqueous antacid suspension having a pH of about 7.5 to about 8.7, which suspension is prepared by a process which comprises the steps of:
a) adding to water an effective amount of particulate calcium carbonate with mixing until the particulate is completely wetted and dispersed; and
b) adding to said mixture of part a) with stirring an amount of a suspending agent for a time sufficient to substantially coat said particulate material, and to produce a suspension; or alternately adding b) to a) and;
c) while stirring, titrating the suspension of part b) with a pH adjusting agent to provide a pH of about 6.4 to 7.0 to the aqueous antacid suspension.
The present invention is also directed to a liquid antacid pharmaceutical formulation for neutralizing excess stomach acid. The present invention is also a method of orally administering to a mammal in need of such treatment an effective amount of said liquid antacid composition.
DETAILED DESCRIPTION OF THE INVENTION
The aqueous suspensions of the present invention have been found to be a stabilized liquid calcium carbonate containing antacid having a pH range of about 7.5 to about 8.7, meeting USP standards. The suspensions of this invention have been found to be stable with regard to antimicrobial, viscosity, defoaming, and acid neutralizing capacity (ANC) parameters, as well as to pH. The present invention has found that the selective order of addition and mixing of the essential components herein provides the stable pH of this suspension and further provides for the formation of a higher concentrated suspension of calcium carbonate than previously available to the marketplace. The higher dose formulation of liquid calcium carbonate, in addition to providing maximum acid neutralizing capacity, may also provide a 1000 mg of calcium per dosage to a mammal in need of such calcium for building bone, for treatment of osteoporosis, for pre-menstrual syndrome, etc.
The present invention is to an aqueous antacid suspension for oral use having a pH of about 7.5 to about 8.7 of calcium carbonate, prepared by a process which comprises:
a) adding to water an effective amount of calcium carbonate with mixing until the calcium carbonate is completely wetted and dispersed; and
b) adding to said mixture of part a) with stirring a suspending agent for a time sufficient to substantially coat said carbonate, and to produce a suspension; alternatively, the suspending agent may be added to water first, and calcium carbonate adding second; and
c) while stirring, titrating the suspension of part b) with a pH adjusting agent to provide a pH of about 6.4 to about 7.0 to the aqueous antacid suspension.
Suitable use of a thickening or suspending agents includes but is not limited to those generally used in aqueous antacid formulations, for example, microcrystalline cellulose, such as Avicel, xanthan gum, guar gum, methyl celluloses such as HPMC and sodium carboxymethylcellulose. Preferably, two suspending agents are used, Avicel and xanthan gum.
An appropriate wetting agent, such as glycerin may be utilized to insure maximum dispersion of the thickening agent in the aqueous system. To such end, the thickening agent, such as xanthan gum is preferably admixed with glycerin in a separate container prior to addition to the suspension/mixture. An alternative to the thickening agent/glycerin premix is the use of appropriate mechanical dispersing means, such as a high shear mixer to assist dispersion of the thickening agent. A commercially available readily dispersible thickening agents may also be used, such as KELTROL RD brand of readily dispersible xanthan gum from Kelco, division of Merck. Such readily dispersible thickening agents may provide adequate dispersion upon direct addition to the aqueous system.
Previous calcium carbonate liquid antacid suspensions have been found to be unstable, and have been found to have to high a resulting pH level. The pH level of the present invention is within the USP standards as has been found to be stable, and can be maintained with an efficient preservative system. Accordingly, a pH adjusting agent is a necessary component of the invention. Citric acid has been found to be a preferred pH adjusting agent, although other carboxylic acids such as tartaric, adipic, benzoic, carbonic, cinnamic, fumaric, glutaric, gluconic, hydroxybenzoic, malonic, malic, phthalic, oxalic, sorbic, succinic and the like may be utilized. The amount of pH adjusting agent should be sufficient to bring about, and maintain the pH of the final product in a range of 7.5 to about 8.7. In general from about 0. 025 to about 0.2% w/w of the pH adjusting agent has been found suitable. As the pH adjusting agent is added at the last step, while mixing, the titrate of the suspension with the pH adjusting agent will be added in an amount sufficient to provide a pH of about 6.4 to 7.0 of the aqueous antacid suspension. It is critical that the pH is measured within 15 minutes after the pH adjusting agent is added. The resulting suspension the next day should have equilibrated to the final desired pH range of from about 7.5 to about 8.7.
Any desired pharmaceutically acceptable adjuvant may be added. For examples, one or more preservatives, such as benzyl alcohol; flavouring agents, such as oil of orange, imitation wintergreen flavour, lemon-lime flavors, mint flavors, or combinations thereof; sorbitol serves to increase shelf life and palatability; wetting agents, an antiflatuent which is preferably simethicone, preferably in an antiflatuent amount of from about 0.1 to about 2.0% w/w is suitable; sweetening agents, such as calcium sacccharin; colouring agents; taste enhancing agents, such as calcium choride; and tetrapotassium pyrophosphate.
A unique aspect of the present invention is the order in which the essential buffering component must be a
Dinner Dara L.
Kinzig Charles M.
Reamer James H.
SmithKline Beecham Corporation
Venetianer Stephen
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