Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-07-11
2002-03-05
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S035000, C514S912000, C514S460000, C424S078040
Reexamination Certificate
active
06352978
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions suitable for topical administration to the eye, ear or nose. In particular, this invention relates to pharmaceutical compositions formulated so that tobramycin and xanthan gum are compatible.
2. Description of Related Art
Xanthan gum is a polysaccharide known to be useful in ophthalmic compositions as a viscosity-enhancing agent. U.S. Pat. No. 4,136,177 discloses ophthalmic compositions containing an ophthalmic drug and from about 0.01 to 2.5% (w/v) of xanthan gum. The '177 patent teaches that if the concentration of xanthan gum is from about 0.02 to about 1.0% (w/v), the composition is suitable for “dropwise” ophthalmic applications In contrast, at concentrations of xanthan gum above about 1.0% and up to about 2.5% (w/v), “a gel-like consistency is attained.” Thus, the '177 patent discloses compositions that are formulated to be either non-gelled liquids or gels before instillation in the eye. The '177 patent does not describe any xanthan gum-containing compositions as capable of being administered as a liquid and gelling upon contact with the eye. According to the '177 patent, any ophthalmic drug can be added to the xanthan gum-containing compositions. The '177 patent does not include tobramycin when it lists examples of suitable antibacterial drugs (see Col. 3, lines 54-58).
WO 99/51273 discloses gel-forming compositions containing xanthan gum where the xanthan gum has an initial bound acetate content of at least about 4% and an initial bound pyruvate content of at least about 2.5%. The entire contents of WO 99/51273 are hereby incorporated by reference.
Tobramycin is an antibiotic drug known to be useful in pharmaceutical compositions. For example, a TOBREX® brand of tobramycin ophthalmic solution and ointment products is marketed by Alcon Laboratories, Inc. (Fort Worth, Tex.).
SUMMARY OF THE INVENTION
The present invention is directed toward pharmaceutical aqueous solutions of tobramycin and xanthan gum that are topically administrable to the eye, ear or nose. According to the present invention, the solution compositions are formulated at a certain pH in order to minimize or eliminate compatibility problems between tobramycin and xanthan gum. The solution compositions have a pH greater than 7.8.
Among other factors, the present invention is based upon the finding that 0.3% tobramycin and 0.6% xanthan gum are incompatible at pH 5-7.8 despite the fact that both tobramycin and xanthan gum are independently sufficiently soluble in aqueous solution to give 0.3% and 0.6% solutions, respectively, but are compatible at a pH greater than 7.8.
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated, all ingredient concentrations are listed as % (W/V).
Xanthan gum is a well-known polysaccharide that is commercially available from a variety of sources. The amount of xanthan gum contained in the compositions of the present invention will depend upon the properties desired for the final composition and the identity and concentration of other ingredients in the composition, but will generally range from about 0.4 to about 0.8%, preferably 0.5-0.7%. Most preferred is a xanthan gum concentration of about 0.6%.
Xanthan gum is generally available in at least two grades from some commercial suppliers, a food or industrial grade and a pharmaceutical grade. Even pharmaceutical grade materials should be polish-filtered so that the finished pharmaceutical product will have increased clarity. As one skilled in the art appreciates, the appropriate filter size for polish filtration depends upon the size of the undesired impurities contained in raw material. For example, in the case of a solution composition, it has been found that the Rhodigel Clear grade of xanthan gum from Rhone- Poulenc Inc. should be filtered through a 0.45 &mgr;m filter in order to remove cell debris and impurities. Multiple stages of filters can be used to increase the overall efficiency of the polish filtration process.
Tobramycin is a known antibiotic drug. See, for example, The Merck Index, Twelfth Edition, page 1619. The concentration of tobramycin in the solution compositions of the present invention will generally be about 0.5% or less. In topically administrable ophthalmic compositions, the preferred concentration of tobramycin is 0.3%.
In addition to xanthan gum and tobramycin, the solution compositions of the present invention contain a buffer agent and a pH-adjusting agent so that the pH is above 7.8. Preferably, the pH of the solution compositions is about 7.9-8.6, more preferably, 7.9-8.2, and most preferably 8.0. Suitable buffering agents include tromethamine; phosphate and borate. The most preferred buffering agent is tromethamine. Suitable pH-adjusting agents include sulfuric acid and hydrochloric acid. The most preferred pH-adjusting agent is sulfuric acid.
The solution compositions of the present invention may include other components. For example, the compositions may include a second active agent (not limited to anti-infective agents). The compositions may also contain one or more pharmaceutically acceptable excipients, including, but not limited to, preservatives (including preservative adjuncts), tonicity-adjusting agents including salts containing monovalent cations, surfactants, solubilizing agents, stabilizing agents, comfort-enhancing agents, emollients, agents and lubricants.
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Cabello Gemma Torrella
Carreras Perdiguer Nuria
Mas Jose Alberto Vallet
Alcon Universal Ltd.
Jarvis William R. A.
Kim Vickie
Ryan Patrick M.
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