Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-09-02
2002-03-19
Rose, Shep K. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S065000
Reexamination Certificate
active
06358935
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to preserved cyclodextrin-containing compositions. More particularly, the invention relates to cyclodextrin-containing compositions, for example, such compositions containing one or more pharmaceutically active components, including preservatives which have substantial preserving efficacy in the presence of cyclodextrin components.
Cyclodextrins are widely known in the literature to increase the solubility of poorly water soluble pharmaceuticals or drugs and/or enhance pharmaceutical/drug stability and/or reduce unwanted side effects of pharmaceuticals/drugs. For example, steroids, which are hydrophobic, often exhibit an increase in water solubility of one order of magnitude or more in the presence of cyclodextrins. However, one substantial problem with pharmaceutical compositions including cyclodextrins, particularly such compositions in multi-dose formats, has to do with preserving such compositions. Typical preservatives are relatively ineffective at normal concentrations in such compositions, that is the compositions including such preservatives are unable to meet or pass standard preservative efficacy tests. It is believed that the preservative becomes complexed with the cyclodextrin and is rendered ineffective or has reduced effectiveness as a preservative.
It would be advantageous to provide cyclodextrin-containing compositions which are effectively preserved.
SUMMARY OF THE INVENTION
New cyclodextrin-containing compositions have been discovered. Such compositions include preservatives which are effective and efficacious in the presence of cyclodextrins. Preferably, the preservatives are present in the compositions in amounts to provide acceptable preservative efficacy and, in addition, are sufficiently innocuous or non-toxic so that the compositions can be administered to humans or animals to obtain desired therapeutic effects without significant detriment resulting from the presence of the preservatives. For example, the present compositions may include a pharmaceutical effective in providing a therapeutic effect when administered to the eyes of a human or animal. The preservative employed is preferably ophthalmically acceptable at the concentration employed so that the human or animal is effectively treated without significant harm caused by the presence of the preservative.
In short, the present compositions effectively take advantage of cyclodextrin components, e.g., in increasing the apparent water solubility of pharmaceuticals, and are effectively preserved and preferably substantially non-toxic in use.
In one broad aspect of the present invention, compositions are provided which comprise a liquid medium, a cyclodextrin component, for example, in an amount in the range of about 0.1% to about 30% (w/v), and a preservative component in an effective preserving amount, preferably of less than about 1% (w/v) or about 0.8% (w/v) and may be in the range of about 10 ppm(w/v) or less to about 200 ppm(w/v). In one embodiment, the preservative component has sufficient preservative efficacy so that the composition including such preservative component passes one or more standard preservative efficacy tests, such as in the United States Preservative Efficacy Test (USPET), the European Preservative Efficacy Test-A (EP-A), the European Preservative Efficacy Test-B (EP-B), and the like standard tests.
Preferably, the preservative component has an increased or greater preservative efficacy in the present composition relative to an identical amount (w/v) of benzalkonium chloride. Benzalkonium chloride, which is a preservative that is often used in pharmaceutical compositions, is relatively ineffective at typical concentrations in compositions including cyclodextrin component. It is believed that the benzalkonium chloride complexes with the cyclodextrin component. This complex renders the benzalkonium chloride antimicrobially ineffective. Thus, benzalkonium chloride has a reduced preservative efficacy in the presence of cyclodextrin component. More preferably, the present preservative component forms a complex with the cyclodextrin component, if at all, to a lesser extent than does benzalkonium chloride.
The present compositions preferably are substantially free of inclusion complexes of the cyclodextrin component and the preservative component.
Using a preservative component in accordance with the present invention which is substantially not affected by the cyclodextrin component allows the preservative component to be more efficacious as a preservative. Alternately, reduced amounts of the preservative component can be used to achieve acceptable preservative results. Such reduced amounts of preservative components reduce the toxicity or sensitivity for the composition as it is being administered to a human or animal.
Any suitable preservative component which functions as described herein is included within the scope of the present invention. The preservative efficacy tests identified herein are standard tests which can be easily and routinely conducted on any prospective preservative component to determine if such preservative component meets the criteria. Of course, the present preservative components should have no substantial detrimental effect on the composition or the active component or components of the composition or the use of the composition or the human or animal to whom the composition is administered. Tests to determine whether a prospective preservative component meets these criteria are well known and can be routinely conducted. In other words, one of ordinary skill in the art can determine, without undue experimentation, whether or not any prospective preservative component is within the scope of the preservative components of the present invention.
In one particularly useful embodiment, the present preservative component is selected from chlorite components, sorbic acid components and mixtures thereof present in an effective preserving amount. More preferably, the preservative component is selected from stabilized chlorine dioxide, alkali metal chlorites, sorbic acid, alkali metal sorbates and mixtures thereof. Chlorite components are very effective in the present compositions since they achieve preservative effectiveness at a relatively reduced concentration. Both the chlorite components and sorbic acid components are effective preservatives in the presence of cyclodextrin. Without wishing to limit the invention to any particular theory of operation, it is believed that the chlorite components and the sorbic acid components are substantially free in the presence of the cyclodextrin component or are substantially not complexed with the chlorodextrin component.
In another broad aspect of the present invention, compositions are provided which comprise a liquid medium, an active component, a cyclodextrin component and a preservative component. The active component is present in an amount effective in providing a desired effect to a human or an animal after the composition is administered to the human or animal. The cyclodextrin component preferably is present in an amount effective to increase the apparent solubility of the active component in the liquid medium and/or enhance the stability of the active component in the composition and/or reduce unwanted side effects of the acting component in the composition. The preservative component is present in an effective preserving amount, preferably less than about 1% (w/v) or about 0.8% (w/v) and may be in the range of about 10 ppm(w/v) or less to about 200 ppm(w/v). The preservative component is as identified elsewhere herein.
The present compositions which include active components, preferably pharmaceutically active components, as described herein, are particularly useful in multi-dose formats in which preservative efficacy is particularly important. Thus, such compositions obtain the advantages of cyclodextrin components, for example, in enhancing the solubility of the active components and, in addition, include effective preservative components, preferably at
Beck Gary J.
Kerslake Edward D. S.
Olejnik Orest
Allergan Sales Inc.
Jagor Donna
Rose Shep K.
Stout, Uxa Buyan & Mullins, LLP
Uxa Frank J.
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