Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Patent
1998-03-10
1999-11-16
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
514 58, 514740, 514743, 514553, A61K 4740, A61K 4718
Patent
active
059853107
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the antimicrobial preservation of aqueous pharmaceutical compositions. In particular, the present invention relates to the antimicrobial preservation of pharmaceutical compositions containing cyclodextrins.
2. Description of Related Art
Cyclodextrins are known to possess a number of uses in pharmaceutical formulations. For example, cyclodextrins are known to increase the solubility of insoluble or poorly soluble drug compounds, to increase the stability of chemically labile drugs in pharmaceutical formulations, and to increase the comfort or mask the taste of active drugs. See, U.S. Pat. No. 4,727,064 (Pitha) and EP 0 149 197 B1 (Janssen Pharmaceutica N.V.).
There have been a number of attempts to derivative cyclodextrins in order to decrease toxicity or increase solubility. For example, hydroxy-propyl-beta-cyclodextrin is a derivative which has been shown to have a relatively low toxicity and a high aqueous solubility as compared to the parent compound, beta-cyclodextrin. In addition to hydroxy-propyl derivative of beta cyclodextrin, a number of other cyclodextrin derivatives are known. See, for example, U.S. Pat. Nos. 5,376,645 (Stella et al.) and 4,870,060 (Muller).
Typically, multi-dose pharmaceutical products contain preservatives in order to maintain sterility after opening and during use. Antimicrobial preservation of cyclodextrin-containing formulations can present special problems. For example, Loftsson et al., Drug Development and Industrial Pharmacy, 18 (13), 1477-1484 (1992), have investigated interactions between several commonly used preservatives and 2-hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD). Loftsson et al. report that the interactions were twofold: (i) the preservative molecule can displace a drug molecule from the cyclodextrin cavity, thus reducing the solubilizing effects of the cyclodextrin; and (ii) the antimicrobial activity of the preservative can be reduced by the formation of preservative-cyclodextrin inclusion complexes. Specifically, Loftsson et al. report that chlorobutanol, methylparaben and propylparaben have little or no preservative activity in the tested HP.beta.CD solutions. Additionally, Loftsson et al. found that benzalkonium chloride (with the possible exception of the micro-organism, Ps. aeruginosa) and chlorhexidine gluconate did possess significant preservative activity. In contrast, Simpson, FEMS Microbiology Letters, 90, 197-200 (1992), reports that cyclodextrins can inactivate the antimicrobial activity of certain quaternary ammonium compounds. See also, Miyajima et al., Chem. Pharm. Bull., 35(1), 389-393 (1987), regarding the interaction of short-chain alkylammonium salts with cyclodextrins in aqueous solutions, which concluded that .alpha.-, .beta.-, and .gamma.-cyclodextrins form complexes with alkylammonium salts having alkyl groups longer than n-butyl, n-hexyl, and n-decyl, respectively.
Benzalkonium chloride (BAC) is the most popular preservative for ophthalmic drug preparations. BAC, as defined in United States Pharmacopeia XIX, is an alkylbenzyldimethyl-ammonium chloride mixture with alkyl chains or homologs beginning with n-C.sub.8 H.sub.17 and extending through higher homologs of C.sub.10 -, C.sub.12 -, C.sub.14 -, and C.sub.16 -alkyl chains. In our attempts to preserve pharmaceutical formulations containing a cyclodextrin with BAC, however, we have found that cyclodextrin-preservative interactions can significantly reduce or inactivate the preservative efficacy of BAC, when BAC is employed at non-toxic levels.
EP 0 119 737 A2 (Takeda Chem. Ind., Ltd.) discloses aqueous pharmaceutical compositions comprising an active ingredient, a cyclodextrin and a phenol derivative as a preservative. The phenol derivative has the formula ##STR2## where R is alkyl, X is halogen, n is an integer of 0 to 2, and m is an integer of 1 to 3. According to this reference, formulations containing a cyclodextrin and a paraben preservative (methyl-, ethyl-, propyl-, and butylp
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Castillo Ernesto J.
Espino Ramon L.
Alcon Laboratories Inc.
Kishore Gollamudi S.
Ryan Patrick M.
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