Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-10-02
2003-10-14
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S443000, C514S428000, C514S422000
Reexamination Certificate
active
06632841
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to aqueous solutions of nonsteroidal triphenyl-ethylene antiestrogens for pharmaceutical use and to methods for the preparation thereof.
Toremifene, tamoxifen, 3-hydroxytamoxifen (droloxifene), 4-hydroxy-tamoxifen, idoxifene, raloxifene, levormeloxifene, centchroman, clomiphene and their pharmaceutically acceptable salts are examples of nonsteroidal triphenyl-ethylene antiestrogens useful in the treatment of estrogen dependent disorders, e.g. in the prevention or treatment of estrogen receptor positive breast cancer. This class of compounds share the triphenylethylene structure and the compounds are generally very poorly soluble to water. There is a need for stable aqueous formulations of nonsteroidal triphenylethylene antiestrogens and their pharmaceutically acceptable salts, which would be suitable for e.g. high concentration parenteral, transdermal or topical formulations. Parenteral formulations of toremifene in the form of an emulsion, liposome or cyclodextrin complex have been described in WO 93/11757. Transdermal formulations of toremifene in DMSO/ethanol/methylcellulose/water have been described in WO 93/19746. Percutaneous hydroalcoholic gel of 4-hydroxytamoxifen has been described in U.S. Pat. No. 4,919,937. However, these prior formulations are cumbersome to prepare, are irritating or do not provide sufficiently high concentration solutions of nonsteroidal triphenylethylene antiestrogens.
SUMMARY OF THE INVENTION
It has been found that aqueous solutions of nonsteroidal triphenylethylene antiestrogens and their pharmaceutically acceptable salts with high drug concentrations can be prepared by using as a solubility enhancing agent a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen. Furthermore, it was found that pH of such formulations can be increased to nearly neutral without precipitation of the triphenylethylene drug if the solubility enhancing agent is used together with an organic water miscible co-solvent, preferably polyethylene glycol (PEG), propylene glycol, ethanol or isopropanol or a combination thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an aqueous composition of a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof comprising as a solubility enhancing agent a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen.
The present invention also provides an aqueous composition of a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof comprising as a solubility enhancing agent a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen together with an organic water miscible co-solvent.
The present invention further provides a method for preparing aqueous composition of a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof comprising contacting a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof with aqueous media and a solubility enhancing agent selected from a group consisting of a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen.
The present invention also provides a method for preparing aqueous composition of a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof comprising contacting a nonsteroidal triphenylethylene antiestrogen or a pharmaceutically acceptable salt thereof with aqueous media, an organic water miscible co-solvent and a solubility enhancing agent selected from a group consisting of a pharmaceutically acceptable mono- or dicarboxylic acid having 1-5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several halogen substituents, or a corresponding anion thereof, or methanesulfonic acid or its corresponding anion, in molar excess with respect to the triphenylethylene antiestrogen.
The solubility enhancing agent is used in molar excess with respect to the nonsteroidal triphenylethylene antiestrogen. Preferably, the solubility enhancing agent is used in at least about 1.5 fold, more preferably at least about 2 fold, molar excess, e.g. from about 2 to about 100 fold, typically from about 2 to about 10 fold, with respect to the nonsteroidal triphenylethylene antiestrogen.
The carbon chain of the solubility enhancing agent of the invention may be straight or branched, saturated or unsaturated carbon chain.
Suitable solubility enhancing agents having branched carbon chain include citramalic acid and isoburyric acid, and the corresponding anions.
Suitable solubility enhancing agents having straight carbon chain include lactic acid, acetic acid, formic acid, methanesulfonic acid, 3-hydroxybutyric acid, glycolic acid, pyruvic acid, acrylic acid, propionic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, tartaric acid and glutaric acid or the corresponding anions (lactate, acetate, formate, mesylate, 3-hydroxybutyrate, glycolate, pyruvate, acrylate, propionate, trifluoroacetate, oxalate, malonate, maleate, tartrate and glutarate).
Preferred solubility enhancing agents are mono- or dicarboxylic acids having 1-4 carbon atoms and dicarboxylic acids having 5 carbon atoms, wherein the carbon chain may further contain 1-4 hydroxyl, 1-3 oxo, or one or several, e.g. 1-3, halogen substituents and the corresponding anions. Preferred halogen substituent is fluorine.
More preferred are mono- or dicarboxylic acids having 1-3 carbon atoms and dicarboxylic acids having 5 carbon atoms, wherein the carbon chain may further contain 1-2 hydroxyl or 1 oxo substituent, and the corresponding anions. Such solubility enhancing agents include lactic acid, acetic acid, formic acid, glycolic acid, pyruvic acid, acrylic acid, propionic acid, glutaric acid, oxalic acid or malonic acid, or the corresponding anions.
Still more preferred are monocarboxylic acids having 1-3 carbon atoms and dicarboxylic acids having 5 carbon atoms, wherein the carbon chain may further contain 1-2 hydroxyl substituent, and the corresponding anions. Lactic acid, acetic acid, formic acid, glycolic acid and glutaric acid and the corresponding anions are particularly preferred. Lactic acid and the corresponding anion (lactate) are most preferred.
Preferably the organic water miscible co-solvent is polyethylene glycol (PEG), propylene glycol, ethanol or isopropanol or a combination thereof. The amount of the organic water miscible co-solvent is usually from about 1% to about 75%, preferably from about 5% to about 50%, more preferably from about 10% to about 30%, by weight of the formulation.
The formulations of the invention can be prepared e.g. by mixing the acid and/or corresponding salt thereof, purified water, and optionally the organic water miscible co-solvent together, and adding thereafter triphenylethylene antiestrogen or salt thereof and agitating the mixture. For example, up to about 50 w-% solutions of a triphenylethylene antie
Af Ursin Kaija
Kananen Mikko
Kiesvaara Juha
Kortesuo Pirjo
Niskanen Heikki
Finnegan Henderson Farabow Garrett & Dunner LLP
Goldberg Jerome D.
Orion Corporation
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