Chemistry: analytical and immunological testing – Including chromatography
Reexamination Certificate
1999-12-15
2001-08-07
Snay, Jeffrey (Department: 1743)
Chemistry: analytical and immunological testing
Including chromatography
C436S180000, C204S450000, C204S451000
Reexamination Certificate
active
06271038
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to apparatus and methods for formulation and solubility testing and ranking, and more specifically to apparatus and methods of using electro-osmotically driven systems for formulation mixing and measurement to produce rank orders of solubility for a variety of formulations and test media.
High throughput synthesis and screening are producing large numbers of potent and selective compounds, but more and more highly lipophilic compounds are emerging from these lead discovery initiatives. Many new lead compounds are relatively insoluble in water, which presents challenges in developing formulations for both oral and intravenous (TV) administration.
Choosing the right formulation can enhance the solubility of these poorly soluble drugs, improve the stability of unstable drugs, assist in controlling and sustaining the delivery of a particular drug, aid in targeted deliver, and minimize the pain during injection or minimize unwanted side effects. In a traditional drug development setting, formulation or test media development is a labor and time intensive task usually performed with several milligrams of compound.
Once compounds have been selected for development, formulating typically consists of dissolving compounds in water-miscible cosolvents—e.g., propylene glycol, polyethylene glycol, glycerin, ethanol, etc. Other methods of formulating water-insoluble drugs involve the use of solubilizing agents, detergents or altering the pH of the solutions. New formulation approaches include the use of emulsions, liposomes, nanospheres, and cyclodextrins (CDs).
The typical procedure for determining suitable formulations involves “dissolving” the compound into various formulations and using conventional analytical methodology for determining maximum concentrations. Analytical methods such as spectroscopic methods (UV-Vis) and high performance liquid chromatography (HPLC) are often used as well as visual examinations. Visual or spectroscopic methods require larger amounts of material.
The large number of lead compounds arising from combinatorial efforts in addition to the small quantities being synthesized have created a need for higher throughput formulating using small amounts of material. Formulating for in vivo testing using micrograms of material is quickly becoming a bottleneck for rapid assessment of a combinatorial chemistry drug's phannacokinetic profile and efficacy. Further, many of the compounds arising from combinatorial libraries are uncharged and highly lipophilic in nature and prevent the use of capillary zonal electrophoresis (CZE).
Hence, the invention is related to apparatus and methods which permit small amounts of material to be rapidly analyzed for solubility in a variety of test media, many of which are potential formulations.
SUMMARY OF THE INVENTION
The present invention provides apparatus and methods for formulation and solubility testing and ranking. More specifically, apparatus and methods of the present invention may use electro-osmotically driven systems for formulation mixing, or off-line mixing, and measurement to produce rank orders of compound solubility in a variety of test media and formulations.
In one embodiment, the present invention provides a method for evaluating the solubility of a chemical in a formulation or test medium. The method includes mixing a volume of a stock solution that has a known concentration of a chemical with a volume of a base liquid to form a control sample. Another volume of the stock solution is mixed with a volume of a formulation to form a test sample. The control sample is passed through a capillary electrochromatography (CEC) tube (where tube refers to a bed or channel) to separate the chemical from the base liquid, and the test sample is passed through a CEC tube to separate the chemical from the formulation. The method includes measuring the amount of chemical passing through the CEC tubes for both the control sample and the test sample, and comparing the measured amount of chemical from the control sample with the measured amount of chemical from the test sample to determine the solubility of the chemical in the formulation relative to the base liquid. In this manner, use of the CEC tube facilitates the rapid determination of a chemical's solubility in a particular formulation. In one aspect, the concentration of the chemical in the formation is calculated based on the comparison and the known concentration of the stock solution.
In one aspect, the method includes mixing known volumes of the stock solution with volumes of other formulations to form multiple test samples. The test samples are passed through CEC tubes, and the amount of chemical passing through each CEC tube is measured. The method includes ranking the test samples based on a comparison of the amount of chemical measured for each test sample with the amount of chemical measured from the control sample. In this manner, rank ordering of a chemical's solubility in a large number of different formulations or test media is rapidly achieved.
In some aspects, the stock solution and/or the base liquid comprises dimethyl sulfoxide (DMSO). In another aspect, the chemical is hydrophobic. In other aspects, the chemical is uncharged and/or lipophilic. In one aspect, the volume of the base liquid is generally equal to the volume of the formulation to facilitate comparisons of chemical concentrations therein.
The measuring step may be accomplished in a number of ways. For example, the chemicals may be measured by counting ions with a mass spectrometer, by measuring a fluorescent signal emitted from the chemical, by measuring the amount of light absorption or reflection by the chemical, and the like.
In one aspect, the method includes moving the control sample and the test sample(s) through channels formed in a substrate using electrical potentials to supply the control sample and the test sample to the CEC tubes. Similarly, in another aspect the mixing steps include moving the stock solution, the base liquid and the formulation through mixing channels in a substrate using electrical potentials.
In another embodiment of the invention, a method for ranking the solubility of a chemical in a plurality of formulations includes providing a substrate having multiple wells and fluid delivery channels, including a stock solution well and formulation wells. A volume of a stock solution having a known concentration of a chemical is placed into the stock solution well. A base liquid and different formulations are placed into the formulation wells. The method includes applying an electrical potential to mix a volume of the stock solution from the stock solution well with a volume of the base liquid from one of the formulation wells to form a control sample; applying electrical potentials to mix other volumes of the stock solution from the stock solution wells with volumes of the formulations from the formulation wells to form multiple test samples; and applying electrical potentials to move the control sample and the test samples through at least some of the fluid channels and into and through CEC tubes. The amount of chemical passing through the CEC tubes is measured for the control sample and the test samples. The method further includes comparing the measured amount of chemical from the control sample with the measured amount of chemical from each of the test samples to determine the solubility of the chemical in the formulations relative to the base liquid.
In one aspect, an electrical potential is applied for a desired period of time to move the volumes of stock solution, base liquid and formulations from their respective wells and into the fluid delivery channels. In another aspect, the control and test samples are mixed by alternating the electrical potential polarity a sufficient number of times to mix the volumes of stock solution and base liquid, and to mix the volumes of stock solution and formulations, respectively.
The invention further includes exemplary devices for practicing methods of
Liu Xiaoli
Takahashi Lori H.
Glaxo Wellcome Inc.
Snay Jeffrey
Townsend and Townsend / and Crew LLP
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