Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-08
1997-11-18
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 13, 514 12, 424 943, 4241931, 424400, A61K 9107, A61K 3816, A61K 3900
Patent
active
056887612
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This is a continuation-in-part of Ser. No. 963,326 filed Oct. 16, 1992, now abandoned which is a continuation-in-part of Ser. No. 885,202 filed May 20, 1992, now U.S. Pat. No. 5,444,041, which is a continuation of PCT application PCT/US92/03086 filed Apr. 15, 1992, which is a continuation-in-part of application Ser. No. 841,931, filed Feb. 25, 1992 now abandoned which is a continuation-in-part of application Ser. No. 837,347, filed Feb. 14, 1992, which in turn is a continuation-in-part of application Ser. No. 687,691, filed Apr. 19, 1991, now abandoned.
This invention relates to microemulsions, and methods of making and using the same. More particularly, it relates to certain unique microemulsion formulations which are phase reversible (i.e., "convertible" as defined below), methods for making and storing them, and their use in administering drugs, proteins, and like biologically-active materials, including therapeutically-active ones.
As used herein, the microemulsions of this invention are self-emulsifying stable dispersions of oil and water, stabilized by interfacial films of surface-active molecules. These microemulsions are also characterized by their small average particle sizes, generally less than about 0.1 micron, by their wide range of temperature stability, typically from about 5.degree. C. to 50.degree. C., and they appear to be thermodynamically-stable, i.e., stable indefinitely over this range. They are also relatively insensitive to the pH or ionic strength of the aqueous internal phase.
These microemulsions are further characterized in that they form spontaneously without the need of high shear equipment, as distinct from conventional emulsions (macroemulsions) which must be prepared by the input of significant amounts of energy, and which are thus subject to extremes of temperature, pressure, and shear, resulting in damage to the contents of the emulsion. For further discussion of these systems, see "Microemulsions," M. Kahlweit, Science, 240:617-621 (1988).
By the term "convertible" or "phase reversible", as used herein to describe the microemulsions of this invention, is meant a microemulsion formulation capable of being changed from a water-in-oil (w/o) system to an oil-in-water (o/w) systemby the addition of water to the former, as described in further detail below.
Also, "conversion," as used herein, is intended to define in particular the reversal of a w/o emulsion to form an o/w emulsion, as distinct from the term "inversion", as used in the art, which describes principally the change of a w/o emulsion to a water-in-oil-in-water (w/o/w) formulation.
BACKGROUND OF THE INVENTION
The preparation and use of microemulsions in the formulation of drugs, proteins, and the like are known in the art. See, for example, U.S. Pat. No. 3,989,843, which discloses the application of microemulsions to medical formulations. Also, in Eur. J. Biochem., Samama et al., 163(3):609-617 (Mar. 16, 1987) describe liver alcohol dehydrogenase in ionic w/o microemulsions, while Lee et al. describe the extraction of epoxide cyclase, using various ionic microemulsions, in FEBS Lett., 244(2):347-50 (Feb. 27, 1989). In each case, however, there is no teaching or suggestion that these microemulsions are phase reversible.
U.S. Pat. Nos. 4,931,210; 4,857,506; 4,714,566; and 4,590,086, on the other hand, disclose methods of preparing water-in-oil emulsions which are then inverted to form well-known water-in-oil-in-water phase (w/o/w) emulsions. These complex preparations, however, are macroemulsion formulations requiring high shear energy to prepare, and the resulting product is a w/o/w emulsion which actually comprises a w/o emulsion mixed into an aqueous phase in such a way that the first internal aqueous phase does not mix with the second continuous aqueous phase.
Emulsion systems for delivery of lipophilic agents via oral, parenteral, or local cutaneous administration and for transdermal delivery of the polypeptide hirudin are disclosed in U.S. Pat. No. 4,719,239 to Muller et al. Microemul
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Owen Albert J.
Sarkahian Ani B.
Yiv Seang H.
Gupta Anish
LDS Technologies, Inc.
Tsang Cecilia J.
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