Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1998-05-11
2002-07-09
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009500, C424S009510, C424S450000, C424S009520
Reexamination Certificate
active
06416740
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel compositions and methods useful in delivering targeted therapeutics. More particularly, the present invention relates to methods for targeting a region of a patient by administering to the patient compositions having a surfactant and a therapeutic.
BACKGROUND OF THE INVENTION
The ability to move active agents from the locus of administration to an area of activity has provided a continuing challenge to investigators. Providing a stable drug delivery vehicle which both preserves the integrity of the drug and allows for a localized release have escaped these efforts. Eye diseases such as diabetic retinopathy and retinitis pigmentosa are uniquely suited for treatment by non-invasive techniques utilizing the delivery of therapeutics to the site of action. Of the many other diseases where targeted release is important, benign prostatic hyperplasia (BPH) and its pharmacological treatment is also particularly amenable to drug delivery vehicles.
Solubilization of a drug in a surfactant and optionally a carrier, preferably a nonpolar carrier, would serve to optimize delivery of many drugs where polar media are inappropriate. The embodiments of the present invention meet the needs for stable, localized non-polar drug delivery and local drug release.
Microspheres consisting of both hydrophilic and relatively hydrophobic domains or layers are known in the art. In PCT Publication WO95/26376 Coombes et al. discloses a composition with a hydrophilic polymer outer coat and a hydrophobic core polymer, the two layers linked by polyethylene glycol.
Ball milling of nanoparticles is also known as, for example, in the disclosure of Wong, U.S. Pat. No. 5,569,448, wherein sulfated nonionic block copolymers form shells for the sequestration of therapeutic or diagnostic agents. Similarly, other dry powder compositions have been formulated combining nucleic acids with hydrophilic excipients, then drying by lyophilization or spray drying. See, for example, Eljamel, et al. in PCT Publication WO96/32116.
The use of surfactants to stabilize preparations of bioactive molecules is reported in the literature. Not all surfactants or conditions of use, however, enhance sorption or binding of particular drugs to a delivery vehicle. One system was reported in Harmia, et al.,
Int. J. Pharm
. 1986 33:45-54. Harmia et al. report that non-ionic surfactants below their critical micelle concentration prior to lyophilization improved sorption of pilocarpine to polymethacrylate.
Another problem to be overcome in the formulation of useful delivery forms for biopolymers relates to denaturation of proteins, especially enzymes. Spray drying, particularly at elevated temperatures and/or pressures selectively denatures some proteins. Broadhead, et al.,
J. Pharm. Pharmocol
. 1994 46:458-467, however, reports conditions of spray drying which maintain 70% yields of active &bgr;-galactosidase.
Treatment of several diseases would be enhanced with improvements in drug delivery technology. Retinal disease, for example, currently is difficult to treat. No effective treatments are available for the most common diseases. Another ophthalmologic disease, diabetic retinopathy, is a common complication of diabetes. In this disease neovascularization results in a proliferation of blood vessels which destroy the retina. Diabetic retinopathy is treated by medical management of diabetes (better control of blood sugar) and ablating neovascularity with laser photocoagulation.
Macular degeneration is probably the most common cause of blindness afflicting the retina. In this disease there are two predominant forms, neovascularization and primary photoreceptor death. Neovascularization results in a proliferation of vessels which irreversibly damage the retina. Primary photoreceptor cell death is associated with Drusen formation. Drusen formation is believed to represent breakdown products from the photoreceptors. Drusen deposits increase as macular degeneration progresses. Currently, there is no good treatment for macular degeneration.
Veno-occlusive disease is caused by venous thrombosis in the retinal vessels and is diagnosed by retinal hemorrhages. There is no effective treatment for retinal venous occlusive disease.
Accordingly, new and/or better targeted therapeutics, as well as methods of delivering and making the same, are needed. The present invention is directed to these, as well as other important ends.
SUMMARY OF THE INVENTION
The present invention is directed to a targeted therapeutic delivery system comprising a gas or gaseous precursor filled microsphere wherein said gas or gaseous precursor filled microsphere comprises an oil, a surfactant, and a therapeutic compound. Methods of preparing the targeted therapeutic delivery system are also embodied by the present invention. The present invention includes a method comprising processing a solution comprising an oil and a surfactant in the presence of a gaseous precursor, at a temperature below the gel to liquid crystalline phase transition temperature of the surfactant to form gas or gaseous precursor filled microsphere, and adding to said microspheres a therapeutic compound resulting in a targeted therapeutic delivery system, wherein said processing is selected from the group consisting of controlled agitation, controlled drying, and a combination thereof.
Methods of administering the compositions of the present invention are also set forth herein.
These and other aspects of the invention will become more apparent from the following detailed description.
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Bristol-Myers Squibb Medical Imaging, Inc.
Dudash Diana
Sharareh Shahnam
Woodcock & Washburn LLP
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