Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-12-13
2001-09-04
Kulkosky, Peter F. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S009500
Reexamination Certificate
active
06284280
ABSTRACT:
The invention relates to the object characterized in the claims, i.e., new microparticles which contain active ingredients and contain at least one gas or a gaseous phase in addition to the active ingredient(s), agents containing these particles (microparticulate systems), their use for ultrasound-controlled in vivo release of active ingredients, for ultrasound-supported cell incorporation of active ingredients (sonoporation), as well as a process for the production of these particles and agents.
There have been microparticulate systems for controlled release of active ingredients for many years. A considerable number of possible shell substances and active ingredients can be used to this end. Also, there is a whole series of different production processes. Summaries on the shell substances and production processes used are found in, e.g.: M. Bornschein, P. Melegari, C. Bismarck, S. Keipert: Mikro- und Nanopartikeln alf; Arzneistofftragersysteme unter besonderer Berucksichtigung der Herstellungsmethoden [Microparticles and Nanoparticles as Pharmaceutical Carrier Systems with Special Consideration of the Production Methods], Pharmazie [Pharmaceutics] 44 (1989) 585-593 and M. Chasin, R. Langer (eds.): Biodegradable Polymers as Drug Delivery Systems, Marcel Dekker, New York, 1990.
The release of active ingredients from microparticulate systems is based mainly on diffusion or erosion processes [cf. C. Washington: Drug Release from Microdisperse Systems: A Critical Review, Int. J. Pharm. 58 (1990) 1-12 and J. Heller: Bioerodible Systems, in: R. S. Langer, D. L. Wice (eds.): Medical Applications of Controlled Release Vol. 1, CRC Press, Florida, 1984, pp. 69-101].
These principles are, however, associated with the drawback that the time controllability of the release of active ingredients from microdisperse systems in vivo is limited to the speed of the erosion process and/or diffusion process and can no longer be influenced after administration.
The previously known concepts for local control of the release of active ingredients in vivo from microparticulate systems are based almost exclusively either on non-specific concentrations of the microparticulate active ingredient carrier in certain target organs such as the liver and spleen or on measures for ensuring specific alteration of the organ distribution in vivo after administration by the alteration of the surface properties of the microparticulate systems by means of surfactants or specificity-mediating substances such as, e.g., antibodies [cf.: R. H. Muller: Colloidal Carriers for Controlled Drug Delivery—Modification, Characterization and In Vivo Distribution—, Kiel, 1989; S. D. Tröster, U. Müller, J. Kreuter: Modification of the Biodistribution of Poly(methylmethacrylate) Nanoparticles in Rats by Coating with Surfactants, Int. J. Pharm. 61 (1991), 85-100; S. S. Davis, L.
Illum, J. G. Mevie, E. Tomlinson (eds.); Microspheres and Drug Therapy, Elsevier Science Publishers B. V., 1984, and H. Tsuji, S. Osaka, H. Kiwada: Targeting of Liposomes Surface-Modified with Glycyrrhizin to the Liver, Chem. Pharm. Bull. 39 (1991) 1004-1008]. Other than this, however, all these processes offer no other means of actively influencing the site of the release of active ingredients after administration. In addition, it is not possible to influence the extent and the speed of the release of active ingredients after administration.
First attempts to actively influence the site of the release of active ingredients are based on the possibility of using existing or induced pH or temperature differences to induce release [cf: H. Hazemoto, M. Harada, N. Kamatsubara, M. Haga, Y. Kato: PH-Sensitive Liposomes Composed of Phosphatidyl-ethanolamine and Fatty Acid, Chem. Pharm. Bull. 38 (1990) 748-751 and J. N. Weinstein, R. L. Magin, M. B. Gatwin, D. S. Zaharko: Liposomes and Local Hyperthermia, Science 204 (1979) 188-191]. These methods are associated with the drawback, however, that they are either limited to cases where the necessary temperature or pH differences already exist (e.g., in tumor tissue) or the suitable parameters that are necessary for release must be created only by expensive, in some cases invasive, measures. Moreover, in the latter case, the local dissolution is small.
Another known process for influencing the site of the release,of active ingredients involves the use of microparticles which can be concentrated by ferrofluids that are encapsulated in the particles over magnetic fields for external application within certain body segments [K. J. Widder, A. E. Senyei: Magnetic Microspheres: A Vehicle for Selective Targeting of Drugs, Pharmac. Ther. 20 (1983) 377-395]. The use of such microparticles, however, requires the simultaneous specific use of powerful, easily focussed magnetic fields. Magnets that produce such fields are little used in medicine, however. In addition, the speed of the release of active ingredients cannot be influenced in this way.
In U.S. Pat. No. 4,657,543, a process in which release is brought about by the action of ultrasound on polymer blocks that contain active ingredients is described. This effect is based basically on an improved erosion of the polymer under the action of sound. The drawback to this process is that it is suitable only for stationary implants. For significant effects, moreover, the use of very high sonic pressures or of continuous acoustic signals is necessary, which can lead to tissue damage.
Liposomes that can be destroyed by irradiation with ultrasound that lies in the range of the resonance frequency of the microbubbles are described in WO 92/22298. In this process, the encapsulated active ingredient emerges. The resonance frequency is indicated as being about 7.5 MHz. Diagnostic ultrasound of such a high frequency exhibits only a small penetration depth (a few centimeters), however, due to the high absorption by body tissue. The liposomes described are therefore suitable for releasing active ingredients only in regions of the body that are near the surface.
When nucleic acids are used as active ingredients, two systems based on viral vectors or nonviral vectors are described in the literature. At this time, retro-, adeno and herpes viruses (or their recombinants) are being studied in vivo as viral vectors, and liposomes and ligands of cell surface-specific receptors are being researched in vivo as nonviral vectors (G. Y Wu & C. H. Wu: Delivery Systems for Gene Therapy, Biotherapy, 3 (1991) 87-95 and F. D. Ledley: Are Contemporary Methods for Somatic Gene Therapy Suitable for Clinical Applications?, Clin Invest Med 16 (1) (1993) 78-88.
Initial studies on the use of gene therapy in humans concentrate on genetically caused diseases, such as, e.g., &agr;-1-antitrypsin deficiency, cystic fibrosis, adenosinedeaminase deficiency and malignant tumors, such as, e.g., melanoma, breast. neoplasms and intestinal carcinomas.
As yet, however, no vectors that make it possible to control the release of nucleic acids in both space and time are known.
Therefore, for a wide variety of purposes, there is still a need for formulations that can be administered specifically and that overcome the mentioned drawbacks of the prior art, i.e., in which both the site and time of the release of active ingredients and the amount of substance released can be controlled specifically by simple, noninvasive measures. The formulations, moreover, should exhibit high stability, especially with respect to mechanical influences.
The object of the invention is thus to make available such formulations, as well as to provide processes for their production.
This object is achieved by the invention:
It has been found that in the case of microparticulate systems that consist of a physiologically compatible suspension medium and microparticles that consist of a biodegradable shell and a core that contains gas and active ingredients, when irradiation is done with diagnostic ultrasound waves that lie in a frequency range which is below the resonance frequency of the partic
Fritzsch Thomas
Hauff Peter
Heldmann Dieter
Stahl Harald
Weitschies Werner
Kulkosky Peter F.
Millen White Zelano & Branigan
Schering Aktiengesellschaft
LandOfFree
Microparticles containing active ingredients, agents... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Microparticles containing active ingredients, agents..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Microparticles containing active ingredients, agents... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2537340