Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-03-07
2004-03-02
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S450000, C424S460000, C424S461000, C424S462000, C424S489000, C424S490000, C424S494000, C424S496000, C424S497000, C424S498000
Reexamination Certificate
active
06699501
ABSTRACT:
This application is a 371 of PCT/EP99/05063 filed Jul. 15, 1999.
The invention relates to a process for producing capsules with a polyelectrolyte shell, and to the capsules obtainable by the process.
Microcapsules are known in various embodiments and are used in particular for controlled release and targeted transport of active pharmaceutical ingredients, and for protecting sensitive active ingredients such as, for example, enzymes and proteins.
Microcapsules can be produced by mechanical/physical processes, or spraying and subsequent coating, chemical processes such as, for example, interfacial polymerization or condensation or polymer phase separation or by encapsulating active ingredients in liposomes. However, processes disclosed to date have a number of disadvantages.
German patent application 198 12 083.4 describes a process for producing microcapsules with a diameter of <10 &mgr;m, where several consecutive layers of oppositely charged polyelectrolyte molecules are applied to an aqueous dispersion of template particles. The template particles described in this connection are, in particular, partially crosslinked melamine-formaldehyde particles. After formation of the polyelectrolyte shell it is possible to disintegrate the melamine-formaldehyde particles by adjusting an acidic pH or by sulfonation.
It has been found, surprisingly, that polyelectrolyte capsules can also be formed with use of templates selected from biological cells, aggregates of biological or/and amphiphilic materials such as, for example, erythrocytes, bacterial cells or lipid vesicles. The encapsulated template particles can be removed by subsequent solubilization or disintegration.
The invention thus relates to a process for producing capsules with a polyelectrolyte shell, where several consecutive layers of oppositely charged polyelectrolyte molecules are applied to a template selected from aggregates of biological or/and amphophilic materials, and the template is subsequently disintegrated where appropriate.
Examples of template materials which can be used are cells, for example eukaryotic cells, such as, for example, mammalian erythrocytes or plant cells, single-cell organisms such as, for example, yeasts, bacterial cells such as, for example,
E.coli
cells, cell aggregates, subcellular particles such as, for example, cell organelles, pollen, membrane preparations or cell nuclei, virus particles and aggregates of biomolecules, for example protein aggregates such as, for example, immune complexes, condensed nucleic acids, ligand-receptor complexes etc. The process of the invention is also suitable for encapsulating living biological cells and organisms. Likewise suitable as templates are aggregates of amphophilic materials, in particular membrane structures such as, for example, vesicles, for example liposomes or micelles, and other lipid aggregates.
Several oppositely charged polyelectrolyte layers are deposited on these templates. This is done by firstly dispersing the template particles preferably in a suitable solvent, for example an aqueous medium. It is then possible—especially when the template particles are cells or other biological aggregates—to add a fixing reagent in sufficient concentration to bring about at least partial fixation of the template particles. Examples of fixing reagents are aldehydes such as formaldehyde or glutaraldehyde, which are preferably added to the medium to a final concentration between 0.1-5% (w/w).
Polyelectrolytes mean in general polymers with groups which are capable of ionic dissociation and may be a constituent or substituent of the polymer chain. The number of these groups capable of ionic dissociation in polyelectrolytes is normally so large that the polymers are water-soluble in the dissociated form (also called polyions). In this connection, the term poly-electrolytes also means ionomers in which the concentration of ionic groups is insufficient for water solubility but which have sufficient charges to enter into self-assembly. The shell preferably comprises “true” polyelectrolytes. Depending on the nature of the groups capable of dissociation, polyelectrolytes are divided into polyacids and polybases.
On dissociation of polyacids there is formation of polyanions, with elimination of protons, which can be both inorganic and organic polymers. Examples of polyacids are polyphosphoric acid, polyvinylsulfuric acid, polyvinylsulfonic acid, polyvinylphosphonic acid and polyacrylic acid. Examples of the corresponding salts, which are also referred to as polysalts, are polyphosphate, polysulfate, polysulfonate, polyphosphonate and polyacrylate.
Polybases contain groups able to take up protons, for example by reaction with acids to form salts. Examples of polybases with groups capable of dissociation located on the chains or laterally are polyallylamine, polyethyleneimine, polyvinylamine and polyvinylpyridine. Polybases form polycations by taking up protons.
Polyelectrolytes suitable according to the invention are both biopolymers such as, for example, alginic acid, gum arabic, nucleic acids, pectins, proteins and others, and chemically modified biopolymers such as, for example carboxymethylcellulose and ligninsulfonates, and synthetic polymers such as, for example, polymethacrylic acid, polyvinylsulfonic acid, polyvinyiphosphonic acid and polyethyleneimine.
It is possible to employ linear or branched polyelectrolytes. The use of branched polyelectrolytes leads to less compact polyelectrolyte multifilms with a higher degree of porosity of the walls. To increase the capsule stability it is possible to crosslink polyelectrolyte molecules within and/or between the individual layers, for example by crosslinking amino groups with aldehydes. A further possibility is to employ amphiphilic polyelectrolytes, for example amphiphilic block or random copolymers with partial polyelectrolyte characteristics to reduce the permeability to small polar molecules. Such amphiphilic copolymers consist of units differing in functionality, for example acidic or basic units on the one hand, and hydrophobic units on the other hand, such as styrenes, dienes or siloxanes etc., which can be arranged as blocks or randomly distributed over the polymer. It is possible by using copolymers which change their structure as a function of the external conditions to control the permeability or other properties of the capsule walls in a defined manner. Suitable examples thereof are copolymers with a poly-(N-isopropylacrylamide) content, for example poly-(N-isopropylacrylamide-acrylic acid), which change their water solubility as a function of the temperature, via the hydrogen bonding equilibrium, which is associated with swelling.
The release of entrapped active ingredients can be controlled via the dissolution of the capsule walls by using polyelectrolytes which are degradable under particular conditions, for example photo-, acid- or baselabile polyelectrolytes. A further possibility for particular possible applications is to use conducting polyelectrolytes or polyelectrolytes with optically active groups as capsule components.
There are in principle no restrictions on the polyelectrolytes or ionomers to be used as long as the molecules used have a sufficiently high charge or/and have the ability to enter into a linkage with the underlying layer via other interactions such as, for example, hydrogen bonding and/or hydrophobic interactions.
Suitable polyelectrolytes are thus both low molecular weight polyelectrolytes or polyions and macromolecular polyelectrolytes, for example also polyelectrolytes of biological origin.
For the application of the polyelectrolyte layers to the template there is preferably firstly production of a dispersion of the template particles in an aqueous solution. A polyelectrolyte species with the same or the opposite charge as the surface of the template particle is then added to this dispersion. After removal of any excess polyelectrolyte molecules present, the oppositely charged polyelectrolyte species used to build up the second layer is added. Subsequently there are
Bäumler Hans
Caruso Frank
Donath Edwin
Möhwald Helmuth
Moya Sergio
Fulbright & Jaworski L.L.P.
Max-Planck-Gesellschaft zur Forderung der Wissenschaften. e.V.
Spear James M.
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