Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1997-11-06
2001-03-06
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S502000, C514S772300, C427S213360, C428S402210, C264S004100, C264S004300, C264S004330, C264S004400
Reexamination Certificate
active
06197349
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the area of administration forms and delivery systems for drugs, vaccines and other biologically active agents such as herbicides. pesticides, insecticides, fungicides, fertilizers. vitamins, nutrition additives and cosmetics. More specifically, the invention is related to particles comprising an interior phase of ubidecarenone or of other poorly water-soluble substances characterized in that these substances, which are solid and primarily crystalline at room temperature in the bulk phase, are primarily present in an amorphous, preferably liquid, physical state in the particles, e.g. as a supercooled melt, hereinafter being referred to as particles of supercooled melts (PSM); to fine dispersions of PSMs in a dispersion medium of pharmaceutically acceptable liquids, preferably aqueous media; as well as to the method of manufacture and the use of such particles and dispersions as delivery systems for the parenteral, enteral, peroral, oral, nasal, pulmonal, ophthalmic, mucosal or (trans)dermal administration of poorly water-soluble bioactive agents, particularly drugs; and to their use in cosmetic, food and agricultural products.
BACKGROUND OF THE INVENTION
Numerous poorly water-soluble bioactive substances, e.g. drugs, are present as solid, in particular crystalline bulk materials at room temperature, primarily in the form of poorly wettable powders with grain sizes in the micro- and millimeter size range. In many cases drugs which share these properties exhibit a poor bioavailability, particularly upon peroral administration. Bioavailability is defined as the rate and the extent of absorption of a bioactive agent into the blood compartment and of the distribution to its site of action. The low absorption rate of poorly water-soluble, in particular lipophilic substances from the gastrointestinal tract (GIT) is generally attributed to the poor solubility of these substances and to their poor wettability in gastrointestinal fluids. Industrially manufactured bioactive substances have generally particle sizes well above 1 &mgr;m since they are preferably processed from cruder materials by mechanical comminution such as milling and micronization. In some cases precipitation from organic solvents is applied. Sjöström et al. (Sjöström B., Kronberg B., Carlfors J., J. Pharm. Sci. 82 (1993) 579-583) describe the manufacturing of submicron drug particles by precipitation in solvent containing o/w emulsions. The method is based on the use of potentially harmful organic solvents such as toluene and chlorinated hydrocarbons. From the technical point, it is virtually impossible to completely remove the solvents from the product so that the solid drug particles contain solvent residues which present a toxicological risk. Moreover, the use of volatile and inflammable organic solvents requires special precautions with respect to manufacturing safety.
Direct injection into the bloodstream (in an aqueous vehicle) is not possible with many drugs due to the poor aqueous solubility of these substances. The size of suspended, poorly water-soluble drug particles/aggregates is generally too large for intravenous administration because it exceeds the diameter of the smallest blood capillaries and would thus lead to capillary blockage and embolism.
In case of extravasal administration of solid drugs with the objective of a systemic drug action, the dissolution process of the substance can become the rate limiting step in absorption and might thus lead to a poor bioavailability. It is common knowledge that the dissolution rate of a substance is affected inter alia by its particle size, its wettability and with crystalline substances also by the energy required to overcome lattice forces. It can therefore be deduced that the bioavailability of poorly water-soluble bioactive agents can in principle be enhanced by the following three technological manipulations:
reduction of particle size,
hydrophilization of particle surfaces to improve the wettability in aqueous media, and
reduction of the crystallinity of the substance.
For example, improvement of the bioavailability after peroral administration due to enhancement of the rate of dissolution by micronization has been described for digoxin (Shaw, T. R. D., Carless. J. E., Europ. J. Clin. Pharmacol., 7 (1974) 269) und griseofulvin (Atkinson, R. M., Bedford, C., Child, K. J., Tomich, E. G., Nature 193 (1962) 588). Micronization is the comminution of agglomerates to microcrystals of a size between 1 and 30 &mgr;m by means of appropriate comminution equipment such as vibration mills, fluid-energy mills and colloid mills. Micronized substances can, however, exhibit wettability problems, e.g. due to aerophilization during the milling process. The reduced wettability counteracts to the increased dissolution rate achievable by micronization as a result of the reduced particle size and can therefore lead to a reduced dissolution rate.
A further reduction from the micrometer to the nanometer size range, e.g. in order to further enhance the bioavailability or to render possible parenteral, in particular intravenous administration, is practically not feasible with the conventional equipment used for micronization or requires a tremendous technological effort, and is therefore extremely costly and in many cases ineffective. Additionally, the reduction of solids to submicron-sized powders can bring about heavy difficulties in handling of these dry products such as an increased risk of dust explosions and cross-contamination problems in a factory environment. Moreover, such systems present a risk to health for persons exposed to the possible inhalation and absorption of potent bioactive materials.
For many applications there is, however, an obvious need to reduce the particle size down to the nanometer range. Thus particle size is an important factor with respect to the parenteral, in particular intravenous administration of drugs. As already mentioned before, many lipophilic drugs can not be formulated as aqueous solutions due to their low aqueous solubility. Intravenous administration of suspensions to sparingly soluble substances in water bears the risk of capillary blockage and embolism since the suspended particles are generally larger than the smallest blood vessels.
So far there are basically only two possible ways of intravenously administering such lipophilic drugs. One possibility is to solubilize the drug in an aqueous medium by use of solubilizing agents such as surfactants and organic solvents. Although the use of these agents may increase the solubility of lipophilic substances to such an extent that therapeutic doses can be achieved, these systems have some considerable disadvantages. Intravenous administration of organic or alcoholic solutions is often associated with pain and local thrombophiebetis at the injection site. The use of high surfactant concentrations, which often are necessary for solubilization, can cause anaphylactoid reactions including anaphylactic shock, and is thus not advisable.
The second possibility is incorporation of poorly water soluble substances into colloidal drug carrier systems. Colloidal carrier systems comprise e.g. polymeric (micro- and) nanoparticles, liposomes, lipid emulsions and lipid suspensions. These drug carriers are vehicles of predominantly colloidal size, i.e. in the nanometer size range, in which the drug is incorporated. Due to their surface characteristics these vehicles can be dispersed in an aqueous medium. Since their size is—with the exception of microparticles—below 1 &mgr;m, they are suited for intravenous administration.
Drug carrier systems in the micrometer size range are represented by microspheres consisting of a solid polymer matrix, and microcapsules in which a liquid or a solid phase is surrounded and encapsulated by a polymer film. Nanoparticles consist, like microspheres, of a solid polymer matrix, however their mean particle size lies in the nanometer range. Both micro- and nanoparticles are generally prepared either by emulsion polymerization
Siekmann Britta
Westesen Kirsten
Azpuru Carlos A.
Keil & Weinkauf
Knoll Aktiengesellschaft
LandOfFree
Particles with modified physicochemical properties, their... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Particles with modified physicochemical properties, their..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Particles with modified physicochemical properties, their... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2459532