Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-04-14
2004-03-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S499000, C427S002140
Reexamination Certificate
active
06703048
ABSTRACT:
The invention relates to spherical microparticles which contain linear polysaccharides, to processes for their preparation and to their use, in particular for controlled delivery of active substances.
Processes for preparing particles, especially microparticles from polymers such as, for example, polysaccharides, for a wide variety of applications are quite complicated processes which require accurate compliance with various parameters. In particular, many processes also result in only low yields and in very wide particle distributions. Mention should be made in this connection in particular of spray drying, interfacial condensation and emulsion processes (for example WO processes=water-in-oil emulsions, WOW=water-in-oil-in-water emulsions, coacervation, phase separation, dispersion). Emulsion processes in particular, but also spray dryings from two-phase systems, require a very accurate procedure and, in most cases, the use of auxiliaries (emulsifiers). Stable emulsions can often be prepared only at great expense and with precise control of a large number of parameters (temperature, stirring speed etc.), and comprehensive removal of the particles involves problems. The yield of particles is often very low and, in particular, the proportion of active substances entrapped is inadequate. This is as an aspect which may prevent application of a technology in the case of costly pharmaceutical active substances.
Spherical microparticles which, besides tartaric acid-containing polycondensates, which may also contain ethyl starch or other polysaccharides are obtained, according to U.S. Pat. No. 5,391,696, on the one hand by the spray-drying process, but with this the particle size and, in particular, the size distribution can be controlled only with great difficulty. Another possibility described in this patent is dissolving the polymer in a solvent or mixture of solvents and dropwise addition of the solution to a cold liquefied gas, for example liquid nitrogen, with formation of spherical particles. The small beads can then be introduced into water, which simultaneously precipitates the polymer and extracts the solvent. This process is time-consuming, costly and uneconomic. The uniformity of the particle dimensions is also unsatisfactory.
EP-B1-0 251 476 describes the preparation of microparticles from polylactides in which a macromolecular polypeptide is dispersed. Intensive control of a wide variety of parameters is necessary in this case too. Uniform spherical particles are not obtained.
Microparticles which contain active substances and gases are described in WO 95/07 072. Preparation takes place by elaborate emulsion processes, and the size distribution of the particles is very inhomogeneous.
Yu Jiugao and Liu Jie report in starch/stärke 46(7)252-5(1994) on the effects of the suspension crosslinking reaction conditions on the size of starch microbeads. The crosslinking takes place in three stages; the medium is a water-in-oil suspension, and a peanut oil/toluene mixture is used as oil phase. Pregelatinized starch is added as aqueous solution which also contains sodium hydroxide and ethylenediaminetetraacetic acid. The presence of a surface-active agent or stabilizer is also necessary.
The disadvantage of the process described therein is that the result depends on a large number of factors, namely on the density, the viscosity and the concentration ratios both of the aqueous and of the oil phase, on the stabilizer and on the stirring speed, and, in addition, the presence of the stabilizer is disadvantageous. It is moreover difficult to control the large number of parameters given, so that the reproducibility is unsatisfactory.
Particles which are loaded with macromolecular active substances and are composed of water-insoluble polymers such as polylactic acid or ethylcellulose are obtained, according to the disclosure of EP-B1-0 204 476, by suspending the particulate active substance in an acetone solution of the polymer, and evaporating off the solvent at room temperature. The particles resulting in this case still do not show the required pharmacological effects, so that further processing to so-called pellets is necessary.
Although microparticles with a spherical shape and processes for preparing them are already known, there is still a need for such microparticles with improved properties, and for more advantageous, in particular economic and easily reproducible, preparation processes. It is therefore an object of the invention to provide microparticles which have a substantially regular spherical shape and which in addition show a size distribution which is as narrow as possible, i.e. a great uniformity, and which can be used for many purposes. Another object of the invention is to provide a process for preparing such microparticles which is simple and economic to carry out and which provides microparticles with regular structures and great uniformity, which have good mechanical properties, which are biodegradable, which can be provided with a wide variety of active substances, and which are particularly suitable for controlled delivery of active substances.
This object is achieved by spherical microparticles having an average diameter of from 1 nm to 100 &mgr;m, consisting wholly or partly of at least one water-insoluble, linear polysaccharide.
Spherical microparticles mean microparticles which have approximately a spherical shape. If a sphere is described by axes of equal length which are directed into space from a common origin and define the radius of the sphere in all directions in space, the length of the axes may deviate from the ideal spherical shape by from 1% to 40% for the spherical microparticles. Spherical microparticles with deviations of up to 25% are preferably obtained, particularly preferably up to 15%. The surface of the spherical microparticles can be compared macroscopically to that of a raspberry, it being intended that the depth of the “recesses” or “indentations” is not more than 20% of the average diameter of the spherical microparticles.
“Linear, water-insoluble polysaccharides” for the purpose of the present invention are polysaccharides which are composed of monosaccharides, disaccharides or other monomeric building blocks in such a way that the monosaccharides, disaccharides or other monomeric building blocks are always linked together in the same way. Each basic unit or building block defined in this way has exactly two linkages, in each case one to another monomer. Exceptions to this are the two basic units which form the start and end of the polysaccharide. These basic units have only one linkage to another monomer. When there are three linkages (covalent bonds), a branch is said to be present. Linear, water-insoluble polysaccharides for the purpose of the invention have no branches or, at the most, to only a minor extent, so that with very small proportions of branches they are not accessible to conventional analytical methods.
The term “water-insoluble polysaccharides” means for the present invention compounds which fall into the categories of ‘sparingly soluble’, ‘slightly soluble’, ‘very slightly soluble’and ‘practically insoluble’ compounds as defined in the German Pharmacopeia (DAB=Deutsches Arzneibuch, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, GoviVerlag GmbH, Frankfurt, 9
th
edition, 1987), corresponding to classes 4 to 7.
Preferred within the scope of the invention are linear, water-insoluble polysaccharides which have been prepared in a biotechnological, in particular in a biocatalytic, also biotransformation, or a fermentation process.
Linear polysaccharides prepared by biocatalysis (also: biotransformation) within the scope of this invention means that the linear polysaccharide is prepared by catalytic reaction of monomeric basic building blocks such as oligomeric saccharides, for example of mono- and/or disaccharides, by using a so-called biocatalyst, normally an enzyme, under suitable conditions.
Linear polysaccharides from fermentations are, in the terminology of the invention, linear polysaccha
Bengs Holger
Böhm Gitte
Grande Jürgen
Schneller Arnold
Celanese Ventures GmbH
Connolly Bove & Lodge & Hutz LLP
Page Thurman K.
Tran S.
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