Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2000-01-03
2002-01-22
Acquah, Samuel A. (Department: 1711)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C428S402240, C428S407000, C524S027000, C524S047000, C524S801000
Reexamination Certificate
active
06340527
ABSTRACT:
The invention relates to a process for the preparation of microparticles which contain an active ingredient in a starch shell.
A process of this type is disclosed in WO 89/03674. According to this known process, microspheres are prepared by suspending an active ingredient, such as paramagnetic particles, in a starch solution, cross-linking the starch with a phosphate and then emulsifying the starch, before or after cross-linking, in a hydrophobic medium.
WO 93/02712 discloses a process for the preparation of microspheres according to which an oil-in-water emulsion of a soluble starch fraction and, for example, dichloromethane is prepared, after which a dehydrating agent, such as an alcohol, is added. The particles are fixed by retrogradation of the starch, which therefore must have a high amylose content.
WO 94/07597 discloses a process for encapsulating an oil phase in a polymeric material that can be cross-linked. The polymeric material is a water-soluble polymer such as polyvinyl alcohol dissolved in water (e.g. at 10%). Acrylamidc polymers, soluble cellulose, starch and other polysaccharide derivatives arc mentioned as alternatives, but the document does dot contain any guidance or illustration on the utility of such soluble polysaccharides. Moreover, solutions put limitations e.g. to the molecular weight and concentration of the polymer.
A process has now been found which leads to convenient particles in which an active ingredient is encapsulated, which active ingredient is released only under specific chosen conditions or after a relatively long period. The process is characterised by the features in the appended claims.
A fine distribution of the active ingredient can be a dispersion of a solid water-insoluble active ingredient or an emulsion of a hydrophobic active ingredient (optionally dissolved in a hydrophobic phase such as an oil). The fine distribution (dispersion or emulsion) is a distribution in an aqueous dispersion of starch or derivative thereof comprising at least 25% starch. Examples of water-insoluble solid active ingredients comprise pigments such as titanium dioxide or zinc oxide, paramagnetic materials such as magnetite, nickel or cobalt, fluorescent materials and the like. The particles size of the solid active ingredient can be in the range of e.g. 10 nm to 50 &mgr;m. In the further specification, the distribution of the active ingredient is illustrated with reference to the oil-in water emulsion; however, the same applies to the solid-in-water dispersion by substituting the oil by the solid active ingredient.
An important constituent of the microparticles is starch, which has the advantage of being able to encase a multiplicity of active ingredients and of being biodegradable. Suitable starches are native starch and fractions and derivatives thereof. Preferably, the starch is granular starch, which can be native or modified native starch and is not water-soluble.
Granular starch is starch having a granular shape similar to the shapes which occur in native starch. Granular starch can have various shapes and sizes (usually in the range of 0.5-175 microns) characteristic of its native source. In most cases, birefringence is seen with polarised light microscopy. Granular starch is usually semi-crystalline. It is not soluble in cold water without the use of chemicals. Granular starch is swellable to a limited extent only. The water uptake is limited (less than 5 times its own weight). As granular starch is also considered chemically or physically modified starch of which most of the original shape and size is maintained during modification. Suitable derivatives are oxidised starch (carboxy starch, dialdehyde starch), carboxyalkylated starch, sulphated or phosphated starch, cationic starch and the like. These modified granular starches usually show still birefringence, but the crystalline nature can be significantly reduced. The modified granular starches do not form gels in cold water without the addition of chemicals. All granular starches show a characteristic gelatinisation endotherm with DSC or an increase in viscosity during heating in water.
The use of granular starches has some advantages over the use of soluble starches. A higher starch concentration can be used, or starch with a higher molecular weight. Thus, a shell can be prepared that has a higher network density, which may be advantageous for the release properties. Another advantage of using granular starch is that various types of starch can be used, such as high-amylose starch, which cannot be used in solution because of rapid retrogradation. Also, the degree of gelatinisation can be controlled through temperature control or adjustment of the amount of alkaline solution added; the degree of gelatinisation allows for adjustment of the network structure; if desired, particles with residual granular structure can be obtained. When the starch is not completely gelatinised, remainders of granular structures will be present. Such granular structures can be observed using (polarised) light microscopy or scanning electron microscopy. Via this route, the swelling behaviour and the release properties of the particles can be adjusted. For example, the release in the gastrointestinal tract may be spread or delayed as a result of the presence of granular structures.
The starch concentration in the aqueous phase before formation of a fine distribution can be e.g. from 5 to 50% by weight, preferably from 15 to 40% by weight, with respect to the water volume. The initial molecular weight of the starch is advantageously above 200,000, especially above 500,000.
It is possible to use a mixture of various types of starch. For instance, partially soluble starch can be added to native starch. Suitable starch fractions are, for example, starch enriched in amylose or specifically in amylopectin. In order to optimise the properties of the particles an auxiliary substance can be added to the starch suspension that modifies the viscosity of the suspension, at a level of 0 to 75 wt. % of the total amount of carbohydrates, preferably 0 to 50 wt. %, more preferably 1 to 25 wt %, in particular 2 to 10 wt. %. This auxiliary substance can be a water-soluble carbohydrate, such as cold water soluble starch, modified starch, cellulosic derivatives such as carboxymethyl cellulose, alginates, pectines and the like.
The oil-in-water emulsion can be prepared in a manner known per se by adding an oil or another hydrophobic substance to the aqueous solution or dispersion of starch. Suitable oils or hydrophobic substances are all water-immiscible liquids, such as hydrocarbons (alkanes, cycloalkanes), ethers, esters, halogenated hydrocarbons and oils. If the active ingredient is also hydrophobic, it can advantageously be added via the oil. The emulsion is formed by adding the hydrophobic phase to the suspension of starch in water. Preferably a soap or another surfactant, which promotes the formation of an oil-in-water emulsion, is added to the aqueous phase before the hydrophobic phase is added. The amount of surfactant is preferably between 0.25 and 5 wt. % with respect to the water volume. Following the addition, a stable emulsion is formed by employing adequate mechanical forces. In this context stable is understood to be stable for the duration of the process. Equipment which can be used for this process is, for example, a top stirrer, an Ultra-Turrax®, a homogeniser or any other suitable emulsion-forming equipment. The dispersion of solid active ingredient can be prepared in the same manner.
After a stable oil-in-water emulsion has been obtained, a particulate material is prepared therefrom by dispersing the emulsion in a hydrophobic phase. The hydrophobic phase can be formed by a water-immiscible solvent, such as an alkane, cycloalkane, ether, ester, halogenated hydrocarbon and the like, or an oil. An oil-in-water-in-oil (o/w/o) emulsion is thus obtained. The conditions for emulsion formation can be the same as those for the formation of the first o/w emulsion. During this stage it is also possible to add, to the second hydr
Gotlieb Kornelis Fester
Van Schijndel Renée Josie Gide
Van Soest Jeroen Johannes Gerardus
Acquah Samuel A.
ATO B.V.
Young & Thompson
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