WO2001064331A1 - Method for producing micro and/or nanocapsules - Google Patents

Abstract

The invention relates to a method for producing micro and/or nanocapsules. The inventive method is characterised in that the starting material for the capsules is mixed together under laminar conditions and is subject to an incapsulation process under said conditions and in an actually known manner. The method can be carried out in a continuous manner and using only small amounts of an emulsifier or no emulsifier at all. Uniform particles having a narrow particle size distribution are obtained.

Description

 Process for the production of micro and / or nanocapsules

The present invention relates to a method for producing microcapsules, which is characterized in that the starting materials for the capsules are laminarly mixed with one another and are subjected to an encapsulation process in a manner known per se under laminar mixing conditions.

Microcapsules are powders or particles with a diameter of approximately 1 to approximately 5000 μm, in which a solid, liquid or gaseous substance is enclosed by a solid material (wall material). Polymers or substances based on wax or lipids are generally suitable as solid materials. Microcapsules are used particularly in pharmaceuticals, e.g. for converting liquid, in particular also volatile compounds, into solid, free-flowing powders, for increasing the stability of the active substances, for retarding active substances, for organ-specific transport of the active substances, for covering the taste and also for avoiding incompatibilities with other active substances and auxiliary substances. So-called solid lipid nanoparticles, small-particle wax and lipid particles with enclosed active ingredients, manufactured using high-pressure homogenization processes, are the subject of current basic research in the medical / pharmaceutical field. Another area of application for microcapsules is the production of carbonless reactive carbonless papers.

By selecting the wall materials, such as natural or synthetic polymers, the wall can be made dense, permeable or semi-permeable. This results in a wealth of possibilities for the controlled release of the encapsulated substance, e.g. by destroying the shell or by permeation or also by chemical reactions that can take place inside the microcapsules.

These microcapsules are produced, for example, by mixing the starting materials, ie the wall materials and the substances to be encapsulated, and then carrying out the encapsulation reaction, for example by drying, ie by means of solvent removal, chemical reactions or cooling. The microencapsulation processes can be carried out batchwise or continuously. However, the continuous processes known from the prior art have the disadvantage that the size distribution of the capsules obtained is relatively wide and capsule sizes smaller than 50 μm cannot be achieved.

The object of the present invention was to provide a process for producing microcapsules and / or nanocapsules which can be produced in a continuous process and which have a particle size distribution which is as narrow as possible, a lower particle size preferably being achieved below 100 m should.

It has surprisingly been found that if the starting materials to be subjected to the encapsulation are mixed under laminar conditions and the encapsulation is carried out under these conditions, particles having a narrow size distribution can be obtained. Another advantage is that the process can be carried out continuously.

The present invention accordingly relates to a method for producing microcapsules and / or nanocapsules, which is characterized in that the starting materials for the capsules are mixed with one another under laminar conditions and are subjected to an encapsulation process in a manner known per se under these conditions.

In the following, homogeneous particles, which consist of a carrier material based on polymer, wax or lipid and substances contained therein in the deficit, are also to be considered as capsules. In this context, homogeneous means that the capsule is not made up of a spherical wall with a core, but is made entirely of carrier material. The encapsulated substance is contained in the carrier material in the form of a solidified melt or enclosed particles.

In order to achieve the laminar flow conditions according to the invention during mixing, it has proven to be particularly advantageous to use so-called micromixers as mixing devices. Such micromixers or microreactors allow rapid and laminar mixing of liquids and liquid reaction mixtures within a short period of time, usually within milliseconds. Such micromixers usually consist of a lamellar structured chamber, the channels of which can have diameters in the range from 20 to 100 μm. Using appropriate feed and discharge lines, reactant mixtures can be converted in the reactor in a targeted manner. In these mixers, the liquids or reactants to be mixed are initially compartmentalized in the channels down to an order of magnitude of <100 μm. Only then is the phase interface formed, for example liquid / liquid. concentration gradient served over longer distances are avoided. This thorough mixing has the further advantage that, if the liquids are compartmentalized down to particle sizes of 25 μm, it is possible to briefly disperse the immiscible liquids even without an emulsifier. It is possible, for example, to initiate the encapsulation process in this state, so that capsules can be produced which have no emulsifier, which leads to greater stability of the capsule produced. It was also found that these capsules have a higher stability towards agglomeration, so that the use of surface modification agents can be reduced.

Silicon-based mixers (TU Ilmenau) can also be used to carry out the process according to the invention. Mixers of this type have channels etched in silicon in the micrometer range which, in conjunction with a geometry suitable for mixing, enable the emulsifier-free or low-emulsifier mixing of two or more non-soluble liquids. These systems are also suitable for the methods described.

The micromixer technique described has the advantage that it is possible to work with small amounts of emulsifier or without an emulsifier. The disadvantage of emulsifiers is that they can interfere with the formation of a closed shell when capsules are formed. Furthermore, they can release active ingredients from the capsule material prematurely and have an allergenic effect or influence the action of substances contained in the capsules. The laminar mixture ensures gentle treatment of the active ingredients to be included. Active substances that are destroyed by the entry of mechanical energy, e.g. DNA are loaded with a minimum of mechanical energy.

The capsules can be produced in a manner known per se, such as by phase separation processes, mechanical-physical processes or polymerization processes, such as suspension and emulsion polymerization, inverse suspension polymerization, micelle polymerization, interfacial polymerization processes, interfacial deposition, in-situ Polymerization, evaporation of solvents from emulsions, suspension crosslinking, formation of hydrogels, crosslinking in solution / suspension, systems of liposomes and on a molecular scale, the phase separation process, also called coacervation, being particularly preferred. Another possibility is the incorporation of active ingredients into melted lipids or waxes. The latter are then emulsified. After the desired droplet size has been set, the molten droplets can solidify, for example by high-pressure homogenization and introducing the melt into water and cooling, and the active substance-containing lipid or wax particles form. Coacervation means that a dissolved polymer in a polymer-rich, still solvent-containing phase by means of desolvation, for. B. by pH change, temperature change, salting out, changing the ionic strength, addition of complexing agents (complex coacervation), addition of non-solvent is transferred. The coacervate attaches to the interface of the material to be encapsulated to form a coherent capsule wall and is solidified by drying or polymerization.

Physical processes for the production of micro and / or nanoparticles are spray drying, fluidized bed processes and extrusion processes.

Mechanical-physical processes are also suitable for coating solid core materials, in which the coating is carried out in the fluidized bed, by spray drying, melt dropletization or twisting (Brace process), spray freeze drying, coextrusion, etc.

In the interface polymerization processes mentioned, the wall is formed by polycondensation or polyaddition from monomeric or oligomeric starting materials at the interface of a water / oil emulsion or oil / water emulsion.

The wall material of the capsules according to the invention can be any material suitable for the production of capsules, such as, for example, natural or synthetic polymers. Examples of such polymers are polysaccharides, such as agarose or cellulose, chitin, chitosan, proteins, such as gelatin, gum arabic, albumin or fibrinogen, ethyl cellulose, methyl cellulose, carboxymethylethyl cellulose, cellulose acetates, polyacrylates and - methacrylates, polyanillin, polypyrrole, polyvinylpyrrolidone , Polyethylene, polypropylene, copolymer of polystyrene and maleic anhydride, epoxy resins, polyethyleneimines, copolymers of styrene and methyl methacrylate, polyacrylates and polymethacrylates, polycarbonates, polyesters, silicones, methyl cellulose, mixtures of gelatin and water glass, gelatin and polyphosphate, cellulose acetate and copolymer and phthalate, gelatin from maleic anhydride and methyl vinyl ether, cellulose acetate butyrate and any mixtures of the above substances.

The wall material can optionally be cross-linked. Common crosslinkers are glutaraldehyde, urea / formaldehyde resins, tannin compounds, such as tannic acid, and mixtures thereof.

Waxes can also be used to manufacture the capsules. "Waxing" is understood to mean a number of natural or artificially obtained substances, which are usually above 35 ° C melt without decomposition and are relatively low-viscosity and not stringy just above the melting point. They have a strongly temperature-dependent consistency and solubility. The waxes are divided into three groups according to their origin, natural waxes, chemically modified waxes and synthetic waxes.

Natural waxes include, for example, vegetable waxes such as candelilla wax, carnauba wax, japan wax, esparto grass wax, cork wax, guaruma wax, rice germ oil wax, sugar cane wax, ouricury wax, or montan wax, animal waxes such as beeswax, shellac wax, walnut, lanolin (wool wax), or broom wax, mineral wax or ozokerite (earth wax), or petrochemical waxes such as petrolatum, paraffin waxes or micro waxes.

The chemically modified waxes include hard waxes such as montan ester waxes, Sassol waxes or hydrogenated jojoba waxes.

Synthetic waxes are generally understood to mean polyalkylene waxes or polyalkylene glycol waxes. It is also possible to use compounds from other classes of material that meet the requirements regarding the softening point. As suitable synthetic compounds have, for example, higher esters of phthalic acid, in particular dicyclohexyl, which is commercially available under the name Unimoll 66 ^® (Bayer AG), proved. Are also suitable Synthetic waxes of lower carboxylic acids and fatty alcohols, such as dimyristyl tartrate, sold under the name Cosmacol ^® ETLP (Condea). Conversely, synthetic or partially synthetic esters from lower alcohols with fatty acids from native sources can also be used. Tegin ^® 90 (Goldschmidt), a glycerol monostearate palmitate, falls into this class of substances. Shellac, for example Shellac-KPS-Dreiring-SP (Kalkhoff GmbH), can also be used as a further substance.

So-called wax alcohols are also included in waxes. Wax alcohols are higher molecular weight, water-insoluble fatty alcohols with usually about 22 to 40 carbon atoms. The wax alcohols occur, for example, in the form of wax esters of higher molecular fatty acids (wax acids) as the main component of many natural waxes. Examples of wax alcohols are lignoceryl alcohol (1-tetracosanol), cetyl alcohol, myristyl alcohol or melissyl alcohol. Likewise suitable as waxes, wool wax alcohols which are understood to be triterpenoid and steroid alcohols, for example lanolin understands, for example, under the trade name Argowax ^® (Pamentier & Co) is available as well as fatty acid glycerol esters, fatty acid alkanolamides and water-insoluble or only slightly water-soluble polyalkylene glycol compounds.

Other suitable waxes are saturated aliphatic hydrocarbons (paraffins).

The components to be encapsulated can consist of any solid, liquid or gaseous materials which are to be produced in encapsulated form. Examples of this are pharmaceutical and cosmetic active ingredients, food additives, adhesives or adhesive components, additives for detergents and cleaning agents. In particular, fragrances, enzymes, catalysts in the form of solutions, dispersions or particles, antibiotics and antibacterial substances on an inorganic and organic basis, fungicides, pesticides, biological units such as cells, DNA, RNA, vitamins etc. can be mentioned. It is also possible to produce so-called hollow capsules. The material to be encapsulated would then be a gas, e.g. B. air.

Examples

In the examples below, a single mixer from the Institute for Microsystem Technology in Mainz (IMM) with a stainless steel housing and nickel on copper was used as the inner material. The channel diameter of the chamber used was 25 μm. A flow rate of 10 ml / minute was achieved by means of two HPLC pumps.

Example 1: Encapsulation of β-carotene in paraffin

0.5 g of β-carotene are dissolved in 50.0 g of paraffin with a melting point of 44-46 ° C. at 60 ° C. This solution is mixed in a micromixer thermostated at 50 ° C with deionized water at a temperature of 50 ° C in a ratio of 1: 5. Before the start of the experiment, the HPLC pumps were preheated with water at 90 ° C. The paraffin in water dispersion thus formed is pumped directly into a stirred receiver from 1 liter of ice water. Here, the paraffin droplets solidify with the carotene embedded therein, forming a sediment. A particle size distribution of 30 - 140 μm is determined by means of dynamic light scattering.

Example 2: Encapsulation of water in polymethyl methacrylate

9.4 g of methyl methacrylate and 1.0 g of ethylene glycol dimetacrylate are placed in 250 ml of n-heptane. The mixture is then heated to 70 ° C. and stirred. Using a micromixer, a solution of 50 mg K ₂ S ₂ O ₈ and 60 mg NaHSO ₃ in 50 ml deionized water is mixed with n-heptane in a ratio of 1: 5 at a temperature of 70 ° C. This mixture is pumped into the methacrylate solution. In order to complete the polymerization, the mixture is stirred at 50 ° C. for 5 hours. Capsules in the size range of 5 - 30 μm were detected using TEMicroscopy and dynamic light scattering.

Example 3: Encapsulation of an aqueous ethylenediamine solution in polyamide A mixture of 6.0 g of ethylenediamine and 24.0 g of water is mixed in a micromixer with cyclohexane in a ratio of 1: 9. The water / amine thus formed in cyclohexane dispersion is pumped into a stirred receiver from 100 ml of cyclohexane and 15.0 g of sebacic acid dichloride. When it is introduced, the polymerization reaction of the acid dichloride with the amine begins at the phase interface of the water droplets with the surrounding cyclohexane to form a polyamide capsule shell. The excess of amine ensures encapsulation of an aqueous amine solution. The particle sizes determined are in the range of 25-100 m.

Claims

claims 1. A process for producing microcapsules and / or nanocapsules, which is characterized in that the starting materials for the capsules are mixed with one another under laminar conditions and are subjected to an encapsulation process in a manner known per se under these conditions. 2. The method according to claim 1, characterized in that the method takes place in a micromixer or reactor. 3. The method according to claim 1 or 2, characterized in that the method is carried out continuously. 4. The method according to any one of claims 1 to 3, characterized in that a capsule size distribution of 10 to 1500 m is obtained. 5. The method according to any one of claims 1 to 4, characterized in that the encapsulation is carried out by means of phase separation processes, mechanical-physical processes or polymerization processes, such as suspension and emulsion polymerization, inverse suspension polymerization, micelle polymerization, interfacial polymerization process, interfacial deposition, in situ -Polymerization, evaporation of solvents from emulsions, suspension crosslinking, formation of hydrogels, crosslinking in solution / suspension, systems of liposomes and on a molecular scale or the introduction of active ingredients into melted lipids or waxes. 6. The method according to any one of claims 1 to 5, characterized in that the wall material of the capsules is selected from natural and synthetic polymers and waxes. 7. The method according to any one of claims 1 to 6, characterized in that the material to be encapsulated is selected from pharmaceutical and cosmetic active ingredients, fragrances, enzymes, food additives, adhesives and adhesive components, fragrances, enzymes, catalysts in the form of solutions, dispersions or particles , Antibiotics and antibacterial substances on an inorganic and organic basis, fungicides, pesticides, biological units such as cells, DNA, RNA, vitamins.