WO2003090920A1 - Formation de microcapsules a partir d'un materiau noyau - Google Patents

Formation de microcapsules a partir d'un materiau noyau Download PDF

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Publication number
WO2003090920A1
WO2003090920A1 PCT/EP2003/004324 EP0304324W WO03090920A1 WO 2003090920 A1 WO2003090920 A1 WO 2003090920A1 EP 0304324 W EP0304324 W EP 0304324W WO 03090920 A1 WO03090920 A1 WO 03090920A1
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WO
WIPO (PCT)
Prior art keywords
polyelectrolyte
core material
template
polyelectrolytes
negatively charged
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PCT/EP2003/004324
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English (en)
Inventor
Ajay J. Khopade
Frank Caruso
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Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften
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Priority to AU2003233068A priority Critical patent/AU2003233068A1/en
Publication of WO2003090920A1 publication Critical patent/WO2003090920A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/20—After-treatment of capsule walls, e.g. hardening
    • B01J13/22—Coating

Definitions

  • the invention refers to a process for producing nanocapsules or/and microcapsules by contacting templates consisting of a core material with a polyelectrolyte.
  • LbL layer- by-layer
  • DE 198 12 083.4, DE 1 99 07 552.2, EP 98 1 1 3 1 81 .6 and WO 99/47252 disclose processes for the production of capsules coated with a polyelectrolyte shell by layer-by-layer application of oppositely charged polyelectrolytes on template particles forming the core of the capsule.
  • An advantage of this process compared to previous processes for the production of microcapsules is that monodisperse capsules with a particularly adjusted wall thickness can be produced.
  • core-shell particles are diverse, ranging from capsule agents for drug delivery, catalysis, coatings, composite materials, as well as for protecting sensitive agents such as enzymes and proteins.
  • An important further development in the field of core-shell particles has been accomplished by the subsequent removal of the core, resulting in hollow capsules or shells.
  • the coated particles at elevated temperature or dissolution of the core material have been described.
  • hollow sub-micron sized shells of yttrium compounds have been produced (Kawahashi and Matijevic, J. Colloid Interface Sci.1991 , 143, 103) by coating cationic polystyrene latex with yttrium basic carbonate and subsequently calcining.
  • silica shells were generated by seeded polymerization of tetraethoxysilane on the surface of polystyrene particles, followed by calcination (Bamnolker et al., J. Mater. Sci.Lett.1997, 16, 1412).
  • monodisperse, hollow silica nanocapsules have been produced by silica coating gold nanoparticles, and by chemically dissolving the cores (Giersig et al., Ber.Bunsenges.Phys.Chem.1997, 101 , 1617).
  • Nano- or microcapsules still including the template core or the hollow shells resulting from the dissolution of the template represent a class of materials which are of great interest in the fields of medicine, pharmaceutics, agriculture and cosmetics. Due to the high requirements concerning uniformity and smoothness of the layer structures, sufficient coverage, control of thickness in combination with the desired stability and permeability, and monodisperse capsule size distribution, there is still need for the development of improved capsule preparation methods.
  • An object of the present invention therefore was to provide a process for the production of capsules, which is improved compared to known processes.
  • a process for producing nanocapsules or/and microcapsules comprising the steps of (a) providing templates consisting of a core material comprising positively charged ions, and (b) contacting the templates with a negatively charged polyelectrolyte, or the steps of
  • the capsules produced in this manner exhibit favorable properties such as adjustable permeability and chemical functionality, biological, chemical and mechanical stability, monodispersity of capsule distribution and adjustable capsule size as required in the field of applications of microcapsules.
  • the process according to the present invention can either comprise steps (a) and (b) or steps (a.,) and (b ⁇ .
  • the core material comprises positively charged ions
  • the template which consists of this core material is contacted with a negatively charged polyelectrolyte, i.e. a polyelectrolyte that is oppositely charged to the ions comprised by the core material.
  • the core material comprises negatively charged ions and the template consisting of said core material is contacted with a positively charged polyelectrolyte, i.e. again a polyelectrolyte that is oppositely charged to the ions comprised by the core material.
  • templates that are suitable in the process of this invention consist of a core material comprising components that are able to assist in the formation of polyelectrolyte layers. Due to their opposite charge compared with the polyelectrolytes the ions comprised in the core material are appropriate for interacting with, binding to or incorporating in the polyelectrolytes surrounding the template. Especially the positively or negatively charged ions in the surface regions of the template can at least partially saturate binding sites on the polyelectrolyte layer, leading to the formation of a stable film. In this way it is possible to provide stable thin-walled nanosized and microsized capsules.
  • At least part of the core material interacts with, binds to or is incorporated in the polyelectrolytes of the contacting step.
  • An advantage of the process of the invention is that sterile, biocompatible and biodegradable polyelectrolytes and core materials can be used. Especially in the field of medicine where capsules are practicable for the delivery or/and controlled release of drugs sterile and biocompatible materials are required. Encapsulated active substances such as drugs can be released by controlled degradation of the shell or by permeation through the shell. Thus, it is also preferred to use biodegradable materials that degrade under certains conditions such as, for example, specific pH changes or salt or enzymatic conditions.
  • both the polyelectrolyte and the core material can be chosen from recyclable materials. It is possible to recycle the polyelectrolyte and the core material after a simple purification process. In the prior art processes, where oppositely charged polyelectrolytes are used, recycling is not possible because of loss of purity of the polyelectrolyte after the adsorption step and because of the difficult and costly purification process. Thus, by using the process of the present invention, hitherto existing problems such as material loss resulting in high costs can be avoided. Still another aspect of the process of the invention is that due to the use of predominantly identically charged polyelectrolytes uniform layers with adjustable permeability are formed.
  • the shell also exhibits high biological, chemical and mechanical stability.
  • the layer-by-layer method according to the prior art requires the sequential depositing of oppositely charged polyelectrolytes on templates implying the risk of the agglomeration of the polyelectrolytes and consequently the risk of non- uniformity of the layers.
  • the polyelectrolytes of the capsule shell preferably > 50% of the polyelectrolytes of the capsule shell have the same charge, more preferably > 70%, even more preferably > 80%, most preferably > 95%.
  • the produced capsules exhibit particularly favorable properties. Since positively charged polyelectrolytes often are toxic, their incorporation in capsules destined, for example, to targeted delivery of drugs through an intravenous route is critical. With this preferred process of the invention it is possible to preferably use solely negatively charged polyelectrolytes and even solely one sort of negatively charged polyelectrolytes, if desired.
  • the resulting one-component polyelectrolyte microcapsules are especially preferred, e.g. if biocompatibility and biodegradability are a major concern. Also in view of the recycling of the capsule materials one-component polyelectrolyte capsules are especially suitable.
  • capsules are produced, by applying above all layers with negatively charged polyelectrolytes, wherein, however, positively charged polyelectrolytes are present additionally as one or more intermediate layer(s) .
  • the positively charged polyelectrolytes are preferably deposited in an inner layer of the shell, i.e. the positively charged polyelectrolytes are not present in the surface area of the capsule and are not directly contacting the template.
  • each of the layers of negatively charged polyelectrolytes in the inner and outer region of the shell independently has a thickness that makes up about 20% of the whole shell thickness, more preferably about 30%, still more preferably about 40%, most preferably about 60%.
  • the template ions contained in the core material can get into the surface area of the template and then migrate through the shell.
  • the ions are kept between the polyelectrolytes by interaction and by saturating binding sites on the polyelectrolytes, respectively, and can thus be involved in the build-up of the capsule shell. Consequently, at least part of the core material is incorporated in the shell. This leads to a stabilization of the shell.
  • the disintegration of the template can be achieved by adjusting the solvent, pH, temperature, salt conditions or by ultrasonic treatment. It is preferred to carry out disintegration for a time period that is sufficient to allow at least partial saturation of the binding sites in the shell.
  • the method employed for disintegration is chosen depending on the composition of the core material. For example, ethylene diamine, tetraacetic acid or/and other chelating agents can be used for disintegration.
  • the disintegration is carried out by at least partially dissolving the core material, i.e. by adding an appropriate solvent, in which the material is soluble or by adjusting the pH such that the core material is at least partially soluble.
  • dissolution can be effected in a gentle manner during a short incubation period, e.g. 1 min to 1 h at room temperature.
  • a short incubation period e.g. 1 min to 1 h at room temperature.
  • an acidic pH around pH 2-4
  • the core material mainly comprises alkaline earth metal salts.
  • a controlled disintegration of the template is carried out, i.e. the amount of the disintegration can be adjusted.
  • Controlled disintegration preferably is achieved by using e.g. ethylene diamine, tetraacetic acid or/and other chelating agents.
  • partially disintegrating the template denotes that part of the ions are released from the solid core material through which they are made capable of migrating in the polyelectrolyte layers.
  • some of the core material is not disintegrated and still in a solid or aggregated form.
  • ions are released by partially dissolving the core material, but this can also be achieved e.g. by ultrasonic treatment.
  • the template are disintegrated, more preferably 95%, still more preferably 80% or less, still more preferably 50% or less and most preferably 25% or less.
  • the minimum degree of disintegration of the template is 0,01 %, preferably 1 %, more preferably 5%, still more preferably 15%, still more preferably 25% and most preferably 35%.
  • step (b) or (b,) or/and step (c) of the process according to the present invention is/are repeated at least once.
  • wall thickness can be controlled.
  • the contacting steps and the disintegrating step are repeated such that step (c) is carried out after the contacting step, but any other sequence of the steps is possible. If desired, only one of the steps is repeated once or several times.
  • the disintegration step and the contacting step can be carried out simultaneously or subsequently.
  • polyelectrolyte can be used or by repeating the contacting step it is possible, for example, to successively use different sorts of polyelectrolytes. These polyelectrolytes can have the same or different charges.
  • the steps can be repeated as often as necessary to achieve the desired shell thickness or/and capsule size, without having upper limit.
  • the step(s) is/are repeated from 2 to 20 times, more preferably from 4 to 15 times, most preferably from 7 to 10 times.
  • the template according to the present invention can have any suitable form to produce nanocapsules or/and microcapsules.
  • the form may, for example, be spherical, rod-shaped, rectangular, square, triangular and various other forms are possible.
  • the average diameter of the template is 500 ⁇ m or less, preferably 50 ⁇ m or less and, more preferably, 10 ⁇ m or less and, most preferably, 2 ⁇ m or less.
  • the minimum diameter of the template is preferably 10 nm, more preferably 100 nm, most preferably 200 nm and, in particular, 1 ⁇ m.
  • the templates consist of a core material which can be crystalline or amorphous. It is also possible to use a single crystal as the template.
  • the core material is built up by ions, which also comprises core material which is able to form or to set free ions under certain conditions.
  • the core material of the templates in step (a) comprises positively charged ions which can be selected from positively charged organic substances, inorganic substances or any combination thereof.
  • the positively charged ions are metal cations.
  • the metal cations can be selected from the group comprising alkaline metal cations, alkaline earth metal cations, cations of main group III metals, transition metal cations and rare earth element cations.
  • Preferred are cations of the metals Al, Ba, Ca, Mg, Y, Tb, Fe, Co, Ni, Cu, Zn and Ag.
  • the metal cations are selected from the group comprising Al 3+ , Ba 2+ , Ca 2+ , Mg 2+ , Y 3+ , Tb 3+ , Fe 2+ , Fe 3+ , Co 2+ to 6+ , Ni 2+ to 6+ , Cu 2+ to ⁇ Zn 2+ and Ag + . Also any suitable combination of metal cations is possible. Especially preferred are Ba 2+ , Ca 2+ or/and Mg 2+ .
  • the core material of the templates in step (a,) comprises negatively charged ions which can be selected from negatively charged organic substances, inorganic substances or any combination thereof.
  • the negatively charged ions are conjugated bases of inorganic or organic acids, in particular, the conjugated bases of inorganic acids.
  • inorganic acids such as water, phosphoric acid, sulfuric acid, nitric acid, carbonic acid, hydrosulfuric acid, sulfurous acid, hydrogen sulfide or hydrohalic acid the respective conjugated bases are formed.
  • polyvalent acids several acid-base pairs are possible accordingly (e.g. in case of H 3 PO 4 ).
  • Preferred conjugated bases of inorganic acids according to the invention are hydroxide, halogenide, nitrate, sulfide, sulfate, carbonate, phosphate, hydrogen phosphate, dihydrogen phosphate and mixtures thereof. Particularly preferred are halogenide, nitrate, sulfate, carbonate and phosphate.
  • the core material may comprise further components such as organic, inorganic or/and biological substances. These substances can be charged or uncharged. Preferably such substances are selected from the group comprising polymers, drugs, vitamins, nutrients, hormones, growth factors, pesticides, antibiotics, catalysts, preservatives or, in general, an active substance. For example, also metals, metal oxides or/and organic salts or/and inorganic salts can be incorporated in the core material.
  • Suitable counterions of the comprised metal cations are also present.
  • Suitable counterions can be conjugated bases of inorganic or organic acids, preferably the conjugated bases of inorganic acids as defined above.
  • metal cations are additionally present.
  • the core material consists of one or several oxides or/and salts of the metals selected from alkaline earth metals, main group III metals, transition metals and rare earth elements.
  • the oxides or/and salts of Al, Ba, Ca, Mg, Fe, Co, Ni, Cu or/and Zn are preferred.
  • suitable salts as the core material the phosphates, sulfates, carbonates, sulfides, hydroxides and halogenides of these metals are used.
  • Ba 3 (PO 4 ) 2 Ca 3 (PO 4 ) 2 and Mg 3 (PO 4 ) 2 .
  • metal oxides for example, CaO, MgO, BaO, Fe 2 O 3 , Fe 3 O 4 and ZnO are preferred.
  • the templates in the process according to the invention are provided as suspension, dispersion or solution in a liquid medium or, if desired, they may also be provided as dry powder.
  • the liquid medium is selected from aqueous solutions, organic solvents and mixtures thereof.
  • organic solvents are hydrocarbons, alcohols, ethers and esters of carboxylic acids.
  • pharmaceutically acceptable organic solvents such as dimethyl acetamide, dimethyl sulfoxide, glycols, polyols, N-methyl pyrrolidene and the like can be used.
  • step (b) of the process according to the present invention the templates are contacted with a negatively charged polyelectrolyte; accordingly, in step (b ⁇ the templates are contacted with positively charged polyelectrolytes.
  • Polyelectrolytes are polymers having ionically dissociable groups which may be a component or substituent of the polymer chain. Usually, the number of these ionically dissociable groups in polyelectrolytes is so large that the polymers in dissociated form (also called polyions) are water- soluble.
  • the term polyelectrolytes is understood in this context to cover also ionomers, wherein the concentration of ionic groups is not sufficient for water-solubility, however, which has sufficient charges for undergoing self-assembly.
  • polyelectrolytes are classified as polyacids, polybases and polyampholytes.
  • Polybases contain groups which are capable of accepting protons, e.g. by reaction with acids, with a salt being formed. By accepting protons polybases form polycations.
  • polybases are polyamines such as polyethylene amine, polyvinylamine and polyvinyl pyridine or poly(ammonium salts), such as poly(diallyl dimethylammonium chloride).
  • Polyacids are capable of splitting off protons and thereby forming polyanions.
  • Examples of polyacids are poly(carboxylic acid), polyphosphoric acid, polyvinyl or polystyrene sulphuric acid, polyvinyl or polystyrene sulfonic acid, polyvinyl or polystyrene phosphonic acid and polyacrylic acid.
  • the respective salts are poly(carboxylate), polyphosphate, polysulphate, polysulfonate, polyphosphonate and polyacrylate.
  • Polyampholytes contain cationic groups as well as anionic groups.
  • the polyelectrolytes are selected from the group comprising biopolymers, chemically modified biopolymers, synthetic polymers and mixtures thereof. Also inorganic polymers can be suitable.
  • the polyelectrolytes can be linear or branched, branched polyelectrolytes leading to less compact polyelectrolyte layers having a higher degree of wall porosity.
  • polyelectrolyte molecules can be crosslinked within or/and between the individual layers, e.g. by crosslinking amino groups with aldehydes.
  • Preferred polyelectrolytes in the process of the present invention are biopolymers such as polyamino acids, in particular, peptides, S-layer proteins, lectins, milk protein, antigen proteins, therapeutic proteins such as insulin and calcitonin, polycarbohydrates such as dextrins, pectins, alginates, glycogens, amyloses, chitins or polysialic acids and polynucleotides such as DNA, RNA and oligonucleotides, and chelatins.
  • biopolymers such as polyamino acids, in particular, peptides, S-layer proteins, lectins, milk protein, antigen proteins, therapeutic proteins such as insulin and calcitonin, polycarbohydrates such as dextrins, pectins, alginates, glycogens, amyloses, chitins or polysialic acids and polynucleotides such as DNA, RNA and oligon
  • Examples of preferred chemically modified biopolymers are carboxymethyl cellulose, carboxymethyl dextran or lignin sulfonates.
  • Examples of possible inorganic polymers are polysilanes, polysilanoles, polyphosphazenes, polysulfazenes, polysulfides and/or polyphosphates.
  • polyelectrolytes which are degradable or biodegradable under certain conditions, e.g. photo-, acid- or base-labile or enzyme labile.
  • polyelectrolytes With such polyelectrolytes the release of enclosed active substances can be further controlled via the dissolution of the capsule shells.
  • conductive polyelectrolytes or polyelectrolytes having optically active groups can be used as capsule components.
  • biodegradable polymers are polyglycolic acid (PGA), polylactic acid (PLA), polyamides, poly-2- hydroxy-butyrate (PHB), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PLGA), and copolymers thereof.
  • polyelectrolytes are labeled polymers, e.g. fluorescence-labeled polymers, conducting polymers, liquid crystal polymers, photoconducting polymers and photochromic polymers as well as copolymers thereof.
  • Preferred negatively charged polyelectrolytes are e.g. polysialic acid, Gellan gum, alginates, PGA, PLA, PLGA and PHB, and a preferred positively charged polyelectrolyte is poly(diallyl dimethylammonium chloride).
  • Contacting the templates with a polyelectrolyte according to the invention can be carried out, for example, by first providing a suspension, dispersion or solution of the templates in a liquid medium as defined above and then adding the appropriate polyelectrolytes purely or also in a liquid medium. It is also possible to add the template purely, i.e. as dry powder to polyelectrolytes in a liquid medium. Another possibility is to to add the templates in a liquid medium to the polyelectrolytes in a liquid medium or that both templates and polyelectrolytes are brought together by adding them simultaneously. Thus, contacting the templates and the polyelectrolytes can be carried out in any manner to ensure that the polyelectrolyte molecules can assemble around the templates, leading to templates surrounded by polyelectrolyte molecules.
  • the process of this invention can be carried out using solely one sort of polyelectrolyte or by using several different polyelectrolytes having the same or different charge.
  • the polyelectrolyte layers are formed by self-assembly.
  • the respective ions of the core material stabilize the forming shell by interacting or/and binding with or/and incorporation in the arranged polyelectrolytes.
  • the disintegration step (c) is carried out, the disintegrated core material or the ions, respectively, has/have to pass through the shell and are thereby captured in the polyelectrolyte layer(s).
  • the released ions bind with the polyelectrolytes and saturate free binding sites on the polyelectrolytes.
  • the core material comprises components suitable for this core-assisted build-up of the shell.
  • templates which consist of a core material selected from the group consisting of the phosphates, sulfates, carbonates, sulfides, hydroxides or/and halogenides or/and the oxides of Al, Ba, Ca, Mg, Fe, Co, Ni, Cu or/and Zn.
  • these templates are contacted with solely negatively charged polyelectrolytes.
  • the metal cations comprised in the core material migrate through the polyelectrolyte surrounding the template and are thereby held between the polyelectrolyte molecules.
  • the process can additionally comprise step (b 2 ) removing excess polyelectrolyte, following step (b) or (b , respectively.
  • step (b 2 ) is carried out by washing with pure water or/and a liquid as used in the contacting step.
  • the washing can be done using centrifugation, filtration, decantation, sedimentation or/and a combination of either processes.
  • Step (b 2 ) is optional and not necessary for carrying out the process of the present invention, but can sometimes be convenient.
  • step (b 2 ) is practicable, if the build-up of the shell is accomplished by repeating the contacting step with a different kind of polyelectrolyte of the same charge or with an oppositely charged polyelectrolyte.
  • excess polyelectrolyte previously used is removed and mixing up of the different polyelectrolytes is avoided.
  • the washing step is particularly preferred, if oppositely charged polyelectrolytes are subsequently used, since these polyelectrolytes may form lumps due to the attraction of the opposite charges. In this case the washing step might be useful to ensure the formation of regular layers leading to a shell exhibiting the required uniformity. Further, it may be helpful to use one or several washing steps (b 2 ) to remove polyelectrolytes and, thus, control film thickness of the shell.
  • positively or negatively charged ions are additionally added at least once during the process. If positively charged ions are additionally added when performing the process comprising steps (a) and (b) these ions can assist in the desposition of the polyelectrolytes around the template. This may lead to further stabilization of the self-assembled film around the template. Accordingly, additional negatively charged ions can be added when practicing the process comprising steps (a ⁇ and (b,). According to the present invention, adding ions during the process additionally, generally is not required to stabilize the shell around the template, since the core material according to this invention is incorporated in the shell.
  • step (d) is carried out after having repeated the contacting or/and disintegrating step (c) as often to having achieved the desired film thickness.
  • step (d) is carried out after having repeated the contacting or/and disintegrating step (c) as often to having achieved the desired film thickness.
  • the disintegration is carried out as described above for step (c) except that the conditions are adjusted such that the template is disintegrated completely. This can be achieved e.g. by using ethylene diamine, tetraacetic acid and other chelating agents.
  • an alkaline earth metal salt as the template is dissolved by adjusting a pH of around 1 .0. This can be achieved by adding an appropriate acid such as aqueous HCI (e.g. 0.5 M).
  • suitable active substances for the loading step are selected from the group comprising reagents, catalysts, enzymes, pharmaceutical substances and drugs.
  • positively charged drugs such as doxorubicin HCI are loaded in the shell or/and the inside of the capsule.
  • the loading can be achieved by any suitable process leading to the incorporation of the active substance in the shell and/or the inside of the capsule.
  • This loading is achieved by ionic or hydrophobic interaction, electrostatic interaction, hydrogen bonding, Van-der-Waals interaction or/and a combination thereof.
  • the loading is achieved by an ion- exchange process. This means that a charged active substance substitutes an ion of the same charge in the shell or/and the inside, i.e. the hollow space or the template. This can be effected without destroying the shell.
  • a positively charged drug is loaded in shell and/or the inside by replacing alkaline earth metal cations such as Ba 2+ , Ca 2+ or Mg 2+ , such that the capsule integrity is not damaged.
  • Another aspect of the present invention is a nanocapsule or/and microcapsule obtainable by the process of the invention.
  • a capsule according to the invention is defined as being
  • the template surrounded by a shell, i.e. the capsule comprising at least parts of the template provided in step (a) or (a ⁇
  • the hollow shell i.e. a capsule, wherein the template has been completely disintegrated 5.
  • the capsule of 4. wherein the shell or/and the hollow space has been loaded with an active substance according to step (e)
  • Chemical modification of the capsules can be achieved e.g. by derivatization of free hydroxyl groups or/and unreacted -COOH groups on the shell material.
  • the capsules according to the invention have an average diameter of 500 ⁇ m or less, preferably 50 ⁇ m or less, more preferably 10 ⁇ m or less, still more preferably 5 ⁇ m or less and particularly preferred 2 ⁇ m or less.
  • the minimum values of the average diameter of the capsules formed in the described manner is 10 nm, preferably 100 nm, more preferably 200 nm and most preferred 1 ⁇ m.
  • the shell thickness of said capsules can vary in a wide range and is preferably 1 ,000 nm or less, particularly preferred 500 nm or less, still more preferred 100 nm or less.
  • the minimum values of the shell thickness are preferably 2 nm, more preferably 5 nm and most preferably 30 nm.
  • the nano- and/or microcapsules obtainable by the process of the invention exhibit properties favorable in the field of applications of nano- and microcapsules.
  • monodisperse capsule size distribution is achieved and the produced capsules show considerably higher uniformity and smoothness of the applied layers.
  • the shells exhibit a desirable biological, chemical and mechanical stability on the one hand, but also, on the other hand, these shells are semi- permeable membrane shells with precisely adjusted permeability. This means the permeability of the membrane is stimuli responsive to stimuli such as solvent, enzyme, photons, pH and ionic concentration. Even if the template is completely disintegrated, the resulting hollow shell is a freestanding stable capsule.
  • the capsules have an ultrathin shell and, in a preferred embodiment, the templates consist of a core material which is sterile, biocompatible, biodegradable and recyclable.
  • the polyelectrolytes used for the build-up of the shell are biocompatible, biodegradable and recyclable.
  • another aspect of the present invention is the use of a nanocapsule or microcapsule obtainable by the process of the present invention for targeted delivery or/and controlled release of active substances and reagents, and in catalysis.
  • the nanocapsule or microcapsule obtainable by a process of the invention is used for targeted delivery or/and controlled release of positively charged drugs.
  • Targeting may be accomplished by selecting specific polyelectrolytes and/or core materials for the construction of the capsule which provide specific functional properties allowing targeting of the resulting capsule and also by attaching target specific ligands on the capsule surface.
  • Controlled release of the encapsulated active substances is obtainable by choosing pH swellable, thermally or environmentally responsive and/or biodegradable polyelectrolyte and/or core material.
  • An encapsulated substance also can be released by migrating through the shell. Depending on the active substance to be encapsulated or/and released, the porosity and permeability of the capsule shell can be adjusted.
  • the use of the capsules according to the invention for targeted delivery and/or controlled release, for example, of drugs may be useful to prevent degradation of the encapsulated material, i.e. the drug, e.g. in the body of animals and humans.
  • the capsules can also be used to control the ability of the encapsulated material to permeate cell walls or bio-membranes. By the nature of the capsule material the resulting capsule can further be used to control the immune reaction of an organism against the encapsulated material.
  • the capsules are also able to adhere to mucosal surfaces such as corneal, nasal, pulmonary, oral, vaginal, rectal mucosa, thereby increasing the retention time of the bioactive substance encapsulated therein to provide enhanced efficacy through prolonged action or/and better permeation.
  • mucosal surfaces such as corneal, nasal, pulmonary, oral, vaginal, rectal mucosa
  • Fig.1 is a schematic illustration of the core-assisted polyelectrolyte deposition of a preferred embodiment of the process according to the invention (cf. Example 1 ) .
  • Fig.2 is a confocal laser scanning image and the corresponding transmission light microscopy image of core-assisted, self- assembled, thin-walled capsules according to the invention loaded with a drug, doxorubicin HCI.
  • the core material used is calcium phosphate.
  • Example 1 The performing of Example 1 is schematically illustrated in Fig.1 .
  • the initial step involves contacting templates consisting of calcium phosphate with sodium alginate (a).
  • the excess alginate is removed by washing with pure water using centrifugation.
  • the film is formed as a result of binding of alginate with surface calcium (a-b).
  • the pH adjustment disintegrates (dissolves) the core material to produce calcium ions that saturate the binding sites on alginate through "calcium jump" process (c).
  • the excess calcium ions remain on the surface and are used to build the next alginate layer (d).
  • the steps are repeated to control film thickness.
  • the core is removed by the immediate complete dissolution resulting in capsule formation (e).
  • a positively charged drug is then partially/fully exchanged for calcium ions (f).
  • the calcium-alginate complex is termed egg-box complex due to typical binding site of calcium ion with gluouronic and galactouronic acids of alginate resembling an egg-box.
  • Film formation through egg-box complexation model is illustrated in elliptical magnification.

Abstract

L'invention concerne un procédé de production de nanocapsules et/ou de microcapsules consistant à mettre des matrices constituées d'un matériau noyau en contact avec un polyélectrolyte.
PCT/EP2003/004324 2002-04-25 2003-04-25 Formation de microcapsules a partir d'un materiau noyau WO2003090920A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003233068A AU2003233068A1 (en) 2002-04-25 2003-04-25 Core-assisted formation of microcapsules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP02009474 2002-04-25
EP02009474.4 2002-04-25

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WO2005089727A1 (fr) * 2004-03-19 2005-09-29 Capsulution Nanoscience Ag Procede pour produire des particules de type coeur-ecorce et des microcapsules au moyen de matrices microporeuses, particules de type coeur-ecorce et microcapsules, et leur utilisation
WO2008124202A2 (fr) * 2007-01-30 2008-10-16 Beckman Coulter, Inc. Particules microsphériques creuses
US8092836B2 (en) 1998-03-19 2012-01-10 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly
CN113604965A (zh) * 2021-08-25 2021-11-05 郑广翔 一种无纺布及其制备方法

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US8092836B2 (en) 1998-03-19 2012-01-10 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly
US8168226B2 (en) 1998-03-19 2012-05-01 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly
WO2005089727A1 (fr) * 2004-03-19 2005-09-29 Capsulution Nanoscience Ag Procede pour produire des particules de type coeur-ecorce et des microcapsules au moyen de matrices microporeuses, particules de type coeur-ecorce et microcapsules, et leur utilisation
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WO2008124202A3 (fr) * 2007-01-30 2009-03-05 Beckman Coulter Inc Particules microsphériques creuses
CN113604965A (zh) * 2021-08-25 2021-11-05 郑广翔 一种无纺布及其制备方法
CN113604965B (zh) * 2021-08-25 2022-08-23 辽宁洁花环保科技装备有限公司 一种无纺布及其制备方法

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