WO2010084060A1 - Copolymères d'amidon et nanoparticules de ceux-ci destinés à des systèmes d'administration de médicaments - Google Patents

Copolymères d'amidon et nanoparticules de ceux-ci destinés à des systèmes d'administration de médicaments Download PDF

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WO2010084060A1
WO2010084060A1 PCT/EP2010/050308 EP2010050308W WO2010084060A1 WO 2010084060 A1 WO2010084060 A1 WO 2010084060A1 EP 2010050308 W EP2010050308 W EP 2010050308W WO 2010084060 A1 WO2010084060 A1 WO 2010084060A1
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starch
copolymer
phosphine
nanoparticles
group
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PCT/EP2010/050308
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Masayuki Hirosue
Harald Keller
Hans-Michael Walter
Arnold Schneller
Gerhard Wenz
Thomas Stauner
Brigitta Loretz
Noha Nafee
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Basf Se
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    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08FMACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5138Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51Nanocapsules; Nanoparticles
    • A61K9/5107Excipients; Inactive ingredients
    • A61K9/513Organic macromolecular compounds; Dendrimers
    • A61K9/5161Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B30/00Preparation of starch, degraded or non-chemically modified starch, amylose, or amylopectin
    • C08B30/12Degraded, destructured or non-chemically modified starch, e.g. mechanically, enzymatically or by irradiation; Bleaching of starch
    • C08B30/18Dextrin, e.g. yellow canari, white dextrin, amylodextrin or maltodextrin; Methods of depolymerisation, e.g. by irradiation or mechanically
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08BPOLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00Preparation of derivatives of starch
    • C08B31/02Esters
    • C08B31/04Esters of organic acids, e.g. alkenyl-succinated starch
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/04Starch derivatives, e.g. crosslinked derivatives
    • C08L3/06Esters
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L51/00Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
    • C08L51/02Compositions of graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers grafted on to polysaccharides

Definitions

  • the present invention relates to novel starch copolymers their preparation via ATRP reaction, to copolymeric starch nanoparticles their preparation and their use for the preparation of drug delivery systems.
  • Nanoparticles are solid, colloidal particles consisting of e.g. inorganic materials or mac- romolecular substances that vary in size from 10 to 1 ,000 nm in a stricter sense from 10 to 100 nm. Such nano sized particles have extremely high surface areas and are able to penetrate through membranes and barriers not normally penetrable by larger materials. Said nanoparticles have attracted increased attention over the past several years in a variety of fields including catalysis, coatings, pharmacy, cosmetics, electronics and polymeric composition.
  • nanoparticles as drug delivery systems for controlled release of drugs has improved the therapeutic methods in recent years. Numerous documents suggest the incorporation of active pharmaceutical agents of low solubility in micelles, liposome, nano capsules or nanoparticles. There are many preparation methods and raw material employed in the development of new nanoparticle drug delivery systems described in the state of art.
  • the nanoparticle matrix usually is composed of a pharmaceutical acceptable polymer, in particular a biodegradable natural or synthetic polymer, such as proteins.
  • Typical materials for pharmaceutically used nanoparticles are synthetic polymers like polyethylenglycol, polyester, various polyacrylates and poly(meth)acrylates, polymeric vinyl aromatic monomers, poly (meth)acrylic acid and substituted ethylene monomers. Also natural materials and derivatives thereof were used to prepare nanoparticles, e.g. starches, celluloses, sugars, dextrans, proteins and alginates. In the least years, the use of polysaccharides as raw material to prepare nanoparticles has been described.
  • the document WO 1996/35414 relates to a pharmaceutical composition containing an active agent having low water-solubility, wherein the active agent is encapsulated in nanoparticles.
  • the nanoparticles comprise pharmaceutically acceptable synthetic polymers, preferably a cationic ethylacrylat/methylacrylat polymer.
  • WO 2006/106521 describes nano sized particles of macromolecules wrapped in an amphiphilic polymer.
  • the macromolecule is for example a polypeptide, protein, poly- saccharide or polynucleotide.
  • the amphiphilic polymer is a polysaccharide or a modified polysaccharide such as starch, chitosan, or alginate. This document does not disclose a nanoparticle system, wherein the outer shell consists of a starch derivative as main component.
  • the high amount of hy- droxyl groups in the polysaccharide backbone allows the incorporation of different spe- cific ligands to obtain poly functional colloidal systems. Due to its high availability, starch presents a good starting material to form polymeric nanoparticles.
  • Starch is a biocompatible, biodegradable, non-toxic polymer, existing in nature as the major storage polysaccharide in higher plants.
  • Starch is composed of glucose units joined together by glycosidic bonds.
  • the main components of natural starch are amy- lose and amylopectin.
  • Amylose is a planar polysaccharide, wherein the glucose units are linked mainly by ⁇ (1 ⁇ 4) glycosidic bonds.
  • Amylopectine is a highly branched polymer, wherein the glucose chain of linear ⁇ (1 ⁇ 4) glycosidic linked units is branched with ⁇ (1 ⁇ 6) glycosidic linked chains. This branches occurs every 24 to 30 glucose units.
  • hydrophilic nature of starch is a major constraint that seriously limits the development of starch-based nanoparticles.
  • a good alternative to solve this problem is the grafting of hydrophobic side chains to the hydrophilic starch backbone. Different polysaccharide nanoparticles and their preparations are described in literature.
  • the publication Lemarchand et al. (Pharmaceutical Research 2003; 20(8):1284-1292) relates to novel core-shell nanoparticles based on a amphiphilic copolymer preferably dextran grafted with poly ⁇ -caprolactone.
  • the preparation method of the nanoparticles is based on a dialysis.
  • One of the objects of the present invention is to provide a nanoparticles system comprising starch copolymers as main component for drug delivery systems and a method of preparing such system.
  • the preparation of the nanoparticles should be technically simple and without using of toxic or harmful organic solvents.
  • the novel nanoparticles system should exhibit good stability and performance for encapsulation and release of different types of drugs. Further these novel nanoparticles should be suitable for the use as carrier in pharmaceutical drug delivery systems, e.g. transdermal drug delivery systems (TDDS) or for oral administration and absorption over the gastro-intestinal-tract.
  • TDDS transdermal drug delivery systems
  • Transdermal drug delivery system means in particular a patch containing one or more layers, which is placed on the skin to deliver a specific dose of medication through the skin e.g. into the bloodstream.
  • An advantage of a transdermal drug delivery route over other types such as oral or topical is that it provides a controlled release of the active pharmaceutical ingredient into the patient.
  • a disadvantage is the fact that the skin can be a very effective barrier for drug compounds.
  • Nanoparticles can be used in several drug delivery systems.
  • Drug delivery systems mean technologies which modify drug release profile, absorption, distribution and elimination of drugs or particularly hydrophobic, water-insoluble drugs.
  • Most common methods of delivery include the preferred non-invasive peroral route via the gastrointestinal tract, topical route (for example administration via skin), transmucosal and inhalation routes.
  • the area of drug delivery include the development of target delivery in which the drug is only active in a target area (e.g. a special organ or in cancerous tissues) and sustained release formulations in which the drug is released in a controlled manner over a period of time.
  • transdermal patches e.g. hormones, nicotine, nitroglycerine and antidepressants.
  • active pharmaceutical ingredients used in transdermal systems must be combined with dermal penetration enhancers such as alcohols, which increase the ability to pass trough the skin.
  • dermal penetration enhancers such as alcohols
  • a Franz Diffusion Cell is composed of a receptor and a donor cell. A membrane is placed between the cells. This system is used to study effects (e.g. of temperature) on the permeated amount of a specific drug trough different membranes.
  • WO 03/010206 and WO 2005/108471 describe graft copolymers and diblockcopolymers based on a cellulose backbone and acrylic acid based monomers and nanoparticles made thereof.
  • Cellulose is not biodegradable in the human body.
  • Copolymers and resulting nanoparticles have the great disadvantage in medical applications that they are not biologically degradable if applied to a human being and therefore would stay and accumulate unfavorable and hazardous acrylic acid derivatives during the time of application.
  • graft polymerizations of polysaccharides use chemically modified starch such as acetylated starch which also inhibits any biodegra- dation in a human organism (Jukka et al, European Polymer Journal, 2007, 43, 1372- 1382).
  • One object of the invention is therefore to provide a copolymer which is biodegradable in the human body if used as e.g. a drug carrier system and therefore does not accumulate unfavorable chemical substances during the time of application and a method for preparation thereof.
  • the present invention concerns new copolymers comprising starch as a backbone molecule, a covalently bound linker and a polymerized chain of monomers comprising at least one olefin group bound to the linker, wherein the degree of substitution of hy- droxy-groups of the backbone is in the range of 0.05 to 3.
  • ATRP atom transfer radical polymerization
  • chemically modified starch such as acetylated starch together with Cu catalysts in toluol as solvent as described in Jukka et al, European Polymer Journal, 2007, 43, 1372-1382 and Liu et al, Carbohydrate Polymers, 2005, 62,159-163.
  • These polym- erization methods have the great disadvantage that the use of Cu catalyst as well as organic solvents such as Toluol is not acceptable for pharmaceutical compositions due to toxic effects.
  • the known Cu catalyst for ATPR reaction show only a low conversion rate of less than 50 % and have only a limited choice of possible monomers.
  • the Cu catalyst is difficult to eliminate from the copolymer and small amounts of re- maining Cu (II) give the polymers a blue or green color.
  • Another object of the invention is to provide a method of preparation of biodegradable copolymers suitable for pharmaceutical purpose with catalysts easy to remove, pharmaceutically acceptable solvents, which allows the use of a broad range of olefin monomers and shows a high conversion rate of monomers.
  • the present invention further concerns a method of preparing a copolymer comprising the steps of reacting starch as a backbone molecule with a linker to give a macro initiator and reacting the macro initiator with monomers comprising at least one olefin-group in the presence of a nickel(ll) catalyst via an ATRP reaction as well as the use of the copolymers for the preparation of nanoparticles.
  • Starch used according to the present invention is a non-chemically modified, especially non acetylated, starch such as native starch or physically modified starch and may be produced from rice, wheat, corn, tapioca, acorn, and potatoes with natural amylase content preferably in the range of 20-25 %, particularly waxy corn starch, a starch with about 100 % amylopectin.
  • non chemically modified, denaturized or hydrolyzed starch can be used to prepare the starch copolymers such as bleached starch, oxidized starch, enzyme-treated starch.
  • starch as used in the present invention means in addition to natural or modified starch-like polysaccharides such as amylose, amylopectin, glycogen dextrin, cyclodextrin, dextran, xanthan, inulin, chitin, chitosan and alginate pectin.
  • starch copolymers according to the invention are used for preparation of starch copolymers according to the invention: native or degraded, preferably hydrolyzed maize starch, potato starch or waxy maize starch.
  • starch from genetically modified organisms in particular plants can be used.
  • a starch from a genetically modified pea with an amylose content of about 60-80 % can be used for preparation of starch copolymers.
  • starch copolymer is prepared from starch selected from the group of native starch, enzymatic modified starch or mechanically modified starch.
  • the starch copolymers are prepared by the use of a maize starch polymer.
  • the starch polymer has an amylose content in the range of 10 to 25 % and a molecular weight in the range of 10 to 25 kDa.
  • the present invention relates to copolymers comprising starch as a backbone molecule, a covalently bound linker and a polymerized chain of monomers comprising at least one olefin group bound to the linker, wherein the degree of substitution of hy- droxy-groups of the backbone is in the range of 0.05 - 3, preferably 0.1 - 2, more preferably 0.15 -1.5, particularly 0.2 - 1 , and most preferred 0.3 - 0.5.
  • the copolymer according to the present invention is a graft polymer.
  • the starch used as the backbone molecule for the copolymer is a native starch as it is obtained from different starch producing plants such as rice, wheat, corn, tapioca or potatoes or the starch is a physically modified starch of said plants.
  • the present invention does not use a chemically modified starch such as acetylated starch because chemically modified starch derivatives are less soluble and less biodegradable in comparison to a native or physically modified starch.
  • the native or physically modified starch can be hydrolyzed to further reduce the molecular weight of the originally very long starch molecules with a molecular weight of above 1 Mio to increase water solubility as well as biodegradability in a human organism.
  • hydrolysis is done by at least one enzyme, particularly by an amylase enzyme and most preferably by a combination of two amylase enzymes such as alpha-amylase and iso-amylase together or one after the other.
  • This preferred combination of amylase enzymes reduces the hyper branched molecular structure and the high molecular weight of native starch and therefore increases the solubility of the copolymer.
  • the starch backbone in the copolymer is preferably a nearly linear macromolecular starch fragment similar to amylose.
  • the hydrolyzed native starch backbone has a molecular weight of from 800 to 500,000 Da, preferably 4,000 to 100,000 Da.
  • the hydrolyzed native starch backbone has a bimodal molecular weight distribution with a first maximum as from 800 to 1 ,000 Da, preferably 1 ,000-2,000 Da, and a second maximum as from 5,000-100,000 Da, preferably 10,000- 50,000 Da.
  • the molecular weight of the starch backbone is most critical and responsible for the solubility of the starch and the copolymer molecules.
  • the starch backbone is water soluble at a degree of at least 30 % w/w at 25 0 C.
  • the reduced molecular weight in relation to unhydrolyzed native or physically modified starch leads to the desired high biodegradability of the copolymer as well as to a higher water solubility of the starch and copolymer.
  • the linker is a carbohydrate di-halide, preferably a carbox- ylic acid di-halide, particularly of the general structure
  • R1 H or CH 3
  • R1 and/or R2 are aromatic, preferably phenyl, residues.
  • the monomer further comprises an amido- and/or an ester- group which is adjacent to the olefin group of the monomer to be polymerized to the polymer chain.
  • the monomer is an acrylate and/or acrylamide, preferably an alkyl-, fluoral- kyl-, hydroxyalkyl-, aminoalkyl- or N,N-dialkylaminoalkyl and/or -acrylamide, particularly the monomer is at least one monomer selected from the group consisting of me- thylacrylate, methacrylate, methylmethacrylat (MMA), Dimethylaminoethylmethacrylate (DMAEMA), hydroxyethylmethacrylate (HEMA), hydroxyethylacrylate (HEA), tertiar- butylacrylate (tBA), N-isopropylacrylamide (NIPAM) and methacrylamide, most preferably tertiar-butylacrylat is used as monomer to give the copolymer according to the present invention.
  • MMA methylacrylate
  • DMAEMA Dimethylaminoethylmethacrylate
  • HEMA hydroxyethylme
  • the monomer is styrene or a styrene derivative, preferably an alkyloxystyrene, particularly methoxystyrene.
  • the molecular weight of the copolymer according to the present invention is preferably 4,500-5,000,000 Da, preferably 5,000-1 ,000,000 Da, in case of a monomodal molecular weight distribution of the starch backbone molecules.
  • the copolymer has preferably a first maximum of from 2,000-800,000 Da and a preferred second maximum of from 14,000-15,000,000 Da.
  • the length of the polymer chain grafted on the starch backbone via the linker molecule is 10-150 monomers long, preferably 50-120, and particularly ca. 100 monomers.
  • This preferred length of the polymer chain gives the copolymer the desired bio- degradability in combination with the desired solubility.
  • the copolymers are obtained by an atom transfer radical polymerization (ATRP) reaction.
  • Another aspect of the present invention is a method of preparing a copolymer comprising the steps of reacting a starch backbone molecule with a linker to give a macro initiator and afterwards reacting the macro initiator together with monomers comprising at least one olefin-group in the presence of a nickel(ll) catalyst via an ATRP reaction.
  • the ATRP reaction has the advantage in contrast to other polymerization reactions, that this so-called living polymerization allows a controlled length of monomers to be polymerized.
  • the applied nickel(ll) catalyst has the advantage of higher monomer conversion rates and a higher choice of monomers to be polymerized in contrast to the generally used Cu catalysts, which in addition are difficult to remove from the reaction solution.
  • the starch used for the method according to the present invention is preferably a na- tive or a physically modified starch and is not chemically modified, especially not acety- lated.
  • the starch is hydrolyzed which can be done by enzyme hydrolysis before reacting the starch with the linker molecules. Any enzyme capable of hydrolyzing starch can be applied, but best results were obtained with at least one amylase enzyme, particularly with a combination of the two enzymes iso-amylase and alpha-amylase which both have a different specificity and cut down the starch molecule to starch fragments of almost linearity, as well as the desired length and water solubility.
  • the molecular weight of the hydrolyzed starch is preferably from 800 to 500,000 Da, preferably 4,000-100,000 Da, in case of a monomodal molecular weight distribution. This molecular weight range gives a sufficient water solubility of the starch fragments during the ATRP reaction as well as the desired biodegradability of the resulting copolymer because enzymes present in living organisms are able to further hydrolyze the starch fragment backbone and copolymer molecules to allow an expulsion via blood and kidney out of the body.
  • the hydrolyzed starch has a bimodal molecular weight distribution with a first maximum of from 800 to 1 ,000 Da, preferably 1 ,000 to 2,000 Da, and a second molecular weight maximum of from 5,000 to 100,000 Da, preferably 10,000 to 50,000 Da.
  • the water solubility of the starch according to the present invention is preferably at least 30 % w/w at 25 0 C. This water solubility allows the use of polar solvents for the above reaction and unfavorable solvents such as toluol, which is currently used with acetylated starch and Cu catalysts in ATRP reactions, are no longer needed.
  • the linker is a carbohydrate di-halide, preferably a carboxylic acid di-halide, particularly of the general structure
  • R1 H or CH 3
  • X 1 and X 2 are independently F, Cl, Br or I and preferably Br or Cl.
  • R1 and/or R2 are aromatic, preferably phenyl, residues.
  • the monomer to be polymerized can further comprise an amido- and/or an ester-group which is adjacent to the olefin-group.
  • the monomer is an acrylate and/or acryl amide, preferably an alkyl-, fluoral- kyl-, hydroxyalkyl-, aminoalkyl-, or N,N-dialkylaminoalkyl-acrylate and/or -acrylamide.
  • the monomer can be at least one selected from the group consisting of methylacrylate, methacrylate, methylmethacrylate (MMA), Dimethylaminoethylmethacrylate (DMAEMA), hydroxyethylmethacrylate (HEMA), hydroxyethylacrylate (HEA), tertiar- butylacrylate (tBA), N-isopropylacrylamide (NIPAM) and methacrylamide.
  • the monomer according to the present invention is tertiar-butylacrylate (tBA).
  • the monomer is styrene or a styrene derivative. More preferred the monomer is alkyloxystyrene and particularly methoxystyrene.
  • the nickel catalyst used for ATRP polymerization is one selected from the group consisting of Ni Br 2 (tris-phenylphosphine) 2 , Ni Br 2 (tris(4-methoxyphenyl)phosphine)2, Ni Br 2 (tris(ortho-methoxyphenyl)phosphine)2, Ni Br 2 (tris(meta-methoxyphenyl)phosphine)2, Ni Br 2 (tris(ortho-tolyl)phosphine)2, Ni Br 2 (tris(meta-tolyl)phosphine) 2 and Ni Br 2 (tris(para-tolyl)phosphine) 2 .
  • the nickel catalyst is Ni Br 2 (tris(4-methoxyphenyl)phosphine) 2 .
  • Ni-catalyst is formed in situ by a ligand exchange of phosphine ligands.
  • the original phosphine ligands tris-phenylphosphine are exchanged for other phosphine ligands with more electrons to allow high polar monomer to be polymerized by ATRP reaction with a high monomer conversion rate of above 60 %.
  • the phosphine ligands with more electrons are preferably ligands selected from the group consisting of tris(4-methoxyphenyl)phosphine, tris(ortho-methoxyphenyl)phosphine, tris(meta-methoxyphenyl)phosphine, tris(ortho-tolyl)phosphine, tris(meta-tolyl)phosphine and tris(para-tolyl)phosphine.
  • the most preferred electron rich phosphine ligand is tris(4-methoxyphenyl)phosphine. This ligand gives an excellent conversion rate and allows a broad range of polar monomers like DMAEMA, MMA or tBA.
  • reaction is carried out at 25-80 0 C, preferably at 60-80 0 C.
  • a method according to the present invention can be carried out in a polar organic solvent, preferably in one solvent selected from the group consisting of DMF, DMAc, NMP, DMSO, THF, AcCN, Acetone, ethyl acetate and mixtures thereof or mixtures with a non-polar solvent in a ratio of 5 - 10:1 , wherein this non-polar solvent is selected from the group consisting of hexane, toluol, cyclohexane and benzene.
  • a mixture of non-polar and polar solvent comprises DMSO as polar solvent.
  • a method according to the present invention is preferably carried out under water free conditions.
  • the method can be carried out under non-oxygen conditions, preferably the reaction is carried out under nitrogen or argon.
  • the invention further relates to a copolymer obtained by a method comprising the steps of reacting starch as a backbone molecule with a linker to give a macro initiator and reacting the macro initiator with monomers comprising at least one olefin group in presence of a nickel(ll) catalyst via an ATRP reaction as described above.
  • the copolymer obtained by the above described method is a graft polymer.
  • nanoparticles from special starch copolymers can be prepared by a simple oil/water emulsion method using organic solvents with reduced hazard properties.
  • These starch copolymer nanoparticle systems exhibit good hydrody- namic and colloidal stability and show good properties of encapsulation and release for different drug compounds. Further the inventive nanoparticle systems show a remarkable release profile without burst effect.
  • the present invention also relates to nanoparticles comprising at least one starch co- polymer comprising starch as a backbone molecule, a covalently bound linker and a polymerized chain of monomers comprising at least one olefin group bound to the linker, wherein the degree of substitution of hydroxyl-groups of the backbone is in the range of 0.05 to 3.
  • the nanoparticles according to the invention can be characterized by different methods.
  • the prepared nanoparticles exhibit a good stability.
  • the stability of the nanoparticle dispersions can be studied as a function of salinity of the medium using sodium chloride and calcium chloride. Particle aggregation was analyzed e.g. by photon correlation spectroscopy (PCS).
  • PCS photon correlation spectroscopy
  • the ccc critical coagulation concentration in mM
  • esc critical stabilization concentration in mM
  • the inventive nanoparticles show no cyto toxicity in in-vitro tests.
  • the nanoparticles show further good encapsulating proper- ties and controlled drug release providing a good permeation of the encapsulated drug through human heat separated epidermis.
  • the nanoparticles preferably have an average hydrodynamic particle size diameter in the range of 20 to 500 nm, preferably in the range of 50 to 500 nm, more preferred in the range of 100 to 200 nm, most preferred in the range of 150 to 200 nm.
  • the average particle size diameter means the hydrodynamic mean particle size measured in deion- ized water or ultra pure water and analyzed by photon correlation spectroscopy (PCS) or Atomic Force Microscopy (AFM).
  • the nanoparticles in general show a spherical shape with a narrow size distribution.
  • the polydispersity index (PDI) normally is in the preferred range of 0.05 to 0.2 for unloaded starch nanoparticles and in the range of 0.5 to 6.0 for loaded starch nanoparticles.
  • the polydispersity is the width of the size distribution, hence the homogeneity of the distribution in solution/suspension.
  • the nanoparticles also contain at least one active ingredient, e.g. a pharmaceutical active ingredient (drug) or a cosmetic or food ingredient.
  • active ingredient e.g. a pharmaceutical active ingredient (drug) or a cosmetic or food ingredient.
  • Such nanoparticles are also mentioned as “loaded nanoparticles” in the following.
  • the active ingredient may be adsorbed onto or into the nanoparticle matrix.
  • the active ingredient may also be dissolved, encapsulated or enwrapped in the nanoparticle matrix.
  • the present invention relates to "loaded” or “unloaded” nanoparticle as described above in form of a dispersion respectively of a emulsion (e.g. as a intermediate) or in dried form, particularly in freeze-dried form (e.g. powder or film).
  • the preferred contained active ingredients are selected from pharmaceutical active ingredients such as drug compounds or compounds or additives known in the state of art for the use of preparing cosmetic or food compositions.
  • starch nanoparticles contain a pharmaceutical active ingredient select from hormones (e.g. testosterone), alkaloide (e.g. caffeine, nicotine), non-steroidal anti-inflammatory drugs
  • chemotherapeutic agents analgetica, antihistamines, anti- rheumatic agents, or antibiotics.
  • the chemotherapeutic agents are selected from the group of anti metabolites such as Methotrexat, Cladribin, Fludarabin, Mercaptopurin, Tioguanin, Pentostatin, Fluorouracil, Cytarabin, Gemcitabin, cytostatic alkylating drugs such as Cyclophoshamid, Trofosfamid, Ifosfamid, Melpha- lan, Chlorambucil, Thiotepa, Busulfan, Treosulfan, Carmustin, Lomustin, Nimustin, Cis- platin, Carboplatin, Oxaliplatin, Procarbazin, dacarbazin, Temozolomid, topoisomerase inhibitors such as Camptothecin, Topotecan, Irinotecan, SN-38,
  • the present invention relates to a method of preparing nanoparticles containing at least one starch copolymer comprising starch as a backbone molecule, a covalently bound linker and a polymerized chain of monomers comprising at least one olefin group bound to the linker, wherein the degree of substitution of hydroxy-groups of the backbone is in the range of 0.05 to 3 comprising the step of preparing an emulsion which contains an aqueous phase comprising an emulsifier and an organic phase comprising an organic solvent and at least one starch copolymer.
  • the present invention relates to a method of preparing nanoparticles containing at least one starch copolymer comprising starch as a backbone molecule, a covalently bound linker and a polymerized chain of monomers comprising at least one olefin group bound to the linker, wherein the degree of substitution of hydroxy-groups of the backbone is in the range of 0.05 to 3 and loaded with at least one active ingredient, comprising the step of preparing an emulsion which contains an aqueous phase com- prising an emulsifier and an organic phase comprising an organic solvent, a starch copolymer and at least one active ingredient.
  • the organic phase comprises at least one starch copolymer as described above or a mixture of starch copolymers as described above in an amount from 0.05 to 5 %, preferably in an amount of 0.05 to 3 %, preferably in an amount of 0.05 to 2 %, more preferably in an amount from 0.1 to 2 %, weight/volume (w/v) of the organic phase.
  • the organic solvent can be selected from pharmaceutical acceptable organic solvents or mixtures of pharmaceutical acceptable organic solvents as long as this solvent forms a two phase system with water and the used starch copolymer exhibits a adequate solubility in the solvent.
  • the pharmaceutically acceptable organic solvent may be one or several selected from the group consisting of: alcohols, like n-propanol, iso propanol n- butanol, t-butanol. propylene glycol, benzyl alcohol, glycerol, polypropylene glycol, polyethylene glycol, poly- oxyethylene glycerol; in particular alkyl alcohols with at least six carbon atoms (e.g.
  • esters like alkyl acetate (e.g. ethyl acetate, butyl acetate), esters from fatty acids with alkyl alcohols (e.g. ethyl oleate, isopropyl palmitate, isopropyl myristate); ethers, like tetrahydrofuran, t-butyl methyl ether, di-isopropyl ether; ketones, like acetone or methyl ethyl ketone; natural or synthetic oils, like castor oil or castor oil derivatives; acetonitrile and N-methylpyrrolidone.
  • alkyl acetate e.g. ethyl acetate, butyl acetate
  • esters from fatty acids with alkyl alcohols e.g. ethyl oleate, isopropyl palmitate, isopropyl myristate
  • ethers like tetrahydrofuran, t-but
  • organic solvents with toxic allergenic or other hazardous properties should be avoided, e.g. dichloromethane, methylenchloride and dimethylsulfoxide.
  • the said emulsion is an oil/water emulsion compris- ing alkyl acetate or acetone as organic solvent, preferably ethyl acetate.
  • said emulsion comprises ethyl acetate or acetone as organic solvent and a starch copolymer in an amount from 0.05 to 5 %, preferably in an amount of 0.1 to 3 %, more preferably in an amount from 0.1 to 2 %, weight/volume (w/v) of the organic phase.
  • the aqueous phase of said emulsion comprises at least one emulsifier , in particular a pharmaceutical acceptable emulsifier.
  • the emulsifier may be selected from the group consisting of anionic, non ionic, cationic and ampholytic emulsifiers which are known to a person skilled in art and which are pharmaceutically acceptable.
  • emulsifiers polyvinyl alcohol, alkyl sulfates, alkyl sulfonates, polyethylenglycole, alkyl poly(ethylene oxide), fatty alcohols (e.g. cetyl alcohol, oleyl alcohol), polysorbate (Tween®), cocamine monoethanol amine, cocamine dietha- nol amine, cocamidopropyl betaine, dodecyl betaine and alkyl polyglucoside.
  • fatty alcohols e.g. cetyl alcohol, oleyl alcohol
  • Tween® polysorbate
  • cocamine monoethanol amine cocamine dietha- nol amine
  • cocamidopropyl betaine dodecyl betaine and alkyl polyglucoside.
  • the emulsifier is a polyvinyl alcohol.
  • Said emulsifier is added to the aqueous phase in an amount from 0 to 5 % w/v (weight/volume) more preferably in an amount from 0.01 to 2 % w/v of the aqueous phase.
  • the method of preparing starch nanoparticles can comprise the following steps:
  • the preparing of the nanoparticles includes the preparation of an oil/water (o/w) emulsion wherein the organic phase comprises at least one starch copolymer.
  • the prepara- tion of the oil/water emulsion particularly includes the mixing of the phases for example with a high shear mixer.
  • the emulsion can be sonicated.
  • the emulsion is mixed for 5 to 30 minutes, more preferably for 5 to 20 minutes.
  • the formation of the nanoparticles may be carried out by an oil/water emulsion diffusion method removing the organic solvent resulting in an aqueous phase of starch nanoparticles (dispersion). Removing the main part of the organic solvent can be carried out for example by evaporation or by dialysis through a membrane against deion- ized water. In a preferred embodiment of the invention the organic solvent is evapo- rated under reduced pressure.
  • an emulsifier in the aqueous phase e.g. polyvinyl alcohol (PVA)
  • PVA polyvinyl alcohol
  • the increase of PVA concentration in the external aqueous phase can result in both, a size reduction and a lower polydisper- sity index (PDI).
  • the nanoparticles Preparing the nanoparticles with encapsulation of a active ingredient
  • the active ingredient is dissolved or dispensed in the organic solvent.
  • the preparation method of drug loaded nanoparticles may carried out similarly to the preparation of the unloaded nanoparticles as aforementioned.
  • the active ingredient and the starch copolymer are added to the organic solvent in a ratio in the range of 0.5:1 to 1 :0.5. More preferred the ratio of active ingredient and starch copolymer represents about 1 :1.
  • the loaded or unloaded nanoparticles can be used for the preparation of pharmaceutical, cosmetic or food compositions in form of an aqueous dispersion respectively emulsion as obtained by the inventive preparation method or in dried, particularly in freeze- dried, form.
  • the contained active ingredient may be adsorbed onto or into the nanopar- tide matrix.
  • the active ingredient may further be dissolved, encapsulated or enwrapped in the nanoparticle matrix. Preparing of the composition can be carried out by methods known in the art.
  • the present invention provides a composition comprising at least one active ingredient contained in nanoparticles comprising at least one starch copolymer, preferably prepared by ATRP reaction and Ni(II) catalyst.
  • the said composition may be a pharmaceutical, cosmetic or food composition.
  • the active ingredient may be adsorbed onto or into the nanoparticle matrix.
  • the active ingredient may also be dissolved, encapsulated or enwrapped in the nanoparticle matrix, preferably the active ingredient is encapsulated in the nanoparticles.
  • Said active ingredient may be selected e.g. from known pharmaceutical active ingredi- ents such as drug compounds or compounds or additives known in the state of art for the use of preparing cosmetic or food compositions. Most preferred said active ingredient is a pharmaceutical ingredient.
  • the active ingredient can be selected from hydrophobic pharmaceutically active ingredients.
  • the active ingredients exhibits a log P value in the range of -1 to 6, more preferred in a range of -0.1 to 5.
  • the log P value means the logarithm of the oc- tanol-water partition coefficient and expresses the hydrophobicity of a compound.
  • the invention is directed to compositions comprising at least one active ingredient contained in nanoparticles wherein said active ingredient is selected from hormones (e.g. testosterone), alkaloide (e.g. caffeine, nicotine) and non-steroidal anti-inflammatory drugs (e.g. flufenamic acid), chemotherapeutic agents, analgetica, antihistamines, anti rheumatic agents, or antibiotics.
  • hormones e.g. testosterone
  • alkaloide e.g. caffeine, nicotine
  • non-steroidal anti-inflammatory drugs e.g. flufenamic acid
  • chemotherapeutic agents e.g. analgetica
  • antihistamines e.g., antihistamines, anti rheumatic agents, or antibiotics.
  • the active agent is a hydrophobic pharmaceutical active ingredient which has the general ability to penetrate the skin (molecular weight is less than 600 Dalton).
  • the said active ingredient is a pharmaceutical ingredient which can be applied in a transdermal dosage form.
  • the invention is directed to a composition comprising at least one active ingredient contained in nanoparticles wherein said active ingredient is selected from the chemotherapeutic agents mentioned above.
  • the inventive pharmaceutical composition can be applied by different routes of administration, e.g. by oral administration, by injection or infusion, all form of enteral administrations, transdermal, transmucosal or by inhalation, preferably by transdermal ad- ministration or by oral administration.
  • routes of administration e.g. by oral administration, by injection or infusion, all form of enteral administrations, transdermal, transmucosal or by inhalation, preferably by transdermal ad- ministration or by oral administration.
  • the active ingredient can be selected from cosmetic ingredients such as additives known in the state of art for hair or skin care products, e.g. pigments, colorants, essential oils, skin soothing or healing agents.
  • the active ingredient can be selected from food ingredients.
  • Food ingredients means any food additives known in the state of art to improve food taste, texture, nutritional value or sensor appeal, e.g. vitamins, oils, coloring agents, nutrification agents.
  • the composition can also comprise other components like additives for the preparation of pharmaceutical, cosmetic or food compositions known in the state of the art.
  • the composition contains cryoprotectant agents like sucrose or trehalose to improve the stability in particular the long-term stability, of the nanoparticles suspension or the stability of nanoparticles during and after a freeze-drying process.
  • cryoprotectant agent is added in an amount in the range of 0.01 to 2 % w/v (weight/volume), more preferably in the range of 0.2 to 1 % w/v, of the composition.
  • the present invention is directed to the use of nanoparticles as described above for the preparation of pharmaceutical, cosmetic or food compositions.
  • the nanoparticles were used in a pharmaceutical drug delivery system (DDS) or a transdermal drug delivery system (TDDS).
  • DDS pharmaceutical drug delivery system
  • TDDS transdermal drug delivery system
  • Drug delivery means a method or process of administering a pharmaceutical active ingredient to achieve a therapeutical effect in humans or animals.
  • Drug delivery systems modify e.g. drug release profile (e.g. sustained or controlled release), adsorption, distribution or elimination; drug delivery include further the targeted delivery in which the drug is only active in the target area of the body (e.g. a special organ or cancerous tissues).
  • the nanoparticles are used for preparation of a con- trolled release delivery or target delivery system for a selected active ingredient, e. g in cancer treatment.
  • the described nanoparticles are used for preparation of a transdermal drug delivery system (TDDS).
  • TDDS transdermal drug delivery system
  • the invention relates to a drug delivery system for hydro- phobic drugs, more preferably to a transdermal drug delivery system (TDDS).
  • TDDS transdermal drug delivery system
  • Nanoparticles were formulated from starch copolymers. A physicochemical characterization of the nanoparticles was carried out (size, size distribution, zeta potential, shape).
  • Enzymatic degradation of starch by ⁇ -amylase Distillated water (1200 g), Ca acetate (Aldrich, 312 mg) und ⁇ -Amylase (BASF EC 3.2.1.1 ; 52.8 mg with 120 KNU/g activities) was put into in a 2000 ml 4 necked flask. 300 g wax corn starch (BASF) was feed into the flask under stirring condition. The pH and reaction temperature were adjusted to 6.5 and 90 0 C respectively. After 4 hours enzyme reaction at 90 0 C the pH was set to 3.5 within 1 minute in order to stop the reaction and deactivate the enzymes.
  • Example 2 Enzymatic degradation of starch by ⁇ -amylase and iso-amylase
  • the degree of substitution is 0.34 per glucose unit (0.11 per hydroxyl group)
  • Example 4 Produce a copolymer(C-1 ) by ATRP from Macro initiator (M1 )
  • NiBr 2 (PPh 3 ) 2 (Aldrich, 97 %, 20 mM)
  • 4-oxisomethyltriohenylphosohine (98 %, Aldrich, 40 mM)
  • 10 ml DMSO (Aldrich) were put into the 3-neck N 2 filled glass flask. These solutions were stirred for 10 hours stirred at 25 0 C.
  • Methylacrylate (BASF, 400OmM) and macro initiator M-1 (20 mM) was dropped into the reaction flask and the flask was filled once again with N 2 in 30 minutes, before heating the flask at 80 0 C.
  • Monomer conversion is 13 % (2h reaction time), 50 % (5h reaction time) and 70 % (24h reaction time). 2-Dichlorobenzene was used as an Internal Standard .
  • the MMA monomer unit in the side chain was 140.
  • the number average molecular weight of obtained copolymer C-1 is 51970. Molecular weight was measured by GPC (Eluent: THF column: PSS SDV 5um, 8.0 * 300mm 1 ,000A Calibration Polystyrol-Standards by polymer Laboratories)
  • Nanoparticles with the starch polymers C-1 were formulated by emulsion diffusion method.
  • the starch derivative (polymer C-1 ) was dissolved in ethyl acetate (0,5 mg/ml), and 1 ml of this organic solution was poured on 4ml of an aqueous phase with 1 % (weight per volume w/v) of polyvinyl alcohol (PVA) as emulsifier.
  • PVA polyvinyl alcohol
  • This biphasic system was emulsified with a high speed homogenizer (Ultra Turrax® Ika®, Brasil Ltda, Taquara, Brasil) at 14000 rpm for 15 minutes.
  • PCS photon correlation spectroscopy
  • Nano-ZS Nano-ZS
  • the size and size distribution analysis was performed with undiluted nanoparticles dispersion in MiIIiQ water, as prepared according to example 5. All measurements were done in triplicates. The following measurement parameters were used: 25 0 C constant temperature, viscosity and refractive index of water as dispersion medium, PLGA as Polymer (with a refractive index of 1.5) and measurement with backscattering angle of 173°. The measurements were performed in the "general purpose (normal resolution)" Mode.
  • the determined mean hydrodynamic diameter (intensity-weighted) of starch nanoparti- cles was 180.6 nm (3.36 nm Standard deviation).
  • Polydispersity index was 0.154 ⁇ 0.004.
  • the particle size distribution is monomodal with a reasonable range of size distribution in comparison to other polymer dispersions produced by Emulsion-diffusion technique.
  • Zeta potential was determined in the undiluted particle dispersion in MiIIiQ water. Measurement duration was set on automatic modus (min. 10 runs, max. 100 runs) continuing measurement until the measurement value gets stable. Smoluchowski was set as autocorrelation function (F-value 1.5). Measurements were performed in the "Auto mode".
  • the determined zeta potential was 2.95 mV ( ⁇ 0.61 mV SD).
  • AFM images were obtained using an Atomic Force Microscopy Nanoscope IV Bio- scopeTM (Veeco Instruments, Santa Barbara, CA, USA). Imaging was done using Taping mode and a silicon cantilever with a spring constant of approximately 40 N/m and a resonance frequency of about 170 kHz. The scan speed applied was 0.2 Hz.
  • AFM pictures of nanoparticles preparations demonstrated that the particles have spherical shape, smooth surface and a good size distribution varying from -70 to 200 nm ( Figure 1 ).

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Abstract

La présente invention concerne un copolymère d'amidon comprenant de l'amidon comme molécule squelette, un lieur lié de manière covalente et une chaîne polymérisée de monomères comprenant au moins un groupe oléfinique lié au lieur, le degré de substitution des groupes hydroxy du squelette étant dans la plage allant de 0,05 à 3, un procédé de préparation, des nanoparticules comprenant les copolymères, leur préparation et leur utilisation pour la préparation des systèmes d'administration de médicaments.
PCT/EP2010/050308 2009-01-21 2010-01-13 Copolymères d'amidon et nanoparticules de ceux-ci destinés à des systèmes d'administration de médicaments WO2010084060A1 (fr)

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WO2012094080A1 (fr) * 2010-12-03 2012-07-12 Pleotint, L.L.C. Agent anti-jaunissement pour systèmes thermochromiques
WO2013127004A1 (fr) 2012-03-02 2013-09-06 The Governing Council Of The University Of Toronto Nanoparticules polymères utiles en théranostique
WO2014052311A1 (fr) * 2012-09-25 2014-04-03 The Board Of Trustees Of The University Of Arkansas Sonolyse faisant appel à des nanoparticules biodégradables
US9023321B2 (en) 2008-03-21 2015-05-05 The Board Of Trustees Of The University Of Arkansas Methods for producing microbubbles
US9580846B2 (en) 2011-06-03 2017-02-28 Ecosynthetix Ltd. Curable sheared or extruded, cross linked starch nanoparticle latex binder for use with mineral, natural organic or synthetic fibre products and non-woven mats
CN108950571A (zh) * 2018-07-02 2018-12-07 安徽坤和电气有限公司 一种电线电缆桥架表面处理工艺
US20210000710A1 (en) * 2018-03-28 2021-01-07 Greenmark Biomedical Inc. Phosphate crosslinked starch nanoparticle and dental treatments
CN113698557A (zh) * 2021-09-09 2021-11-26 安徽工程大学 一种接枝支链由亲水嵌段、疏水嵌段构成的淀粉接枝双嵌段聚合物浆料的制备方法和应用
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US9023321B2 (en) 2008-03-21 2015-05-05 The Board Of Trustees Of The University Of Arkansas Methods for producing microbubbles
WO2012094080A1 (fr) * 2010-12-03 2012-07-12 Pleotint, L.L.C. Agent anti-jaunissement pour systèmes thermochromiques
US8623243B2 (en) 2010-12-03 2014-01-07 Pleotint, Llc Anti-yellowing for thermochromic systems
US9580846B2 (en) 2011-06-03 2017-02-28 Ecosynthetix Ltd. Curable sheared or extruded, cross linked starch nanoparticle latex binder for use with mineral, natural organic or synthetic fibre products and non-woven mats
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WO2014052311A1 (fr) * 2012-09-25 2014-04-03 The Board Of Trustees Of The University Of Arkansas Sonolyse faisant appel à des nanoparticules biodégradables
US11453798B2 (en) 2013-12-05 2022-09-27 Ecosynthetix Ltd. Formaldehyde free binder and multi-component nanoparticle
US20210000710A1 (en) * 2018-03-28 2021-01-07 Greenmark Biomedical Inc. Phosphate crosslinked starch nanoparticle and dental treatments
US11666515B2 (en) * 2018-03-28 2023-06-06 Greenmark Biomedical Inc. Phosphate crosslinked starch nanoparticle and dental treatments
CN108950571A (zh) * 2018-07-02 2018-12-07 安徽坤和电气有限公司 一种电线电缆桥架表面处理工艺
CN113698557A (zh) * 2021-09-09 2021-11-26 安徽工程大学 一种接枝支链由亲水嵌段、疏水嵌段构成的淀粉接枝双嵌段聚合物浆料的制备方法和应用
CN113698557B (zh) * 2021-09-09 2023-05-12 安徽工程大学 一种接枝支链由亲水嵌段、疏水嵌段构成的淀粉接枝双嵌段聚合物浆料的制备方法和应用

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