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WO2010084088A2 - Nanoparticules d'amidon destinées à des systèmes d'administration de médicaments - Google Patents

Nanoparticules d'amidon destinées à des systèmes d'administration de médicaments Download PDF

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Publication number
WO2010084088A2
WO2010084088A2 PCT/EP2010/050488 EP2010050488W WO2010084088A2 WO 2010084088 A2 WO2010084088 A2 WO 2010084088A2 EP 2010050488 W EP2010050488 W EP 2010050488W WO 2010084088 A2 WO2010084088 A2 WO 2010084088A2
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Prior art keywords
starch
nanoparticles
starch derivative
hydrophobic
active ingredient
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WO2010084088A3 (fr
Inventor
Manuel J. Santander Ortega
Thomas Stauner
Brigitta Loretz
Gerhard Wenz
Ulrich Schaefer
Claus-Michael Lehr
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BASF SE
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BASF SE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B31/00—Preparation of derivatives of starch
    • C08B31/08—Ethers
    • C08B31/10—Alkyl or cycloalkyl ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/04—Starch derivatives, e.g. crosslinked derivatives
    • C08L3/06—Esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/04—Starch derivatives, e.g. crosslinked derivatives
    • C08L3/08—Ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • the present invention relates to novel polymeric nanoparticles comprising hydrophobic and/or amphiphilic starch derivatives, 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 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 methods of preparation and raw material employed in the development of nanoparticle drug delivery systems described in the state of art.
  • the nanoparticle matrix usually is composed or comprises 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 polyethylenglycole, polyester, polyacrylate, poly(meth)acrylate, polymers based on vinyl aromatic monomers, poly(meth)acryl acid, and/or 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 other polysaccharides as raw material for preparation of 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 at least one pharmaceutically acceptable synthetic polymer, preferable 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, polysaccharide, or polynucleotide.
  • the amphiphilic polymer is a polysaccharide or a modified polysaccharide such as starch, chitosan, or alginate. This document does not dis- close a nanoparticle system, wherein the outer shell consists of a hydrophobic starch derivative as main component.
  • the high amount of hydroxyl groups in the polysaccharide backbone allows the incorporation of different specific ligands to obtain polyfunctional colloidal systems. Due to its high availability, starch presents a good starting material to prepare and develop 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.
  • Amylopectin is a highly branched poly- mer, wherein the glucose chain of linear ⁇ (1-4) glycosidic linked units is branched with ⁇ (1-6) glycosidic linked chains. These branches occur roughly 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 the various problems is the grafting of hydrophobic side chains to the hydrophilic starch back- bone. Different polysaccharide nanoparticles of that type 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 dialysis.
  • One of the objects of the present invention is to provide a nanoparticles system comprising at least one starch derivative as main component for drug delivery systems and a method of preparing such systems.
  • the preparation of the nanoparticles should be technically simple (e.g. avoiding complex multi-step procedures) and without using toxic and/or harmful organic solvents.
  • the nanoparticles system should exhibit good stability and performance for encapsulation and release of different types of drugs.
  • 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 a drug compound through the skin, e.g. into the blood- stream.
  • An advantage of a transdermal drug delivery route over other types is that it provides a multitude of possibilities for a controlled release of the active pharmaceutical ingredient into the patient.
  • One disadvantage is the fact that the skin can be a very effective barrier for drug compounds. Nanoparticles can be used in several types of drug delivery systems.
  • Drug delivery systems mean in particular those technologies which modifies drug release profile, absorption, distribution and/or elimination of drugs e.g. of particularly hydrophobic, water-insoluble drugs.
  • Most common methods of delivery includes the preferred non- invasive peroral route via the gastro-intestinal 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, heterocyclic compounds such as nicotine, nitroglycerine and antidepressants.
  • Most of 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
  • the properties of transdermal systems are often studied by the use of a so-called Franz Diffusion Cell.
  • a Franz Diffusion Cell FdC
  • 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.
  • nanoparticles from hydrophobic starch derivatives such as propyl starch
  • these starch derivative nanoparticles systems exhibit good hydrodynamic and colloidal stability and show good properties for encapsulation and release for different drug compounds. Further, the nanoparticle systems show a remarkable release profile without undesired burst effect.
  • the present invention in particular relates to nanoparticles comprising at least one starch derivate wherein the starch derivative is a hydrophobic starch derivative with an average degree of substitution of the hydroxyl-groups (D 5 ) in the range of 0.5 to 2.75, preferably in the range of 1 to 2.0. In a particular embodiment, this average degree of substitution is in the range of 1 to 1.8.
  • the average degrees of substitution (D s ) of the prepared starch derivatives can e.g. be determined by NMR spectroscopy (nuclear magnetic resonance spectroscopy) after degradation of the starch product to glucose units in mixtures of deuterated water and deuterated sulphuric acid.
  • the nanoparticles comprise at least one hydrophobic starch derivative selected from the group consisting of starch derivatives with hydrocarbon side chains.
  • Hydrophobic starch derivatives in the meaning of the present invention are starch derivatives wherein at least a part of the hydroxyl groups of the starch molecule are substituted with hydrophobic groups.
  • the hydrophobic group (side chain) may for example be linked to the hydroxyl group of the starch chain via ether and/or ester bond.
  • the nanoparticles comprise a hydrophobic starch derivate wherein the hydrocarbon side chain is linked via an ester bond and/or an ether bond.
  • the hydro- phobic group is linked via an ether bond.
  • Said starch derivatives therefore, can be for example starch ester, such as acetyl starch, or starch ether, such as alkyl starch.
  • a hydrocarbon side chain is in particular an alkyl, haloalkyl, alkenyl or aryl hydrocarbon group, wherein the terms alkyl, haloalkyl, alkenyl and aryl have the following meanings:
  • alkyl group saturated, linear hydrocarbon group having 1 to 50 (CrC 50 ), preferably 1- 20 (Ci-C 20 ) more preferably 1-6 (CrC 6 ) carbon atoms, or saturated branched or cyclic hydrocarbon group having 3 to 50 (C 3 -C 50 ), preferably 3-20 (C 3 -C 20 ), more preferably 3- 6 (C 3 -C 6 ) carbon atoms.
  • Preferred alkyl groups are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, t-butyl, pentyl, hexyl and isomers thereof.
  • haloalkyl group saturated, linear, branched or cyclic alkyl group as defined above substituted with at least one fluorine, chlorine, bromine or iodine radicals wherein the halo- gen may be in any position.
  • Preferred haloalkyl groups are chloromethyl, bromomethyl, dichlorometyl, trichlorometyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoro- methyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl and isomers thereof.
  • alkenyl group unsaturated, linear hydrocarbon group having 2 to 50 (C 2 -C 50 ), prefera- bly 2 to 20 (C 2 -C 20 ), more preferably 3 to 6 (C 3 -C 6 ) carbon atoms or unsaturated branched or cyclic hydrocarbon group having 3 to 50 (C 3 -C 50 ), preferably 3 to 20 (C 3 -
  • alkenyl groups are ethenyl, allyl, 1-propenyl, 1- methylethenyl, 1-butenyl, 1-methyl-1-propenyl, 1-pentenyl, 1-methyl-1-butenyl, 1 ,2- dimethyl-1-propenyl, 1-hexenyl, 1-methyl-1-pentenyl, 1 ,1-dimethyl-2-butenyl, cyclopen- tenyl, cyclohexenyl and isomers thereof.
  • aryl group unsaturated hydrocarbon group having 6 to 50 (C 6 -C 50 ), preferably 6 to 20 (C 6 -C 20 ), more preferably 6 to 10 (C 6 -Ci 0 ) carbon atoms, wherein at least one aromatic radical, like phenyl, may be in any position.
  • aromatic groups are phenyl, benzyl, methylphenyl, ethylphenyl and isomers thereof.
  • the starch derivative is selected from CrC 6 alkyl, CrC 6 haloalkyl, C 3 -C 6 alkenyl or C ⁇ -Cio aryl starch derivatives.
  • the present invention relates to nanoparticles comprising at least one hydrophobic starch derivative, wherein the hydrophobic starch derivative is selected from the group consisting of C-i-C ⁇ alkyl, allyl and benzyl starch derivatives.
  • the invention relates to nanoparticles comprising at least one starch derivative wherein the said starch derivate is selected from the group consisting of C3-C6 alkyl.
  • the starch derivative is a propyl, butyl or hexyl starch derivative.
  • a particular embodiment of the invention relates to a propyl starch derivative.
  • the hydrophobic starch derivate can be a mixed derivate.
  • a mixed derivate exhibits at least two different types of side chains along one starch chain selected from the above mentioned groups.
  • the hydrophobic group (side chain) in a mixed starch derivative may be linked e.g. via an ester bond and/or an ester bond.
  • the starch derivative is a mixed derivative comprising at least one of the following side chains: propyl, butyl, hexyl.
  • the said nanoparticles comprise at least one hydrophobic starch derivative selected from the group consisting of C3-C6 alkyl starch derivatives and having an average degree of substitution (D 5 ) in the range of 0.5 to 2.75, preferably in the range of 1 to 2.0, most preferred in the range of 1 to 1.8.
  • the said starch derivatives are propyl starch derivates with an average degree of substitution (D s ) in the range of 0.5 to 2.75, preferably in the range of 1 to 2.0, most preferred in the range of 1 to 1.8.
  • the starch derivative can be cross linked e.g. with sodium triphosphate.
  • the cross linking is however not considered obligatory for the stability of the starch nanoparticles.
  • the starch used as a basis for the derivation can e.g. be a native starch, such as starch produced from rice, wheat, corn, and potatoes with natural amylase content in the range of 20-25 %.
  • modified, denaturized or hydrolyzed starch can be used to prepare the hydrophobic starch derivatives like alkaline-modified starch, bleached starch, oxidized starch, enzyme-treated starch, waxy maize starch (about 100 % amy- lopectin).
  • starch as used in the present invention means in addition to natural or modified starch other polysaccharides such as starch-like polysaccharides, such as amylose, amylopectin, glycogen, dextrin, cyclodextrin, dextran, xanthan, inulin, chitin, chitosan and alginate, pectin.
  • starch derivative is prepared from starch selected from the group of native starch; enzymatic modified starch; acid modified starch or mechanically modified starch.
  • starch can advantageously be used in the preparation of hydrophobic starch derivatives, particularly in the preparation of alkyl starch derivatives: natural maize starch, natural potato starch, natural wheat starch, degraded maize starch, waxy maize starch, partially acid degraded potato starch (e.g. Avebe starch), enzymatically degraded maize starch, enzymatically degraded waxy maize starch (degraded with alpha-amylase).
  • starch from a genetically modified organism in particular plants, can be used.
  • a starch from a genetically modified pea with an amylose content of about 60-80% is used to preparation of starch derivative.
  • the hydrophobic starch derivatives are prepared by the use of a maize starch polymer.
  • the starch polymer has a amylose content in the range of 10 to 25 % and a molecular weight in the range of 10 to 25 kDa. Further preferred is the use of enzymatic ally degraded starch.
  • the nanoparticles according to the invention can be characterized by different methods. For example stability of the nanoparticle dispersions can be studied as a function of salinity of the medium, using sodium chloride and calcium chloride. Particle aggrega- tion was analyzed e.g. by photon correlation spectroscopy (PCS). The ccc (critical coagulation concentration in mM) and esc (critical stabilization concentration in mM) were determined. Further, the swelling behavior of the nanoparticles can be studied. The nanoparticles prepared according to this invention exhibit a good stability.
  • PCS photon correlation spectroscopy
  • the nanoparticles show no cytotoxicity in various in-vitro tests.
  • the nanoparticles show good encapsulating properties and controlled drug release, providing a good permeation of the encapsulated drug through human heat separated epidermis.
  • the nanoparticles prepared often 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. In one embodiment the range is from150 to 200 nm.
  • the average particle size diameter means the hydrodynamic mean particle size, measured in deionized water or ultra pure water and analyzed by Photon Correla- tion Spectroscopy (PCS) or Atomic Force Microscopy (AFM).
  • PCS Photon Correla- tion Spectroscopy
  • AFM Atomic Force Microscopy
  • the nanoparticles in general show a spherical shape with a narrow size distribution.
  • the polydispersity index (PDI) is preferably in the 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 (de- scribed in the following).
  • the polydispersity is the width of the size distribution, hence the homogeneity of the distribution in solution/suspension.
  • the above mentioned 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” and “unloaded” nanoparticles as described above in particular in particular 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. a powder or film).
  • the preferred active ingredients which can be contained in the nanoparticles described above are selected from pharmaceutical active ingredients such as drug compounds or active compounds ("Wirkstoffe") or additives known in the state of art for the use of preparing cosmetic or food compositions.
  • the above described starch nanoparticles contain a pharmaceutically active ingredient select from hormones (e.g. testosterone), alkaloids (e.g. caffeine, nicotine), non-steroidal anti-inflammatory drugs (e.g. flufenamic acid), and chemotherapeutic agents, analgetica, antihistamines, anti- rheumatic agents, and/or antibiotics.
  • hormones e.g. testosterone
  • alkaloids e.g. caffeine, nicotine
  • non-steroidal anti-inflammatory drugs e.g. flufenamic acid
  • chemotherapeutic agents analgetica, antihistamines, anti- rheumatic agents, and/or antibiotics.
  • the chemotherapeutic agents are selected from the group of
  • antimetabolites 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, Eto- posid, Teniposid,
  • mitotic inhibitors such as Vinblastin, Vincristin, Vindesin, Vinorelbin, Paclitaxel, Do- cetaxel,
  • cytostatic antibiotics such as Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, Mi- toxantron, Amsacrin, Bleomycin, Mitomycin,
  • hormones and hormones antagonists applied in cancer treatment such as Buserelin, Goserelin, Leuprorelin, Triptorelin, Fosfestrol, Estramustin, Tamoxifen, Toremifen, Aminoglutethimid, Anastrozol, Letrozol, Exemestan, Formestan, Testolacton, Me- droxyprogesteronacetat, Megestrolactat, Flutamid, Bicalutamid,
  • cytostatic drugs such as Asperiginase, Pergaspargase, Hydroxycarbamide, Milte- fosin, Tretinoin,
  • antibodies and cytokine such as Rituximab, Trastuzumab, zytokine such as Aldesleukin, Interferon ⁇ 2a, Interferon ⁇ 2b, Interferon ⁇ , Tasonermin.
  • the present invention relates to a method of preparing nanoparticles containing at least one starch derivative, preferably with an average degree of substitution of the hydroxyl-groups (D s ) in the range of 0.5 to 2.75, comprising the step of preparing an emulsion which contains an aqueous phase, preferably comprising a emulsifier, and an organic phase, comprising an organic solvent, and at least one hydrophobic starch derivative.
  • the present invention relates to a method of preparing nanoparticles loaded with at least one active ingredient.
  • the present invention in particular relates to a method of preparing nanoparticles containing at least one starch derivative with an average degree of substitution of the hydroxyl-groups (D s ) in the range of 0.5 to 2.75, comprising the step of preparing an emulsion which contains an aqueous phase comprising a emulsifier and an organic phase comprising an organic solvent, at least one hydrophobic starch derivative and at least one active ingredient.
  • the said organic phase comprises at least one hydrophobic starch derivative as described above or a mixture of starch derivatives 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 derivative exhibits a adequate solubility in the solvent.
  • the pharmaceutically acceptable organic solvent may be e.g. one or several selected from the group consisting of:
  • alcohols like n-propanol, isopropanol n- butanol, t-butanol.
  • 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
  • organic solvents with toxic allergenic or other hazard properties should preferably be avoided, e.g. dichloromethane, methylenchlorid and dimethylsulfoxid.
  • the said emulsion is an oil/water emulsion comprising alkyl acetate as organic solvent, preferably ethyl acetate.
  • the organic phase comprises a hydrophobic starch derivative selected from the group consisting of C3-C6 alkyl starch derivatives 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.
  • a hydrophobic starch derivative selected from the group consisting of C3-C6 alkyl starch derivatives 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 aqueous phase of the said emulsion comprises at least one emulsifier, in particular a pharmaceutical acceptable emulsifier.
  • the emulsifier may be selected from the group containing of anionic, nonionic, cationic or ampholytic emulsifiers which are known to a person skilled in art and which are pharmaceutical acceptable.
  • anionic, nonionic, cationic or ampholytic emulsifiers which are known to a person skilled in art and which are pharmaceutical acceptable.
  • the following emulsifiers are mentioned: polyvinylalcohol, alkyl sulfates, alkyl sulfonates, polyethylenglycole, alkyl poly(ethylene oxide), fatty alcohols (e.g.
  • the emulsifier in the aqueous phase is selected from the group polyvinyl alcohol.
  • the said emulsifier often 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 described starch derivatives may be formed by techniques generally known to those skilled in art. These techniques include but not limited to esterification and etheri- fication of the starch.
  • the described starch nanoparticles can be prepared by an improved synthesis method comprising the disintegration of the used starch in a solvent by heating up to 30 to 90 0 C before derivatiza- tion reaction. This improved synthesis method results in higher degree of substitution, even for longer alkyl chains. This is described in more detail below.
  • the preparation of the nanoparticles includes the preparation of an oil/water (o/w) emulsion wherein the organic phase comprises at least one starch derivatives.
  • the preparation of the oil/water emulsion particularly includes the mixing of the phases for example with a high shear mixer.
  • the emulsion can be sonicated, but sonication is not always essential.
  • the emulsion is mixed for a period of time of 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 wherein removing of the organic solvent results an aqueous phase of the 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 deionized water.
  • the organic solvent is evaporated under reduced pressure.
  • PVA polyvinyl alcohol
  • the active ingredient is dissolved or dispensed in the organic solvent.
  • the preparation method of drug loaded nanoparticles may in principle be carried out similarly to the preparation of the unloaded nanoparticles as mentioned before.
  • the active ingredient and the starch derivative are added (separately or together) 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 derivative is about 1 :1. This ratio depends on the nature of the active ingredient and of the starch derivative.
  • the loaded or unloaded nanoparticles can be used for the preparation of pharmaceutical, cosmetic or food compositions in form of an aqueous dispersion respectively emul- sion 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 nanoparticle 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 generally known in the art.
  • the present invention provides a composition comprising at least one active ingredient contained in nanoparticles as described above and wherein the nanoparticles comprise at least one hydrophobic starch derivative with an average degree of substitution of the hydroxyl-groups (D 5 ) in the range of 0.5 to 2.75.
  • 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 nanoparti- cles.
  • Said active ingredient may be selected e.g. from known pharmaceutical active ingredients such as drug compounds or active compounds ("Wirkstoffe") 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 e.g. be selected from hydrophobic pharmaceutically active ingredients.
  • the active ingredient 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 octanol-water partition coefficient and expresses the hydrophobicity of a compound.
  • a further preferred embodiment of the invention is directed to a composition
  • a composition comprising at least one active ingredient contained in nanoparticles wherein said active ingredient is select from the group consisting of hormones (e.g. testosterone), alkaloide (e.g. caf- feine, nicotine), non-steroidal anti-inflammatory drugs (e.g. flufenamic acid), chemo- therapeutic agents, analgetica, antihistamines, antirheumatic agents, and/or antibiotics.
  • hormones e.g. testosterone
  • alkaloide e.g. caf- feine, nicotine
  • non-steroidal anti-inflammatory drugs e.g. flufenamic acid
  • chemo- therapeutic agents e.g. analgetica
  • antihistamines e.g. antirheumatic agents
  • antibiotics e.g. antibiotics
  • the active agent is a hydrophobic pharmaceutical active ingredient which has the general ability to penetrate the skin (often with a 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 pharmaceutical composition can be applied by different routes of administration, e.g. by oral administration, by injection or infusion, all forms of enteral administrations, transdermal, transmucosal or by inhalation, preferably by transdermal administration or by oral administration.
  • routes of administration e.g. by oral administration, by injection or infusion, all forms of enteral administrations, transdermal, transmucosal or by inhalation, preferably by transdermal administration or by oral administration.
  • the active ingredient can be selected from cosmetic ingredients such as compounds known in the state of art for hair and/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 comprises 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.
  • the 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 de- scribed above for the preparation of pharmaceutical, cosmetic and/or food compositions.
  • the nanoparticles are used in a pharmaceutical drug delivery system (DDS) or a transdermal drug delivery system (TDDS).
  • 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).
  • the invention relates to a drug delivery system for hydrophobic drugs, more preferably to a transdermal drug delivery system (TDDS).
  • the present invention provides an improved method for preparing starch derivatives, in particular CrC ⁇ alkyl starch derivatives.
  • the synthesis of alkylated starch derivatives is described in the literature, but the described alkylated derivatives only show a low degree of substitution.
  • the literature e.g. describes for the ethyla- tion a complete alkylation, but for longer alkyl chains only DS values up to 20% (DS 0.6).
  • Only few derivatives with a higher degree of substitution like the permethylation and the perbenzylation, are known in the state of the art.
  • Hydroxyethyl starch described in the state of art has a substitution of about 27% of the hydroxyl groups of the anhy- droglucose units.
  • Hydroxypropylated starches show a DS of up to 0.14 or 0.18
  • O- amino-propylstarch derivatives show only a low DS-valve of up to 0.3.
  • alkyl starch derivatives with a higher degree of substitution as described in the state of the art can be obtained.
  • the degree of substitution preferably reaches from 1.45 to 2.75 and was shown as depending on the kind of starch.
  • the starches used for derivation can e.g. be a native starch produced from rice, wheat, corn, peas and potatoes with natural amylase content in the range of 20-25 %.
  • modified, denaturized, hydrolyzed, chemically or enzymatic degraded starch can be used to prepare the hydrophobic starch derivatives (e.g.
  • alkaline-modified starch bleached starch, oxidized starch, enzyme- treated starch, and waxy maize starch with about 100 % amylopectin).
  • partially acid degraded potato starch e.g. Avebe starch
  • enzymatically degraded starches e.g. waxy maize starch, degraded with alpha-amylase
  • starch from genetically modified organism in particular plants can be used.
  • a starch from a genetically modified pea with an amylose content of about 60-80% is used to preparation of starch derivative.
  • the degree of substitution further depends on the amount of Brome derivative and the temperature.
  • the present invention further includes a method for preparing starch derivatives comprising the disintegration of the used starch types by heating up to 30 to 90 0 C, preferably by heating up to 60 to 80 0 C, more preferably by heating up to 65 to 75 0 C, before the synthesis of the different starch derivatives. This opens the possibility of getting higher degrees of substitution of the starch-derivatives which are able to form nanoparticles by routes described detailed above.
  • One embodiment of the invention is directed to a method for preparing starch deriva- tives, in particular CrC 6 alkyl starch derivatives, comprising the use of a starch selected from the group of enzymatically degraded starches (e.g. waxy maize starch, degraded with alpha-amylase), partially acid degraded starches and genetically modified starch (e.g. pea starch) and further comprising the disintegration of the used starch types by heating up to 65 to 75 0 C, before the synthesis of the different starch deriva- tives.
  • a starch selected from the group of enzymatically degraded starches (e.g. waxy maize starch, degraded with alpha-amylase), partially acid degraded starches and genetically modified starch (e.g. pea starch) and further comprising the disintegration of the used starch types by heating up to 65 to 75 0 C, before the synthesis of the different starch deriva- tives
  • Nanoparticles were formulated from two propyl-starch derivatives with average degree of substitution (D s ) 1.07 respectively 1.45 (PS-1 and PS-1.45).
  • D s average degree of substitution
  • PS-1 and PS-1.45 propyl-starch derivatives with average degree of substitution 1.07 respectively 1.45
  • Example 1a Materials, chemicals and solvents
  • Table 1 shows the materials, chemicals and solvents used.
  • Table 2 shows the apparatus, analytics and methods used.
  • the starch (maize starch, amylase content of 25%, starch I) was dried overnight at 70 0 C.
  • the starch (5.00 g, 30.8 mmol) was stirred in 200 ml of dry DMSO in a dried flask under nitrogen (N 2 ) and heated at 70 0 C for 1 hour. After cooling to 25°C NaH (8.88 g, 185 mmol) and bromo propane (50.5 ml, 555 mmol) were added alternating to the solu- tion in small portions.
  • D s average degree of substitution
  • the starch (pea starch, amylose content 70%, starch II) was dried overnight at 70 0 C.
  • the DMSO Micros Organics, dried over molecular sieve
  • the base NaH was a 55-65% dispersion in oil).
  • the starch (5.00 g, 30.8 mmol) was stirred in 200 ml of dry DMSO in a dried flask under N 2 and heated at 70°C for 1 hour. After cooling to 25°C NaH (8.88 g, 185 mmol) and bromo propane (64.6 ml, 710 mmol) were added to the solution alternately in small portions. The solution changed its colour to yellow while a precipitation and a vigorous evolution of gas was observed.
  • the average degree of substitution (D s ) was determined as described in example 2a. A Yield of 3,2g of a lightly yellow solid with a degree of substitution (DS) of 2.2 was obtained.
  • the starch (pea-starch, amylose content 70%, starch II) was dried overnight at 70 0 C.
  • the DMSO Micros Organics, dried over molecular sieve
  • the base NaH was a 55-65% dispersion in oil).
  • the starch (5.00 g, 30.8 mmol) was stirred in 200 ml of dry DMSO in a dried flask under N 2 and heated at 70 0 C for 1 hour. After cool- ing to 25°C NaH (8.88 g, 185 mmol) and bromo butane (83.2 ml, 771 mmol) were added to the solution alternately in small portions.
  • the average degree of substitution (D s ) was determined as described in example 2a. A Yield of 1.6g of a lightly yellow solid with a degree of substitution (DS) of 2.1 was obtained.
  • the starch (pea-starch, amylose content 70%, starch II) was dried overnight at 70 0 C.
  • the DMSO (Acros Organics, dried over molecular sieve) is used as received.
  • the base NaH was a 55-65% dispersion in oil).
  • the starch (5.00 g, 30.8 mmol) was stirred in 200 ml of dry DMSO in a dried flask under N 2 and heated at 70 0 C for 1 hour. After cooling to 25°C NaH (8.88 g, 185 mmol) and bromo hexane (100.2 ml, 771 mmol) were added to the solution alternately in small portions. The solution changed its colour to yellow while a precipitation and a vigorous evolution of gas was observed. After com- plete addition the reaction was stirred for 3 days at 25°C.
  • the insoluble product was filtered off and suspended in water. After stirring for 30 min the heterogeneous mixture was neutralised with phosphoric acid and stirred for another 30 min. The water was decanted and the yellow pasty solid was washed with water and then dissolved in ethyl acetate. This solution was filtered over Celite filter CeI and then ultrafiltrated over a Koch-membrane (SeIRoOM P F-U20-S, exclusion limit 2OkDa) with ethyl acetate. The residual solution was concentrated in vacuo.
  • the average degree of substitution (D s ) was determined as described in example 2a. A Yield of 1.2 g of a lightly yellow solid with a degree of substitution (DS) of 2.3 was ob- tained.
  • Nanoparticles with the starch polymers PS-1 and PS-1.45 were formulated by oil/water emulsion diffusion method.
  • the starch derivative (polymer PS-1 alternatively polymer PS-1.45) was dissolved in ethyl acetate (1 mg/ml), and 1 ml of this organic solution was poured on 4ml of an aque- ous phase with different percentages (weight per volume w/v) of polyvinyl alcohol (PVA) (0, 0.1 , 0.5 and 1 ).
  • PVA polyvinyl alcohol
  • This biphasic system was emulsified with a high spead ho- mogenizer (Ultra Turrax ® Ika ® , Brasil Ltda, Taquara, Brasil) at 14000 rpm during 15 minutes.
  • MiIIiQ water was added up to 10 ml to force the complete diffusion of the organic solvent to the aqueous phase. Finally, the organic solvent was evaporated under reduced pressure at 35 0 C (Rotavapor B ⁇ chi ® , Labortechnik AG, Flawil, Switzerland). After nanoparticles preparation, MiIiQ water was added to obtain a formulation with a final volume of 10 ml.
  • Size and zeta-potential of the nanoparticles were analyzed by photon correlation spectroscopy (PCS) using a Nano-ZS (Malvern Instruments, Malvern, UK).
  • PCS photon correlation spectroscopy
  • Nano-ZS Nano-ZS
  • the size distribution of starch nanoparticles is influenced by the amount of PVA included in the preparation. Unmodified starch polymer does not form nanoparticles at all. Starch derivative form particles without PVA but results in a broad multi-modal size distribution. A mono-modal size distribution can be achieved with PVA concentrations >0.5 % in the aqueous phase. At the optimum concentration of 1% PVA the size distribution is narrowest and particle size about 150-180 nm mean size, with a PDI of 0.08 to 0.12.
  • Table 3 summarizes the hydrodynamic mean particle size diameter and the polydisper- sity index (PDI) of these PS-1 and PS-1.45 nanoparticles.
  • AFM images were obtained using an Atomic Force Microscopy Nanoscope IV BioscopeTM (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 pic- tures of nanoparticles preparations demonstrated that the particles have spherical shape, smooth surface and a narrow size distribution. The encapsulation of model drugs (FFA, caffeine, testosterone) and the lyophilisation of PS1.45 particles have no remarkable effects on the particle shape, size and size distribution.
  • FFA model drugs
  • PS1.45 particles have no remarkable effects on the particle shape, size and size distribution.
  • the stability of the o/w emulsions of ethyl acetate and water including the starch deriva- tives and optionally a emulsifier, which were used in preparing the starch derivatives nanoparticles was determined by the turbiscan technique.
  • the turbis- can technique is a method to determine the emulsion stability and to observe the coalescence between the organic phase droplets.
  • the stability of the ethyl acetate/water emulsion was analyzed by Photon correlation spectroscopy (PCS) using a Turbiscan Classic MA 2000 (Formulaction, L'Union, France). The stability of this emulsion was determined for three different organic phases, pure ethyl acetate, polymer PS-1 dissolved in ethyl acetate and polymer PS 1.45 dissolved in ethyl acetate. Moreover, a emulsion with 1 % (w/v) PVA in the aqueous phase was also tested.
  • Samples of 5 ml prepared as described in example 3 were placed in a cylindrical glass cell, which was inserted in turbiscan device.
  • Two synchronous optical sensors receive respectively light transmitted (T) through the sample (180 ° from the incident light), and light backscattered (BS) by the sample (45 ° from the incident light).
  • the detection head scanned the entire height of the sample, acquiring T and BS data each 40 ⁇ m at different time interval up to at least 10 h.
  • the study on emulsion stability was performed by measurement of the variation of transmission as a function of time in emulsions with various compositions of aqueous and organic phase. This enables the calculation of migration of organic droplets in the aqueous phase.
  • the study on emulsion stability was performed by measurement of variation of backscattered light. This enables the estimation of coalescence between organic phase droplets.
  • the stability ratio also called Fuch's factor (W) is a criterion broadly used to study the stability of colloidal systems. It can be obtained by the following expression
  • the extent of swelling of both nanoparticles was determined by osmotic effect as a function of ionic strength using NaCI, where the salt concentration in the bulk solution of the suspension was varied from 0.01 to 5 mM NaCI.
  • the extent of swelling was determined from the change in the hydrodynamic diameter using PCS (photon correlation spectroscopy).
  • the extent of particle de-swelling is expressed as the de-swelling ratio ( ⁇ ), which is: wherein do is the fully swollen hydrodynamic diameter and d is the measured hydro- dynamic diameter at a given ionic strength.
  • the swelling ratio ⁇ was calculated from 10-20 minutes after mixing, when the nanoparticles size was constant.
  • PS- 1 and PS-1.45 nanoparticles exhibited a very similar dependence of its size with the salt concentration.
  • Example 8 Stability of stored nanoparticles suspension at 4 0 C and 25 0 C
  • both nanoparticles systems PS-1 and PS-1.45, were formulated as described in example 3, one sample of these systems was stored at 4 0 C and 25 0 C and their size was measured by Photon Correlation Spectroscopy (PCS) at regular time period up to 25 days.
  • PCS Photon Correlation Spectroscopy
  • Table 3 summarized the hydrodynamic mean particle size and polydispersity index (PDI) of both colloidal systems incubated at room temperature for 25 days.
  • PS-1.45 nanoparticles showed a negligible change in size or PDI within the period of 25 days.
  • Nanoparticles stored at 4 0 C showed no change in size or PDI within the period of 25 days.
  • PS-1 and PS-1.45 nanoparticles prepared as described in example 3, were lyophilized by using a Freeze-drier Alpha 2-4 LSC (Christ, Osterode, Germany) and sucrose or trehalose as cryoprotectant agent. Different volumes from a solution of Sucrose or Trehalose of 10% (w/v) were poured onto different aliquots of nanoparticles in order to obtain a cryoprotectant range between 0-1 % weight per volume (w/v). Previously to the lyophilization step, the different samples were frozen at -8O 0 C for 2h. Hydrodynamic mean size of these aliquots was measured before and after the lyophilization step.
  • cryoprotectant agents sucrose is a more potent cryoprotectant than trehalose. 0.1% sucrose or 0.5% trehalose are sufficient for a good cryopreservation.
  • PS 1.45 Nanoparticles the mean size of the particles does not change much even by lyophilisation without cryoprotectant. However, addition of 0.5% sugar (sucrose or trehalose) leads to a lower polydispersity after re- suspension.
  • Caco-2 cell line clone C2BBe1 (ATCC No CRL-2102) between passage no 64 and 70 was used as test system.
  • Subculture was done once a week at a subcultering ratio of 1 :10 using trypsin-EDTA (No 25300, Gibco).
  • LDH assay is a test detecting the leakage of cell membrane and is useful in the investigation of nanoparticle toxicity since the plasma membrane is the main place of contact between particles and cells.
  • Cytotoxicity detection Kit (LDH) from Roche (Mannheim, Germany) was used to assess the cell membrane damage induced by exposure to starch nanoparticles. 5x10 4 Caco-2 cells were seeded into 24-well plates (Greiner, Frickenhausen, Germany). After 6 days propagation, at the state of a confluent monolayer the toxicity assay was performed. Cells were washed once with PBS (phosphate buffered saline) and incubated with the test samples. Samples were prepared by dilution of aqueous suspension of starch particles with cell culture medium at ratios 1 :3, 1 :6, 1 :12 and 1 :24 resulting in concentrations of 0.0042 to 0.033mg/ml starch nanoparticles.
  • PBS phosphate buffered saline
  • MTT assay monitors the mitochondrial metabolism of cells as an indicator of their viability.
  • Thiazolyl Blue Tetrazolium Bromide (M5655, Sigma Aldrich) was dissolved in PBS (phosphate buffered saline) pH 7.4 to yield a final concentration of 5 mg/ml for the stock solution. Cells were seeded, maintained until reaching confluence and exposed to particle suspension as reported for LDH assay in example 1 1.
  • Cytotoxicity was calculated as described in example 11. The results show that propyl starch particles up to a concentration of 0.033 mg/ml are not cytotoxic in the Caco-2 test model. The same holds true for longer time incubation.
  • Example 13 Preparation and testing of drug loaded nanoparticles, encapsulation of Flufenamic Acid, Testosterone and Caffeine in starch derivatives nanoparticles
  • FFA Flufenamic Acid
  • Flufenamic acid (FFA) and testosterone have a hydrophobic character. FFA is higher hydrophobic than testosterone.
  • Caffeine is hydrophilic.
  • the preparation method of drug loaded PS-1 and PS-1.45 nanoparticles was not modified with respect to unloaded nanoparticles. The specific molecule and PS-1 or PS-1.45 polymer were dissolved in the organic phase (1 :1 ratio), following the same procedure described in example 3. The characterization of these nanoparticles was performed as described previously for the unloaded nanoparticles (examples 6 to 12).
  • Encapsulation efficiency was calculated using a Franz diffusion cell and can be defined as:
  • F D is the amount of free drug present in the receptor compartment at time close to zero and T D is the total amount of drug dissolved in the organic phase.
  • T D is the total amount of drug dissolved in the organic phase. The exact amount of each drug was calculated by HPLC.
  • FdC Franz-diffusion Cells
  • the medium consisted in phosphate buffer pH 7 (2mM) with addition of 2% (v/v) Igepal ® CA-630 and 0.4% (v/v) ethanol.
  • donor and receptor compartment were separated by a cellulose membrane with a pore size of 12-14 kDa. (Medicell Int. Ltd, London, UK.).
  • FdCs were incubated at 32° C for a period of time of 72 hours. Samples of 0.4 ml were removed from the receptor compartment at regular time intervals up to 72h and replaced with an equal volume of fresh buffer. The con- centration of free drug from the receptor was analyzed by HPLC.
  • FdC Permeation studies of the three encapsulated drugs in PS- 1 or PS-1.45 nanoparticles were carried out using FdC.
  • a heat separated epidermis (HSE) disk was mounted on a cellulose membrane disk. Donor and receptor compartment were separated by these disks. All experimental conditions were the same that in the case of example 14, except in the case of the testosterone.
  • the receptor compartment was filled only with phosphate buffer pH7 (2 mM), due to that the interaction of the epidermis with Igepal ® CA-630 can generate epidermis degradation products that interfere in the quantification of the testosterone.
  • FdCs were incubated at 32 0 C for a period of time of 30 hours. Samples of 0.4 ml were removed from the receptor at regular time intervals up to 3Oh and replaced with an equal volume of fresh buffer. The concentration of free drug from the receptor was analyzed by HPLC.
  • P app is defined as the drug transport speed trough the membrane, and can be used to know the potential of a colloidal system as TDDS.
  • the drug permeation can be described by diffusion and Fick's first law. P app was calculated from
  • J ss is the flux at steady state. J ss correspond to the slope of the linear part of the diagram of the permeated amount of drug per area as a function of the time.
  • the drug content of each sample was determined by HPLC: Chromeleon TM version 6.5 SP2, build 968; P580 pump; ASI-100 automated sample injector; STH 585 column oven; UVD 170S detector (Dionex Softro GmbH, Germering, Germany); column LiChrospher 100 RP-18, 5 ⁇ m, 125 * 4 mm (Merck, Darmstadt, Germany). The used methods for each drug have been previously validated.

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Abstract

La présente invention concerne des nanoparticules polymères comprenant des dérivés hydrophobes et/ou amphiphiles de l'amidon, leur préparation et leur utilisation pour la préparation de systèmes d'administration de médicaments. Les nanoparticules préférées comprennent au moins un dérivé d'amidon, le dérivé d'amidon étant un dérivé hydrophobe d'amidon ayant un degré de substitution moyen des groupes hydroxyles (Ds) dans la plage allant de 0,5 à 2,75.
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US10285943B2 (en) 2010-12-02 2019-05-14 Greenmark Biomedical Inc. Aptamer bioconjugate drug delivery device
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
US9616696B2 (en) 2013-10-23 2017-04-11 Ecosynthetix Inc. Coating for paper adapted for inkjet printing
US11453798B2 (en) 2013-12-05 2022-09-27 Ecosynthetix Ltd. Formaldehyde free binder and multi-component nanoparticle
WO2016054522A1 (fr) 2014-10-03 2016-04-07 Ntercept, Llc Compositions et procédés pour inhiber l'activité biologique de biomolécules solubles
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WO2017070578A1 (fr) 2015-10-21 2017-04-27 The Regents Of The University Of Michigan Détection et traitement de caries et de microcavités avec des nanoparticules
EP4088744A1 (fr) 2015-10-21 2022-11-16 The Regents Of The University Of Michigan Détection et traitement de caries et de microcavités avec des nanoparticules
US12023388B2 (en) 2015-10-21 2024-07-02 The Regents Of The University Of Michigan Detection and treatment of caries and microcavities with nanoparticles
WO2017176762A1 (fr) 2016-04-06 2017-10-12 Nanotics, Llc Particules comprenant des sous-particules ou des échafaudages d'acide nucléique
US10993910B2 (en) 2016-12-07 2021-05-04 Seoul National University R&Db Foundation Biopatch, bioheater, biosensor and bioelectronic patch device
WO2018105779A1 (fr) * 2016-12-07 2018-06-14 서울대학교산학협력단 Bio-timbre, bio-chauffage, biocapteur et dispositif de timbre bioélectronique
US11666515B2 (en) 2018-03-28 2023-06-06 Greenmark Biomedical Inc. Phosphate crosslinked starch nanoparticle and dental treatments
US12508212B2 (en) 2018-03-28 2025-12-30 Greenmark Biomedical Inc. Phosphate crosslinked starch nanoparticle and dental treatments

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