WO2010142660A2 - Système d'administration de médicaments - Google Patents

Système d'administration de médicaments Download PDF

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Publication number
WO2010142660A2
WO2010142660A2 PCT/EP2010/057965 EP2010057965W WO2010142660A2 WO 2010142660 A2 WO2010142660 A2 WO 2010142660A2 EP 2010057965 W EP2010057965 W EP 2010057965W WO 2010142660 A2 WO2010142660 A2 WO 2010142660A2
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sirna
water
microparticles
oil
cationic lipid
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PCT/EP2010/057965
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WO2010142660A3 (fr
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Michael Keller
Geoffrey Gogniat
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Novartis Ag
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Publication of WO2010142660A3 publication Critical patent/WO2010142660A3/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2320/00—Applications; Uses
    • C12N2320/30—Special therapeutic applications
    • C12N2320/32—Special delivery means, e.g. tissue-specific

Definitions

  • the present invention relates generally to the fields of molecular biology, medicine, oncology and gene silencing.
  • the present invention relates to pharmaceutically active formulations comprising microparticles of short interfering RNA (siRNA), a highly hydrophobic biodegradable polymer such as poly-lactide-co-glycolic acid (PLGA), and a cationic lipid, as well as a process for making and delivering the formulations to the lung.
  • siRNA short interfering RNA
  • PLGA poly-lactide-co-glycolic acid
  • siRNAs Short interfering RNAs
  • RNAi RNA interference
  • Delivery of siRNA in vivo is known to be difficult due to poor intracellular uptake and susceptibility to degradation following uptake.
  • nano and micro-sized carriers such as cationic liposomes, polymers and lipids have been used.
  • the presently available nano and micro-sized carriers comprising siRNAs suffer from a number of drawbacks.
  • many of the techniques available for preparing siRNA compositions result in siRNA bound only to the outside of the microparticles.
  • known processes for preparing microparticles with siRNA involve first preparing the microparticles followed by attaching the siRNA to the microparticles in a number of steps. Additionally, procedures available for producing microparticles comprising siRNA do not quantitatively encapsulate siRNA into microparticles of defined size.
  • the present invention provides pharmaceutically active formulations in the form of microparticles of defined size comprising siRNA , a highly hydrophobic biodegradable polymer, and a cationic lipid which acts as an emulsifier and siRNA binding entity.
  • the siRNA and cationic lipid are encapsulated into the microparticle.
  • the cationic lipid is DC-Choi or DOTAP and the highly hydrophobic biodegradable polymer is poly-lactide-co-glycolic acid (PLGA).
  • PLGA poly-lactide-co-glycolic acid
  • the siRNA present in the microparticle is a double stranded oligonucleotide of about 19-23 bp in length and is preferably targeted to a pathogenic or endogenous sequence present in lung tissue.
  • the formulations of the present invention are useful for pulmonary delivery and are therefore useful in treating pulmonary diseases.
  • the formulation is in the form of an inhalable powder such as a powder spray.
  • the present invention also provides a method for producing the microparticle formulations of the present invention.
  • the method comprises the steps of: a) combining an siRNA/aqueous solution with a hydrophobic biodegradable polymer dissolved in an organic solvent solution and homogenizing to form a water/oil emulsion; b) combining the water/oil emulsion of step a) with a cationic lipid to obtain a water/oil/water double emulsion containing the microparticles; and c) removing the organic solution.
  • a secondary emulsifier may be added to the water/oil/water emulsion of step b).
  • the secondary emulsifier is polyvinyl alcohol (PVA).
  • spray drying is performed after the water/oil/water double emulsion is obtained.
  • a method of delivering a pharmaceutically active formulation to the lung comprises the steps of a) combining an siRNA/aqueous solution with a hydrophobic biodegradable polymer dissolved in an organic solvent solution and homogenizing to form a water/oil emulsion; b) combining the water/oil emulsion of step a) with a cationic lipid to obtain a water/oil/water double emulsion; c) spray drying the water/oil/water double emulsion of step b) to obtain the microspheres comprising encapsulated siRNA; and d) delivering the microspheres to the lung by use of a powder spray device.
  • Figure 1 schematically depicts the general procedure of the double emulsion process for generating the siRNA microparticles of the present invention.
  • Figure 2 illustrates the general process of forming the water/oil/water (w1/o/w2) double emulsion used in making the microparticles of the present invention.
  • Figure 3a is a photograph of a gel electrophoreses analysis of Novartis star ® PLGA based microspheres.
  • Figure 3b is a photograph of a gel electrophoreses analysis of Alkermes ® PLGA based microspheres.
  • Figure 4 graphically depicts results of an in vitro cellular toxicity assay (measured in relative units of WST- 1 levels) performed on human lung epithelial cells incubated with different quantities of siRNA microparticles prepared using lipoplexes from commercial suppliers (siRNA-Luc, Luc 8548) as well as those made according to the present invention.
  • Figures 5a and 5b are SEM photographs of Alkermes ® and Novartis star ® , respectively, PLGA/DC-chol microspheres prepared by the double emulsion procedure followed by filtration of the microspheres and lyophilisation.
  • Figure 6 is an SEM photograph of Novartis star ® PLGA/DC-chol microspheres prepared by the emulsion procedure followed by spray drying. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides pharmaceutically active formulations in the form of microparticles of defined size comprising siRNA, a highly hydrophobic biodegradable polymer, and a cationic lipid that functions as both an amphipathic emulsifier and siRNA binding entity. Methods for making the microparticles are also provided.
  • the term "pharmaceutical composition” means a mixture or solution containing at least one therapeutic compound or nucleic acid molecule to be administered to a mammal, e.g., a human.
  • therapeutic compound means any nucleic acid or amino acid sequence having a therapeutic or pharmacological effect, and which is suitable for administration to a mammal. This term can refer to short interfering ribonucleic acids (“siRNAs").
  • siRNA short interfering RNA
  • siRNA means double stranded ribonucleotide sequences of typically 15-50 base pairs and preferably 19-27 base pairs in length that are highly negatively charged and soluble predominantly in water.
  • siRNA may be composed of either two annealed ribonucleotide sequences or a single ribonucleotide sequence that forms a hairpin structure.
  • siRNA is responsible for RNA interference, the process of sequence-specific post-transcriptional gene silencing in animals and plants.
  • siRNAs are generated by ribonuclease III cleavage from longer double-stranded RNA (dsRNA) which are homologous to the silenced gene or by delivering synthetic RNAs to cells. Techniques for the design of such molecules for use in targeted inhibition of gene expression are well known to one of skill in the art.
  • dsRNA double-stranded RNA
  • compositions and methods of the present invention are an improvement over the prior art since the siRNA is incorporated within the microparticles rather than only bound to the outside.
  • a further advantage is that the siRNA microparticles may be formulated in as little as one step ( Figure 1 ).
  • the siRNA may be quantitatively encapsulated into a neutral biodegradable polymer resulting in microparticles of defined size.
  • microparticles of the present invention are especially useful for pulmonary delivery of siRNA and therefore useful for treating pulmonary diseases. Due to the methodology used to generate the pharmaceutical composition, the described processes are industrially scalable.
  • microparticle compositions comprising a highly hydrophilic siRNA, a highly hydrophobic biodegradable polymer, and a cationic lipid (also referred to herein as a cationic amphiphile).
  • the cationic lipid functions as both an amphipathic emulsifier and siRNA binding entity.
  • the siRNA is a highly negatively charged double stranded RNA oligonucleotide of approximately 19-23 bp in length and about 46 negative charges.
  • microparticles of tailored sizes may be used as microparticles in pharmaceutical compositions to mediate the down regulation (silencing) of a specific target gene defined by the choice of the siRNA sequence.
  • biodegradable hydrophobic polymers which may be used in the compositions and methods of the present invention, include, e.g., polylactides, polycarprolactone, polymers of lactide and glycolide, polymers of lactide and carprolactone, polymers of lactide and 1 ,4-dioxan-2-one, polyorthoesters, polyanhydrides, polyphosphazines, poly(amino acid)s and polycarbonates.
  • the hydrophobic polymer is poly-lactide-co-glycolic acid (PLGA) having an LG molar ratio of 50:50, MW 40,000-75000.
  • cationic lipids which function as emulsifiers and siRNA binding entities (also referred to herein as cationic amphiphiles) and which may be used in the present invention, include for example, cholesteryl-3(beta)N-dimethyl aminoethyl (DC- Chol), ⁇ /-[1-(2,3-dimyristyloxy)propyl- ⁇ /, N,N,N,-trimethyl-2-bis[(1-oxo-9- octadecenyl)oxy]-(Z,Z)-1 propanaminium methyl sulfate, 1 ,2-dioleoyl-3- trimethylammonium-propane (DOTAP), and N[1-(2,3-dioleyloxy) propyl]-N,N,N- trimethylammonium chloride (DOTMA), and dimethyldioctadecylammonium bromide (DDAB).
  • compositions of the present invention may additionally be used in the compositions of the present invention.
  • pharmaceutically acceptable excipients include lipid oxidation inhibitors (U.S. Pat. No. 5,605,703 and WO 9202208), stabilizing agents such as sterols, polyethyleneglycol (PEG) or tocopherol, antioxidants, such as ⁇ -tocopherol or its acetate salt; vitamin E; ⁇ -carotene; carotenoids, such as ⁇ -carotene, lycopene, lutein, zeaxanthine, and the like; and buffering agents such as citrate buffer, tris-buffer, phosphate buffer and the like; or acidifying agents, such as citric acid, maleic acid, oxalic acid, succinic acid, tartaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and the like.
  • stabilizing agents such as sterols, polyethyleneglycol (PEG) or tocopherol, antioxidants,
  • siRNAs are well known in the art.
  • at least one siRNA is targeted to a specific gene sequence of interest leading to a down-regulation of the protein encoded by this mRNA.
  • Any drugable or non-drugable gene of interest may be targeted by designing an siRNA sequence homologous to the mRNA of interest. With the entire human genome now sequenced, any portion thereof may serve as a target sequence in designing an siRNA for use in a pharmaceutical compositions of the present invention.
  • siRNA could be designed to target an oncogene such as BCI-2, resulting in downregulation and prevention of cancer cell proliferation. Sequences of many oncogenes are known and readily available.
  • EphA2 focal adhesion kinase (FAK), ⁇ 2 - adrenergic receptor ( ⁇ 2 AR), ESR1 , tumor suppressor protein pRB, MDR-1 , NKkappaB and Nek2.
  • siRNA for use in the present invention may be obtained from plasma DNA or the human genome.
  • siRNA may be generated by ribonuclease III cleavage from longer double-stranded RNA (dsRNA) which are homologous to the silenced gene or by delivering synthetic RNAs to cells.
  • the target gene sequence may be drugable or non-drugable.
  • siRNAs for use in the pharmaceutical compositions and methods of the present invention may also be derived from known anti-sense sequences.
  • the siRNA for use in the present invention are double stranded ribonucleotide sequences of typically 15 to 50 base pairs in length that are highly negatively charged and soluble predominantly in water.
  • the siRNA sequence of the present invention ranges from about 19 to about 27 base pairs in length and is highly homologous or 100% homologous to the target sequence.
  • the siRNA may be blunt ended or else have base pair overhangs.
  • the siRNA further may include a repeating amino acid sequence consisting of serine-aspartic acid-threonine and/or phosphorothioate backbone modifications.
  • RNA may serve as siRNA for use in a pharmaceutical compositions and methods of the present invention.
  • siRNA double stranded RNA
  • miRNA micro-RNA
  • shRNA short hairpin RNA
  • siRNAs examples include. e.g, those targeted to sequences involved in respiratory diseases, and can include both pathogen and endogenous sequences.
  • siRNAs targeted to viral pathogen sequences include but are not limited to respiratory syncytial virus (RSV) sequences, as well as PIV, SARS-SCV and influenza.
  • RSV respiratory syncytial virus
  • PIV respiratory syncytial virus
  • SARS-SCV SARS-SCV
  • influenza siRNAs targeted to sequences common to all flu genomes, including those of avian origin such as the H5N1 strain can be used in the compositions of the present invention.
  • siRNAs targeted to IKK2 IKK-beta
  • siRNAs targeted to pro-inflammatory cytokines such as TNF-alpha and IL-1beta may also be used in the microparticles of the present invention in order to provide in vivo silencing of target genes in the lung for the treatment of respiratory disease.
  • siRNAs directed to sequences involved in asthma, chronic obstructive pulmonary disorder (COPD), cystic fibrosis, and idiopathic pulmonary fibrosis (IPF) may be used.
  • siRNAs targeted to sequences involved in lung cancer such as sequences of the pituitary transforming gene (PTTG) may also be used as siRNAs in microparticle formulations of the present invention.
  • COPD chronic obstructive pulmonary disorder
  • IPF idiopathic pulmonary fibrosis
  • microparticle compositions comprising siRNA, a highly hydrophobic biodegradable polymer, and a cationic lipid.
  • highly hydrophilic siRNA for example, about 46 negative charges, is encapsulated into a highly hydrophobic polymer scaffold through assistance of a cationic lipid.
  • the cationic lipid functions as both an amphipathic emulsifier and siRNA binding entity and is itself incorporated into the microparticles. This process is illustrated in Figure 1.
  • microparticles comprising siRNA, a highly hydrophobic biodegradable polymer, and a cationic lipid are prepared by a double emulsion process.
  • the process comprises the steps of: a) combining an siRNA/aqueous solution with a hydrophobic biodegradable polymer dissolved in an organic solvent solution and homogenizing to form a water/oil emulsion; b) combining the water/oil emulsion of step a) with a cationic lipid to obtain a water/oil/water double emulsion containing the microparticles; and c) removing the organic solvent to obtain the microparticles.
  • the siRNA is dissolved in water or any appropriate aqueous buffer solution.
  • suitable aqueous buffers include any salt of acetic acid, including sodium acetate and potassium acetate, succinate buffer, phosphate buffer, citrate buffer, HEPES, PBS and any others known to the art.
  • the organic solvent used in the present invention is selected depending on the solubility of the siRNA and polymer in the solvent, the degree to which the solvent is miscible in water and the toxicity of the solvent.
  • DCM chloroform and dichloromethane
  • DMSO dimethylsulfoxide
  • DMA dimethylacetamide
  • dimethylformamide various alcohols such as ethanol, glycols, glycerin, propylene glycol, and various polyethylene glycols
  • the organic solvent may be removed by methods known in the art e.g. evaporation.
  • the microparticles are filtered and lyophilized to a white powder.
  • a secondary emulsifier is preferably added to the water/oil/water double emulsion of step b).
  • the secondary emulsifier does not incorporate into the microparticle.
  • secondary emulsifiers which may be used include, PEG such as PEG 20O00, pluronic F68 and polyvinyl alcohol (PVA).
  • PVA polyvinyl alcohol
  • PVA is used as the secondary emulsifier.
  • the water/oil/water emulsion is spray dried to obtain microspheres.
  • the microsphere size can be tightly controlled by the flow rate, the concentration of the three component mix, and the inlet/outlet temperature. This process results in increased homogeneity of the microspheres.
  • spray drying allows the morphology, size, density and flowability of the powder to be tailored and adapted for direct passive targeting within the lung tissue.
  • the present invention also provides a method of preparing microspheres having siRNA encapsulated within.
  • the method comprises the steps of a) combining an siRNA/aqueous solution with a hydrophobic biodegradable polymer dissolved in an organic solvent solution and homogenizing to form a water/oil emulsion; b) combining the water/oil emulsion of step a) with a cationic lipid to obtain a double water/oil/water emulsion; c) spray drying the water/oil/water double emulsion of step b) to obtain the microspheres.
  • Microparticles prepared by the methods of the present invention may range in size up to 500 nanometers, preferably 2-20 micrometers, and most preferably smaller diameters of 1-2 micrometers.
  • the molar ratios between the hydrophobic polymer, siRNA and cationic amphiphile may be adapted in order to obtain microparticles with differential surface potential.
  • a preferred ratio of hydrophobic polymer : siRNA : cationic amphiphile is 5:25:50 (mass), to quantitatively encapsulate the siRNA.
  • the pharmaceutical compositions of the present invention can be formulated into a variety of suitable formulations and administered orally, in aerosol form, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, interperitoneally, rectally, topically and vaginally.
  • a device such as a powder spray (e.g. Penn Century ® DP4) to mediate the microparticle powders to the lung of rodents.
  • a method of delivering an siRNA targeted to the lung comprises the steps of a) combining an siRNA/aqueous solution with a hydrophobic biodegradable polymer dissolved in an organic solvent solution and homogenizing to form a water/oil emulsion; b) combining the water/oil emulsion of step a) with a cationic lipid to obtain a double water/oil/water emulsion; c) spray drying the water/oil/water double emulsion of step b) to obtain the microspheres comprising encapsulated siRNA; and d) delivering the microspheres to the lung by use of a powder spray device.
  • Example 1 Process of formulation of PLGA/siRNA microspheres using WJoIw 2 double emulsion process that quantitatively incorporates the emulsifier.
  • aqueous solution containing 5mg of siRNA (Luciferase) solution (1mg/ml_) is added within 10min to a solution of 1 mg of PLGA dissolved in 2OmL dichloromethane (DCM).
  • DCM dichloromethane
  • This first wi/o phase is then added to a solution of 20OmL DC-Choi at 9500 rpm within 30min.
  • the DCM is evaporated overnight under a flow hood and the W 1 ZoZw 2 emulsion is lyophilized (Alnmemo 2390-5, MultiTemp Scientific AG, Kloten) to obtain a white powder.
  • Different PLGA were tested and analyzed by gel electrophoresis (GE) and HPLC as indicated in Table 1. Units are mg/ml.
  • Example 2 Process of formulation of PLGA/siRNA microspheres using w ⁇ lolw 2 double emulsion process
  • a secondary emulsifier (e.g. PVA) is added to the DC-chol solution of Example 1 to homogenize the particles.
  • Table 2 indicates the secondary emulsifiers were tested:
  • microparticles were evaluated for in vitro cellular toxicity and compared to lipoplexes from commercial suppliers (siRNA-Luc, Luc 8548). H1291 human lung epithelial cells were incubated with differential quantities (0-15OnM) of siRNA formulated as microspheres and the impact on the WST-1 production quantified. As can be seen by the result of the WST-1 assay (commercial kit utilizing cell proliferation reagent WST-1 , Roche ® ' Basel), the microparticles exhibited no toxicity (constant level of WST-1 production) whereas the liposomal siRNA controls reduced the WST-1 levels substantially.
  • Figure 6 is an SEM picture with NVS star PLGA/DC-Chol microspheres prepared by the emulsion procedure followed by spray drying.
  • the SEM picture clearly shows improved homogeneity in particle size and shape.

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Abstract

La présente invention concerne des formulations pharmaceutiquement actives constituée, d'une part de microparticules d'ARN interférent court de dimensions définies, d'autre part d'un polymère biodégradable hautement hydrophobe, et enfin d'un lipide cationique servant à la fois d'émulsifiant amphipathique et d'entité de liaison à l'ARN interférent court. L'invention concerne également des procédés de fabrication de ces microparticules. Ces formulations de microparticules, qui sont particulièrement adaptées à l'administration pulmonaire d'ARN interférent court, sont indiquées dans le cas d'un traitement d'affections pulmonaires.
PCT/EP2010/057965 2009-06-09 2010-06-08 Système d'administration de médicaments WO2010142660A2 (fr)

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WO2013045455A1 (fr) * 2011-09-28 2013-04-04 Ethris Gmbh Système de pulvérisation permettant de produire une matrice formée in situ
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Cited By (12)

* Cited by examiner, † Cited by third party
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CN103796639A (zh) * 2011-07-06 2014-05-14 诺华股份有限公司 阳离子水包油乳液
CN103796639B (zh) * 2011-07-06 2017-05-31 诺华股份有限公司 阳离子水包油乳液
CN102389756A (zh) * 2011-08-11 2012-03-28 长春金赛药业股份有限公司 复乳法制备微球的方法
CN102389756B (zh) * 2011-08-11 2014-01-01 长春金赛药业有限责任公司 复乳法制备微球的方法
WO2013045455A1 (fr) * 2011-09-28 2013-04-04 Ethris Gmbh Système de pulvérisation permettant de produire une matrice formée in situ
US20140243395A1 (en) * 2011-09-28 2014-08-28 Ethris Gmbh Spray system for production of a matrix formed in situ
EA026717B1 (ru) * 2011-09-28 2017-05-31 Этрис Гмбх Распылительная система для производства матрицы, образуемой in situ
DE102017100317A1 (de) 2017-01-10 2018-07-12 Friedrich-Schiller-Universität Jena Nanostrukturiertes Trägersystem zum Gentransport
WO2018130247A1 (fr) 2017-01-10 2018-07-19 Friedrich-Schiller-Universität Jena Système support nanostructuré de principe actif
IT202100032393A1 (it) * 2021-12-23 2023-06-23 Torino Politecnico Metodo per la preparazione di nanoparticelle polimeriche ibride per il rilascio di farmaci oligonucleotidici nelle terapie farmacologiche a scopo rigenerativo, curativo e preventivo
WO2023119222A1 (fr) * 2021-12-23 2023-06-29 Politecnico Di Torino Procédé de préparation de nanoparticules polymères hybrides pour la libération de médicaments oligonucléotidiques dans des thérapies pharmacologiques à des fins de régénération, de traitement et de prévention
WO2023172747A1 (fr) * 2022-03-11 2023-09-14 W. L. Gore & Associates, Inc. Particules bioabsorbables et procédé d'utilisation

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