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EP1793810A1 - Nanoparticules et procede permettant de les produire - Google Patents

Nanoparticules et procede permettant de les produire

Info

Publication number
EP1793810A1
EP1793810A1 EP05783457A EP05783457A EP1793810A1 EP 1793810 A1 EP1793810 A1 EP 1793810A1 EP 05783457 A EP05783457 A EP 05783457A EP 05783457 A EP05783457 A EP 05783457A EP 1793810 A1 EP1793810 A1 EP 1793810A1
Authority
EP
European Patent Office
Prior art keywords
nanoparticles
gelatin
molecular weight
proportion
kda
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05783457A
Other languages
German (de)
English (en)
Inventor
Michael Ahlers
Conrad Coester
Klaus Zwiorek
Jan Zillies
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gelita AG
Original Assignee
Gelita AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gelita AG filed Critical Gelita AG
Publication of EP1793810A1 publication Critical patent/EP1793810A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • 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
    • 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
    • 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
    • A61K9/5192—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present patent application relates to nanoparticles, the use of nanoparticles for the production of medicaments and a method for the production of nanoparticles.
  • Nanoparticles as carrier systems for pharmaceutical substances have been known since the 1970s. They allow a targeted transport of the active ingredients in a ge desired area of the body, wherein the release takes place only at the destination (so-called drug delivery systems). At the same time, the active ingredient, which has not yet been released, is effectively shielded against metabolic influences of the body. Thus, side effects can be minimized by the Wirkstoff ⁇ molecules predominantly and targeted arrive at their actual site of action and less burden on the whole organism.
  • Fibronectin various polysaccharides, albumin, collagen and gelatin are known, among other things, as natural, degradable carrier materials.
  • Another difficulty with the known nanoparticles consists in the sometimes wide size distribution, which is disadvantageous in terms of a uniform release and transport behavior.
  • the size distribution of such nanoparticles can be made narrower to a certain extent by complicated centrifugation and other separation methods, this does not lead to a satisfying result.
  • the object underlying the present application is therefore to provide biodegradable nanoparticles which ensure uniform and definable drug delivery.
  • the object is to specify a suitable method for producing this nanoparticle.
  • nanoparticles of the type mentioned consist essentially of an aqueous gelatin gel, wherein the average diameter of the nanoparticles is at most 350 nm and the polydispersity index of the nanoparticles is less than or equal to 0.15.
  • Gelatine has as starting material! for nanoparticles a number of advantages. It is available in defined composition and purity and has a relatively low antigenic potential. Gelatine is also approved for parenteral use, including as a plasma expander.
  • amino acid side chains of gelatin offer the simple possibility of chemically modifying the surface of the nanoparticles, of crosslinking the latins or of covalently binding active ingredient molecules to the particles.
  • aqueous gelatin gel is to be understood as meaning that the gelatin contained in the nanoparticles in hydrated form, ie as hydrocolloid. Since the nanoparticles are always surrounded by an aqueous solution during their preparation and use, all information on the size and polydispersity of the nanoparticles relates to this hydrated form. The determination of these parameters is carried out using the standard method of photon correlation spectroscopy (PCS), which is described in more detail below.
  • PCS photon correlation spectroscopy
  • the expression “consisting essentially of” is to be understood as meaning that the nanoparticles are at least 95% by weight or more, preferably 97% by weight or more, even more preferably up to 98% by weight or more and most preferably 99% by weight or more of the aqueous gelatin gel.
  • the polydispersity index is a measure of the size distribution of the nanoparticles, whereby theoretically values between 1 (maximum scattering) and 0 (identical size of all particles) are possible.
  • the low polydispersity index of the nanoparticles according to the invention of not more than 0.15 ensures targeted and controllable drug delivery as well as the release of the drug at the desired target site, in particular when uptake of the nanoparticles by body cells.
  • nanoparticles having a polydispersity index of less than or equal to 0.1 are particularly preferred.
  • the size of the nanoparticles is a decisive factor for their applicability and may vary depending on the field of application. In many cases, nanoparticles with an average diameter of at most 200 nm are preferred.
  • Another embodiment of the invention relates to nanoparticles having an average diameter of at most 150 nm, preferably from 80 to 150 nm. These can be used by utilizing the so-called EPR effect (enhanced permeability and retention). This effect makes it possible to specifically treat tumor cells which have a higher uptake rate than nanoparticles of the stated size range than healthy cells.
  • Another parameter for the size distribution of the nanoparticles is the band width of the diameter, which is preferably at a maximum of 20 nm above and below the mean value.
  • the bandwidth can also be determined by means of PCS.
  • the properties of the nanoparticles according to the invention can also be influenced by the molecular weight distribution of the gelatin contained.
  • the proportion of low molecular weight gelatin in particular the proportion of gelatin having a molecular weight below 65 kDa, based on the total gelatin contained in the nanoparticles. This proportion is preferably below 40 wt .-%. Particularly advantageous is a proportion of less than 30 wt .-%, preferably 20 wt .-% and Weni ⁇ ger.
  • nanoparticles are usually described which, in addition, contain further structural polymers (for example nanoparticles produced by the coacervation process, as described in WO 01/47501 A1).
  • the nanoparticles made of pure gelatin prepared hitherto are either unstable or do not have the parameters described above with regard to particle diameter and size distribution which are advantageous for selective drug delivery.
  • the gelatin contained in the nanoparticles is crosslinked. Networking will increase the stability of the nanoparticles!
  • the degree of decomposition of the nanoparticles can be deliberately adjusted by the degree of crosslinking selected. This is advantageous since different application areas usually require defined degradation times of the nanoparticles.
  • Non-crosslinked nanoparticles are suitable for extracorporeal, in particular diagnostic, applications in which, below the melting point of gelatin, e.g. can be operated at room temperature.
  • crosslinked nanoparticles are particularly suitable for therapeutic applications.
  • the gelatin may be chemically crosslinked, e.g. by formaldehyde, dialdehyde, isocyanates, diisocyanates, carbodiimides or alkyldihaiogenides.
  • enzymatic crosslinking e.g. by transglutaminase or laccase.
  • the nanoparticles according to the invention are dried, preferably up to a water content of not more than 15% by weight.
  • Another embodiment of the invention relates to nanoparticles, on the surface of which a pharmaceutical active substance is bound.
  • the surface of the nanoparticles is chemically modified, e.g. by the reaction of free amino or carboxyl groups of the gelatin, whereby charged So ⁇ chains or side chains with a new chemical functionality entste ⁇ hen.
  • the binding of the pharmaceutical active substance to the nanoparticles or to the chemically modified nanoparticles can be effected by adsorption forces, by covalent bonds or by ionic bonds.
  • nanoparticles whose surfaces are positively charged by a corresponding chemical modification, DNA or RNA fragments are ionically bound ge ⁇ .
  • the binding of the active ingredient to the nanoparticles takes place via a spacer.
  • the nanoparticles described above can be used according to the invention for the production of medicaments.
  • nanoparticles for intracellular drug delivery systems, in particular as a carrier for nucleic acids or peptides.
  • Medicaments containing nanoparticles according to the invention can preferably be used in gene therapy.
  • the present invention further relates to a process for the preparation of nanoparticles of the type described above.
  • the object underlying the invention with regard to the method is achieved by using a gelatin as the starting material for the preparation process whose maximum amount of gelatin having a molecular weight of less than 65 kDa, based on the total gelatin 40 wt .-% is.
  • nanoparticles having a low polydispersity and bandwidth of the particle diameter can be produced in a simple manner, in particular the nanoparticles according to the invention having a polydispersity index of less than or equal to 0.15.
  • an aqueous solution is first prepared from such a gelatin, the pH of which is then adjusted to a value below 7.0.
  • a suitable precipitating agent By adding a suitable precipitating agent to this solution, the dissolved gelatin is desolvated in the form of nanoparticles, which are then separated from the solution by simple centrifugation. Fractionation of the nanoparticles, e.g. by gradient centrifugation, is not necessary, since its polydispersity is already in a sufficiently low range as a result of the production process according to the invention.
  • Nanoparticles according to the invention are therefore preferably substantially free of the stated additives.
  • the inventive method thus enables the production of Nanoparticles, which essentially consist only of an aqueous gelatin gel.
  • gelatin with the molecular weight distribution described above ensures the formation of stable nanoparticles.
  • Gelatins with a higher low molecular weight fraction in this process increasingly lead to the formation of larger aggregates or unstable particles.
  • the proportion of gelatin having a molecular weight of less than 65 kDa is at most 30% by weight, most preferably at most 20% by weight.
  • the adjusted pH of the gelatin solution is less than or equal to 3.0, preferably in the range of 1.5 to 3.0.
  • the pH can be z.T. an influence on the mean particle size are exerted, with a lower pH tends to result in smaller nanoparticles.
  • acetone In a further preferred embodiment acetone, alcohols, e.g. Ethanol, or mixtures of these precipitants used in succession or with water, acetone is be ⁇ preferred as the precipitating agent.
  • the use of volatile precipitants of this kind largely avoids the fact that fractions of the precipitant are incorporated into the nanoparticles and / or remain so that they consist essentially only of the aqueous gelatin gel.
  • the proportion of gelatin having a molecular weight below 65 kDa is preferably 20% by weight or less in order to counteract agglomeration of the particles upon crosslinking.
  • FIG. 1 shows the gel permeation chromatograms of two gelatins (FIGS. 1A and 1B, respectively) representing the molecular weight distribution of the respective gelatin;
  • FIG. 2 an electron micrograph of nanoparticles according to the invention.
  • FIG. 3 shows a size distribution of nanoparticles produced according to the invention.
  • the molecular weight distribution of the gelatin can be used to influence the properties of the nanoparticles produced therefrom.
  • the molecular weight distribution can be determined by gel permeation chromatography (GPC). The determination is carried out on an HPLC system with the following components:
  • Plasticizer 1% by weight SDS, 100 mmol / l Na 2 SO 4 ,
  • the assignment between elution volume and molecular weight is carried out by calibrating the system with a standard gelatin having a known molecular weight distribution. By dividing the chromatogram into defined ranges and integrating the UV detector signal, the proportion of gelatin which lies in the respective molecular weight range can be calculated.
  • FIG. 1 shows by way of example the gel permeation chromatograms of two different gelatins:
  • FIG. 1A shows the GPC of a commercial pork rind gelatin (Type A gelatin) with a bloom value of 175. Due to the high proportion of gelatin with a molecular weight below 65 kDa, which is above 45% by weight, this gelatin is for the production process according to the invention are not suitable for nanoparticles and leads to particles with too high polydispersity or agglomeration of the particles.
  • FIG. 1B shows the GPC of a pigskin gelatin having a bloom value of 310 and a proportion of gelatin having a molecular weight of less than 65 kDa of about 15% by weight. This gelatin is very well suited for the production process according to the invention.
  • Photon correlation spectroscopy allows the determination of the mean particle diameter of the nanoparticles, the polydispersity index and the bandwidth of the particle diameter above and below the mean value.
  • nanoparticle suspensions were used with a concentration of 10 to 50 ug / ml in de-mineralized water.
  • This example describes the preparation of crosslinked nanoparticles from gelatin, the GPC of which is shown in FIG. 1B (with a proportion of gelatin having a molecular weight below 65 kDa of about 15% by weight).
  • Crosslinked nanoparticles are prepared as described in Example 1, with a pigskin gelatin having a bloom value of 270, whose proportion of gelatin having a molecular weight below 65 kDa being about 19% by weight, being used as starting material.
  • an average particle diameter of about 173 nm and a polydispersity index of about 0.08 were determined by the PCS method described above.
  • the size distribution was comparable to the nanoparticles prepared according to Example 1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Biophysics (AREA)
  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Processes Of Treating Macromolecular Substances (AREA)
  • Jellies, Jams, And Syrups (AREA)

Abstract

L'invention vise à mettre au point des nanoparticules biodégradables, permettant d'assurer un transport de principe actif, de manière homogène et définissable, ainsi que simultanément un procédé approprié pour produire lesdits nanoparticules. A cet effet, il est prévu que les nanoparticules se composent essentiellement de gel de gélatine aqueux. Le diamètre moyen des nanoparticules s'élève au maximum à 350 nm. L'indice de polydispersivité des nanoparticules est inférieur ou égal à 0,15 et le matériau de départ utilisé pour le processus de production est une gélatine, dont la proportion de gélatine atteint au maximum 40 % en poids, pour un poids moléculaire inférieur à 65 kDa, par rapport à l'ensemble de la gélatine.
EP05783457A 2004-08-20 2005-08-18 Nanoparticules et procede permettant de les produire Withdrawn EP1793810A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004041340A DE102004041340A1 (de) 2004-08-20 2004-08-20 Nanopartikel und Verfahren zu deren Herstellung
PCT/EP2005/008954 WO2006021367A1 (fr) 2004-08-20 2005-08-18 Nanoparticules et procede permettant de les produire

Publications (1)

Publication Number Publication Date
EP1793810A1 true EP1793810A1 (fr) 2007-06-13

Family

ID=35276582

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05783457A Withdrawn EP1793810A1 (fr) 2004-08-20 2005-08-18 Nanoparticules et procede permettant de les produire

Country Status (14)

Country Link
US (1) US20080003292A1 (fr)
EP (1) EP1793810A1 (fr)
JP (1) JP2008510688A (fr)
KR (1) KR20070046850A (fr)
CN (1) CN1988892A (fr)
AU (1) AU2005276675A1 (fr)
BR (1) BRPI0514524A (fr)
CA (1) CA2575407A1 (fr)
DE (1) DE102004041340A1 (fr)
IL (1) IL180954A0 (fr)
MX (1) MX2007001996A (fr)
NO (1) NO20071458L (fr)
NZ (1) NZ551326A (fr)
WO (1) WO2006021367A1 (fr)

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EP1973608A1 (fr) 2005-12-14 2008-10-01 Cytos Biotechnology AG Particules emballees avec des acides nucleiques immunostimulateurs pour le traitement de l hypersensibilite
WO2007072982A1 (fr) * 2005-12-20 2007-06-28 Fujifilm Corporation Nanoparticules de proteines et leur utilisation
JP2007224012A (ja) * 2006-01-30 2007-09-06 Fujifilm Corp 酵素架橋したタンパク質ナノ粒子
NZ573622A (en) 2006-06-12 2011-12-22 Cytos Biotechnology Ag Processes for packaging oligonucleotides into virus-like particles of rna bacteriophages
JP2008001764A (ja) * 2006-06-21 2008-01-10 Gunma Univ タンパク質からなる粒子状成形体の製造方法及び、該方法により得られたタンパク質からなる粒子状成形体
JP5275561B2 (ja) * 2006-10-30 2013-08-28 富士フイルム株式会社 水分散可能なナノ粒子
DE602007002784D1 (de) * 2007-03-16 2009-11-26 Univ Nat Chi Nan Bioabbaubares Material mit Nanoporen und elektrischer Leitfähigkeit sowie Herstellungsverfahren dafür
JP2008260705A (ja) * 2007-04-11 2008-10-30 Fujifilm Corp 注射用組成物
JP2008297241A (ja) * 2007-05-31 2008-12-11 Fujifilm Corp ニキビ用皮膚外用剤
DE102007041625A1 (de) * 2007-09-03 2009-03-05 Sinn, Hannsjörg, Dr. Neue Gelatine-Wirkstoff-Konjugate
KR102302069B1 (ko) 2010-11-10 2021-09-14 인리젠 장기 확대를 위한 주사가능 제제
EP2540287A1 (fr) 2011-07-01 2013-01-02 FutureChemistry Produit de débit continu de nanoparticules de gélatine
DE102011052396A1 (de) * 2011-08-04 2013-02-07 Gelita Ag Verfahren zur Herstellung einer stabilen Dispersion von Nanopartikeln, hergestellte Dispersion und deren Verwendung
US20190002530A1 (en) * 2015-12-25 2019-01-03 Konica Minolta, Inc. Gelatin particles, method for producing gelatin particles, gelatin particle-containing cell, and method for producing gelatin particle-containing cell
US11207258B2 (en) 2016-01-25 2021-12-28 Suntory Holdings Limited Capsule containing functional substance and method for manufacturing said capsule
CN107376008B (zh) 2017-07-21 2019-10-22 深圳华诺生物科技有限公司 一种无机纳米颗粒-明胶核壳结构复合材料颗粒的制备方法
WO2021132741A1 (fr) * 2019-12-23 2021-07-01 주식회사 피엘마이크로메드 Particules d'embolisation et leur procédé de préparation
KR102386631B1 (ko) * 2020-04-09 2022-04-15 주식회사 피엘마이크로메드 색전 시술용 마이크로 비드 및 증식성 질환 치료용 조성물
WO2021206440A1 (fr) * 2020-04-09 2021-10-14 주식회사 피엘마이크로메드 Microbilles pour embolisation et composition pour traiter des maladies prolifératives
KR102645182B1 (ko) * 2021-08-23 2024-03-07 전남대학교산학협력단 젤라틴 가교입자의 제조 방법
US20240049705A1 (en) * 2022-07-26 2024-02-15 Industry Foundation Of Chonnam National University Composition for enhancing growth of plants

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Also Published As

Publication number Publication date
KR20070046850A (ko) 2007-05-03
MX2007001996A (es) 2007-05-10
CN1988892A (zh) 2007-06-27
NZ551326A (en) 2010-04-30
JP2008510688A (ja) 2008-04-10
AU2005276675A1 (en) 2006-03-02
US20080003292A1 (en) 2008-01-03
NO20071458L (no) 2007-03-19
DE102004041340A1 (de) 2006-02-23
WO2006021367A1 (fr) 2006-03-02
BRPI0514524A (pt) 2008-06-10
CA2575407A1 (fr) 2006-03-02
IL180954A0 (en) 2007-07-04

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