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WO2008149215A2 - Procédé pour la préparation de microparticules et nanoparticules lipidiques solides - Google Patents

Procédé pour la préparation de microparticules et nanoparticules lipidiques solides Download PDF

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Publication number
WO2008149215A2
WO2008149215A2 PCT/IB2008/001463 IB2008001463W WO2008149215A2 WO 2008149215 A2 WO2008149215 A2 WO 2008149215A2 IB 2008001463 W IB2008001463 W IB 2008001463W WO 2008149215 A2 WO2008149215 A2 WO 2008149215A2
Authority
WO
WIPO (PCT)
Prior art keywords
acid
nanoparticles
concentration
group
salt
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.)
Ceased
Application number
PCT/IB2008/001463
Other languages
English (en)
Other versions
WO2008149215A3 (fr
Inventor
Luigi Sebastiano Battaglia
Michele Trotta
Roberta Cavalli
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.)
Universita degli Studi di Torino
Original Assignee
Universita degli Studi di Torino
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 Universita degli Studi di Torino filed Critical Universita degli Studi di Torino
Publication of WO2008149215A2 publication Critical patent/WO2008149215A2/fr
Publication of WO2008149215A3 publication Critical patent/WO2008149215A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/5123—Organic compounds, e.g. fats, sugars

Definitions

  • the present invention concerns a new method for the preparation of solid lipid micro and nanoparticles .
  • Solid lipid micro and nanoparticles are widely used in the pharmaceutical field as a vehicle for active ingredients, due to their low toxicity and the fact that they are simple to prepare .
  • the precipitation of lipids by acidification of the salts of the fatty acids is generally used for their purification.
  • the purification consists in separation of the fatty acid from a solution by the addition of a strong acid at high ' temperatures, generally concentrated sulphuric acid.
  • the precipitate consists of lipid crystals with an irregular shape, in particular needle-shaped.
  • said purification technique does not permit control of the form and dimensions of the precipitate.
  • the object of the present invention is therefore to find a method for the production of solid micro- and nanoparticles of fatty acids of controlled form, with a reduced size distribution, which provides easily reproducible results and which permits the incorporation of active ingredients, including thermosensitive active ingredients .
  • the invention furthermore aims to find a method which does not require the use of complex equipment and toxic solvents and which is therefore inexpensive not only for laboratory application but also for industrial application. According to the present invention said object is achieved by means of a method as claimed in claim 1.
  • Said method is based on a process of acidification of salts of fatty acids in the presence of specific stabilising agents, which overcomes the problems of the methods known in the art .
  • the term “micellar aqueous solution” indicates a solution comprising lipid aggregates in a colloidal phase;
  • nanoparticles indicates particles with dimensions from 10 to 1000 nm, the term “microparticles” indicates particles with dimensions from 1 to 100 ⁇ m,
  • biocompatible indicates a substance biologically compatible with tissues, organs and functions of the organism and which does not cause toxic or immunological responses in the organism;
  • acid solution indicates a solution of a biocompatible acid with pH between 1 and 7.
  • the method according to the present invention permits the preparation of micro and nanoparticles of solid fatty acids, the form and dimensions of which can be controlled by control of the reaction conditions .
  • the precipitation of the micro and nanoparticles is performed by mixing an acid solution with a micellar aqueous solution comprising at least one salt soluble in water of a fatty acid in the presence of an amphiphilic polymeric stabilising agent which is non-ionic and biocompatible .
  • the salt of the fatty acid is selected from alkaline salt, ammonium salt and amine salt.
  • the fatty acid is a solid fatty acid at room temperature, more preferably selected from the group consisting of stearic acid, palmitic acid, myristic acid, lauric acid, arachidonic acid, behenic acid.
  • the salt of the fatty acid is preferably present in a concentration of between 0.1 and 30% w/w, more preferably between 1 arid 5% w/w, and is selected from • the group consisting of sodium stearate, sodium palmitate, sodium myristate, sodium laurate, sodium arachidonate , sodium behenate .
  • the stabilising agent present in a concentration of between 0.1 and 30% w/w, preferably between 1 and 5% w/w, is a non- ionic amphiphilic polymer, preferably selected from the group consisting of partially hydrolysed polyvinyl acetate, polyoxyethylene/polyoxy-propylene copolymers, polyacrylamides , polyvinyl pyrrolidone and its derivatives, stabilising agents derived from polysaccharides, for example derivatives of dextran and agarose of various molecular weights, derivatives of cellulose, non-ionic gums, cyclodextrins and their derivatives .
  • a non- ionic amphiphilic polymer preferably selected from the group consisting of partially hydrolysed polyvinyl acetate, polyoxyethylene/polyoxy-propylene copolymers, polyacrylamides , polyvinyl pyrrolidone and its derivatives, stabilising agents derived from polysaccharides, for example derivatives of
  • the acid solution used in the present method preferably comprises at least one acid selected from hydrochloric acid and an acid with pKa between 2 and 6.
  • the acid is selected from the group consisting of acetic acid, carbonic acid, lactic acid, glycolic acid, tartaric acid, maleic acid, pyruvic acid, malic acid, succinic acid, citric acid, hydrochloric acid, phosphoric acid, acid polyphosphates, acid salts of ammonium and their derivatives, amino acids, polyamino acids, polymers containing acid groups, for example alginic acid and chitosan.
  • the acid solution comprises an acid in a concentration from 0.01M to 5M.
  • the micellar solution is mixed with the acid solution at a temperature below the melting temperature of the fatty acid.
  • the mixing temperature varies from 25°C to 80 0 C, more preferably between 4O 0 C and 50 0 C.
  • biocompatible co-solvent selected from the group consisting of ethanol, propylene glycol, glycerol and butyl lactate up to a concentration of 30% w/w of the aqueous phase.
  • the method of the present invention permits the incorporation or superficial adsorption by the micro or nanoparticles of an active ingredient for therapeutic, diagnostic, cosmetic and alimentary use.
  • the active ingredient is selected from the group consisting of antitumoral molecules, antioxidant molecules, antibiotics, metals, immunosuppressors .
  • the active ingredient is selected from azulene, amphotericin B, cisplatin, tocopherol, cyclosporin, retinol.
  • micellar aqueous solution For said purpose an active ingredient can be added to the micellar aqueous solution.
  • the active ingredient can be dissolved directly in the micellar solution or alternatively can be dissolved in a small volume of biodegradable solvent miscible with water.
  • the solution thus obtained is then mixed with the micellar aqueous solution of the fatty acid.
  • the active ingredient is incorporated in the solid particles when the acid solution is mixed.
  • the active ingredient is soluble in water with basic pH, it can be dissolved in a small volume of basic aqueous solution and then added to the micellar aqueous solution of the fatty- acid. In this way, the active ingredient co-precipitates with the particles of fatty acid as the pH is lowered.
  • the active . ingredient forms salts or complexes that are insoluble with ⁇ the components of the micelles, it cannot be added directly to ' the micellar solution. It can, however, be dissolved in the acid solution for combination with the micellar aqueous solution. In this way the insoluble salts or complexes of the active ingredient with the fatty acids will precipitate with the lipids.
  • the sodium stearate is dissolved in water at a concentration of 1%.
  • 1% of PVA 9000 hydrolysed to 80% under agitation at 47 0 C is added to the resulting solution.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • the TEM microphotograph of the nanoparticles of 1% stearic acid obtained according to the method illustrated in the present example is provided in Figure 1 and shows the formation of spherical particles .
  • the DSC analysis ( Figure 2) shows an endothermic transition at 53 0 C (Tp eak ) and the X-ray analysis ( Figure 3) reveals a crystalline structure, a characteristic of the form B of stearic acid.
  • the sodium palmitate is dissolved in water at a concentration of 1%.
  • 1% of PVA 120000 hydrolysed to 89% under agitation at 47 0 C is added to the solution obtained.
  • the nanoparticles of palmitic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspension is then cooled slowly at room temperature .
  • the TEM microphotograph of the nanoparticles of 1% stearic acid obtained according to the method illustrated in the present example is provided in Figure 4 and shows the formation of spherical particles .
  • the DSC analysis ( Figure 5) shows an endothermic transition at 58 0 C (Tpi CCO ) and the X-ray analysis ( Figure 6) reveals a crystalline structure similar to the one obtained for the nanoparticles of 1% stearic acid.
  • the sodium stearate is dissolved in water at a concentration of 1% with 0.1% cetomacrogol 1000.
  • 1% of PVA 9000 hydrolysed to 80% under agitation at 47 0 C is added to the solution obtained.
  • the lipid nanoparticles are precipitated by adding lactic acid IM dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • the sodium stearate is dissolved in water at a concentration of 1%.
  • 1% of PVA 14000 hydrolysed to 89% under agitation at 47 0 C is added to the solution obtained.
  • the sample is then divided into two solutions.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation, while in the other the same operation is performed by adding citric acid IM.
  • the suspensions are then cooled slowly at room temperature.
  • micellar solutions Three different micellar solutions are prepared containing sodium stearate at a concentration of 1%, 2% and 5% respectively.
  • PVA 9000 hydrolysed to 80% is added to each micellar solution obtained in a concentration of 1%, 2% and 5% respectively under agitation at 47 0 C.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM, 2M and 5M respectively dropwise under agitation and the suspensions are then cooled slowly at room temperature .
  • the sodium stearate is dissolved in water at a concentration of 2%.
  • the solution obtained is divided into two parts and PVA 9000 hydrolysed to 80% is added under agitation at a concentration of 2% and 4% respectively at 47 0 C.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid 2M dropwise under agitation and the suspensions are then cooied slowly at room temperature.
  • the DSC ( Figure 11) shows a slight change in the melting temperature, but not in the relative enthalpy.
  • the sodium stearate is dissolved in water at a concentration of 1%.
  • the solution obtained is divided into five parts and a different stabilising agent is added to each one, 1% PVA 9000 hydrolysed to 80%, 1% PVA 14000 hydrolysed to 89%, 1% PVA 120000 hydrolysed to 89%, 1% Pluronic ® F- 68 and 1% Pluronic ® F- 127 respectively at 47°C.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspensions are then cooled slowly at room temperature.
  • the mean diameters and size distributions are illustrated in Table II.
  • the DSC analysis shows the influence of the type of stabilising agent used on the melting temperature and on the form of the peak and relative enthalpy, since the interaction between the stabilising agent and the lipid matrix changes .
  • the sodium stearate is dissolved in water at a concentration of 1% and 1% PVA 9000 hydrolysed to 80% is added.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspensions are then cooled slowly at room temperature .
  • Said nanoparticles are then lyophilised for one night with and without trehalose 5% as cryoprotector.
  • Table III below shows the data relative to lyophilised samples dispersed again in water by simple mechanical agitation (following page) .
  • the samples can be easily dispersed again, especially when the cryoprotector is present .
  • the sodium stearate is dissolved in water at a concentration of 1%.
  • 1% PVA 9000 80% hydrolysed under agitation at 47 0 C is added to the solution obtained.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • the sodium stearate is dissolved in water at a concentration of 1%.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid .INT.,dropwise _ under agitation and the suspension is then cooled slowly at room temperature.
  • the preparation carried out at low temperatures protects the tocopherol from thermal degradation and its incorporation in nanoparticles is useful for increasing its stability in both cosmetic and pharmaceutical products .
  • the sodium stearate is dissolved in water at a concentration of 2%.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid 2M dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • azulene into nanoparticles is useful to increase its long-term photostability in cosmetic products.
  • the sodium stearate is dissolved in water at a concentration of 2%.
  • the nanoparticles of stearic acid are precipitated by adding lactic acid 2M dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • the preparation at low temperatures protects the amphotericin B from thermal degradation.
  • amphotericin B >85% of the dose
  • the nanoparticles of stearic acid are precipitated by adding lactic acid IM dropwise under agitation and the suspension is then cooled slowly at room temperature.
  • cisplatin >60%
  • nanoparticles The incorporation of cisplatin (>60%) into nanoparticles is useful for vehiculation of the drug and for the production of modified-release pharmaceutical forms.
  • the sodium stearate is dissolved in water at a concentration of 1%.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un procédé pour la préparation de microparticules et nanoparticules lipidiques solides comprenant l'étape de mélange d'une solution acide avec une solution aqueuse micellaire comprenant au moins un sel soluble dans l'eau d'un acide gras en présence d'un agent stabilisant polymérique non ionique et biocompatible. Les microparticules et nanoparticules peuvent en outre incorporer un ingrédient actif, en particulier un ingrédient actif thermosensible.
PCT/IB2008/001463 2007-06-08 2008-06-06 Procédé pour la préparation de microparticules et nanoparticules lipidiques solides Ceased WO2008149215A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITTO2007A0004111 2007-06-08
ITTO20070411 ITTO20070411A1 (it) 2007-06-08 2007-06-08 Metodo per la preparazione di micro e nanoparticelle lipidiche solide

Publications (2)

Publication Number Publication Date
WO2008149215A2 true WO2008149215A2 (fr) 2008-12-11
WO2008149215A3 WO2008149215A3 (fr) 2009-01-29

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PCT/IB2008/001463 Ceased WO2008149215A2 (fr) 2007-06-08 2008-06-06 Procédé pour la préparation de microparticules et nanoparticules lipidiques solides

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IT (1) ITTO20070411A1 (fr)
WO (1) WO2008149215A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127568A1 (fr) 2012-02-28 2013-09-06 Vincenza Dolo Composition biocide
WO2015007398A1 (fr) 2013-07-18 2015-01-22 Ferbi Srl Procédé de préparation de nanoparticules lipidiques solides contenant des anticorps sous forme de paires d'ions au moyen de la technique de coacervation d'acides gras
IT1423780B1 (en) * 2014-03-31 2016-08-22 Policlinico Di Monza Spa Solid lipid nanoparticles to convey anti-tumor drugs beyond blood brain barrier for treating brain tumors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1292142B1 (it) * 1997-06-12 1999-01-25 Maria Rosa Gasco Composizione farmaceutica in forma di microparticelle lipidiche solide atte alla somministrazione parenterale

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013127568A1 (fr) 2012-02-28 2013-09-06 Vincenza Dolo Composition biocide
WO2015007398A1 (fr) 2013-07-18 2015-01-22 Ferbi Srl Procédé de préparation de nanoparticules lipidiques solides contenant des anticorps sous forme de paires d'ions au moyen de la technique de coacervation d'acides gras
IT1423780B1 (en) * 2014-03-31 2016-08-22 Policlinico Di Monza Spa Solid lipid nanoparticles to convey anti-tumor drugs beyond blood brain barrier for treating brain tumors

Also Published As

Publication number Publication date
WO2008149215A3 (fr) 2009-01-29
ITTO20070411A1 (it) 2008-12-09

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