US20110111019A1 - Novel Method for Producing Nanocapsules in the Absence of an Organic Solvent, and Nanocapsules Produced Thereby - Google Patents

Novel Method for Producing Nanocapsules in the Absence of an Organic Solvent, and Nanocapsules Produced Thereby Download PDF

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US20110111019A1
US20110111019A1 US12/988,380 US98838009A US2011111019A1 US 20110111019 A1 US20110111019 A1 US 20110111019A1 US 98838009 A US98838009 A US 98838009A US 2011111019 A1 US2011111019 A1 US 2011111019A1
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nanocapsules
mass
mixture
surfactant
oil
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Fabrice Pirot
Francoise Falson
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Universite Claude Bernard Lyon 1 UCBL
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Universite Claude Bernard Lyon 1 UCBL
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Assigned to UNIVERSITE CLAUDE BERNARD LYON I reassignment UNIVERSITE CLAUDE BERNARD LYON I ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PIROT, FABRICE, FALSON, FRANCOISE
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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
    • A61K9/5192—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/10—Complex coacervation, i.e. interaction of oppositely charged particles

Definitions

  • the present invention relates to the technical field of nanocapsules, in particular nanocapsules which are of use as agents for transporting an active ingredient.
  • the subject of the invention is a method for producing nanocapsules, and also the nanocapsules which can be obtained by means of such a method.
  • Nanoparticles belong to a family of colloidal vectors which can be used, for example, for administering active ingredients, such as therapeutic molecules, in humans or animals. Such colloidal vectors preserve these active ingredients and can enable their controlled and/or sustained release at their site of action. Nanocapsules and nanospheres constitute two distinct groups of nanoparticles. Nanocapsules are formed from an aqueous or oily core coated with a polymeric membrane; nanospheres are formed from a polymeric matrix. The polymers which are part of the composition of nanoparticles are characterized by a high hydrophobicity (e.g. polyesters).
  • aqueous suspension of polymeric nanocapsules is most commonly produced according to two techniques:
  • the technique of obtaining an aqueous suspension of polymeric nanoparticles by interfacial polymer deposition is based on the deposition of preformed polymers at the interface between (i) an organic solvent mixed with an oil and (ii) an aqueous solution.
  • a solution is prepared containing, e.g., an active ingredient in an organic solvent which is soluble or very soluble in water, such as acetone (with or without lipophilic surfactant).
  • An oil which is miscible in the organic solvent but immiscible in water is added to the previous organic solution.
  • the organic solution is then dispersed, by mechanical stirring, in the polar phase most commonly containing a hydrophilic surfactant (e.g., poloxamer, polysorbate 80).
  • a hydrophilic surfactant e.g., poloxamer, polysorbate 80.
  • the organic solvent diffuses in the polar phase and this results in aggregation of the polymer around the lipid droplets responsible for the formation of the nanocapsules.
  • the organic solvent can be dispersed in the polar phase by tangential membrane filtration followed by mechanical stirring (I. Limayem Blouza, C. Charcosset, S. Sfar and H. Fessi. Preparation and characterization of spironolacton-loaded nanocapsules for paediatric use International Journal of Pharmaceutics 325:124-131(2006)).
  • the organic solvent is removed either by dialysis or, most commonly, by evaporation under reduced pressure.
  • the emulsion-diffusion technique (D. Moinard-Checot, Y. Chevalier, S. Briancon, L. Beney, and H. Fessi. Mechanism of nanocapsules formation by the emulsion-diffusion process. Journal of Colloid and Interface Science In Press, Corrected Proof: 77), for its part, consists in forming an emulsion in which the oily phase contains a biodegradable polymer and a partially water-miscible solvent (e.g., ethyl acetate, solubility: 8.3 g/100 ml at 20° C.) and or the polar phase containing an emulsifier is saturated with ethyl acetate.
  • a partially water-miscible solvent e.g., ethyl acetate, solubility: 8.3 g/100 ml at 20° C.
  • the current methods for producing nanocapsules all comprise a preliminary step of dissolving the hydrophobic polymers in a mixture of one or more volatile organic solvents (e.g., acetone, ethyl acetate).
  • the “spontaneous” formation of the nanocapsules is provided by the dispersion of the organic solutions of hydrophobic polymers in a polar mixture (e.g., most commonly aqueous solutions).
  • the final production step requires evaporation under vacuum or dialysis of the organic solvents. The verification of the elimination of these solvents and the detection of possible traces thereof in the final preparation both constitute procedures which are lengthy and expensive and which require, on the industrial scale, the designing and setting up of complex infrastructures.
  • the present invention proposes to provide a novel method for preparing nanocapsules which is easier to carry out and which is suitable for an industrial scale.
  • one of the essential objectives of the present invention is to provide a method for preparing nanocapsules which are free of toxic products and stable in colloidal suspension, and which allows good protection of the encapsulated active ingredient, along with sustained and/or controlled release of said active ingredient in vivo.
  • Another essential objective of the present invention is to provide a method for preparing nanocapsules of the abovementioned type and which is also easy to carry out and cost-effective on the industrial scale since it does not require laborious and expensive purification steps.
  • Another objective of the invention is to provide a method for preparing nanocapsules which makes it possible to reliably and reproducibly obtain nanocapsules having a size of less than 1 ⁇ m.
  • the method according to the invention does not use any organic solvent, which makes it possible to exempt it from the long and expensive steps of eliminating the organic solvent, which are indispensible in the prior art techniques.
  • the invention relates to a method for preparing an aqueous suspension of nanocapsules comprising an oily core surrounded by a polymeric shell, in which method the following phases are mixed:
  • a first phase called an oily phase, comprising:
  • this oily phase being brought to a temperature T 1 higher than the melting point of the hydrophobic polymer, the hydrophobic polymer being miscible, at this temperature T 1 , with the mixture of the surfactant TA 1 and the oil or mixture of oils, and the active ingredient being miscible, soluble or solubilized in the mixture of the surfactant TA 1 and the oil or mixture of oils;
  • a second phase comprising a hydrophilic polymer in the form of a hydrogel in an aqueous solution containing a surfactant TA 2 ,
  • the subject of the invention is also nanocapsules which can be obtained according to the method of the invention, in particular nanocapsules comprising an oily core in which an active ingredient is homogeneously dispersed and a polymeric shell formed from a hydrophobic polymer and from a hydrophilic polymer, which can be obtained according to the method of the invention, and also aqueous suspensions of such nanocapsules.
  • the invention relates to the pharmaceutical, cosmetic or food compositions comprising nanocapsules according to the invention or an aqueous suspension of nanocapsules according to the invention, in combination with at least one pharmaceutically or physiologically acceptable excipient.
  • solubility, miscibility and solubilization are well known to those skilled in the art. Reference may in particular be made to Physical Pharmacy (4 th edition, Alfred Martin (ed.), Lea & Febiger Philadelphia, London) chapter 10, pp 212-250, chapter 15, pp 393-422. Unless otherwise indicated, in the context of the invention, the solubility, miscibility or solubility is obtained at ambient temperature, in particular at 20° C.
  • miscible is intended to mean completely miscible.
  • Two liquid compounds will be considered to be completely miscible when they mix together in any proportion. Consequently, the term “miscibility” refers to the mutual solubility of the compounds in the liquid systems.
  • a solid compound will be considered to be soluble in a liquid or mixture of liquids when this compound disperses homogeneously in the molecular state under the effect of spontaneous solid/liquid interactions.
  • An active ingredient is considered to be soluble in a liquid or mixture of liquids when 1 g of active ingredient is dissolved in 10 to 30 ml of liquid or mixture of liquids (US Pharmacopeia).
  • a solid or liquid (inorganic or organic) compound will be considered to be solubilized in a liquid or mixture of liquids in particular when an association of colloids forming micelles increases the solubility of the compound initially insoluble in the dispersing medium.
  • hydrophilic polymer is intended to mean a polymer which is soluble in water.
  • polymer soluble in an aqueous solution is intended to mean a polymer which, when introduced into water at 20° C., at a concentration by weight equal to 1%, makes it possible to obtain a solution which has a maximum light transmittance value, at a wavelength at which the polymer does not absorb, through a sample 1 cm thick, of at least 70%, preferably of at least 80%.
  • hydrophobic polymer is intended to mean a polymer which is insoluble in water.
  • oil is intended to mean a lipophilic fatty substance which is liquid at ambient temperature (20° C.) and which is immiscible with water or weakly miscible with water.
  • water-dispersible oil is intended to mean an oil which disperses in water in the molecular, colloidal or micrometric state.
  • the HLB hydrophilic lipophilic balance
  • Griffin W C Classification of Surface-Active Agents by ‘HLB,’ Journal of the Society of Cosmetic Chemists 1 (1949): 311. Griffin W C: Calculation of HLB Values of Non-Ionic Surfactants, Journal of the Society of Cosmetic Chemists 5 (1954): 259).
  • the diameter of the nanocapsules which corresponds to the largest dimension of the nanocapsules, will be determined by photon correlation spectroscopy.
  • hydrogel is intended to mean a gelatinous homogeneous mixture forming a single phase containing water, and preferably comprising at least 0.1% to 5% by mass, preferably 0.15% to 2% by mass, of water.
  • the method according to the invention makes it possible to obtain an aqueous suspension of nanocapsules by means of a gelling emulsion method which does not involve any organic solvent.
  • the hydrophilic polymer present within the polymeric shell makes it possible to reduce the interfacial tension existing between the hydrophobic polymer and the water, and thus increases the stability of the suspension obtained. It is thus possible to spontaneously obtain the formation of nanocapsules during the mixing of the two phases, without the use of a volatile organic solvent, as was the case in the prior techniques.
  • the oily phase comprises a hydrophobic polymer, an oil, or a mixture of oils, at least one active ingredient, and a surfactant TA 1 .
  • This oily phase is homogeneous.
  • the oil(s) used is (are) by nature hydrophobic and can, in certain cases, be water-dispersible. This oil or mixture of oils is intended to form the core of the nanocapsules.
  • oil or the mixture of oils can have an HLB included in the range of from 3 to 6.
  • triglycerides in particular medium-chain triglycerides, propylene glycol dicaprylocaprate, and oleoyl, lauroyl and linoleoyl macrogolglycerides.
  • the oily phase advantageously comprises from 5% to 20% by mass, preferably from 8% to 12% by mass, of oil or mixture of oils.
  • this percentage relates only to the oil or mixture of oils and especially does not comprise the active ingredient and/or the surfactant TA 1 , even when the latter are also in an oily form.
  • the oily phase contains a hydrophobic polymer in the molten state, the oily phase being maintained at a temperature T 1 higher than the melting point of the polymer.
  • the hydrophobic polymer will be chosen in such a way that its melting point is compatible with the physiochemical stability of the oil, of the active ingredient and of the surfactant TA 1 .
  • the hydrophobic polymer will have a melting point of preferably lower than or equal to 120° C.
  • the hydrophobic polymer can be chosen from vinyl polymers, polyesters, polyamides, polyurethanes and polycarbonates, preferably having a melting point lower than 120° C., such as poly- ⁇ -caprolactones.
  • the oily phase can in particular comprise from 5% to 20% by mass, preferably from 8% to 12% by mass, of hydrophobic polymer.
  • the oily phase also contains an active ingredient which is dispersed, in a miscible, soluble or solubilized form, in said oily phase.
  • the active ingredient is miscible, soluble or solubilized in the mixture composed of the surfactant TA 1 and of the oil or mixture of oils, at the temperature T 1 .
  • the active ingredient is also miscible, soluble or solubilized in the mixture composed of the surfactant TA 1 and of the oil or mixture of oils, at ambient temperature, in particular at 20° C.
  • the active ingredient is solubilized, its solubilization is realised through the action of the surfactant TA 1 , acting as a solubilizing agent.
  • the oily phase will comprise from 0.5% to 5% by mass, preferably from 1% to 3% by mass, of active ingredient.
  • the oily phase also comprises a surfactant TA 1 , which may in particular act as a solubilizing agent for the active ingredient.
  • This surfactant TA 1 may be of the anionic, cationic, amphoteric or nonionic type.
  • the surfactant TA 1 can be in the form of an oil.
  • the surfactant TA 1 can have an HLB included in the range of from 3 to 6.
  • a surfactant TA 1 mention may be made of propylene glycol laurates, propylene glycol caprylates, polyglyceryl oleates and caprylocaproyl macrogolglycerides.
  • the oily phase comprises from 55% to 89.5% by mass, preferably from 73% to 83% by mass, of surfactant TA 1 .
  • the oily phase may contain a single or several active ingredients and/or a single or several hydrophobic polymers and/or a single or several surfactants TA 1 , which meet the above criteria.
  • the oily phase can, for example, be prepared by heating the hydrophobic polymer to a temperature higher than its melting point, and then adding the oil or the mixture of oils and then the active ingredient.
  • the surfactant TA 1 can be introduced at any stage. The mixing can be carried out in an entirely different order or the components as a whole can all be mixed simultaneously. It is also possible to heat the oil or the mixture of oils to the temperature T 1 and then to add the hydrophobic polymer in the liquid state, and then the other components.
  • the oily phase obtained will have to be homogeneous, and, if necessary, will be homogenized, for example with mechanical stirring.
  • the polar phase for its part, contains, in an aqueous solution, a hydrophilic polymer in the form of a hydrogel and a surfactant TA 2 .
  • the hydrophilic polymer can be chosen from synthetic cellulosic derivatives, preferably from cellulose ethers, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethyl methylcellulose, hydroxypropylmethylcellulose, methylethylcellulose and sodium carboxymethylcellulose.
  • the polar phase comprises from 0.1% to 5% by mass, preferably from 0.15% to 2% by mass, of hydrophilic polymer.
  • the surfactant TA 2 may be of the anionic, cationic, amphoteric or nonionic type.
  • the surfactant TA 2 has an HLB of greater than or equal to 15, and is preferably chosen from neutral surfactants (e.g., polysorbate 20, 60, 80; macrogol stearate; macrogol cetostearyl ether; macrogol lauryl ether; macrogol oleyl ether; macrogol oleate; polyoxyl castor oil; hydrogenated polyoxyl castor oil; source: Eur. Ph.).
  • the polar phase comprises from 0.1% to 5% by mass, preferably from 0.2% to 2% by mass, of surfactant TA 2 .
  • the polar phase may contain a single or several hydrophilic polymers and/or a single or several surfactants TA 2 , which meet the above criteria.
  • the polar phase comprises, most commonly, from 90% to 99.8% by mass, preferably from 96% to 99.65% by mass, of water or of a mixture of water with one or more polar solvents.
  • polar solvents mention may be made of ethanol, 1-propanol and 2-propanol.
  • the proportion of polar phase relative to the oily phase is variable.
  • Use may in particular be made of a hydrophobic polymer/hydrophilic polymer mass ratio of less than or equal to 0.4.
  • the mixing of the oily phase and the polar phase can be carried out in various ways. It is possible to pour the oily phase into the polar phase or to mix the two phases by means of a Y-shaped mixer circuit, each of the two phases being conveyed in one of the two arms of the Y. However, the mixing of the two phases is preferably carried out by adding the polar phase to the oily phase, with stirring. The oily phase is then maintained at the desired temperature T 1 during the mixing.
  • the oily phase is at a temperature T 1 higher than the melting point of the hydrophobic polymer.
  • a temperature which is 10 to 30° C. higher than the melting point of the hydrophobic polymer will in particular be used. Of course, this temperature will not be too high, so as to avoid any degradation of the other components used in the method according to the invention.
  • T 1 the mixture composed of the oil or the mixture of oils and of the surfactant TA 1 is miscible with the hydrophobic polymer, and the active ingredient is also miscible, soluble or solubilized, optionally by virtue of the surfactant TA 1 , in the mixture composed of the oil or the mixture of oils and of the surfactant TA 1 .
  • the polar phase may be at ambient temperature, in particular at 20° C., or, according to one embodiment variation, the polar phase may also be heated. In particular, the polar phase is brought to a temperature T 2 which is 2 to 5° C. lower than the melting point of the hydrophobic polymer. It is nevertheless important to preserve, under the mixing conditions, the hydrogel nature of the hydrophilic polymer.
  • the mixing of the two phases is carried out with moderate stirring, preferably using mechanical means operating at a speed included in the range of from 4000 to 16000 rpm, preferably in the range of from 6000 to 8000 rpm.
  • mechanical means operating at a speed included in the range of from 4000 to 16000 rpm, preferably in the range of from 6000 to 8000 rpm.
  • a mechanical propeller stirrer or a homogenizer Ultra-Turrax®
  • the method according to the invention results in nanocapsules having a diameter of less than 1000 nanometers. These nanocapsules are obtained in an aqueous suspension which is in the form of a gelatinous homogeneous mixture.
  • the active ingredient can be encapsulated in the oily core of the nanocapsules, or else can be adsorbed within the polymeric shell.
  • the hydrophilic polymer probably forms a protective colloid around the nanocapsules, ensuring greater stability of the colloidal suspension obtained and an improvement in the emulsification process.
  • the concentration of hydrophilic polymer may be adjusted according to the targeted application and, in particular, in the case of the therapeutic compositions, to the selected method of administration.
  • the gelatinous aqueous suspension of nanocapsules obtained can be diluted in water, without notable modification of the stability of the colloidal suspension.
  • the electric charge carried by the nanocapsules will depend on the nature and on the concentration of the protective colloid which coats or is entangled with the hydrophobic polymer constituting the wall of the nanocapsules.
  • the nanocapsules obtained have a diameter included in the range of from 200 to 1000 nm, preferably in the range of from 300 to 500 nm.
  • the stability in colloidal suspension of these nanocapsules is established. They confer on the active ingredient which they encapsulate in their core, or which is adsorbed within the polymeric shell, protection during storage and also during their transport to their site of action. These nanoparticles are therefore entirely suitable for use as a colloidal system for delivering active ingredients, in particular pharmaceutical or cosmetic active ingredients.
  • the nanocapsules according to the invention can be used, in particular, in pharmaceutical, cosmetic or food compositions.
  • the nanocapsules are, in general, present in combination with at least one pharmaceutically or physiologically acceptable excipient or vehicle, in particular an excipient which can be administered to humans and/or applied to the skin or the mucous membranes.
  • compositions according to the invention contain an active ingredient chosen from pharmaceutical or cosmetic active agents, mention may be made, by way of example, of chlorhexidine base, minoxidil, albendazole and ketoconazole.
  • Such compositions according to the invention contain a medium or at least one pharmaceutically or physiologically acceptable excipient.
  • Such compositions may in particular be administered enterally, parenterally or topically.
  • the PCL is melted at approximately 65° C. in a beaker.
  • the water-dispersible oils (Labrafil® M 1944 CS and Plurol® oleique) are mixed with the molten PCL, with moderate mechanical stirring using an Ultra-Turrax®.
  • the chlorhexidine base is dispersed with the molten PCL and the water-dispersible oils until a clear mixture is obtained.
  • a hydrogel of carboxymethylcellulose at 1% in distilled water is heated to 60° C. in order to be dispersed, with moderate mechanical stirring using an Ultra-Turrax®, in the molten PCT/water-dispersible oils/chlorhexidine base mixture.
  • the formation of the nanocapsules is spontaneous under the effect of the aggregation of the PCL on contact with the hydrogel. However, the stability of the nanocapsule suspension is maintained through the protective effect of the hydrophilic colloid (i.e., sodium carboxymethylcellulose) against the PCL flocculation phenomena.
  • the hydrophilic colloid i.e., sodium carboxymethylcellulose
  • the size and the zeta potential of the nanocapsules are 450 nm and ⁇ 40 mV, respectively.
  • the concentration of free (i.e. nonencapsulated) chlorhexidine in the nanocapsule suspension was determined after filtration of the colloidal suspension through a 0.22 ⁇ m filter. After dilution in distilled water, the concentration of chlorhexidine base free in the filtrate, determined by high performance liquid chromatography (HPLC) (H. Lboutounne, V. Faivre, F. Faison, and F. Pirot, Skin Pharmacology and Applied Skin Physiology 17: 176-182 (2004); H. Lboutounne, J.-F. Chaulet, C.
  • the total concentration of encapsulated chlorhexidine base was determined after dilution of an aliquot of colloidal suspension in a mixture of acetonitrile/sodium acetate (30 mM) (50/50, v/v). The diluting in this mixture has the effect of dissolving the nanocapsules and releasing the encapsulated chlorhexidine base.
  • the concentration of encapsulated chlorhexidine was 0.082% (percentage by mass/volume), i.e. an encapsulation yield of close to 90%.
  • the appearance of the nanocapsules of chlorhexidine base is given in the single figure which shows the image obtained by microscopic examination ( ⁇ 1000) (Axioskop 50 Microscope, Zeiss).

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US12/988,380 2008-04-18 2009-04-14 Novel Method for Producing Nanocapsules in the Absence of an Organic Solvent, and Nanocapsules Produced Thereby Abandoned US20110111019A1 (en)

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FR0852648A FR2930176B1 (fr) 2008-04-18 2008-04-18 Nouveau procede de fabrication de nanocapsules, en l'absence de solvant organique, et nanocapsules ainsi obtenues
FR0852648 2008-04-18
PCT/FR2009/050680 WO2009138606A1 (fr) 2008-04-18 2009-04-14 Nouveau procede de fabrication de nanocapsules, en l'absence de solvant organique, et nanocapsules ainsi obtenues

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FR2958150B1 (fr) 2010-04-01 2012-06-15 Univ Claude Bernard Lyon Elements orthodontiques elastiques aptes a liberer de la chlorhexidine faiblement soluble dans la salive
FR3009682B1 (fr) * 2013-08-13 2016-11-11 Polaar Suspension aqueuse de nanocapsules encapsulant des filtres solaires
US11534375B2 (en) * 2017-03-28 2022-12-27 Agency For Science, Technology And Research Solvent-free method of encapsulating a hydrophobic active

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104768539A (zh) * 2012-08-31 2015-07-08 生物实验萨纽斯药物有限公司 非那雄胺聚合物纳米粒子、含有该粒子的水悬液、用于治疗脱发的组合物、制备所述组合物的方法及其用途
EP2891487A4 (de) * 2012-08-31 2016-04-20 Biolab Sanus Farmacéutica Ltda Polymere finasteridnanopartikel, wässrige zusammensetzungen damit, zusammensetzung zur behandlung von alopezie, verfahren zur herstellung dieser verbindung und verwendung davon
US9895302B2 (en) 2012-08-31 2018-02-20 Biolab Sanus Farmaceutica Ltda. Finasteride polymeric nanoparticle, aqueous suspension containing the same, composition for the treatment of alopecia, process of preparation of said composition, and its use

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US20130207286A1 (en) 2013-08-15
FR2930176A1 (fr) 2009-10-23
EP2265364B1 (de) 2016-07-13
EP2265364A1 (de) 2010-12-29
US9233079B2 (en) 2016-01-12
WO2009138606A1 (fr) 2009-11-19
FR2930176B1 (fr) 2011-03-18

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