EP1578404A2 - Verfahren zurverkapselung einer lipidlöslichen wirksubstanz durch herstellung einer pit-emulsionund erhaltene emulsion - Google Patents

Verfahren zurverkapselung einer lipidlöslichen wirksubstanz durch herstellung einer pit-emulsionund erhaltene emulsion

Info

Publication number
EP1578404A2
EP1578404A2 EP03814493A EP03814493A EP1578404A2 EP 1578404 A2 EP1578404 A2 EP 1578404A2 EP 03814493 A EP03814493 A EP 03814493A EP 03814493 A EP03814493 A EP 03814493A EP 1578404 A2 EP1578404 A2 EP 1578404A2
Authority
EP
European Patent Office
Prior art keywords
temperature
phase
emulsion
phase inversion
aqueous phase
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Withdrawn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
EP03814493A
Other languages
English (en)
French (fr)
Inventor
Luc Jugla
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.)
Cosnessens
Original Assignee
Cosnessens
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 Cosnessens filed Critical Cosnessens
Publication of EP1578404A2 publication Critical patent/EP1578404A2/de
Withdrawn legal-status Critical Current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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals

Definitions

  • the present invention relates to the field of vectorization of active principles.
  • Nanoparticles are colloidal particles ranging in size from 1 to 1000 nm. They are macromolecules in which the active principle is dissolved, trapped or encapsulated. These nanoparticles refer to very different systems such as nanospheres and nanocapsules which are respectively matrix systems for nanospheres and reservoir systems for nanocapsules.
  • Nanospheres are solid matrix particles in which the active principle is finely dispersed in the polymer matrix.
  • Nanocapsules are particles made up of a liquid or semi-liquid core at room temperature which contains the active principle, coated with a solid film at room temperature.
  • Nanocapsules are aqueous suspensions of small vesicles (generally between 100 and 400 nm), whose rigid wall, of small thickness, consists of macromolecules of natural, synthetic or semi-synthetic origin. These systems make it possible to encapsulate in the lipophilic heart relatively large quantities of active principles, most often lipophilic, they can be obtained either by polymerization reactions or from preformed polymers. Numerous methods for formulating nanocapsules by emulsification are described, for example, the methods described in patents US 5079322 or EP0717989 which make it possible to obtain emulsions incorporating liposoluble active principles.
  • liposoluble active principles we mean in particular any chemical compound or mixture soluble in oily bodies for cosmetic, food, pharmaceutical or veterinary use or any compound of interest due to its properties.
  • the liposoluble active ingredients are, for some, sensitive to exposure to temperatures above 50 ° C, sensitive to light and to oxidation.
  • One of the solutions currently used to vectorize these active principles is their formulation in emulsions. But because of their instability, when these liposoluble active principles are used in emulsified systems, they are introduced at the end of the process in an oil-in-water emulsified system at a temperature below 50 ° C. for example, and these will then distribute randomly, particularly in the aqueous phase and will then be partially destroyed by the surrounding medium.
  • the phases of temperature rise to obtain the phase inversion which can be optionally repeated are not compatible with the formulation of active principles liable to undergo physical or chemical degradation due to too long exposure to a temperature above 50 ° C.
  • the lipid nanocapsules are formulated by a process of emulsification by phase inversion caused by passage of the emulsion beyond the phase inversion temperature but making it possible to preserve the active principle thanks to its incorporation in phase. continuous oily therefore without contact with the aqueous phase, beyond the phase inversion temperature.
  • the incorporation of the liposoluble active principle in the formulation at a temperature higher than the phase inversion temperature, that is to say when the emulsion is in the oily continuous phase (water-in-oil emulsion), allows to obtain a good distribution of the active principle in the oily phase, limits its contact with the aqueous phase, and surprisingly although the temperature is high, the residence time at this temperature is very short since this incorporation is followed by the quenching of the emulsion, the degradation phenomena are limited or eliminated.
  • the present invention relates to a process for encapsulating a liposoluble active principle in nanocapsules by preparation of an emulsion characterized in that: a) an aqueous phase and a fatty phase are available, b) the temperature of the two phases up to a temperature higher than the phase inversion temperature, c) the two phases are mixed, d) the liposoluble active principle is incorporated into the liposoluble phase, e) the temperature is left to lower to the phase inversion temperature, f) as soon as the phase inversion is effective and the emulsion is in aqueous continuous phase, the emulsion obtained is quenched to lower its temperature.
  • a step c ′) is carried out which consists in lowering the temperature to a temperature immediately above the phase inversion temperature before the incorporation of the active principle.
  • step c) is carried out before step b).
  • step c) is carried out before step b).
  • step c) is carried out before step b).
  • the two phases are mixed before the temperature rises or during the temperature rise, but before the latter reaches the phase inversion temperature.
  • the emulsion obtained is then brought to a temperature higher than the phase inversion temperature, then the active principle is incorporated.
  • the emulsion obtained is then concentrated by removal of part of the aqueous phase.
  • this concentration step can be carried out by tangential ultrafitration.
  • step f is carried out by adding an additional aqueous phase brought to a temperature at least lower than the phase inversion temperature, and optionally lower than ambient temperature.
  • This brutal and rapid cooling step makes it possible to lower the temperature of the emulsion and reduce the time of exposure of the active principle to a higher high temperature.
  • This quenching can also be carried out using a cooling system by heat exchange or by adding liquefied gas, for example nitrogen.
  • phase inversion temperature a temperature a few degrees higher, in practice 1 or 2 ° C than the phase inversion temperature.
  • the phase inversion temperature of the system having been previously determined experimentally by monitoring the conductivity of the system or by visual observation.
  • the liposoluble active ingredients capable of being encapsulated by this process, mention will be made more particularly of the liposoluble active ingredients called unstable, that is to say capable of degrading if they are exposed to temperatures above 40 ° C. for times greater than 30 min, or sensitive to oxidation due to the presence of water in the formulation, or degraded by pH variations, by UN radiation. or by the presence of products capable of causing parasitic reactions with said active ingredients.
  • unstable that is to say capable of degrading if they are exposed to temperatures above 40 ° C. for times greater than 30 min, or sensitive to oxidation due to the presence of water in the formulation, or degraded by pH variations, by UN radiation. or by the presence of products capable of causing parasitic reactions with said active ingredients.
  • the fat-soluble vitamins and their derivatives such as the retinoid family (retinol, retinaldehyde, retinoic acid), carotenoids, tocopherol and its derivatives, - Polyphenols such as flavonoids (ex: isoflavonoids, quercetin), stylbenes (ex : resveratrol), catechins (e.g. epicatechin-3-gallate, epigallocatechine-3-gallate)
  • perfume components such as vanillin, indol, more generally essential oils such as essential oils of citrus, lavender
  • - liposoluble active pharmaceutical ingredients such as: Fluvastatin, Ketoprofen, Verapamil, Atenolol, Griseofulvin, Ranitidine
  • the emulsion comprises from 5 to 30% of fatty substance constituting the fatty phase and from 45 to 92% of water constituting the aqueous phase.
  • the proportion of the fatty phase relative to the aqueous phase which is associated with it depends on the amount of active principle to be encapsulated and on the type of emulsion. The proportion of fatty phase can also have an influence on the size of the nanocapsules obtained.
  • the constituents of the fatty phase can be chosen from paraffinic derivatives or more or less complex triglycerides. The choice of these constituents will depend on the nature of the lipophilic active principle to be encapsulated but also on their potential influence on the phase inversion temperature or even on their influence on the size of the nanocapsules obtained.
  • the nature of the active principle to be encapsulated will have an influence on the choice of the constituents of the fatty phase because the constituents will be selected according to:
  • phase inversion temperature When the phase inversion temperature is too high, ingredients capable of lowering this phase inversion temperature will be added to the medium. Indeed, the more marked lipophilic nature of certain constituents which may be chosen for example because of their ability to dissolve the active ingredients can cause the phase inversion temperature to rise because the accentuation of the hydrophobic bonds between the agent surfactant and oil causes an increase in the energy needed to reverse the system.
  • the polarity of the constituents of the fatty phase also has an influence on the phase inversion temperature, the more the constituents are polar the more the phase inversion temperature is increased.
  • the saturated constituents, with the lowest possible iodine index are capable of reducing the phase inversion temperature. Although the residence time at a temperature higher than the phase inversion temperature is extremely short, it will nevertheless be sought to formulate emulsions whose phase inversion temperature is as low as possible.
  • the constituents of the fatty phase will therefore preferably be chosen from mineral oils or mineral oil substitutes such as isohexadecane, silicones, in particular cyclomethicones or polydimethylsiloxane, C8 to C12 triglycerides, for example triglycerides of capric and caprylic acids and their mixtures.
  • mineral oils or mineral oil substitutes such as isohexadecane, silicones, in particular cyclomethicones or polydimethylsiloxane, C8 to C12 triglycerides, for example triglycerides of capric and caprylic acids and their mixtures.
  • the choice of the emulsifying system is also an important criterion having an influence on the stability of the emulsions obtained and on the size of the particles.
  • Two values characterize an emulsifying system, the ratio of lipophilic surfactant / hydrophilic surfactant (RTL / RTH) and the overall percentage of surfactants.
  • the emulsifying systems used in the present invention will be chosen from systems whose RTL / RTH ratio is between 1/1 and 1/50.
  • the percentage of water-soluble surfactant will preferably be between 2 and 10% and the percentage of lipophilic surfactant will be between 1 and 5%.
  • the water-soluble surfactants are especially chosen from esters of glycol, glycerol, itol, sorbitan, polyethylene glycol.
  • polyethylene glycol esters in particular those whose carbon chain is between 10 and 22 carbon atoms will be chosen, and whose number of polyethylene glycol monomers is between 5 and 30.
  • These water-soluble surfactants may also be chosen from ethers of fatty alcohols and of polyethylene glycol, the fatty alcohol of which is chosen from those comprising from 10 to 22 carbon atoms and the number of monomers of which is between 5 and 30.
  • Lipophilic surfactants will also be added to the mixture, these surfactants are characterized by their ability to give W / O emulsions when used as emulsifiers alone or mainly.
  • these emulsifiers mention will be made of esters of monoglycerols, esters of polyglycerol and of fatty acids, silicone emulsifiers such as cetyl dimethicone copolyol, esters of polyhydroxystearic acid and of polyethylene glycol.
  • salt can be added to the aqueous phase. It has been shown that the addition of salt reduces the interaction between the polar groups and water and decreases the hydrophilicity of the surfactant, therefore the CMC, in addition it produces a screen effect facilitating the rimpedement between the polar groups.
  • constituents may be added in one or other of the phases, for example, preservatives intended to avoid the development in the aqueous phase of certain microorganisms,
  • Antioxidant agents are added to the system to avoid the alteration of certain easily oxidizable compounds in the lipid phase, they are for example chosen from the group consisting of butylhydroxylanisole (BHA), butylhydroxytoluene (BHT), propyl gallate, ⁇ -tocopherol, EDTA. These antioxidants will be used at concentrations varying from 0.01 to 3%, for example BHT will be used at concentrations varying from 0.01 to 1%, ⁇ -tocopherol at concentrations varying from 0.1 to 3% and EDTA at concentrations varying from 0.05 to 2%.
  • BHA butylhydroxylanisole
  • BHT butylhydroxytoluene
  • EDTA propyl gallate
  • ⁇ -tocopherol EDTA
  • the stirring speed will be between 100 and 3000 revolutions / min.
  • the speed of agitation affects rupture and coalescence, this speed of agitation will therefore have an influence on the size distribution and on the stability of the emulsion.
  • the detection of phase inversion is carried out:
  • the PIT zone is defined as being a zone in which the conductivity of the medium varies from a zero value (characterizing an oily continuous phase) to a value of a few ⁇ s / cm. This development takes place over a temperature range called the PIT zone.
  • the diameter of the particles is measured by an optical method of measuring light called light scattering, which is based on various physical and mathematical laws including SPC (Photon Correlation Spectroscopy).
  • SPC Photon Correlation Spectroscopy
  • the principle of measurement can be described as the study of the speed of particles subjected to Brownian motion, small particles vibrating a lot and moving quickly while those of a larger diameter vibrate little and move more slowly.
  • the interaction of a light beam with the particles allows, after mathematical modeling, to approach the diameter of the particles.
  • the present invention also relates to the lipid nanocapsules obtained by the method according to the invention whose average size is less than 300 nm and is preferably on average 150 nm.
  • Emulsions according to the invention are described below.
  • vitamin E acetate 0.5%
  • the two previously formulated phases are heated to a temperature of 85 ° C.
  • the two phases are combined by adding the aqueous phase to the fatty phase with shearing stirring at 700 rpm.
  • the active ingredient RETINOL in solution in a triglyceride of caprylic acid, 7% is then incorporated into the emulsion obtained by mixing the aqueous phase and the fatty phase at a temperature in the region of 81 ° C.
  • phase inversion occurs at 73 ° C, this phase inversion is identified by an increase in the conductivity greater than 1 ⁇ S / cm.
  • a complementary aqueous phase containing a preservative Glydant Plus Liquid (DMDM hydantoin and iodopropynyl butylcarbamate (sold by the company LONZA Inc. (0.5%) and the water 51, 9% is quickly incorporated into the emulsion containing the RETINOL previously obtained.
  • DMDM hydantoin and iodopropynyl butylcarbamate sold by the company LONZA Inc. (0.5%) and the water 51, 9% is quickly incorporated into the emulsion containing the RETINOL previously obtained.
  • the emulsion can then be concentrated by tangential ultrafiltration.
  • an emulsion is prepared from the following phases. :
  • Aqueous phase Aqueous phase :
  • the phase inversion takes place at 71 ° C.
  • an emulsion is prepared from the following phases. :
  • Fat phase - PEG-30 dipolyhydroxystearate 2%
  • Aqueous phase - 0.2% EDTA disodium
  • the phase inversion takes place at 80 ° C.
  • the size of the droplets obtained less than 300 nm which has the following advantages:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Dermatology (AREA)
  • Toxicology (AREA)
  • Nutrition Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)
  • Colloid Chemistry (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP03814493A 2002-12-26 2003-12-24 Verfahren zurverkapselung einer lipidlöslichen wirksubstanz durch herstellung einer pit-emulsionund erhaltene emulsion Withdrawn EP1578404A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0216723A FR2849379B1 (fr) 2002-12-26 2002-12-26 Encapsulation d'actifs liposolubles
FR0216723 2002-12-26
PCT/FR2003/003900 WO2004060358A2 (fr) 2002-12-26 2003-12-24 Procede d'encapsulation d'un principe actif liposoluble par preparation d'une emulsion pit et emulsion obtenue

Publications (1)

Publication Number Publication Date
EP1578404A2 true EP1578404A2 (de) 2005-09-28

Family

ID=32480214

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03814493A Withdrawn EP1578404A2 (de) 2002-12-26 2003-12-24 Verfahren zurverkapselung einer lipidlöslichen wirksubstanz durch herstellung einer pit-emulsionund erhaltene emulsion

Country Status (8)

Country Link
US (1) US20060134222A1 (de)
EP (1) EP1578404A2 (de)
JP (1) JP2006517141A (de)
CN (1) CN100402019C (de)
AU (1) AU2003303610B2 (de)
CA (1) CA2513273A1 (de)
FR (1) FR2849379B1 (de)
WO (1) WO2004060358A2 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1628626B2 (de) * 2003-05-07 2013-12-04 OTC GmbH Zusammensetzungen zur gezielten freisetzung von duftstoffen und aromen
US20110281957A1 (en) * 2008-11-26 2011-11-17 Lipoprotein Technologies, Inc. Enhanced bioactive formulations of resveratrol
BE1020154A5 (nl) 2012-03-22 2013-05-07 Omega Pharma Innovation & Dev Nv Samenstelling voor de behandeling van pediculose en overeenkomstig productiewerkwijze.
KR101645440B1 (ko) * 2014-07-23 2016-08-05 코스맥스 주식회사 다량의 유분을 포함하면서 피부개선효과가 우수한 하이드로겔 마스크의 제조방법 및 이를 통하여 제조된 하이드로겔 조성물
CN109330914B (zh) * 2018-11-28 2022-02-01 广州艾卓生物科技有限公司 一种纳米神经酰胺乳液及其制备工艺和应用

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Publication number Priority date Publication date Assignee Title
US5079322A (en) * 1990-05-30 1992-01-07 The Dow Chemical Company Multifunctional cyclobutarene peroxide polymerization initiators
FR2715843B1 (fr) * 1994-02-09 1996-04-12 Oreal Compositions cosmétiques antisolaires, procédé de préparation et utilisation.
DE19923785A1 (de) * 1999-05-25 2000-11-30 Cognis Deutschland Gmbh Verwendung von PIT-Emulsionen in Fermentationsverfahren
DE19950089A1 (de) * 1999-10-18 2001-04-19 Beiersdorf Ag Kosmetische und dermatologische Lichtschutzformulierungen in Form von O/W-Makroemulsionen oder O/W-Mikroemulsionen, mit einem Gehalt an einem oder mehreren Filmbildnern, welche aus der Gruppe der Copolymere des Polyvinylpyrrolidons gewählt werden
FR2805761B1 (fr) * 2000-03-02 2002-08-30 Mainelab Nanocapsules lipidiques, procede de preparation et utilisation comme medicament

Non-Patent Citations (1)

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Title
See references of WO2004060358A2 *

Also Published As

Publication number Publication date
FR2849379A1 (fr) 2004-07-02
JP2006517141A (ja) 2006-07-20
FR2849379B1 (fr) 2005-02-11
AU2003303610B2 (en) 2009-01-08
AU2003303610A1 (en) 2004-07-29
CA2513273A1 (fr) 2004-07-22
CN1731986A (zh) 2006-02-08
WO2004060358A3 (fr) 2005-07-21
CN100402019C (zh) 2008-07-16
US20060134222A1 (en) 2006-06-22
WO2004060358A2 (fr) 2004-07-22

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