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
  • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
  • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• • 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
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
  • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
  • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
  • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
  • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof

Definitions

• the subject of the present invention is new cyclodextrin derivatives, which can be used in particular for the incorporation in aqueous medium of hydrophobic chemical compounds such as pharmaceutically active molecules, molecules for cosmetic applications and molecules used as contrast agents for imaging. medical.
• amphiphilic derivatives of cyclodextrins having self-organizing properties in an aqueous medium and being capable of being incorporated into organized surfactant systems leading to the formation of mixed systems.
• This incorporation into organized surfactant systems such as small phospholipid vesicles is intended to allow the transport of hydrophobic molecules included in the cyclodextrin, for example of an active principle, in particular by transmembrane route, for example transdermal.
• hydrophobic molecules included in the cyclodextrin for example of an active principle, in particular by transmembrane route, for example transdermal.
• Cyclodextrins or cyclomaltooligosaccharides are compounds of natural origin formed by the chain of 6, 7 or 8 glucose units linked in ⁇ -1— »4. Numerous studies have shown that these compounds can form inclusion complexes with hydrophobic molecules, thus allowing their solubilization in aqueous media. Many applications have been proposed to take advantage of this phenomenon, in particular in the pharmaceutical field, as described by D. Duchêne, in "Pharmaceutical Applications of Cyclodextrins", published in “Cyclodextrins and their industrial uses", Editions de Santé , Paris 1987, pp. 213-257 [1]. Pharmaceutical compositions using cyclodextrins have already been marketed in Japan, Italy and more recently in France, for example by Pierre Fabre Médicament pour le Brexin® which is an inclusion complex of Piroxicam in ⁇ -cyclodextrin.
• ⁇ -cyclodextrin (comprising 7 glucose units), is the most suitable for the size of its cavity and the least expensive of the three. Chemical modifications of ⁇ -cyclodextrin have been described in order to make it amphiphilic with the aim of incorporating it into organized systems.
• ⁇ -cyclodextrin derivatives comprising aliphatic chains located in primary and secondary positions, with a view to incorporating these cyclodextrin derivatives in phosphatidylcholine vesicles.
• These derivatives are amphiphilic and can be incorporated into the vesicles, but the internal cavity of cyclodextrin is no longer accessible due to the large steric hindrance of the aliphatic chains. Consequently, these derivatives are incapable of including hydrophobic molecules, in particular molecules of active principle.
• Bilboquet molecules have been shown to be not very stable in a physiological medium, ie at pH equal to and greater than 7, and their capacities for incorporation into organized systems remain limited.
• these Bilboquet molecules do not spontaneously self-organize in an aqueous medium to give particles of well defined size and shape.
• the present invention specifically relates to amphiphilic cyclodextrin derivatives, stable in physiological medium, capable of including hydrophobic compounds, having good capacities for incorporation in organized systems and moreover exhibiting self-organization properties in medium aqueous.
• the amphiphilic derivative of cyclodextrin corresponding to the formula:
• R represents a group derived from a steroid
• R, 2 represents an optionally substituted alkyl or aryl group
• R 3 represents H or R 2
• all R 4 represent OR2, or
• R 4 represents -NHCO (CH 2 ) m CONHR 1 and the others
• R represent OR provided that there is at least one glucose unit with R representing OR between the two glucose units comprising the substituent - HCO— (CH 2 ) m —CONH — R 1 , m is an integer ranging from 1 to 8, and n is 5, 6 or 7.
• steroids are compounds derived from a polycyclic nucleus of formula:
• R represents a linear or branched hydrocarbon group of 1 to 9 carbon atoms, and in which the polycyclic ring can comprise one or more double bonds, and one or more substituents chosen from CH 3 , OH and 0, on one or more carbon atoms of the rings
• R can represent a group derived from sterols by elimination of the hydroxyl group of the first ring, having a degree of unsaturation from 0 to 6. It can also be groups derived from sterones. For example R can represent a group derived from cholesterol such as the group of formula:
• the amphiphilic properties are obtained thanks to the presence of one or two substituents having a group derived from a steroid.
• the derivative has two substituents of this type, it is necessary that they are not on two adjacent glucose units of the cyclodextrin, because of their bulk.
• the two glucose units comprising these substituents are separated by one or two glucose units having an OR substituent.
• the cyclodextrin derivative has only one substituent of this type, all of the
• the group R 2 represents a linear or branched alkyl group or aryl, optionally substituted.
• an alkyl group When an alkyl group is used, it usually has from 1 to 4 carbon atoms and is preferably linear.
• the aryl group may for example be the phenyl group or the benzyl group.
• the optional substituents of these alkyl or aryl groups can be, for example, halogen atoms and hydroxyl, carboxyl and
• R represents the methyl group.
• R can represent a hydrogen atom
• R represents H
• the aliphatic chain connecting the group derived from a steroid to the glucose unit can comprise between the two amido groups, from 1 to 8 carbon atoms. Good results are obtained with two carbon atoms, i.e. with m equal to 2.
• the cyclodextrin derivatives of the invention can be derivatives of a-, ⁇ - or ⁇ -CD.
• the derivatives of ⁇ -CD are used, which corresponds in formula (I) given above in the case where n is equal to 6.
• cyclodextrin derivatives of the invention can be prepared by conventional methods from the mono-azido or diazido derivatives of corresponding cyclodextrins.
• R represents —N 3 and the others R represent OH a provided that there is at least one glucose unit with R representing OH between the two glucose units comprising the substituent N 3 , and n is equal to 5, 6 or
• R represents N 3 and the other R represents OR, and R and n are as defined above, b) carrying out a Staudinger reaction on the derivative of formula (V) using triphenylphosphine and ammonia to convert N 3 in NH 2 and obtain the derivative of formula: I ⁇
• R represents NH2 and the other R represent OR, and R 2 and n are as defined above, c) reacting the derivative of formula (VI) with an acid anhydride of formula:
• the monoazido or diazido derivatives used as starting material in the process can be obtained from the corresponding cyclodextrin derivative monotosylated or ditosylated by the action of lithium azide in water.
• step a) of the process described above the cyclodextrin derivative of
• step b) the derivative of formula (V) is reacted with triphenylphosphine in an organic solvent such as DMF and then 20% ammonia is added.
• the derivative of formula (VI) thus obtained can be purified by evaporation of the solvent, elimination by filtration of the white precipitate formed then separation by ion exchange chromatography.
• step c) the derivative of formula is reacted
• step d) is carried out directly in the same reaction medium.
• Peptide coupling reagents such as N, N '- diisopropylcarbodiimide and 1 hydroxybenzotriazole are then added.
• the derivative of formula (VIII) then reacts with the compound of formula H 2 NR such as cholest-5-en-3 ⁇ -ylamine.
• the derivative of formula I thus obtained can be separated from the reaction medium by evaporation of the solvent and purification by chromatography on a column of silica gel.
• step a) the method comprises the same steps as above, but in step a), a 1 ⁇
• R represents - 3 and the others R represent OH provided that there is at least one glucose unit, with R representing OH between the two glucose units comprising the substituent N 3 , and n is equal to 5, 6 or
• R f represents N 3 and the other R fi represents OR 2
• R and n are as defined above, b) carry out a Staudinger reaction on the derivative of formula (IX) using triphenylphosphine and ammonia to convert N 3 to NH 2 and obtain the derivative of formula:
• R represents NH and the other R represent OR, and R 2 and n are as defined above, c) reacting the derivative of formula (X) with an acid anhydride of formula:
• R 7 2 in which all the R represent OR or one of the R 7 represents - HCO— (CH 2 ) m — COOH and the other R 7
• a subject of the invention is also the inclusion complexes of the cyclodextrin derivative of formula (I) with a hydrophobic compound with a view to solubilizing this hydrophobic compound in an aqueous medium.
• the hydrophobic chemical compounds capable of being dissolved in aqueous media by means of these cyclodextrin derivatives (I) can be of different types. Examples of such compounds include cosmetic products, vitamins, pharmaceutically active molecules and molecules used as contrast agents for medical imaging, for example, the compounds described by Uekama and Irie in Chemical Revie (1998), 98, pp. 2045-2076 [7].
• the hydrophobic chemical compound is a pharmaceutically active molecule.
• examples of such molecules include steroids, for example prednisolone, neurotropes such as dothiepine, bacteriostats such as chloramphenicol, vitamins such as vitamin A, vascular wall tonics such as esculin, and contrast agents for medical imaging such as 16-iodo-3-methylhexadecanoic acid.
• inclusion complexes can be prepared by conventional methods, for example by adding to a solution or a suspension of the cyclodextrin of formula (I) used, a solution of the hydrophobic compound in a suitable organic solvent, for example acetone . 1
• the cyclodextrin derivatives of formula (I) have the property of spontaneously self-organizing in an aqueous medium to give nanoparticles of 25 to 30 ⁇ of medium radius and of perfectly spherical shape.
• the average number of monomers is 24 molecules of cyclodextrin derivatives per nanoparticle.
• the invention therefore also relates to an aqueous solution of nanoparticles of a cyclodextrin derivative of formula (I) alone or in the form of an inclusion complex with a hydrophobic compound.
• This nanoparticle solution can be prepared by forming an aqueous solution of the cyclodextrin derivative or of an inclusion complex of this derivative having a concentration of derivative or complex greater than the critical micellar concentration of the derivative.
• amphiphilic cyclodextrins into nanoparticles in an aqueous medium makes it possible to transport a hydrophobic molecule, for example an active principle, in particular by transmembrane or parenteral route.
• the cyclodextrin derivatives of the invention are more particularly advantageous because they can be incorporated into organized systems of surfactants such as small phospholipid vesicles or micelles. This incorporation is intended to allow the solubilization of organized systems, with a view to ensuring the transport of active principles included in the cyclodextrin derivative.
• the invention also relates to an organized surfactant system comprising a cyclodextrin derivative or an inclusion complex of this derivative in accordance with the invention.
• the surfactants capable of forming such organized systems can be of different types.
• phospholipids corresponding to the following general formula:
• R 3 represents CH 3 - (CH 2 ) p -CO with p being an integer ranging from 6 to 18.
• p is an integer ranging from 6 to 18.
• DMPC dimyristoylphosphatidylcholine
• the cyclodextrin derivative or an inclusion complex of this derivative in accordance with the invention into the organized system of surfactants, it is possible beforehand to form small vesicles of DMPC by sonication and then add the cyclodextrin derivative or the inclusion complex.
• the mixed system thus obtained then becomes perfectly soluble in water, leading to a clear solution.
• the mixed system obtained in this specific case is a mixed micelle with an average radius of 60 ⁇ .
• the subject of the invention is also an aqueous solution comprising in solution a mixed system formed from phospholipid vesicles or membrane proteins, and at least one cyclodextrin derivative or at least one derivative inclusion complex cyclodextrin according to the invention.
• FIG. 1 illustrates the experimental neutron scattering spectrum, on a logarithmic scale, of an aqueous solution of nanoparticles of the cyclodextrin derivative obtained in Example 1 with three theoretical scattering curves of spherical micelles, cylindrical micelles and bilayers.
• Figure 2 illustrates the appearance of different mixtures of cyclodextrin and phospholipid.
• Figures 3, 4 and 5 respectively illustrate the nuclear magnetic resonance spectra of 31 P obtained from sample a (figure 3), b (figure 5) and d (figure 4) of example 3.
• FIG. 6 illustrates the experimental neutron scattering spectrum, on a logarithmic scale, of a DMPC / cyclodextrin derivative mixture (sample d) obtained in the example
• FIG. 7 illustrates the scattering spectra of experimental neutrons on a logarithmic scale of mixtures of 16-iodo-3-methylhexadecanoic acid and the cyclodextrin derivative of Example 1 (1/1 and 0.5 / 1 mol) as well as the neutron scattering spectrum of the cyclodextrin derivative of Example 1 alone with the theoretical scattering curve of nanoparticles alone.
• Example 1 Synthesis of mono-6- (cholest-5-en-3 ⁇ -ylamido) succinylamido-6-deoxy-2, 2 ', 2'',2''', 2 '''', 2 ⁇ ⁇ ⁇ ⁇ 2 ''''', 6 ', 6' I , 6 ''',6'' , ', 6 '''',6'' 1 ''' - triréca-O-methyl-cyclomaltoheptaose .
• This compound is the derivative of formula (I) with R 1 representing the group of formula (III), R 2 being the methyl group, R 3 representing H, all R 4 representing OCH 3 , m being equal to 2 and n being equal to 6.
• R 1 representing the group of formula (III)
• R 2 being the methyl group
• R 3 representing H
• all R 4 representing OCH 3
• m being equal to 2
• n being equal to 6.
• the product is precipitated by adding 100 ml of n-hexane, filtered, washed with 100 ml of n-hexane and dried under vacuum. 0.80 g (0.60 mmol) of mono-6-azido-6-deoxy-2,2 ', 2'',2''', 2 '''', 2 ''''are collected, 2 ''''', 6 ', 6'',6''', 6 '''', 6 '''', 6 '''',6''''''-tridéca-O- methyl-cyclomaltoheptaose which present in the form of a white powder.
• 0.75 g (0.56 mmol) of the compound obtained in a) is dissolved in 30 ml of DMF.
• 0.75 g (2.86 mmol) of triphenylphosphine in 5 ml of DMF is added dropwise and with stirring at room temperature.
• the reaction medium is kept at room temperature for 2 hours, cooled to 0 ° C and treated with 14 L of 20% ammonia.
• the mixture is left for 18 hours at room temperature with stirring, then the solvent is removed under reduced pressure and the residual solid is taken up in 30 ml of water.
• the abundant insoluble triphenylphosphine and the corresponding oxide is removed by filtration.
• Example 2 Preparation of mono-6- nanoparticles (choiest-5-en-3 ⁇ -ylamido) succinylamido-6-deoxy-2,2 ', 2'',2''', 2 'I', 2 '''', I 2 '' ', 6', 6 '', 6 '*', 6, I ', 6' ⁇ ⁇ ⁇ ⁇ g ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ -tridéca-O- methyl-cyclomaltoheptaose.
• the cmc of the cyclodextrin of Example 1 was determined by surface tension measurements. The value of the cmc is 9.10 "6 mol / L.
• the average hydrodynamic diameter of the nanoparticles was measured by quasi-elastic light scattering.
• the mean diameter (MD) value calculated according to the Stokes-Einstein approximation based on the model of perfect spheres without interactions is 0.6 nra (60 ⁇ ).
• Analysis by static light scattering of aqueous solutions of nanoparticles at different concentrations (2.5.10 ⁇ 3 , 5.10 "3 and 10 ⁇ 2 mol / L) gives an average mass of the aggregates of 43000 g / mol, which corresponds at an average of 24 monomers per nanoparticle.
• the perfectly spherical shape as well as the size of the nanoparticles were confirmed by neutron scattering.
• the scattering spectrum obtained from a 10 "2 mol / 1 solution in D 2 0 of the derivative of Cyclodextrin of Example 1 is shown in Figure 1 (spectrum 1).
• FIG. 1 also shows the theoretical spectra simulating spheres (spectrum 2), cylinders (spectrum 3) or lamellae (spectrum 4) formed from the cyclodextrin derivative of Example 1, at a concentration of 10 ⁇ 2 mol / L in D 2 0.
• the superposition of the spectrum 2 simulating the spheres with the experimental spectrum 1 proves the spherical form of the cholesteryl-cyclodextrin aggregates. These aggregates are lined on the surface of cyclodextrin cavities available for the inclusion of active hydrophobic molecules, the heart being made up of groups cholesterol.
• the theoretical spectrum simulating the spheres gives an average diameter of 0.5 nm (50 ⁇ ) and an average number of monomers per nanoparticle of 24.
• Example 1 The cyclodextrin of Example 1 is added to the suspension of MLVs or SUVs of DMPC so that the final concentration of cyclodextrin in the aqueous cyclodextrin / DMPC mixture is 0.5 ⁇ 10 ⁇ 3 or 2.5 ⁇ 10 ⁇ 3 mol / L.
• FIG. 2 illustrates the appearance of the various mixtures after 12 h at 25 ° C.
• tube a it is an aqueous suspension of unilamellar vesicles of 15 mM DMPC.
• Tubes c and d correspond to the DMPC / cyclodextrian mixtures: 15.10 " 3/0, 5.10 " 3 and 15.10 " 3/2, 5.10 " 3 mol / L respectively.
• Tube b is a "control" tube corresponding to the DMPC / heptakis (2, 6-di-O-methyl) cyclomaltoheptaose 15.10 " 3/2, 5.10 " 3 mol / L mixture, ie a mixture of DMPC with a cyclodextrin containing no steroid substituent.
• FIG. 3 represents the spectrum corresponding to tube a (DMPC only).
• FIG. 4 represents the spectrum corresponding to the tube d (DMPC / cyclodextrin mixture; 15.10 "3 /2.5.10 " 3 mol / L).
• FIG. 5 represents the spectrum corresponding to tube b (DMPC / cyclodextrin mixture of the prior art).
• FIG. 4 which corresponds to the perfectly transparent sample d is reduced to a single fine peak centered at 0 ppm, indicating the presence of aggregates smaller than the unilamellar vesicles of tube a.
• the spectrum corresponding to the "control" tube b indicates the formation of vesicles larger than the starting vesicles. There is no reorganization of the medium with this cyclodextrin.
• tube c the amount of cyclodextrin of the invention is too small compared to the amount of DMPC to lead to a transparent solution as in tube d. A two-phase mixture is obtained.
• the mean hydrodynamic diameter of the mixed aggregates of sample d was measured by quasi-elastic light scattering.
• the mean diameter (MD) value calculated according to the Stokes-Einstein approximation based on the model of perfect spheres without interactions is 13 nm (130 ⁇ ).
• the sample d is then examined by neutron scattering.
• FIG. 6 illustrates the diffusion spectrum obtained (spectrum 5).
• FIG. 6 also shows the theoretical spectra simulating spheres (spectrum 6), cylinders (spectrum 7) or lamellae (spectrum 8) formed from the DMPC / cyclodextrin mixture of Example 1 with the ratio 15.10 ⁇ 3/2, 5.10 ⁇ 3 mol / L in D 2 0.
• the superposition of the spectrum 6 simulating spheres with the experimental spectrum 5 proves the spherical shape of the mixed aggregates DMPC / cyclodextrin of example 1.
• These mixed spherical systems have on the surface of cyclodextrin cavities likely to include active hydrophobic molecules.
• FIG. 7 represents the neutron scattering spectra obtained with:
• This figure also shows the theoretical spectrum (Spectrum 12) simulating the spheres.

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