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
• • 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
• • 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
  • 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
  • A61K9/5176—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

• the invention relates to biocompatible polysaccharide-based capsules templated on liquid cores of diameter below 1 ⁇ , stabilized by hydrophobically modified charged polysaccharides without low molecular weight surfactants, able to efficiently encapsulate hydrophobic compounds and having long-term stability in aqueous suspension and process of preparation and stabilization thereof.
• Stable and biodegradable oil-in-water nanoemulsion is one of the most common type of nanoformulation used as delivery system of various active compounds, particularly drugs, vitamins, hormones, dyes, antioxidants, pesticides, Magnetic Resonance Imaging (MRI) and Positron emission tomography (PET) contrast agents.
• active compounds particularly drugs, vitamins, hormones, dyes, antioxidants, pesticides, Magnetic Resonance Imaging (MRI) and Positron emission tomography (PET) contrast agents.
• MRI Magnetic Resonance Imaging
• PET Positron emission tomography
• Another strategy towards improvement of stability of nanoemulasions is implementation of layer by layer technique (LbL) leading to formation of ultrathin polymer films formed in a process of alternate adsorption of oppositely charged polyelectrolyte.
• the resulting structures are referred to nanocapsules templated on liquid cores.
• the use of low molecular weight ionic surfactants allows to cover the oil cores with polymer shells, however, the dynamic nature of interactions within micellar systems is a serious limitation.
• the most important drawback is that the excessive dilution of the system can result in reduction in surfactant concentration below the critical micelle concentration (CMC) leading to disintegration of the aggregate stabilizing the oil droplets and thus to uncontrolled release of encapsulated compounds before reaching the target.
• CMC critical micelle concentration
• Amphiphilic graft copolymers enable to achieve aforementioned goals as they are able to anchor hydrophobic arms in the oil droplets ensuring their stabilization [F. Liu et al., Polymer Chemistry, 2014, 5, 1381-1392]. Those polymers play dual role in nanoemulsions, on the one hand they act as droplets stabilizers, on the other hand, they constitute the first layer of the shell. Moreover, the use of graft polyelectrolytes enables formation of multilayer capsules of enhanced stability [J. Szafraniec et al., Nanoscale, 2015, 7, 5525-5536].
• U.S. Patent No. 20060063676 describes nanoemulsions encapsulating pesticides in oil cores stabilized by ionic or non-ionic surfactants.
• U.S. Patent No. 2007036831 is directed to nanoemulsions having high anti -inflammatory properties, being stabilized by ionic and/or non-ionic surfactants.
• Biodegradable polymers of low toxicity such as poly(glutamic acid), polypeptides such as poly(L-lysine) and poly(L-arginine) as well as modified polysaccharides (e.g. chitosan and dextran) are used to minimize such a risk [A. Karabasz et al., Journal of Nanoparticles Research, 2014, 16, 1-14; R. Vecchione et al., Nanoscale, 2014, 6, 9300-9307], however, the oil cores of capsules are still stabilized by typical surface-active agents.
• Patent No. EP2266546 describes nanoemulsions templated on cores composed of saturated or unsaturated fatty acids having 12-24 carbon atoms in chains being stabilized by anionic phospholipids and covered by thin chitosan layer. Such capsuled were described as carriers of lipophilic compounds used in cosmetics and pharmacy.
• Patent No. EP2266546 discloses formulations of diameter not exceeding 1 ⁇ in which oil cores stabilized by lecithin and covered by chitosan, being able to efficient encapsulation of cyclosporine A.
• WO2013001124 describes technique of preparation of nanoemulsions templated on isoprenoids stabilized by anionic or non-ionic surfactants and covered by poly(D-glucosamine) that were used as carriers of vaccines.
• Russian Patent No. RU 2494728 describes nanocapsules templated on eucalyptus oil stabilized by block copolymer of poly(ethylene oxide) and poly(propylene oxide) (PEO- block-W ) suspended in aqueous solution of polysaccharides (e.g. chitosan) being used as carriers of biologically active lipophilic compounds.
• PEO- block-W poly(propylene oxide)
• the invention relates to novel biocompatible system of core-shell architecture and the process of preparation thereof.
• Nanocapsules templated on liquid cores are stabilized by charged hydrophobically modified polysaccharides without the use of low molecular weight surfactants.
• Such capsules are then covered by ultrathin polyelectrolytes' films what leads to enhancement in their stability, improvement of biocompatibility and pharmacokinetic profile of encapsulated compounds.
• hydrophobically modified ionic oligo- and polysaccharides such as chitosan, chitosan oligosaccharide, dextran, carrageenan, amylose, starch, hydroxypropyl cellulose, pullulan and glycosaminoglycans (e.g.
• hyaluronic acid heparan sulfate, heparin sulfate, keratan sulfate, chondroitin sulfate, dermatan sulfate
• stabilizers are believed to be hyaluronic acid, chitosan and chitosan oligosaccharide derivatives.
• Any polysaccharide can be hydrophobically modified.
• molar mass of polysaccharide used as emulsion stabilizer should exceed 2000 g/mol, however the most suitable are polysaccharides of molar mass above 5000 g/mol.
• polysaccharides used as emulsion stabilizers should possess stable electrostatic charge provided by ionic groups within polymeric chains, such as carboxylic, sulfonic, sulfate, phosphate, ammonium, pyridine or phosphono groups.
• ionic groups within polymeric chains, such as carboxylic, sulfonic, sulfate, phosphate, ammonium, pyridine or phosphono groups.
• the content of ionic groups should not be less than 10%, more suitable it should exceed 40%, while the most suitable for good stabilization of emulsion droplets it to use polymers having at least 60% of ionic groups.
• stabilization of oil cores of the capsules can be provided by polysaccharides modified with hydrophobic groups of either linear or branched alkyl chains having 3-30 carbon atoms being single or/and multiple- bounded. It is also acceptable to use cyclic compounds and/or aromatic compounds as hydrophobic side chains that may also contain weakly polar groups such as ether or disulfide groups or halogens. Preferably, the degree of substitution of hydrophobic chains into polysaccharide molecules should not exceed 40%. To achieve good solubility in water less than 10%) of substitution of hydrophobic groups is recommended, however in order to provide the best stabilization of oil cores of capsules it should not exceed 5%. It is recommended to use hydrophobic compounds having 6-18 carbon atoms, however the most suitable is to use 12-carbon side chains.
• ultrasound-assisted process is used to obtain nanoemulsions: sonication should be carried out for 15-120 minutes at temperature between 4-40°C. Preferably, it should last 30-60 minutes at 20-35°C, however the most suitable conditions providing preparation of nanocapsules are: 30-minute sonication performed at room temperature.
• Polysaccharide-based nanocapsules are manufactured using aqueous solution of hydrophobically modified polysaccharide at pH 2-12, concentration varying between 0.1- 30 g/L and ionic strength between 0.001 M and 3 M.
• the ionic strength of the solution of polysaccharides should be in the range of 0.015-0.15 M and concentration between 1-10 g/L.
• Oil cores of invented capsules are composed of non-toxic hydrophobic compounds, either natural or synthetic, such as oleic acid, isopropyl palmitate, PROVINOL, fatty acids and pure natural oils (both, vegetable and animal origin) or mixtures thereof including linseed oil, soybean oil, argan oil, among others.
• the resulting capsules have a wide range of applications such as carriers of lipophilic compounds of low bioavailability or nanoreactors for enzymatic and/or biological processes.
• Lipophilic active compounds and substrates for enzymatic reactions may be either core material or compound dissolver therein. Mixing delivered lipophilic compounds with oil phase at the first stage of the process of preparation of capsules minimizes the risk of damage of vulnerable molecules and ensures high encapsulation efficiency.
• Dissolving of dyes in oil cores leads to formation of capsules that can be easily microscopically imaged and studied in order to determine the release profiles of cargo from the cores.
• concentrations of encapsulated dyes vary in the range of approx. 10 "5 M up to concentrations obtained for saturated solutions.
• Capsules used for bioimaging should encapsulate dyes for which excitation and emission wavelength are in the red part of the spectrum, since it facilitates in vivo visualization as the emission of the dye does not overlap with the autofluorescence of cells.
• invented nanocapsules should be coated with ultrathin films of polyelectrolytes.
• biocompatible polyelectrolytes and their derivatives of natural origin including chitosan derivatives, dextran, starch, hydroksypropyl cellulose, glycosaminoglycans (including hyaluronic acid derivatives, heparin, heparan sulfate, keratan sulfate, chondroitin and dermatan), carrageenan, alginate and synthetic polyelectrolytes such as poly-L-lysine, polyornityne, poly (D-glutamic acid), derivatives of poly (lactic acid), polystyrenesulfonate, poly (diallildimethylammonium chloride), polyallylamine hydrochloride or polyethyleneimine. Fluorescently labelled polysaccharides are recommended in order to manufacture multilayer capsules for in vivo imaging.
• Covering capsules with multilayer films is of crucial importance as it enables to control the charge of capsules and thus avoid aggregation of the product with blood cells what is essential for biomedical applications. Moreover, such strategy provides an increase in stability of the capsules as well as improvement of their bioavailability and biocompatibility.
• the outer layer of the capsules should be anionically charged. It is particularly preferred to use an anionic derivative of chitosan and glycosaminoglycans. It is also recommended to modify the outer layer of the capsules with polyethylene glycol (PEG) as it results in an improvement of bioavailability of the capsules and prolongation of circulation time in the bloodstream.
• PEG polyethylene glycol
• An advantage of the invention is the possibility of preparation of biocompatible, stable nanoemulsion without the use of low molecular weight surfactant.
• Invented capsules can encapsulate hydrophobic compounds that are dissolved directly in the oil cores that provides highly efficient encapsulation.
• the simplicity of preparation, low energy and financial inputs in the production process, resistance to changes in environmental parameters (such as pH and concentration) and low complexity of biocompatible system allows it to be widely used as carriers of lipophilic biologically active compounds.
• Tables 1 and 2 contain data on stability of the capsules described in examples I-IV.
• Table 3 shows how pH affects the morphology and stability of the capsules described in examples VIII-IX.
• Table 4 includes data on parameters of the capsules templated on various types of oil cores as described in examples X-XII.
• Table 5 contains data on stability of the capsules described in example XVI.
• Fig. 1-4 show size distribution of capsules described in examples I- VI.
• Fig. 5 is size distribution of capsules described in example V.
• Fig. 6 i 7 show confocal micrographs of the capsules presented in examples VI i VII.
• Fig. 8 is size distribution of capsules described in example VII.
• Fig. 9 is size distribution of capsules described in example VII.
• Fig. 10 i 11 show size distribution of capsules described in examples VIII-IX.
• Fig. 12 shows size distribution of capsules described in examples X-XI.
• Fig. 13 is size distribution of capsules described in example XII.
• Fig. 14 shows SEM micrographs of the capsules templated on n-dodecane core described in example XIII.
• Fig. 15 i 16 show size and zeta potential of the capsules covered by cationically and anionically chitosan as presented in example XIV.
• Fig. 17 is size distribution of capsules described in example XV.
• Fig. 18 is size distribution of capsules described in example XVI.
• Fig. 19 is cryo-TEM micrograph of the capsules described in example XVI.
• Fig. 20 is size distribution of capsules described in example XVII.
• Fig. 21 i 22 show size and zeta potential of the capsules described in example XVIII.
• Fig. 23 is size distribution of capsules described in example XIX.
• Fig. 24 i 25 show size and zeta potential of the capsules described in example XX.
• Fig. 26 is size distribution of capsules described in example XXI.
• Hyaluronic acid modified with hexyl side chains was dissolved in O. l M NaCl (1 g/L) and mixed with oleic acid (100: 1 v/v). Both phases were vortexed for 5 minutes and emulsified for 30 minutes at room temperature in ultrasonic bath (540 W, 1-second pulse, 2- second break). Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 500 nm. The obtained capsules showed at least 2-week stability as confirmed by hydrodynamic diameter as well as zeta potential measurements. Two days after preparation a decrease in particle size was observed (to ca. 360nm) what suggests destabilization of the aggregates and/or bigger capsules and formation of an emulsion containing only smaller and more stable particles (Fig. 1, Table 1).
• DLS dynamic light scattering technique
• Example 1 Mixture of an aqueous solution of hyaluronic acid modified with octyl side chains (Hy-C8) and oleic acid was prepared according to the procedure described in Example I. Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 700 nm. The obtained capsules showed at least 2-week stability as confirmed by hydrodynamic diameter as well as zeta potential measurements. Two days after sonication significant decrease in particle size was observed (to ca. 300nm) what suggests destabilization of the aggregates and/or bigger capsules and formation of an emulsion containing only smaller and more stable ones. (Fig. 2, Table 1).
• DLS dynamic light scattering technique
• Example III Preparation of nanocapsules templated on oleic acid cores stabilized by hyaluronic acid modified with dodecylamine
• Hyaluronic acid modified with dodecyl side chains was dissolved in 0.1 M NaCl (1 g/L) and mixed vigorously for 60 minutes using magnetic stirrer (500 rpm) in order to provide complete dissolution of the polysaccharide. Such an aqueous solution was then mixed with oleic acid (100: 1 v/v), vortexed for 5 minutes and emulsified for 30 minutes at room temperature in ultrasonic bath (540 W,
• Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 200 nm.
• the obtained capsules showed at least 2- week stability as confirmed by hydrodynamic diameter as well as zeta potential measurements. As the size of resulted capsules decreased slightly after 3 days following sonication, destabilization of aggregates and/or bigger capsules of and formation of an emulsion containing only smaller and more stable particles is postulated. (Fig. 3, Table 1).
• Example IV Preparation of nanocapsules templated on oleic acid cores stabilized by hyaluronic acid modified with octadecylamine Mixture of an aqueous solution of hyaluronic acid modified with octadecyl side chains (Hy- C18) and oleic acid was prepared according to the procedure described in Example III. Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 320 nm. The obtained capsules showed at least 2-week stability as confirmed by hydrodynamic diameter as well as zeta potential measurements. As the size of resulted capsules decreased to ca. 250 nm after 3 days following sonication destabilization of aggregates and/or bigger capsules of and formation of an emulsion containing only smaller and more stable particles is postulated (Fig. 4, Table 1).
• DLS dynamic light scattering technique
• Example V Determination of the effect of concentration of polysaccharide and saline on the size and stability of capsules templated on oleic acid cores stabilized by Hy-C12
• Hyaluronic acid modified with dodecyl side chains dissolved in 0.15 M NaCl (5 g/L) was used to prepare nanocapsules templated on oleic acid cores according to procedure described in Example III. Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 280 nm (Fig. 5).
• DLS dynamic light scattering technique
• Example VI Determination of the efficiency of encapsulation of hydrophobic dye by capsules Hy-C12 templated on oleic acid cores.
• Example VIII Determination of the effect of low pH on size and stability of capsules Hy- C12 templated on oleic acid cores
• Example K Determination of the effect of low pH on size and stability of capsules Hy-C18 templated on oleic acid cores
• Example VIII Mixture of an aqueous solution of hyaluronic acid modified with octadecyl side chains (Hy- C18) and oleic acid was prepared according to procedure described in Example VIII. Size of the resulted capsules was determined using dynamic light scattering technique (DLS) to be ca. 125 nm before and 130 nm after acidification. Optical microscopy confirmed that decrease in pH of suspension does not affect the stability of capsules (Fig. 11, Table 4).
• DLS dynamic light scattering technique
• Example III Mixture of an aqueous solution of hyaluronic acid modified with dodecyl side chains (Hy- C12) and linseed oil was prepared according to the procedure described in Example III.
• the resulted capsules were characterized using DLS: size was determined to be ca. 320 nm and zeta potential ca. -22 mV. The obtained results indicate that nanocapsules can be formed regardless the type of oil used as a core (Fig. 12, Table 5).
• Example X Mixture of an aqueous solution of hyaluronic acid modified with octadecyl side chains (Hy- C18) and linseed oil was prepared according to the procedure described in Example X.
• the resulted capsules were characterized using DLS: size was determined to be ca. 530 nm and zeta potential ca. -21 mV. The obtained results indicate that nanocapsules can be formed regardless the type of oil used as a core(Fig. 12, Table 5)
• Example X Mixture of an aqueous solution of hyaluronic acid modified with dodecyl side chains (Hy- C12) and argan oil was prepared according to procedure described in Example X.
• the resulted capsules were characterized using DLS: size was determined to be ca. 710 nm and zeta potential ca. -20 mV. The obtained results indicate that nanocapsules can be formed regardless the type of oil used as a core (Fig. 13, Table 5).
• Capsules stabilized by hyaluronic acid modified with dodecyl side chains (Hy-C12) and templated on oleic acid cores were prepared according to procedure described in Example III. DLS measurements indicated formation of capsules of 170 nm in diameter and zeta potential equal to -19 mV. The resulted capsules were then covered by multilayer shells using layer by layer saturation technique - small quantities of either cationically or anionically modified chitosan (1 g/L in 0, 15M NaCl) were added to suspension and after each step both, size of zeta potential were measured to control the process of adsorption of each layer.
• the resulted 4-layer-capsules were characterized to be 315 nm in diameter and have zeta potential equal to -28 mV.
• Gradual increase in average diameters of capsules as well as typical zigzag shape of the zeta potential plot confirms alternating adsorption of the polyelectrolytes and strong electrostatic stabilization of the capsules (Fig.15 and 16).
• obtained results indicate that anionic layers are more preferred and provide better stabilization of capsules.
• Example XV Determination of the effect of concentration of polyelectrolyte on the process of preparation of multilayer Hy-C12 capsules templated on oleic acid cores
• Capsules stabilized by hyaluronic acid modified with dodecyl side chains (Hy-C12) and templated on oleic acid cores were prepared according to procedure described in Example III. DLS measurements indicated formation of capsules of 210 nm in diameter and zeta potential equal to -24 mV. The resulted capsules were then covered by multilayer shells using layer by layer saturation technique - small quantities of either cationically or anionically modified chitosan (10 g/L in 0,15M NaCl) were added to suspension and after each step both, size of zeta potential were measured to control the process of adsorption of each layer.
• the resulted 2-layer-capsules were characterized to be 240 nm in diameter and have zeta potential equal to -39 mV what indicates high stability of nanoemulsion (Fig. 17).
• Fig. 17 By using concentrated chitosan solutions the dilution of the sample was minimized what is of significant importance for biomedical applications.
• one bilayer of chitosan was sufficient to obtain system of stability higher than for capsules described in Example XIV.
• obtained results confirmed that anionic layers are more preferred and provide better stabilization of capsules.
• Cationic derivative of chitosan modified with dodecyl side chains was dissolved in O. l M NaCl (1 g/L) and vigorously mixed for 4 days in order to provide complete dissolution of polysaccharide.
• the resulted solution of CChit-C12 was mixed with oleic acid (100: 1 v/v). Both phases were vortexed for 5 minutes and emulsified for 30 minutes at room temperature in ultrasonic bath (540 W, 1 -second pulse, 2-second break). Size of the resulted capsules was determined using DLS to be ca. 320 nm.
• the obtained capsules showed at least 2-week stability confirmed by hydrodynamic diameter as well as zeta potential measurements. (Fig. 18, Fig. 19, Table 6 5).
• C12 nanocapsules templated on oleic acid cores Capsules stabilized by cationic derivative of chitosan modified with dodecyl side chains (CChit-C12) and templated on oleic acid cores were prepared according to modified procedure described in Example XVI - chitosan was dissolved in acetic acid (0.12 M) acetic acid. It resulted in decrease in time of dissolution of chitosan to less than 30 minutes. The resulted capsules were characterized to be 400 nm nm in diameter and have zeta potential equal to 25 mV (DLS measurements) (Fig. 20).
• Example XVIII Preparation of multilayer CChit-C12 capsules templated on oleic acid cores
• Capsules stabilized by cationic derivative of chitosan modified with dodecyl side chains (CCHit-C12) and templated on oleic acid was prepared according to procedure described in Example XVI.
• the resulted capsules were characterized to be 260 nm in diameter and have zeta potential equal to +25 mV.
• the obtained capsules were then covered by multilayer shells using layer by layer saturation technique - small quantities of either cationically or anionically modified chitosan (1 g/L in 0,15M NaCl) were added to suspension and after each step both, size of zeta potential were measured to control the process of adsorption of each layer.
• the resulted 2-layer-capsules were characterized to be 340 nm in diameter and have zeta potential equal to +21 mV.
• Gradual increase in average diameters of capsules as well as typical zigzag shape of the zeta potential plot confirms alternating adsorption of the polyelectrolytes and strong electrostatic stabilization of the capsules (Fig. 21, Fig. 22).
• obtained results confirmed that anionic layers are more preferred and provide better stabilization of capsules.
• Example XIX Preparation of capsules templated on oleic acid cores and stabilized by octadecyl derivative of anionically modified chitosan oligocaccharide
• Capsules templated on oleic acid was prepared according to modified procedure described in Example I - octadecyl derivative of anionically modified chitosan oligocaccharide (oChit- C18-sulf) was used as emulsion stabilizer.
• the resulted capsules were characterized using DLS to be 150 nm in diameter (Fig. 23).
• Example XX Preparation of multilayer capsules templated on oleic acid cores and stabilized by octadecyl derivative of anionically modified chitosan oligocaccharide
• Capsules templated on oleic acid was prepared according to procedure described in Example XIX.
• the resulted capsules were characterized to be 170 nm in diameter and have zeta potential equal to -17 mV.
• Capsules were covered by multilayer shells according to procedure describing in Example XVIII.
• the resulted 8-layer-capsules were characterized to be 260 nm in diameter and have zeta potential equal to -29 mV.
• Gradual increase in average diameters of capsules as well as typical zigzag shape of the zeta potential plot conforms alternating adsorption of the polyelectrolytes and strong electrostatic stabilization of the capsules (Fig. 24, Fig. 25).
• anionic layers are more preferred and provide better stabilization of capsules.
• Example XXI Determination of the effect of degree of hydrophobic modification and concentration of polysaccharide on the parameters describing nanocapsules templated on oleic acid cores stabilized by Hy-C18x.
• Hyaluronate modified with octadecyl side chains (4.5% of substitution) was dissolved in 0.1M NaCl (1 g/L or 5 g/L) and mixed vigorously for 60 minutes using magnetic stirrer (500 rpm) in order to provide complete dissolution of polysaccharide. Such aqueous solutions were then mixed with oleic acid (100: 1 v/v), vortexed for 5 minutes and emulsified for 30 minutes at room temperature in ultrasonic bath (540 W, 1- second pulse, 2-second break). Size of the resulted capsules was determined using DLS to be ca.

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