WO2008028264A1 - Procédé de production de microcapsules ayant des propriétés magnétiques, produits obtenus à partir desdites microcapsules et procédé pour la libération contrôlée de substances actives - Google Patents

Procédé de production de microcapsules ayant des propriétés magnétiques, produits obtenus à partir desdites microcapsules et procédé pour la libération contrôlée de substances actives Download PDF

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WO2008028264A1
WO2008028264A1 PCT/BR2007/000224 BR2007000224W WO2008028264A1 WO 2008028264 A1 WO2008028264 A1 WO 2008028264A1 BR 2007000224 W BR2007000224 W BR 2007000224W WO 2008028264 A1 WO2008028264 A1 WO 2008028264A1
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particles
fact
set forth
alginate
micro
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PCT/BR2007/000224
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WO2008028264A8 (fr
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Priscilla Vanessa Finotelli
Marcos Antonio Morales Torres
Alexandre Malta Rossi
Maria Helena Miguez ROCHA LEÃO
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Centro Brasileiro De Pesquisas Fisicas-Cbpf
Universidade Federal Do Rio De Janeiro - Ufrj
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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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin

Definitions

  • the present invention is related to the production process for microcapsules endowed with magnetic properties, the products related to this process and to a method for the controlled release of active substances. More specifically, the process and the product resulting from the present invention are useful in the controlled release of active substances such as drugs, catalysts and other active substances.
  • the production process constituting the present invention encompasses the in situ synthesis of nano-particles in the presence of polymers such as alginate and / or chitosan and the inclusion of ingredients with magnetic properties in the micro-capsules. The product obtained through this process allows the controlled release of active substances through the application of an oscillating magnetic field.
  • Micro-encapsulation technology involves complex processes that allow new functional and "smart" properties to be incorporated into an active material, such as controlled release or activation in specific media, all under appropriate conditions, making the material of which it is a part more efficacious (foods, cosmetics, medications, human organisms, means of reaction, etc.).
  • micro-encapsulation of active substances offers the advantage of resolving the problem of the instability of active materials, and also of some drugs that are used regularly over time, such as insulin.
  • Some substances used in medical practice require tighter controls over release rates, as they reach their peak right after administration, generally at a higher value than normal in the plasma.
  • the micro-capsules must release the material from the core through outside stimuli and regulation (KOST et al, 2001; SIEGEL et al, 1995). Similar to biological processes through which the amount of the drug released is the function of the physiological requirements, these systems are known as “open-loop” systems, in counterpart to "closed-loop” systems, but are still not available commercially (SERSHEN et al, 2002).
  • the external action mechanisms that stimulate release from the core of the capsules in the "open-loop" systems are based on their magnetic electrical and thermal properties, or on the ultra-sound and radiation actions when applied to the micro-capsules.
  • the strategy of these systems is pre-scheduled pulsed.
  • SIEGEL et al, 1995 mentions three examples of applications: hormones (insulin, growth, etc), that must be release endogenously on a pulsed basis; drugs that display tolerance and may not be released constantly (narcotics and antagonists, nitrate); and finally chemotherapeutic drugs for treating cancer.
  • Micro-capsules containing insulin that can be modulated by oscillating magnetic fields may well adjust perfectly to the demands of the body, if implanted in diabetic patients through minimally invasive surgery (LANGER, 1990; SIEGEL et al, 1995).
  • Critical factors for release control rates in a magnetically modulated system may be divided into two main groups: (1) magnetic field characteristics (frequency and intensity); (2) structural mechanical properties of the polymer matrix system and nano-particles system (KOST et al, 2001). Another important point to be dealt with is the mechanisms through which these micro-capsules may be subject to bio-degradation in the human body. If the polymer matrix does not degrade in the body, it must be surgically removed, resulting in high costs and risks for the patient. For example, there are already records of alternative systems used in the past to administer vaccines (PREIS et al, 1979).
  • Bio-degradable polymer matrixes are already bio-compatible and degradable, meaning that they degrade in vivo into small fragments that may be excreted by the body. These degradation products are not toxic and should not create any inflammatory response. Another important characteristic is that the degradation must occur within a reasonable period of time as required by the application.
  • alginate is one of the most versatile bio-polymers currently used in the foods, pharmaceuticals and bio-engineering sectors, particularly as a matrix for trapping drugs, macro-molecules and biological cells.
  • Alginate is a linear co- polymer consisting of ⁇ -D-manuronic acid (M) and ⁇ -L-guluronic acid (G), with these monomers being arranged in a block structure, whose composition and distribution varies according to the source of the alginate. This block structure determines the physical properties of the polysaccharide and particularly the type of gel formed.
  • the alginate may be subject to gelification in the presence of divalent cation salts (such as Ca 2+ , Cu 2+ , Zn 2+ or Mn 2+ ).
  • divalent cation salts such as Ca 2+ , Cu 2+ , Zn 2+ or Mn 2+ .
  • the gelification of the alginate is based on the affinity of the alginate with certain ions and its ability to bond selectively and cooperatively with these ions. This gelification is conventionally described in terms of the egg-box model, where divalent cations are bonded in a coordinated manner to the carboxylates of the guluronic acids. The conformation of the guluronic acid takes place at an appropriate distance from the carboxyl and hydroxyl groups, resulting in a high level of coordination with the calcium ions. Alginates rich in G-blocks form stronger but more brittle gels, while even the balanced (MG) alginates, or those in which M-blocks predominate, result in weaker but elastic gels.
  • the system generally used to obtain calcium alginate spheres consist of the extrusion method, through which a sodium alginate solution is dripped from a syringe into a calcium chloride solution.
  • Micro-encapsulation requires the use of a needle with a fairly small diameter in order to produce capsules in micro- metric dimensions.
  • the active substance must be blended with the sodium alginate solution.
  • the replacement of the sodium ions by the calcium ions begins in the alginate structure (gelification process).
  • the diffusion process of the calcium ions into the sphere takes place during a period called the cure time, and is not uniformly distributed, with a high concentration on the surface which gradually spread into the centre of the sphere. This may be explained by the diffusion barrier that forms immediately on the surface of the sphere, so that the ions encounter more resistance when moving into the centre.
  • Alginate spheres have been covered with positive-loaded polymers, such as
  • Alginate presents bio-compatibility, and is available in abundance, at low prices. Well-established bio-compatibility has allowed alginate to be used industrially in medical and bio-technological applications (DONATI et al, 2003). As alginate is hydrophilic, it does not generate any surface tension with surrounding tissue and fluid, minimising the adsorption of proteins and cellular adhesion. As it is a light and flexible gel, it causes minimal mechanical and friction irritation around the target tissue. The combination of these two factors results in high bio-compatibility.
  • Chitosan is a polysaccharide consisting of glucosamine and N- acetylglucosamine copolymers, and may be derived from the partial desacetylation of chitin taken from crustacean shells (CANELLA et al, 2001).
  • Chitosan may be used to prepare various polyelectrolyte complexes with natural polyanions such as carboxymethylcellulose, heparin, alginate, carrageenan and hyaluronate.
  • Chitosan / polyanion complexes have been quite widely investigated for drug and protein release applications, cell transplants and enzyme immobilisation.
  • the chitosan / alginate complex may be the most important for drug release systems.
  • the strong electrostatic interaction of the chitosan amino groups with the alginate carboxyl groups leads to the formation of the chitosan / alginate complex (MURATA et al, 1999; HUGUET et al, 1996). Due to the protonation of the chitosan amino group and the ionisation of the alginate carboxyl acid group, the stability of their chitosan / alginate complex may be influenced by parameters such as pH and ion force.
  • Nano-particles are ideal elements for constructing nano-structured devices with adjustable physical and chemical properties.
  • the application of small iron oxide particles for in vitro diagnoses has been used for some forty years.
  • SREERAM et al, 2004 managed to make the Fe ions (III) bond to specific sites on the alginate, and also formed spatially separated
  • Fe (III) centres on the structure, avoiding any coating with FeOOH precipitates.
  • NESTEROVA et al, 2000 synthesised superparamagnetic clusters of Fe (III) complexes in the form of slightly crystalline ferrihydrite in the presence of polymers such as poly vinyl-alcohol, polyacrylic and alginate. They concluded that these iron particles were superparamagnetic and that the presence of the polymer exercises a significant influence on the stability and organisation of the hydrolytic Fe (III) products formed.
  • the nanoscopic magnetic systems present a wide variety of interesting physical properties, forming a unique set for the study of various solid state physics problems, such as superparamagnetism (MORUP, 1994; GARCIA-
  • the full characterisation of magnetic materials involves a series of experimental techniques based on magnetisation measurements that may be defined as being the sum of all the elementary magnetic moments of the sample, divided by its volume, and magnetic susceptibility, which is the magnitude characterising a magnetic material according to its response to an applied magnetic field, which may be static (dc) or dynamic (ac).
  • magnetisation is measured as a function of the applied magnetic field at a constant temperature: these are the magnetisation curves or isotherms (MxH)T.
  • the susceptibility (generally ac) is a function of the temperature is another technique that is widely used, as it is simple and does not require magnetic fields, providing information on how the initial part of the magnetisation varies according to the temperature.
  • the magnetic properties of the nano-particles are studied using magnometry measurements, M ⁇ ssbauer spectroscopy (MS) and paramagnetic electronic resonance (RPE).
  • MS M ⁇ ssbauer spectroscopy
  • RPE paramagnetic electronic resonance
  • CHATTERJEE et al, 2002 studied maghemite nano-particles (Y-Fe 2 Os) covered with polyethylene; particles with diameters of 50 to 500 nm had a blocked temperature of 60 K.
  • BERGER et al, 2001 studied the behaviour of maghemite nano-particles formed in silicate as a function of the temperature through RPE. They found that the blocked temperature of the superparamagnetic particles was 90 K.
  • FIORINI et al, 2002 investigated the magnetic properties of maghemite nano-particles dispersed in polyvinyl alcohol, using Susceptibility and M ⁇ ssbauer spectroscopy. The findings indicated that the interactions between the particles and the surface effect control the magnetic properties.
  • PARDOE et al, 2001 used magnetisation and M ⁇ ssbauer spectroscopy to investigate the magnetic properties of the magnetite particles and maghemite synthesised in the presence of dextran or polyvinyl alcohol. They found that the superparamagnetic blocked temperature depends on the nature of the polymer.
  • Magnetite (Fe 3 O 4 ) is one of the ores most widely used to obtain iron.
  • This ore is an ion oxide mixed with FeO and Fe 2 O 3, with an inverted spinel structure, with the cubic packing of O 2" ions and the larger Fe 2+ ions (ion radius of 0.74 A) in the octahedral interstices, with half the Fe 3+ ions (ion radius of 0.64 A) in octahedral sites and the remaining half in tetrahedral positions (SIDHU et al, 1978).
  • the magnetic behaviour of the magnetite particles is strongly influenced by their size and shape, as well as the precursor conversion temperature. Magnetites with different Fe (II) / Fe (III) proportions are formed, depending on temperature variations (LELIS, 2003). Moreover, differences in the magnetic behaviour are observed not only in similar materials coming fro different synthesis routes, but also in materials that have undergone the same heat treatment. According to LELIS, 2003, thermodynamic balance is attained when some re-arrangements occur in the crystal network, implying changes in the magnetisation direction and/or the spatial distribution of the magnetic ions.
  • these particles may be in the superparamagnetic state.
  • Superparamagnetic particles are interesting, as they do not conserve any magnetism after the removal of the magnetic field. Their efficacy in the released device depends on:
  • Nanoscopic magnetic systems present a wide variety of interesting physical properties, forming a single set for the study of assorted problems in solid state physics, such as superparamagnetism and grain nucleation and growth kinetics.
  • Magnetite is a very well-known material and its toxicity has been demonstrated as being very low, according to ARIAS et al, 2001 , (LD50 in rats: 400 mg / kg), and well tolerated in humans. Furthermore, magnetite particles associated with polymers do not demonstrate toxicity in animals.
  • Maghemite ( ⁇ -Fe 2 O 3 ) is another mineral with a strongly magnetic nature that presents a non-stoichiometric structure of the spinel, as there is not enough Fe 3+ to fill all the tetrahedral (A) and octahedral (B) sites.
  • Diabetes mellitus is a group of dysfunctions characterised by hyperglycemia, and an altered metabolism for lipids, carbohydrates and proteins, with higher risks of complications due to vascular disease (GOODMAN & GILMAN, 1996).
  • the normal blood sugar level when fasting hovers between 80 and 120 mg per 100 mL of blood, and may vary a little, depending on the measurement method used.
  • glucose appears in the urine (glycosuria).
  • Glucose homeostatis is dependent on the glucose and insulin concentrations in the plasma (OWENS et al, 2001).
  • Insulin is the basic treatment for almost all patients with insulin-dependent diabetes mellitus, and many patients with non- insulin-dependent diabetes mellitus. When necessary, insulin may be administered either intravenously or by intramuscular means. However, long-term treatment is based mainly on the sub-cutaneous injection of the hormone.
  • the sub-cutaneous administration of insulin differs from physiological insulin secretion in at least two important ways: the kinetics do not mimetise the rapid rise and fall of normal insulin secretion level in response to the ingestion of nutrients, and the insulin spreads through the peripheral circulation, instead of being released in the port circulation; the preferential effect of insulin secreted during metabolic hepatic processes is thus eliminated.
  • Intermediate action insulin was selected for the development of this invention.
  • This insulin is obtained through the addition of a substance that retards the absorption of protein: phenol.
  • the combination of insulin and a delaying substance generally results in the formation of crystals (dimmers) that give the liquid a turbid appearance (suspension).
  • the first insulin molecules take approximately an hour and half to reach the bloodstream. The largest number of molecules reaches the bloodstream between the fourth and twelfth hours after administration, with the dose being fully absorbed after some 24 hours.
  • US Patent 6,861 ,064 is related to an encapsulation method for active substances in a bio-degradable polymer (polyethyleneglycol).
  • the preparation of these micro- or nano-particles endowed with biologically active matter, such as proteins, is performed through the use of small quantities or organic solvents.
  • the synthesised microcapsules have diameters of less than 10 ⁇ m and are preferably between 0.5 and 3 ⁇ m.
  • the international application for Patent WO 04071386 describes the administration of biologically active molecules, more particularly compositions encompassing micro-capsules of liposomes with magnetic nano-particles and biologically active molecules.
  • One of the objects of the present invention is to provide a process for the production of micro-capsules endowed with magnetic properties.
  • Another of the objects of the present invention is to provide microcapsules with nano-particles for the controlled release of active substances.
  • Another of the objects of the present invention is to provide a method for the controlled release of active substances through the application of an oscillating magnetic field.
  • the production process constituting the present invention provides the synthesis of nano-particles inside the micro-capsules.
  • another object of the present invention is to provide a process for the production of polymer micro-capsules bio-compatible with nano-particles, in which the synthesis of nano-particles is performed inside the micro-capsules.
  • Another object of the present invention is the polymer product that is biocompatible with nano-particles for the release of substances biologically active.
  • it provides a magnetically modulated system for the controlled release of active substances from polymer matrixes, in which the nano-particles attribute magnetic properties to the product.
  • Another object of the present invention is to provide the covering of polymer micro-capsules bio-compatible with polysaccharide in order to enhance the stability and resistance of the system.
  • the present invention provides a production process for alginate micro-capsules with iron oxide nano-particles. This product is useful for the release of molecules biologically active molecules with this matter consequently constituting yet another object of the present invention.
  • the present invention provides a production process for iron oxide nano-particles in the alginate micro-capsules.
  • the iron oxide nano-particles endow the product with magnetic properties and the release of biologically active molecules takes place through the application of an oscillating magnetic field, with this matter consequently constituting yet another object of the present invention.
  • the alginate micro-capsules are coated with chitosan.
  • the strong electrostatic interaction of the chitosan amino groups with the alginate carboxyl groups leads to the formation of the chitosan / alginate complex, due to the protonation of the chitosan amino group and the ionisation of the alginate carboxyl acid group, the stability of the chitosan / alginate may be influenced by parameters such as pH and ionic force, with this material constituting yet another object of the present invention.
  • Figure 1 Scheme representing the micro-encapsulation method based on the alginate gelification property in the presence of di- and tri-valent cations.
  • Figure 2 Formation of the alginate / chitosan system.
  • Figure 3 Scheme of the formation methods for two types of alginate gel.
  • Figure 5 Standard insulin curve in a phosphate buffer pH at 7.4 to 266 nm.
  • Figure 9 M ⁇ ssbauer spectroscopy measurements of magnetic [missing word in the original] composite (Sample B: 0.5 mols / L Fe) conducted at different temperatures.
  • Figure 10 Susceptibility and magnetisation measurements of the alginate magnetic composite (Sample B: 0.5 mols / L Fe), obtained at the temperature as shown in the Figure.
  • Figure 11 - X-ray diffraction pattern for Sample B: (•) positions of the main peaks of the iron hydroxide.
  • Figure 12 - X-ray diffraction of alginate spheres with Fe 3 O 4 nano-particles produced after the alginate gelification (Sample C).
  • the solid line is an adjustment by the Langevin function with a lognormal distribution of particle sizes.
  • Figure 19 Absorption area for the M ⁇ ssbauer spectroscopy (RAA) in function of the temperature.
  • Figure 20 Micrography I of a calcium alginate sphere with magnetic nano- particles, Sample C.
  • Figure 21 Micrography Il of a calcium alginate sphere with magnetic nano- particles, Sample C.
  • Figure 22 Micrography III of a calcium alginate sphere with magnetic nano- particles, Sample C.
  • Figure 25 Image of a clear field obtained by electronic transmission microscopy for a calcinate alginate sphere with magnetic nano-particles.
  • Figure 27 Insulin release profile for alginate micro-capsules.
  • Figure 28 Insulin release profile for alginate / chitosan micro-capsules.
  • Figure 29 Comparison of the in vitro release profile for the alginate / chitosan micro-capsules. Bar: standard deviation.
  • Figure 30 Comparison of the insulin release profiles in distilled water from micro-capsules containing different insulin concentrations in an alginate chitosan / matrix. A1: 56%; A2: 38%; A3: 34%; A4: 26%; A5: 25%.
  • Figure 31 Comparison of the insulin release profiles in a CaCI 2 solution from the micro-capsules with different concentrations of insulin in an alginate chitosan / matrix. B1 : 73%; B2: 53%; B3: 38%; B4: 31%; B5: 30%.
  • Figure 32 Insulin profile from alginate / chitosan micro-capsules with magnetic iron oxide nano-particles. Bar: standard deviation.
  • One of the objectives of the specific presentation of the invention is to associate the use of natural polymer, using nano-technology for embodying the modulator responsible for the polymer response to an external stimulus that may control the outflow of the encapsulated active material. Synthesising iron oxide particles of nano-metric size, directly structured in a polymer network displayed by the alginate is one of the main obstacles in this technique, as a practical solution should not simply produce the particles and embody them in the polymer.
  • the system generally used to obtain calcium alginate spheres consists of the extrusion method through which a sodium alginate solution is dripped from a syringe into a calcium chloride solution.
  • Micro-encapsulation requires the use of a needle with a fairly small diameter in order to produce capsules in micro-metric dimensions.
  • the active substance must be blended with the sodium alginate solution.
  • the replacement of the sodium ions by the calcium ions begins in the alginate structure (gelification process).
  • the diffusion process of the calcium ions into the sphere takes place during a period called the cure time, and is not uniformly distributed, with a high concentration on the surface which gradually spread into the centre of the sphere. This may be explained by the diffusion barrier that forms immediately on the surface of the sphere, so that the ions encounter more resistance when moving into the centre.
  • the process covered by the specific presentation of the invention was idealised to produce insulin micro-capsules insulin micro-capsules in an alginate chitosan matrix with the magnetic nano-particles for subcutaneous implant.
  • the chitosan is bonded to the alginate matrix in order to enhance its capacity to trap the insulin through the bio-material.
  • the interaction of the magnetic particles with the external oscillating magnetic field applied is able to trigger the outflow of the trapped insulin.
  • insulin was the molecule selected for testing in terms of its release, this system is a model that may be applied to different molecules.
  • the system for the controlled release of substances through the application of a magnetic field is useful for administering insulin to patients with diabetes mellitus.
  • the present invention makes provision for sundry other applications, such as the use of drugs by patients with heartbeat disorders, gastric acid inhibitors for ulcer control, nitrate for people with angina pectoris, as well as selective beta blockers, birth control and hormone replacement, chemotherapy and immunosuppressants taken over the long term.
  • the presence of calcium ions in the chitosan solution during incubation has an important effect on the ability of the alginate sphere to bond with the chitosan.
  • the stability of the chitosan alginate complex is enhanced by the presence of the calcium ions, because although the chitosan rapidly bonds to the surface of the alginate drop, its diffusion into the inner portion of the sphere is limited.
  • the calcium ions are engaged in the gelification reaction and the polyelectrolyte complex results in the formation of a more porous gel, allowing the diffusion of the chitosan.
  • the stability and permeability of the alginate chitosan spheres may be improved by initially dripping the alginate solution in CaCI 2 to form the calcium alginate spheres, after which the spheres will be treated with chitosan solution to form a chitosan alginate complex membrane ( Figures 2 and 3).
  • Atomic absorption spectroscopy (EAA) measurements were conducted to determine the iron concentration in the sample. To do so, a spectrophotometer was used, fitted with a hollow cathode light-bulb and an air-acetylene flame under oxidising conditions.
  • EAA Atomic absorption spectroscopy
  • DRX X-ray diffraction
  • EM EM
  • RPE paramagnetic electronic resonance
  • M(H) magnetisation
  • ⁇ susceptibility
  • Mossbauer spectra were obtained in the transmission mode, using as a source 57 Co dispersed in a research matrix.
  • a helium dip was used with the source and the absorber maintained at the same temperature.
  • the high temperature measurements (10 to 300 K) were conducted through a closed cycle in a helium gas refrigerator, and in this case the source was maintained at 300K.
  • the Centre Shift (CS) reported is for the iron bcc at room temperature.
  • the magnetic characterisation was conducted through a magnometer.
  • Zero-field-cooled ( ⁇ ZFC) susceptibility measurements were obtained through cooling the Sample from 300 K to 4.2 K in a zero field, and the magnetic moment measurement of the sample was conducted in a magnetic field of 100
  • the RPE measurements were conducted at 300 K using a Bruker ESP
  • the morphology of the calcium / alginate micro-spheres was observed through an electronic sweep microscope.
  • the voltage acceleration used was 15 or 20 kV.
  • the spheres were affixed on cylindrical metal racks with a diameter of 10 mm, using double-faced adhesive tape. The samples were then coated with gold and analysed.
  • micrographics were conducted using an electronic transmission microscope. The sample was fixed in glutaraldehyde / formaldehyde and subsequently set in a block of epon resin. Finally, fine slices were cut for observation under the microscope.
  • a spectrophotometer sweep was conducted to ascertain the maximum absorbance wave length for the insulin used in the study. It was ascertained that the peak absorbance occurred at 266 nm, and from then on this wave length was established for the insulin analyses.
  • a standard insulin curve was prepared in a pH 7.4 for phosphate buffer that provided a straight equation that was subsequently used for the calculations of the insulin concentrations in the samples. The insulin concentration in the samples was assessed through spectrophotometric analysis, using a wave-length of 266 nm. To do so, a mass of alginate spheres with insulin was treated with pH 7.4 buffer for phosphate buffer until they dissolved completely.
  • Encapsulation Efficiency (%) ⁇ (real insulin mass / micro-capsules mass) / (theoretical insulin mass / micro-capsules mass) ⁇ x 100.
  • the findings were expressed as the mean ⁇ standard deviation (DP) of three experiments.
  • the straight equation was used to calculate the insulin concentrations in the samples.
  • Example 1 In situ synthesis of iron oxide nano-particles in an alginate matrix.
  • alginate spheres were prepared by dripping a 3% sodium alginate solution in an aqueous iron chloride III solution. Two samples were prepared: Sample A with 0.01 mols / L and Sample B with 0.5 mols / L of the iron chloride III solution. The process was agitated magnetically in an argon atmosphere at 25 0 C. Samples A and B remained in the iron III solution for a period of five minutes and two hours respectively. The spheres were then removed from the solution and washed several times with MiIIi-Q water. They were dried in a hot-box at 35 0 C for twelve hours.
  • Example 2 In situ synthesis of iron oxide nano-particles in an alginate matrix.
  • the iron oxide nano-particles were prepared in the presence of calcium alginate.
  • Calcium alginate spheres were prepared through the extrusion method.
  • a sodium alginate solution (2%) was dripped into a calcium chloride solution of
  • 0.55x20 24 G 3 ' 4 was used as the instrument to produce the spheres. After the gelification of the spheres, which continued for an hour, the spheres were removed from the calcium chloride solution by filtration and were then washed in a 50% methanol solution.
  • a Fe (III) and Fe (II) equimolar solution was prepared from FeCI 3 .6H 2 O 0.5 mols / L and FeCI 2 0.5 mols / L.
  • the calcium alginate spheres were then added to this solution and kept at a constant temperature of 6O 0 C for fifteen minutes under magnetic agitation.
  • the 25% ammonium hydroxide solution was then dripped into the iron-polymer mixture in order to obtain a pH between 11 and 12, after which the mixture was kept at 6O 0 C for a further fifteen minutes, still under magnetic agitation.
  • the spheres with the iron oxide nano-particles were washed in a 50% methanol solution and dried in a hot-box at 35 0 C during 24 hours.
  • the iron oxide nano-particles were prepared previously, in the absence of calcium alginate.
  • an equimolar Fe (III) and Fe (II) solution was prepared from FeCI 3 .6H 2 O 0.5 M and FeCI 2 0.5 M, maintained at a constant temperature of 6O 0 C for fifteen minutes under magnetic agitation.
  • a 25% ammonium hydroxide solution was then dripped in to obtain a pH between 11 and 12, while the mixture was kept at 6O 0 C for a further fifteen minutes, still under magnetic agitation.
  • the powder formed from the iron oxide nano- particles was separated fro the iron solution and added to the sodium alginate solution (2%).
  • the sodium alginate solution (2%) with the iron oxide nano-particles was then dripped into a calcium chloride solution of 0.16 mols / L.
  • the calcium alginate spheres were prepared at 25 0 C and under magnetic agitation. After the gelification of the spheres, which continued for an hour, the spheres were removed from the calcium chloride solution and washed in a 50% methanol solution, and dried in a hot-box at 35 0 C for 24 hours.
  • Example 3 Characterisation of the iron oxide nano-particles in an alginate matrix from Example 1
  • the superparamagnetic sub-spectrum (projection of the points for magnetic extension) indicates that the magnetic moment is relaxing in a time of less than 10 "8 -10 "9 seconds, which is related to the precession time of the nuclear magnetic moment of the 57 Fe.
  • Figure 8a shows the dependence on temperature of the RPE measurements.
  • the species resonance field at g ⁇ 2 drops when the Sample is cooled.
  • the behaviour observed for the line at g « 2 is typical of superparamagnetic particles.
  • Figure 9 presents the M ⁇ ssbauer measurements for Sample B at various temperatures.
  • t 47.4 Tesla
  • IS 0.37 mm / s
  • eQVzz / 2 -0.2 mm / s
  • the susceptibility and magnetisation measurements are shown in Figure 10.
  • the curve shows a peak with its centre at temperatures of less than 4.2 K; thus, it can be said that the magnetic moments block temperature is below 4.2 K.
  • the magnetisation curve measurement at 5 K displays a non-saturated regime up to 5 The, indicating that some particles are already blocked at this temperature.
  • the curve displays only paramagnetic behaviour because all the magnetic iron nano-particles are unblocked and the isolated iron ions bonded to the polymer structure are paramagnetic.
  • the DRX standard is characterised as an iron oxide hydroxide, but this is not compliant with an anti-ferromagnetic phase such as goethite, which supports the MS and RPE findings.
  • Example 4 Characterisation of the iron oxide nano-particles in an alginate matrix from Example 2
  • the DRX of the alginate spheres whose nano-particles were produced in the presence of calcium alginate may be seen in Figure 12.
  • This is a typical DRX of the crystalline mineral phase of maghemite or magnetite, which crystallises in the inverted spinel structure (spatial group Fd3m ). Due to the similarity of the DRX profiles of the iron oxide, is it impossible to characterise the content of each of these iron phases in Sample C. Magnetite is obtained through the following reaction:
  • Maghemite (7-Fe 2 O 3 ) is usually formed by the oxidation of magnetite.
  • the width of the DRX line for the superparamagnetic magnetite is caused by the diffraction of the x-rays on the crystal volumes whose dimensions are comparable to the x-ray wave length. This effect may be used to calculate the dimensions of the crystal with Scherrer's formula:
  • t K ⁇ / ⁇ cos ⁇
  • K 0.89 (CULLITY, 1978).
  • the size of the crystal was estimated at 4.3 and 9.5 nm for Sample A and Sample B respectively.
  • iron oxide nano- particles prepared through the co-precipitation of Fe +2 and Fe +3 salts present diameters of around 10 nm.
  • Experts in the technique will know that nano- magnetite particles (Fe 3 O 4 ) may also be synthesised using the Fe (II) and Fe (III) salt chemical co-precipitation method with tetramethylammonium hydroxide (N(CH 3 )OH) in an aqueous solution that results in particles with a diameter of 9 nm and a nano-crystalline structure of iron oxide species.
  • the reduction in the size of the particle of approximately 50% may be explained by the presence of the calcium alginate polymer, whose structural polymer conformation serves as scaffold, curtailing the growth of the iron ore particles.
  • the M ⁇ ssbauer spectrum in 300 K, shown in Figure 15a for the iron oxide synthesised in the absence of calcium alginate (Sample D) shows peaks of a sextet and a doublet (close to the centre of the spectrum), indicative of an iron in a magnetic and paramagnetic configuration respectively.
  • the hyperfine parameters of the magnetic component were: isomer shift (IS) of 0.36 (7) mm / s, quadrupolar shift (QS) of 0.72 (1) mm / s, and hyperfine magnetic field of (Hhf) de 55.7 T.
  • the Sample was washed several times and new MS spectrum was prepared. This spectrum displayed only a magnetic component with hyperfine parameters similar to those of the unwashed sample, as shown in Figure 15b. These variations in the MS spectra may be explained by the non- removal of very small particles of iron oxide during the washing process. The remaining spectrum may be attributed to larger particles with low relaxation times or to the magnetic interactions of the particle clusters. Due to the hydrophobic interactions among the particles, they clump together into large clusters. These clusters may display strong dipole-dipole type magnetic attractions, giving rise to ferromagnetic behaviour.
  • Figure 15c shows the Mossbauer for Sample C obtained at 300 K.
  • the Sample presents a spectrum consisting of a doublet indicating superparamagnetic particles of magnetite or maghemite. This is an indication that the iron oxide particles are smaller than the particles formed in the absence of the bio-polymer.
  • the absence of hyperfine magnetic extensions in the sample A component suggests that smaller particles are produced when iron oxide nano-particles were synthesised in the presence of calcium alginate.
  • the saturation magnetisation (M s ) of Sample A, obtained from hysteris loop was 60 emu / g or 56 emu / g, depending on whether the Sample contained magnetite or maghemite respectively.
  • the ratio between the remainder (M r ) and M s (M r / M s ) was 0.248.
  • the M(H) loop showed insignificant coerciveness.
  • the loop was adjusted by a Langevin function with a lognormal distribution of particle sizes. The average size and the standard deviation were 5.8 nm and 3.2 nm, respectively.
  • Figure 17 presents the Zero Field Cooled (ZFC) susceptibility measurement for Sample C.
  • ZFC Zero Field Cooled
  • the real magnetic behaviour depends on the measurement time (t m ) of the specific experimental with respect to the relaxation time (f "1 ) associated with overcoming the energy barriers.
  • This constant anisotropy value is of the same value order as the findings published previously for iron oxide particles with a diameter of 6.5 nm (COEY et al, 1997).
  • the M r / M 5 « 0.25 ratio obtained from M(H) at 20 K is lower than expected at 0.5, for the uniaxial symmetry magnetic anisotropy constant and non-inter agent monodomain particles oriented randomly (STONNER et al, 1948).
  • the lower value of M r / M 5 may be due to a fraction of nano-particles that are still superparamagnetic at 2OK, and thus contribute to the M s , but not to the M r , consequently lowering the M r / M s ratio.
  • Figure 18 shows the Mossbauer spectra for Sample C at different temperatures (300 - 4 K).
  • 300 K 1 the spectrum displays an overlap of two components that correspond to particles of different sizes: a doublet as indicative of paramagnetic iron oxide with an IS of 0.34 (2) mm / s, QS of 0.72 (2) mm / s, and a broad component indicative of slowly relaxed iron oxide particles with a relaxation time close to the MS measurement time of 10 "8 -10 "9 s, the Larmor nuclear precession time.
  • the hyperfine component consisting of six lines, dominates the spectrum.
  • FIG 19 shows dependence on temperature with the relative absorption area (RAA) of the magnetic component.
  • RAA relative absorption area
  • T TM Mossbauer block temperature
  • the A 7 ⁇ w is defined as the temperature at which the RAA of the component arranged magnetically is equal to the RAA of the coexisting superparamagnetic component (MORUP, 1994).
  • the calcium alginate spheres with iron oxide nano-particles produced by Method Il A present a surface that is relatively smooth, in macroscopic terms.
  • the spherical shape associated with the tangential cross-links that occur as soon as each drop of sodium alginate enters into contact with the calcium chloride solution. While the calcium ions spread through the internal structure of the sphere, the additional cross-links are being formed and connect with the gelified surface, progressing internally. Looking at the micrographies ( Figures 20, 21 and 22), imperfect spheres are noted with distortions and extremely rough surfaces.
  • the level of integrity and porosity of the micro-capsules is what will indicate the efficiency of the polymer as the encapsulating matrix.
  • the drying conditions may be responsible for distortions in the sphere structure, as a reduction in their roundness was visibly apparent after drying. These alterations in the morphology of the spheres may occur during the drying process. Due to high viscosity of sodium alginate, obtaining spheres through the dripping technique may be critical. When coming into contact with the calcium chloride solution, the drip comes under the influence of the difference in the surface tension, and may form imperfect spheres. Consequently, the most appropriate sodium alginate concentration may vary, with the preferable concentration range being 1% to 8%, depending on molecular weight of the alginate. Analysing the surface of the sphere in greater detail as presented in
  • Figures 23 and 24 present the morphology in MEV of the outer and inner faces respectively of the calcinate alginate sphere with iron oxide nano- particles. Cuboidal granules of around five micrometers are observed on both sides of the sphere, and this characteristic presented by its inside demonstrates that this is not a hollow sphere. This morphology will limit the growth of the iron oxide particles, as shown previously by the DRX and M ⁇ ssbauer findings.
  • Figures 25, 26 (a) and 26 (b) present a micro-structure in MET of the calcinate alginate sphere with iron oxide nano-particles.
  • the nano-particles are formed in the shape of crystalline clusters.
  • the pale points scattered throughout a typically amorphous structure (alginate) noted in Figure 25 correspond to the iron oxide nano-particles.
  • Figures 26 (a) and (b) highlight the distribution of the iron element and the oxygen respective.
  • the dark points scattered throughout a typically amorphous structure (alginate), noted in Figure 26 (a) correspond to the iron oxide nano-particles.
  • Example 5 Formulation of the insulin micro-capsules in an alginate matrix
  • the insulin micro-capsules in an alginate matrix were prepared in triplicate through the extrusion method. To do so, 2 ml_ of 3% sodium alginate solution were prepared with 10% by weight of insulin that was then dripped into
  • Example 6 Formulation of the insulin micro-capsules in an alginate / chitosan matrix
  • the insulin micro-capsules in an alginate / chitosan matrix were prepared in triplicate, similar to the process for obtaining the insulin micro-capsules in an alginate matrix described in the previous sub-item.
  • 10 ml_ of chitosan solution 3 mg / ml_ were added and kept under magnetic agitation at room temperature for an hour.
  • the chitosan was dissolved in an acetate buffer at pH 5.0; prepared previously from sodium acetate 0.02 mols / L with the pH adjusted by the addition of acetic acid 1%.
  • the spheres were collected through filtration and weighed while still wet, being set aside for analysis. The samples were called TQ1 , TQ2 and TQ3.
  • Example 7 Trapping insulin in the micro-capsules as a protein concentration function.
  • samples with different insulin concentrations were produced in duplicate.
  • the insulin micro-capsules in an alginate / chitosan matrix were prepared from 2 ml_ of 3% sodium alginate solution with insulin quantities as shown in Table 1. The procedure for obtained them followed the same path as that presented above. The samples were called A1 , A2, A3, A4 and A5.
  • the insulin used for the preparation of the micro-capsules was presented in the form of a suspension. According to the specifications supplied by the manufacturer, 1 millilitre of insulin suspension is equivalent to 100 Ul and, according to international conventions, 26 Ul corresponds to 1 milligram. Thus, the insulin concentration in the suspension was de 3.85 mg / mL.
  • Example 8 Efficiency of the micro-encapsulation of insulin micro-capsules in an alginate matrix
  • the micro-capsules formed using the external gelification method has a large polymer gradient in regions close to the surface of the micro-capsules. This gradient is formed during gelification as the result of the ions diffusing into the sphere, and is governed by the diffusion rate that may be affected by the polymer concentration, the molecular weight of the alginate, the gelification ion concentration, and the presence of other non-gelifying ions.
  • spheres of 2 mm are prepared from sodium alginate 2% and CaCI 2 0.1 mols / L require six minutes to stabilise the calcium concentration, meaning the length of time required under these conditions for the alginate spheres to form.
  • a cure time of ten minutes was established, which should be sufficient to prepare the insulin micro-capsules.
  • the micro-capsules were treated with phosphate buffer, as the phosphate ions function as calcium sequestrators from the alginate structure, weakening the spheres and causing the gel to fall away, thus insulin is released from the micro-capsules for analysis.
  • phosphate buffer As the phosphate ions function as calcium sequestrators from the alginate structure, weakening the spheres and causing the gel to fall away, thus insulin is released from the micro-capsules for analysis.
  • the micro-capsules took some 24 hours to dissolve completely. Drawing an analogy between the microcapsules opening phenomenon and the alginate gelification process, both of them involve diffusion processes. Just as the calcium ions spread into the sphere to form calcium alginate, these same calcium ions will spread to the outside of the sphere in order to bond with the phosphate ions.
  • This reverse process of "de-gelification" is far slower, particularly because the chitosan is weakly soluble at this pH, and requires care with stirring in order to avoid the formation
  • Table 2 shows the micro-capsules masses obtained through their preparation in an alginate matrix. The average mass was (1.02 ⁇ 0.16) g.
  • the low efficiency of the encapsulation may be due to insulin losses during the gelification process, such as the retention of the protein, for example, on the syringe shaft walls, due to the viscosity of the polysaccharide.
  • this protein is presented as an insulin suspension, its distribution in the micro- capsules takes place on a random basis, with the portion adsorbed on the otter surface of the sphere being subject to loss during the process washings.
  • Example 9 Preparation of insulin micro-capsules in an alginate / chitosan matrix with magnetic nano-particles for release trials.
  • the insulin micro-capsules were prepared in triplicate at room temperature, following the procedure set forth in detail in Example 5.
  • the micro-capsules were added to a calcium chloride solution mixture, used initially with iron Il and III chloride solutions (0.5 mols / L), in a proportion of 1 :1 :1.
  • This mixture was kept at 60 0 C for ten minutes under magnetic agitation and subsequently an ammonia hydroxide solution at 25% was added in order to reach a pH between 11 and 12, with the mixture kept at 6O 0 C under agitation for a further ten minutes.
  • the spheres were washed in distilled water and as a final step each replica was divided into two parts as shown in Table 5.
  • the samples were called L1 PM(n), L2PM(n), with n ranging from 1 to 3.
  • Table 5 Quantity of insulin micro-capsules in an alginate / chitosan matrix containing magnetic nano-particles for in vitro release trials.
  • Example 10 Examples of in vitro insulin release.
  • the release in vitro release of insulin from the alginate matrix was monitored periodically until its concentration in the solution reached a constant value, corresponding to the end of the protein release process by the micro- capsules (Figure 27).
  • the total loading capacity of the micro-capsules by volume of water used in this test was 0.034 mg / ml_ of insulin. It was ascertained that 20% of the insulin is released during the first minutes of the trial, corresponding to the protein fraction adsorbed on the surface of the sphere. At a second stage, the insulin is released in a more gradual manner until reaching almost 50% of the initial quantity in the micro-capsules. This release may be attributed to the diffusion of the protein through the polymer matrix and also to wear and tear on the surface of the sphere (erosion). After 100 hours of the trial, the insulin release reached its peak value and its concentration remained constant until the end of the study time ( ⁇ 800 hours).
  • the insulin is released from the alginate / chitosan micro-capsules more gradually than from the alginate micro-capsules.
  • the total loading capacity of the micro-capsules by volume of water used was also 0.034 mg / mL of insulin.
  • the spheres were more stable, with a less abrupt insulin release.
  • the protein was no longer released from the micro-capsules, with the insulin concentration remaining steady in the solution.
  • This rapid release effect noted in the insulin released from the alginate matrix is frequently found in proteins released from hydrogels formed by swellable polymer matrixes, such as alginate.
  • the association of the alginate with the chitosan reduced this initial effect as it upgraded the morphology of the polymer matrix.
  • Figure 29 presents the two cumulative insulin release curves related to the percentage of total insulin percentage in the micro-capsules.
  • the initial intension was to associate alginate and chitosan in order to obtain an encapsulation system that would retain the insulin for a longer period.
  • this conjugate polymers system it appeared that the insulin release from the microcapsules is reduced by a factor of 50%. The objective was thus attained, demonstrating the efficiency of the alginate / chitosan membrane as an encapsulating matrix.
  • the more effective trapping of the protein may be attributed to the electrostatic interaction between the alginate carboxyl groups and the chitosan amines clusters that generated the formation of the alginate chitosan complex which was responsible for the reduction in the pores of the micro-capsules.
  • insulin micro-capsules in an alginate matrix when not reinforced by chitosan, probably have insufficiently dense cross-links to prevent the diffusion of the molecules.
  • the micro-capsules made from polymer matrixes presented a certain permeability, which was reflected in the insulin release.
  • the crystalline nature of the polymer material and the pore structure may determine the control of this diffusion.
  • the links between the calcium and alginate carboxyl ions may be weakened, or between the chitosan amines and the alginate carboxyl amines, resulting in the weakening of the sphere structure.
  • Figure 31 presents the behaviour in 2% calcium chloride solution of the micro-capsules with 3% to 73% of insulin. Similar to the previous test, no significant difference is noted in the insulin release profiles of the different samples. In principle, there is no behavioural standard that may be related to the micro-capsules being more or less loaded with insulin. The amount of protein released from the micro-capsules in 700 hours of tests remained between 20% to 30% of the total. The delayed release of the insulin by the calcium ions did not occur, and the micro-capsules presented the same profile for the protein release, whether in water or in a calcium chloride solution.
  • FIG. 32 presents the insulin outflow profile from the micro-capsules with iron oxide nano-particles whose matrix consists of alginate / chitosan.
  • micro-capsules with magnetic nano-particles present a release profile similar to that of the insulin micro-capsules in an alginate / chitosan matrix without the nano-particles. This indicates that the production stage of the nano-particles has no significant influence on the morphology of the microcapsules which might alter the insulin release.

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Abstract

La présente invention concerne un procédé de production de microcapsules ayant des propriétés magnétiques avec de nanoparticules pour la libération contrôlée de substances actives, ainsi que des produits associés à ce procédé et des procédés de libération contrôlée de substances actives grâce à l'application d'un champ magnétique oscillatoire. D'une manière préférée, la synthèse des nanoparticules est réalisée in situ, en présence d'alginate ou de chitosane, incorporant les propriétés magnétiques dans les microcapsules. La libération contrôlée de substances actives telles que l'insuline, par exemple, se produit grâce à l'application d'un champ magnétique oscillatoire.
PCT/BR2007/000224 2006-09-05 2007-09-03 Procédé de production de microcapsules ayant des propriétés magnétiques, produits obtenus à partir desdites microcapsules et procédé pour la libération contrôlée de substances actives WO2008028264A1 (fr)

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EP2174657A1 (fr) * 2008-10-08 2010-04-14 AB-Biotics Producciones Industriales De Microbiotas, S.L. Produit source de fer sous forme de capsules et son procédé de préparation
EP2266596A1 (fr) * 2008-03-19 2010-12-29 David Anatol'evich Noga Composition pharmaceutique et procédé de fabrication correspondant
CN102323424A (zh) * 2011-06-02 2012-01-18 浙江大学 环境颗粒物表面外源生物分子的原位检测试剂及方法
WO2013179206A1 (fr) * 2012-06-01 2013-12-05 Dsm Ip Assets B.V. Supplémentation minérale de boissons
CN113480857A (zh) * 2021-07-02 2021-10-08 宁波诺丁汉大学 可控磁力释放微胶囊、制备方法、释放控制方法及其应用
CN114621599A (zh) * 2022-03-17 2022-06-14 中南大学 一种纳米水铁矿-麦糟复合胶体材料及其制备和应用

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EP2266596A1 (fr) * 2008-03-19 2010-12-29 David Anatol'evich Noga Composition pharmaceutique et procédé de fabrication correspondant
EP2266596A4 (fr) * 2008-03-19 2013-06-05 Shishkuv Mlyn A S Cz Composition pharmaceutique et procédé de fabrication correspondant
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CN102323424A (zh) * 2011-06-02 2012-01-18 浙江大学 环境颗粒物表面外源生物分子的原位检测试剂及方法
CN104394710A (zh) * 2012-06-01 2015-03-04 帝斯曼知识产权资产管理有限公司 饮料的矿物质补充
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CN113480857A (zh) * 2021-07-02 2021-10-08 宁波诺丁汉大学 可控磁力释放微胶囊、制备方法、释放控制方法及其应用
CN114621599A (zh) * 2022-03-17 2022-06-14 中南大学 一种纳米水铁矿-麦糟复合胶体材料及其制备和应用
CN114621599B (zh) * 2022-03-17 2023-03-10 中南大学 一种纳米水铁矿-麦糟复合胶体材料及其制备和应用

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