WO2007139854A2 - Procédé de préparation de gélifiants hydro-organiques à partir de sucres disaccharides par biocatalyse et leur utilisation dans l'administration de médicaments déclenchée par une enzyme - Google Patents

Procédé de préparation de gélifiants hydro-organiques à partir de sucres disaccharides par biocatalyse et leur utilisation dans l'administration de médicaments déclenchée par une enzyme Download PDF

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WO2007139854A2
WO2007139854A2 PCT/US2007/012333 US2007012333W WO2007139854A2 WO 2007139854 A2 WO2007139854 A2 WO 2007139854A2 US 2007012333 W US2007012333 W US 2007012333W WO 2007139854 A2 WO2007139854 A2 WO 2007139854A2
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enzyme
gel
drug
gelators
curcumin
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WO2007139854A3 (fr
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George John
Praveen Kumar Vemula
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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

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  • the present invention relates to hydro/organo gelators, and more particularly, the present invention relates to a method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in enzyme-triggered drug delivery, cosmetic components delivery, and making of templated materials to generate inorganic and soft nanomaterials.
  • Stephan Harrera 2 An article by Stephan Harrera 2 illustrates that industrial or 'white' biotechnology 3 is making an increasingly important contribution to the development of a sustainable, biobased economy by an environmental benign approach. 4 It uses enzymes and micro- organisms to make products in sectors, such as chemistry, food and feed, paper, textile,
  • Hydrogels have a range of biomedical applications in areas such as tissue engineering, 8 controlled released drug delivery systems, 9 and medical implants. 10 Design and synthesis of low-molecular- weight hydrogelators has received considerable attention in soft materials research in terms of its potential applications in cosmetics, toiletries, and pharmaceutical formulations. Literature study reveals that there are only limited reports on easily achievable and efficient low-molecular-weight gelators that are able to gel water or even water mixtures with other solvents," and which are often achieved by multi-step
  • biocatalysis as a tool to make gelators from biomass and their assembly to form hierarchical superstructures in water, i.e., formation of hydrogel and soft nanomaterials, encapsulation of hydrophobic drug or hydrophobic cosmetic components; as well as enzyme mediated hydrogeJ degradation, which will give new insights into low-molecular-weight hydrogelators-based drug delivery.
  • Controlled delivery of drugs or cosmetic material occurs when a polymer, whether natural or synthetic, is judiciously combined with a drug or other active agent in such a way that the active agent is released in a pre-designed manner. 12 While these advantages can be significant, the potential disadvantages cannot be ignored, such as the possible toxicity or non-bibcompatibility of the materials used, the undesirable by-products from gel degradation, and the higher cost of controlled-release systems compared with traditional pharmaceutical formulations.
  • D-Amygdalin is a naturally occurring glycoside found in many food plants, for example, the kernels of apples, almonds, peaches, cherries, and apricots. 13 Amygdalin (a by-product of apricot, ' almonds and peach industry, see FIGURE 1, which are pictures of: (a) an apricot pit that is a source of amygdalin; (b) Curcuma longa ⁇ and, (c) powdered curcumin 14 that is commonly known as turmeric and used in traditional Indian culinary
  • Curcumin is just one example as a drug model. and medicine — has been used as a main ingredient in commercial preparations of laetrile, a purported therapeutic agent. 15
  • amygdalin derivatives that can form nanoaggregates through self-assembly and encapsulation of a hydrophobic drug followed by release of the encapsulated drug upon enzyme mediated degradation, i.e., enzyme- triggered drug-delivery.
  • sugar moiety can facilitate the stacking of molecules through hydrogen bonding
  • phenyl ring can facilitate intermolecular interactions through ⁇ - ⁇ stacking
  • hydrophobic hydrocarbon chain not only decreases the solubility in water, it also helps the molecular association through the van der Waals interactions.
  • hydrogelators of the present invention were synthesized from renewable resources in a single-step process in high yields (>90%), and unpurified crude products showed unprecedented gelation abilities like their counter pure products, allowing the development of versatile gelators which can be made from low cost starting materials and without purification.
  • FIGURE 2 is a synthetic scheme of amygdalin-based amphiphiles.
  • an object of the present invention is to provide a method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in enzyme- triggered drug delivery, which avoids the disadvantages of the prior ark
  • another object of the present invention is to provide a method for preparing hydro/organo gelatefrs from disaccharide sugars by biocatalysis and their use in enzyme-triggered drug delivery. Controlled delivery of an anti-inflammatory, chemopreventive drug is achieved by an enzyme-triggered drug release mechanism via degradation of encapsulated hydrogels.
  • the hydro- and organo- gelators are synthesized in high yields from renewable resources by using a regioselective enzyme catalysis and a known chemopreventive and anti-inflammatory drug, curcumin, is encapsulated in the .gel matrix and released by enzyme triggered delivery.
  • the release of the drug occurs at the physiological temperature, and control of the drug release rate is achieved by manipulating the enzyme concentration and temperature.
  • the by-products formed after the gel degradation clearly demonstrate the site specificity of degradation of the gelator by enzyme catalysis.
  • the present invention has applications in developing cost effective, controlled drug delivery vehicles from renewable resources, with a potential impact on pharmaceutical research and molecular design and delivery strategies.
  • Another object of the present invention is to provide a method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in enzyme- triggered or thermo-triggered cosmetic delivery.
  • Controlled delivery of components of cosmetic formula is achieved by an enzyme-triggered release mechanism via degradation of encapsulated hydrogels.
  • the hydro- and organo- gelators are synthesized in high yields from renewable resources by using a regioselective enzyme catalysis.
  • the release of the cosmetic components occurs at the physiological temperature and control of their release rate is achieved by manipulating the enzyme concentration and temperature.
  • the present invention has applications in developing cost effective, controlled cosmetic delivery vehicles from renewable resources.
  • Another object of the present invention is to provide a method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in making templated materials to develop inorganic nanomaterials.
  • FIGURE 1 are pictures of: (a) an apricot pit that is a source of amygdalin; (b)
  • Curcuma longa and, (c) powdered curcumin that is commonly known as turmeric and used in traditional Indian culinary and medicine. It is also a known chemopreventive and anti-inflammatory drug;
  • FIGURE 2 is a synthetic scheme of amygdalin-based amphiphiles;
  • FIGURE 3 is a table of gelation ability of amygdalin derivatives 1-3 in various solvents;
  • FIGURE 4 are SEM micrographs, wherein scale bar is equivalent to 1 ⁇ M, of: (a) the organogel of derivative 1 prepared from acetonitrile; (b) the aqueous gel from derivative 2; (c) the aqueous gel from derivative 3; and, (d) a higher magnification of hydrogel derivative 2;
  • FIGURE 5 are scanning electron micrographs of curcumin-embedded hydrogels of derivative s
  • FIGURE 6 are: (a) the crystal structure analysis of derivative 1 in water; and, (b) a top view showing the ⁇ - ⁇ stacking of phenyl rings and hydrogen boding between two amygdalin molecules, wherein hydrogen bonding acts as a bridge between the stacked amygdalin molecules along the b-axis shown as blue arrows and between these two stacks along the a-axis shown as black arrows, and wherein: oxygen is shown as red; nitrogen is shown as blue; carbon is shown as white circles; and, hydrogen-bonding is shown as black dashed lines;
  • FIGURE 7 are schematic representations of possible molecular packing models for the: (a) hydrogels; and, (b) organogels of derivative 2;
  • FIGURE 8 are: (a) a schematic representation of drug encapsulation in a supramolecular hydrogel and subsequent release of the drug by enzyme mediated degradation of hydrogel at physiological temperature; and, (b) real images of the hydrogels of derivative 3 with (i-iv) and without (v-vi) curcumin, wherein after complete gel degradation, the remained white fluffy powder thai settled at the bottom was characterized as a water insoluble fatty acid that formed after gel degradation by the enzyme;
  • FIGURE 9 are UV absorption spectra of curcumin in various types of solution mixtures, including: (a) an curcumin-entrapped hydrogel in the presence of an enzyme; (b) an enzyme added to the hydrogel that does not contain curcumin; (c) an curcumin-entrapped hydrogel in the absence of an enzyme; and, (d) a methanolic solution of curcumin;
  • FIGURE 10 is a table of the effect of enzyme concentration and temperature on drug release time;
  • FIGURE 1 1 are a comparison of
  • FIGURE 12 is a comparison of the 1 H-NMR spectra of commercially available stearic acid and the white fluffy solid obtained after gel degradation, which was filtered, freeze-dried, and NMR recorded in Chloroform; and
  • FIGURE 13 is a table of the crystallographic parameters of derivative 1.
  • Amygdalin is a disaccharide containing one primary hydroxyl group that forms ester bonds with fatty acids. Vinyl esters were used as acyl donors. The detailed synthesis procedures are shown in the METHODS section below and the synthetic route to the amphophilic amygdalin derivatives is shown FIGURE 2. In general, multi-step synthesis, arduous separation p-ocedures, and lower yields often keep low-molecular-weight gelators away from commercial use due to high production cost.
  • the hydrogeiators of the present invention were synthesized from renewable resources in a single-step process in high yields (>90%), and unpurified crude products showed unprecedented gelation abilities like their counter pure products, allowing the development of versatile gelators which can be made from low cost starting materials and without purification. In particular, this property gives the opportunity to develop these gelators in industrial scales for various applications in cosmetics, toiletries, drug deliveries, nanomaterials, and pharmaceutical formulations. 17
  • Amygdalin derivatives 1 -3 encompass all required functional groups, such as hydrogen bond forming 'sugar' headgroup, phenyl ring for ⁇ - ⁇ stacking, and hydrocarbon chain for van der Waals interactions. These groups together can synergistically act to form strong intermolecular interactions leading to the gelation.
  • the gelation abilities of the derivatives 1 -3 in water and in organic — polar and nonpolar — solvents are compared in FIGURE 3, which is a table of gelation ability of amygdalin derivatives 1-3 in various solvents.
  • a gelator (0.0 1 -2 mg) in a required solvent (0.1-1 mL) was heated until the solid was completely dissolved. The resulting solution was slowly allowed to cool to room temperature and gelation was visually observed. The gel sample obtained exhibited no gravitational flow in an inverted tube. All gels obtained were thermally reversible. Above their gelation temperature, the gels dissolved in water but could be returned to their original gel state upon cooling.
  • amygdalin amphiphiles derivatives 1-3 showed unprecedented gelation abilities in a broad range of solvents at extremely low concentrations [0.05-0.2 wt% (MGC)], while displaying excellent thermal and temporal stabilities.
  • FIGURE 4 which are SEM micrographs, wherein scale bar is equivalent to 1 ⁇ M, of: (a) the organogel of derivative 1 prepared from acetonitrile; (b) the aqueous gel from derivative 2; ⁇ ) the aqueous gel from derivative 3; and, (d) a higher magnification of hydrogel derivative 2 — presents the scanning electron microscope (SEM) images of the organogels formed by derivative 1 shown in FIGURE 4(a) and the aqueous gels formed by derivatives 2 and 3 shown in FIGURES 4(b) and ⁇ ), respectively.
  • SEM scanning electron microscope
  • the images of their xerogels reveal two different types of morphologies.
  • the organogel formed in acetonitrile by derivative 1 showed 'grass' like morphology.
  • Hydrogels of derivatives 2 and 3 showed helical ribbon morphology at microscopic level. Analysis of these aggregates clearly showed that the individual fibers are approximately 50 nm in width, about 100-125 nm in pitch, and up to several micrometers in length. These helical nanofibers are entangled and formed a dense fibrous network resulting in immobilization of the solvent.
  • Gels were also made in the presence of the drug curcumin, and SEM images suggest that inclusion of curcumin does not change the basic twisted fibrous morphology of the hydrogel. See FIGURE 5, which are scanning electron micrographs of curcumin embedded hydrogels of derivative 3.
  • the crystal structure of derivative 1 is shown in FIGURE 6, which are: (a) the crystal structure analysis of derivative 1 in water; and, (b) a top view showing the ⁇ - ⁇ stacking of phenyl rings and hydrogen boding between two amygdalin molecules, wherein hydrogen bonding acts as a bridge between the stacked amygdalin molecules along the b-axis shown as blue arrows and between these two stacks along the a-axis shown as black arrows, and wherein: oxygen is shown as red; nitrogen is shown as blue; carbon is shown as white circles; and, hydrogen-bonding is shown as black dashed lines.
  • the information obtained from the single crystal analysis was combined with the XRD data to postulate possible molecular packing of amygdalin amphiphiles within the hydro- and organogels.
  • Solubilization of hydrophobic drugs and developing suitable drug delivery systems is a challenging task in drug discovery research.
  • 18 A conceptual approach of single-step enzyme-triggered drug delivery at physiological conditions was performed where a hydrophobic drug molecule was encapsulated — solubilized without chemical modification — in a hydrogel and subsequent release of the drug by breaking the gel by using hydrolase enzyme (Lipolase 100L, Type EX). The preformed hydrogel was degraded completely by the lipolase while the encapsulated chemopreventive hydrophobic drug curcumin was released. See FIGURES 1 (b) and (c) for images of curcum ⁇ n. Drug release was monitored by absorbance spectra of the drug.
  • Control of the drug release rate was achieved by manipulating the enzyme concentration and/or temperature.
  • the by-products formed after the gel degradation were characterized and the cleavage site of the gelator by enzyme was determined. Gel degradation occurred due to the cleavage of the ester bond in the gelator by the hydrolase enzyme.
  • amphiphiles of derivatives 1 -3 were generated by attaching a fatty acid chain to amygdalin via regiospecific transesterification reaction on a primary sugar hydroxyl.
  • amygdalin derivatives are versatile gelators for water and polar/nonpolar organic solvents, derivative 1 formed gels in two solvents out of ten tested, whereas derivative 3 gelled in all ten solvents. This explains the importance of chain length on gelation ability. Noteworthy to mention is that derivatives 2 and 3 did not require any co-solvent to form the hydrogel despite their gelation ability in less polar solvents like benzene, toluene, and xylene. These gelators showed excellent gelation in a broad range of solvents.
  • Robustness of a gelator can be determined by considering three parameters: i) gelation ability in a broad range of solvents; ii) low minimum gelation concentration
  • these gelators formed gels in highly polar solvents like water, methanol, and non-polar solvents like nonane, benzene, and toluene.
  • Minimum gelation concentration (MGC) of these gels are very low, typically 0,05 and 0.2 wt% for derivative 3 in water and benzene, respectively. This is one of the lowest gelation concentrations reported in the literature for any class of gelators.
  • the other derivatives also exhibit lower MGC values for various solvents typically between 0.07 to 0.5 wt%. In addition, they show good thermal and temporal stabilities.
  • T &el Gel to solution transition temperature was determined by typical 'inversion tube method' 20 ahd from differential scanning calorimeter (DSC). The 7 ⁇ 1 values of these gels were in the range of 40 to 85°C for 0.5 wt% gels depending on the solvent used. All gels were stable for months. Hence, together satisfying all three parameters, the reported amygdalin based gelators could be considered as excellent gelators.
  • FIGURES 7(a) and (b) are schematic representations of possible molecular packing models for the: (a) hydrogels; and, (b) organogels of derivative 2.
  • Amygdalin butyrate — - derivative 1 — gives single crystals in water.
  • the isolated single crystal was successfully analyzed by X-ray crystallography. Interestingly, these molecules were well packed in the crystal lattice due to the extensive hydrogen bonding. Strong well-arranged intra- and inter- molecular hydrogen bonding was observed.
  • Intramolecular hydrogen bonding between N (nitrogen) of the nitrile group and of sugar hydroxyl (O — H) hydrogen helps to form a locked conformation that apparently participated in forming the " stacked structures.
  • Water molecules were involved in two types of hydrogen bonding. In one type, water molecules formed hydrogen bonding with sugar hydroxyls while acting as bridged molecules between stacked amygdalin amphiphiles and stabilized the stacked layers as shown in open arrows in FIGURE 6(b). In the second mode, water molecules were involved in hydrogen bonding with sugar hydroxyls while acting as bridged molecules between two different stacks of amygdalin amphiphiles to stabilize the two adjacent layers as shown in filled arrow in FIGURE 6(b). In addition to that, the intermolecular hydrogen bonding between sugar hydroxyls of two amygdalin molecules from opposite stacks, which also indicates the greater ability to form self-assembled structures by amygdalin derivatives, was observed.
  • curcumin is an efficient inhibitor of Epstein-Barr virus BZLF l transcription in Raji DR-LUC cells. MoI. Carcinog. 33, 137-145 (2002). integrace, 25 HIV-I and H1V-2 proteases, 27 and HIV-I long terminal repeat-directed gene expression of acutely or chronically infected HIV-I cells. 28 Despite such extraordinary drug activity, unfortunately curcumin has an extremely low aqueous solubility and poor bioavailability limiting its pharmaceutical use. 29 One possible way to increase its aqueous solubility is to form inclusion complexes, i.e. to encapsulate curcumin as a guest within the internal cavities of a water-soluble host or encapsulate within the nanoaggregates — formed by self-assembly — that have hydrophobic pockets within.
  • FIGURE 8(a) Schematic representation of Curcumin encapsulation and enzyme-mediated release is depicted in FIGURE 8(a) wherein FIGURE 8 are (a) a schematic representation of drug encapsulation in a supramolecular hydrogel and subsequent release of the drug by enzyme-mediated degradation of hydrogel at physiological temperature; and, (b) real images of the hydrogels of derivative 3 with (I-iv) and without (v-vi) curcumin, wherein after complete gel degradation, the remained white fluffy powder that settled at the bottom was characterized as a water insoluble fatty acid that formed after gel degradation by the enzyme. The release of curcumin into the solution in the presence of enzyme was monitored by measuring the curcumin UV-absorption spectrum.
  • curcumin is an efficient inhibitor of Epstein-Barr virus BZLF l transcription in Raji DR-LUC cells. MoL Carcinog. 33, 137- 145 (2002); Mazumder, A., Raghavan, K., Weinstein, J., Kohn, K. W. & Pommier, Y. Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem. Pharm. 49, 1 165- 1 17Q ( 1995).
  • lipase units 100 KLU/g were added to the preformed gel and kept at 37°C — far lower than gel melting temperature. Initially the added solution was colorless as shown in FIGURE 8(b)(iii). After 12 hrs visual changes occurred as shown in FIGURE 8(b)(iv), i.e., 100% of the gel has been degraded and the top solution has became yellow in color, which indicates that upon enzyme mediated gel degradation, encapsulated curcumin has been released into the solution. This was confirmed by spectroscopic experiments. Aliquots were collected after addition of an enzyme to the hydrogel after 10 min and 12 hrs and absorbance spectrum were recorded.
  • FIGURE 9 are UV absorption spectra of curcumin in various types of solution mixtures, including: (a) an curcumin-entrapped hydrogel in the presence of an enzyme; (b) an enzyme added to the hydrogel that does not contain curcumin; ⁇ ) an curcumin-entrapped hydrogel in the absence of an enzyme; and, (d),a methanolic solution of curcumin.
  • FIG. 9(b) The absorption spectrum of the solution shown in FIGURE 9(b) was then recorded. Absence of the absorption peak at 425 nm suggested that the previously observed peak, FIGUElE 9(c), 'corresponded to the curcumin released into the solution.
  • FIGUElE 9(c) the role of enzyme concentration and temperature on gel degradation or controlled drug release was investigated. In a first set of experiments, the temperature was changed while keeping enzyme concentration constant. After addition of the enzyme to the preformed gel, the vial was kept at room temperature for two days, and as explained previously, curcumin release was monitored by absorption spectra. Interestingly, even after two days at room temperature in the presence of the enzyme, there was no gel degradation observed, and thus, there was no- release of encapsulated curcumin.
  • FIGURE 10 is a table of the effect of enzyme concentration and temperature on drug release time
  • FIGURE 1 1 are a comparison of curcumin-drug-release time at different concentrations and different temperatures from hydrogels of amygdalin derivatives by enzyme degradation, wherein: (a) is the time required for 5% release; and, (b) is the time required for 100% — which clearly demonstrate the achieved control over the release of an encapsulated drug from a hydrogel.
  • FIGURE 12 is a comparison of the 1 H-NMR spectra of commercially available stearic acid and the white fluffy solid obtained after gel degradation, which was filtered, freeze-dried, and NMR recorded in Chloroform. Hence, it is undoubtedly suggesting that gel degradation is occurring through the cleavage of the ester bond of amygdalin derivatives by lipolase enzyme.
  • Amygdalin and curcumin was purchased from Acros Chemicals (Fisher Scientific Company, Suwane, GA).
  • the Novozyme 43.5 [lipase B from Candida Antarctica,(CALR) ⁇ ⁇ and Lipolase IOOL were obtained from Novozymes through
  • the gelator (0.01 -2 mg) and required solvent (0.1-1 mL) were placed into a 2 mL scintillation vial, which was then sealed with a screw cap. The vial was heated and shook until the solid was completely dissolved. The solution was set aside • and allowed to cool to room temperature. Gelation was considered to have occurred when no gravitational flow in the inverted tube was observed.
  • the Gel to Sol transition temperature was determined by two methods.
  • T sei was determined by using a Mettler DSC-822 Differential Scanning Calorimeter equipped with a nitrogen-gas intra cooling system. The gel was hermitically sealed in a silver pan and measured against a pan containing alumina as reference.
  • Thermograms were recorded at a heating rate of 5°C/min.
  • the r ge] values determined by these two methods were identical.
  • the xerogel samples were prepared by the freezing-and-pumping method from their gel phases below the sol-gel transition temperature. It is important to note that the SEM images of xerogels and the following drying under ambient condition show similar morphologies. Therefore, morphology with the gels dried under ambient conditions, which was called xerogels, was studied.
  • GADDS diffractometer using graded J-space elliptical side-by-side multilayer optics, monochromaled Cu-Ka radiation (40 kV, 40 mA), and an imaging plate.
  • the gels were used as prepared in the wet condition for the analysis. A small portion of the gel sample was transferred to the sample holder and sealed off immediately using capstone tape to avoid any drying off of the solvent.
  • the typical exposure time was 1 min for self- assembled structures with a 100 mm camera length.
  • X-ray quality colorless single crystals of derivative 1 were obtained from water in a flat rod shape.
  • Data collection, data reduction, and structure solution refinement were carried out using the software package of SHELX97. 33 All structures were solved by direct methods (S 1 R92) and refined in a routine manner. Non-hydrogen atoms were treated anisotropicaliy. Whenever possible, the hydrogen atoms weie located on a different Fourier map and refined.
  • the crystal lographic parameters are listed in FIGURE 13, which is a table of the crystallographic parameters of derivative 1.
  • hydro/organogelators from renewable resources were successfully developed.
  • Low-molecular-weight hydrogelators were synthesized by regioselective enzyme catalysis for the first time. Yields were quantitative and crude reaction mixtures exhibited equally unprecedented gelation properties like their counter pure products. This capability may allow development of hydrogelators in industrial scale for future applications.
  • 34 The hierarchical structural characteristic of supramolecular gels were clearly demonstrated and the self-assembly based on XRD and single crystal analysis were explained.
  • the gel fibers were self-assembled and stabilized by various interactions, such as intra- and inter- molecular hydrogen bonding, ⁇ - ⁇ stacking, and van der Waals interactions.
  • the encapsulation of chemopreventive curcumin in the hydrogel was shown, and enzyme-triggered gel degradation was performed to release the encapsulated drug into the solution at physiological temperature. Controlled drug release rate was achieved by manipulating the concentration of enzyme or temperature.

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Abstract

L'invention concerne un procédé de préparation de gélifiants hydro-organiques à partir de sucres disaccharides par biocatalyse, et leur utilisation dans l'administration de médicaments déclenchée par une enzyme. L'administration régulée d'un médicament anti-inflammatoire et chimiopréventif est effectuée au moyen d'un mécanisme de libération de médicament déclenché par une enzyme par dégradation d'hydrogels encapsulés. Les gélifiants hydro-organiques sont synthétisés à haut rendement à partir de ressources renouvelables par catalyse enzymatique stéréosélective et au moyen d'un médicament chimiopréventif et anti-inflammatoire, la curcumine, qui est encapsulé dans la matrice de gel et administré par libération déclenchée par une enzyme. La libération du médicament s'effectue à la température physiologique, et la régulation de la vitesse de libération du médicament s'effectue sous l'effet de la concentration enzymatique et de la température. Les sous-produits obtenus après dégradation du gel montrent clairement la spécificité du site de dégradation du gélifiant par catalyse enzymatique. Cette invention peut être utilisée dans le développement d'excipients employés dans l'administration régulée et de faible coût de médicaments à partir de ressources renouvelables, avec un impact potentiel sur la recherche pharmaceutique, la conception moléculaire et les stratégies d'administration.
PCT/US2007/012333 2006-05-22 2007-05-22 Procédé de préparation de gélifiants hydro-organiques à partir de sucres disaccharides par biocatalyse et leur utilisation dans l'administration de médicaments déclenchée par une enzyme Ceased WO2007139854A2 (fr)

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US14/605,046 US9539215B2 (en) 2006-05-22 2015-01-26 Method for preparing hydro/organo gelators from disaccharide sugars by biocatalysis and their use in enzyme-triggered drug delivery

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WO2011097664A3 (fr) * 2010-02-10 2012-03-22 Forschungsholding Tu Graz Gmbh Dispositif de test
US20130034538A1 (en) * 2009-06-25 2013-02-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Reverse hexagonal mesophases (hii) and uses thereof

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US20130034538A1 (en) * 2009-06-25 2013-02-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Reverse hexagonal mesophases (hii) and uses thereof
US10149824B2 (en) * 2009-06-25 2018-12-11 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Reverse hexagonal mesophases (HII) and uses thereof
WO2011097664A3 (fr) * 2010-02-10 2012-03-22 Forschungsholding Tu Graz Gmbh Dispositif de test
US8785142B2 (en) 2010-02-10 2014-07-22 Eva Sigl Test arrangement

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