WO1996003147A1 - Synthese de gels chimiques a partir de polysaccharides polyelectrolytiques par irradiation gamma - Google Patents

Synthese de gels chimiques a partir de polysaccharides polyelectrolytiques par irradiation gamma Download PDF

Info

Publication number
WO1996003147A1
WO1996003147A1 PCT/US1995/007224 US9507224W WO9603147A1 WO 1996003147 A1 WO1996003147 A1 WO 1996003147A1 US 9507224 W US9507224 W US 9507224W WO 9603147 A1 WO9603147 A1 WO 9603147A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
irradiation
polysaccharide
gamma
hydrogels
Prior art date
Application number
PCT/US1995/007224
Other languages
English (en)
Inventor
Kinam Park
Annamaria Paparella
Luca Benedetti
Original Assignee
Fidia Advanced Biopolymers, S.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fidia Advanced Biopolymers, S.R.L. filed Critical Fidia Advanced Biopolymers, S.R.L.
Priority to AU28187/95A priority Critical patent/AU2818795A/en
Publication of WO1996003147A1 publication Critical patent/WO1996003147A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/732—Starch; Amylose; Amylopectin; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/28—Polysaccharides or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices

Definitions

  • the present invention is directed to a method for the synthesis of chemical gels or hydrogels by gamma- irradiation, starting with polyelectrolyte polysaccharides, such as alginic acid, hyaluronic acid and the esters thereof.
  • the present invention is also directed to the chemical gel or hydrogel produced by this method. Gels synthesized by the described method can be used as slow release systems for drugs. FIELD OF THE INVENTION
  • Gels for pharmaceutical use are generally prepared from polymers by chemical means, such as by cross- linking the polymeric chain.
  • a method for synthesizing biocompatible chemical gels or hydrogels which includes reacting polyelectrolyte polysaccharides with a functionalizing agent in order to introduce double bonds into the structure so as to produce functionalized polyelectrolyte polysaccharides; and subjecting the functionalized polyelectrolyte polysaccharides to gamma- irradiation in order to produce the chemical gels.
  • Figures 1, 2 and 3 show the conditions needed for the formation of gels from alginic acid, hyaluronic acid, and the 25% benzyl ester of hyaluronic acid.
  • Figure 1 is a graph showing the effect of the duration of gamma-irradiation and the effect of the concentration of sodium alginate on gel formation.
  • Figure 2 is a graph showing the effect of the duration of gamma-irradiation and of the concentration of hyaluronic acid on gel formation.
  • Figure 3 is a graph showing the affect of the duration of gamma-irradiation and of the concentration of the 25% benzyl ester of hyaluronic acid (HA-25) on gel formation.
  • Figure 4 is a schematic diagram which shows in the upper portion a representation of the functionalization reaction between a polysaccharide (PS) with glycidyl acrylate; and in the lower portion a representation of the formation of one type of crosslinkage between two functionalized polysaccharides that are subjected to gamma-irradiation.
  • PS polysaccharide
  • the present invention has made it possible to synthesize chemical gels or hydrogels from polyelectrolyte polysaccharides using gamma-irradiation.
  • Polyelectrolyte polysaccharides are natural polymeric substances which contain ionic constituents.
  • Polyelectrolyte polysaccharides tend to swell when placed in water in order to minimize the repulsion between like positive or negative charges of the ionic constituents. These properties result in the so-called "polyelectrolyte" effect.
  • polyelectrolyte polysaccharides include alginic acid, alginates, hyaluronic acid, hyaluronic acid esters including benzyl esters, polysialic acid, gellan, xanthane, welan, pectin, and glycosaminoglycans including condroitin sulphates, heparin sulphates, etc., as well as derivatives of these polysaccharides.
  • These polyelectrolyte polysaccharides contrast with other natural polymeric substances, such as dextran and gelatin, which do not exhibit similar electrolytic properties and do not have the same chemical structure containing such ionic constituents.
  • the method of the present invention provides for acidification of solutions of polyelectrolyte polysaccharides which have been functionalized with glycidyl acrylate, within a suitable pH range. Following irradiation, the acidified solutions give rise to the formation of gels at lower concentrations of polymers and for shorter irradiation times.
  • the functionalization reaction for introducing double bonds into the polyelectrolyte polysaccharides involved the use of an appropriate functionalizing agent, such as glycidyl acrylate.
  • an appropriate functionalizing agent such as glycidyl acrylate.
  • the upper reaction illustrates the reaction between glycidyl acrylate and the hydroxy group of a polyelectrolyte polysaccharides (i.e. "PS") .
  • PS polyelectrolyte polysaccharides
  • Figure 4 shows in the lower reaction scheme a simplified illustration of the functionalized polyelectrolyte polysaccharide containing a number "n" of double bonds which is subjected to gamma-irradiation in order to form one type of a crosslinked structure after the opening of the double bonds and the formation of radicals.
  • the resulting crosslinks constitute aliphatic chains of a given length and result in the formation of gels having a three- dimensional structure which exhibits certain strength and resistance properties.
  • the resulting gels may be defined as polyelectrolytes having unique properties including a significant dependence on the pH and a significant dependence on the ionic strength of the aqueous medium in which the resulting gels are allowed to swell .
  • the method of synthesis of gels is conducted using solutions of polyelectrolyte polysaccharides at various concentrations.
  • concentration range of 1-3% w/v may be used for alginic acid, hyaluronic acid and benzyl esters of hyaluronic acid with 25% esterification.
  • polyelectrolyte polysaccharides may be functionalized using different quantities of an appropriate functionalizing agent such as glycidyl acrylate, for example in the range of 0.8-1.3 ml/1 g of polyelectrolyte polysaccharide.
  • an appropriate functionalizing agent such as glycidyl acrylate
  • Acidification of the polyelectrolyte polysaccharides in solution may be performed by the addition of a suitable acid, such as citric acid, hydrochloric acid or acetic acid, preferably without significantly altering the initial concentration of the polyelectrolyte polysaccharide.
  • the polyelectrolyte polysaccharides are acidified in a pH range of from 1 to 6, more preferably a pH range of from 1 to 5, still more preferably of from 3 to 6, and most preferably between 2.5 and 3.5, before being subjected to gamma- irradiation.
  • the acidification of the polyelectrolyte polysaccharide solution makes it possible to obtain gel formation at lower concentrations of the polymer and lower doses of irradiation.
  • the polyelectrolyte polysaccharides are subjected to gamma-irradiation at a preferable dose range of from at least 0.01 to 0.5 Mrad, more preferably from 0.05 to 0.5 Mrad, and most preferably from about 0.0606 to 0.485 Mrad.
  • the time periods during which the polyelectrolyte polysaccharides are subjected to gamma-irradiation is generally in the range of from 1 to 8 hours.
  • the gamma-irradiation dose may be 0.0606 Mrad/h for time intervals varying from about 1 to 8 hours.
  • the polyelectrolyte polysaccharides may also be subjected to direct gamma-irradiation before acidification. It is preferable not to increase the irradiation dose above 0.5 Mrad because of the degradation effects that may occur. For example, the swelling ratio (Q) of the gels increases at doses of gamma-irradiation at 0.485 Mrad which suggests some degradation of the crosslinked structure of the gels. Also, if the produced gels are intended to be used in "drug delivery" systems, the use of lower doses of irradiation minimizes the possibility of damaging the biological activity of the active drug or principle incorporated into the gel.
  • the gels thus obtained swell when placed in water.
  • Some of the synthesized gels described below were characterized by calculating their equilibrium swelling ratio (Q) , based on the weight of the dry gel and that which has swollen to equilibrium (W. S. W. Shalaby, K. Park , Pharm . Res . , 7 , 816 - 823 , 1990 ) .
  • Figures 1, 2 and 3 show the conditions needed for the formation of gels, in the case of alginic acid, hyaluronic acid and the 25% benzyl ester of hyaluronic acid (HA-25) , respectively.
  • the lines in Figures 1-3 indicate the minimum concentration needed for the formation of three-dimensional gels at set gamma-- irradiation times.
  • the acidification of such solutions before irradiation therefore, allows the formation of gels with lower polymer concentrations and shorter irradiation times, thus avoiding possible degradation of the polymer.
  • the gels synthesized according to the methods of the present invention can be used in the fields of medicine, health care, surgery and cosmetics, as well as in reconstructive and cosmetic surgery.
  • gels in the form of films or membranes can be used in various medical fields, such as in ophthalmology, dermatology, otorhinolaryngology and neurology, as tissue substitutes or organ coatings, as well as in tissue and organ transplants.
  • the gels can generally be used as a biocompatible material in cell cultures in three-dimensional systems, as well as in the form of fibers or threads for surgical suture, or in the form of gauzes for wound dressings.
  • the gels of the present invention preferably include crosslinkage throughout the entire product such that all the polyelectrolyte molecules crosslink to form a single chemical entity.
  • Another important use for the compounds obtained by the method of synthesis of the present invention is as a controlled release system of one or more active principles, such as proteins, growth factors, enzymes, drugs or biologically active substances for oral, topical, s.c, i.m. or i.v. administration. Indeed, according to the dose of gamma-irradiation used, it is possible to obtain three-dimensional gels for use as drug release systems for topical or oral administration, or viscoelastic solutions in order to administer by the subcutaneous, intramuscular or intravenous routes.
  • active principles such as proteins, growth factors, enzymes, drugs or biologically active substances for oral, topical, s.c, i.m. or i.v. administration.
  • biocompatible characteristics of the chemical gels or hydrogels of the present invention allows for their employment in potential and actual biomedical applications similar to those of conventional hydrogels, such as coatings for sutures, catheters, IUD's, blood detoxicants, electrode Sensors, vascular grafts, electrophoresis cells and cell culture substrates; homogeneous-type materials including electrophoresis gels, contact lenses, artificial corneas, vitreous humor replacements, estrous-inducers, breast or other soft tissue substitutes, burn dressings, bone ingrowth sponges, dentures, ear drum plugs, synthetic cartilages, hemodialysis membranes and particulate carriers of tumor antibodies; and devices such as enzyme therapeutic systems, artificial organs and drug delivery systems.
  • the incorporation of the active principle in the gel can be achieved either by swelling the dry product in an aqueous solution containing the compound to be incorporated, or by mixing the active principle with the functionalized and purified polymer solution, and then by irradiating the same to obtain a gel.
  • This last method is particularly useful when large molecules are to be incorporated, such as peptides or proteins, which would be unlikely to penetrate a gel left to swell in an aqueous solution. It is, therefore, important to synthesize gels at low doses of gamma-irradiation, so as not to alter the biological activity of the incorporated drug.
  • EXAMPLE 2 1 gr of sodium alginate (medium viscosity) was dissolved in 20 ml of deionized distilled water (5% w/v) . To this solution was added 1.3 ml of glycidyl acrylate. The reaction was performed at ambient temperature while stirring constantly. After 24 hours, the reaction was blocked by the addition of 6.5 ml of glycine at 20% w/v. The solution was then stirred for another 30 minutes, dialyzed for 48 hours in deionized distilled water and lastly centrifuged at 3,000 rpm for about 20 minutes. The final concentration of the solution proved to be about 1% w/v and the pH was 6.
  • Solutions at concentrations of 1.5, 2, 2.5 and 3% were obtained by concentrating the solution to 1% in a rotor evaporator.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 1.
  • the three-dimensional gels obtained from alginic acid were cut (1 cirr) and dried at ambient temperature for 24 hours and at a temperature of 60°C for 12 hours.
  • the samples, ' in threes were weighed dry, left to swell in deionized, distilled water until their equilibrium had been reached, and then weighed again in their completely swollen state.
  • the Q values relative to 1 and 8 hours of gamma-irradiation were 4.5-5.55 for 3% gels and 5.6-6.5 for 2.5% gels. The longer the gamma- irradiation time, the higher the Q value.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 1.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 1.
  • the three-dimensional gels obtained from alginic acid were cut (1 cirr) and dried at ambient temperature for 24 hours and at a temperature of 60°C for 12 hours.
  • the samples, in threes, were weighed dry, left to swell in deionized, distilled water until their equilibrium had been reached, and then weighed again in their completely swollen state.
  • the Q values relative to 1 and 8 hours of gamma-irradiation were 4.8-7.25 for 3% gels and 6.1-8.21 for 2.5% gels. The longer the gamma- irradiation time, the higher the Q value.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 2.
  • Solutions at concentrations of 1.5, 2, 2.5 and 3% were obtained by concentrating the solution to 1% in a rotor evaporator.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 2.
  • the three-dimensional gels obtained from hyaluronic acid were cut (1 c ⁇ r) and dried at ambient temperature for 24 hours and at a temperature of 60°C for 12 hours.
  • the samples, in threes, were weighed dry, left to swell in deionized, distilled water until their equilibrium had been reached, and then weighed again in their completely swollen state.
  • the Q values relative to 1 and 8 hours of gamma-irradiation were 5.5-8.71 for 3% gels and 6.62-11.3 for 2% gels. The longer the gamma- irradiation time, the higher the Q value.
  • EXAMPLE 7 1 gr of the benzyl ester of hyaluronic acid, partially esterified (25%) , was dissolved in 20 ml of deionized, distilled water (5% w/v) . To this solution were added 0.8 ml of glycidyl acrylate. The reaction was performed at ambient temperature while stirring constantly. After 24 hours, the reaction was blocked by the addition of 4 ml of glycine at 20% w/v. The solution was then stirred for another 30 minutes, dialyzed for 48 hours in deionized, distilled water and lastly centrifuged at 3,000 rpm for about 20 minutes. The final concentration of the solution proved to be about 1% w/v and the pH was 6.
  • Solutions at concentrations of 1.5, 2, 2.5 and 3% were obtained by concentrating the solutions to 1% in a rotor evaporator.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 3.
  • Solutions at concentrations of 1.5, 2, 2.5 and 3% were obtained by concentrating the solution to 1% in a rotor evaporator.
  • the purified solutions of functionalized polymer were then gamma-irradiated at a dose of 0.0606 Mrad/h for periods varying between 1 and 8 hours (0.0606-0.4848 Mrad) .
  • the minimum concentrations - necessary for the formation of gels at the irradiation times indicated above are reported in Fig. 3.
  • the three-dimensional gels obtained from HA-25 were cut (1 c ⁇ r) and dried at ambient temperature for 24 hours and at a temperature of 60°C for 12 hours.
  • the samples, in threes, were weighed dry, left to swell in deionized, distilled water until their equilibrium had been reached, and then weighed again in their completely swollen state.
  • the Q values relative to 1 and 8 hours of gamma-irradiation were 4-5.62 for 2.5% gels and 4.6- 5.95 for 2% gels. The longer the gamma-irradiation time, the higher the Q value.

Abstract

Un procédé de synthèse de gels ou d'hydrogels chimiques à partir de polysaccharides polyelectrolytiques consiste à rendre fonctionnel un tel polysaccharide pour introduire des doubles liaisons dans sa structure, puis à soumettre ce polysaccharide rendu fonctionnel à une irradiation gamma pour produire l'hydrogel qui constitue une structure réticulée. L'hydrogel obtenu peut être conçu de façon à être biocompatible et on peut l'utiliser pour la diffusion lente de médicaments.
PCT/US1995/007224 1994-07-26 1995-06-07 Synthese de gels chimiques a partir de polysaccharides polyelectrolytiques par irradiation gamma WO1996003147A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU28187/95A AU2818795A (en) 1994-07-26 1995-06-07 Synthesis of chemical gels from polyelectrolyte polysaccharides by gamma-irradiation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT94PD000139A IT1268718B1 (it) 1994-07-26 1994-07-26 Sintesi di gel chimici da polisaccaridi polielettroliti tramite gamma irradiazione
ITPD94A000139 1994-07-26

Publications (1)

Publication Number Publication Date
WO1996003147A1 true WO1996003147A1 (fr) 1996-02-08

Family

ID=11390781

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/007224 WO1996003147A1 (fr) 1994-07-26 1995-06-07 Synthese de gels chimiques a partir de polysaccharides polyelectrolytiques par irradiation gamma

Country Status (3)

Country Link
AU (1) AU2818795A (fr)
IT (1) IT1268718B1 (fr)
WO (1) WO1996003147A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0842657A1 (fr) * 1996-11-19 1998-05-20 OctoPlus B.V. Microsphères pour la libération contrÔlée et procédés pour la préparation de telles microsphères
WO1998022093A1 (fr) * 1996-11-19 1998-05-28 Octoplus B.V. Procede de preparation d'un systeme a liberation retardee
WO2001048470A1 (fr) * 1999-12-28 2001-07-05 Amersham Biosciences Ab Fabrication de matrices support ameliorees
WO2002072862A2 (fr) 2001-03-13 2002-09-19 Phillips Hydrocolloids Research Limited Nouveaux biopolymeres obtenus par exposition au rayonnement a l'etat solide dans une atmosphere gazeuse non saturee
WO2003035716A1 (fr) * 2001-10-25 2003-05-01 Massachusetts Institute Of Technology Procedes de fabrication de films minces decomposables de polyelectrolytes et leurs utilisations
GB2401043A (en) * 2003-04-25 2004-11-03 Chisso Corp Degradable gels for the sustained delivery of pharmaceuticals
WO2005011772A2 (fr) * 2003-07-31 2005-02-10 Scimed Life Systems, Inc. Dispositifs medicaux implantables ou inserables contenant un polymere traite par rayonnement pour l'administration amelioree d'un agent therapeutique
US8105652B2 (en) 2002-10-24 2012-01-31 Massachusetts Institute Of Technology Methods of making decomposable thin films of polyelectrolytes and uses thereof
US9198875B2 (en) 2008-08-17 2015-12-01 Massachusetts Institute Of Technology Controlled delivery of bioactive agents from decomposable films
US9393217B2 (en) 2007-06-14 2016-07-19 Massachusetts Institute Of Technology Self assembled films for protein and drug delivery applications
US9463244B2 (en) 2013-03-15 2016-10-11 Massachusetts Institute Of Technology Compositions and methods for nucleic acid delivery
US9737557B2 (en) 2013-02-26 2017-08-22 Massachusetts Institute Of Technology Nucleic acid particles, methods and use thereof
US10278927B2 (en) 2012-04-23 2019-05-07 Massachusetts Institute Of Technology Stable layer-by-layer coated particles
US11419947B2 (en) 2017-10-30 2022-08-23 Massachusetts Institute Of Technology Layer-by-layer nanoparticles for cytokine therapy in cancer treatment
US11964026B2 (en) 2022-08-22 2024-04-23 Massachusetts Institute Of Technology Layer-by-layer nanoparticles for cytokine therapy in cancer treatment

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3826678A (en) * 1972-06-06 1974-07-30 Atomic Energy Commission Method for preparation of biocompatible and biofunctional materials and product thereof
US4321117A (en) * 1978-03-09 1982-03-23 Japan Atomic Energy Research Institute Process for preparing a polymer composition
WO1982002716A1 (fr) * 1981-02-09 1982-08-19 Patent Dev Corp Nat Hydrogels synthetiques modifies
EP0174849A2 (fr) * 1984-09-11 1986-03-19 The Secretary of State for Defence in Her Britannic Majesty's Government of the United Kingdom of Great Britain and Matériaux hydrogel
GB2222081A (en) * 1988-07-20 1990-02-28 Univ Salford Business Services Sterilising pharmaceutical formulations
WO1992003172A1 (fr) * 1990-08-17 1992-03-05 Sebapharma Gmbh & Co. Systeme de pansement

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3826678A (en) * 1972-06-06 1974-07-30 Atomic Energy Commission Method for preparation of biocompatible and biofunctional materials and product thereof
US4321117A (en) * 1978-03-09 1982-03-23 Japan Atomic Energy Research Institute Process for preparing a polymer composition
WO1982002716A1 (fr) * 1981-02-09 1982-08-19 Patent Dev Corp Nat Hydrogels synthetiques modifies
EP0174849A2 (fr) * 1984-09-11 1986-03-19 The Secretary of State for Defence in Her Britannic Majesty's Government of the United Kingdom of Great Britain and Matériaux hydrogel
GB2222081A (en) * 1988-07-20 1990-02-28 Univ Salford Business Services Sterilising pharmaceutical formulations
WO1992003172A1 (fr) * 1990-08-17 1992-03-05 Sebapharma Gmbh & Co. Systeme de pansement

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
E. BARTHOLOME et al. "Ullmanns EnzyklopÛdie der technischen Chemie", 4th edition, vol. 22, published 1982 by Verlag Chemie, Weinheim pages 198-199, especially page 198, left column, line 16 - page 199, left column; 8th line after fig. 41. *
K.R. KAMATH et al. "Preparation and Character- ization of Enzyme-Digestible Hydrogels from Natural Poly- mers by Gamma Irradiation", 204th National Meeting of the ACS, ACS Symposium 1992, cited in ACS Symposium Series 545, American Chemical Society, Washington, DC, 1994, pages 55-65, especially page 55; abstract; page 56, line 15 - page 57, line 16; page 58, lines 12-23; page 61, line after fig. 5 - page 63, last line (cited in the application). *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022093A1 (fr) * 1996-11-19 1998-05-28 Octoplus B.V. Procede de preparation d'un systeme a liberation retardee
EP0842657A1 (fr) * 1996-11-19 1998-05-20 OctoPlus B.V. Microsphères pour la libération contrÔlée et procédés pour la préparation de telles microsphères
WO2001048470A1 (fr) * 1999-12-28 2001-07-05 Amersham Biosciences Ab Fabrication de matrices support ameliorees
US7208532B2 (en) 1999-12-28 2007-04-24 Ge Healthcare Bio-Sciences Ab Manufacture of improved support matrices
WO2002072862A2 (fr) 2001-03-13 2002-09-19 Phillips Hydrocolloids Research Limited Nouveaux biopolymeres obtenus par exposition au rayonnement a l'etat solide dans une atmosphere gazeuse non saturee
JP2004536624A (ja) * 2001-03-13 2004-12-09 フィリップス ハイドロコロイド リサーチ リミテッド 不飽和ガス雰囲気中での固体照射により得られる新規なバイオポリマー
EP1565483A4 (fr) * 2001-03-13 2008-03-05 San Ei Gen Ffi Inc Nouveaux biopolymeres obtenus par exposition au rayonnement a l'etat solide dans une atmosphere gazeuse non saturee
EP1565483A2 (fr) * 2001-03-13 2005-08-24 San-Ei Gen F.F.I., Inc. Nouveaux biopolymeres obtenus par exposition au rayonnement a l'etat solide dans une atmosphere gazeuse non saturee
US7112361B2 (en) 2001-10-25 2006-09-26 Massachusetts Institute Of Technology Methods of making decomposable thin films of polyelectrolytes and uses thereof
WO2003035716A1 (fr) * 2001-10-25 2003-05-01 Massachusetts Institute Of Technology Procedes de fabrication de films minces decomposables de polyelectrolytes et leurs utilisations
US8105652B2 (en) 2002-10-24 2012-01-31 Massachusetts Institute Of Technology Methods of making decomposable thin films of polyelectrolytes and uses thereof
GB2401043B (en) * 2003-04-25 2007-10-17 Chisso Corp Drug
GB2401043A (en) * 2003-04-25 2004-11-03 Chisso Corp Degradable gels for the sustained delivery of pharmaceuticals
WO2005011772A3 (fr) * 2003-07-31 2005-04-14 Scimed Life Systems Inc Dispositifs medicaux implantables ou inserables contenant un polymere traite par rayonnement pour l'administration amelioree d'un agent therapeutique
WO2005011772A2 (fr) * 2003-07-31 2005-02-10 Scimed Life Systems, Inc. Dispositifs medicaux implantables ou inserables contenant un polymere traite par rayonnement pour l'administration amelioree d'un agent therapeutique
US7914805B2 (en) 2003-07-31 2011-03-29 Boston Scientific Scimed, Inc. Implantable or insertable medical devices containing radiation-treated polymer for improved delivery of therapeutic agent
US9393217B2 (en) 2007-06-14 2016-07-19 Massachusetts Institute Of Technology Self assembled films for protein and drug delivery applications
US9198875B2 (en) 2008-08-17 2015-12-01 Massachusetts Institute Of Technology Controlled delivery of bioactive agents from decomposable films
US10278927B2 (en) 2012-04-23 2019-05-07 Massachusetts Institute Of Technology Stable layer-by-layer coated particles
US9737557B2 (en) 2013-02-26 2017-08-22 Massachusetts Institute Of Technology Nucleic acid particles, methods and use thereof
US9463244B2 (en) 2013-03-15 2016-10-11 Massachusetts Institute Of Technology Compositions and methods for nucleic acid delivery
US11419947B2 (en) 2017-10-30 2022-08-23 Massachusetts Institute Of Technology Layer-by-layer nanoparticles for cytokine therapy in cancer treatment
US11964026B2 (en) 2022-08-22 2024-04-23 Massachusetts Institute Of Technology Layer-by-layer nanoparticles for cytokine therapy in cancer treatment

Also Published As

Publication number Publication date
IT1268718B1 (it) 1997-03-06
ITPD940139A1 (it) 1996-01-26
AU2818795A (en) 1996-02-22
ITPD940139A0 (it) 1994-07-26

Similar Documents

Publication Publication Date Title
EP0296078B1 (fr) Nouveaux biomatériaux à base de mélanges de collagène, de chitosan et de glycosaminoglycanes, leur procédé de préparation ainsi que leurs applications en médecine humaine
US10265436B2 (en) Immobilized bioactive hydrogel matrices as surface coatings
JP4214051B2 (ja) エラスチン架橋体およびその製造方法
US5324775A (en) Biologically inert, biocompatible-polymer conjugates
JP4458852B2 (ja) 光硬化によるハイドロゲル材料の調製のためのヒアルロン酸のエステル誘導体
US6703444B2 (en) Process for cross-linking hyaluronic acid to polymers
US6586493B1 (en) Polysaccharide-based hydrogels and pre-gel blends for the same
US4946450A (en) Glucan/collagen therapeutic eye shields
CN109734825B (zh) 用于制造成形的交联的透明质酸产物的方法
CN106822183B (zh) 一种光敏富血小板血浆凝胶及其制备方法和用途
EP0648239A1 (fr) Conjugues polymeres biocompatibles
FR2889449A1 (fr) Preparations implantables
WO1996003147A1 (fr) Synthese de gels chimiques a partir de polysaccharides polyelectrolytiques par irradiation gamma
JP2006506110A (ja) 硫酸化多糖及び線維状タンパク質の凝集性共沈殿物及びその使用
CN115400260B (zh) 一种含重组人源化胶原蛋白的修复凝胶及其制备方法
CN110624103A (zh) 用于治疗皮肤异常的生物材料装置和局部组合物
CN113599507A (zh) 葡萄糖触发的活性氧响应注射型复合水凝胶的制备方法
CN111012803A (zh) 用于引导组织再生的生物材料装置和局部组合物
Sionkowska 11 Natural Polymers as
Sionkowska Natural Polymers as Components of Blends for Biomedical Applications
CN114452436B (zh) 一种胶原基可注射自修复水凝胶及其制备方法
EP3882279A1 (fr) Échafaudages biopolymères pdrn-sacran réticulés à la génipine
JPH0622580B2 (ja) サクシニルキトサンより構成された医用材料
Sionkowska 11 NC atural Polymers as omponents of Blends
JPH0567300B2 (fr)

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IS JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TT UA UG US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase