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WO2000047644A1 - Systeme adhesif biocompatible et systeme d'administration de medicaments bioadhesifs a liberation controlee - Google Patents

Systeme adhesif biocompatible et systeme d'administration de medicaments bioadhesifs a liberation controlee Download PDF

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Publication number
WO2000047644A1
WO2000047644A1 PCT/EP2000/001107 EP0001107W WO0047644A1 WO 2000047644 A1 WO2000047644 A1 WO 2000047644A1 EP 0001107 W EP0001107 W EP 0001107W WO 0047644 A1 WO0047644 A1 WO 0047644A1
Authority
WO
WIPO (PCT)
Prior art keywords
bioadhesive
acid
graft
glucoside
poly
Prior art date
Application number
PCT/EP2000/001107
Other languages
English (en)
Inventor
Jean Paul Remon
Shimona Geresh
Joseph Kost
Original Assignee
Universiteit Gent
Ben-Gurion University Of The Negev Research And Development Authority
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Filing date
Publication date
Application filed by Universiteit Gent, Ben-Gurion University Of The Negev Research And Development Authority filed Critical Universiteit Gent
Priority to AU25479/00A priority Critical patent/AU2547900A/en
Publication of WO2000047644A1 publication Critical patent/WO2000047644A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J151/00—Adhesives based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Adhesives based on derivatives of such polymers
    • C09J151/02—Adhesives based on graft polymers in which the grafted component is obtained by reactions only involving carbon-to-carbon unsaturated bonds; Adhesives based on derivatives of such polymers grafted on to polysaccharides

Definitions

  • the present invention relates to a biocompatible adhesive system and a bioadhesive drug delivery system with controlled release.
  • the bioadhesive system in accordance with the present invention is particularly useful in a skin or mucosal drug delivery system with which the release time of the drug may be designed appropriately for the application, and it can also be applied as an oral delivery system for an active component, e.g. a drug, for sustained release of the active component.
  • an active component e.g. a drug
  • Polyacrylic acid is known as one candidate polymer for mucoadhesives and combinations of hydroxypropylmethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose and starch with polyacrylic acid such as polycarbophil or Carbopol 934 are known.
  • polyacrylic acid such as polycarbophil or Carbopol 934
  • the potential irritation associated with the use of polyacrylic acid in buccal bioadhesives has often been disregarded. In practice, these conventional systems have severe limitations because of their irritation potential. A mixture of starches and polyacrylic acid has been shown to yield a less irritant bioadhesive matrix.
  • a mucoadhesive or cutaneous adhesive drug delivery system should preferably allow adaption to specific targets, to specific active components and/or release times. Successful drug application requires not only a system which is capable of delivering a specific drug but also a controllable release of that drug.
  • a complete mucoadhesive or cutaneous adhesive delivery system should preferably be designable, i.e. the system should have sufficient design parameters that a range of release times can be predetermined even for the same drug.
  • the release should preferably be non-Fickian, i.e. not purely dictated by simple diffusion of the drug. The rate of Fickian diffusion depends on the difference in drug concentration between the drug delivery system and the target, hence, the rate is high at the start and then reduces rapidly. It would be preferred if the rate of delivery were more constant.
  • a mucoadhesive or cutaneous adhesive should also preferably be preparable in a variety of suitable physical forms, e.g. as tablets, monolayered or multilayered patches, as beads, pellets or microspheres for inclusion in other systems, and/or in bulk layers suitable for external or internal application.
  • US 5,707,644 describes small particle compositions for intranasal drug delivery including a plurality of bioadhesive microspheres (at least 90% of which have a diameter between 0.1 micron and 10 micron) and an active drug associated with each microsphere.
  • bioadhesive microspheres at least 90% of which have a diameter between 0.1 micron and 10 micron
  • active drug associated with each microsphere Possible biocompaible materials suggested for preparation of the bioadhesive microspheres are starch or dextran derivatives including grafted starches. No examples of grafted starches are given.
  • a biodegradable plastic and methods of grafting methyl acrylate to starch using cerium ammonium nitrate are known from the article "A new biodegradable plastic made from starch graft poly(methyl acrylate) copolymer", by Dennenberg et al. Journal of
  • acrylic-starch grafted copolymers is as superabsorbent materials, e.g. saponified gelatinised starch-polyacrylonitrile graft polymers as known from US 3,935,099 and saponified starch-acrylonitrile graft copolymers are known for use in sustained release dosage forms from US 4,713,237.
  • Starch-polyacrylonitrile graft polymers have found use as moisture absorbing polymers in methods for promoting growth of seeds, e.g. US 5,317,834 and in insecticidal delivery systems as known from US 4,818,534.
  • An object of the present invention is to provide a bioadhesive, preferably a mucoadhesive or a cutaneopus adhesive, more preferably a buccal adhesive which is substantially non-toxic and, in particular, has a reduced irritation potential.
  • Another object of the present invention is to provide a bioadhesive comprising nontoxic compounds and allowing incorporation of an active component such as a drug while not inhibiting its release.
  • a further object of the present invention is to provide a biocompatible adhesive system.
  • a further object of the present invention is to provide a bioadhesive which may be used for adhering to any human or animal internal or external mucosa or skin or to plants or trees.
  • bioadhesive whose adhesive property is resistant to saliva, other mucosal fluids or other forms of water as well as to physical movement of the target substrate, in particular, to swallowing.
  • Still a further object of the present invention is to prepare a bioadhesive which allows controlled release of active compounds such as chemicals, medical drugs or active compounds, cosmetics.
  • Another object of the present invention is to provide a bioadhesive system which is designable, i.e. has sufficient design parameters that release times may be adapted to the application, the active component to be delivered, and the required release time of the active component.
  • the present invention may provide a bioadhesive agent wherein the bioadhesive property of the agent is provided mainly or substantially by a graft copolymerof a poly- ⁇ - glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • the present invention may provide a bioadhesive agent wherein the bioadhesive property of the agent is provided mainly or substantially by a copolymer of a poly- ⁇ -glucoside and at least an ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • the present invention also includes a bioadhesive system comprising a bioadhesive agent, the bioadhesive agent comprising or consisting essentially of a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • the present invention also includes a bioadhesive system comprising a bioadhesive agent, the bioadhesive agent comprising or consisting essentially of copolymer of a poly- ⁇ -glucoside and at least an ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative
  • the bioadhesive agent may include other solid or liquid components.
  • the other component may be releasable from the bioadhesive agent such as, for instance, an active component,. No limits are anticipated on the active component other than it should be preferably incorporatable into the bioadhesive agent.
  • a therapeutic substance or a pharmaceutically active agent such as a drug, a non-therapeutic substance such as a cosmetic substance, a local or general anaesthetic or pain killer, e.g. lidocaineTM or novocaineTM or an opiate, a vaccine, an antigen, a microorganism, a sterilizing substance, a contraceptive composition, a protein or peptide such as insulin, an insecticide, a herbicide, a hormone such as a growth hormone or a seed germination hormone, a steroid, a toxin, a marker substance, e.g. a radioactively labeled compound.
  • another component of the bioadhesive agent may be an excipient such as a binder.
  • the present invention also includes an adhesive material for animal or human mucosa, skin, body parts or tissue or vegetable or plant parts or tissue, the adhesive material including a bioadhesive agent, the bioadhesive agent comprising or consisting essentially of a graft copolymer of a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • a bioadhesive agent comprising or consisting essentially of a graft copolymer of a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • the present invention also includes the use of a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative as a bioadhesive agent. Both therapeutic and non-therapeutic, e.g. cosmetic or pest control, applications are included within the scope of the present invention.
  • the present invention also includes the use of a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative in the manufacture of a bioadhesive agent for use in compositions for therapeutic or non- therapeutic, e.g. cosmetic or pest control purposes.
  • the graft copolymerof a poly- ⁇ - glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative in accordance with the present invention also may exhibit swelling properties and can take up and controllably release an active component, such as a drug.
  • the present invention also includes a controlled release active component delivery vehicle comprising a bioadhesive agent, the bioadhesive agent comprising or consisting essentially of a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative.
  • the active component may be incorporated into the bioadhesive agent.
  • the present invention also includes the use of a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative as a bioadhesive agent in a controlled release active component delivery vehicle. Both therapeutic and non-therapeutic applications are included within the scope of the present invention.
  • the present invention also includes the use of a graft copolymerof a poly- ⁇ - glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative as a bioadhesive agent in the manufacture of a controlled release active component delivery vehicle.
  • Controlled release includes prolonged or sustained release as well as rapid release.
  • the release time may be designed by the appropriate adaption of the bioadhesive agent. No limits are anticipated on the active component other than it should be preferably incorporatable into the bioadhesive agent. It may be, for instance, a therapeutic substance or a pharmaceutically active agent such as a drug, a non-therapeutic substance such as a cosmetic substance, a local or general anaesthetic or pain killer, e.g.
  • lidocaineTM or novocaineTM or an opiate a vaccine, an antigen, a microorganism, a sterilizing substance, a contraceptive composition, a protein or peptide such as insulin, an insecticide, a herbicide, a hormone such as a growth hormone or a seed germination hormone, a steroid, a toxin, a marker substance, e.g. a radioactively labeled compound.
  • active components e.g.
  • bioadhesive agent a component which provides bioadhesive properties to a composition in which it is included rather than, for instance, an excipient in a bioadhesive composition.
  • Bioadhesive properties means that adhesive properties are developed on contact with animal or human mucosa, skin or body tissue or vegetable or plant tissues, i.e. the bioadhesive develops adhesive properties when used as a mucosal or transdermal adhesive, that is on those living surfaces which include some water or an aqueous solution. Pressure may need to be applied to the bioadhesive agent when applied to the animal or human mucosa, skin or body tissue or vegetable or plant tissue to activate the adhesive properties.
  • a bioadhesive agent in accordance with the present invention may provide a biocompatible, hydrophilic adhesive which may be pressure sensitive.
  • the adhesive action of a bioadhesive agent in accordance with the present invention may be based on the interpenetration of the chains of the graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative or the poly- ⁇ - glucoside moiety of the graft copolymer in accordance with the present invention with polymeric chains formed on the surface of the substrate, e.g. glycoprotein chains of the oral mucosa.
  • a bioadhesive agent in accordance with the present invention may be described generally as providing an interpenetrating bioadhesive.
  • a bioadhesive agent in accordance with the present invention does not necessarily develop adhesive properties when contacted with bulk water or a bulk aqueous solution (i.e. without a suitable biological substrate as well).
  • the bioadhesive agent in accordance with the present invention does not form an adhesive surface when in contact with bulk water.
  • Preferred embodiments of the present invention form non-adhesive gels when contacted with bulk water or aqueous solutions, e.g.
  • bioadhesive agent in accordance with the present invention is used as an active component delivery system, e.g. as a controlled release drug delivery buccal adhesive.
  • the bioadhesive system in accordance with the present invention is preferably deliverable in a non-adhesive and dry form for instance, as a tablet, and the adhesive properties are only activated when the system is placed in contact with mucosa, body tissue, skin, vegetable or plant tissue or a similar surface.
  • the bioadhesive agent in accordance with the present invention is preferably biocompatible, in particular, non-cytotoxic.
  • graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative as used herein means any such monomer which can be grafted onto a poly- ⁇ -glucoside under suiatble conditions such as free radical intiation or high energy radiation may include: monocarboxylic acids such as acrylic acid, methacrylic acid, ethacrylic acid, alkenoic acid, acrylic acid being preferred; esters of the said acids with an alcohol or aminoalcohol having from 1 to 18 carbon atoms such as alkyl acrylates and methacrylates, the alkyl group being selected from methyl, ethyl, n-propyl, isopropyl, n- butyl, iosbutyl, sec-butyl, tert-butyl, hexyl, n-octyl, ethylhexyl, nonyl, dodecyl, stearyl, and possibly being substitute
  • hydroxyethyl) or halo- atoms such as fluoro, dimethylaminoethyl acrylate and methacrylate, and the like; acrylonitrile, methacrylonitrile; and alkaline or alkaline earth salts, e.g. sodium, potassium, calcium of the above acids.
  • other comonomers may be included from the above with the monocarboxylic monomer during the grafting to a poly- ⁇ -glucoside, e.g. esters of acrylic or methacrylic acids and derivatives such as 2-dimethylaminoethyl methacrylate.
  • the poly- ⁇ -glucoside may be any chemically or physically modified starch or oligosaccharides, in particular, any poly- ⁇ 1,4-glucoside or poly- ⁇ 1,6-glucoside.
  • Poly- ⁇ l,6-glucoside includes dextran.
  • Poly- ⁇ 1,4-glucosides include leguminous, cereal or tuber starches or a hydrolysate of such a starch.
  • a non-limiting list of starch sources includes corn, wheat, barley, oats, pea, waxy maize, arrowroot, sorghum, rice, waxy sorghum, waxy rice, soya, potato.
  • poly- ⁇ -glucoside may include branched or unbranched polymaltoses such as amylopectin or amylose or thinned starches (hydolysates of starch) including maltodextrose.
  • the graft copolymer in accordance with the present invention may be or may not be at least partly saponified.
  • the graft copolymer in accordance with the present invention is preferably not water soluble.
  • the poly- ⁇ -glucoside forms the backbone
  • the moiety derived from the graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative forms the branches of the grafted copolymer.
  • the grafted acrylic moiety may be partly ionised.
  • the side chains, i.e. the grafted acrylic moiety include salts, preferably monovament or divalent salts, e.g.
  • preferred embodiments of the present invention include acrylic-poly- ⁇ -glucoside grafted copolymers in which the graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative side chains are cross-linked among themselves.
  • the present invention includes a graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ - ethylenically unsaturated monocarboxlic acid or acid derivative which forms a three- dimensional cross-linked matrix or gel which exhibits bioadhesive properties, i.e. has inherent bioadhesive properties without addition of other components.
  • the present invention includes graft copolymers manufacturable by at least two methods as well as the methods themselves: free radical or chemical initiation and initiation by irradiation, the choice of the method depending, in part, on the particular monomer or combination of monomers to be polymerized.
  • graft coplymers of a poly- ⁇ - glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative and methods of their manufacture are included within the present invention based on at least two initiation methods 1) gamma irradiation, e.g.
  • irradiation initiated poly- ⁇ -glucoside graft copolymers Particularly preferred are copolymers which are manufactured by irradiating mixtures of a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative and a poly- ⁇ -glucoside, i.e.
  • the present invention also includes preirradiation of a poly- ⁇ - glucoside to form free radicals followed by addition of the acrylic monomer as well as chemical initiation.
  • the poly- ⁇ -glucoside such as starch may be gelatinised before grafting to the acrylic monomer or granules may be grafted directly.
  • Various parameters such as irradiation times and the weight percentages of the poly- ⁇ -glucoside and/or the graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative monomer may be adjusted to provide selectable adhesive properties and/or selectable release rates for the desired active compounds to be included in the bioadhesive agent in accordance with the present invention.
  • the graft copolymerof a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative in accordance with the present invention may be characterised by physicochemical methods and the size and nature of the acrylic moiety grafted to the poly- ⁇ -glucoside.
  • grafted copolymers may be characterized by FT-LR spectroscopy and by ⁇ -NMR spectroscopy, from which the molecular weights of the acrylic moiety grafted onto the a poly- ⁇ -glucoside may be determined.
  • Coventional molecumar weights (average number) of the acrylic moiety obtainable by the above- referenced intiation methods lie in the range 5,000 to 100,000, preferably from 10,000 to 50,000.
  • Variation of the parameters of the grafting process may be used to design suitable controlled release bioadhesives in which both the release time of the active component, e.g. a drug, and the extent of bioadhesion may be tailored to specific applications.
  • the kinetics of the controlled release of model drugs sodium salicylate and theophylline
  • model drugs sodium salicylate and theophylline
  • the present invention also includes a process for manufacturing a bioadhesive agent by the steps of: a) graft copolymerising a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ - ethylenically unsaturated monocarboxlic acid or acid derivative; b) mixing the graft copolymer with an additional substance.
  • the present invention also includes a process for manufacturing a bioadhesive agent by the steps of: a) copolymerising a poly- ⁇ -glucoside and at least a copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative; b) mixing the graft copolymer with an additional substance.
  • the colymerisation is preferably carried out in the presence of high energy radiation which also induces cross- linking.
  • the additional substance may be releasable from the bioadhesive agent such as an active component, for instance. No limits are anticipated on the active component other than it should be preferably incorporatable into the bioadhesive agent, for example by means of encapsulation or microencapsulation.
  • a therapeutic substance such as a drug, a vaccine, an antigen, a microorganism, a non-therapeutic substance such as a cosmetic substance, a local or general anaesthetic or pain killer or an opiate, a sterilising substance, a contraceptive composition, a protein such as insulin, an insecticide, a herbicide, a hormone such as a growth hormone or a seed germination hormone, a steroid, a toxin, a marker substance, e.g. a radioactive compound.
  • the additional substance may be an excipient such as a binder.
  • the present invention also includes a method of adhering a material to animal or human mucosa, skin, body tissue or vegetable or plant tissue using a bioadhesive agent, the bioadhesive agent comprising or consisting essentially of an acrylic-poly- ⁇ -glucoside graft copolymer. Both therapeutic and non-therapeutic applications are included within the scope of the present invention.
  • the present invention also includes a method of fabricating a controlled release active component delivery vehicle comprising the steps of a) forming the delivery vehicle from at least a bioadhesive agent by graft copolymerising a poly- ⁇ -glucoside and at least a graft copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative; b) including an active component in the delivery vehicle.
  • the present invention also includes a method of fabricating a controlled release active component delivery vehicle comprising the steps of a) forming the delivery vehicle from at least a bioadhesive agent by copolymerising a poly- ⁇ -glucoside and at least a copolymerizable ⁇ , ⁇ -ethylenically unsaturated monocarboxlic acid or acid derivative; b) including an active component in the delivery vehicle.
  • the active component may be incorporated into the bioadhesive agent.
  • Fig. 1 is a reaction scheme showing eerie ammonium nitrate (CAN) initiated graft polymerization of acrylonitrile (AN) onto starch (top) and alkaline hydrolysis of the starch- j -polyacrylonitrile (bottom) in accordance with embodiments of the present invention.
  • Fig. 2 is an FT-IR spectrum of starch-j -polyacrylonitrile (1 : 1.5) in accordance with an embodiment of the present invention.
  • Fig. 3 is an FT-LR spectrum of starch-j -polyacrylic acid (1 : 1.5) in accordance with an embodiment of the present invention.
  • Fig. 4 is a general representation of a scheme of acid hydrolysis of starch-g- polyacrylonitrile.
  • Fig. 5 is a graph showing swelling (swollen weight/dry weight) of starch-j - polyacrylic acid in accordance with an embodiment of the present invention in water and different buffers at various pH values.
  • Fig. 6 shows the effect of irradiation time on the kinetics of release of salicyclic acid from potato starch- -acrylic acid (1.2.5) in accordance with an embodiment of the present invention.
  • Fig. 7 shows the effect of irradiation time on the kinetics of release of theophylline from potato starch- -acrylic acid (1:2.5) in accordance with an embodiment of the present invention.
  • Fig. 8 shows the effect of irradiation time of grafting on the drug release rate of a grafted starch in accordance with an embodiment of the present invention.
  • Fig. 9 shows release of salicylic acid from a potato starch-g-acrylic acid copolymer in accordance with an embodiment of the present invention.
  • Fig. 10 shows release of salicylic acid from a rice starch- -acrylic acid copolymer in accordance with an embodiment of the present invention.
  • Fig. 11 shows release of salicylic acid from a grafted potato starch (5 wt.%) in accordance with an embodiment of the present invention using two different amounts of acrylic acid.
  • Fig. 12 shows release of salicylic acid from graft copolymers of acrylic acid with various amounts of potato starch in accordance with an embodiment of the present invention.
  • Fig. 13 shows the rate of release of theophylline from graft copolymers obtained from grafting starch with acrylic acid in weight ratios of 1:12.5; 1:25, and 1:37.5 in accordance with embodiments of the present invention.
  • Fig. 14 shows release of theophylline from a dry piece of grafted starch (1) and from a tablet (2) manufactured in accordance with embodiments of the present invention.
  • Fig. 15 shows the release of theophylline from tablets (without binder) of grafted copolymers of two different starches with acrylic acid in accordance with embodiments of the present invention.
  • Fig. 16 shows the release of theophylline from tablets (with binder) of grafted copolymers of two different starches with acrylic acid in accordance with embodiments of the present invention.
  • Fig. 17 shows release of theophylline from starches grafted with partially neutralized acrylic acid (dissolution medium at pH 5) in accordance with an embodiment of the present invention.
  • Fig. 18 shows release of theophylline from various starches grafted with acrylic acid partially neutralized with MgO (dissolution medium at pH 3) in accordance with an embodiment of the present invention.
  • Fig. 19 shows release of theophylline from various starches grafted with acrylic acid partially neutralized with CaO (dissolution medium at pH 7) in accordance with an embodiment of the present invention.
  • Fig. 20 shows release of theophylline from malto-dextrose (#1924) grafted with partially neutralized acrylic acid (dissolution medium at pH 5) in accordance with an embodiment of the present invention.
  • Fig. 21 shows release of theophylline from maltodextrose (#1910) grafted with partially neutralized acrylic acid (dissolution medium at pH 5) in accordance with an embodiment of the present invention.
  • Fig. 22 shows release rates of salicylic acid (S A) and theophylline as model drugs from tablets of grafted rice starch (prepared with a starch: acrylic acid ratio of 1:5 in the presence of Ca ⁇ + ) in accordance with an embodiment of the present invention.
  • Fig. 23 shows the release rate of increasing concentrations of theophylline from tablets of grafted corn starch (prepared with a starch: acrylic acid ratio of 1 :5 in the presence of Na + or Ca ⁇ + ) in accordance with an embodiment of the present invention.
  • Fig. 24 shows release rates at pH 5 of theophylline from tablets obtained from maltodextroses grafted with acrylic acid (1 :5) in accordance with an embodiment of the present invention.
  • Fig. 25 shows release rates at pH 7 of theophylline from tablets obtained from maltodextroses grafted with acrylic acid (1:5) in accordance with an embodiment of the present invention.
  • Fig. 26 shows the release rate at pH 5 of theophylline from tablets of potato starch grafted in the presence of organic solvents in accordance with an embodiment of the present invention.
  • Fig. 27 shows the release rate of theophylline from tablets of potato starch grafted in the presence of organic solvents with or without calcium ions in accordance with embodiments of the present invention.
  • Fig. 28 shows the effect of mono- and divalent cations on work of adhesion for grafted starches in accordance with the present invention.
  • Fig. 29 is a schematic diagram of the test apparatus for measuring bioadhesion.
  • Fig. 30 is a graph of force (Y-wxis) against extension (X-axis) for a sample to be tested for bioadhesion.
  • the present invention will be described with reference to certain embodiments and to certain drawings but the present invention is not limited thereto but only by the claims.
  • the present invention will be described with reference to starches from different sources being grafted with acrylic monomers using two initiation methods: initiation by radioactive 60co and initiation by CAN, but the present invention is not limited thereto but only by the claims.
  • the present invention is not limited to radioactive 60c o irradiation but may include other methods of irradiation, e.g. electron beam irradiation, or irradiation with other nuclear particles or high energy radiation, e.g. ultra-violet radiation, X-ray radiation.
  • the present invention will be described mainly with reference to rice or potato starch but the present invention is not limited thereto but includes any form of starch, e.g. from other sources such as wheat starch and those given above.
  • the present invention will mainly be described with reference to the controlled release of one of two drugs, salicylic acid and theophylline, from a bioadhesive carrier whose adhesive component is provided by an acrylic grafted starch or starch hydrolysate copolymer but the present invention is not limited thereto but only by the claims.
  • the present invention will mainly be described with reference to a mucoadhesive but the present invention is not limited thereto.
  • the present invention includes other applications such as those applications where a bioadhesive is required which maintains its adhesive in wet conditions, for example, in the germination of seeds, the bioadhesive according to the present invention may used to adhere active compounds such as herbicides, fertilisers or germination enhancers or other plant hormones to wetted seed or vegetable or plant tissue.
  • active compounds such as herbicides, fertilisers or germination enhancers or other plant hormones to wetted seed or vegetable or plant tissue.
  • the bioadhesive functionality may be used to advantage to allow these compounds to remain in place even after initial or subsequent wetting in soil until the germination period is complete.
  • the active ingredient in the bioadhesive may be a germination or growth hormone, an insecticide, fungicide, herbicide or any other pest control agent which is adhered to plants, crops or trees or foliage or roots thereof, or aquatic flora or fauna such as fish or other aquatic animals using the bioadhesive in accordance with the present invention.
  • the bioadhesive in accordance with the present invention may be used for controlled drug release to mucosal membranes of humans or animals such as membranes of the mouth, nose, lungs and bronchia, intestine, throat, vagina, rectum, eye or may be used for external use, e.g.
  • bioadhesive carrier in accordance with the present invention may be applied directly to an open wound and will bond thereto.
  • Pharmaceutically active agents may be included in the bioadhesive carrier which may then be released in a controlled manner into the wound.
  • the bioadhesive carrier may also absorb exudate from the wound.
  • the present invention also includes use in or on implantations in the human, animal or vegetable body. The uses of the present invention may include controlled drug release but this is not essential to the present invention, i.e.
  • the bioadhesive in accordance with the present invention also includes use for mechanical fixation purposes only or for the delivery of other active ingredients.
  • the bioadhesive in accordance with the present invention may be used in or on dental prostheses, e.g. in localisation and fixation of dentures or for the delivery of drugs or similar to specific regions of the mouth, e.g. the controlled delivery of local anaesthetics, antibiotics, antimyotics, antiseptics, antiviral drugs.
  • the bioadhesive in accordance with the present invention may also be used in tablet form, e.g.
  • bioadhesive agents in accordance with the present invention may be used in any suitable form, e.g. in beads or pellets, in microspeheres or micro-or nano-capsules, in a mono-layer or in multi-layers, e.g. on a patch, or similar.
  • Starches from potato (S-4251), corn (S-4126) and rice (S-7260) were purchased from Sigma Chemical Co.
  • Salicylic acid, acrylonitrile, polyacrylonitrile, acrylic acid and polyacrylic acid were bought from Aldrich Chemical Co.
  • Acrylonitrile was freshly distilled before use.
  • Theophylline was obtained from Ludeco, Belgium.
  • Ceric ammonium nitrate (CAN) was Fisher Certified ACS grade or bought from Aldrich. Irradiation with 60co at an intensity of 1300 rad/min were performed at the Nuclear Engineering Department of Ben-Gurion University.
  • Intrinsic viscosity The intrinsic viscosity of polyacrylonitrile was determined by measuring the viscosities of solutions at various dilutions with an Ubbelohde viscometer at 25°C. Spectra
  • the apparatus used for the determination of the bioadhesive characteristics consisted of a tensile testing machine (type L1000R, Lloyd Instruments, Segenwordt, Fareham, UK), equipped with a 20 N load cell with an accuracy of less than 1%.
  • the apparatus was connected to a computer.
  • Porcine gingiva were obtained from a slaughter house directly after slaughtering. They were rapidly frozen and stored in isotonic phosphate-buffered saline pH 7.4 (2.38 g Na2HPO4.2H2O, 0.19 g KH2PO4 and 8.0 g NaCl made up to 1000 mL with deminerahzed water).
  • Tablets of 100 mg of the material to be tested were directly compressed at a pressure of 1500 kg with the given polymers without any other excipient.
  • An eccentric compression machine (Korsch, type EKO, Frankfurt, Germany) equipped with 7-mm flat punches was used.
  • the test equipment for measuring bioadhesion is shown schematically in Fig. 29.
  • the tablet 10 under test was attached to the upper aluminum support 14, connected to the superior cross-sectional bar 16 of the tensile tester with cyanoacrylate glue (Loctite Super Glue gel, Loctite Belgium, Kontich, Belgium).
  • the porcine gingival tissue ( ⁇ 100 mm 2 ) 10 was glued (mucosal side out) with the same adhesive to a Teflon support 18, which was connected to a PVC cylinder 20 situated at the bottom of a 150 mL thermostatted beaker 22 fixed on the base on the tensile tester.
  • 15 ⁇ L of isotonic phosphate buffer (pH 7.4) was spread evenly over the mucosa 10, and the crosspiece 16 (bearing the tablet 12) was lowered at a crosshead speed of 1 mm.min" ⁇ .
  • the thermostatted beaker 22 was filled with the buffer solution up to a total volume of 125 mL to act as a counterweight.
  • the mucosa 10 and the tablet 12 were then pressed together with a force of 0.5 N for 5 min, after which the tablet 12 and mucosa 10 were pulled apart at a constant extension rate of 5 mm.min " l until complete rapture of the tablet-mucosa bond was obtained.
  • a force vs extension diagram (Fig. 30) was constructed, and the maximal detachment force and the work of adhesion necessary to break the bond between tablet and mucosa were calculated. The work of adhesion is calculated from the area under the force/extension diagram.
  • graft copolymers were prepared by chemical initiation.
  • a stirred slurry of 10 g of starch in 167 ml of water was heated for 30 min at 85°C, while a stream of nitrogen was allowed to bubble slowly through the mixture.
  • the mixture was then cooled to 25°C.
  • Acrylonitrile (15.0 g, 0.283 mole) was added to the starch suspension, followed after about 1 min by a solution of eerie ammonium nitrate (0.338 g, 6.17 x 10 ⁇ 4 mole) in 3 ml of 1 N nitric acid.
  • the reaction mixture was stirred under nitrogen for 2 h, and in most reactions sodium hydroxide solution was then added to give a pH of 7.
  • the acrylic acid monomer was partially neutralized with mono-valent and/or divalent cations, e.g. sodium hydroxide, calcium oxide or magnesium oxide, and the pH of the mixture of acrylic acid and the acrylate salt formed was measured. Thereafter, grafting was performed as described above. The effect of the mono- and divalent cations was to introduce salts of the acrylic side chains of the graft copolymer. In particular, the effect of the mono- and divalent cations on the behavior of graft copolymers with regard to swelling, release rates and bioadhesion were determined.
  • mono-valent and/or divalent cations e.g. sodium hydroxide, calcium oxide or magnesium oxide
  • the model drug was incorporated into tablets.
  • tablets were prepared with a binder as an excipient. Samples of graft copolymers were dried at room temperature, and then ground in a blender cooled with liquid nitrogen. The powder was sieved through a 20-mesh sieve.
  • the obtained material was mixed with the relevant model drug and polyvinylpyrolidone as a binder in a ratio of graft colpolymer: model drug:polyvinylpyrolidone of 10:1:0.5.
  • the solid mixture was wetted with ethanol and mixed further.
  • the paste was dried in a thermostatically controlled oven at 50°C to a constant weight.
  • Each tablet weighed 0.25 ⁇ 0.02 g and had a diameter of 9.0 ⁇ 0.2 mm and a height of4.0 ⁇ 0.2 mm.
  • the same procedure was followed, except that no binder was used and after sieving, the drug was added to the graft copolymer at a ratio of 1:10.
  • acrylonitrile (AN) may be used as monomer and grafting may be performed according to the method of Fanta et al. described in "Adbsorbent polymers from starch and flour through graft polymerization of acrylonitrile and comonomer mixtures", Starch, vol 30, 1978, 237-242, and shown schematically in Fig. 1. The results obtained for various weight ratios of starch to AN are presented in Table 1.
  • redox system was based on CAN (eerie ammonium nitrate); ⁇ Total nitrogen content before extraction of homopolymer with DMF.
  • AN acrylonitrile
  • PAA polyacrylic acid
  • Intrinsic viscosity was measured with a Ubbelohde capillary viscometer.
  • Attachment frequency reflects the number of glucose units between PAN chains.
  • the PAN obtained from the acid hydrolysis of the chemically grafted potato or rice starches was soluble in DMF (Table 4).
  • the molecular weight (M n ) of the PAN residues was calculated using the relationship between the intrinsic viscosity and the molecular weight (equation 1).
  • the constants in eq. 1 were obtained from studies on molecular weight determination of polyacrylonitrile (see Onyon, P.F., J. Polym. Sci. XXIL1956, 19- 23, or Cleland, R.L., Stockmayer, W.H., J. Polym. Sci. XVH, 1955, 473-477):
  • the intrinsic viscosity was determined by measuring the viscosity of diluted solutions of PAN in DMF. The results are presented in Table 5.
  • the extent of swelling of the chemically prepared grafted starches with PAN in accordance with the first embodiment is an important parameter since the extent of swelling strongly influences the bioadhesive properties.
  • the extent of swelling was tested in water at pH 2, 5 and 7 and in citrate, acetate and phosphate buffers, having different pH values.
  • the results presented in Fig. 5 describe the swelling behavior of a sample of rice starch grafted with polyacrylic acid (weight ratio 1 : 1.5 rice starch to acrylonitrile). Both in water and in citrate buffer at low pH, the swelling was low, probably due to the presence of non-ionized -COOH groups. With an increase in pH to pH 4.5-5.0, the swelling increased due to ionization of the carboxylic groups. Between pH 5-8 the swelling leveled off.
  • Fig. 6 and Fig. 7 The effect of irradiation time on the release of salicylic acid and theophylline from grafted starches in accordance with the second and third embodiments is shown in Fig. 6 and Fig. 7, respectively. Grafting by ⁇ Co irradiation was performed for various periods of time. After stopping the irradiation, drugs were incorporated in the starch-grafted copolymers, and the kinetics of drug release were followed. Although it is clear from Fig. 6 and Fig. 7 that longer irradiation times increased the time required to release the loaded drug, the behavior of each model drug is better understood from the correlation of the rate of drug release with irradiation time, as presented in Fig. 8.
  • Grafting of starch (2 wt.%) solutions with various amounts of acrylic acid was carried out using two types of starch (potato starch and rice starch) grafted with acrylic acid by the irradiation method of the second embodiment. Grafting of potato starch was performed with various amounts of acrylic acid (0.2, 0.5, and 1.0 g). The release of salicylic acid as a function of time is presented in Fig. 9 which also shows the weight ratios of potato starch to acrylic acid. When acrylic acid was grafted onto rice starch, similar or even higher amounts of acrylic acid were used (Fig. 10). For the potato starch-g-acrylic acid copolymers obtained with ⁇ 1 g of acrylic acid (weight ratio 1 : 1), the release was relatively fast (about 1 h).
  • the slow release of theophylline from starch-g-acrylic acid copolymers obtained from 2 wt.% starch and higher amounts of acrylic acid was also investigated (Fig. 13).
  • the release of theophylline was significantly delayed as the amount of acrylic acid in the graft copolymer was increased.
  • the ratio of starch to acrylic acid was 1 : 12.5, total release of the model drug was obtained in about 10 h.
  • the ratio was tripled by increasing the amount of acrylic acid, only about 60% of the drug was released in the same period of time.
  • the incorporation of the active component was performed by allowing dry grafted starches in accordance with the present invention to swell during the incorporation of the respective model drug.
  • a comparative experiment was performed with a sample of dry grafted starch and a tablet obtained from the powdered form of the same grafted copolymer. Powders obtained after milling under liquid nitrogen were used to prepare tablets with the model drugs as described above. Tablets with binder (polyvinylpyrolidone) were also prepared. The results in Fig. 14 show better release of the drugs from the tablets.
  • Fig. 15 The release of theophylline from tablets obtained with graft copolymers from both potato and rice starch in accordance with the present invention with the same amount of theophylline is presented in Fig. 15.
  • the release of the drug was significantly slower from the rice starch- -acrylic acid copolymer (only about 70% release after 8 h).
  • the release of theophylline (Fig. 16) was similar for both rice and potato starch grafted copolymers. According to these results the binder may be used advantageously in accordance with the present invention to eclipse the differences observed above and shown in Fig. 15.
  • Acid hydrolysis of grafted copolymers obtained by irradiation in accordance with the second and third embodiments was performed in order to free the polyacrylic acid chains for molecular weight determination. However, the remaining polyacrylic acid was found to be insoluble in water. In order to avoid what seems to be crosslinking of polyacrylic acid during irradiation, acrylic acid partially neutralized with NaOH, CaO and MgO was mixed with the respective starch prior to the grafting process. Thus, acrylic acid neutralized with increasing amounts of base was grafted onto potato starch. After grafting, drying and milling, samples of these copolymers were subjected to acid hydrolysis. The same behavior was obtained: the polyacrylate chains formed weak gels in water. It seems that during the grafting process, some cross-linking of the polyacrylic acid in the graft occurs, which affects the solubility of the polyacrylic acid chains in aqueous solutions over a wide range of pH values (pH 1-8).
  • the effect of partly neutralising and partial ionisation of the acrylic moiety of the grafted starch copolymer was determined.
  • mono- and divalent cations were included in the grafted starches in accordance with the third embodiment and their effect on the release rate of theophylline from tablets and on the extent of bioadhesion determined.
  • the effects of different cations, of the pH of the dissolution medium and of the type of starch on release kinetics of theophylline from tablets were determined.
  • the kinetics of theophylline release from the corn starch polymer as a function of time (Fig. 17) were similar in the presence or absence of sodium ions.
  • the release of the drug was modified by incorporation of the divalent cations tested, Mg 2+ and Ca 2+ .
  • Mg 2+ and Ca 2+ In the case of calcium ions, only about 55% of theophylline was released after about 10 h, while in the presence or absence of Na + , 90% of the drug was released in about 6 h .
  • the release rate of theophylline was similar irrespective of the type of starch used in the graft polymerization (Fig. 18 and 19).
  • higher amounts of cations (x 2, x 4) were added to acrylic acid before grafting, the release of theophylline was faster in the presence of calcium ions than in the presence of sodium or magnesium cations.
  • the rate of theophylline release was tested in dissolution medium at various pH values (pH 3, 5 and 7), it was found that the release rate did not depend on the pH (Fig. 17-19).
  • the tablets were prepared from corn starch grafted with acrylic acid partially neutralized with NaOH or CaO in accordance with the third embodiment.
  • copolymers prepared with Na + the same kinetics of drug release were observed for 10% and 20% theophylline.
  • increasing the theophylline content to 50% slowed down the release rate of the drug.
  • the release rate of theophylline (10 and 20%) slowed dramatically (about 50% after 10 h).
  • the presence of calcium - rather than the degree of loading - became the factor determining the release rate of the drug.
  • a series of maltodextroses of various oligomer sizes i.e., various degrees of dextrose equivalency (DE) were grafted with acrylic acid (ratio 1:5) in the presence (fourth embodiment) or absence (fifth embodiment) of calcium ions.
  • the release of theophylline from tablets prepared with the grafted maltodextroses was tested in two dissolution media, i.e., pH 7 and pH 5.
  • Results presented in Fig. 24 and Fig. 25 show a correlation between the size of the maltodextrose oligomer (DE) and the release rate of theophylline.
  • the sample 19-39-10 which contained calcium ions, was prepared from maltodextrose #1906, with a DE of 6.
  • acrylic acid was dissolved in organic solvents such as ethanol and acetone was added to the pregelatinized starch in water, and the mixture was then subjected to 60 Co radiation in accordance with the third embodiment.
  • partially neutralized acrylic acid in the form of calcium acrylate was used.
  • Fig. 26 describe the release of theophylline from tablets prepared from copolymers grafted in acetone:water (1 :9), acetone:water (1 :5) and ethanol:water (3:7).
  • Fig. 27 the drug release obtained with potato starch grafted in either ethanol:water (1 :9) or acetone:water (1 :9) with or without calcium ions is presented.
  • the results show that longer periods of time were required to release theophylline from tablets prepared with starch grafted in a mixture of water and organic solvent. However, under these conditions, the higher the content of organic solvent, the more rapid the release of drug from the tablets. In contrast to starches grafted in aqueous media, the presence of calcium in the organic solvents did not have any effect on the release rates of theophylline.
  • a bioadhesive e.g. a buccal bioadhesive
  • one of the important characteristics can be the extent of swelling. It is desirable for the preparation to have moderate swelling: low swelling will prevent adhesion, while a high degree of swelling will result in "slippery" materials, which may not adhere satisfacorily to the mucus membrane.
  • the last number in the sample designation represents the slice from a large-scale preparation of graft copolymer of potato starch and acrylic acid (weight ratio 1 :5) obtained with 60Co initiation.
  • AA acrylic acid
  • PAA polyacrylic acid.
  • Table 9 The extent of swelling of grafted maltodextroses with partially neutralized acrylic acid is presented in Table 9. Although very high swelling was obtained with both maltodextroses in the presence of mono- and divalent cations, the presence of calcium lowered the swelling significantly, especially in the case of maltodextrose #1910 . In conclusion, it is evident that the extent of swelling as well as the release rate of theophylline from this type of graft copolymer can be modified and controlled by addition of divalent ions.
  • BIOADHESION MEASUREMENTS Representative samples of grafted starches obtained by the two initiation methods
  • Fig. 28 The extent of bioadhesion due to the presence of mono- and divalent cations in the graft copolymers is presented in Fig. 28 and in Table 11. The materials tested could be divided into three categories (Fig. 28): 1. Grafted rice starch prepared by chemical initiation with the Ce ⁇ + /Ce 4+ redox system;
  • Starches (potato, corn, rice) grafted with acrylic acid partially neutralized with Na + , Ca2 + or Mg 2+ ; prepared by radiation with 6 ⁇ £ 0;
  • Graft copolymers in accordance with the present invention achieve a work of adhesion greater than 0.1 mJ (6 x 10 "3 mJ/mm 2 ), and preferably a work of adhesion greater than 0.3 mJ (18 x 10 "3 mJ/mm 2 ). Some embodiments of the present invention achieved a work of adhesion greater than lmJ (6 xlO "2 mJ/mm 2 ) .
  • Tablets prepared from some grafted copolymers (Table 12) in accordance with the present invention were attached to the inside of the mouths of dogs (gingiva). The purpose of the experiments was to test whether toxicity and/or irritation developed with time. Data on the bioadhesion time of the tablets in the dogs' mouths is presented in Table 12. No irritation or toxicity was detected, even after the long periods of time.

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Abstract

On a élaboré des bioadhésifs et des systèmes d'administration de médicaments à libération contrôlée à partir d'une série d'amidons gréffés avec des monomères acryliques, ceci selon deux méthodes d'initiation différents: chimique et par rayonnement. De façon générale, les amidons greffés obtenues par initiation chimique avec système redox Ce4+/Ce3+ ont présenté une moindre bioadhésion, pour une libération relativement plus rapide des médicaments modèles. On peut caractériser ces matériaux en mesurant leur gonflement dans l'eau et pour divers pH. Il est également possible de déterminer le poids moléculaire du polymère acrylique ramifié greffé sur l'amidon. On a également obtenu des bioadhésifs et des systèmes d'administration de médicaments à libération contrôlée à partir d'une série d'amidons de provenance diverse greffées avec de l'acide acrylique sous un rayonnement de 60Co. Ces matériaux se sont révélés supérieurs sous l'angle des propriétés adhésives et de la diffusion contrôlée de médicaments. Grâce à l'effet des cations monovalents ou divalents présents, ces copolymères greffés offrent un potentiel élevé en tant que bioadhésifs pour des systèmes d'administration de médicaments par voie orale.
PCT/EP2000/001107 1999-02-12 2000-02-11 Systeme adhesif biocompatible et systeme d'administration de medicaments bioadhesifs a liberation controlee WO2000047644A1 (fr)

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WO2001058430A1 (fr) * 2000-02-11 2001-08-16 National Starch And Chemical Investment Holding Corporation Composition bioadhesive
WO2002098272A2 (fr) 2001-06-05 2002-12-12 Barnev Ltd. Element d'ancrage pour sonde
US7576067B2 (en) 2001-08-22 2009-08-18 Isis Pharmaceuticals, Inc. Pulsatile release compositions and methods for enhanced intestinal oligonucleotide drug absorption
US7846478B2 (en) 2002-01-31 2010-12-07 Henkel Ag & Co. Kgaa Bioadhesive composition
CN102863933A (zh) * 2012-10-15 2013-01-09 中南林业科技大学 一种高强耐水淀粉基木材胶黏剂及其制备方法
CN104804137A (zh) * 2015-01-31 2015-07-29 武汉纺织大学 水溶性阳离子接枝淀粉的制备方法
CN111569797A (zh) * 2020-05-26 2020-08-25 中国科学技术大学 一种反蛋白石型大孔/介孔氮掺杂碳微球及其制备方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058430A1 (fr) * 2000-02-11 2001-08-16 National Starch And Chemical Investment Holding Corporation Composition bioadhesive
US6284235B1 (en) 2000-02-11 2001-09-04 National Starch And Chemical Company Investment Holding Corporation Bioadhesive composition
US6824792B2 (en) 2000-02-11 2004-11-30 Universiteit Gent Bioadhesive composition
WO2002098272A2 (fr) 2001-06-05 2002-12-12 Barnev Ltd. Element d'ancrage pour sonde
US7207941B2 (en) 2001-06-05 2007-04-24 Barnev Ltd. Birth monitoring system
US7576067B2 (en) 2001-08-22 2009-08-18 Isis Pharmaceuticals, Inc. Pulsatile release compositions and methods for enhanced intestinal oligonucleotide drug absorption
US7846478B2 (en) 2002-01-31 2010-12-07 Henkel Ag & Co. Kgaa Bioadhesive composition
CN102863933A (zh) * 2012-10-15 2013-01-09 中南林业科技大学 一种高强耐水淀粉基木材胶黏剂及其制备方法
CN102863933B (zh) * 2012-10-15 2014-05-28 中南林业科技大学 一种高强耐水淀粉基木材胶黏剂及其制备方法
CN104804137A (zh) * 2015-01-31 2015-07-29 武汉纺织大学 水溶性阳离子接枝淀粉的制备方法
CN111569797A (zh) * 2020-05-26 2020-08-25 中国科学技术大学 一种反蛋白石型大孔/介孔氮掺杂碳微球及其制备方法
CN111569797B (zh) * 2020-05-26 2021-10-19 中国科学技术大学 一种反蛋白石型大孔/介孔氮掺杂碳微球及其制备方法

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