WO2008128193A1 - Biodegradable polyanhydrides with natural bioactive molecules - Google Patents

Biodegradable polyanhydrides with natural bioactive molecules Download PDF

Info

Publication number
WO2008128193A1
WO2008128193A1 PCT/US2008/060254 US2008060254W WO2008128193A1 WO 2008128193 A1 WO2008128193 A1 WO 2008128193A1 US 2008060254 W US2008060254 W US 2008060254W WO 2008128193 A1 WO2008128193 A1 WO 2008128193A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymer
biologically active
composition
acid
food
Prior art date
Application number
PCT/US2008/060254
Other languages
French (fr)
Inventor
Kathryn E. Uhrich
Ashley Carbone
Almudena Prudencio
Original Assignee
Rutgers, The State University Of New Jersey
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 Rutgers, The State University Of New Jersey filed Critical Rutgers, The State University Of New Jersey
Priority to EP08799782.1A priority Critical patent/EP2146701B1/en
Priority to US12/595,591 priority patent/US8747832B2/en
Publication of WO2008128193A1 publication Critical patent/WO2008128193A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00—Macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing oxygen or oxygen and carbon, not provided for in groups C08G2/00 - C08G65/00
    • C08G67/04—Polyanhydrides

Definitions

  • the invention provides a method for inhibiting biofilm formation on a personal care product, oral care product, feminine hygiene product, or a wound care product, comprising contacting the personal care product, oral care product, feminine hygiene product, or the wound care product with a polymer or a composition of the invention.
  • the invention provides anhydride polymers having bioactive molecules as a side chain of a polymer.
  • the polymers of the invention have repeating units that comprise residues of two or more bioactive molecules. Accordingly, the polymers of the invention have a high drug loading capacity, which is beneficial.
  • At least one of the biologically active molecules is carvacrol, eugenol, thymol, mescaline, withaferin A, capsaicin, lawsone, lupulone or ⁇ - resercyclic acid, austalol, geraniol, linalool, thujanol, myrcenol, terpineol, menthol, piperitol, borneol or citronellol.
  • the invention provides a polymer comprising repeating units that form a biodegradable backbone wherein one or more repeating unit comprises at least two pendant residues of a biologically active molecule.
  • the polymer is a polyanhydride.
  • the polymer is a polyester, polyamide, or a polycarbonate.
  • Bioactive molecules are typically incorporated into the polymers of the invention as pendant groups that are not part of the backbone of the polymer. As such, a tracing of the chain of atoms that form the backbone of the polymer would not include the atoms of the residues of the bioactive molecules.
  • the pendant groups can be considered to be sidechains of the polymer.
  • Bioactive molecules can be attached to the remainder of the polymer of the invention through labile (e.g. anhydride, ester, amide or thioester linkages) bonds, that allow for release of the bioloactive molecules upon degradation (e.g. hydrolysis).
  • the invention provides a polymer comprising 1 or more units of formula I, II, III, IV, V or VI:
  • R 1 -X- and R 2 -X- are each independently a residue of a biologically active molecule
  • X is O, S or NR a ; and R 3 is hydrogen, (Ci-C 6 )alkyl or (C 3 -C 6 )cycloalkyl.
  • the polymer comprises at least 2 units of formula I II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 5 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 10 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 25 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 50 units of formula I, II, III, IV, V or VI.
  • R 1 -X- and R 2 -X- are each independently a residue of a biologically active molecule
  • the invention provides a composition further comprising salicylic acid or salicylsalicylic acid. In one embodiment the invention provides a composition further comprising an antibiotic. In one embodiment the invention provides a composition further comprising at least one of triclosan, propylparaben, nisin, and polylysine.
  • the invention provides a composition further comprising at least one of triclosan, propylparaben, nisin, polylysine ⁇ -polysine, nanomyicin, sorbic acid, wintergreen, polyarginine, chitosan, ⁇ -tocoperol, alliin, allicin, ferulic acid, lutein, cichoric acid, cinnamic aldehyde, neral, geranial, citronellal, cuminal, verbenone, thujone, borneone, pinocamphone, cryptone, carvone, fenchone, piperitone, menthone, estragole, anethole, phtalids, cineole or phellandral.
  • bioactive molecules with one reactive functional group may be attached prior to polymerization, so the number of bioactive molecules attached is well defined.
  • These polymers should typically degrade and release the incorporated bioactive molecules, e.g. to prevent the formation of biofilms.
  • biodegradable polymers can be formulated into food products and various active food packaging materials. In addition, these polymers may be effective for control of biofilms and bacterial growth in medical devices, oral care and personal care products.
  • di-anhydrides can be ring-opened to generate ester bonds with the bioactive molecules.
  • symmetrical di-anhydrides are used, which simplifies the chemical characterization, and likely the degradation products of the polymer.
  • Asymmetrical di-anhydrides can also be utilized.
  • pyromellitic acid can be incorporated into the polymer of the invention.
  • ethylenediaminetetraacetic acid can be incorporated into the polymer of the invention.
  • 3,3',4,4'-benzophenone tetracarboxylic acid can be incorporated into the polymer of the invention.
  • aromatic monomers may be used, for easy identification during polymer degradation studies.
  • the invention also provides methods for preparing polymers of the invention and methods for preparing intermediate diacid monomers that are useful for preparing polymers of the invention.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with a symmetrical cyclic pyromellitic dianhydride to provide the diacid with the bioactives attached through ester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with ethylenediaminetetraacetic acid dianhydride to form the diacid, with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,3 ',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through ester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1,4,5,8- naphthalene tetracarboxylic dianhydride to form the diacid with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9, 10-perylene tetracarboxylic dianhydride to form the diacid with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through ester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,3',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1 ,4,5,8-naphthalene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9,10- perylene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through amide linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with symmetrical cyclic pyromellitic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with ethylenediaminetetraacetic acid dianhydride to form the diacid, with the bioactives attached through thioester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3, 3 ',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1,4,5,8-naphthalene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages.
  • the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9,10- perylene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through thioester linkages.
  • (CrC 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3- pentyl, or hexyl and (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • This invention provides polymers that allow an expanded number of bioactive molecules to be chemically incorporated into the polymer structure.
  • Such polymers have applications in a broad range of fields including medical and food-related applications.
  • the polymers can release the bioactive chemically incorporated into the sidechain of the polymer as well as an additional bioactive, e.g., if previously admixed.
  • the polymers and compositions comprising the polymers are active against P. aeruginosa, E. coli, Listeria monocytogenes, or Salmonella.
  • the polymers and compositions comprising the polymers can be applied on medical devices, food, or areas that come into contact with medical devices or food.
  • Polyanhydrides were synthesized using solution polymerization (Scheme 2) (Domb, A.; Ron, E.; Langer, R. Macromolecules 1988, 21, 1925).
  • the diacid (6) was prepared by a ring-opening of pyromellitic anhydride (5; 7.5 mmol) with the mono- functional antimicrobial compound (4; 15 mmol) in the presence of a base (e.g., triethylamine; 53 mmol) and in an appropriate solvent (e.g., THF; 40 mL). After the reaction was stirred for 2 h under nitrogen, it was poured over water ( ⁇ 400 mL) and acidified using concentrated HCl.
  • a base e.g., triethylamine; 53 mmol
  • an appropriate solvent e.g., THF; 40 mL
  • the solid formed (6) was vacuum filtered, washed with water (3 x 100 mL) and dried under vacuum at room temperature.
  • Diacid (6) (4.6 mmol) was dissolved 20 % (w/v) CH 2 Cl 2 and triethylamine (20 mmol).
  • the reaction was cooled to 0 °C.
  • the coupling reagent, triphosgene (5.1 mmol), dissolved in CH 2 Cl 2 (5 mL) was added drop- wise to the reaction mixture.
  • the reaction was allowed to stir for 2 h at 0 °C under nitrogen. It was then poured over diethyl ether ( ⁇ 100 niL), and the polymer formed (7) was vacuum filtered, washed with acidified water (3 x 100 mL; pH 2 using concentrated HCl) and dried under vacuum at room temperature.
  • Scheme 2 Synthetic scheme for the chemical incorporation of a mono- functional antimicrobial (4) into the polyanhydride (7).
  • Polymers comprising bioactive molecules linked to the polymer by thioester bonds can be prepared by following the reaction sequence outlined in Scheme 3.
  • the ROH (4) starting material is replaced with bioactive molecules of formula RSH.
  • Polymers comprising bioactive molecules linked to the polymer by amide bonds can be prepared by following the reaction sequence outlined in Scheme 3 as well.
  • the ROH (4) starting material is replaced with bioactive molecules of formula RNHR 3 wherein R a is hydrogen, (CrC 6 )alkyl or (C 3 - C 6 )cycloalkyl.
  • Antimicrobial-based polyanhydrides have been successfully synthesized by incorporating the bioactive agent into the polymer backbone via an ester linkage.
  • the polymer drag loadings were 58-60 % by weight with nearly uniform polymer chain lengths and a T g near body temperature (see Table 1).
  • S. typhimurium MAE52 was used to study inhibition of biofilm formation on polymer-coated glass coverslips. The results are depicted in Table 2.
  • Polymers based on plant and spice extracts are unique as their components are not synthetic, but natural, antimicrobials. This may be desirable if the polyanhydrides are to be mixed with foods, used in food processing and/or packaging materials.
  • Biodegradable polyanhydrides with natural antimicrobial properties were synthesized and characterized to be used to inhibit/prevent biofilm formation. Since the polymers can degrade to release the bioactives, they will be very useful in controlled delivery applications for the food industry and other such areas.
  • Polyanhydrides were designed and prepared from antimicrobials derived from natural sources such as spices and plant extracts. Incorporation of these bioactive molecules into the polymers results in biodegradable polyanhydrides that slowly release the bioactive agents to reduce or prevent biofilm formation, e.g., when incorporated into food and food packaging materials.
  • Plant-based Polymers Choice of Bioactive Molecules Plant and plant extract-based polymers were designed using the natural antimicrobials carvacrol, eugenol, and thymol. Polymers were derived from these bioactive molecules to prevent biofilm formation, e.g., when formulated into food products, food packaging materials and food processing equipment.
  • the biocompatible food-grade chelating EDTA was used as a polymer precursor. EDTA is widely used as preservative in packaged foods, vitamins, and personal care products. As depicted below, ring-opening with symmetrical EDTA dianhydride to form diacids with the bioactives attached as ester linkages was performed via procedures similar to those of Example 1.
  • Scheme 3 Synthetic scheme for the chemical incorporation of an antimicrobial into a representative polymer of the invention.
  • Antimicrobial-based polyanhydrides were successfully synthesized.
  • the polymer drug loadings were 54-56 % by weight with nearly uniform polymer chain lengths and a T g well above body temperature (see Table 3).
  • hydrolytic degradation of representative polymers of the invention can be evaluated as described in Example 3.
  • Hydrolytic degradation of representative polymers can be studied to determine the rate of release of the natural antimicrobial from the polymer backbone.
  • Polymers will be incubated in PBS (pH 7.4) at 37 °C.
  • the media will be replaced with fresh media, and the spent media will be analyzed by HPLC.
  • HPLC HPLC

Abstract

The invention provides polymers that include a biologically active molecule and methods for their use.

Description

BIODEGRADABLE POL YANH YDRIDE S WITH NATURAL BIOACTIVE MOLECULES
Priority of Invention This application claims priority to United States Provisional Patent
Application Number 60/956,689, filed 18 August 2007 and to United States Provisional Patent Application Number 60/911,484, filed 12 April 2007. The entire content of each of these provisional applications is hereby incorporated herein by reference. Background
Biofilms and bacterial growth are currently a major problem in many industries including food, medicine and personal care. In essentially every field relating to hygiene, prevention of biofilms is a primary concern. Biofilm prevention is particularly important in the food processing industry as the attachment of bacteria and development of biofilms is a major cause of food spoilage and contamination. It is also critical to control biofilms on medical devices, wound care devices, personal care products and within surgical suites. Thus, products useful for inhibiting or preventing biofilm formation and thereby limiting bacterial growth are needed. Methods to incorporate bioactive molecules with two or more functional groups into polymers have been described in US 7,122,615, US 6,613,807, US 2005/0089506 and US 2003/0035787. However, these methods are directed to bioactive molecules with two functional groups that allow the molecules to be incorporated into the backbone of the polymer. Summary of Certain Embodiments of the Invention
Applicant has discovered a method to incorporate bioactive molecules into polymers, and in particular polyanhydrides, utilizing only one reactive functional group of the bioactive molecule. This discovery greatly increases the number and diversity of bioactive molecules that can be covalently linked to polyanhydrides. In one embodiment the invention provides polymer comprising repeating units that form a biodegradable backbone wherein each repeating unit comprises at least two pendant residues of a biologically active molecule. In one embodiment, the invention provides food products comprising a polymer or composition of the invention.
In one embodiment, the invention provides a confectionery (e.g. a chewing gum) comprising a polymer or composition of the invention.
In one embodiment, the invention provides a method for inhibiting biofilm formation on an area, comprising contacting the area with an effective amount of a polymer or composition of the invention.
In one embodiment, the invention provides a method for inhibiting biofilm formation on an area of the body (e.g., the skin of a mammal such as a human), the surface of a food, a medical device, a table, floor, or an area that comes into contact with a food or a medical device, comprising contacting the area of the body (e.g., the skin of a mammal such as a human), the surface of a food, the medical device, the table, floor, or the area that comes into contact with a food or a medical device with a polymer or a composition of the invention. In one embodiment, the invention provides a method for inhibiting biofilm on food storage or food processing equipment comprising contacting the food storage or food processing equipment with a polymer or a composition of the invention.
In one embodiment, the invention provides a method for inhibiting biofilm formation on a personal care product, oral care product, feminine hygiene product, or a wound care product, comprising contacting the personal care product, oral care product, feminine hygiene product, or the wound care product with a polymer or a composition of the invention.
In one embodiment, the invention provides polymers and compositions as described herein for use in medical treatment or diagnosis. In one embodiment, the invention provides the use of a polymer or composition described herein to prepare a medicament useful for treating a microbial infection in a mammal.
In one embodiment, the invention provides the use of a polymer or composition described herein to prepare, coat or impregnate a medical device.
In one embodiment, the invention provides a pharmaceutical composition comprising a polymer of the invention, and a pharmaceutically acceptable carrier. In one embodiment, the invention provides a composition comprising a polymer as described herein and an acceptable carrier.
The invention also provides processes and intermediates disclosed herein that are useful for preparing polymers and compositions of the invention. Detailed Description
The invention provides anhydride polymers having bioactive molecules as a side chain of a polymer. The polymers of the invention have repeating units that comprise residues of two or more bioactive molecules. Accordingly, the polymers of the invention have a high drug loading capacity, which is beneficial.
Bioactive Molecules
Bioactive molecules, also known as bioactives or biologically active molecules, include naturally occurring compounds that are derived from a variety of sources including but not limited to plants, sea creatures, fungi, animals and other microorganisms. Bioactive molecules possess some inherent desirable biological activity, for example, activity directed to macromolecules, cells, tissues, microorganisms, viruses, invertebrates, bacteria, animals, mammals or humans. Sources of bioactive molecules include, for example, essential oils, food, food extracts, plant extracts, natural antimicrobials, nutrachemicals, preservatives, nutraceuticals, phytochemicals and food additives. In one embodiment of the invention, at least one of the biologically active molecules is an antimicrobial molecule. In one embodiment of the invention, at least one of the biologically active molecules is an antiseptic molecule. In one embodiment of the invention, at least one of the biologically active molecules is an antibiotic molecule.
In one embodiment of the invention, at least one of the biologically active molecules can be obtained from a food. In one embodiment of the invention, at least one of the biologically active molecules can be obtained from a plant. In one embodiment of the invention, at least one of the biologically active molecules can be obtained from an essential oil.
In one embodiment of the invention, at least one of the biologically active molecules is thymol, carvacrol, o-cresol, phenol, guaiacol, eugenol or capsaicin. In one embodiment of the invention, at least one of the biologically active molecules is thymol, carvacrol, eugenol or capsaicin. In one embodiment of the invention, at least one of the biologically active molecules is carvacrol, eugenol, thymol, mescaline, withaferin A, capsaicin, lawsone, lupulone or β-resercyclic acid. In one embodiment of the invention, at least one of the biologically active molecules is carvacrol, eugenol, thymol, mescaline, withaferin A, capsaicin, lawsone, lupulone or β- resercyclic acid, austalol, geraniol, linalool, thujanol, myrcenol, terpineol, menthol, piperitol, borneol or citronellol. In one embodiment of the invention, at least one of the biologically active molecules is thiosalicylic acid, 2-mercaptoethanol, erythro- and threo-3-mercapto-2-methylbutanol, (±)2-mercapto-2-methylpentan- 1 -ol, 3-mercapto-2-methylpentan- 1 -ol, 3 - mercapto-2-methylpentanal, 4-mercapto-4-methyl-2-pentanone, (±)ethyl 3- mercaptobutyrate, 2-methylfuran-3 -thiol, 2-furylmethanethiol, trans-p- menthane-8-thiol-3-one, furfuryl mercaptan, l-p-menthene-8-thiol, 8- mercapto-/?-menthan-3-one, 3-mercaptopropionic acid or 11- mercaptoundecanoic acid. In one embodiment of the invention, the polymers incorporate thymol, carvacrol, o-cresol, phenol or guaiacol. In one embodiment of the invention, the, polymers incorporate other food-based bioactives such as eugenol and capsaicin.
In one embodiment the invention provides polyanhydrides with food or nutrachemicals chemically attached as pendant groups.
Polymers of the Invention
The invention provides a polymer comprising repeating units that form a biodegradable backbone wherein one or more repeating unit comprises at least two pendant residues of a biologically active molecule. In one embodiment, the polymer is a polyanhydride. In another embodiment, the polymer is a polyester, polyamide, or a polycarbonate.
In one embodiment of the invention, the polymer can comprise 2, 5, 10, 25, 50, 75, Or 100 repeating units. Typically the polymers of the invention have molecular weights of up to about 50,000 amu. As used herein, a "polyanhydride" is a polymer that has anhydride bonds in the backbone of the polymer. In one embodiment the polyanhydride is formed from monomer units that react to provide the anhydride bonds.
Bioactive molecules are typically incorporated into the polymers of the invention as pendant groups that are not part of the backbone of the polymer. As such, a tracing of the chain of atoms that form the backbone of the polymer would not include the atoms of the residues of the bioactive molecules. In certain embodiments of the invention, the pendant groups can be considered to be sidechains of the polymer. Bioactive molecules can be attached to the remainder of the polymer of the invention through labile (e.g. anhydride, ester, amide or thioester linkages) bonds, that allow for release of the bioloactive molecules upon degradation (e.g. hydrolysis). In one embodiment, the invention provides a polymer comprising 1 or more units of formula I, II, III, IV, V or VI:
Figure imgf000007_0001
II
Figure imgf000007_0002
III IV
Figure imgf000007_0003
VI
wherein;
R1-X- and R2-X- are each independently a residue of a biologically active molecule;
X is O, S or NRa; and R3 is hydrogen, (Ci-C6)alkyl or (C3-C6)cycloalkyl. In one embodiment of the invention the polymer comprises at least 2 units of formula I II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 5 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 10 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 25 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 50 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 75 units of formula I, II, III, IV, V or VI. In one embodiment of the invention the polymer comprises at least 100 units of formula I, II, III, IV, V or VI. In one embodiment of the invention, the units of formula I, II, IH, IV, V or VI are repeating units.
In another embodiment, the invention provides an intermediate of formula Ib, lib, IHb, IVb, Vb or VIb:
Figure imgf000008_0001
Ib lib
Figure imgf000008_0002
nib IVb
Figure imgf000009_0001
Vb VIb
or a salt thereof, wherein: R1-X- and R2-X- are each independently a residue of a biologically active molecule;
X is O, S or NRa; and
Ra is hydrogen, (CrC6)alkyl or (C3-C6)cycloalkyl, that is useful for preparing the polymers of the invention. In one embodiment of the invention the polymer comprises at least two different biologically active residues, i.e. R1-X- and R2-X- differ.
Combinations
Additional bioactive agents can be incorporated into the polymer backbone, included as pendant groups, or dispersed in the matrix of the polymers of the invention. Accordingly, the invention also comprises compositions comprising such combinations.
In one embodiment the invention provides a composition further comprising salicylic acid or salicylsalicylic acid. In one embodiment the invention provides a composition further comprising an antibiotic. In one embodiment the invention provides a composition further comprising at least one of triclosan, propylparaben, nisin, and polylysine. In one embodiment the invention provides a composition further comprising at least one of triclosan, propylparaben, nisin, polylysine ε-polysine, nanomyicin, sorbic acid, wintergreen, polyarginine, chitosan, α-tocoperol, alliin, allicin, ferulic acid, lutein, cichoric acid, cinnamic aldehyde, neral, geranial, citronellal, cuminal, verbenone, thujone, borneone, pinocamphone, cryptone, carvone, fenchone, piperitone, menthone, estragole, anethole, phtalids, cineole or phellandral.
Preparation of Polymers of the Invention
Polymers of the invention with the bioactives attached as a pendant group can be prepared using standard polymer techniques that are well known in the art for preparing such polymers, e.g. polyesters, polyamides, polycarbonates, and polyanhydrides. For example, representative polymers of the invention can be prepared by melt-condensation polymerization or by solution polymerization techniques starting with appropriate monomers (see Chem. Rev, 1999, 99, 3181-3198).
Synthetic procedures for incorporating bioactive molecules with one reactive functional group into polymers have been established and are described herein. In these methods, the bioactive molecule may be attached prior to polymerization, so the number of bioactive molecules attached is well defined. These polymers should typically degrade and release the incorporated bioactive molecules, e.g. to prevent the formation of biofilms. These biodegradable polymers can be formulated into food products and various active food packaging materials. In addition, these polymers may be effective for control of biofilms and bacterial growth in medical devices, oral care and personal care products.
As described herein, di-anhydrides can be ring-opened to generate ester bonds with the bioactive molecules. In some embodiments, symmetrical di-anhydrides are used, which simplifies the chemical characterization, and likely the degradation products of the polymer. Asymmetrical di-anhydrides can also be utilized. In one embodiment of the invention, pyromellitic acid can be incorporated into the polymer of the invention. In one embodiment of the invention ethylenediaminetetraacetic acid can be incorporated into the polymer of the invention. In one embodiment of the invention 3,3',4,4'-benzophenone tetracarboxylic acid can be incorporated into the polymer of the invention. In one embodiment of the invention 1,4,5,8-naphthalene tetracarboxylic acid can be incorporated into the polymer of the invention. In one embodiment of the invention 3,4,9, 10-perylenetetracarboxylic acid can be incorporated into the polymer of the invention. In one embodiment of the invention diethylenetriaminepentaacetic dianhydride can be incorporated into the polymer of the invention.
In one embodiment of the invention, aromatic monomers may be used, for easy identification during polymer degradation studies. The invention also provides methods for preparing polymers of the invention and methods for preparing intermediate diacid monomers that are useful for preparing polymers of the invention. For example, in one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with a symmetrical cyclic pyromellitic dianhydride to provide the diacid with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with ethylenediaminetetraacetic acid dianhydride to form the diacid, with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,3 ',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1,4,5,8- naphthalene tetracarboxylic dianhydride to form the diacid with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9, 10-perylene tetracarboxylic dianhydride to form the diacid with the bioactives attached through ester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through ester linkages.
In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with a symmetrical cyclic pyromellitic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with ethylenediaminetetraacetic acid dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,3',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1 ,4,5,8-naphthalene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9,10- perylene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through amide linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through amide linkages.
In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with symmetrical cyclic pyromellitic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with ethylenediaminetetraacetic acid dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3, 3 ',4,4' - benzophenone tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 1,4,5,8-naphthalene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with 3,4,9,10- perylene tetracarboxylic dianhydride to form the diacid, with the bioactives attached through thioester linkages. In one embodiment, the invention provides a method for preparing a diacid monomer comprising reacting a bioactive molecule with diethylenetriaminepentaacetic dianhydride to form the diacid, with the bioactives attached through thioester linkages.
Specific Values Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other values or other values within defined ranges for the radicals and substituents, Specifically, (CrC6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3- pentyl, or hexyl and (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, regioisomeric or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase). This invention provides polymers that allow an expanded number of bioactive molecules to be chemically incorporated into the polymer structure. Such polymers have applications in a broad range of fields including medical and food-related applications. The polymers can release the bioactive chemically incorporated into the sidechain of the polymer as well as an additional bioactive, e.g., if previously admixed. In some embodiments, the polymers and compositions comprising the polymers are active against P. aeruginosa, E. coli, Listeria monocytogenes, or Salmonella. In some embodiments, the polymers and compositions comprising the polymers can be applied on medical devices, food, or areas that come into contact with medical devices or food.
Certain embodiments of the invention will now be illustrated by the following non-limiting Example.
Example 1: Preparation of Representative Polymers of the Invention
Polyanhydrides prepared from antimicrobials derived from natural sources such as spices and plant extracts were designed and synthesized (Schemes 1 and 2) (Cowan, M.M. Clinical Microbiology Reviews 1999 12, 564-582) One application of these polymers is their formulation into micro- or nanospheres, which can then be mixed with foods. The polymers could also be used to coat food processing equipment. Alternatively, other bioactive agents can be physically admixed into the antimicrobial-based polyanhydrides to result in a dual action delivery device.
Figure imgf000015_0001
Figure imgf000015_0002
Scheme 1: Natural antimicrobial agents incorporated into polyanhydrides.
Experimental Instrumentation. Polymers and intermediates were characterized by proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared spectroscopy (FTIR). Polymer properties were determined using gel permeation chromatography (GPC) for molecular weights and polydispersity, thermogravimetric analysis (TGA) for decomposition temperatures (Td), and differential scanning calorimetry (DSC) for glass transition (Tg) and melting (Tm) temperatures.
Synthesis of Polyanhydrides. Polyanhydrides were synthesized using solution polymerization (Scheme 2) (Domb, A.; Ron, E.; Langer, R. Macromolecules 1988, 21, 1925). In brief, the diacid (6) was prepared by a ring-opening of pyromellitic anhydride (5; 7.5 mmol) with the mono- functional antimicrobial compound (4; 15 mmol) in the presence of a base (e.g., triethylamine; 53 mmol) and in an appropriate solvent (e.g., THF; 40 mL). After the reaction was stirred for 2 h under nitrogen, it was poured over water (~ 400 mL) and acidified using concentrated HCl. The solid formed (6) was vacuum filtered, washed with water (3 x 100 mL) and dried under vacuum at room temperature. Diacid (6) (4.6 mmol) was dissolved 20 % (w/v) CH2Cl2 and triethylamine (20 mmol). The reaction was cooled to 0 °C. The coupling reagent, triphosgene (5.1 mmol), dissolved in CH2Cl2 (5 mL) was added drop- wise to the reaction mixture. The reaction was allowed to stir for 2 h at 0 °C under nitrogen. It was then poured over diethyl ether (~ 100 niL), and the polymer formed (7) was vacuum filtered, washed with acidified water (3 x 100 mL; pH 2 using concentrated HCl) and dried under vacuum at room temperature.
Figure imgf000016_0001
Triphosgene
CH2CI2ZNEt3
O 0C
Figure imgf000016_0002
Scheme 2: Synthetic scheme for the chemical incorporation of a mono- functional antimicrobial (4) into the polyanhydride (7).
Polymers comprising bioactive molecules linked to the polymer by thioester bonds can be prepared by following the reaction sequence outlined in Scheme 3. For these polymers the ROH (4) starting material is replaced with bioactive molecules of formula RSH. Polymers comprising bioactive molecules linked to the polymer by amide bonds can be prepared by following the reaction sequence outlined in Scheme 3 as well. For these polymers the ROH (4) starting material is replaced with bioactive molecules of formula RNHR3 wherein Ra is hydrogen, (CrC6)alkyl or (C3- C6)cycloalkyl. Antimicrobial-based polyanhydrides have been successfully synthesized by incorporating the bioactive agent into the polymer backbone via an ester linkage. The polymer drag loadings were 58-60 % by weight with nearly uniform polymer chain lengths and a Tg near body temperature (see Table 1).
Due to the instability of the anhydride and ester bonds, these polymers should degrade to release the active antimicrobial compounds.
Table 1
Figure imgf000017_0001
Biofilm Assays on Polymer Surfaces
S. typhimurium MAE52 was used to study inhibition of biofilm formation on polymer-coated glass coverslips. The results are depicted in Table 2.
Table 2. Pyromellitic Acid Polymers
Figure imgf000017_0002
Polymers based on plant and spice extracts are unique as their components are not synthetic, but natural, antimicrobials. This may be desirable if the polyanhydrides are to be mixed with foods, used in food processing and/or packaging materials. Conclusions
Biodegradable polyanhydrides with natural antimicrobial properties were synthesized and characterized to be used to inhibit/prevent biofilm formation. Since the polymers can degrade to release the bioactives, they will be very useful in controlled delivery applications for the food industry and other such areas.
Example 2: Preparation of Representative Polymers of the Invention
Polyanhydrides were designed and prepared from antimicrobials derived from natural sources such as spices and plant extracts. Incorporation of these bioactive molecules into the polymers results in biodegradable polyanhydrides that slowly release the bioactive agents to reduce or prevent biofilm formation, e.g., when incorporated into food and food packaging materials.
Plant-based Polymers: Choice of Bioactive Molecules Plant and plant extract-based polymers were designed using the natural antimicrobials carvacrol, eugenol, and thymol. Polymers were derived from these bioactive molecules to prevent biofilm formation, e.g., when formulated into food products, food packaging materials and food processing equipment.
Ethylenediaminetetraacetic Acid (EDTA) Polymers
The biocompatible food-grade chelating EDTA was used as a polymer precursor. EDTA is widely used as preservative in packaged foods, vitamins, and personal care products. As depicted below, ring-opening with symmetrical EDTA dianhydride to form diacids with the bioactives attached as ester linkages was performed via procedures similar to those of Example 1.
Figure imgf000019_0001
Scheme 3: Synthetic scheme for the chemical incorporation of an antimicrobial into a representative polymer of the invention.
Antimicrobial-based polyanhydrides were successfully synthesized. The polymer drug loadings were 54-56 % by weight with nearly uniform polymer chain lengths and a Tg well above body temperature (see Table 3).
Table 3
Figure imgf000019_0002
BioΩlm Assays on Polymer Surfaces
S. typhimurium MAE52 was used to study inhibition of biofilm formation on polymer-coated glass coverslips. The results are depicted in Table 4. Table 4. EDTA Linker
Figure imgf000020_0001
The hydrolytic degradation of representative polymers of the invention can be evaluated as described in Example 3.
Example 3: Hydrolytic degradation of representative polymers
Hydrolytic degradation of representative polymers can be studied to determine the rate of release of the natural antimicrobial from the polymer backbone. Polymers will be incubated in PBS (pH 7.4) at 37 °C. At predetermined time intervals, the media will be replaced with fresh media, and the spent media will be analyzed by HPLC. See for example: Whitaker- Brothers, K.; Uhrich, K. E. J. Biomed. Mater. Res. 2006, 76A, 470-479; Prudencio, A.; Schmeltzer, R. C; Uhrich, K. E. Biomacromolecules 2005, 38, 6895-6901; and Bryers, J. D.; Jarvis, R. A.; Lebo, J.; Prudencio, A.; Kyriakides, T. R.; Uhrich, K. Biomaterials 2006, 27, 5039-5048.
All publications, patents and patent applications cited herein are incorporated herein by reference. While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein may be varied considerably without departing from the basic principles of the invention.

Claims

Claims What is claimed is:
1. A polymer comprising repeating units that form a biodegradable backbone wherein one or more repeating unit comprises at least two pendant residues of a biologically active molecule.
2. The polymer of claim 1 wherein each repeating unit comprises at least two pendant residues of a biologically active molecule.
3. The polymer of claim 1 that comprises at least 10 repeating units.
4. The polymer of claim 1 that comprises at least 50 repeating units.
5. The polymer of claim 1 which is a polyanhydride.
6. The polyanhydride of claim 5 that comprises 1 or more units of formula I, II, III, IV,V or VI:
Figure imgf000021_0001
II
Figure imgf000022_0001
III IV
Figure imgf000022_0002
VI
wherein;
R1-X- and R2-X- are each independently a residue of a biologically active molecule; X is O, S or NRa; and Ra is hydrogen, (Q-C^alkyl or (C3-C6)cycloalkyl.
7. The polyanhydride of claim 5 that comprises or more units of formula Ia or Ha:
Figure imgf000023_0001
Ia Ha
wherein R1-O- and R2-O- are each independently a residue of a biologically active molecule.
8. The polyanhydride of claim 5 that comprises or more units of formula Ia, Ha, Ilia, IVa, Va or Via:
Figure imgf000023_0002
Ia Ha
Figure imgf000024_0001
HIa IVa
Figure imgf000024_0002
Va Via
wherein R1-O- and R2-O- are each independently a residue of a biologically active molecule.
9. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules is an antimicrobial molecule.
10. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules is an antiseptic molecule.
11. The polymer of any one of claims 1 -8, wherein at least one of the biologically active molecules is an antibiotic molecule.
12. The polymer of any one of claims 1 -8, wherein at least one of the biologically active molecules can be obtained from a plant.
13. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules can be obtained from an essential oil.
14. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules is thymol, carvacrol, o-cresol, phenol, guaiacol, eugenol or capsaicin.
15. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules is thymol, carvacrol, eugenol or capsaicin.
16. The polymer of any one of claims 1 -8, wherein at least one of the biologically active molecules is carvacrol, eugenol, thymol, mescaline, withaferin A, capsaicin, lawsone, lupulone or β-resercyclic acid, austalol, geraniol, linalool, thujanol, myrcenol, terpineol, menthol, piperitol, borneol or citronellol.
17. The polymer of any one of claims 1-8, wherein at least one of the biologically active molecules is carvacrol, eugenol, thymol, mescaline, withaferin A, capsaicin, lawsone, lupulone or β-resercyclic acid.
18. The polymer of any one of the claims 1-8 wherein at least one of the biologically active molecules is thiosalicylic acid, 2-mercaptoethanol, erythro- and threo-3 -mercapto-2-methylbutanol, (±)2-mercapto-2-methylpentan- 1 -ol, 3 - mercapto-2-methylpentan- 1 -ol, 3 -mercapto-2-methylpentanal, 4-mercapto-4-methyl- 2-pentanone, (±)ethyl 3-mercaptobutyrate, 2-methylfuran-3 -thiol, 2- furylmethanethiol, trans-p-menthane-8-thiol-3-one, furfuryl mercaptan, 1-/7- menthene-8-thiol, 8-mercapto-/?-menthan-3-one, 3-mercaptopropionic acid or 11- mercaptoundecanoic acid.
19. A pharmaceutical composition comprising a polymer as described in any one of claims 1-18 and a pharmaceutically acceptable carrier.
20. A composition comprising a polymer as described in any one of claims 1-18 and an acceptable carrier.
21. The composition of claim 19 or 20, further comprising salicylic acid.
22. The composition of claim 19 or 20, further comprising salicylsalicylic acid.
23. The composition of any one of claims 19-22, further comprising an antibiotic.
24. The composition of any one of claims 19-23, further comprising at least one of triclosan, propylparaben, nisin, polylysine ε-polysine, nanomyicin, sorbic acid, wintergreen, polyarginine, chitosan, α-tocoperol, alliin, allicin, ferulic acid, lutein, cichoric acid, cinnamic aldehyde, neral, geranial, citronellal, cuminal, verbenone, thujone, borneone, pinocamphone, cryptone, carvone, fenchone, piperitone, menthone, estragole, anethole, phtalids, cineole and phellandral.
25. The composition of any one of claims 19-23, further comprising at least one of triclosan, propylparaben, nisin, and polylysine.
26. A food product comprising the polymer or composition of any one of claims
1-25.
27. A confectionery comprising the polymer or composition of any one of claims
1-25.
28. A method for inhibiting biofilm formation on an area, comprising contacting the area with an effective amount of the polymer, composition or food product of any one of claims 1-25.
29. The method of claim 28, wherein the area is an area of a body, the surface of a food, a medical device, table, floor, personal care product, oral care product, feminine hygiene product, wound care product or an area that comes into contact with a food or a medical device.
30. The method of claim 28, wherein the area is an area of a body, the surface of a food, a medical device, table, floor or an area that comes into contact with a food or a medical device.
31. A medical device comprising the polymer or composition of any one of claims 1-25.
32. A medical device of claim 30 wherein the polymer or composition is coated onto or impregnated within the device.
33. A polymer as described by any one of claims 1-18 for use in medical treatment or diagnosis.
34. The use of a polymer as described in any one of claims 1 -18 to prepare a medicament useful for treating a microbial infection in a mammal.
35. A compound of formula Ib, lib, HIb, IVb, Vb or VIb:
Figure imgf000028_0001
Ib lib
Figure imgf000028_0002
HIb IVb
Figure imgf000028_0003
Vb VIb
or a salt thereof, wherein:
R1-X- and R2-X- are each independently a residue of a biologically active molecule;
X is O, S or NRa; and
Ra is hydrogen, (CrC6)alkyl or (C3-C6)cycloalkyl.
PCT/US2008/060254 2007-04-12 2008-04-14 Biodegradable polyanhydrides with natural bioactive molecules WO2008128193A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP08799782.1A EP2146701B1 (en) 2007-04-12 2008-04-14 Biodegradable polyanhydrides with natural bioactive molecules
US12/595,591 US8747832B2 (en) 2007-04-12 2008-04-14 Biodegradable polyanhydrides with natural bioactive molecules

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US91148407P 2007-04-12 2007-04-12
US60/911,484 2007-04-12
US95668907P 2007-08-18 2007-08-18
US60/956,689 2007-08-18

Publications (1)

Publication Number Publication Date
WO2008128193A1 true WO2008128193A1 (en) 2008-10-23

Family

ID=39864377

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/060254 WO2008128193A1 (en) 2007-04-12 2008-04-14 Biodegradable polyanhydrides with natural bioactive molecules

Country Status (3)

Country Link
US (1) US8747832B2 (en)
EP (1) EP2146701B1 (en)
WO (1) WO2008128193A1 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7985415B2 (en) 1997-09-10 2011-07-26 Rutgers, The State University Of New Jersey Medical devices employing novel polymers
US8221790B2 (en) 2000-07-27 2012-07-17 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US8263060B2 (en) 2005-05-23 2012-09-11 Rutgers, The State University Of New Jersey Fast degrading polymers
US8361453B2 (en) 2006-06-06 2013-01-29 Rutgers, The State University Of New Jersey Iodinated polymers
WO2014134689A1 (en) 2013-03-08 2014-09-12 Polyactiva Pty Ltd Polymer conjugate for delivery of a bioactive agent
US9108070B2 (en) 2006-09-13 2015-08-18 Polymerix Corporation Active agents and their oligomers and polymers
US9144579B2 (en) 2012-08-17 2015-09-29 Rutgers, The State University Of New Jersey Polyesters and methods of use thereof
US9387250B2 (en) 2013-03-15 2016-07-12 Rutgers, The State University Of New Jersey Therapeutic compositions for bone repair
US9782432B2 (en) 2012-10-25 2017-10-10 Rutgers, The State University Of New Jersey Polymers and methods thereof for wound healing
US9862672B2 (en) 2013-05-29 2018-01-09 Rutgers, The State University Of New Jersey Antioxidant-based poly(anhydride-esters)
CN107759788A (en) * 2017-09-27 2018-03-06 温州大学 A kind of polymer and preparation method thereof based on cinnamic acid and with acid, light degradation property
US10023521B2 (en) 2014-06-13 2018-07-17 Rutgers, The State University Of New Jersey Process and intermediates for preparing poly(anhydride-esters)
US10543162B2 (en) 2015-04-10 2020-01-28 Rutgers, The State University Of New Jersey Kojic acid polymers

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6486214B1 (en) * 1997-09-10 2002-11-26 Rutgers, The State University Of New Jersey Polyanhydride linkers for production of drug polymers and drug polymer compositions produced thereby
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US8741317B2 (en) 2010-08-19 2014-06-03 Rutgers, The State University Of New Jersey Slow-degrading polymers comprising salicylic acid for undelayed and sustained drug delivery
WO2013055315A1 (en) * 2011-10-11 2013-04-18 Elc Management Llc Method and compositions for treating skin
US8795941B2 (en) * 2012-12-18 2014-08-05 Xerox Corporation Thymol derivatives in polyester polymer toner resin
CN104629045B (en) * 2015-01-30 2016-11-09 中国科学院长春应用化学研究所 The method of epsilon-polylysine is prepared in a kind of ring-opening polymerisation
JP6389212B2 (en) * 2016-07-20 2018-09-12 株式会社ロッテ Oral composition
WO2018235424A1 (en) * 2017-06-21 2018-12-27 Dic株式会社 Active ester compound and composition and cured product obtained using same
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
CA3138100A1 (en) 2019-04-17 2020-10-22 Compass Pathfinder Limited Treatment of depression and other various disorders with psilocybin

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115169A (en) * 1977-01-06 1978-09-19 Rohm And Haas Company Polyfunctional ester ketimines, adhesives derived therefrom and method for adhering materials
US20030035787A1 (en) 1999-10-21 2003-02-20 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
US6613807B2 (en) 2000-07-27 2003-09-02 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US20050113549A1 (en) * 2003-11-25 2005-05-26 Devlin Brian G. Crosslinkable polyurea prepolymers
US20050131199A1 (en) * 2001-11-23 2005-06-16 Uhrich Kathryn E. Synthesis of polyanhydrides
US20050260651A1 (en) * 2004-04-13 2005-11-24 Pericles Calias Enhanced biologically active conjugates
US20060188546A1 (en) * 1997-09-10 2006-08-24 Polymerix Corporation Medical devices employing novel polymers
US7122615B1 (en) 1998-09-10 2006-10-17 Rutgers, The State University Of New Jersey Polyanhydrides with therapeutically useful degradation products

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4018826A (en) * 1974-11-04 1977-04-19 Dynapol Corporation Process for preparing polyvinylamine and salts thereof
US5451401A (en) * 1993-09-29 1995-09-19 The Procter & Gamble Company Diphosphonic acid esters as tartar control agents
FR2751882B1 (en) * 1996-07-31 1998-10-02 Inst Curie HYPERBACTERICIDAL SURFACES
US5747011A (en) * 1996-11-25 1998-05-05 Schering-Plough Healthcare Products, Inc. Sunscreen with disappering color indicator
WO1999012990A1 (en) 1997-09-10 1999-03-18 Rutgers, The State University Polyanhydrides with therapeutically useful degradation products
JP3816697B2 (en) * 1999-07-07 2006-08-30 大日精化工業株式会社 Functional agent bound with polymer, method for producing the same, method for using them, and article using the same
WO2001041753A2 (en) 1999-12-07 2001-06-14 Rutgers, The State University Of New Jersey Therapeutic compositions and methods for treating periodontitis with antiinflamatory compounds
US6685928B2 (en) * 1999-12-07 2004-02-03 Rutgers, The State University Of New Jersey Therapeutic compositions and methods
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US6315987B1 (en) * 2000-05-10 2001-11-13 Isp Investments Inc. Polymeric delivery and release systems for oral care actives
DE10035991A1 (en) * 2000-07-24 2002-02-14 Polichem Sa Nail polish composition
MXPA03000821A (en) * 2000-07-27 2004-03-18 Univ Rutgers Therapeutic polyesters and polyamides.
AU2001279064A1 (en) * 2000-07-27 2002-02-13 Rutgers, The State University Therapeutic azo-compounds for drug delivery
JP2004538342A (en) * 2001-03-27 2004-12-24 フイルメニツヒ　ソシエテ　アノニム Compounds for controlled release of active compounds
US7034059B2 (en) * 2001-07-02 2006-04-25 Sepracor Inc. Methods of using norfluoxetine
WO2003066053A1 (en) 2002-02-07 2003-08-14 Rutgers, The State University Antibiotic polymers
CA2475187A1 (en) * 2002-02-07 2003-08-14 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
KR20050013529A (en) * 2002-02-07 2005-02-04 루트거스, 더 스테이트 유니버시티 오브 뉴 저지 Therapeutical polyanhydride compounds for drug delivery
FR2839451B1 (en) 2002-05-07 2006-05-05 Oreal COMPOUND COMPRISING A POLYMER, A SPACER AND AN ACTIVE INGREDIENT, COMPOSITION CONTAINING THE COMPOUND AND USES
WO2004006863A2 (en) 2002-07-17 2004-01-22 Rutgers, The State University Therapeutic devices for patterned cell growth
US20070098800A1 (en) * 2002-10-28 2007-05-03 Giroux Karen J Therapeutic compositions
DK1572154T3 (en) 2002-11-18 2012-05-14 Univ Rutgers Medical devices using new polymers
CA2527495A1 (en) 2003-06-04 2005-05-12 Polymerix Corporation High molecular weight polymers, devices and method for making and using same
US7662864B2 (en) * 2003-06-04 2010-02-16 Rutgers, The State University Of New Jersey Solution polymerization processes to prepare a polymer that degrades to release a physiologically active agent
WO2005039489A2 (en) 2003-09-24 2005-05-06 Polymerix Corporation Compositions and methods for the inhibition of bone growth and resorption
JP2008545695A (en) * 2005-05-23 2008-12-18 ラトガーズ， ザ ステイト ユニバーシティ オブ ニュー ジャージー Rapid degradation polymer
AU2007221052B2 (en) * 2006-02-28 2013-05-16 Covidien Lp Antimicrobial releasing polymers
EP2032614A2 (en) 2006-06-06 2009-03-11 Rutgers, The State University Of New Jersey Iodinated polymers
WO2008034019A2 (en) * 2006-09-13 2008-03-20 Polymerix Corporation Active agents and their oligomers and polymers
WO2008103744A1 (en) 2007-02-20 2008-08-28 Rutgers, The State University Of New Jersey Nerve guidance tubes
WO2009026544A1 (en) 2007-08-22 2009-02-26 Rutgers, The State University Of New Jersey Ampicillin and amoxicillin-based poly(anhydride-amides)
US8741317B2 (en) * 2010-08-19 2014-06-03 Rutgers, The State University Of New Jersey Slow-degrading polymers comprising salicylic acid for undelayed and sustained drug delivery

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4115169A (en) * 1977-01-06 1978-09-19 Rohm And Haas Company Polyfunctional ester ketimines, adhesives derived therefrom and method for adhering materials
US20050089506A1 (en) 1997-09-10 2005-04-28 Rutgers, The State University Of New Jersey. Polyanhydride linkers for production of drug polymers and drug polymer compositions produced thereby
US20060188546A1 (en) * 1997-09-10 2006-08-24 Polymerix Corporation Medical devices employing novel polymers
US7122615B1 (en) 1998-09-10 2006-10-17 Rutgers, The State University Of New Jersey Polyanhydrides with therapeutically useful degradation products
US20030035787A1 (en) 1999-10-21 2003-02-20 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
US6613807B2 (en) 2000-07-27 2003-09-02 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US20050131199A1 (en) * 2001-11-23 2005-06-16 Uhrich Kathryn E. Synthesis of polyanhydrides
US20040062778A1 (en) * 2002-09-26 2004-04-01 Adi Shefer Surface dissolution and/or bulk erosion controlled release compositions and devices
US20050113549A1 (en) * 2003-11-25 2005-05-26 Devlin Brian G. Crosslinkable polyurea prepolymers
US20050260651A1 (en) * 2004-04-13 2005-11-24 Pericles Calias Enhanced biologically active conjugates

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2146701A1

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7985415B2 (en) 1997-09-10 2011-07-26 Rutgers, The State University Of New Jersey Medical devices employing novel polymers
US8221790B2 (en) 2000-07-27 2012-07-17 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US8241668B2 (en) 2000-07-27 2012-08-14 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US8263060B2 (en) 2005-05-23 2012-09-11 Rutgers, The State University Of New Jersey Fast degrading polymers
US8361453B2 (en) 2006-06-06 2013-01-29 Rutgers, The State University Of New Jersey Iodinated polymers
US10092578B2 (en) 2006-09-13 2018-10-09 Polymerix Corporation Active agents and their oligomers and polymers
US9108070B2 (en) 2006-09-13 2015-08-18 Polymerix Corporation Active agents and their oligomers and polymers
US9144579B2 (en) 2012-08-17 2015-09-29 Rutgers, The State University Of New Jersey Polyesters and methods of use thereof
US9782432B2 (en) 2012-10-25 2017-10-10 Rutgers, The State University Of New Jersey Polymers and methods thereof for wound healing
WO2014134689A1 (en) 2013-03-08 2014-09-12 Polyactiva Pty Ltd Polymer conjugate for delivery of a bioactive agent
US9387250B2 (en) 2013-03-15 2016-07-12 Rutgers, The State University Of New Jersey Therapeutic compositions for bone repair
US9862672B2 (en) 2013-05-29 2018-01-09 Rutgers, The State University Of New Jersey Antioxidant-based poly(anhydride-esters)
US10023521B2 (en) 2014-06-13 2018-07-17 Rutgers, The State University Of New Jersey Process and intermediates for preparing poly(anhydride-esters)
US10543162B2 (en) 2015-04-10 2020-01-28 Rutgers, The State University Of New Jersey Kojic acid polymers
CN107759788A (en) * 2017-09-27 2018-03-06 温州大学 A kind of polymer and preparation method thereof based on cinnamic acid and with acid, light degradation property
CN107759788B (en) * 2017-09-27 2020-10-27 温州大学 Cinnamic aldehyde-based polymer with acid and photodegradable properties and preparation method thereof

Also Published As

Publication number Publication date
EP2146701A4 (en) 2011-06-29
EP2146701B1 (en) 2013-10-16
US8747832B2 (en) 2014-06-10
EP2146701A1 (en) 2010-01-27
US20100272670A1 (en) 2010-10-28

Similar Documents

Publication Publication Date Title
US8747832B2 (en) Biodegradable polyanhydrides with natural bioactive molecules
EP1372674B1 (en) Facially amphiphilic polymers as anti-infective agents
US8455490B2 (en) Facially amphiphilic polymers and oligomers and uses thereof
AU2002254133A1 (en) Facially amphiphilic polymers as anti-infective agents
JP6417404B2 (en) Compositions and methods comprising polyamines
KR102541633B1 (en) Branched polyamino acid antimicrobial agents and uses thereof
EP1771183A2 (en) Antimicrobial copolymers and uses thereof
JP2005510571A (en) Improved synthesis of polyanhydrides
JP2008510850A (en) Amphiphilic polynorbornene derivatives and methods of use thereof
WO2015191742A1 (en) Process and intermediates for preparing poly(anhydride-esters)
CN109730067A (en) A kind of gemini quaternary ammonium salt fungicide and its preparation method and application of the rigid connection base containing naphthalene nucleus
JP2011521984A (en) New antibacterial peptide
Cirillo et al. Synthesis, characterization and antimicrobial activity of conjugates based on fluoroquinolon-type antibiotics and gelatin
EP4086317A1 (en) Antibacterial polymer composition
EP4339186A1 (en) Antibacterial compound
Metzcar et al. Synthesis and Evaluation of Antimicrobial Biobased Waxes as Coating Materials
JP2022523527A (en) Coatings containing antibacterial particles, preparation methods and their use
Song Ring opening metathesis polymerization of 1-substituted cyclobutene derivatives and its application to antimicrobials: From homopolymers to alternating copolymers

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08799782

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008799782

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12595591

Country of ref document: US