US20030035787A1 - Polyanhydrides with biologically active degradation products - Google Patents

Polyanhydrides with biologically active degradation products Download PDF

Info

Publication number
US20030035787A1
US20030035787A1 US10254191 US25419102A US2003035787A1 US 20030035787 A1 US20030035787 A1 US 20030035787A1 US 10254191 US10254191 US 10254191 US 25419102 A US25419102 A US 25419102A US 2003035787 A1 US2003035787 A1 US 2003035787A1
Authority
US
Grant status
Application
Patent type
Prior art keywords
composition
method
host
administered
polyanhydrides
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US10254191
Inventor
Kathryn Uhrich
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rutgers State University of New Jersey
AMT Capital Ltd
Original Assignee
Rutgers 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

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/60Salicylic acid; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/74Synthetic polymeric materials
    • A61K31/765Polymers containing oxygen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/30Cosmetics or similar toilet preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toilet preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms or aromatic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K8/00Cosmetics or similar toilet preparations
    • A61K8/18Cosmetics or similar toilet preparations characterised by the composition
    • A61K8/72Cosmetics or similar toilet preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84Cosmetics or similar toilet preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85Polyesters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/18Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08GMACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G67/00Macromolecular 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
    • C08G67/04Polyanhydrides
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L73/00Compositions of macromolecular compounds obtained by reactions forming a linkage containing oxygen or oxygen and carbon in the main chain, not provided for in groups C08L59/00 - C08L71/00; Compositions of derivatives of such polymers
    • C08L73/02Polyanhydrides
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L77/00Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q17/00Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005Antimicrobial preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q19/00Preparations for care of the skin
    • A61Q19/08Anti-ageing preparations
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILET PREPARATIONS
    • A61Q5/00Preparations for care of the hair
    • A61Q5/006Antidandruff preparations

Abstract

Polyanhydrides which degrade into biologically active salicylates and alpha-hydroxy acids and methods of using these polyanhydrides to deliver the salicylates and alpha-hydroxy acids to a host are provided.

Description

  • This application is a continuation-in-part of PCT Application No. PCT/US98/18816, filed Sep. 10, 1998, which claims the benefit of provisional Application Serial No. 60/058,328, filed Sep. 10, 1997.[0001]
  • FIELD OF THE INVENTION
  • Biocompatible polyanhydrides having improved degradation properties and processability with useful degradation products have now been developed. In one embodiment, the polyanhydrides are ortho-substituted aromatic polyanhydrides produced from ortho-substituted bis-aromatic carboxylic acid anhydrides which degrade into biologically active materials such as salicylates. In another embodiment, the polyanhydrides are aliphatic in structure and degrade into alpha-hydroxy acids. Salicylates are used routinely as anti-inflammatory, antipyretic, analgesic, and anti-oxidant agents, while alpha-hydroxy acids are incorporated into many skin moisturizers, cleansers, lotions, creams shampoos, tanning products and lipsticks to promote smoother, clearer skin with fewer wrinkles. Thus, the biocompatible polyanhydrides of the present invention can be administered to a host via a variety of routes including, but not limited to orally, subcutaneously, intramuscularly, intradermally and topically, depending upon the degradation product of the polyanhydride and the selected use for the degradation product. [0002]
  • BACKGROUND OF THE INVENTION
  • Polymers comprising aromatic or aliphatic anhydrides have been studied extensively over the years for a variety of uses. For example, in the 1930s fibers comprising aliphatic polyanhydrides were prepared for use in the textile industry. In the mid 1950s, aromatic polyanhydrides were prepared with improved film and fiber forming properties. More recently, attempts have been made to synthesize polyanhydrides with greater thermal and hydrolytic stability and sustained drug release properties. [0003]
  • U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparation of polyanhydrides with improved sustained drug release properties from pure, isolated prepolymers of diacids and acetic acid. However, these biocompatible and biodegradable aromatic polyanhydrides have radical or aliphatic bonds resulting in compounds with slow degradation times as well as relatively insoluble degradation products unless incorporated into a copolymer containing a more hydrophilic monomer, such as sebacic acid. The aromatic polyanhydrides disclosed in the '128 Patent and the '904 Patent are also insoluble in most organic solvents. A bioerodible controlled release device produced as a homogenous polymeric matrix from polyanhydrides with aliphatic bonds having weight average molecular weights greater than 20,000 and an intrinsic velocity greater than 0.3 dL/g and a biologically active substance is also described in U.S. Pat. No. 4,888,176. Another bioerodible matrix material for controlled delivery of bioactive compounds comprising polyanhydride polymers with a uniform distribution of aliphatic and aromatic residues is disclosed in U.S. Pat. No. 4,857,311. [0004]
  • Biocompatible and biodegradable aromatic polyanhydrides prepared from para-substituted bis-aromatic dicarboxylic acids for use in wound closure devices are disclosed in U.S. Pat. No. 5,264,540. However, these compounds exhibit high melt and glass transition temperatures and decreased solubility, thus making them difficult to process. The disclosed polyanhydrides also comprise radical or aliphatic bonds which can not be hydrolyzed by water. [0005]
  • Polyanhydride polymeric matrices have also been described for use in orthopedic and dental applications. For example, U.S. Pat. No. 4,886,870 discloses a bioerodible article useful for prosthesis and implantation which comprises a biocompatible, hydrophobic polyanhydride matrix. U.S. Pat. No. 5,902,599 also discloses biodegradable polymer networks for use in a variety of dental and orthopedic applications which are formed by polymerizing anhydride prepolymers. [0006]
  • Biocompatible and biodegradable polyanhydrides have now been developed with improved degradation, processing and solubility properties, as well as utilities based upon their degradation products. [0007]
  • SUMMARY OF THE INVENTION
  • An object of the present invention is to provide biocompatible and biodegradable polyanhydrides which degrade into biologically active products. In one embodiment, aromatic polyanhydrides which degrade into biologically active salicylates are prepared from ortho-substituted bis-aromatic carboxylic acid anhydrides. Ortho substitution disrupts the crystallinity of the resulting polymer, enhancing solubility and processability, as well as degradation properties. The use of hydrolyzable bonds such as esters, amides, urethanes, carbamates and carbonates as opposed to radical or aliphatic bonds in these compounds further enhances these properties. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula I: [0008]
    Figure US20030035787A1-20030220-C00001
  • wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, non-steroidal anti-inflammatory naphthyl or phenyl propionates such as ibuprofen, ketoprofen, naproxen, and the like, or other aromatic anti-inflammatory compounds such as indomethacin, indoprofen, and the like. Ar is preferably a phenyl group and R is preferably —Z[0009] 1—R1—Z1— in which R1, is a difunctional moiety and both Z1s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. R1 is preferably an alkylene group containing from 1 to 20 carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (—CH2—CH2—O—)m, (CH2—CH2—CH2—O—)m and (—CH2—CHCH3—O—)m.
  • Ortho-substituted bis-aromatic carboxylic acid anhydrides are used in the preparation of the aromatic polyanhydrides of the present invention. The ortho-substituted bis-aromatic carboxylic acid anhydrides have the structure of Formula II: [0010]
    Figure US20030035787A1-20030220-C00002
  • wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I and R is substituted on each Ar ortho to the anhydride group. [0011]
  • In another embodiment, polyanhydrides which degrade into biologically active alpha-hydroxy acids are prepared from bis-carboxylic acid anhydrides. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula III: [0012]
    Figure US20030035787A1-20030220-C00003
  • wherein, R is preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling an alpha-hydroxy acid. In this embodiment, R is preferably an alkylene group containing from 1 to 20 carbon atoms, —(CH[0013] 2)x— wherein x is from 1 to 20, or
    Figure US20030035787A1-20030220-C00004
  • wherein x is from 1 to 20 and Z[0014] 1 and Z2 are OH so that the R group contains from 1 to 40 hydroxyl groups.
  • The present invention relates to compositions and methods of using compositions comprising polyanhydrides of Formula (I) or (III) in applications wherein delivery of a salicylate or an alpha-hydroxy acid to a host is desired. By “host” it is meant to include both animals and plants. [0015]
  • A more complete appreciation of the invention and other intended advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out. [0016]
  • DETAILED DESCRIPTION OF THE INVENTION
  • Polyanhydrides which degrade into useful biologically active products such as salicylates and alpha-hydroxy acids have now been developed. Compounds comprising these polyanhydrides are useful in a variety of applications wherein delivery of a salicylate or alpha-hydroxy acid is desired. [0017]
  • In one embodiment, the polyanhydride comprises repeating units with the structure of Formula I: [0018]
    Figure US20030035787A1-20030220-C00005
  • wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. In this embodiment, Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, nonsteroidal anti-inflammatory naphthyl or phenyl propionates such as ibuprofen, ketoprofen, naproxen, and the like, or other aromatic anti-inflammatory compounds such as indomethacin, indoprofen, and the like. Examples of the biologically active salicylates include, but are not limited to, thymotic acid, 4,4-sulfinyldinailine, 4-sulfanilamidosalicylic acid, sulfanilic acid, sulfanilylbenzylamine, sulfaloxic acid, succisulfone, salicylsulfuric acid, salsallate, salicylic alcohol, orthocaine, mesalamine, gentisic acid, enfenamic acid, cresotic acid, aminosalicylic acid, aminophenylacetic acid, acetylsalicylic acid, and the like. The identification of Ar and R moieties that provide aromatic polyanhydrides that hydrolyze to form such biologically active salicylates can be readily determined by those of ordinary skill in the art without undue experimentation. In particular, Ar is preferably a phenyl group and R is preferably —Z[0019] 1—R1—Z1— in which R1, is a difunctional moiety and both Z1s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. R1 is preferably an alkylene group containing from 1 to 20 carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (—CH2—CH2—O—)m, (CH2—CH2—CH2—O—)m and (—CH2—CHCH3—O—)m, or R1 may have the structure —R2—Z2—R3-1 wherein R2 and R3 are independently alkylene groups containing from 1 to 19 carbon atoms or groups having from 2 to 18 carbon atoms having a structure selected from (—CH2—CH2—O—)m, (—CH2—CH2—CH2—O—)m, and (—CH2—CHCH3—O—)m, and Z2 is selected from the difunctional moieties described above with respect to Z1.
  • Ar may be an alkylaryl group, in which a difunctional organic moiety is positioned between each anhydride carbonyl group and the corresponding aromatic ring. Preferably, however, each carbonyl group is directly substituted on the corresponding aromatic ring. [0020]
  • Preferred polymers of this embodiment have repeating units with the structure of Formula I in which Ar is a phenyl ring and R is selected from —Z[0021] 1—(—CH2—)n—Z1—, —Z1(—CH2—CH2—0—)m—Z1—, —Z1(—CH2—CH —2CH —02—) —Z —ml,1 and —Z (—CH —CHCH 2—0—) —3Z—, wherein Z1 is an ester or amide group and n is from 1 to 20 inclusive, and preferably is 6, and m is selected so that R has from 2 to 20, and preferably 6, carbon atoms.
  • The aromatic polyanhydrides of this embodiment of the present invention may be prepared by the method described in Conix, Macromol. Synth., 2, 95-99 (1996), in which dicarboxylic acids are acetylated in an excess of acetic anhydride at reflux temperatures followed by melt condensation of the resulting carboxylic acid anhydride at 180° C. for 2-3 hours. The resulting polymers are isolated by precipitation into diethylether from methylene chloride. The described process is essentially the conventional method for polymerizing bisaromatic dicarboxylic acid anhydrides into aromatic polyanhydrides. [0022]
  • Aromatic polyanhydrides in accordance with this embodiment of the present invention have average molecular weights of at least about 1500 daltons, up to about 100,000 daltons, calculated by Gel Permeation Chromatography (GPC) relative to narrow molecular weight polystyrene standards. [0023]
  • These aromatic polyanhydrides are produced from ortho-substituted bis-aromatic carboxylic acid anhydrides having the structure of Formula II: [0024]
    Figure US20030035787A1-20030220-C00006
  • in which Ar, R and the preferred species thereof are the same as described above with respect to Formula I. As noted above, ortho-substituted bis-aromatic carboxylic acid anhydrides are prepared by acetylation of the corresponding ortho-substituted bis-aromatic carboxylic acids in an excess of acetic anhydride at reflux temperatures. The dicarboxylic acids have the structure of Formula IV, [0025]
    Figure US20030035787A1-20030220-C00007
  • wherein Ar, R and the preferred species thereof are the same as described above with respect to Formula I. [0026]
  • The dicarboxylic acids are prepared by reacting a stoichiometric ratio of aromatic carboxylic acid having the structure Z[0027] 3—Ar—COOH and a compound having a structure Z4—R—Z4 wherein Ar is a substituted or unsubstituted aromatic ring on which Z3 is substituted ortho to the carboxylic acid group, R is a difunctional organic moiety and Z3 and Z4 are functional groups selected to provide the linkage desired between the difunctional organic moiety and the two aromatic rings.
  • Suitable Z[0028] 3 and Z4 functional groups, and the manner in which they may be reacted to produce the bis-aromatic dicarboxylic acids of the present invention, may be readily determined by those of ordinary skill in the art without undue experimentation. For example, for aromatic polyanhydrides having the structure of Formula I in which Ar is a phenyl group and R is —O—(CH2—)6—O—, the ortho-substituted bisaromatic dicarboxylic acid starting material may be prepared by reacting o-salicylic acid with 1,6-dibromohexane.
  • In another embodiment, the polyanhydrides degrade into biologically active alpha-hydroxy acids and comprise a repeating unit within the structure of Formula III: [0029]
    Figure US20030035787A1-20030220-C00008
  • In this embodiment, R is preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling an alpha-hydroxy acids. In this embodiment, R is preferably an alkylene group containing from 1 to 20 carbon atoms, —(CH[0030] 2)x— wherein x is from 1 to 20, or
    Figure US20030035787A1-20030220-C00009
  • wherein x is from 1 to 20 and Z[0031] 1 and Z2 are OH so that the R group contains from 1 to 40 hydroxyl groups. Examples of biologically active alpha-hydroxy acids include, but are not limited to, citric acid and malic acid. These polyanhydrides are prepared in the same fashion as described for aromatic polyanhydrides.
  • Polyanhydrides used in the present invention can be isolated by known methods commonly employed in the field of synthetic polymers to produce a variety of useful products with valuable physical and chemical properties. The new polymers can be readily processed into pastes or solvent cast to yield films, coatings, microspheres and fibers with different geometric shapes for design of various medical implants, and may also be processed by compression molding and extrusion. Medical implant applications include the use of aromatic polyanhydrides to form shaped articles such as vascular grafts and stents, bone plates, sutures, implantable sensors, implantable drug delivery devices, stents for tissue regeneration, and other articles that decompose harmlessly within a known time period. Polyanhydrides of the present invention can also be incorporated into oral formulations and into products such as skin moisturizers, cleansers, pads, plasters, lotions, creams, gels, ointments, solutions, shampoos, tanning products and lipsticks for topical application. [0032]
  • The quantity of aromatic polyanhydride that hydrolyzes to form an amount of biologically active salicylate or alpha-hydroxy acid effective for the selected use can be readily determined by those of ordinary skill in the art without undue experimentation. The quantity essentially corresponds stoichiometrically to the amount of salicylate or alpha-hydroxy acid known to produce an effective treatment for the selected use. [0033]
  • The present invention relates to methods of using compositions comprising these polyanhydrides in any application wherein delivery of a salicylate or alpha-hydroxy acid is desired. For example, salicylates such as salicylic acid are used routinely to treat many skin disorders including, but not limited to, acne, dandruff, psoriasis, seborrheic dermatitis of the skin and scalp, calluses, corns, common warts and plantar warts. Salicylic acid is also topically applied as an antiseptic for wounds, ulcers, and skin abscesses as it is known to exert powerful static effects against Gram-negative and Gram-positive bacteria, yeasts, dermatophytes, molds and other microbes. These antifungal properties also render salicylic acid useful in the treatment of athlete's foot. Accordingly, topical application of a composition comprising an aromatic polyanhydride of the present invention which degrades to a biologically active salicylate is expected to be useful in the treatment of all of these conditions and/or injuries. [0034]
  • The anti-bacterial activity of salicylic acid also renders these polyanhydrides useful in agricultural applications. Solutions comprising a polyanhydride of Formula (I) can be applied topically to plants to establish microbial resistance against a wide range of pathogens. Salicylic acid treatment has also been shown to induce thermotolerance in mustard seedlings. Accordingly, topical application of polyanhydrides of Formula (I) is also expected to induce thermotolerance in plants. [0035]
  • Salicylic acid has also been shown to have anti-cataract activity in patients suffering from galactosemic cataracts. Accordingly, a solution comprising an aromatic polyanhydride of Formula (I) can also be topically applied to the eye to inhibit cataract formation. [0036]
  • Salicylic acid is also a powerful anti-oxidant, neutralizing highly reactive, cell damaging molecules called free radicals. In fact, salicylic acid is often the standard by which the effectiveness of other anti-oxidants is measured. Anti-oxidants are administered orally and/or topically as antiviral agents. Anti-oxidants also inhibit UV-induced signal transduction and can be used as chemopreventative agents for skin cancer. In addition, the anti-oxidant properties of salicylates have been associated with anti-aging properties, protection against ischemia and reperfusion injury, and lowering of cholesterol levels and inhibition of clotting of blood. It is believed that compositions comprising an aromatic polyanhydride of Formula (I) will also exhibit these antioxidant properties. Thus, compositions comprising an aromatic polyanhydride of Formula (I) can also be used as antiviral agents, chemopreventative agents for skin cancer, anti-aging agents, and anti-clotting agents, and to provide protection against ischemia and reperfusion injury. [0037]
  • Compositions of the present invention comprising a polyanhydride of Formula (III) which degrades to an alpha-hydroxy acid can be incorporated into various topical formulations and applied to the skin to promote smoother, clearer skin with less wrinkles. It is generally accepted that regular use of alpha-hydroxy acids improves the appearance of the skin by minimizing fine lines, softening dry, rough skin patches and fading age spots. Alpha-hydroxy acids are effective exfoliators which dissolve the links that bind surface skin cells together causing dead cells to slough off. This process reveals the more youthful looking skin underneath which has more even skin tone, retains moisture and is less likely to form wrinkles. Topical application of a composition comprising a polyanhydride of Formula (III) provides an effective means for delivering alpha-hydroxy acids to the skin to promote smoother, clearer skin with less wrinkles. [0038]
  • The following non-limiting examples set forth hereinbelow illustrate certain aspects of the invention. All parts and percentages are by weight unless otherwise noted and all temperatures are in degrees Celsius. Except for acetic anhydride and ethyl ether (Fisher Scientific), all solvents and reagents were obtained from Aldrich Chemical. All solvents were HPLC grade. All other reagents were of analytical grade and were purified by distillation or recrystallization. [0039]
  • All compounds were characterized by a proton nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, gel permeation chromatography (GPC), high performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). Infrared spectroscopy was performed on an ATI Mattson Genesis (M100) FTIR Spectrophotometer. Samples were prepared by solvent casting on NaCl plates. [0040] 1H and 13C NMR spectroscopy was obtained on a Varian 200 MHZ or Varian 400 MHZ spectrometer in solutions of CDCl3 or DMSO-d6 with solvent as the internal reference.
  • GPC was performed on a Perkin-Elmer Advanced LC Sample Processor (ISS 200) with PE Series 200 LC Pump and a PE Series LC Refractive Index Detector to determine molecular weight and polydispersity. The data analysis was carried out using Turbochrom 4 software on a DEC Celebris 466 computer. Samples were dissolved in tetrahydrofuran and eluted through a mixed bed column (PE PL gel, 5 μm mixed bed) at a flow rate of 0.5 mL/minute. Samples (about 5 mg/mL) were dissolved into the tetrahydrofuran and filtered using 0.5 μm PTFE syringe filters prior to column injection. Molecular weights were determined relative to narrow molecular weight polystyrene standards (Polysciences, Inc.). [0041]
  • Thermal analysis was performed on a Perkin-Elmer system consisting of a TGA 7 thermal gravimetric analyzer equipped with PE AD-4 autobalance and Pyris 1 DSC analyzer. Pyris software was used to carry out data analysis on a DEC Venturis 5100 computer. For DSC, an average sample weight of 5-10 mg was heated at 10° C./minute at a 30 psi flow of N[0042] 2. For TGA, an average sample weight of 10 mg was heated at 20° C./minute under a 8 psi flow of N2. Sessile drop contact angle measurements were obtained with an NRL Goniometer (Rame-hart) using distilled water. Solutions of polymer in methylene chloride (10% wt/volume) were spun-coated onto glass slips, at 5,000 rpm for 30 seconds.
  • EXAMPLES Example 1
  • Preparation of 1,6-Bis(o-Carboxyphenoxy) Hexane Dicarboxylic Acid [0043]
  • To a mixture of salicylic acid (77.12 g, 0.5580 mole) and distilled water (84 mL) sodium hydroxide (44.71 g, 1.120 mole) was added. The reaction was brought to reflux temperature before 1,6-dibromohexane (45.21 g, 0.2790 mole) was added drop-wise. Reflux was continued for 23 hours after which additional sodium hydroxide (11.17 g, 0.2790 mole) was added. The mixture was refluxed for 16 more hours, cooled, filtered, and washed with methanol. The yield was 48.8%. [0044]
  • Example 2
  • Preparation of 1,6-Bis(o-Carboxyphenoxy) Hexane Monomer (o-CPH) [0045]
  • The dicarboxylic acid of Example 1 was acetylated in an excess of acidic anhydride at reflux temperature. The resulting monomer was precipitated with methylene chloride into an excess of diethyl ether. The yield was 66.8%. [0046]
  • Example 3
  • Preparation of Poly(1,6-Bis(o-Carboxyphenoxy) Hexane) (Poly(o-CPH)) [0047]
  • The monomer of Example 2 was polymerized in a melt condensation performed at 180° C. for 3 hours under vacuum in a reaction vessel with a side arm. The polymerization vessel was flushed with nitrogen at frequent intervals. The polymer was isolated by precipitation into diethyl ether from methylene chloride. The yield was quantitative. [0048]
  • All compounds were characterized by nuclear magnetic resonance spectroscopy, GPC, differential scanning calorimetry (DSC), thermal gravimetric analysis, contact angle measurements, UV spectroscopy, mass spectroscopy, elemental analysis and high pressure liquid chromatography (HPLC). [0049]
  • The o-CPH monomer was polymerized by melt polycondensation for 60 minutes at temperatures ranging from 100° C. to 300° C. Analysis of the resulting polymers by GPC indicated that the highest molecular weight, coupled with the lowest polydispersity index occurred at 260° C. [0050]
  • The poly(o-CPH) was generally soluble in methylene chloride and chloroform, while the poly(p-CPH) was not. The poly(o-CPH) was slightly soluble in tetrahydrofuran, acetone and ethyl acetate. [0051]
  • Disks of poly(o-CPH), poly(p-CPH) and, as a reference, poly(lactic acid glycolic acid) were prepared and placed in 0.1 phosphate buffer solution at 37° C. for 4 weeks. The degradation media was replaced periodically. The degradation profile was linear up to three weeks time. In prior art polyanhydride systems, the aromatic groups are para-substituted. This substitution pattern results in higher melt and glass transition temperatures and decreased solubility, thus ultimately making these parasubstituted polymers difficult to process. [0052]
  • Poly(o-CPH), unlike poly(p-CPH), has both a lower melting point (65° C. vs. 143° C.) and glass transition temperature (35° C. vs. 47° C.). It is also possible to solution cast poly(o-CPH) using low-boiling solvents whereas poly(p-CPH) is relatively insoluble in most organic and aqueous solvents. This structural modification gives a polymer whose hydrolysis products are chemically similar to aspirin. Aspirin is an anti-inflammatory agent derived from salicylic acid, which is one of the reagents used to synthesize the inventive polyanhydrides. Therefore, the degradation products of this polymer actually aid in patient recovery. Because of pliability and ease of processing, the aromatic polyanhydrides of the present invention have great potential as polymer scaffolds for wound healing. [0053]
  • Example 4
  • Preparation of 1,3-bis(o-carboxyphenoxy)propane dicarboxylic acid [0054]
  • 1,3-dibromopropane (14.7 mL, 0.145 mole) was added to a mixture of salicylic acid (40.0 g, 0.290 mole), distilled water (44 mL) and sodium hydroxide (23.2 g, 0.580 mole) using the method described in Example 1. After 4 hours, additional sodium hydroxide (5.79 g, 0.145 mole) was added to the reaction mixture. Reflux was continued for another 4 hours, after which the mixture was cooled, filtered and washed using the methods described in Example 1. The yield was 37.7% [0055]
  • Example 5
  • Preparation of poly(1,3-bis(o-carboxyphenoxy) propane) [0056]
  • The dicarboxylic acid of Example 4 was acetylated using the methods of Example 2. The acetylated dicarboxylic acid was then polymerized using the methods described in Example 3. The resulting polymer had a M[0057] w of 8,500 daltons and a polydispersity of 2.3.
  • Contact angle measurements on solvent-cast films demonstrated that the hexyl chain of the polymer of Example 3 increased the surface hydrophobicity relative to the shorter propyl chain of the polymer of Example 5. A comparison of thermal characteristics emphasized the effects of lengthening the alkyl chain. In particular, the polymer of Example 3 has a T[0058] g of 34° C. and a Td of 410° C., while the polymer of Example 5 had a Tg of 50° C. and a Td of 344° C. Thus, the hexyl chain decreased the glass transition temperature (Tg) relative to the propyl chain, reflecting the increased flexibility of the polymer chain. The opposite trend was observed for decomposition temperatures (Td), with the longer alkyl chain increasing the Td.
  • Optimum polycondensation conditions were determined for the polymer of Example 3. Optimum conditions were defined as those that yielded a crude polymer with the highest molecular weight and highest T[0059] g. Higher reaction temperatures decreased the Mw values (measured by GPC) with a concurrent increase in polydispersity. As expected for a condensation polymerization, longer reaction times yielded polymers with higher molecular weights. However, over longer reaction times, there appeared a subsequent decrease in Tg. Based on these results, the optimum conditions were defined as temperatures of 220° C. for 150 minutes under a vacuum.
  • Example 6
  • Preparation of 1,8-bis[o-(benzylcarboxy)carboxy phenyl] octane dicarboxylic acid ester [0060]
  • The initial synthesis of poly(anhydride-ester) dicarboxylic acid monomers was attempted using the same methodology used for the poly(anhydride-ether) dicarboxylic monomers of Example 3. It was found, however, that the reactivity of the phenol was enhanced by benzylation of the carboxylic acid group. In addition, the solubility of benzyl salicylate in organic media increased the ability of the reaction to move forward. [0061]
  • Thus, benzyl salicylate (1.530 g, 6.720 mmole) and distilled tetrahydrofuran were combined under an inert atmosphere in a reaction flask. An ice-salt bath was placed under the reaction flask and the addition of 60% sodium hydride (0.4840 g, 12.10 mmole) followed. After one hour, sebacoyl chloride (0.7850 g, 3.280 mmole) was added drop-wise to the 0° C. reaction mixture. After 30 minutes, the reaction mixture was vacuum filtered, the filtrate collected and the solvent removed to yield the free carboxylate as a white solid residue. Purification was performed using a chromatron with ethyl acetate/methylene chloride (20/80) as the solvent system. The yield was 43%. [0062]
  • Example 7
  • Polymerization of Poly(1,8-bis(o-dicarboxyphenyl) octane) [0063]
  • To remove the benzyl protecting groups, the 1,8-bis[(benzylcarboxy)carboxyphenyl]octane dicarboxylic acid ester of Example 6 (0.06000 g, 0.9620 mmole) was dissolved in methylene chloride in a reaction flask (60.00 mL). The catalyst Pd-C (10%, 1.200 g) was added to the reaction flask. After 30 minutes, the reaction was complete. The reaction mixture was filtered and the solvent removed to yield the free dicarboxylic acid as a white solid residue which was recrystallized using petroleum ether and methylene chloride. The yield was 45%. [0064]
  • The dicarboxylic acid was acetylated using the methods described in Example 2 and the acetylated dicarboxylic acid was then polymerized using the methods described in Example 3. The resulting polymer had a M[0065] w of 3,000 daltons and a polydispersity of 1.40.
  • Subsequent polymerizations yielded polymers with M[0066] w's ranging from 2,000 to 5,000 daltons with corresponding polydispersities of approximately 1.40.
  • The poly(anhydride esters) of Example 7 were compression molded into circular discs and placed in phosphate buffered saline solution under acidic, neutral and basic conditions. Over the course of a three-week degradation study, the polymers in the acidic and neutral solutions showed no observable changes, whereas the polymer in the basic media showed significant morphological changes over time. [0067]
  • Example 8
  • Preparation of Poly[(1,8-bis(o-dicarboxyphenyl) octane)-(1,6-bis(p-carboxyphenoxy)hexane]copolymers [0068]
  • The 1,8-bis(o-dicarboxyphenyl) octane of Example 2 was copolymerized with 1,6-bis(p-carboxyphenoxy) hexane using the methods described in Example 3. In an in vivo mouse study, each mouse was implanted with 2 polymers, the copolymer of Example 8 and poly(1,6-bis(p-carboxyphenoxy)hexane). Each polymer was compression molded for 1 to 5 minutes at 1 to 20 K psi depending on the thickness of polymer needed. The polymer was placed under the palatal gingival mucosa adjacent to the first maxillary molars. [0069]

Claims (15)

    What is claimed is:
  1. 1. A composition comprising a polyanhydride which degrades to a biologically active salicylate or alpha-hydroxy acid, said polyanhydride comprising a repeating unit having the structure of Formula (I):
    Figure US20030035787A1-20030220-C00010
    wherein Ar is a substituted or unsubstituted aromatic ring and R is —Z1—R1—Z1— substituted on each Ar ortho to the anhydride group, wherein R1 is a difunctional organic moiety and Z1 is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates; or the structure of Formula (III):
    Figure US20030035787A1-20030220-C00011
    wherein R is an alkylene group containing from 1 to 20 carbon atoms, —(CH2)x— wherein x is from 1 to 20, or
    Figure US20030035787A1-20030220-C00012
    wherein x is from 1 to 20 and Z1 and Z2 are OH so that the R group contains from 1 to 40 hydroxyl groups.
  2. 2. A method of delivering a salicylate to a host comprising administering to a host a composition of claim 1 wherein the polyanhydride comprises Formula (I).
  3. 3. The method of claim 2 wherein the composition is administered topically.
  4. 4. The method of claim 3 wherein the composition is topically administered to the host to treat a skin disorder selected from the group consisting of acne, dandruff, psoriasis, seborrheic dermatitis of the skin and scalp, calluses, corns, common warts and plantar warts.
  5. 5. The method of claim 3 wherein the composition is topically administered to a host to prevent microbial infection.
  6. 6. The method of claim 5 wherein the host is an animal and the composition is topically applied as an antiseptic to a wound, ulcer or skin abscess.
  7. 7. The method of claim 5 wherein the host is a plant.
  8. 8. The method of claim 2 wherein the composition is administered to the host so that the salicylate can act as an anti-oxidant thereby neutralizing free radicals.
  9. 9. The method of claim 8 wherein the composition is administered to treat viral infections.
  10. 10. The method of claim 8 wherein the composition is administered to inhibit UV-induced signal transduction and development of skin cancer.
  11. 11. The method of claim 8 wherein the composition is administered to prevent blood clotting.
  12. 12. The method of claim 8 wherein the composition is administered to prevent tissue injury caused by ischemia and reperfusion.
  13. 13. The method of claim 2 wherein the composition is administered topically to the eye to inhibit cataract formation.
  14. 14. A method of delivering an alpha-hydroxy acid to a host comprising administering to a host a composition of claim 1 wherein the polyanhydride comprises Formula (III).
  15. 15. The method of claim 14 wherein the composition is administered topically to promote smoother, clearer skin with less wrinkles.
US10254191 1997-09-10 2002-09-24 Polyanhydrides with biologically active degradation products Abandoned US20030035787A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US09422294 US6468519B1 (en) 1997-09-10 1999-10-21 Polyanhydrides with biologically active degradation products
US10254191 US20030035787A1 (en) 1999-10-21 2002-09-24 Polyanhydrides with biologically active degradation products

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US10254191 US20030035787A1 (en) 1999-10-21 2002-09-24 Polyanhydrides with biologically active degradation products

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US09422294 Continuation US6468519B1 (en) 1997-09-10 1999-10-21 Polyanhydrides with biologically active degradation products

Publications (1)

Publication Number Publication Date
US20030035787A1 true true US20030035787A1 (en) 2003-02-20

Family

ID=23674230

Family Applications (2)

Application Number Title Priority Date Filing Date
US09422294 Expired - Fee Related US6468519B1 (en) 1997-09-10 1999-10-21 Polyanhydrides with biologically active degradation products
US10254191 Abandoned US20030035787A1 (en) 1997-09-10 2002-09-24 Polyanhydrides with biologically active degradation products

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US09422294 Expired - Fee Related US6468519B1 (en) 1997-09-10 1999-10-21 Polyanhydrides with biologically active degradation products

Country Status (6)

Country Link
US (2) US6468519B1 (en)
EP (2) EP1464673A3 (en)
JP (1) JP2003511550A (en)
CA (1) CA2387558A1 (en)
DE (1) DE60025272D1 (en)
WO (1) WO2001028492A3 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US20040096476A1 (en) * 2002-07-17 2004-05-20 Uhrich Kathryn E. Therapeutic devices for patterned cell growth
US20050053577A1 (en) * 2000-07-27 2005-03-10 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US20050255079A1 (en) * 2004-05-14 2005-11-17 Santerre Paul J Polymeric coupling agents and pharmaceutically-active polymers made therefrom
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
JP2007537168A (en) * 2004-05-14 2007-12-20 インターフェース バイオロジクス インコーポレーティッド Polymers with a high molecular coupling agent and pharmaceutically active made therefrom
WO2008128193A1 (en) 2007-04-12 2008-10-23 Rutgers, The State University Of New Jersey Biodegradable polyanhydrides with natural bioactive molecules
US20090253806A1 (en) * 2006-03-23 2009-10-08 Varshney Sunil K Polyanhydride polymers and their uses in biomedical devices
WO2010148104A2 (en) * 2009-06-16 2010-12-23 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
WO2010148101A2 (en) * 2009-06-16 2010-12-23 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
US20110045049A1 (en) * 2006-11-06 2011-02-24 Ifat Rubin-Bejerano Immunomodulating compositions and methods of use
US20110223232A1 (en) * 2006-10-23 2011-09-15 Olexander Hnojewyj drug-release composition having a therapeutic carrier
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
US9457047B2 (en) 2006-11-06 2016-10-04 Whitehead Institute Immunomodulating compositions 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
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)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6468519B1 (en) * 1997-09-10 2002-10-22 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
DE60043075D1 (en) * 1999-12-07 2009-11-12 Univ Rutgers Therapeutic compositions and methods for treatment of periodontitis with entzündunshemmenden forward
US6527801B1 (en) 2000-04-13 2003-03-04 Advanced Cardiovascular Systems, Inc. Biodegradable drug delivery material for stent
EP1309354A2 (en) 2000-07-27 2003-05-14 Rutgers, The State University Therapeutic polyesters and polyamides
CN1684582A (en) * 2001-11-23 2005-10-19 拉特格斯州立大学 Improved synthesis of polyanhydrides
US6932930B2 (en) 2003-03-10 2005-08-23 Synecor, Llc Intraluminal prostheses having polymeric material with selectively modified crystallinity and methods of making same
US9445901B2 (en) * 2003-03-12 2016-09-20 Deger C. Tunc Prosthesis with sustained release analgesic
EP1626748B1 (en) * 2003-05-13 2012-07-11 Medtronic, Inc. Moisture curable materials for delivery of agents, methods, and medical devices
US20050249697A1 (en) * 2003-09-24 2005-11-10 Uhrich Kathryn E Compositions and methods for the inhibition of bone growth and resorption
US8352712B2 (en) * 2004-05-06 2013-01-08 International Business Machines Corporation Method and system for specualtively sending processor-issued store operations to a store queue with full signal asserted
US7691364B2 (en) * 2005-01-28 2010-04-06 Bezwada Biomedical, Llc Functionalized drugs and polymers derived therefrom
US7858077B2 (en) * 2005-01-28 2010-12-28 Bezwada Biomedical Llc Functionalized phenolic esters and amides and polymers therefrom
US20060193891A1 (en) 2005-02-25 2006-08-31 Robert Richard Medical devices and therapeutic delivery devices composed of bioabsorbable polymers produced at room temperature, method of making the devices, and a system for making the devices
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
US8318973B2 (en) * 2005-10-21 2012-11-27 Bezwada Biomedical, Llc Functionalized sinapic acid and methyl sinapate
US8007526B2 (en) 2005-12-01 2011-08-30 Bezwada Biomedical, Llc Difunctionalized aromatic compounds and polymers therefrom
US7935843B2 (en) * 2005-12-09 2011-05-03 Bezwada Biomedical, Llc Functionalized diphenolics and absorbable polymers therefrom
US9603941B2 (en) * 2006-01-24 2017-03-28 Minghui Chai Method of preparing dendritic drugs
EP2032614A2 (en) * 2006-06-06 2009-03-11 Rutgers, The State University Of New Jersey Iodinated polymers
EP2102144A4 (en) 2006-09-13 2011-03-23 Univ Rutgers Active agents and their oligomers and polymers
US8217134B2 (en) * 2007-08-30 2012-07-10 Bezwada Biomedical, Llc Controlled release of biologically active compounds
US8026285B2 (en) 2007-09-04 2011-09-27 Bezwada Biomedical, Llc Control release of biologically active compounds from multi-armed oligomers
US8048980B2 (en) * 2007-09-17 2011-11-01 Bezwada Biomedical, Llc Hydrolysable linkers and cross-linkers for absorbable polymers
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

Citations (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4062855A (en) * 1971-09-27 1977-12-13 University Of Washington Synthetic polymers furnishing controlled release of a biologically active component during degradation
US4287174A (en) * 1978-03-31 1981-09-01 The Proctor & Gamble Company Anti-ulcer composition
US4298595A (en) * 1978-12-20 1981-11-03 Dynapol Pharmaceutical preparations containing a polymeric agent for releasing 5-aminosalicylic acid or its salts into the gastrointestinal tract
US4363815A (en) * 1975-07-23 1982-12-14 Yu Ruey J Alpha hydroxyacids, alpha ketoacids and their use in treating skin conditions
US4483854A (en) * 1983-04-12 1984-11-20 Key Pharmaceuticals, Inc. Systemic treatment of psoriasis using certain salicylates
US4612302A (en) * 1983-11-14 1986-09-16 Brigham And Women's Hospital Clinical use of somatostatin analogues
US4665063A (en) * 1983-06-13 1987-05-12 Rafa Laboratories Ltd. Method of treating acne
US4684620A (en) * 1984-09-04 1987-08-04 Gibson-Stephens Neuropharmaceuticals, Inc. Cyclic polypeptides having mu-receptor specificity
US4757128A (en) * 1986-08-01 1988-07-12 Massachusetts Institute Of Technology High molecular weight polyanhydride and preparation thereof
US4857311A (en) * 1987-07-31 1989-08-15 Massachusetts Institute Of Technology Polyanhydrides with improved hydrolytic degradation properties
US4868274A (en) * 1988-05-23 1989-09-19 Hoechst Celanese Corp. Polyanhydride from carboxy aryloxy alkanoic acid
US4886870A (en) * 1984-05-21 1989-12-12 Massachusetts Institute Of Technology Bioerodible articles useful as implants and prostheses having predictable degradation rates
US4888176A (en) * 1984-05-21 1989-12-19 Massachusetts Institute Of Technology Controlled drug delivery high molecular weight polyanhydrides
US4891225A (en) * 1984-05-21 1990-01-02 Massachusetts Institute Of Technology Bioerodible polyanhydrides for controlled drug delivery
US4906474A (en) * 1983-03-22 1990-03-06 Massachusetts Institute Of Technology Bioerodible polyanhydrides for controlled drug delivery
US4916204A (en) * 1987-07-31 1990-04-10 Massachusetts Institute Of Technology Pure polyanhydride from dicarboxylic acid and coupling agent
US4938949A (en) * 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
US4997904A (en) * 1989-08-25 1991-03-05 Nova Pharmaceutical Corporation Aromatic polyanhydride compositions
US4999417A (en) * 1989-03-30 1991-03-12 Nova Pharmaceutical Corporation Biodegradable polymer compositions
US5055524A (en) * 1987-07-16 1991-10-08 Ppg Industries, Inc. Polyol-modified polyanhydride curing agent for polyepoxide powder coatings
US5082925A (en) * 1990-08-16 1992-01-21 Ethicon, Inc. Homopolymers and copolymers of salicylate lactones
US5151415A (en) * 1991-05-23 1992-09-29 Dallas Sirany Method of treating a papova-type viral infection
US5175235A (en) * 1990-06-04 1992-12-29 Nova Pharmaceutical Corporation Branched polyanhydrides
US5259968A (en) * 1988-02-29 1993-11-09 Exxon Chemical Patents Inc. Dispersant additive comprising the reaction product of a polyanhydride and a mannich condensation product
US5264540A (en) * 1992-07-20 1993-11-23 Ethicon, Inc. Aromatic polyanhydrides
US5422352A (en) * 1989-07-07 1995-06-06 Nycomed Dak A/S Slimming pharmaceutical composition
US5498729A (en) * 1989-12-26 1996-03-12 Domb; Abraham J. Prodrug compositions
US5514764A (en) * 1990-11-19 1996-05-07 Cornell Research Foundation, Inc. Hyperbranched polyesters and polyamides
US5545409A (en) * 1989-02-22 1996-08-13 Massachusetts Institute Of Technology Delivery system for controlled release of bioactive factors
US5660851A (en) * 1989-12-26 1997-08-26 Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem Ocular inserts
US5703122A (en) * 1993-04-26 1997-12-30 Avon Products, Inc. Ascorbic acid compositions for reducing irritation of topically applied active ingredients
US5798115A (en) * 1996-02-15 1998-08-25 Santerre; Paul J. Bioresponsive pharmacologically-active polymers and articles made therefrom
US5837278A (en) * 1994-01-06 1998-11-17 Ed Geistlich Sohne Ag Fur Chemische Industrie Resorbable collagen membrane for use in guided tissue regeneration
US5869069A (en) * 1994-07-22 1999-02-09 Coletica Lipophilic hydroxylated acid, its use in cosmetics and pharmacy, and its process of preparation
US5882665A (en) * 1997-11-18 1999-03-16 Elizabeth Arden Co., Division Of Conopco, Inc. Phytosphingosine salicylates in cosmetic compositions
US5902110A (en) * 1995-12-18 1999-05-11 The Block Drug Company Bone regeneration
US5942252A (en) * 1986-10-24 1999-08-24 Southern Research Institute Method for delivering bioactive agents into and through the mucosally-associated lymphoid tissues and controlling their release
US6025331A (en) * 1996-02-16 2000-02-15 Children's Medical Center Corporation Pharmaceutical compositions comprising troponin subunits, fragments and analogs thereof and methods of their use to inhibit angiogenesis
US6071530A (en) * 1989-07-24 2000-06-06 Atrix Laboratories, Inc. Method and composition for treating a bone tissue defect
US6153212A (en) * 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US6468519B1 (en) * 1997-09-10 2002-10-22 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
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
US6602915B2 (en) * 2000-07-27 2003-08-05 Rutgers, The State University Of New Jersey Therapeutic azo-compounds for drug delivery
US6685928B2 (en) * 1999-12-07 2004-02-03 Rutgers, The State University Of New Jersey Therapeutic compositions and methods
US6689350B2 (en) * 2000-07-27 2004-02-10 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US20040096476A1 (en) * 2002-07-17 2004-05-20 Uhrich Kathryn E. Therapeutic devices for patterned cell growth

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE288311C (en) 1915-10-27
DE288387C (en)
DE246341T1 (en) 1986-05-20 1989-03-30 Massachusetts Institute Of Technology, Cambridge, Mass., Us Bioerodible products suitable for use as implants or prosthesis having a predictable resorbierungsgrad.
CA2028136A1 (en) 1989-02-28 1990-09-29 Marc N. Benhuri Method and composition for treatment of periodontal disease
US5317079A (en) * 1990-01-19 1994-05-31 Nova Pharmaceutical Corporation Fatty acid terminated polyanhydride
NL9000237A (en) 1990-01-31 1991-08-16 Re Novative Drugs For Dermatol Topical pharmaceutical compositions for the oral cavity and vagina.
US5198572A (en) * 1991-02-04 1993-03-30 General Electric Company Copolymers of dicarboxylic acids and salicylic acids
WO1996003110A1 (en) * 1994-07-22 1996-02-08 Coletica Lipophilic hydroxylated acid, cosmetic and pharmaceutical use thereof and method for preparing same
US5902599A (en) 1996-02-20 1999-05-11 Massachusetts Institute Of Technology Biodegradable polymer networks for use in orthopedic and dental applications
US5955096A (en) * 1996-06-25 1999-09-21 Brown University Research Foundation Methods and compositions for enhancing the bioadhesive properties of polymers using organic excipients
WO1998036013A1 (en) 1997-02-18 1998-08-20 Rutgers, The State University Monomers derived from hydroxy acids and polymers prepared therefrom
JP2001513503A (en) * 1997-08-06 2001-09-04 スミスクライン・ビーチャム・コーポレイション Macrophage scavenger receptor antagonists of use in the treatment of cardiovascular diseases
DE19754063A1 (en) 1997-12-05 1999-06-10 Bayer Ag Degradation of biodegradable polymers
US6060212A (en) * 1998-06-11 2000-05-09 Clariant Finance (Bvi) Limited 193 nm positive-working photoresist composition

Patent Citations (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4062855A (en) * 1971-09-27 1977-12-13 University Of Washington Synthetic polymers furnishing controlled release of a biologically active component during degradation
US4126445A (en) * 1971-09-27 1978-11-21 University Of Washington Synthetic polymers furnishing controlled release of a biologically active component during degradation
US4363815A (en) * 1975-07-23 1982-12-14 Yu Ruey J Alpha hydroxyacids, alpha ketoacids and their use in treating skin conditions
US4287174A (en) * 1978-03-31 1981-09-01 The Proctor & Gamble Company Anti-ulcer composition
US4298595A (en) * 1978-12-20 1981-11-03 Dynapol Pharmaceutical preparations containing a polymeric agent for releasing 5-aminosalicylic acid or its salts into the gastrointestinal tract
US4906474A (en) * 1983-03-22 1990-03-06 Massachusetts Institute Of Technology Bioerodible polyanhydrides for controlled drug delivery
US4483854A (en) * 1983-04-12 1984-11-20 Key Pharmaceuticals, Inc. Systemic treatment of psoriasis using certain salicylates
US4665063A (en) * 1983-06-13 1987-05-12 Rafa Laboratories Ltd. Method of treating acne
US4612302A (en) * 1983-11-14 1986-09-16 Brigham And Women's Hospital Clinical use of somatostatin analogues
US4891225A (en) * 1984-05-21 1990-01-02 Massachusetts Institute Of Technology Bioerodible polyanhydrides for controlled drug delivery
US4888176A (en) * 1984-05-21 1989-12-19 Massachusetts Institute Of Technology Controlled drug delivery high molecular weight polyanhydrides
US4886870A (en) * 1984-05-21 1989-12-12 Massachusetts Institute Of Technology Bioerodible articles useful as implants and prostheses having predictable degradation rates
US4684620A (en) * 1984-09-04 1987-08-04 Gibson-Stephens Neuropharmaceuticals, Inc. Cyclic polypeptides having mu-receptor specificity
US4757128A (en) * 1986-08-01 1988-07-12 Massachusetts Institute Of Technology High molecular weight polyanhydride and preparation thereof
US5942252A (en) * 1986-10-24 1999-08-24 Southern Research Institute Method for delivering bioactive agents into and through the mucosally-associated lymphoid tissues and controlling their release
US5055524A (en) * 1987-07-16 1991-10-08 Ppg Industries, Inc. Polyol-modified polyanhydride curing agent for polyepoxide powder coatings
US4857311A (en) * 1987-07-31 1989-08-15 Massachusetts Institute Of Technology Polyanhydrides with improved hydrolytic degradation properties
US4916204A (en) * 1987-07-31 1990-04-10 Massachusetts Institute Of Technology Pure polyanhydride from dicarboxylic acid and coupling agent
US5259968A (en) * 1988-02-29 1993-11-09 Exxon Chemical Patents Inc. Dispersant additive comprising the reaction product of a polyanhydride and a mannich condensation product
US4868274A (en) * 1988-05-23 1989-09-19 Hoechst Celanese Corp. Polyanhydride from carboxy aryloxy alkanoic acid
US4938949A (en) * 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
US5629009A (en) * 1989-02-22 1997-05-13 Massachusetts Institute Of Technology Delivery system for controlled release of bioactive factors
US5545409A (en) * 1989-02-22 1996-08-13 Massachusetts Institute Of Technology Delivery system for controlled release of bioactive factors
US4999417A (en) * 1989-03-30 1991-03-12 Nova Pharmaceutical Corporation Biodegradable polymer compositions
US5422352A (en) * 1989-07-07 1995-06-06 Nycomed Dak A/S Slimming pharmaceutical composition
US6071530A (en) * 1989-07-24 2000-06-06 Atrix Laboratories, Inc. Method and composition for treating a bone tissue defect
US4997904A (en) * 1989-08-25 1991-03-05 Nova Pharmaceutical Corporation Aromatic polyanhydride compositions
US5498729A (en) * 1989-12-26 1996-03-12 Domb; Abraham J. Prodrug compositions
US5660851A (en) * 1989-12-26 1997-08-26 Yissum Research Development Company Of The Hebrew Univ. Of Jerusalem Ocular inserts
US5175235A (en) * 1990-06-04 1992-12-29 Nova Pharmaceutical Corporation Branched polyanhydrides
US5082925A (en) * 1990-08-16 1992-01-21 Ethicon, Inc. Homopolymers and copolymers of salicylate lactones
US5514764A (en) * 1990-11-19 1996-05-07 Cornell Research Foundation, Inc. Hyperbranched polyesters and polyamides
US5151415A (en) * 1991-05-23 1992-09-29 Dallas Sirany Method of treating a papova-type viral infection
US5264540A (en) * 1992-07-20 1993-11-23 Ethicon, Inc. Aromatic polyanhydrides
US5703122A (en) * 1993-04-26 1997-12-30 Avon Products, Inc. Ascorbic acid compositions for reducing irritation of topically applied active ingredients
US5837278A (en) * 1994-01-06 1998-11-17 Ed Geistlich Sohne Ag Fur Chemische Industrie Resorbable collagen membrane for use in guided tissue regeneration
US5869069A (en) * 1994-07-22 1999-02-09 Coletica Lipophilic hydroxylated acid, its use in cosmetics and pharmacy, and its process of preparation
US5902110A (en) * 1995-12-18 1999-05-11 The Block Drug Company Bone regeneration
US5798115A (en) * 1996-02-15 1998-08-25 Santerre; Paul J. Bioresponsive pharmacologically-active polymers and articles made therefrom
US6025331A (en) * 1996-02-16 2000-02-15 Children's Medical Center Corporation Pharmaceutical compositions comprising troponin subunits, fragments and analogs thereof and methods of their use to inhibit angiogenesis
US6468519B1 (en) * 1997-09-10 2002-10-22 Rutgers, The State University Of New Jersey Polyanhydrides with biologically active degradation products
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
US5882665A (en) * 1997-11-18 1999-03-16 Elizabeth Arden Co., Division Of Conopco, Inc. Phytosphingosine salicylates in cosmetic compositions
US6153212A (en) * 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US6685928B2 (en) * 1999-12-07 2004-02-03 Rutgers, The State University Of New Jersey Therapeutic compositions and methods
US6613807B2 (en) * 2000-07-27 2003-09-02 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US6689350B2 (en) * 2000-07-27 2004-02-10 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US6602915B2 (en) * 2000-07-27 2003-08-05 Rutgers, The State University Of New Jersey Therapeutic azo-compounds for drug delivery
US20040044125A1 (en) * 2000-07-27 2004-03-04 Rutgers, The State University Of New Jersey Therapeutic AZO-compounds for drug delivery
US20050031577A1 (en) * 2000-07-27 2005-02-10 Rutgers, The State University Of New Jersey Therapeutic polyesters and polyamides
US20050053577A1 (en) * 2000-07-27 2005-03-10 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US20040096476A1 (en) * 2002-07-17 2004-05-20 Uhrich Kathryn E. Therapeutic devices for patterned cell growth

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070213500A1 (en) * 1997-09-10 2007-09-13 Rutgers, The State University Of New Jersey Polyanhydrides with therapeutically useful degradation products
US20100074937A1 (en) * 1997-09-10 2010-03-25 Uhrich Kathryn E Polyanhydrides with therapeutically useful degradation products
US8017714B2 (en) 1997-09-10 2011-09-13 Rutgers, The State University Of New Jersey Polyanhydrides with therapeutically useful degradation products
US7534852B2 (en) 1997-09-10 2009-05-19 Rutgers, The State University Of New Jersey Polyanhydrides with therapeutically useful degradation products
US20060188546A1 (en) * 1997-09-10 2006-08-24 Polymerix Corporation Medical devices employing novel polymers
US7985415B2 (en) 1997-09-10 2011-07-26 Rutgers, The State University Of New Jersey 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
US20040038948A1 (en) * 1999-12-07 2004-02-26 Uhrich Kathryn E. Therapeutic compositions and methods
US8088405B2 (en) 1999-12-07 2012-01-03 Rutgers, The State University of New Jersery Therapeutic compositions and methods
US20050053577A1 (en) * 2000-07-27 2005-03-10 Rutgers, The State University Of New Jersey Therapeutic polyanhydride compounds for drug delivery
US20040096476A1 (en) * 2002-07-17 2004-05-20 Uhrich Kathryn E. Therapeutic devices for patterned cell growth
US20110112259A1 (en) * 2004-05-14 2011-05-12 Interface Biologics, Inc Polymeric coupling agents and pharmaceutically-active polymers made therefrom
US20050255079A1 (en) * 2004-05-14 2005-11-17 Santerre Paul J Polymeric coupling agents and pharmaceutically-active polymers made therefrom
JP2007537168A (en) * 2004-05-14 2007-12-20 インターフェース バイオロジクス インコーポレーティッド Polymers with a high molecular coupling agent and pharmaceutically active made therefrom
US8349309B2 (en) 2004-05-14 2013-01-08 Interface Biologics Inc. Polymeric coupling agents and pharmaceutically-active polymers made therefrom
US20090253806A1 (en) * 2006-03-23 2009-10-08 Varshney Sunil K Polyanhydride polymers and their uses in biomedical devices
US7674285B2 (en) 2006-03-23 2010-03-09 Bioabsorbable Therapeutics, Inc. Polyanhydride polymers and their uses in biomedical devices
US20110223232A1 (en) * 2006-10-23 2011-09-15 Olexander Hnojewyj drug-release composition having a therapeutic carrier
US9457047B2 (en) 2006-11-06 2016-10-04 Whitehead Institute Immunomodulating compositions and methods of use thereof
US8580253B2 (en) 2006-11-06 2013-11-12 Whitehead Institute Immunomodulating compositions and methods of use
US20110045049A1 (en) * 2006-11-06 2011-02-24 Ifat Rubin-Bejerano Immunomodulating compositions and methods of use
WO2008128193A1 (en) 2007-04-12 2008-10-23 Rutgers, The State University Of New Jersey Biodegradable polyanhydrides with natural bioactive molecules
WO2010148101A3 (en) * 2009-06-16 2011-05-05 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
WO2010148101A2 (en) * 2009-06-16 2010-12-23 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
WO2010148104A2 (en) * 2009-06-16 2010-12-23 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
WO2010148104A3 (en) * 2009-06-16 2011-05-05 L'oreal S.A. Topical compositions containing a polymer for releasing at least one salicylic acid compound
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
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)

Also Published As

Publication number Publication date Type
EP1464673A2 (en) 2004-10-06 application
EP1246627A4 (en) 2003-04-02 application
WO2001028492A3 (en) 2001-09-13 application
WO2001028492A2 (en) 2001-04-26 application
CA2387558A1 (en) 2001-04-26 application
JP2003511550A (en) 2003-03-25 application
US6468519B1 (en) 2002-10-22 grant
EP1246627A2 (en) 2002-10-09 application
EP1464673A3 (en) 2007-12-19 application
EP1246627B1 (en) 2005-12-28 grant
DE60025272D1 (en) 2006-02-02 grant

Similar Documents

Publication Publication Date Title
Kricheldorf et al. Polylactides‐synthesis, characterization and medical application
Sawhney et al. Bioerodible hydrogels based on photopolymerized poly (ethylene glycol)-co-poly (. alpha.-hydroxy acid) diacrylate macromers
US8535655B2 (en) Biodegradable polymer—bioactive moiety conjugates
US6048521A (en) Copolymers of tyrosine-based polyarlates and poly(alkylene oxides)
US5171812A (en) Polyanhydrides of oligomerized unsaturated aliphatic acids
US5618552A (en) Absorbable polyoxaesters
US6984393B2 (en) Biodegradable elastomer and method of preparing same
US6319492B1 (en) Copolymers of tyrosine-based polyarylates and poly(alkylene oxides)
US5548035A (en) Biodegradable copolymer as drug delivery matrix comprising polyethyleneoxide and aliphatic polyester blocks
US6475477B1 (en) Radio-opaque polymer biomaterials
US5968543A (en) Polymers with controlled physical state and bioerodibility
US20060013851A1 (en) Therapeutic polyanhydride compounds for drug delivery
US5658995A (en) Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)
US4806621A (en) Biocompatible, bioerodible, hydrophobic, implantable polyimino carbonate article
US5198507A (en) Synthesis of amino acid-derived bioerodible polymers
US6602497B1 (en) Strictly alternating poly(alkylene oxide ether) copolymers
US6590059B2 (en) Bioerodible polyorthoesters from dioxolane-based diketene acetals
US6251435B1 (en) Hydrogels containing absorbable polyoxaamides
US4209607A (en) Polyesteramides derived from bis-oxamidodiols and dicarboxylic acids
US4226243A (en) Surgical devices of polyesteramides derived from bis-oxamidodiols and dicarboxylic acids
US5597579A (en) Blends of absorbable polyoxaamides
US7772352B2 (en) Bioabsorbable and biocompatible polyurethanes and polyamides for medical devices
US5270419A (en) Polyanhydrides of oligomerized unsaturated aliphatic acids
US20040096476A1 (en) Therapeutic devices for patterned cell growth
US4757128A (en) High molecular weight polyanhydride and preparation thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: AMT CAPITAL, LTD., TEXAS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:POLYMERIX CORPORATION;REEL/FRAME:014250/0921

Effective date: 20030519

AS Assignment

Owner name: POLYMERIX CORPORATION, NEW JERSEY

Free format text: RELEASE OF SECURITY INTEREST;ASSIGNOR:AMT CAPITAL, LTD.;REEL/FRAME:014683/0487

Effective date: 20031023