WO1993009790A1 - Methods of inhibiting restenosis - Google Patents

Methods of inhibiting restenosis Download PDF

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Publication number
WO1993009790A1
WO1993009790A1 PCT/US1992/009754 US9209754W WO9309790A1 WO 1993009790 A1 WO1993009790 A1 WO 1993009790A1 US 9209754 W US9209754 W US 9209754W WO 9309790 A1 WO9309790 A1 WO 9309790A1
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WO
WIPO (PCT)
Prior art keywords
derivative
cyclodextrin
tissue
composition
saccharide
Prior art date
Application number
PCT/US1992/009754
Other languages
English (en)
French (fr)
Inventor
Howard C. Herrmann
Elliot Barnathan
Paul B. Weisz
Original Assignee
The Trustees Of The University Of Pennsylvania
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
Priority claimed from IL10002391A external-priority patent/IL100023A/en
Application filed by The Trustees Of The University Of Pennsylvania filed Critical The Trustees Of The University Of Pennsylvania
Priority to BR9206736A priority Critical patent/BR9206736A/pt
Priority to AU30742/92A priority patent/AU678760B2/en
Priority to JP5509395A priority patent/JPH07500843A/ja
Priority to EP92924424A priority patent/EP0612249A4/en
Publication of WO1993009790A1 publication Critical patent/WO1993009790A1/en
Priority to FI942166A priority patent/FI942166A/sv
Priority to NO941738A priority patent/NO941738L/no

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
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    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
    • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/475—Growth factors; Growth regulators
    • C07K14/50—Fibroblast growth factor [FGF]
    • C07K14/503—Fibroblast growth factor [FGF] basic FGF [bFGF]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/23—Carbohydrates
    • A61L2300/232—Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • the present invention is directed to compounds, compositions and methods for healing wounded living tissue, an particularly to saccharide-based compounds and compositions which remain localized at the site of a wound for extended 5 periods of time.
  • the injury of tissue initiates a series of events tha result in tissue repair and healing of the wound.
  • the macrophages and fibroblasts which migrate to the wound site are activated, thereby resulting in endogenous growth factor production, synthesis of a provisional extracellular matrix, proliferation of fibroblasts and collagen synthesis.
  • heparin binding growth factors HBGFs
  • HBGFs have been shown to have mitogenic and non-mitogenic effects on virtually all mesoderm and neuroectoderm derived cells in vitro .
  • HBFGs are also known to promote the migration, proliferation and differentiation of these cells in vivo. It was suggested by Lobb (1988, Eur. J. Clin. Invest., 18:321-328) that HBGFs coul therefore effect the repair of soft tissue. It was further suggested that HBGFs may be used to effect the repair of hard tissue such as bone and cartilage. In contrast to their beneficial effects, it is also known that growth factors may over-stimulate the wound healing response, resulting in the excessive smooth muscle cell proliferation and migration which occur, for example, in restenosis following angioplasty.
  • U.S. Patent 5,019,562 to Folk an et al. (the Folkma et al. patent) , which is in the lineage leading to the present application, is directed to the use of highly soluble cyclodextrin derivatives to treat undesirable cell or tissue growth.
  • the cyclodextrin derivatives disclosed in this patent are combined with growth inhibiting steroids or administered alone to absorb growth factors present in the blood stream.
  • Th cyclodextrin derivatives disclosed in the Folkman et al. patent are highly hydrophilic and therefore highly soluble.
  • the high solubility of these derivatives is said to be an important factor which cooperatively interacts with the inherent complexing ability of the cyclodextrin structure for exogenous steroids.
  • the high solubility of these compounds is said to facilitate introduction of the compounds into the body and to aid in dispersal via the blood stream.
  • a compound possessing both a high affinity for growth factor and a low solubility can be used to remain at the site of an injury and to absorb at least some portion of the growth factors released by the injured tissue, thereby reducing the probability of over-stimulation of the wound healing process, as is observed in restenosis following angioplasty.
  • compositions which regulate the concentration and/or diffusion of growth.factors in the area of a wound so as to optimize the wound healing process. Accordingly, the present invention provides low solubility polyanionic saccharide derivatives having a high negative charge density for affecting the growth of living tissue in mammals. Also provided are compositions comprising active agent comprising low solubility polyanionic saccharide derivative and a physiologically acceptable carrier for the saccharide derivative.
  • the saccharide derivative preferably has a body temperature solubility of less than about 15 grams per 100 ml water. According to certain preferred embodiments, the saccharide derivatives have substantially no solubility in wat at body temperature.
  • body temperature refers to the range of body temperatures expected for a living mammal, including the lowered body temperatures used in variou surgical techniques and the elevated body temperatures encountered in physiological responses to infection. Unless otherwise indicated, solubility refers to solubility in distilled water.
  • compositions of the present invention offer a number of advantages over prior art compositions due, at least in part, to the low solubility of the active ingredient in body tissues and fluid.
  • the low solubility of the present saccharid derivatives is advantageous in wound healing methods which provide for administration directly to the site of a wound. Th compositions remain substantially at the administered location for an extended period of time.
  • the saccharide derivatives of the present invention facilitate controlled release of the growth factors at the woun site, thereby regulating and greatly enhancing the wound healin process.
  • the present compositions can, by virtue of their affinity for growth factors, reduce the local concentration and/or diffusion of growth factors produced by cells at the wound site as well as growth factors present in the blood stream.
  • compositions are capable of preventing or substantially reducing over-stimulation of the wound healing response, thereby avoiding the pathological grow of cells that results in such conditions as restenosis followi angioplasty, vein graft inti al hyperplasia, and native vessel atherosclerosis.
  • the present invention also provides methods for the preparation of beneficial wound healing compositions.
  • These compositions comprise relatively insoluble solid forms of highl anionic polysaccharides.
  • the method aspects comprise reacting saccharide with an anionic derivatizing agent to generate a polyanionic derivative of the saccharide, followed by salt formation of the largely insoluble product.
  • saccharides are reacted with a suitable coupling agent to generate a sparsely soluble polymer or copolymer of that saccharide, followed by a reaction with an anionic derivatizing agent.
  • these derivatized saccharides are then combined with one or more growth factors.
  • the compositions provided by these methods of preparation have the advantageous properties of very low solubility and high growth factor affinity.
  • the present invention also provides wound healing methods. According to these methods, the present low solubility, polyanionic saccharide derivatives are applied to the area to be treated. Such methods are adaptable for use in the prevention of restenosis, promotion of angiogenesis, treatment of transplanted tissue or organs and treatment of damaged or transplanted bone or cartilage.
  • PCTA percutaneous transluminal angioplasty
  • compositions of the present invention may include growth factors to promote angiogenesis at the site of the infarcted tissue.
  • FIG. 1 (A and B) is a schematic representation of (A the chemical structure of ⁇ -, ⁇ - and ⁇ -cyclodextrin monomer; a (B) of the three-dimensional shape of these cyclodextrin monomers.
  • FIG. 2 is a schematic representation of the chemical structure of sucrose with the sites of anionic substituent groups indicated.
  • FIG. 3 shows the affinity of beta-cyclodextrin tetradecasulfate polymer for basic fibroblast growth factor.
  • FIG. 4 shows polyacrylamide gel electrophoresis of basic fibroblast growth factor and Chrondosarcoma-derived grow factor purified by cyclodextrin copper biaffinity chromatography.
  • Lane 1 shows the protein profile of the protei markers (phosphorylase b, bovine serum albumin, ovalbumin, carbonic anhydras ,soybean trypsin inhibitor, beta lactoglobulin, and lysozyme) .
  • Lanes 2 and 3 show the 18,000 molecular weight polypeptide bands of basic fibroblast growth factor and Chrondosarcoma derived growth factor, respectively.
  • FIG. 5 compares the affinities of heparin and beta- cyclodextrin tetradecasulfate polymer for Chrondosarcoma deriv growth factor.
  • the invention is directed to compounds, compositions and methods for affecting the growth of living tissue in mammals.
  • the novel compounds of the present invention are derivatized cyclodextrin polymers having low solubility in distilled water at body temperature and a high negative charge density.
  • the present compositions comprise a low solubility, polyanionic saccharide derivative having a relatively high density of anionic substituents and a carrier for such derivative.
  • One important aspect of the present compounds and compositions is the strong affinity of such materials for proteinic growth factors. Although applicants do not intend to necessarily be bound by or limited to any particular theory, it is thought that the density of the anionic groups on the saccharide compounds of the present invention is important in providing the high affinity of these compounds for tissue and growth factors.
  • the affinity o the present compounds and compositions for growth factors combined with the low solubility of the present saccharide derivatives provides the ability to regulate and control the concentration of growth factors in the area of a wound.
  • the present compounds and compositions provide active agents in the form of the present derivatized saccharides which tend to adhere to living tissue.
  • Such compositi and compounds have the highly desirable ability to provide active wound healing agents at the site of an injury for extended periods of time.
  • the invention is also directed to methods for preparing these compositions and to methods for treating a variety of wounds resulting from accidents or surgical procedures. As the term is used herein, "wound healing" refe to the repair or reconstruction of cellular tissue.
  • the woun may be the result of accident, such as injury or burns.
  • the wounds treatable by the present compositions and methods also include wounds resulting from surgical procedures of any type, from minor intrusive procedures, such as catheterization or angioplasty resulting in wounding of vascular or organ surfac to major surgical procedures, such as bypass or organ transpla operations. Included in this concept of wound healing is the repair of injured or fragmented bone or cartilage and the promotion of the establishment of bone grafts or implants.
  • compositions comprising a an active agent polyanionic saccharide derivatives having a hi negative charge density and low solubility can be useful wound healing materials.
  • polyanionic cyclodextrin polymers are especially preferred.
  • polyanionic saccharide derivative refers broadly to saccharide based compounds havin 1.3 or more anionic substituents per sugar unit.
  • sug unit refers to an elementary monosaccharide building block which may, for example, be a hexose or pentose.
  • Exemplary monosaccharides are glucose, fructose, amylose, etc. It is contemplated that all compounds which include a basic saccharide structure, as well as homologues, analogues and isomers of such compounds, are within the scope of the term "saccharide” as used herein.
  • the saccharide compounds hereof may comprise, for example, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides and polymers of such saccharides.
  • oligosaccharide refers to saccharides of from about 5 to about 10 sugar units having molecular weights, when unsubstituted, from about 650 to about 1300.
  • polysaccharide refers to saccharides comprising greater than about 10 sugar units per molecule. Polysaccharides are understood to be saccharides having many sugar units possessing a variety of structures and various substituent groups.
  • polymer as used herein refers to structures of repeated and similar saccharide compounds, based on monomers which are linked together to form the polymer.
  • the relationship between the structure of the derivatized saccharide and the level of negative charge density can influence the effectiveness of the present compounds, compositions and methods.
  • the anionic substituents are preferably present in the molecule to an extent of from, on average, about 1.0 to about 4 substituents per sugar unit.
  • Especially preferred compounds are those based on saccharides having on average at least about 1.4 anionic substituents per sugar unit.
  • the anionic substituents on the derivatized saccharide correspond substantially to about the following:
  • anionic substituents of the present invention may be selected from a large group of known and available anionic substituents, it is generally preferred that the anionic substituents be selected from the group consisting of sulfate, carboxylate, phosphate. sulfonate, and combinations of two or more of these.
  • Preferred compositions are based on saccharides having 6 or more sugar units and from about 2 to about 3 substituents per sugar unit, wherein the substituents comprise sulfate, sulfonate and/or phosphate substituents.
  • the saccharide derivatives of the present invention have a low solubility in distilled water at body temperature.
  • low solubility refers to solubility of much less than about 15 grams per 100 ml of water. It refers to the ability of the present saccharide compounds to remain localized in a solid state for a substantial length of time in an aqueous medium such as physiological or distilled water.
  • the saccharide derivatives have substantially no solubility in distilled water at body temperature. That is, it is preferred that the solubility of the saccharide derivative is much less than about 1 gram per 100 ml of distilled water, and even more preferably less than about 1 milligram per 100 ml.
  • Such insolubility is achieved, for example, by utilizing saccharide compositions comprising polymer aggregates or dispersions of substantially solid polymer particles. While it is contemplated that various particle sizes and shapes may be utilized, it is preferred that the particles have an average particle size ranging from about a millimicron to about 1000 microns in diameter. Expressed in terms of molecular weight, the polymers comprising the polymer have, on average, a molecular weight of about one billion or greater. The high molecular weight of the preferred polymers is due to the presence of many millions of sugar units within any of the discrete undissolved entities.
  • particles having the desired insolubility are produced by forming a salt comprising an anionic saccharide in combination or associated with a polyvalent cationic constituent.
  • compositions of the present invention may be produced from the soluble saccharides as starting materials, as indicated above, it is also possible to employ as starting materials a sparsely soluble, quasi solid or solid saccharides, such as cellulose or starch. Utilization of these saccharide sources preferably comprises chemically or enzymatically degrading the solid saccharide, followed by providing the substituent groups in accordance with this invention.
  • A. Cyclodextrin Derivatives Especially preferred according to the present invention are compositions containing a cyclodextrin derivative.
  • the cyclodextrins may be represented as a torus, as shown in FIG. 1(B) , the upper rim of which is lined with primary -CH 2 OH groups, and the lower rim with secondary hydroxyl groups.
  • Coaxially aligned with the torus is a channel-like cavity of about 5, 6 or 7.5 A.U. diameter for the ⁇ -, ⁇ -, and ⁇ -cyclodextrins, respectively. These cavities make the cyclodextrins capable of forming inclusion compounds with hydrophobic guest molecules of suitable diameters.
  • compositions of the present invention preferably include polyanionic cyclodextrin derivatives.
  • the terms "derivatized CD,” “CD derivative” and the like refer to chemically modified CDs formed by reaction of the primary or secondary hydroxyl groups attached to carbons 2,3 or 6 of the CD molecule without disturbing the ⁇ (1 ⁇ 4) hemiacetal linkages.
  • a review of such preparations is given in "Tetrahedron Report Number 147, Synthesis of Chemically Modified Cyclodextrins , " A. P. Croft and R. A. Bartsch, Tetrahedron 39 (9) :1417-1474 (1983), incorporated herein by reference in the background (hereinafter referred to as "Tetrahedron Report No. 147”) .
  • the CD derivatives are preferably derivatized cyclodextrin monomers, dimers, trimers, polymers or mixtures of these.
  • the cyclodextrin derivatives of the present invention are comprised of or formed from derivatized cyclodextrin monomeric units consisting of at least six glucopyranose units having ⁇ (1 ⁇ 4) hemiacetal linkages.
  • the preferred derivatized cyclodextrin monomers of the present invention generally have the formula (I) :
  • R groups per onomeric unit are anionic substituents and the remainder of said R groups, when present, are nonanionic groups selected from well known and available substituent groups.
  • the remaining, nonanionic R groups may be, for example, H, alkyl, aryl, ester, ether, thioester, thioether and -COOH.
  • Exemplary alkyl groups include methyl, ethyl, propyl and butyl.
  • the remaining nonanionic R groups may be hydrophilic, hydrophobic or a combination thereof, depending upon the particular requirements of the desired composition. However, it is generally preferred that the remaining nonionic R substituents be hydrophobic in order to minimize the solubility of the compounds.
  • CD monomers having the structure of Formula I wherein n is from about 6 to about 8 it is preferred that the compound have on average at least about 9 anionic R substituents per monomer unit, more preferably at least about 12 anionic R substituents per monomer, and even more preferably at least about 14 anionic R substituents per monomer.
  • the anionic substituents be relatively evenly distributed on the monomer molecule, and accordingly compounds having the structure of Formula I wherein n is from about 6 to about 8 preferably have from about 1 to about 3 anionic R substituents per n unit, more preferably from about 1.3 to about 2.5 anionic R substituents per n unit and even more preferably from about 1.4 to about 2.2 anionic R substituents per n unit.
  • Such structures are believed to provide the high negative charge density found to be therapeutically beneficial, with the highest charge density molecules providing excellent results.
  • the polyanionic cyclodextrin monomers of the type described above are important components of the preferred compositions of the present invention.
  • the monomeric units may be present in the composition in the form of, for example, insoluble polymeric or co-polymeric structures or as insoluble precipitated salts of derivatized cyclodextrin monomer, dimer o trimer.
  • Such salts may be formed by methods which comprise derivatizing the CD with anionic substituent and then complexing or associating the derivatized CD with an appropriate polyvalent cation to form an insoluble derivatized CD salt.
  • the basic monomeric structure identified above comprises the repeating unit of novel insoluble polymeric cyclodextrins, as described more fully hereinafter.
  • the present compositions comprise derivatized cyclodextrin polymers.
  • the present polymers have a structure corresponding to polymers formed from derivatized cyclodextrin monomers of the type illustrated above.
  • polymeric materials having such structure may be formed by a variety of methods.
  • derivatized cyclodextrin polymers may be produced by polymerizing and/or cross-linking one or more derivatized cyclodextrins monomers, dimers, trimers, etc. with polymerizing agents, e.g.
  • the derivatized cyclodextrin polymers may be produced by first polymerizing and/or cross-linking one or more underivatized cyclodextrin monomers, dimers, trimers, etc. (eg., cyclodextrins having the structure of Fig 1) and then derivatizing the resulting polymer with anionic substituents.
  • Underivatized cyclodextrin polymer is available from American Maize Products Co., Hammond, IN in the form of an epichlorhydrin linked polymer of jS-cyclodextrin. Underivatized commercially available polymers may be derivatized to produce the desired form of derivatized cyclodextrin polymer. The derivatized cyclodextrin polymers may also be formed by reacting mixtures of derivatized monomers and underivatized monomers, or by copolymerizing and/or crosslinking derivatized cyclodextrin polymers and underivatized cyclodextrin polymers.
  • the polymerization method employed result in a solid polymer product of sufficient porosity to allow diffusion penetration of molecules between the external solvent and a substantial portion of the internal anionic monomer sites.
  • the solubility of the present CD polymers will depend, inter alia, on the molecular weight and size of the polymer.
  • the present derivatized CD polymers are of large molecular weight so as to remain substantially in the solid state. They are solid particulates of generally about l to 300 micron size.
  • the derivatized cyclodextrin polymer of the present invention may be available in a variety of physical forms, and all such forms are within the scope of the present invention. Suitable forms include beads, fibers, resins or films. Many such polymers have the ability to swell in water.
  • the characteristics of the polymeric product, chemical composition, swelling and particle size distribution are controlled,at least in part, by varying the conditions of preparation.
  • the cyclodextrin polymer derivative preferably comprises a polyanionic derivative of an alpha-, beta-, or gamma-cyclodextrin polymer.
  • the anionic substituents are selected from the group consisting of sulfate, sulfonate, phosphate and combinations of two or more of the foregoing. Although it is possible that other anionic groups such as nitrate might possess some therapeutic capacity, the sulfate, sulfonate and phosphate derivatives are expected to possess the highest therapeutic potential. In preferred embodiments, at least about 10 molar percent of the anionic substituents, and even more preferably at least about 50 molar percent, are sulfate groups.
  • alpha-, beta-, and gamma-cyclodextrin polymers containing about 10-16 sulfate groups per cyclodextrin monomer, with beta-cyclodextrin tetradecasulfate polymer being especially preferred.
  • beta-cyclodextrin tetradecasulfate polymer being especially preferred.
  • compositions may include derivatized insoluble saccharide salt precipitates, and preferably derivatized insoluble oligosaccharide salt precipitates.
  • salt precipitate means a polyanionic saccharide derivative which has been associated or complexed with a suitable, non-toxic, physiologically acceptable cation to produce a salt which is substantially insoluble at body temperature.
  • Suitable polyvalent cations which may be used to produce an insoluble salt precipitate of the present invention include Mg, Al, Ca, La, Ce, Pb, and Ba. The cations herein listed are presented generally in order of decreasing solubility, although this order may be different for saccharides of different types and degrees of anionic substitution.
  • the derivatized oligosaccharides are preferred. Such oligosaccharides typically have unsubstituted molecular weights ranging from about 650 to about 1300. Oligosaccharides are usually obtained by procedures of degradation of starches or cellulose which result in oligosaccharide fragments in a broad range of sizes. Cyclodextrins are generally obtained from starches in the presence of specific enzymes that favor the formation of the cyclic saccharide structures.
  • the cyclodextrin salt precipitates are obtained by reacting the desired cyclodextrin monomer or monomers with agents that will produce the desired anionically substituted product and subsequently exchanging the cations which were introduced by the synthesis for cations of the desired polyvalent type. This latter step will result in precipitation of the insoluble saccharide salt precipitate.
  • the Al, Ca and Ba salts of ⁇ -, ⁇ - and 7-CD sulfate are preferred for use in the compositions of the present invention, with Al jS-CD sulfate salts being preferred in certain embodiments.
  • various degrees of sulfation per glucose unit can be employed. It is generally preferred, however, that the derivatized cyclodextrin salts have an average of at least about 1.3 sulfate groups per sugar unit, and even more preferably about two sulfate groups per sugar unit.
  • j ⁇ -CD-TDS which has an average of about two sulfate groups per glucose unit.
  • Sucralfate is an ⁇ -d-glucopyranoside, jS-d-fructofuranosyl-,octakis(hydrogen sulfate) aluminum complex. Sucralfate is used to treat ulcers and was developed during studies of sulfated polysaccharides that bind pepsins but lack anti-ulcer efficacy. The sulfation of sucrose and its conjugation with a basic aluminum salt resulted in a pepsin-inhibiting molecule suitable for treatment of ulcers. Denis M. McCarthy, Sucralfate, 325:14 New Eng. J. Med., 1017-1025 (1991).
  • sucralfate and other polyionic derivatives of sucrose have some properties in common with the derivatized cyclodextrins of the present invention and may provide similar solubility and affinity for growth factors. It is believed that sulfonate or phosphate derivatives of sucrose combined with polyvalent cations such as Mg, Al, Ca, La, Ce, Pb or Ba may result in compositions of low solubility which can be combined with growth factors to facilitate therapeutic delivery of these growth factors to the site of a wound. Oral administration of sucralfate has been described to have therapeutic usefulness in the treatment of stomach ulcers. According to the present invention, sucralfate and other salts of sucrose octasulfate may be used to deliver growth factor proteins to tissues or bone in need of repair, by prior complexing with growth factors, and delivering the complex physically to the site of repair.
  • Aluminum uptake is known or suspected to be associated with a number of diseases. See, for example, the extensive discussions in the books ALUMINUM AND HEALTH; A CRITICAL REVIEW (Hillel and Gitelman, Ed.), Mark Decker, Publisher, 1989 and ALUMINUM IN RENAL FAILURE, Mark E. de Broi and Jack W. Coburn, Klewer,
  • Aluminum is known to produce abnormalities in bone metabolism, such as osteodystrophy, osteomalacia, impaired mineralization, etc.
  • the introduction of aluminum into the blood stream, such as can occur in dialysis, can be particularly harmful.
  • oral administration of aluminum salts can also produce a variety of harmful effects including osteomalacia and osteitis; see, e.g., S.P. Andredi, J.M.
  • Alzheimer's disease particularly Alzheimer's disease, in which aluminum is suspected to play an important role, although by a mechanism not yet understood.
  • neural abnormalities particularly Alzheimer's disease, in which aluminum is suspected to play an important role, although by a mechanism not yet understood.
  • D.R. Crapper McLachlan, B.J. Farnell Aluminum in Neuronal Degeneration, in Metal Ions in Neurology and Psychiatry, pp. 69- 87, 1985, Alan R. Liss Inc.
  • D.P. Perl, P.F. Good Uptake of Aluminum into Central Nervous System Along Nasal-Ol factory Pathways, The Lancet, May 2, P. 1028, 1987; J.D. Birchall, J.S. Chappell, Aluminum, Chemical Physiology, and Alzheimer's Disease, The Lancet, October, P. 1008, 1988.
  • the non- aluminum salt forms of the highly sulfated polysaccharides are preferable over the aluminum salts forms in some and perhaps all therapeutic applications.
  • the polymeric embodiments which do not require salt precipitate formation are particularly preferred.
  • the compositions of the present invention are particularly useful for oral administration in the healing of stomach ulcers.
  • the non-aluminum salt-containing forms of sucrose octasulfate, and most preferably the polymeric solid form of highly sulfated cyclodextrin are especially advantageous because of the absence of aluminum and its side effects.
  • compositions of this invention may take numerous and varied forms, depending upon the particular circumstance of each application.
  • the derivatized saccharide may be incorporated into a solid pill or may in the form of a liquid dispersion or suspension.
  • the compositions of the present invention preferably comprise a derivatized saccharide and a suitable, non-toxic, physiologically acceptable carrier for the saccharide.
  • carrier refers broadly to materials which facilitate administration or use of the present compositions for wound healing.
  • a variety of non-toxic physiologically acceptable carriers may be used in forming these compositions, and it is generally preferred that these compositions be of physiologic salinity.
  • compositions of this invention may be incorporated in solid forms such as rods, needles, or sheets. They may thus be introduced at or near the sites of tissue damage or sites of implantation, or applied externally as wound dressings, etc.
  • the compositions and compounds of the present invention are preferably combined with a solid carrier which itself is bio- acceptable, or the compositions comprise suitably shaped polymer or co-polymer of the present saccharide derivatives.
  • compositions of the present invention are prepared in the form of an aqueous dispersion, suspension or paste which can be directly applied to the site of a wound.
  • a polyanionic saccharide derivative such as polyanionic cyclodextrin polymer
  • a fluid carrier such as saline water. This will be the case when the product, saccharide salt, saccharide polymer or the saccharide co-polymer has been synthesized such as to produce a particle form of precipitate, dispersion or suspension.
  • the solid derivative may also be dried, milled, or modified to a desired particle size or solid form.
  • the particle size can be optimized for the intended therapeutic use of the composition.
  • the solid particles range in size from about l micron to about 600 microns, with from about 200- 600 microns being even more preferred.
  • Particles ranging from about 1 to about 30 microns offer the best dispersion of growth factor and fast reactivity. For a given weight quantity of particles delivered to the biological environment, a smaller particle size assures exposure of greater particle surface area allowing greater diffusion of proteinic active ingredients into or out of the administered solid.
  • Particles ranging from about 30 to about 100 microns offer fair dispersion of growth factors, medium reactivity and a longer period of delivery of growth factor.
  • Particles possessing a size in excess of 100 microns will have low reactivity, but provide the longest delivery time for growth factors. In certain preferred embodiments, these large particles (>100 micron) will be used to absorb, rather than deliver growth factors in vivo .
  • the carrier is an aqueous medium and the compositions are prepared in the form of an aqueous suspension of solid particulate saccharide derivative.
  • the amount of the derivatized saccharide preferably ranges from about 1 to 30% by weight of the composition, and even more preferably from about 5 to about 15% by weight.
  • the compositions and compounds include and/or are combined with biologically active proteins.
  • the biologically active protein exhibits a specific affinity for heparin, and, more specifically, is heparin-binding growth factor, i.e., a class of growth factors, many of which are mitogenic for endothelial cells.
  • heparin-binding growth factor i.e., a class of growth factors, many of which are mitogenic for endothelial cells.
  • An example of such a growth factor is basic fibroblast growth factor.
  • HBGF's heparin-binding growth factor proteins, commonly referred to as HBGF's, which may be combined with the saccharide derivatives of the present invention.
  • a HBGF protein is one that remains substantially bound to heparin (e.g., using a derivatized column) even in the presence of an aqueous medium having a salt concentration of substantially greater than about 0.6 molar strength of NaCl.
  • substantially bound refers to at least about 80% of such bound protein remaining attached under such conditions.
  • IL-1 Interleukin-1
  • Henderson & Pettipher 1988, Biochem. Pharmacol. 37:4171;
  • FGF Fibroblast Folkman and Klagsbrun, 1987, growth factor, Science 235:442-447 acidic and basic
  • IGF-1 Insulin-like Blundell and Humbel, 1980, growth factor- Nature 287:781-787; Schoenle et 1) al., 1982, Nature 296:252-255 IGF-2 (Insulin-like Blundell and Humbel growth factor- 2)
  • TGF- ⁇ Transforming Cheifetz et al. , 1987, Cell growth factor- 48:409-416 ⁇
  • the proteinic growth factor complexing ability of the precipitates, polymers, or co-polymers of the compositions of the present invention may be determined using dye complexing assays.
  • the growth factor containing compositions derivatized saccharide is contacted with a solution containing a growth factor or combination of growth factors.
  • the cyclodextrin derivative is thereafter separated from the contact fluid, resulting in an enrichment of the growth factor on the cyclodextrin derivative, and a corresponding removal of the growth factor from the fluid.
  • the contacting solution may contain a single preseparated, preconcentrated growth factor purified from tissue or bodily fluids or growth factor obtained from recombinant DNA methods.
  • the contact solution may comprise viable tissue or organ materials (hereinafter organic sources) which contain a variety of growth factors.
  • organic sources When combined with tissue or organ material containing growth factors, the saccharide derivatives of the present invention may act as extractants of these growth factors.
  • organic sources are used as the source for growth factors, it is preferred that the organic source used for the contacting solution have a volume greater than about 10 to about 100 times the volume of the tissue to be treated by the combined derivative and growth factor(s) .
  • the solid phase After contacting the partially or wholly complexed saccharide derivative, the solid phase, can be easily separated from the fluid phase that was the source of protein to be complexed. It is preferable that the source of growth factor contains the protein as a dissolved component in the absence of solids other than the saccharides to be complexed. However, some solids in the growth factor source solution, may not necessarily be undesirable or disturbing contaminants. Separation of solids, such as tissue or organ fragments from the saccharides, may be accomplished by sedimentation, suitable filtering, centrifugation or other mechanical or other methods. II. METHODS FOR THERAPEUTIC REGULATION OF WOUND HEALING
  • One aspect of the present invention relates to methods for the therapeutic regulation, and preferably in vivo regulation, of wound healing, and particularly to in vivo regulation of the concentration and diffusion of protein factors.
  • Such methods generally comprise therapeutic biodelivery of the present compositions and compounds to the wound site.
  • the low solubility, i.e. the solid immobilized state, of the present materials allows the compositions and compounds to be administered directly to the site of a wound an for the active ingredients to remain at the site of application for an extended period of time.
  • Vascular cell proliferation and abnormal accumulation of extracellular matrix in the vessel wall are common pathological features observed in arteriosclerosis, hypertensio and diabetes. Such conditions are also observed following vascular injuries, such as angioplasty. Intimal hyperplasia is thought to be mediated in part by a variety of growth factors, such as platelet derived growth factor (PDGF) , acting through receptors to stimulate vascular smooth muscle cell proliferatio and migration from the media into the intima.
  • PDGF platelet derived growth factor
  • PDGF platelet derived growth factor
  • applicants have discovered methods for regulating migration and proliferation of the smooth muscle cells, thereby affecting the degree of intimal thickening noted after vascular injury.
  • /3-cyclodextrin tetradecasulfate can inhibit human vascular smooth muscle cell proliferation and migration in vitro when stimulated with fetal calf serum, which contains potent growth factor activity.
  • the present compositions and compounds can be used to beneficially regulate and control biologically active proteins, such as growth factor, at the site of a wound.
  • biologically active proteins such as growth factor
  • the present compounds and compositions when the present compounds and compositions are combined with growth factors prior to biodelivery as described herein, the compositions and compounds slowly release this growth factor into the immediate vicinity of the wound, thereby accelerating the wound healing process.
  • all growth factors known to accelerate or facilitate wound healing are usable in the present compositions and methods. Growth factors suitable for this acceleration of wound healing include those listed in Table I, as well as brain endothelial cell growth factor and retina-derived growth factor.
  • heparin binding growth factors can be used to effect the repair of both soft and hard tissue. The potential uses for interferons, interleukins, and tissue growth factors are well known in the art.
  • the invention also relates to methods for the therapeutic administration of polyanionic saccharide derivatives, or complexes thereof, with a protein factor, wherein the saccharide derivative is combined with or comprises a portion of a biocompatible porous solid.
  • biocompatible porous solid as used herein means a solid which may be applied or administered to a mammal without provoking a substantial inflammatory response or other substantial adverse effect.
  • biocompatible porous solids include membranes such as collagen-based polymeric membranes, amniotic membranes, and amentum membranes (reviewed in Cobb, 1988, Eur. J. Clin. Investig. 18:321-326).
  • Biocompatible porous solids may also include polymers of ethylene vinyl acetate, methylcellulose, silicone rubber, polyurethane rubber, polyvinyl chloride, polymethylacrylate, polyhydroxyethylacrylate, polyethylene terephthalate, polypropylene, polytetrafluoroethylene, polyethylene, polyfluoroethylene, propylene, cellulose acetate, cellulose and polyvinyl alcohol (reviewed in Hoffman, Synthetic Polymeric Biomaterials in
  • the cyclodextrin starting materials are co-polymerized with monomers of the biocompatible polymer material of the final product composition, so as to create a porous co-polymer.
  • This co- polymer is subsequently reacted chemically to provide the saccharide portion with the anionic substituents required by this invention.
  • Cyclodextrins can be coupled with reactive groups, such as amine, amide, carboxylate end groups, etc. , contained in the biocompatible polymer and then subsequently derivatized with ionic substituents.
  • the polysaccharide such as a cyclodextrin is introduced as a co- reagent in a monomer formulation to be polymerized to a solid polymer or co-polymer, and the product is contacted subsequently with suitable agents to derivatize the saccharide component to add anionic substituents to the degree taught by this invention.
  • suitable agents to derivatize the saccharide component to add anionic substituents to the degree taught by this invention.
  • Particularly advantageous for such process and products are those methods that will produce a polymer or co-polymer example of a flat polymer product of polyamide polymer, manufactured by 3M Corporation, and used as a bio-compatible patch or dressing on wounds. This biocompatible patch or dressing is designed to physically protect a wound from invasion of pathogens, and yet to have sufficient porosity to allow passage of moisture, air, etc.
  • Applicants' invention contemplates the coupling of the active polyanionic polysaccharide with a carrier comprising such polymer, or, the coupling of the active anionic saccharide and a proteinic factor together with a polymeric carrier.
  • a carrier comprising such polymer
  • Such combination is designed expressly for applications of deliberate promotion or inhibition of cellular growth processes.
  • the HBGFs bind to the immobilized, derivatized saccharide-based molecules, either incorporated into or already present in biomembranes.
  • Biological membranes such as omentum and amnion are well known in the art as wound dressings. Collagen based synthetic biomembranes are being used in the treatment of burns.
  • Arteriosclerosis is a disorder involving thickening and hardening of the wall portions of the larger arteries of mammals, and is largely responsible for coronary artery disease, aortic aneurisms and arterial diseases of the lower extremities. Arteriosclerosis also plays a major role in cerebral vascular disease.
  • Angioplasty has heretofore been a widely used method for treating arteriosclerosis.
  • percutaneous transluminal coronary angioplasty hereinafter "PTCA" was performed over 200,000 times in the United States alone during 1988.
  • PTCA procedures involve inserting a deflated balloon catheter through the skin and into the vessel or artery containing the stenosis. The catheter is then passed through the lumen of the vessel until it reaches the stenotic region, which is characterized by a build up of fatty streaks, fibrous plaques and complicated lesions on the vessel wall, which result in a narrowing of the vessel and blood flow restriction.
  • the balloon is inflated, thus flattening the plaque against the arterial wall and otherwise expanding the arterial lumen.
  • restenosis This thickening of the cell wall and narrowing of the lumen following treatment of arteriosclerosis is referred to herein as restenosis.
  • restenosis is due in part to the presence of growth factors produced by injured endothelium which activate excessive proliferation of the smooth muscle cells which are exposed to the endothelial injury.
  • the present saccharide derivatives when substantially free of growth factors prior to biodelivery, are extremely effective for preventing or at least substantially reducing intimal thickening following balloon angioplasty.
  • such compositions can provide an in vivo absorption or reduction of the local concentration and/or diffusion of such growth factors. That is, such wound site growth factors, whether they are produced by the cells at the wound site or are otherwise in the bloodstream, can be taken up by the present saccharide derivatives, thereby reducing the restenoic effect of such materials on the wounded tissue.
  • mammals including humans, which have arterial regions subject to angioplasty, are treated by administering to the mammal a polyanionic saccharide derivative of the present invention in an amount effective to inhibit arterial smooth muscle cell proliferation.
  • the degree of restenosis inhibition may vary within the scope hereof, depending upon such factors as the patient being treated and the extent of arterial injury during angioplasty.
  • the saccharide derivative be administered in an amount effective to cause a substantial reduction in restenosis.
  • substantial reduction in restenosis means a post treatment restenosis value of no greater than about 50%.
  • the post treatment restenosis value is no greater than about 25%.
  • post-treatment restenosis value refers to the restenosis value measured at about one month after angioplasty.
  • restenosis value refers to the restenosis rate calculated as a loss of greater than or equal to 50% of the initial gain in minimum lumen diameter achieved by angioplasty.
  • the present invention contemplates a method of inhibiting restenosis in a patient which comprises administering to the patient an amount of a saccharide-based derivative effective to inhibit formation of a restenotic lesion in a patient who has undergone angioplasty. It is contemplated that the saccharide derivative may be administered before, during and/or after angioplasty treatment of the stenosed artery.
  • the administration comprise administering the compound locally at the wound site.
  • local administration comprises infusing the saccharide derivative directly into the injured tissue.
  • such step preferably comprises infusing the compound directly into the arterial wall at the site of the angioplasty.
  • a preferred administration step comprises infusing an aqueous suspension or dispersion of saccharide derivative directly into the arterial wall at the site of balloon angioplasty.
  • This is preferably accomplished using a modified infusion balloon catheter having a plurality of holes in the wall of the balloon portion of the catheter. These holes are configured and sized to allow the balloon to be both inflated and to leak the inflation solution through the wall of the balloon.
  • the balloon is inflated under relatively low pressure conditions, such as 2 - 3 atmospheres.
  • porous balloon catheters which may be used to apply the compositions of the present invention are made by U.S.C.I.- Bard and Schneider. Balloons of this type are referred to as Wolinsky balloons or "sweating balloons.” It is anticipated that a variety of infusion angioplasty balloon catheters may be used for application of the compositions of the present invention and that one skilled in the art would be readily able to determine which types of balloon infusion catheters would be appropriate.
  • Another technique which involves the local administration of the saccharide derivatives of the present invention utilizes bioabsorbable intravascular stents.
  • the saccharides of the present invention may be incorporated into a bioabsorable stent and that stent positioned at or near the site of tissue damage. It will be appreciated by those skilled in the art that the particular characteristics and properties of the suspension containing the saccharide derivative may vary widely depending upon numerous factors not necessarily related to the present invention.
  • the administration step preferably comprises infusing an aqueous suspension or dispersion of polyanionic saccharide derivate particles, and preferably a suspension of sulfated beta-cyclodextrin polymer particles, ranging in size from about 1 to 600 microns directly into the arterial wall at the site of balloon angioplasty.
  • the aqueous suspension comprises a aqueous carrier of physiological salinity and an active saccharide derivative.
  • the active saccharide derivative is preferably present in an amount ranging from about 1 to about 30% by weight, and even more preferably from about 5 to about 15% by weight of the composition.
  • derivatized saccharides, and preferably cyclodextrin sulfate polymer particles are applied at about the time of angioplasty.
  • angiogenesis it may be desirable to prevent restenosis but allow angiogenesis.
  • sucralfate an aluminum salt of sucrose octasulfate available from the Marian Merrill Dow Company, Kansas City, MO.
  • Venous segments are frequently harvested at the time of surgery and used as bypass grafts to treat vascular occlusive disorders. Specifically, they have been used in the coronary, renal, femoral and popliteal arterial circulations, by way of example.
  • intimal thickening occurs which compromises the luminal cross- sectional area and results in reduced flow. This frequently, but not exclusively occurs at the anastomosis.
  • Angiogenesis is the formation of new blood vessels.
  • Angiogenic stimuli cause the elongation and proliferation of endothelial cells and the generation of new blood vessels.
  • a number of the HBGFs are known to promote angiogenesis.
  • the new blood vessels produced by angiogenesis result in neovascularization of tissue.
  • a deficiency of this kind may be due to the functional constriction or actual obstruction of a blood vessel.
  • These diseases can be grouped into cardiac, cerebral and peripheral ischemic diseases.
  • Cardiac ischaemia may result in chronic angina or acute myocardial infarction.
  • Cerebral ischaemia may result in a stroke.
  • Peripheral ischaemia may result in a number of diseases including arterial embolism and frostbite.
  • necrosis of the tissues supplied by the occluded blood vessels necessitates amputation.
  • an alternative blood supply to the affected tissue must be established.
  • angiogenesis is promoted by first contacting a saccharide derivative of the present invention with growth factor(s) and then administering the composition locally to the location of the ischemic tissue, by hypodermic injection for example, to promote angiogenesis and the formation of collateral blood vessels.
  • collateral blood vessels are blood vessels which are absent under normal physiological conditions but develop in response to appropriate stimuli, such as the presence of HBGFs. It is anticipated that administration of compositions which include saccharide derivative and growth factor will result in the formation of collateral blood vessels and revascularization of ischemic tissue.
  • angiogenesis is promoted by methods in which the saccharide derivative comprises a highly anionic cyclodextrin derivative or a salt form of same, and even more preferably a polysulfated polymer or copolymer of a cyclodextrin. It is preferred that the cyclodextrin derivative be combined with basic fibroblast growth factor at a cyclodextrin:basic fibroblast growth factor weight ratio of from about 10:1 to 100:1.
  • HBGFs are known to stimulate neovascularization and endothelial cell growth.
  • the graft represents a wound, and success of the grafting procedure depends critically on the rapidity of establishing an adequate blood supply to the grafted or transplanted tissue.
  • the growth factor-containing compositions may be coated on the surfaces to be joined, sprayed on the surfaces, or applied in the form of an aqueous suspension with or without viscosity enhancers such as glycerol.
  • the organ or tissue to be grafted or transplanted may be presoaked in a treating solution containing the compositions of the present invention, prior to transplantation.
  • the compositions of the present invention may also be injected into the transplant site or surface of both items to be joined.
  • the saccharide derivatives of the present invention are precontacte with growth factor containing organic sources (e.g., tissue or organ debris, ground matter, or liquid extract) so as to extract the growth factors present in these sources.
  • organic sources e.g., tissue or organ debris, ground matter, or liquid extract
  • the organic source used for contact is about 10 to about 100 times greater in volume than the transplanted or grafted tissue to be treated by the composition.
  • a more direct and often more economic method will involve contacting the saccharide derivatives of the present invention with growth factor substances created by recombinant biochemical and biotechnological procedures. In this manner specific growth factor proteins are more readily chosen for a contemplated therapeutic application.
  • HBGFs can induce neovascularization and the proliferation of bone forming cells. It is therefore contemplated to use the present compounds in combination with growth factor for the purposes of aiding the healing of bone fractures, the joining of implanted and host bone, and the mineralization of bone (where such is intended) .
  • the present saccharide derivatives are combined with growth factors and powdered bone substance and/or finely dispersed demineralized bone matter to form a paste.
  • the bone tissue used to produce the paste may be obtained from iliac crest or calvarium. It is preferred to use autogenous bone for implant purposes and to use partially demineralized bone over fully demineralized bone powder. Demineralized bone powder obtained from allogenic and xenogeneic sources may be used in preparing the bone powder. To make a soft paste absorbable cellulose cotton or similar material may be used.
  • the bone paste produced by these methods functions as an induction matrix from which new bone will form after being invaded with a network of blood vessels.
  • the paste is applied to the surfaces of bone to be joined in implant procedures or used to fill fractures of contour bone to be repaired.
  • the control of blood vessel growth is an important aspect of normal and of pathological states encountered in dermatology.
  • the abnormal growth of cellular materials and vessels accompanies several pathological sates, psoriasis being one prominent example.
  • excesses of growth stimulating protein factors are involved.
  • Abnormalities of this type are often associated with imbalances 5 in proteinic growth factors.
  • extracts from involved skin had 15-fold higher levels of chymotryptic activity than extracts of uninvolved ski or from control samples of patients without such deficiency.
  • epidermal plasminogen activator Another example of a growth promoting factor involved in dermal abnormalcies is epidermal plasminogen activator, which 0 is elevated in a variety of dermal pathologies (See Epidermal Plasminogen Activator is Abnormal in Cutaneous Lesions ' , P. J. Jensen et al., J. Invest. Dermat. 90-777-782, 1988).
  • Certain embodiments of this invention namely highly sulfated solid dispersions or other physical variants of highly 5 sulfated polysaccharides, and preferably those comprising cyclodextrin structures, are particularly amenable to dermal therapy in those cases where excess growth of cellular components is involved.
  • the agents of the present invention can be introduced at or near the tissue involved. 0 This may be accomplished by cutaneous or sub-cutaneous injection of fine particle dispersion of the agent, or the implantation of solid polymer shapes suitably shaped for effective contact, or the agent may be comprised in material such as patches, or other suitable forms of externally applied materials containing agents of the invention.
  • the mixture was stirred vigorously for 4 hours and then poured into about 4000 ml of ethanol. After standing overnight, the mixture was filtered to recover the crystallized solids. The filter cake was washed with ethanol (absolute) followed by diethyl ether. The product was then dried under vacuum over P 2 0 5 . About 10.3 grams of white powder was recovered. The product was hygroscopic.
  • Rat chondrosarcoma-derived growth factor was isolated from the transplantable tumor as previously described (Shing et al., 1984, Science 223:1296-1298). About one hundred 15 ml of the crude extract prepared by collagenase digestion of the tumor was diluted (1:1) with about 0.6 M NaCl in about 10 mM Tris, pH 7 and loaded directed onto a heparin-Sepharose ® column (1.5 x 9 cm) pre-equilibrated with the same buffer. The column was rinsed with about 100 ml of about 0.6 M NaCl in about 10 mM 0 Tris, pH 7. ChDGF was subsequently eluted with about 18 ml of about 2 M NaCl in about 10 mM Tris, pH7.
  • EXAMPLE 4 BETA-CYCLODEXTRIN AFFINITY CHROMATOGRAPHY OF FGF
  • the insoluble sulfated beta-cyclodextrin polymer 5 (about 0.5 ml bed volume), was incubated with about 0.5 ml of about 0.1 M NaCl, about 10 mM Tris, about pH 7 containing about 1,000 units of human recombinant bFGF at about 4°C for about 1 hour with mixing. Subsequently, the polymer was rinsed stepwise with about 2 ml each of about 0.1, 0.6, and 2 M NaCl in about 10 0 mM Tris, pH 7. All fractions eluted from the polymer were assayed for growth factor activity.
  • EXAMPLE 5 GROWTH FACTOR ASSAY Growth factor activity was assessed by measuring the incorporation of [ 3 H]thymidine into the DNA of quiescent, confluent monolayers of BALB/c mouse 3T3 cells in 96-well plates. One unit of activity was defined as the amount of growth factor required to stimulate half-maximal DNA synthesis in 3T3 cells (about 10,000 cells/0.25 ml of growth medium/well) .
  • protein concentrations of the crude extract and the active fraction eluted from heparin-Sepharose column were determined by the method of Lowry et al. (1952, J. Biol. Chem. 193:265-275). Protein concentrations of the pure growth factor were estimated by comparing the intensities of silver-stained polypeptide bands of
  • Human recombinant bFGF (about 1000 units) was incubated with sulfated beta-cyclodextrin polymer. The polymer was subsequently eluted stepwise with about 0.1 M, 0.6 M, and 2 M NaCl. The results are shown in Figure 3.
  • Chondrosarcoma extracts which contained about 500 units of growth factor activity were incubated individually with heparin-Sepharose ® and beta-cyclodextrin tetradecasulfate polymer. The beads were subsequently eluted stepwise with about 0.1 M, 0.6 H, and about 2 M NaCl. The results are shown in Figure 5. Approximately 32% and 68% of the total activity was recovered at 2 M NaCl with heparin Sepharose ® and beta- cyclodextrin tetradecasulfate polymer, respectively.

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PCT/US1992/009754 1991-11-11 1992-11-10 Methods of inhibiting restenosis WO1993009790A1 (en)

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BR9206736A BR9206736A (pt) 1991-11-11 1992-11-10 Composição para afetar o crescimento de tecido vivo em mamíferos processos para promover a angiogenese em mamíferos para tratar tecido transplantado ou órgãos em mamíferos e para tratar osso danificado ou transplantado
AU30742/92A AU678760B2 (en) 1991-11-11 1992-11-10 Methods of inhibiting restenosis
JP5509395A JPH07500843A (ja) 1991-11-11 1992-11-10 再狭窄を抑制する方法
EP92924424A EP0612249A4 (en) 1991-11-11 1992-11-10 Methods of inhibiting restenosis.
FI942166A FI942166A (sv) 1991-11-11 1994-05-10 Förfarande för inhibering restenos
NO941738A NO941738L (no) 1991-11-11 1994-05-10 Fremgangsmåte for inhibering av restenose

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IL10002391A IL100023A (en) 1991-11-11 1991-11-11 Pharmaceutical composition comprising a cyclodextrin derivative for the inhibition of undesired smooth muscle cell growth following angioplasty
IL100023 1991-11-11
US79032091A 1991-11-12 1991-11-12
US07/790,320 1991-11-12
US90059292A 1992-06-18 1992-06-18
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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0589578A2 (en) * 1992-09-24 1994-03-30 Terumo Kabushiki Kaisha Sulfonated compounds of beta-cyclodextrin polymer and inhibitory drug for vascular wall hyperplasia containing the same
WO1995007097A1 (en) * 1993-09-08 1995-03-16 Genentech, Inc. Inhibition of heparin-binding
US5464827A (en) * 1994-06-20 1995-11-07 American Home Products Corporation Esterified polyanionic cyclodextrins as smooth muscle cell proliferation inhibitors
US5498775A (en) * 1994-11-07 1996-03-12 American Home Products Corporation Polyanionic benzylglycosides as inhibitors of smooth muscle cell proliferation
US5545569A (en) * 1993-05-13 1996-08-13 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US5565432A (en) * 1994-11-07 1996-10-15 American Home Products Corporation Smooth muscle cell proliferation inhibitors
US5773420A (en) * 1994-11-07 1998-06-30 American Home Products Corporation Acylated benzylglycosides as inhibitors of smooth muscle cell proliferation
EP0954326A1 (en) * 1996-04-19 1999-11-10 Alpha Therapeutic Corporation A process for viral inactivation of lyophilized blood proteins
US6171609B1 (en) 1995-02-15 2001-01-09 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US6187755B1 (en) 1998-11-24 2001-02-13 American Home Products Corporation Benzylmaltosides as inhibitors of smooth muscle cell proliferation
US6258784B1 (en) 1998-11-24 2001-07-10 American Home Products Corp. Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
US6291434B1 (en) 1998-11-24 2001-09-18 American Home Products Corp. Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation
US6339064B1 (en) 1998-11-24 2002-01-15 American Home Products Corporation Benzylglycosylamides as inhibitors of smooth muscle cell proliferation
FR2811572A1 (fr) * 2000-07-17 2002-01-18 Adir Utilisation de cyclodextrines polysulfatees pour le traitement de l'arthrose
US6340670B1 (en) 1998-11-24 2002-01-22 American Home Products Corporation Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
US6362170B1 (en) 1998-11-24 2002-03-26 American Home Products Corporation Benzylglycosylamides as inhibitors of smooth muscle cell proliferation
US6451767B1 (en) 1998-11-24 2002-09-17 Wyeth Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation
FR2827799A1 (fr) * 2001-07-27 2003-01-31 Sofradim Production Endoprothese vasculaire recouverte d'un derive fonctionnalise de dextrane et son procede de preparation
US6638916B1 (en) 1997-09-01 2003-10-28 The Australian National University Use of sulfated oligosaccharides as inhibitors of cardiovascular disease
US6664243B1 (en) 1998-11-24 2003-12-16 Wyeth Benzyllactobionamides as inhibitors of smooth muscle cell proliferation
US7081448B2 (en) 1998-11-24 2006-07-25 Wyeth Benzyllactobionamides as inhibitors of smooth muscle cell proliferation
US7132402B2 (en) 1998-11-24 2006-11-07 Wyeth Acylated benzylmaltosides as inhibitors of smooth muscle cell proliferation
FR2923391A1 (fr) * 2007-11-08 2009-05-15 Biocydex Soc Par Actions Simpl Compositions pour conserver des cellules, des tissus ou des organes, procede d'obtention et utilisations.
WO2010031876A1 (en) * 2008-09-22 2010-03-25 Universiteit Gent Carboxyethylated cyclodextrin polysulfates useful as medicaments
US9498488B2 (en) 2003-06-27 2016-11-22 Biorest Ltd. Method of treating acute coronary syndromes
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL125336A0 (en) * 1998-07-14 1999-03-12 Yissum Res Dev Co Compositions for inhibition and treatment of restinosis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4020160A (en) * 1975-08-15 1977-04-26 American Cyanamid Company Cyclodextrin sulfate salts as complement inhibitors
WO1987005808A1 (en) * 1986-04-04 1987-10-08 Larrian Gillespie Composition for arresting angiogenesis and capillary, cell or membrane leakage
EP0325199A2 (en) * 1988-01-19 1989-07-26 Takeda Chemical Industries, Ltd. Fumagillin as angiostatic agent

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5019562A (en) * 1988-01-19 1991-05-28 The Trustees Of The University Of Pennsylvania/Childrens Hospital Corporation Growth inhibiting agent and the use thereof
AU614137B2 (en) * 1988-06-06 1991-08-22 Takeda Chemical Industries Ltd. Stabilized fgf composition and production thereof
US4990610A (en) * 1988-08-25 1991-02-05 Applied Analytical Industries, Inc. Method for preparing high potency sucralfate
US5482929A (en) * 1991-12-26 1996-01-09 Kaken Pharmaceutical Co., Ltd. Composition of stabilized fibroblast growth factor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4020160A (en) * 1975-08-15 1977-04-26 American Cyanamid Company Cyclodextrin sulfate salts as complement inhibitors
WO1987005808A1 (en) * 1986-04-04 1987-10-08 Larrian Gillespie Composition for arresting angiogenesis and capillary, cell or membrane leakage
EP0325199A2 (en) * 1988-01-19 1989-07-26 Takeda Chemical Industries, Ltd. Fumagillin as angiostatic agent

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Science, Vol. 230, issued 20 December 1985, R. CRUM, "A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment", pages 1376-1378, entire document. *
Science, Vol. 243, issued 17 March 1989, J. FOLKMAN et al., "Control of Angiogenesis with Synthetic Heparin Substitutes", pages 1490-1493, entire document. *
See also references of EP0612249A4 *

Cited By (46)

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EP0589578A2 (en) * 1992-09-24 1994-03-30 Terumo Kabushiki Kaisha Sulfonated compounds of beta-cyclodextrin polymer and inhibitory drug for vascular wall hyperplasia containing the same
EP0589578A3 (en) * 1992-09-24 1995-01-18 Terumo Corp Sulphonated compounds from beta-cyclodextrin polymer and medication containing them which inhibits the hyperplasia of the walls of the vessels.
US5512665A (en) * 1992-09-24 1996-04-30 Terumo Kabushiki Kaisha Sulfonated compounds of β-cyclodextrin polymer and inhibitory drug for vascular wall hyperplasia containing the same
US5545569A (en) * 1993-05-13 1996-08-13 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US5464815A (en) * 1993-09-08 1995-11-07 Genentech, Inc. Inhibition of heparin-binding
WO1995007097A1 (en) * 1993-09-08 1995-03-16 Genentech, Inc. Inhibition of heparin-binding
US5849689A (en) * 1993-09-08 1998-12-15 Genentech, Inc. Method of extending the plasma half-life of deletion variants of hepatocyte growth factor
US5851989A (en) * 1993-09-08 1998-12-22 Genentech, Inc. Method of extending the plasma half-life of vascular endothelial cell growth factor
WO1995035322A1 (en) * 1994-06-20 1995-12-28 American Home Products Corporation Esterified polyanionic cyclodextrins as smooth muscle cell proliferation inhibitors
US5464827A (en) * 1994-06-20 1995-11-07 American Home Products Corporation Esterified polyanionic cyclodextrins as smooth muscle cell proliferation inhibitors
US5498775A (en) * 1994-11-07 1996-03-12 American Home Products Corporation Polyanionic benzylglycosides as inhibitors of smooth muscle cell proliferation
US5565432A (en) * 1994-11-07 1996-10-15 American Home Products Corporation Smooth muscle cell proliferation inhibitors
US5773420A (en) * 1994-11-07 1998-06-30 American Home Products Corporation Acylated benzylglycosides as inhibitors of smooth muscle cell proliferation
US6171609B1 (en) 1995-02-15 2001-01-09 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
EP0954326A1 (en) * 1996-04-19 1999-11-10 Alpha Therapeutic Corporation A process for viral inactivation of lyophilized blood proteins
EP0954326A4 (en) * 1996-04-19 2002-11-20 Alpha Therapeutic Corp PROCESS FOR INACTIVATION OF VIRUSES IN LYOPHILIZED BLOOD PROTEINS
US6638916B1 (en) 1997-09-01 2003-10-28 The Australian National University Use of sulfated oligosaccharides as inhibitors of cardiovascular disease
US6362170B1 (en) 1998-11-24 2002-03-26 American Home Products Corporation Benzylglycosylamides as inhibitors of smooth muscle cell proliferation
US6187755B1 (en) 1998-11-24 2001-02-13 American Home Products Corporation Benzylmaltosides as inhibitors of smooth muscle cell proliferation
US7081448B2 (en) 1998-11-24 2006-07-25 Wyeth Benzyllactobionamides as inhibitors of smooth muscle cell proliferation
US6340670B1 (en) 1998-11-24 2002-01-22 American Home Products Corporation Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
US6664243B1 (en) 1998-11-24 2003-12-16 Wyeth Benzyllactobionamides as inhibitors of smooth muscle cell proliferation
US6291434B1 (en) 1998-11-24 2001-09-18 American Home Products Corp. Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation
US6451767B1 (en) 1998-11-24 2002-09-17 Wyeth Benzylmaltotriosides as inhibitors of smooth muscle cell proliferation
US6258784B1 (en) 1998-11-24 2001-07-10 American Home Products Corp. Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
US6339064B1 (en) 1998-11-24 2002-01-15 American Home Products Corporation Benzylglycosylamides as inhibitors of smooth muscle cell proliferation
US7514411B2 (en) 1998-11-24 2009-04-07 Wyeth Acylated benzylmaltosides as inhibitors of smooth muscle cell proliferation
US7132402B2 (en) 1998-11-24 2006-11-07 Wyeth Acylated benzylmaltosides as inhibitors of smooth muscle cell proliferation
WO2002005826A1 (fr) * 2000-07-17 2002-01-24 Les Laboratoires Servier Utilisation de cyclodextrines polysulfatees pour le traitement de l'arthrose
US6930098B2 (en) 2000-07-17 2005-08-16 Universiteit Gent Use of polysulphated cyclodextrins for treating osteoarthritis
FR2811572A1 (fr) * 2000-07-17 2002-01-18 Adir Utilisation de cyclodextrines polysulfatees pour le traitement de l'arthrose
FR2827799A1 (fr) * 2001-07-27 2003-01-31 Sofradim Production Endoprothese vasculaire recouverte d'un derive fonctionnalise de dextrane et son procede de preparation
WO2003011355A1 (fr) * 2001-07-27 2003-02-13 Sofradim Production Endoprothese vasculaire recouverte d'un derive fonctionnalise de dextrane
US9498488B2 (en) 2003-06-27 2016-11-22 Biorest Ltd. Method of treating acute coronary syndromes
US10517883B2 (en) 2003-06-27 2019-12-31 Zuli Holdings Ltd. Method of treating acute myocardial infarction
US10213446B2 (en) 2003-06-27 2019-02-26 Biorest Ltd. Method of treating acute coronary syndromes
US9827254B2 (en) 2003-06-27 2017-11-28 Biorest Ltd. Method of treating acute coronary syndromes
FR2923391A1 (fr) * 2007-11-08 2009-05-15 Biocydex Soc Par Actions Simpl Compositions pour conserver des cellules, des tissus ou des organes, procede d'obtention et utilisations.
WO2009068798A1 (fr) * 2007-11-08 2009-06-04 Biocydex Compositions a base de cyclodextrines chargees positivement pour conserver des cellules, des tissus ou des organes, procede d ' obtention et utilisations
EA018959B1 (ru) * 2008-09-22 2013-12-30 Аркариос Б.В. Карбоксиэтилированные полисульфаты циклодекстрина, подходящие для применения в качестве лекарственных средств
US8466278B2 (en) 2008-09-22 2013-06-18 Arcarios B.V. Carboxyethylated cyclodextrin polysulfates useful as medicaments
CN102300880A (zh) * 2008-09-22 2011-12-28 阿尔卡里奥斯有限责任公司 用作药物的羧基烷基环糊精多硫酸酯
WO2010031876A1 (en) * 2008-09-22 2010-03-25 Universiteit Gent Carboxyethylated cyclodextrin polysulfates useful as medicaments
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
US10265269B2 (en) 2013-03-14 2019-04-23 Biorest Ltd. Liposome formulation and manufacture
US11633357B2 (en) 2013-03-14 2023-04-25 Zuli Holdings, Ltd. Liposome formulation and manufacture

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