WO2000009018A9 - Compositions hemostatiques a base de collagene de type i et de type iii, a utiliser en tant que produit de scellement vasculaire et pansement - Google Patents

Compositions hemostatiques a base de collagene de type i et de type iii, a utiliser en tant que produit de scellement vasculaire et pansement

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Publication number
WO2000009018A9
WO2000009018A9 PCT/US1999/018095 US9918095W WO0009018A9 WO 2000009018 A9 WO2000009018 A9 WO 2000009018A9 US 9918095 W US9918095 W US 9918095W WO 0009018 A9 WO0009018 A9 WO 0009018A9
Authority
WO
WIPO (PCT)
Prior art keywords
composition
collagen
collagen type
type iii
iii
Prior art date
Application number
PCT/US1999/018095
Other languages
English (en)
Other versions
WO2000009018A1 (fr
Inventor
Chunlin Yang
James W Polarek
Thomas B Neff
Original Assignee
Fibrogen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fibrogen Inc filed Critical Fibrogen Inc
Priority to MXPA01001510A priority Critical patent/MXPA01001510A/es
Priority to EP99943668A priority patent/EP1105051A4/fr
Priority to JP2000564526A priority patent/JP2002524110A/ja
Priority to CA002339575A priority patent/CA2339575A1/fr
Priority to AU56718/99A priority patent/AU5671899A/en
Publication of WO2000009018A1 publication Critical patent/WO2000009018A1/fr
Publication of WO2000009018A9 publication Critical patent/WO2000009018A9/fr

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Classifications

    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A61L15/325—Collagen
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/043—Mixtures of 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/00491—Surgical glue applicators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention is directed to polymerized recombinant type I and/or type III collagen-based compositions and combinations thereof, including gelatin- based compositions, for medical use as sealants and wound dressings.
  • the present invention is further directed to the preparation of such compositions.
  • These compositions are useful as sealants in a variety of medical applications, including vascular plug type devices, wound closure devices, tendon wraps for preventing the formation of adhesion following surgical procedures, and dressings for use to treat incisions, seeping wounds, and the like, and as medical adhesives for bonding tissues.
  • the compositions include agents which induce wound healing or provide additional beneficial characteristics desired in a tissue sealant. More particularly, the compositions of the present invention are can be used as vascular sealants.
  • sutures and staples For example, the conventional methods of choice to close incisions in soft tissue following surgery, injury, and the like have been sutures and staples. These techniques and methods are limited by, for example, tissue incompatibility with sutures or staples which may cause painful and difficult to treat fistulas granulomas and neuromas. Mechanical means can also be limited to being purely adhesive, and thus not fully satisfactory as compared to sealants, applied to close wounds that are bleeding or seeping, etc. Sutures and staples may also tend to cut through weak parenchymatous or poorly vascularized tissue.
  • Sutures can leave behind a tract which can allow for leakage of fluids and organisms. Sutures can be further problematic in that the needle for any suture is larger than the thread attached to it and the needle tract is thus larger than can be filled by the thread used to form the sutures.
  • fibrinogen has been obtained as a fraction of whole blood, contains other blood elements, such as clotting factors.
  • Moazami N. et al. (1990) Arch. Surg. 125(11):1452-1454; and Oz et al. (1990).
  • direct application in humans was prevented due to the need to isolate the necessary protein fibrinogen from the patient prior to the procedure to avoid risks of infection from donor plasma.
  • Other proteins, for example, albumin were unsatisfactory substitutes as welds of comparable strength were not achieved.
  • combination products have been devised for use as tissue adhesives and sealants.
  • the use of a combination of three separately prepared substances, human fibrinogen cryoprecipitate, thrombin in the presence of calcium ion, and Factor XIII concentrate, to obtain a glue for application in skin graft applications, myringoplasty, repair of dural defects, hemeostatis after tonsillectomy, and tracheoplasty has been described. (See, Staindl (Ann.
  • vascular sealants One critical aspect of tissue adhesion is the sealing of wounds, and, in particular, vascular punctures and other vascular wounds resulting from, for example, surgery.
  • percutaneously accessing major vascular structures is a key step in a variety of diagnostic and therapeutic procedures, including Percutaneous Transluminal Coronary Angioplasty (PTCA), Percutaneous Coronary Angiography, and Percutaneous Coronary Atherectomy.
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • Percutaneous Coronary Angiography Percutaneous Coronary Angiography
  • Percutaneous Coronary Atherectomy Percutaneous Coronary Atherectomy.
  • access to the vascular space is generally obtained using the so-called Seldinger technique where, first, a hollow needle is used to create a puncture wound through the skin, the underlying muscle tissue, and the wall of a selected blood vessel, such as the femoral artery.
  • a guidewire is inserted through the tubular needle until its distal end is located in the blood vessel, at which time the needle is stripped off of the guidewire and replaced with an introducer sheath and dilator.
  • the introducer sheath typically includes a self-sealing hemostatic valve on its proximal end for sealing around the guidewire.
  • the guidewire is then advanced into the vascular space through the introducer and directed to a preselected area of the vascular system. Once the guidewire is positioned, a catheter is advanced over the guidewire to the desired area.
  • the catheter and the introducer sheath are removed from the puncture site, there may be profuse bleeding, especially when the patient has been on anticoagulant therapy such as heparin, coumadin, aspirin, or thrombolytic agents.
  • anticoagulant therapy such as heparin, coumadin, aspirin, or thrombolytic agents.
  • the most common method used to prevent post- procedure bleeding at the access site involves the application of direct pressure to the perforation site until normal physiologic pathways have sealed the access site. There are several problems with this method.
  • the pressure application technique may fail to prevent hemorrhage. Such a hemorrhage may be life-threatening or can lead to a large hematoma. A large hematoma in the groin, for instance, may compromise the major nerve supply to the anterior lower extremity.
  • the pressure application technique extends the length of the in- hospital stay.
  • a PTCA may be completed in 2 to 3 hours, but the patient will typically be hospitalized for several additional hours or overnight to allow the access site to seal physiologically.
  • the patient is required to stay immobile, often with a sand bag taped to the patient's thigh, such as in the case of femoral artery access.
  • 5,290,310 describes a device for delivering a collagen plug subcutaneously against a penetration site in a wall of a blood vessel.
  • An instrument containing a toroidal-shaped collagen plug within a barrel thereof is made to surround the exterior of a tubular introducer.
  • the instrument includes a pusher mechanism for ejecting the collagen plug into the puncture wound and against the exterior wall of the blood vessel at the site of the puncture.
  • This device relies upon a collagen plug which is derived from animal sources and is therefore comprised primarily of heterotrimer collagen type I.
  • U.S. Patent No. 5,129,882 also discloses a surgical implement for injecting a hemostatic agent in a puncture wound by routing the injection device through the lumen of the introducer sheath after it has been retracted sufficiently so that the distal end thereof is no longer in the blood vessel. Deploying a plunger, the hemostatic agent is forced out of the instrument and against the exterior wall of the artery proximate the puncture wound.
  • U.S. Patent Nos. 4,744,364, 4,852,974, 4,890,612, 5,021,059, and 5,222,974 each describe a method and apparatus for effecting hemostasis by inserting an anchoring device through the puncture wound and into the blood vessel while using a filament attached to the anchoring device to inject an appropriate sealant into the wound.
  • the anchoring device prevents entrance of the sealing material into the blood vessel and serves as an anchor and guide for addressing selected vessels.
  • Still other devices for injecting a hemostatic agent into a puncture wound following a vascular procedure are described in U.S. Patent Nos. 5,281,197, 4,838,280, 5,192,300, and 4,738,658 and in published European Patent Application 0 476 178A1.
  • Collagen/Gelatin As A Biomaterial. Collagen, the major connective tissue protein in animals, possesses numerous characteristics not seen in synthetic polymers. Characteristics of collagen include good compatibility with living tissue, promotion of cell growth, and absorption and assimilation of implantations. (See, e.g., Shimizu, R. et al. Biomat. Med. Dev. Art. Org., 5(1): 49-66 (1977).) These same characteristics are also true of gelatins, derivation products of collagens. Various applications of collagen as a biomaterial are being tested, for example, the use of collagens in dialysis membranes of artificial kidney, artificial cornea, vitreous body, artificial skin and blood vessels, hemostatic agents, soft contact lesnes, and in surgery.
  • Natural collagen fibers are basically insoluble in mature tissues because of covalent intermolecular cross-links that convert collagen into an infinite cross-linked network. Dispersal and solubilization of native collagen can be achieved by treatment with various proteolytic enzymes which disrupt the intermolecular bonds and remove immunogenic non-helical end regions without affecting the basic rigid triple-helical structure which imparts the desired characteristics of collagen. (See, e.g., U.S. Pat. Nos. 3,934,852; 3,121,049; 3,131,130; 3,314,861; 3,530,037; 3,949,073; 4,233,360, and 4,488,911 for general methods for preparing purified soluble collagen.)
  • the prior modified collagen-based adhesives suffer from various deficiencies, including (1) cross-linking/polymerization reactions that generate exothermic heat, (2) long reaction times, and (3) reactions that are inoperative in the presence of oxygen and physiological pH ranges.
  • cross-linking/polymerization reactions that generate exothermic heat
  • long reaction times and (3) reactions that are inoperative in the presence of oxygen and physiological pH ranges.
  • reactions that are inoperative in the presence of oxygen and physiological pH ranges See, e.g., Lee M. L. et al. Adhesion in Biological Systems, R. S. Manly, ed., Academic Press, New York, 1970, Chap. 17.
  • many of the prior modified collagen-based adhesives contain toxic materials, rendering them unsuitable for biomedical use.
  • Buonocore M. G. (1970) and U.S. Pat. No. 3,453,222.
  • collagen-based adhesives also presents inrmuno logical concerns as such adhesives have been derived from animal sources and typically bovine sources. Studies with respect to the use of such collagens as injectible devices have reported minor inflammatory responses. More recently, potential issues regarding the transmission of disorders to humans related to bovine spongiform encephalopathy ("mad cow disease”) have focused attention, especially in Europe, to limiting the use of animal, and particularly, bovine-sourced materials.
  • type I collagen as isolated from natural sources typically contains approximately 10-20% type III and other collagens, depending upon the tissue source used, and about 90-80%) type I collagen.
  • collagen type I mixtures
  • the literature further teaches only the use of collagen as an adhesive as a consequence of its structural characteristics, or, alternatively, the use of predominantly collagen type I heterotrimers, as compared to collagen type I homotrimers which have been implicated in the epithelial cell attachment. (See, e.g., Ghersi, et al., 1989, Eur. J. Cell Biol. 50:279-84)).
  • compositions useful as sealants and wound dressings that permit faster and safer healing, that minimize the risks of infection from donor, including non-human, sources, that increase convenience and permanence, that minimize demands on surgical resources and time, and that demonstrate superior biocompatibility.
  • biologically- derived adhesives that offer improved convenience and permanence over currently available formulations, and that promote less-invasive treatment, resulting in improved patient comfort and shorter time under medical supervision. Additionally, such compositions would preferably offer improved bond strength.
  • non-adhesive compositions that provide the above-named advantages of safer and more effective healing and that are biologically compatible.
  • the present invention includes biologically compatible, collagen type III and/or type I products with sealant properties which can be formed using soluble recombinantly derived collagen type III and/or type I monomers or gelatin derived from collagen type III and/or type I monomers (the collagen and gelatin products are collectively hereinafter referred to as "collagen") wherein said monomers are polymerized to form a collagen type III and/or type I composition having sealant properties.
  • the collagen is human and is derived using recombinant technology.
  • Collagen type III was selected for its unexpectedly superior hemostatic characteristics, as compared to other collagen types.
  • Collagen type I was selected for its structural characteristics, as well as for the hemostatic properties of certain collagen type I forms (e.g., collagen type I homotrimers).
  • the polymerization reaction may be initiated with an appropriate polymerization initiator such as a chemical oxidant, ultraviolet irradiation, a suitable oxidative enzyme, or atmospheric oxygen.
  • an appropriate polymerization initiator such as a chemical oxidant, ultraviolet irradiation, a suitable oxidative enzyme, or atmospheric oxygen.
  • cross-linking agents including glutaraldehyde, dye-mediated photooxidation , PEG and its derivatives, acyl azide, plyepoxy fixatives, oxidized starch (periodate) and water soluble carbodiimide (“WSC”) may be used in the polymerization process to form a collagen composition having sealant properties.
  • the product is comprised of a combination of pure recombinant type I and type III collagen
  • the ratio of pure recombinant collagen type III to pure recombinant collagen type I is preferably about 30% and greater type III collagen to about 70% or less type I collagen (heterotrimer). More preferably, the ratio of pure recombinant type III collagen to pure recombinant type I collagen (heterotrimer) is about 30% to about 50% type III collagen to about 70% to about 50%) type I collagen (heterotrimer). Most preferably, the ratio of pure recombinant type III collagen to pure recombinant type I collagen (heterotrimer) is about 30% to about 40%> type III collagen to about 70%> to about 60%> type I collagen (heterotrimer).
  • the ratio of pure recombinant type I homotrimer to a combination of recombinant collagen type I heterotrimer and recombinant collagen type III is about 90:10. More preferably, the ratio of pure recombinant type I homotrimer to a combination of recombinant collagen type I heterotrimer and recombinant collagen type III is about 75:25. Most preferably, the ratio of pure recombinant type I homotrimer to a combination of recombinant collagen type I heterotrimer and recombinant collagen type III is about 50:50.
  • the glueing effect is increased by a combination of agents, such as those described below, and collagen type III and/or collagen type I.
  • agents such as those described below
  • collagen type III and/or collagen type I are examples of agents, such as those described below
  • collagen type III and/or collagen type I are examples of agents, such as those described below.
  • Wound healing The sealant promotes the growth of fibroblasts which, in combination with efficient hemostasis and adhesion between the wound surfaces provides for an improved healing process.
  • the use of the present compositions as anti- adherence/wound healing compositions is expected to result in a normal
  • compositions also reduce the inflammatory response.
  • the present invention is directed to compositions useful in sealing punctures and incisions in large blood vessels and the heart.
  • the polymerized materials may assume a number of sizes and shapes consistent with their intended biomedical applications, which include use in ophthalmology, plastic surgery, orthopedics, and cardiology.
  • the vascular sealant compositions of the present invention, comprising collagen type III and/or I may be used alone or in combination with a tissue sealant device, including, for example, the devices set forth in U.S. Patent Nos.
  • the collagen type III and/or type I composition is further comprised of agents which will confer additional desirable characteristics for a vascular sealant or wound dressing.
  • agents which will confer additional desirable characteristics for a vascular sealant or wound dressing for example, fibrin, fibrinogen, thrombin, calcium ion, and Factor XIII may be included in the composition to better effect the formation of a three-dimensional network of polymerized collagen.
  • the recombinant collagen type III composition incorporates a compound having wound healing capabilities.
  • the compound is connective tissue growth factor and is incorporated in the composition to effect slow-release of the compound to the wound.
  • the drug improves vascularization, for example, tumour necrosis factor, as described in U.S. Patent No. 4,808,402 (issued February 28, 1989).
  • Figure 1 shows SDS-PAGE analysis of recombinant type III collagen produced by pichia pastoris.
  • Figure 2 shows data relating to the biocompatibility of recombinant type III collagen and a commercially available collagen hemostat.
  • Figure 3 shows data relating to platelet aggregation experiments of recombinant type III and bovine collagen type I.
  • Figure 4 shows data relating to the bleeding time of spleen treated with recombinant collagen type III and bovine collagen type I.
  • Figure 5 shows a SDS-PAGE analysis of bovine collagen I cross-linked with water soluble carbodiimide.
  • Figure 6 shows a SDS-Page analysis of recombinant collagen type III cross- linked with water soluble carbodiimide.
  • biologically compatible refers to recombinant collagen type III and/or type I modified in accordance with the present invention (i.e., a polymerized collagen type III recombinant product) which is incorporated or implanted into or placed adjacent to the biological tissue of a subject and more particularly, does not deteriorate appreciably over time or induce an immune response or deleterious tissue reaction after such incorporation or implantation or placement.
  • the term "pure recombinant collagen type I” refers to collagen type I manufactured by recombinant techniques which is substantially free from other collagen types. Unless otherwise specifically referenced, the term pure recombinant collagen type I includes both collagen type I homotrimer and collagen type I heterotrimer and mixtures thereof. The term includes any other forms of recombinant collagen type I and any modifications made thereto that may be categorized as a subset of collagen, such as gelatins. The term excludes collagen type I isolated from natural sources.
  • the term "pure recombinant collagen type III” refers to human collagen type III manufactured by recombinant techniques which is substantially free from other collagen types.
  • the term includes any other forms of recombinant collagen type III and any modifications made thereto that may be categorized as a subset of collagen, such as gelatins.
  • the term excludes collagen type III isolated from natural sources.
  • the term “substantially free” refers to a recombinant collagen type that is substantially pure of any other collagen type or unmixed with any other collagen type, and is preferably at least 90%> free from other collagen types.
  • the term “vascular sealant” refers to any composition useful in closing vascular wounds, including plugs, which possesses hemostatic properties.
  • wound refers to any opening in the skin, mucosa or epithelial linings, most such openings generally being associated with exposed, raw or abraded tissue.
  • wounds including, but are not limited to, first, second, and third degree burns (especially second and third degree); surgical incisions, including those of cosmetic surgery; wounds, including lacerations, incisions, and penetrations; and ulcers, including decubital ulcers (bed-sores) and ulcers or wounds associated with diabetic, dental, haemophilic, malignant, and obese patients.
  • the present invention may also be useful for minor wounds, and for cosmetic regeneration of epithelial cells.
  • the wounds to be treated are burns and surgical incisions, whether or not associated with viral infections or tumors
  • Types of collagen useful in forming the biologically compatible collagen products of the invention with adhesive and hemostatic properties are recombinant collagen type I and type III.
  • Monomeric soluble collagen types I and III is obtained by recombinant processes, including processes involving the production of collagen type III in transgenic animals. Such recombinant processes are set forth, for example, in U.S. Patent No. 5,593,859, which is incorporated herein by reference.
  • collagen types I or III will be recombinantly manufactured by culturing a cell which has been transfected with at least one gene encoding the polypeptide comprising collagen type I or III and genes encoding the ⁇ and ⁇ subunits of the post-translational enzyme prolyl 4- hydroxylase and purifying the resultant collagen monomer therefrom.
  • the monomeric soluble collagen type I and III material exhibits a viscous consistency and varying degrees of transparency and clarity.
  • Polymerization Of Collagen Type I and III Monomers may be subsequently subjected to polymerization or cross-linking conditions to produce the polymerized collagen composition of the present invention.
  • Polymerization may be carried out using irradiation, e.g., UN, gamma, or fluorescent light.
  • UN irradiation may be accomplished in the short wave length range using a standard 254 nm source or using UN laser sources. With a standard 254 nm source, 4-12 watts, polymerization occurs from 10 to 40 minutes, preferably 20 to 30 minutes, at an exposure distance of from 2.5-10 cm, preferably from 2.5 to 5 cm distance. Excess UN exposure will begin to depolymerize the collagen polymers.
  • Polymerization using gamma irradiation can be done using from 0.5 to 2.5 Mrads. Excess gamma exposure will also depolymerize collage polymers.
  • Polymerization in the presence of oxygen can be achieved by adding an initiator to the fluid prior to exposure.
  • initiators include sodium persulfate, sodium thiosulfate, ferrous chloride tetrahydrate, sodium bisulfite, and oxidative enzymes such as peroxidase or catechol oxidase.
  • polymerization occurs in 30 seconds to 5 minutes, usually from 1 to 3 minutes.
  • the polymerizing agent is preferably UN irradiation.
  • the polymerization or cross-linking of the monomeric substituents can be carried out by any of the methods will known in the art, including simply exposing the material to atmospheric oxygen, although the rate of polymerization is appreciably slower than in the case of UN irradiation or chemical agents.
  • difunctional monomeric cross-linking agents may be added to the monomer compositions of this invention to effect polymerization.
  • cross-linking agents are known in the art, for example, in U.S. Pat. No. 3,940,362 which is hereby incorporated by reference herein.
  • polymerization methods and cross-linking agents such as glutaraldehyde, dye-mediated photooxidation , PEG and its derivatives, acyl azide, plyepoxy fixatives; oxidized starch (periodate) and water soluble carbodiimide ("WSC") well known in the art may be used to produce the polymerized collagen composition of the present invention.
  • WSC water soluble carbodiimide
  • polyaldehyde compositions to effectuate polymerization can be also utilized.
  • polyaldehyde compositions to effectuate polymerization can be also utilized.
  • formation of Gelatin The recombinant collagen protein of the present invention may be further modified and processed into gelatin using procedures known in the art. (See, e.g., Veis, 1965, International Review of Connective Tissue Research, "The Physical Chemistry of Gelatin", Academic Press, New York and London.)
  • a common feature of all standard collagen to gelatin conversion processes is the loss of the secondary structure of the collagen protein, and in the majority of instances, an alteration in either the primary or tertiary structure of the collagen.
  • the collagens of the present invention can be processed using different procedures depending on the type of gelatin desired.
  • modifications may occur to unpurified collagen or procollagen present in the cell mass or in the culture medium or any further modifications can be made to the purified collagen as described above.
  • recombinant collagen or procollagen may be modified and processed into recombinant gelatin.
  • Gelatin may be produced directly from the cell mass or the culture medium by taking advantage of gelatin's solubility at elevated temperatures and stability at conditions of low or high pH, low or high salt concentration, and high temperatures.
  • the cell mass or culture medium may further be treated to extract gelatin by denaturing the triple helical structure of collagen using detergents, heat or denaturing agents.
  • tissue-derived gelatin can be applied to the production of recombinant gelatin. This includes, but is not limited to, treatments with strong alkali or strong acids, heat extraction in aqueous solution, ion exchange chromatography, cross-flow filtration, and heat drying.
  • compositions of the present invention are comprised of polymerized type I and III collagen wherein said composition is manufactured by a process comprising the steps of: (1) production of collagen type I and III monomers by the recombinant methods described above; and (2) polymerization of such monomers.
  • the process includes a step wherein the collagen is converted into gelatin.
  • the product is comprised preferably of a combination of pure recombinant type I and type III collagen
  • the ratio of pure recombinant collagen type III to pure recombinant type I (heterotrimer) is about 30%) and greater type III collagen to about 70% or less type I collagen
  • the ratio of pure recombinant type III collagen to pure recombinant type I collagen is about 30%> to about 50%> type III collagen to about 70%oto about 50%> type I collagen (heterotrimer). Most preferably, the ratio of pure recombinant type III collagen to pure recombinant type I collagen (heterotrimer) is about 30% to about 40% type III collagen to about 70% to about 60%) type I collagen (heterotrimer).
  • tissue sealants and adhesives of the present invention can be determined by methods well-known in the art.
  • compositions of the present invention may be further comprised of other agents useful in gluing or sealing vascular tissues, and more generally, soft tissue.
  • the composition will preferably comprise transglutaminases such as Factor XIII and/or fibrin/ fibrinogen/fibronectin and/or plasminogen.
  • transglutaminases such as Factor XIII and/or fibrin/ fibrinogen/fibronectin and/or plasminogen.
  • the suitable concentrations of these components can be selected by methods-well known in the art.
  • fibrinogen can be present in plasma concentrations, such as from about 1.5 to about 4.0 mg/ml, or higher. Fibrinogen can also be present in lower concentrations, for example, to monitor performance.
  • the composition will also include clotting enzymes, i.e.
  • thrombin especially in combination with bivalent calcium, such as calcium chloride.
  • concentration of calcium chloride can vary, for example, from between 40 mM to 0.2 M, depending on the specific purpose of the tissue adhesive composition. High concentrations of calcium chloride inhibit fibroblast growth and are therefore preferred for anti-adherence applications (fibronectin, which stimulates the growth of fibroblasts, can be absent in such compositions). It may further be valuable to include a fibrinolysis inhibitor, such as a plasmin inhibitor, e.g.
  • aprotinin e.g., PAI-1 or PAI-2.
  • the proportions of the previously known ingredients in the tissue adhesive compositions of the invention may be selected according to methods well- known in the art, the necessary amount of the viscosity-enhancing polymer can readily be determined by a person skilled in the art depending on the particular polymer and the intended use form.
  • concentration and/or molecular weight of the viscosity-enhancing polymer is too low, the viscosity increase will be insufficient, and a too high concentration and/or molecular weight will inhibit the fibrin polymerization and the adhesion to the tissue.
  • the polymerization of composition of the present invention may be quickened, reducing the time until the glue sets.
  • the fibrin of the composition will remain more or less fluid for several minutes after application.
  • a further beneficial effect of increasing the viscosity with a viscosity-enhancing polymer in accordance with the invention is therefore that lower concentrations of thrombin, required in situations where the parts to be sealed require subsequent adaptation even on non-horizontal surfaces, can be used.
  • compositions of the present invention may, rather than including a combination of the agents described herein, include a fusion protein wherein the collagen type I and/or type III and, for example, fibrin, are combined to form one molecule.
  • fusion proteins may be manufactured according to recombinant techniques described herein.
  • the composition of the present invention includes agents useful in wound healing, either by inducing or promoting the formation of tissue, or, alternatively, by limiting the formation of fibrotic adhesions.
  • agents include antibiotics, or growth factors, such as connective tissue growth factor, described in, for example, U.S. Patent No. 5,408,040 and 5,585,270, incorporated herein by reference.
  • the drug improves vascularization, for example, tumour necrosis factor, as described in U.S. Patent No. 4,808,402 (issued February 28, 1989).
  • vascular sealant compositions comprising collagen type III and/or I may be used alone or in combination with a tissue sealant device, including, for example, the devices set forth in U.S. Patent Nos. 5,782,860 (issued July 21, 1998), 5,759,194 (issued June 2, 1998) and 5,728,132 (issued March 17, 1998). Fields Of Use
  • the polymerized collagen type III and/or type I products of the present invention may be useful to produce mechanical sealants and adhesive systems.
  • Vascular Adhesive Systems Fields of application include, but are not limited to, general surgery, dentistry, neurosurgery, plastic surgery, thorax and vascular surgery, abdominal surgery, orthopaedics, accident surgery, gynaecology, urology, and opthalmology.
  • the collagen sealants of the present invention have also been used for local application of drugs, such as antibiotics, growth factors, and cytostatics. Sealant Films and Wound Dressings.
  • the polymerized collagen products can be made in the form of a sealant film.
  • a collagen- based film will be flexible and elastic with the consistency and feel of plastic film, but can exhibit high biological compatibility.
  • Uses of sealant films include, but are not limited to, prevention of adhesion formation following tendon surgery (i.e., use as a wrap around tendons), use as a synthetic tympanic membrane, and uses as substitute facial tissue and wound dressing components. Additional examples of potential uses of sealant films include, treatment of corneal abrasions, wound closure, coating of catheters and instruments, and use as a material to prevent adhesion formation in tissues and tendons (e.g., peritoneal cavity).
  • sealant and adhesive formulations which can be used in systems specific for delivery of numerous drugs and pharmaceutical compositions, including growth factors, antibiotics, and other biologically beneficial compounds. Such materials can be added to the collagen adhesive or sealant to promote cell migration, cell adhesion, and wound healing.
  • Angioplasty is a diagnostic procedure whereby dye is injected into an artery, preferably the femoral artery, to detect the presence or absence of coronary disease.
  • Angioplasty also known as PCT A, is a therapeutic procedure which involves the inflation of a balloon in an artery, such as the coronary artery, for the purpose of relieving arterial blockages. After puncturing the femoral artery, a balloon-catheter is introduced through the femoral artery and navigated through to the coronary artery blocked by atherosclerosis (plaque).
  • plaque atherosclerosis
  • balloon catheters are commonly used in angioplasty and angiography, including over-the-wire catheters which utilize an independent guidewire to the site of the disease; 2) fixed- wire catheters, which combine a balloon catheter with a guidewire into one device; 3) rapid-exchange or single-operator exchange catheters, which are over-the-wire catheters that can be exchanged more conveniently than standard over-the-wire catheters; and 4) perfusion catheters, which allow blood flow during the procedure.
  • a rotational tip catheter removes plaque buildup on arterial walls.
  • These devices utilize a technique called differential cutting. Calcified material is rendered into microscopic particles without damaging the artery due to the elastic nature of the arterial walls.
  • Angioplasty is a more invasive and complicated procedure than angiography, requiring the insertion of a larger sheath than that used in angiography.
  • the sheath is used as a vehicle for introducing the catheter into the artery.
  • angioplasty also requires the use of blood thinners, such as heparin, to prevent clotting during and after the surgical procedure.
  • the anti-clotting agent prevents the body's natural sealing/clotting mechanism and, thus, sealing punctures requires a significant length of time.
  • an adhesive applicator may optionally be inserted into the sheath and placed into a position near to or contacting the puncture in the artery.
  • recombinant collagen type III and/or type I monomer of the present invention may be applied to the puncture on the external surface of the artery and/or within the puncture track.
  • the monomer then is polymerized and/or cross-linked by the techniques described herein, for example, UV irradiation, such that polymerization takes place within 0 to 300 seconds, preferably within 0 to 120 seconds, more preferably within 0 to 30 seconds, and most preferably 3 to 10 seconds.
  • collagen monomer composition By applying the collagen monomer composition on the outside of the artery, the incidence of embolism (blockage of the artery or circulatory system) is virtually eliminated.
  • polymerization may be achieved according to the methods set forth in PCT WO 97/29715 and EP 747,066 A2, incorporated herein by reference.
  • a polymerized collagen type III and/or type I may be used and the polymerization step may be avoided. Because of the bonding strength of the adhesive of the present invention, only small amounts of the adhesive are required to seal a punctured artery. Moreover, because the surgical adhesive according to the present invention can polymerize almost immediately, the adhesive can polymerize on the surface and/or along the puncture track of the artery without penetrating the interior of the artery. Accordingly, large pieces or particles of material will not enter the circulatory system, thereby substantially reducing risk of embolism. Due to the fast and strong bonding of preferred adhesives of the invention, the patient will need to be immobilized for only a minimal period of time. Administration
  • the tissue treatment composition of the present invention may be presented in the same type of preparations as prior art fibrin sealants.
  • the components may be provided in deep frozen solution form or as lyophilized powders, to be diluted prior to use with appropriate aqueous solutions, e.g. containing aprotinin and calcium ions, respectively.
  • the vascular sealants of the present invention may be formulated and shaped in the form of collagen plugs, as described in the art and known to one of ordinary skill in the art.
  • the compositions of the present invention can additionally comprise pharmaceutical agents, such as, for example, an antibiotic or a growth factor, by incorporating the agent into the tissue adhesive so as to be enclosed in the collagen network formed upon application of the tissue adhesive.
  • compositions of the present invention constitute an advantageous slow-release preparation for proteoglycans such as hyaluronic acid and its salts and derivatives, which considerably increases the bioavailability thereof.
  • compositions of the present invention are not restricted to those having adhesive properties.
  • Non-adhesive compositions are also included, especially when these compositions are primarily intended for wound healing. These compositions may in particular include non-adhesive proteins such as albumin and/or growth factors. Substantially non-adhesive compositions may also be obtained when the polymer part of the composition inhibits the adhesive properties of the protein part. It should in this context be emphasized that the invention comprises both adhesive and substantially non-adhesive compositions, although it has for simplicity reasons often has been referred to as an "adhesive" in this specification.
  • compositions of the present invention may be applied using a variety of dispensing devices.
  • the surgical adhesive may be applied using the devices set forth in U.S. Patent Nos. 4,900,303 (Lemelson) and 5,372,585 (Tiesenbrun) while monitoring the application process through an optical viewing system.
  • the composition of the present invention may also be applied by the devices set forth in U.S. Patent No. 5,129,882 (Weldon et al.), or the other devices referenced above, or other devices as well known in the art.
  • compositions according to the present invention may also be applied in conjunction with other sealing means.
  • adhesive compositions may be applied to puncture sites which have been closed using surgical suture or tape, such as in the sealing of a puncture or incision in vascular tissues, including the heart.
  • the adhesive in this instance will provide a complete seal, thereby reducing the risk of body fluid leakage from the organ or vessel, e.g., leakage from artery puncture sites.
  • the surgical adhesive of the present invention may additionally be used in conjunction with other sealing means, such as plugs, and the like. Such techniques are set forth in, for example, U.S. Patent Nos.
  • compositions of this invention can be used to join together two surfaces by applying the particular composition to at least one of the surfaces.
  • the adhesive compositions of this invention can be applied by known means, such as with, for example, a glass stirring rod, sterile brush, or medicine dropper, in many situations, a pressurized aerosol dispensing package is preferred in which the adhesive composition is in solution with a compatible anhydrous propellant. Aerosol application of the monomers is particularly advantageous for use in hemostasis. Mechanisms for aerosol applications are well known in the art.
  • purified rhc III was tested by SDS-PAGE as shown in Figure and amino acid analysis was performed and amino acid composition of purified rhc III shown as below at TABLE 1.
  • Human Platelet Rich Plasma was then prepared from fresh blood of an apparently healthy donor.
  • the PRP was then adjusted to 200K/ ⁇ l and the collagen fibril slurry was added into the PRP.
  • the platelet aggregation profile with an aggregometer was detected.
  • the minimal amount of collagen to induce complete platelet aggregation is estimated from the amount of collagen to induce a fall in optical density of at least 30%> occurred within 5 minutes.
  • Experimental Results The platelet aggregation capacity of recombinant human collagen III was compared to the platelet aggregation capacity of bovine skin derived collagen according to the methods set forth above and as more fully described in Balleisen, et al, 1975, Klin. Wschr 53:903-905.
  • fibrils generated from recombinant human collagen III has a lower minimal amount in inducing human platelet aggregation than fibrils generated from bovine skin collagen.
  • Recombinant human collagen III also has a shorter onset time to induce platelet aggregation.
  • platelets were obtained from three healthy donors and were adjusted to 200K/ml in plasma. Collagen fibril slurry was added to the platelet suspension and the aggregation was measured with an Aggregometer. The minimal amount of collagen capable of inducing complete platelet aggregation was determined by stepwise decreasing the amount of collagen added. It was assumed that complete aggregation had occurred when a fall in OD of at least 30% occurred within 5 minutes. It was shown that rhc III has a lower minimal amount to induce complete aggregation of platelet, and indicates that rhc III is more hemostatic than bovine collagen I. This results depicted in Figure 1 demonstrate that collagen III fibrils are more hemostatic than collagen I fibrils.
  • Rhc III was prepared as follows:
  • Rhc III was expressed in pichia pastoris .
  • a selected expression clone was cultivated in a bioreactor under defined conditions.
  • Rhc III was purified from the harvested cell pellets by limited pepsin digestion and differential salt precipitation.
  • Purified rhc III was formulated into fibrils at first by neutralization with phosphate buffer and incubation at room temperature overnight. The fibrils were collected by centrifugation and then resuspended in water. After homogenization, the rhc III gel was transferred into a mould and lyophilized into a sponge. This type of sponge has very poor water absorption.
  • Water absorptive capacity is critical for applications of rhc III as a hemostat and vascular sealant.
  • a process to formulate water absorptive rhc III sponge was developed. Essentially, a sponge was cross-linked, first with UV irradiation and then with 1%> WSC. The residual cross-linking reagent was removed by incubation in PBS and the sponge was washed with water. Cross-linked sponges are lyophilized for animal testing and formulation of tissue sealant. This process not only enhanced the water absorption of rhc III sponge, but also significantly increased the mechanical strength of rhc III sponges.
  • bovine collagen I was also formulated into sponges following the same procedures.
  • Acclimatized New Zealand White Rabbits were deeply anesthetized and laparotomies were performed to expose the spleens.
  • Using a scapel blade uniform incisions about 1.0 cm long and 0.3cm deep were made into the spleens.
  • the incisions were then treated with rhc III sponges or with bovine collagen I sponges.
  • the time interval from the application of the test article or positive control material until the bleeding ceases was recorded.
  • Statistical analysis of the mean time to hemostasis was performed using Anova and Student's two sample T-test. It was observed that the bleeding time of spleens treated with rhc III sponges was significantly shorter than that of those treated with bovine collagen I. The results are shown in Figure 4. Formulation of RhC III Sealant
  • rhc III sealant To prepare a rhc III sealant, a three-step experimental approach was pursued involving: 1) preparing a cross-linked rhc III sponge; 2) coating the sponge with human thrombin; and 3) subsequently coating the sponge with human fibrinogen.
  • a collagen sponge cross-linked with water soluble carbodiimide was rinsed with 100%> ethanol and placed in a filtration funnel.
  • Human thrombin suspended in ethanol (25U/ml) was used to coat the sponge by filtration. The amount of thrombin on the sponge was about 10U/cm 2 .
  • Human fibrinogen dissolved in water at concentration of 4mg/ml was precipitated by mixing with 3 volume of ethanol. The precipitated fibrinogen was filtered through the sponge by vacuum. The amount of fibrinogen on the sponge was about 3mg/ cm 2 .
  • the coated sponge was lyophilized and used for animal tests. Acclimatized New Zealand White Rabbits were deeply anesthetized and laparotomies were performed to expose kidneys and spleens.
  • Bovine collagen I in lOmM HCl was neutralized with 1/10 volume of 0.2M Na2HPO4, pH 11.2 and incubated overnight at room temperature. The fibrils were washed with water and concentrated to 50 mg/ml by centrifugation. The homogenized gel was transferred to a small cell culture dish and lyophilized to form a sponge.
  • the bovine collagen sponge was incubated in a solution of water soluble carbodiimide ("WSC”) at room temperature overnight, then washed with PBS and water.
  • WSC water soluble carbodiimide
  • the cross-linked sponge was then dried and tested for solubility and water absorption, and compared to a commercially available collagen sponge (collagen sponge for Angioseal TM). The data is shown in Table 5.
  • Rhc III collagen fibrils were prepared by neutralizing rhc III in 1 OmM HCl with 1/10 volume of 0.2M Na2HPO4, pH 11.2, and incubated overnight at room temperature. Rhc III fibrils were harvested by centrifugation and washed with water. The fibrils were concentrated to 60 mg/ml and homogenized into a gel. The gel was transferred into a mold and lyophilized into a sponge with a thickness of about 2.5mm.
  • the collagen sponge was cross-linked with 1%> WSC in 25% ethanol at room temperature for 16 hours. Ethanol was added to accelerate the wetting of collagen sponges in the reaction solution. The cross-linked sponge was then washed with PBS for 2 hours, and subsequently washed three times with water. After lyophilization, collagen sponges of about 1.4 cm 2 in size were used to test for water reabsorption. In addition, 2 mg of the collagen sponge was used to test for solubility. As shown in Table 6, cross-linking of the rhc III sponge improved its water absorptive capacity. The wetting time of the cross-linked rhcIII sponge was reduced to about 10 seconds, and water uptake increased from 76mg to 433mg. The cross-linked rhc III sponge remained intact after incubation in water for 24 hours at room temperature, while the non-cross-linked rhc III did not remain intact.
  • the collagen sponges were also tested with SDS-PAGE. As shown in Figure 6, lane 1 and lane 6 represent rhc III; lane 2 represents the collagen sponge for AngiosealTM; lane 3 represents cross-linked bovine collagen I sponge; lane 4 represents cross-linked rhc III sponge; and lane 5 represents non-cross-linked rhc III sponge.
  • the collagen sponge AngiosealTM, cross-linked bovine collagen I sponge, and cross-linked rhc III sponge is not soluble in SDS-PAGE buffer.

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Abstract

L'invention concerne des compositions à base de collagène de type I et/ou de type III polymérisé, à usage médical sous forme de produits de scellement vasculaire et de pansements, et la préparation desdites compositions. Avant la polymérisation, des monomères de collagène sont préparés par recombinaison, des modifications chimiques du collagène n'étant pas nécessaires pour la formation desdits monomères. Les compositions à base de collagène de type I et/ou III, comprennent une gélatine constituée de collagènes de type I et III, et sont utiles en tant qu'adhésifs médicaux pour la liaison de tissus mous et comme produit de scellement pour une grande variété d'usages médicaux. Selon un autre aspect de l'invention, les compositions à base de collagène de type I et/ou III polymérisé, comprennent des agents induisant la cicatrisation ou conférant les caractéristiques supplémentaires bénéfiques voulues à un produit de scellement de tissus ou à un pansement. Les compositions de l'invention sont également utiles sous forme non adhésive.
PCT/US1999/018095 1998-08-10 1999-08-10 Compositions hemostatiques a base de collagene de type i et de type iii, a utiliser en tant que produit de scellement vasculaire et pansement WO2000009018A1 (fr)

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MXPA01001510A MXPA01001510A (es) 1998-08-10 1999-08-10 Composiciones hemostaticas de colageno tipo i y tipo iii para usarse como sellador vascular y vendaje para heridas.
EP99943668A EP1105051A4 (fr) 1998-08-10 1999-08-10 Compositions hemostatiques a base de collagene de type i et de type iii, a utiliser en tant que produit de scellement vasculaire et pansement
JP2000564526A JP2002524110A (ja) 1998-08-10 1999-08-10 血管密封材および創傷被覆材として用いるためのｉ型コラーゲンおよびｉｉｉ型コラーゲン止血性組成物
CA002339575A CA2339575A1 (fr) 1998-08-10 1999-08-10 Compositions hemostatiques a base de collagene de type i et de type iii, a utiliser en tant que produit de scellement vasculaire et pansement
AU56718/99A AU5671899A (en) 1998-08-10 1999-08-10 Collagen type i and type iii hemostatic compositions for use as a vascular sealant and wound dressing

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