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WO1998000161A1 - Systemes a base de fibrine permettant d'effectuer l'administration regulee de produits medicinaux - Google Patents

Systemes a base de fibrine permettant d'effectuer l'administration regulee de produits medicinaux Download PDF

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Publication number
WO1998000161A1
WO1998000161A1 PCT/US1997/008909 US9708909W WO9800161A1 WO 1998000161 A1 WO1998000161 A1 WO 1998000161A1 US 9708909 W US9708909 W US 9708909W WO 9800161 A1 WO9800161 A1 WO 9800161A1
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Prior art keywords
medicinal
protein
gel
inhibitor
fibrin
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PCT/US1997/008909
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English (en)
Inventor
Garfield P. Royer
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Buford Biomedical, 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.)
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Publication date
Application filed by Buford Biomedical, Inc. filed Critical Buford Biomedical, Inc.
Priority to AU31431/97A priority Critical patent/AU3143197A/en
Publication of WO1998000161A1 publication Critical patent/WO1998000161A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin

Definitions

  • This invention relates generally to a fibrin based bio-erodible delivery system which enables timed release of medicinals including proteins and small molecules. Fibrinogen is converted to fibrin in the presence of the medicinal which is entrapped when the fibrin gels.
  • Proteins either currently being administered by physicians or under investigation include growth factors, interferons, colony stimulating factors, and interleukins. In nature, these molecules may act locally as paracrine agents; i.e., they interact with and activate nearby cells. Further, they can be pleiotropic, i.e., they can activate or stimulate more than one kind of cell.
  • BGH bovine growth hormone
  • Bio-erodible polymers have been used for encapsulation of numerous classes of drugs (U.S. Patent No. 4,349,530; Royer, G.P., et al, J. Parenteral Science & Technol.. 37, 34 (1983); Lee, T.K., et al, Science. 213, 233 (1981); WO91/06287 (1991); WO93/25221 (1993), all of which are hereby incorporated by reference).
  • Synthetic polymers and copolymers of lactic acid and glycolic acid have been extensively investigated (U.S. Patent 5,122,367; Langer, Science, 249, 1927 (1990); U . S . Patent 4,983,393 (1991)).
  • U.S. Patent 4,983,393 discloses a composition for use as an intra-vaginal insert comprising agarose, agar, saline solution glycosaminoglycans, collagen, fibrin and an enzyme.
  • U.S. Patent 3,089,815 discloses an injectable pharmaceutical preparation composed of fibrinogen and thrombin. No provisions are made for protection of the medicinals from the action of thrombin.
  • PCT Application WO/92/09301 discloses fibrin glue that is supplemented with at least one growth factor.
  • U.S. Patents, 4,377,572 and 4,627,879 describe the use of fibrin in externally applied tissue sealant and topical wound treatments.
  • bio-erodible carriers are hydrophobic in nature and produce acid in conjunction with their hydrolysis. Examples include polymers of alpha hydroxy acids and various dicarboxylic acids. Although useful for delivery of small molecules and some polypeptides of low molecular weight, PLGA (co-polymer of lactic acid and glycol ic acid), for example, is not generally useful for proteins (Langer, R., Science 249, 1527 (1990).
  • fibrinogen is converted to fibrin which aggregates to form a strong gel.
  • factor XIII is present the gel is further stabilized by a specific enzyme-catalyzed transpeptidation reaction which covalently links fibrin segments. Formation of a fibrin -natri- ⁇ from fibrinogen
  • thrombin catalyzes the conversion of fibrinogen to fibrin, it also activates Factor XIII to become Factor XIII.
  • the primary function of thrombin is to convert fibrinogen to fibrin Similar to most proteases, thrombin will catalyze the rapid hydrolysis of small molecules and proteins, other than its natural substrate, examples include
  • Pre-formed fibrin has been used as an excipient for formation of implants combination with various inorganic chemicals (Brown, R G , et al , US Patent 4,393,0 1) These implants have been used for delivering steroids in farm animals Fibrin is isolated, dried at high temperature and powdered to form the starting material A drug, of low molecular weight, and other components are mixed prior to pelletization Similar pre-formed fibrin preparations of bov ine origin hav e been used (again in combination with other materials) for formation of human prosthetic devices (Capperauld, R., et al., Surgery. Gyn. and Ob. 144, 3 (1977)).
  • Plasmin results from the activation of the precursor protein plasminogen. This process is inhibited by low molecular weight compounds such as amino caproic acid and trans-4-(aminomethyl) cyclohexanecarboxylic acid (AMCHA). The latter compound is more potent than amino caproic acid and is the active ingredient in an FDA approved hemostatic having the trade name "Cyklokapron.”
  • AMCHA trans-4-(aminomethyl) cyclohexanecarboxylic acid
  • the subject invention relates to a medicinal delivery system based on the enzyme-catalyzed conversion of fibrinogen to fibrin, which forms a gel thus entrapping the medicinal.
  • a thrombin inhibitor is added along with the medicinal protein to protect the medicinal protein from fragmentation by the action of thrombin.
  • the erosion rate of the matrix is altered by incorporation of fibrinolysis inhibitors, adjusting the concentration of matrix components, and including Factor XIII at various levels.
  • the invention also includes methods for obtaining sustained release of a medicinal and treating pain comprising administering the delivery systems of the invention to a mammal.
  • the invention includes methods of synthesizing a drug delivery system comprising the steps of mixing fibrinogen, thrombin, medicinal, and other optional components such as inhibitors of fibrinolysis, Factor XIII, albumin and collagen, and shaping the mixture.
  • kits comprising the components needed to make the delivery system.
  • FIGURE 1 shows an idealized release profile of the subject invention.
  • FIGURE 2 shows a release profile of azo-albumin from a disc of fibrin matrix (13mm x 3mm).
  • the attributes of a delivery system for medicinal proteins include.
  • the release profile is adjustable by varying preparative conditions, components, and component concentrations.
  • the present invention relates to a fibrin based delivery system for the controlled release of medicinals including proteins and small molecules.
  • Thrombin catalyzed polymerization of fibrinogen can be employed to entrap medicinal proteins to produce bio-erodible dosage forms in a variety of shapes. Absence of chemical cross-linking agents prevents potentially harmful modification of the medicinal protein or non-protein drug
  • Fibrinogen is available commercially or it can be isolated from plasma, for example, by alcohol fractionation. Cryoprecipitates containing fibrinogen are alternatively used.
  • thrombin is also commercially available Alternatively, some fractions of fibrinogen contain sufficient thrombin to catalyze the gelation reaction in the presence of added CaCl 2 .
  • Thrombin inhibitors such as antithrombin III, hirudin and hirudin fragments (see 1995 Sigma Catalog) are commercially available. These inhibitors are useful when the medicinal protein can be cleaved (and rendered inactive) by thrombin Calcium is available in the form of CaCl 2 solution, CaCl 2 finely ground, poorly soluble calcium compounds such as encapsulated calcium CaCO 3 , and calcium propionate. Calcium ion can be withheld until after the dosage form is shaped. For example, after dispersion of the mixture (Ca-free) into droplets, finely ground Ca salts or solutions of Ca 2+ can be added to bring about gelation.
  • Biocompatible additives such as albumin, collagen, globulin, polyvinylpyrrolidone, polyethyleneglycol, polylysine, etc. are optionally added to alter the release profile of the delivery system.
  • Fibrinolysis catalyzed by the enzyme plasmin, is slowed by Factor XIII- induced stabilization. Therefore, including Factor XIII will reduce the erosion rate and extend the lifetime of the dosage form.
  • the erosion rate is reduced and the lifetime of the dosage form is extended by incorporation of fibrinolysis inhibitors such as alpha-2-antiplasmin, aprotinin, and AMCHA.
  • fibrinogen 10-90 mg/ml
  • medicinal protein .01-15 mg/ml
  • thrombin inhibitor 0.01 -10 unit/ml
  • thrombin 0.01-10 unit/ml
  • calcium .1-1M
  • the medicinal protein is mixed and allowed to react at room temperature.
  • the medicinal protein and the optional thrombin inhibitor are added and the mixture dispersed with stirring into a water-immiscible medium such as mineral oil or vegetable oil.
  • the temperature is optionally raised, for example, to 37°C. The temperature should not be high enough to denature the protein.
  • Factor XIII typically, .1-1 ⁇ M is used.
  • an amine-acceptor is used with the Factor XIII such as a lysine containing peptide (e.g., polylysine).
  • a fibrinolysis inhibitor is optionally added.
  • the delivery system can be formed as beads, granules, microspheres (100-200 microns), threads, cylinders, disks, films or cell-sized microspheres (less than 100 microns) using techniques presented herein and known to those skilled in the art.
  • Microbeads can be formed by dispersing a mixture of components in a water- immiscible medium with stirring. Subsequently, bead stabilization is accelerated by increasing the temperature to 37°C. Other geometric forms are produced using a similar two-step process. Adjustments of component concentrations and order of addition also permit direct injection of a reaction mixture which solidifies at 37°C in the body.
  • Implantable discs can be made, for example, by mixing all components at room temperature or below, pouring the mixture into a cylindrical mold and then curing at 37°C. The extruded fibrin cylinder is then sliced into discs.
  • Sub-batches of beads can be prepared with relatively low levels of Factor XIII or an inhibitor of fibrinolysis. These sub-batches can be used to constitute blends of beads. To illustrate, when these blends of beads contain proportionately more of Factor XIII, the release is relatively slow. Blends of beads weighted toward low levels of Factor XIII release drug relatively quickly in proportion to the faster erosion rate.
  • proportions of thrombin and fibrinogen see e.g., Example 3
  • direct injection of a liquid is possible.
  • fibrinogen, thrombin, calcium chloride, along with optional additives such as Factor XIII, a fibrinolysis inhibitor, albumin, etc. are mixed and allowed to react. Prior to gelation, the medicinal protein and the optional thrombin inhibitor are added. The mixture is injected, s.c, after which the formulation becomes a solid at body temperature.
  • Fibrinolysis inhibitors are optionally added to extend the residence time of the formulation.
  • Inhibitors can be included in microbeads which are included within the formulation or which are delivered separately. These "guardian" beads release inhibitor at a rate which controls erosion of the fibrin matrix.
  • Simultaneous use of free and bead-entrapped fibrinolysis inhibitor such as AMCHA can be used advantageously to control fibrinolysis and therefore the residence time.
  • this approach can be employed to preserve the fibrin depot for a period sufficiently long to permit release of most of the drug AMCHA can be entrapped in PLGA (50:50) microspheres which are small enough to be injected using commonly used procedures and instruments.
  • Fibrin dosage forms of the subject invention exhibit residence times in vivo of up to three weeks or more.
  • the term “medicinal” includes proteins as well as small molecule agents.
  • the term “protein” includes naturally occurring proteins, recombinant proteins, protein derivatives and polypeptides.
  • Medicinal proteins useful in the subject invention include colony stimulating factors (CSF) including G-CSF, GM-CSF, and M-CSF; erythropoietin (EPO); interleukins, IL-2, IL-4, IL-6, etc; interferons; growth factors (GF) including epidermal-GF, nerve-GF; tumor necrosis factor (TNF); hormones/bioactive peptides; ACTH; angiotensin, atrial natriuretic peptides, bradykynin, dynorphins/endorphins/ ⁇ -lipotropin fragments, enkephalin, gastrointestinal peptides including gastrin and glucacon; growth hormone and growth hormone releasing factors; luteinizing hormone and releasing hormone; melanocyte stimulating hormone; neuroten
  • the matrices of the invention are very suitable for the continuous release of therapeutically active proteins and peptides (see table below) over extended periods of time, i.e., 1-6 days, 1, 2, 3 or 4 weeks or 1-2 months.
  • extended periods of time i.e., 1-6 days, 1, 2, 3 or 4 weeks or 1-2 months.
  • the extent of the systemic (parenteral) treatment indications in humans is reflected by the examples in the following table.
  • G-CSF Hematopoietic growth factor bone marrow failure.
  • G-CSF, GM-CSF, M-CSF, IL-3 Also im uno adjuvant, adjunct to myelosuppressive chemotherapy
  • adenosine deaminase heritable immunodeficiencies nucleoside phosphorylase
  • enzymes such as ceredase heritable lysosomal diseases such as Gaucher disease enzymes such as arylsulfatases heritable mucopolysaccharidoses such as Hurlers
  • pituitary hormones such as pituitary failure syndromes (hypothalamic growth hormone, gonadotrophins, pituitary disorders) vasopressin, et al
  • cytokines such as TNF, or immunoadjuvant in vaccine administration GM-CSF, interleukins such as hepatitis, herpes viruses, parasitic as IL-l, IL-2, IL-12 diseases, and cancer
  • interferons alpha, beta and hairy cell leukemia, viral infections gamma
  • blood clotting factors such as bleeding disorders such as hemophilia factor VIII
  • vaccines such as hepatitis prevention of bacterial viral and vaccines, herpes vaccines, parasitic diseases, cancers such as antimicrobial vaccines, cancer melanoma vaccines
  • the medicinal protein is protected as described in commonly owned U.S. Serial No. 08/571,613 hereby incorporated by reference in its entirety.
  • Medicinal proteins can be protected from proteolysis or other reactions by chemical modification of sidechains adjacent to susceptible bonds or which constitute reactive functional groups.
  • the medicinal protein can be physically protected, that is, it can be employed as a crystal or solid matrix such as gelatin micro-beads. Such small particles can be dispersed into the fibrin liquid prior to gelation and then trapped within the depot. Any matrix which does not react with medicinal can be employed as long as it is safe, bio- erodible, and does not interfere with the release.
  • microbeads of the subject invention containing medicinal are encapsulated in the delivery system described in commonly owned U.S. Ser. No. 08/571,613, for example microbeads of the subject invention in a delivery system comprising albumen and/or collagen crosslinked with oxidized dextran.
  • the present delivery system is also applicable to formulations with non-protein medicinals, including but not limited to alkaloids, steroids, terpenoids, amino acid derivatives, nucleoside/nucleotide derivatives, polynucleotides, carbohydrates, polysaccharides, lipids, lipopolysaccharides, purines, pyrimidines and derivatives of same.
  • non-protein medicinals including but not limited to alkaloids, steroids, terpenoids, amino acid derivatives, nucleoside/nucleotide derivatives, polynucleotides, carbohydrates, polysaccharides, lipids, lipopolysaccharides, purines, pyrimidines and derivatives of same.
  • Advantageous small molecule drugs include: analgesics, anesthetics (e.g., lidocaine or pramocaine), antialcohol preparations, anti-infectives, antiseptics (e.g., compounds of monovalent silver, silver benzoate, PVP-I 2 ), anticoagulants, anticancer drugs, antidepressants, antidiabetic agents, antihypertensive drugs, antiinflammatory agents (e.g., hydrocortisone), antinauseants, anorexics, antiulcer drugs, cardiovascular drugs, contraceptives, decongestants, diuretics, hormones/antihormones, immunosuppressives, narcotic detoxification agents, uricosuric agents, and wound healing promoters such as deoxyribonucleosides (see table below).
  • analgesics e.g., lidocaine or pramocaine
  • antialcohol preparations e.g., anti-infectives, antiseptics (
  • the delivery systems of the invention are also suitable for the prolonged, controlled release of non-proteinaceous compounds with therapeutic activity.
  • a matrix can be constructed that will enable the steady release of a local anesthetic such as lidocaine over several weeks such that an adequate concentration can be maintained for 1-6 days, 1, 2, 3 or 4 weeks or 1-2 months, in the immediate vicinity of nerve roots damaged by a pathologic vertebral fracture due to cancer thus relieving severe pain without causing irreparable loss of function.
  • fibrin discs containing local anesthetic are fibrin discs containing local anesthetic.
  • the discs e.g., 0.8cm in dia. x .3cm
  • anesthetic e.g., lidocaine or marcaine
  • one disc is implanted laterally and one disc medially. This approach obviates systemic use of narcotic pain killers.
  • antibiotics such as penicillins, bacterial infections, e.g., bone and joint beta-lactams, amino-glycosides, infections, soft tissue infections in areas macrolides, tetracyclines, etc. not sufficiently vascularized, Streptococcal sore throat or E. Coli urinary tract infection
  • Antifungals such as nystatin thrush and other localized fungal infections
  • immunosuppressants such as organ/tissue heterotransplantation cyclosporin
  • anticoagulants such as heparin, pulmonary embolus, vascular diseases coumadin diuretics such as furosemide cardiac failure
  • vermifuge such as mebendazole various helminth parasitism
  • antimalarials such as treatment and prophylaxis of malarial chloroquine parasitism
  • anesthetics such as lidocaine, cancer pain, arthritis pain, post surgical pain marcaine or pramocaine
  • Formulations made possible by this invention enable the local therapeutic application of medicinals.
  • infected wounds or chronically infected ulcers such as those seen in patients with diabetes or vascular insufficiency to the lower extremities benefit from preformed films based on this invention that release debriding enzymes in combination with antibiotics and growth factors such as TGF- ⁇ or PDGF, to promote healing.
  • the healing of clean surgical incisions is enhanced by the local application of beads or implants that release growth factors and optionally anti-infectives or a local anesthetic to relieve patient pain
  • Particularly advantageous compounds for use in the subject invention are those in crystalline form.
  • Preformed films for transdermal delivery or for topical application as bandages can also be used.
  • the film may be used to deliver non-proteinaceous drugs such as anti-infectives and wound healing promoters.
  • FIG. 1 An idealized release profile is shown in Figure 1.
  • the concentration of medicinal in the vicinity of the bead reflects the rate of internal degradation of the three different classes of gel matrices.
  • the profile shown depicts the system with identical medicinal concentration in all classes. For example, to have higher levels of medicinal released at a later period, more medicinal would be incorporated in the Class III beads as shown in this example. Release profiles can be obtained from zero order release to those involving late-stage bursts. It is also possible to administer more than one medicinal in the same treatment regimen. The drugs can be released simultaneously or sequentially.
  • rate DA(d[m]/dx) (1)
  • D is the diffusion coefficient
  • A is the surface area d[m]/dx is the medicinal gradient Stokes law is also applicable
  • r is the radius of the medicinal
  • v is the viscosity of the medium.
  • the diffusion coefficient (D) is inversely related to the viscosity of the medium (v), the size of medicinal (r), and also the erosion rate of the device.
  • the matrix density and degree of cross-linking influence the viscosity. As the fibrin matrix is broken down, v is reduced which increases D which in turn increases the rate of diffusion. In the extreme case involving a dense matrix and a large medicinal molecule, the rate will be very low or zero until the breakdown occurs.
  • the volume of a sphere is given by (4)
  • V 4/3 ⁇ r 3 (4)
  • a bead of a given volume will have less surface area than multiple beads with the same aggregate volume.
  • a blend of beads with a range of radii will tend to give a release profile resembling zero order.
  • Medicinal matrix of the invention is administered to a human or other mammal as beads, disks, threads and implants of various other shapes using techniques known to those skilled in the art Beads would be normally administered via needle subcutaneously, intramuscularly, intraperitoneally, or intravenously for cell-sized microbeads Tablets and capsules are used for oral delivery
  • a liquid formulation can be directly injected subcutaneously, intramuscularly and intraperitoneally, which solidifies soon after injection
  • the liquid formulations are made such that the mixture remains a liquid until after injection See Example 3
  • Films can be cast using the preparations described herein, for example the preparation of Example 4
  • One approach is to use a multi-channel pipette and apply the preparation to a glass plate
  • the texture of the resulting material varies depending on the humidity and temperature
  • the preparation is applied directly to the wound or to a bandage which is in turn placed on the wound
  • Medicinals for topical preparations include, for example, anesthetics (lidocaine, pramocaine), antiseptics (PVP-I 2 , compounds of monovalent silver, polymyxin B, neomycin, gramicidin) and living cells.
  • the preparations of the invention provide beneficial osmotic draw as well as protection, pain relief and infection control
  • agents such as growth factors or cultured cells
  • Medicinal matrix can be administered concomitant with surgical procedures. Examples of this include 1) an antibiotic matrix following abdominal surgery, 2) matrix containing cytotoxic chemotherapeutic drug following tumor removal, and 3) matrices containing adjuvants/antigens following tumor removal.
  • implants can be placed under the skin adjacent to the joint capsule, or elsewhere following orthopedic surgery.
  • Solution A 400 ⁇ l was made containing fibrinogen (25 mg/ml) in buffer-- Hepes, 30 mM, pH 7.2, 0.15 M in NaCI.
  • Solution B 100 ⁇ l was made containing the enzyme thrombin (about 5 units) and CaCl 2 (1.6 M) in the same buffer.
  • Solution C (lOO ⁇ l) was made containing protein (azo-albumin)(2mg/ml), and antithrombin III/heparin in sufficient quantity to neutralize the thrombin. Solutions were equilibrated to temperature (20°C).
  • Microspheres were made using known methods with or without low concentrations of surfactants.
  • the mixture was injected into the stirred water-immiscible medium at room temperature The temperature was then raised to 37°C and the stirring was continued for 3 hr.
  • the microspheres were collected by centrifugation and then washed quickly with ether on a filter.
  • thrombin concentration is adjusted to allow direct injection.
  • Solutions A, B and C are mixed as previously described and the mixture is injected s.c. into a mammal.
  • Example 4
  • Example 1 The procedure of Example 1 is repeated using other geometric configurations including films containing antibiotics and wound healing promoters.
  • the reaction mixture is poured onto a flat glass plate with borders to provide boundaries of the desired dimensions.
  • the glass plate is warmed to 37°C and allowed to stand for 3-8 hours in a humidity controlled chamber.
  • Solution A 400 ⁇ l was made containing fibrinogen (25mg/ml) in buffer— Hepes, 30 M, pH 7.2, 0 15 M in NaCI. Finely ground lidocaine (50 mg) was then suspended therein.
  • Solution B (lOO ⁇ l) was made containing thrombin (5 units) and CaCl 2 (1.6 M) in the same buffer. Solutions A and B were equilibrated to 20°C and mixed When using a matrix protectant, such as AMCHA, it is included in Solution A by direct dissolution or by suspension if in the form of PLGA microspheres AMCHA should be at least 10 ⁇ g/ml in the immediate vicinity of the drug depot
  • Example 7 The procedure of Example 1 was repeated but with 10-40% by weight of a crystalline or amorphous solid medicinal protein suspended in the reaction mixture.
  • Example 7 The procedure of Example 1 was repeated but with 10-40% by weight of a crystalline or amorphous solid medicinal protein suspended in the reaction mixture.
  • Fibrin stock solution (1 ml/3%) was mixed with 50 mg of gentamicin sulfate.
  • Thrombin solution (25 ⁇ l/2.5 units) was added and the mixture was dispensed in 200 ⁇ l aliquots to screw-cap vials. After incubation for 1 hr at 37° the vials were allowed to stand at room temperature overnight. The samples were stored at 0-4°.
  • the buffer (1 ml/PBS with 0.01% azide) was pipetted into four vials, two of which served as controls. The buffer was changed at 24-hr intervals. Gentamicin concentration was determined using a standard curve prepared with known amounts using the TNBS test (Habeeb, A.F.S. A. 1966 Anal. Biochem. 14, 328). A release profile is shown below:

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Abstract

Cette invention concerne une matrice bio-érodable à base de fibrine, laquelle permet d'effectuer l'administration régulée de produits médicinaux, y compris de produits thérapeutiques à base de protéines. Cette invention concerne également un procédé permettant d'effectuer l'administration régulée de médicaments.
PCT/US1997/008909 1996-05-24 1997-05-27 Systemes a base de fibrine permettant d'effectuer l'administration regulee de produits medicinaux WO1998000161A1 (fr)

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AU31431/97A AU3143197A (en) 1996-05-24 1997-05-27 Fibrin-based systems for the controlled release of medicinals

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US08/653,615 1996-05-24

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1015570A1 (fr) * 1997-09-19 2000-07-05 V.I. Technologies, Inc. Microbilles de fibrine et leurs utilisations
US6942880B1 (en) * 2001-04-09 2005-09-13 Medtronic, Inc. Autologous platelet gel having beneficial geometric shapes and methods of making the same
US9446166B2 (en) 2013-01-24 2016-09-20 Ethicon, Inc. Fibrin sealant compositions with chemical crosslinking

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3089815A (en) * 1951-10-11 1963-05-14 Lieb Hans Injectable pharmaceutical preparation, and a method of making same
US4393041A (en) * 1980-04-25 1983-07-12 International Minerals & Chemical Corp. Fibrin binder/carrier for active biochemical agents
US4548736A (en) * 1983-08-29 1985-10-22 Wisconsin Alumni Research Foundation Preparation of protein films
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
US5290552A (en) * 1988-05-02 1994-03-01 Matrix Pharmaceutical, Inc./Project Hear Surgical adhesive material
US5631011A (en) * 1991-06-17 1997-05-20 Wadstroem; Jonas Tissue treatment composition comprising fibrin or fibrinogen and biodegradable and biocompatible polymer
US5643596A (en) * 1993-11-03 1997-07-01 Clarion Pharmaceuticals, Inc. Hemostatic patch

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3089815A (en) * 1951-10-11 1963-05-14 Lieb Hans Injectable pharmaceutical preparation, and a method of making same
US4393041A (en) * 1980-04-25 1983-07-12 International Minerals & Chemical Corp. Fibrin binder/carrier for active biochemical agents
US4548736A (en) * 1983-08-29 1985-10-22 Wisconsin Alumni Research Foundation Preparation of protein films
US5290552A (en) * 1988-05-02 1994-03-01 Matrix Pharmaceutical, Inc./Project Hear Surgical adhesive material
US5631011A (en) * 1991-06-17 1997-05-20 Wadstroem; Jonas Tissue treatment composition comprising fibrin or fibrinogen and biodegradable and biocompatible polymer
US5171579A (en) * 1991-10-11 1992-12-15 Genetics Institute, Inc. Formulations of blood clot-polymer matrix for delivery of osteogenic proteins
US5643596A (en) * 1993-11-03 1997-07-01 Clarion Pharmaceuticals, Inc. Hemostatic patch

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 1994, Volume 20, Number 4, HO et al., "Fibrin-Based Drug Delivery Systems. II. The Preparation and Characterization of Microbeads", pages 535-546. *
JOURNAL OF BURN CARE REHABILITATION, May/June 1994, Volume 15, BOYCE et al., "Delivery and Activity of Antimicrobial Drugs Released from Human Fibrin Sealant", pages 251-255. *
JOURNAL OF CONTROLLED RELEASE, 1995, Volume 34, HO et al., "Fibrin-Based Drug Delivery Systems III: The Evaluation of the Release of Macromolecules from Microbeads", pages 65-70. *
JOURNAL OF PARENTERAL SCIENCE AND TECHNOLOGY, January-February 1991, Vol. 45, No. 1, SENDEROFF et al., "Fibrin Based Drug Delivery Systems", pages 2-6. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1015570A1 (fr) * 1997-09-19 2000-07-05 V.I. Technologies, Inc. Microbilles de fibrine et leurs utilisations
EP1015570A4 (fr) * 1997-09-19 2003-08-06 Vi Technologies Inc Microbilles de fibrine et leurs utilisations
US6737074B2 (en) 1997-09-19 2004-05-18 Hadasit Medical Research & Development Ltd. Methods of separating cells, transplanting cells and engineering tissue using fibrin microbeads
US6942880B1 (en) * 2001-04-09 2005-09-13 Medtronic, Inc. Autologous platelet gel having beneficial geometric shapes and methods of making the same
US9446166B2 (en) 2013-01-24 2016-09-20 Ethicon, Inc. Fibrin sealant compositions with chemical crosslinking

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