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WO2008132233A1 - Composition, procédés et kits destinés à la prévention d'adhérences - Google Patents

Composition, procédés et kits destinés à la prévention d'adhérences Download PDF

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Publication number
WO2008132233A1
WO2008132233A1 PCT/EP2008/055363 EP2008055363W WO2008132233A1 WO 2008132233 A1 WO2008132233 A1 WO 2008132233A1 EP 2008055363 W EP2008055363 W EP 2008055363W WO 2008132233 A1 WO2008132233 A1 WO 2008132233A1
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WIPO (PCT)
Prior art keywords
matrix
adhesions
histone deacetylase
composition
tributyrin
Prior art date
Application number
PCT/EP2008/055363
Other languages
English (en)
Inventor
Serge Gisler
Anna Jen
Manuela Maissen
Peter Richards
Original Assignee
Kuros Biosurgery Ag
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Publication date
Application filed by Kuros Biosurgery Ag filed Critical Kuros Biosurgery Ag
Publication of WO2008132233A1 publication Critical patent/WO2008132233A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/046—Fibrin; Fibrinogen
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • 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
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes

Definitions

  • the present invention is in the field of pharmaceutical compositions for the treatment and/or prevention of adhesions.
  • adhesions which is a process in which adjacent tissues or organs bind to each other, can be caused by infections, inflammation diseases, surgery procedures or trauma. Following abdominal surgery, the incidence of the formation of adhesions may be as high as 90%.
  • adhesions Pain, discomfort, immobility and retarded wound healing are common complications due to adhesions formation; moreover, depending on the tissues involved, adhesions can cause various disorders. In the eye, adhesion of the iris to the lens can lead to glaucoma. In the intestines, adhesions can cause partial or complete bowel obstruction which is life threatening. Intrauterine adhesions are known as the Asherman syndrome. Pelvic adhesions can lead to infertility and reproductive problems. Problems associated with adhesions often require a further operative procedure in order to remove the adhesions. This could have the major drawback of leading to new adhesion formation.
  • adjunctive treatments have been investigated to reduce or prevent post surgical adhesions. Most of these treatments, however, show inconsistent results. In an attempt to reduce the inflammatory reaction at the wounded site following surgery, the use of corticosteroids, NSAIDS, histamine antagonists and calcium channel blockers have been investigated. More recently, barrier materials have been suggested for the prevention of post surgical adhesions. These include, but are not limited to, Hyskon®, Ringer's lactate, Interceed® (oxidized regenerated cellulose), Polaxamer 407® (temperature dependent polymer), Gore-Tex® (expanded polytetrafluorethylene) and SepraFilm® (hyaluronic acid derivative film).
  • Hyskon® may lead to serious side-effects such as anaphylactic shock (Trimbos Kemper and Veering, 1989), Interceed® and poloxamer 407® can only be applied on dry, non bleeding surfaces while GoreTex® is non-degradable and generally require a second operative procedure to be removed.
  • U.S. Patent No. 6,051,648 to Rhee et al. describes the use of a crosslinked polyethylene glycol polymer for preventing the formation of adhesions following surgery.
  • the polyethylene glycol polymer is applied as a coating to act as a protective barrier layer around the tissues. This activity is similar to the fabric barrier previously noted, functioning only as a physical degradable barrier between adjacent tissues.
  • WO 02/087563 to Angiotech Pharmaceuticals describes compositions and methods for the treatment of inflammatory conditions and more particularly for the prevention of adhesions.
  • the composition comprises a polypeptide or a polysaccharide and an anti-micro tubule agent dispersed in a carrier.
  • Administration of cytotoxic drugs such as paclitaxel, docetaxel, vincristine and colchicine dispersed first in a carrier and subsequently into hyaluronic acid hydrogels are exemplified.
  • WO 92/22312 to Wadstrom describes combinations of fibrin sealants and biocompatible polymers which may be useful for the prevention of post surgical adhesions.
  • the present invention is related to a composition comprising an effective amount of one or more histone deacetylase inhibitors for use in the treatment and/or prevention of adhesions.
  • said composition further comprises a matrix, most preferably a fibrin matrix.
  • the matrix may be a synthetic matrix
  • the medicament further comprises a carrier, such as albumin, preferably serum albumin.
  • a carrier such as albumin, preferably serum albumin.
  • the histone deacetylase inhibitor is selected from the group consisting of butyrate salts, isovalerate, valerate, 4- phenylbutyrate, sodium phenyl butyrate, propionate, butrymide, isobutyramide, phenylacetate, 3-bromopropionate, valproic acid, tributyrin and mixtures thereof, preferably tributyrin.
  • composition of the present invention is preferably used for the treatment and/or prevention of adhesions which occur after a surgical treatment, i.e. post-surgery.
  • the present invention is also related to a kit comprising a) a first precursor component, b) a second precursor component capable of forming a three-dimensional matrix when combined with the first precursor component of step a) and c) one or more histone deacetylase inhibitors, as described above.
  • the first precursor component comprises thrombin. According to another preferred embodiment, the first precursor component further comprises a calcium ion source.
  • the second precursor component comprises fibrinogen.
  • the histone deacetylase inhibitor is dispersed in a carrier.
  • the histone deacetylase inhibitor is mixed with the carrier. More preferably, the histone deacetylase inhibitor and the carrier are mixed with the first precursor component.
  • the carrier is as described above.
  • the present invention is also related to a method for preparing a composition for preventing adhesion comprising a matrix comprising one or more histone deacetylase inhibitors, the method comprising: a) providing a first precursor component, b) providing at least a second precursor component capable of forming a three-dimensional matrix when combined with the first precursor component of step a), c) providing one or more histone deacetylase inhibitors, and d) mixing the components provided in steps a), b) and c) to form the composition
  • the matrix, the first precursor component, the second precursor component, the one or more histone deacetylase inhibitors and the carrier are as described above.
  • the present invention is also related to the use of the above described composition in the manufacture of a medicament for the prevention of adhesions.
  • compositions for the prevention of adhesions and methods of making and using thereof are described herein.
  • the composition contains a matrix, at least one active agent, such as a histone deacetylase inhibitor, and optionally at least one carrier.
  • kits containing a first precursor component, a second precursor component capable of forming a three- dimensional matrix when combined with the first precursor component, at least one or more active agents, such as a histone deacetylase inhibitor, and optionally one or more carriers and/or excipients.
  • the histone deacetylase inhibitor is a short chain fatty acid compound selected from the group consisting of butyrate salts, isovalerate, valerate, 4-phenylbutyrate, sodiumphenyl butyrate, propionate, butyrimide, isobutyramide, phenylacetate, 3-bromopropionate, valproic acid, tributyrin and mixtures thereof.
  • the histone deacetylase inhibitor is tributyrin.
  • the histone deacetylase inhibitor(s) may be solubilised or dispersed in a carrier.
  • the carrier is an oil-in-water emulsion.
  • the emulsion contains an oil component containing a therapeutically effective amount of a histone deacetylase inhibitor, dispersed in an aqueous continuous phase.
  • the carrier is albumin.
  • the carrier is serum albumin and more preferably Human Serum Albumin (HSA).
  • the matrix is a fibrin matrix containing one or more histone deacetylase inhibitors. Fibrin matrices are generally formed by combining a first and a second precursor component.
  • the first precursor component contains thrombin and the second precursor component contains fibrinogen.
  • the first precursor component can further contain a calcium ion source.
  • Histone deacetylase inhibitors may be mixed with either one of the precursor components, although preferably with the first precursor component.
  • the matrix is a synthetic matrix.
  • the histone deacetylase inhibitor can be incorporated in the matrix (also referred to herein as "supplemented matrix") using a variety of methods.
  • the histone deacetylase inhibitor is directly mixed into the matrix, resulting in the histone deacetylase inhibitor being physically entrapped in the matrix.
  • the histone deacetylase inhibitor is first solubilised or dispersed in a carrier prior to be incorporated into the matrix, thus the combination of carrier and histone deacetylase inhibitor is physically entrapped within the matrix.
  • the histone deacetylase inhibitor is preferably releasably incorporated into the matrix.
  • the incorporation of histone deacetylase inhibitor in a matrix leads to a controllable release profile of the drug from the matrix.
  • the release profile can further be tailored by the choice of a carrier.
  • the supplemented matrices described herein are preferably injectable and are formed in situ at the application site at physiological conditions from liquid (at 25°C, or at physiological temperature) precursor component(s).
  • the supplemented matrices can be in the form of a gel, a hydrogel, a film, a paste, a cream, a spray, an ointment, a powder, a bandage, or a wrap.
  • compositions described herein can be used to treat and/or prevent adhesions, such as post-surgical adhesions.
  • Post-surgical adhesions can be the result of, for example, spinal or neurosurgical procedures, gynecological procedures, abdominal procedures, cardiac procedures, orthopedic procedures, reconstructive procedures, and cosmetic procedures.
  • the compositions may be used in other conditions in which unwanted tissue proliferation occurs, such as restenosis of arteries, repair of keloid or hypertrophic scars, hypertrophy which obstructs ducts, such as benign prostatic hypertrophy, and endometriosis.
  • Figure 1 shows the release profiles of radiolabelled tributyrin (percent retained radioactivity in fibrin) vs. time of buffer exchange (days) from a fibrin matrix where radiolabelled tributyrin is incorporated in the fibrin matrix with and without a carrier.
  • FIG 2 shows the release profiles of radiolabelled tributyrin solubilised or dispersed in a carrier from a first fibrin matrix (fibrin matrix No. 1) and a second fibrin matrix (Fibrin matrix No. 2) (percent retained radioactivity in fibrin) vs. time of buffer exchange (days).
  • the first fibrin matrix is prepared with a second precursor component comprising a higher amount of Factor XIII than the second precursor component of the second fibrin matrix.
  • Figure 3 shows the effect of tributyrin concentration (millimolar) on the recurrence of adhesion formation (percent adhesion formation).
  • Figure 4A shows the entrapment amount of tributyrin into Tissucol fibrin sealant prepared by the homogenization or vortexing methods.
  • Figure 4B shows the entrapment amount of tributyrin into Tissucol fibrin sealant or Tisseel fibrin sealant VHSD prepared by the homogenization method.
  • Figure 5A shows the release profile of tributyrin into Tissucol fibrin sealant prepared by the homogenization or vortexing methods.
  • Figure 5B shows the release profile of tributyrin into Tissucol fibrin sealant or Tisseel fibrin sealant VHSD prepared by the homogenization method.
  • Figure 6A shows the release profile of tributyrin into Tissucol fibrin sealant prepared by the homogenization or vortexing methods.
  • Figure 6B shows the release profile of tributyrin into Tissucol fibrin sealant or Tisseel fibrin sealant VHSD prepared by the homogenization method.
  • Figure 7 shows the effect of different tributyrin formulations on cell proliferation.
  • Microx refers to a material intended to interface with biological systems to treat, augment, or replace any tissue or function of the tissue depending on the material either permanently or temporarily.
  • the matrix can serve as a delivery device for active agents incorporated therein.
  • the matrices described herein are formed from liquid precursor components which are able to form a gel in the body at the site of need.
  • matrix gel
  • silant three- dimensional network
  • matrix three- dimensional network
  • matrix encompass partially or fully crosslinked polymeric networks. They may be in the form of a semi-solid, such as a paste, or a solid. Depending on the type of precursor materials, the matrix may be swollen with water but not dissolved in water, i.e. form a hydrogel, which stays in the body for a certain period of time.
  • Fibrin Matrix refers to a three-dimensional matrix formed from precursor components containing fibrinogen and thrombin, which crosslink in the presence of a calcium source, Factor XIIIa and optionally, one or more excipients present in the precursor components.
  • Synthetic matrix refers to a three-dimensional matrix formed from synthetic precursor components.
  • Naturalally occurring precursor components or polymers refers to molecules which can be found in nature.
  • Synthetic precursor components refers to molecules which do not exist in nature.
  • Crosslinking as generally used herein means the formation of covalent linkages. “Crosslinking” can also occur through the formation of non-covalent linkages, such as ionic bonds, hydrogen bonds, hydrophobic interactions, Van der Waals forces, etc., or combinations of covalent and non-covalent linkages.
  • “Supplemented matrix” as generally used herein refers to a matrix in which an active agent, such as one or more histone deacetylase inhibitors, is incorporated therein.
  • the matrix release the active agent over time by a variety of mechanisms including diffusion, degradation of the matrix, and combinations thereof.
  • Carrier as used herein means an agent that enhances the solubility or dispersability of an active agent or stabilizes an active agent, such as one or more histone deacetylase inhibitors, in an aqueous medium or a non-aqueous medium.
  • prevention refers to inhibiting completely or partially a biological response, as well as inhibiting an increase in a biological response.
  • prevention of adhesion refers to partially or completely inhibiting adhesion formation and adhesion reformation, as well as inhibiting an increase in adhesion formation and adhesion reformation.
  • Active agent or “Drug” as generally used herein refers to a compound which affects or modifies a biological process. Active agents are used for the treatment, prevention, or diagnosis (e.g., therapeutic, diagnostic, and prophylactic agents) of a disease or disorder in an animal, such as a human. In one embodiment, the active agent or drug is one or more histone deacetylase inhibitors.
  • Biocompatibility refers to the ability of a material to perform with an appropriate host response in a specific application. In the broadest sense, this means a lack of adverse effects to the body in a way that would outweigh the benefit of the material and/or treatment to the patient.
  • Conjugated unsaturated bond can refer both to alternation of carbon- carbon, carbon-heteroatom or heteroatom-heteroatom multiple bonds with single bonds. Double bonds spaced by a CH or CH 2 unit are referred to as "homoconjugated double bonds”.
  • Electrophilic group refers to functional groups which are capable of accepting an electron pair from a nucleophile in a polar-bond forming reaction.
  • electrophile and electrophilic groups are used synonymously.
  • Frunctionality as generally used herein means the number of reactive sites on a precursor molecule.
  • Reactive sites refer to nucleophilic and electrophilic groups that are able to react with each other at least, but not exclusively, under conditions in the human or animal body.
  • In situ formation refers to the ability of mixtures of precursor molecules which are substantially not crosslinked prior to and at the time of injection to form covalent or non-covalent linkages with each other at a physiological temperature at the site of injection in the body.
  • Multifunctional as generally used herein means more than one functional group per precursor molecule.
  • nucleophilic group refers to functional groups which are capable of donating an electron pair to an electrophile in a polar-bond forming reaction.
  • nucleophile is more nucleophile than H 2 O at physiological pH.
  • An example of a strong nucleophile is a thiol and refers to molecules which contain these functional groups.
  • nucleophile and nucleophic group are used synonymously.
  • Oligomer and polymers are used in the usual sense of the terms.
  • An oligomer is a low-molecular weight polymer. Oligomers typically contain between two and ten monomer units. As used herein, polymers typically contain more than 10 monomeric units.
  • physiological means conditions as they can be found in living vertebrates.
  • physiological conditions refer to the conditions in the human body such as temperature, pH, etc.
  • Physiological temperature means in particular a temperature range of between 35°C to 42°C, preferably around 37°C.
  • Polymeric network refers to the product of a process in which substantially all of the monomers, oligomers, or polymers used as precursor molecules are bound by intermolecular covalent linkages through their available functional groups to form a macromolecule.
  • Precursor molecules refers to molecules forming the polymeric network. Precursor molecules can be selected from functionalized monomers, oligomers and polymers.
  • Albumin refers generally to any protein with water solubility, which is moderately soluble in concentrated salt solutions, and experiences heat coagulation (protein denaturation).
  • compositions containing one or more active agent for the prevention and treatment of adhesions, methods of making and using thereof, and kits containing the composition are described herein. Further, uses of one or more active agents, such as one or more histone deacetylase inhibitors, for the manufacture of a medicament for prevention of adhesions, in particular for the prevention of adhesions following pelvic/abdominal or spinal surgery are also described herein.
  • the compositions contain natural or synthetic matrices having one or more active agents, such as histone deacetylase inhibitors, incorporated therein. The active agent(s) are released from the matrix over time.
  • the natural and synthetic matrices are biocompatible and biodegradable and can be formed in-vitro or in-vivo at the application site.
  • the active agent(s) is one or more histone deacetylase inhibitors.
  • Histone deacetylase inhibitors can be solubilised or dispersed in a carrier prior to their incorporation into the matrix and retain their full bioactivity.
  • Histone deacetylase inhibitors are releasably incorporated into matrices, using techniques that provide control over how and when and to what degree the histone deacetylase inhibitors are released, so that the matrix can be used as a medicated adhesion barrier (MAB), using the matrix as a controlled release vehicle.
  • MAB medicated adhesion barrier
  • compositions described herein contain one or more therapeutic, prophylactic, and/or diagnostic agents.
  • the active agent is a differentiating agent, such as a histone deacetylase inhibitor.
  • Differentiation therapy causes cells to differentiate to a more mature state where the cell does not proliferate but may remain functional.
  • Differentiation therapy has the main advantage of allow treatment of a disease or disorder, such the treatment of cancer, without the severe side-effects that are often observed with cytotoxic or cytostatic drugs.
  • the differentiation ability of cells is caused by gene reactivation due to the inhibition of histone deacetylase. This inhibition results in induction of the cyclin-dependant kinase inhibitor p27 and consequently downstream effects on Rb phosphorylation.
  • compositions containing one or more differentiating agents, and more particularly histone deacetylase inhibitors, such as tributyrin are particularly efficient in the prevention of adhesions formation.
  • histone deacetylase inhibitors can be utilized in the compositions described herein.
  • Histone deacetylase inhibitors have been shown to be potent inducers of growth arrest, differentiation, and/or apoptotic cell death of transformed cells in vitro and in vivo. Numerous such compounds are known in the literature. See, e.g., P. Dulski, Histone Deacetylase as Target for Antiprotozoal Agents, PCT Application WO 97/11366 (Mar. 27, 1997). Examples of such compounds include, but are not limited to: Trichostatin
  • Trichostatin C Trichostatin C
  • peptides such as: oxamflatin [(2E)- 5-[3-[(phenylsufonyl) aminol phenyll]-pent-2-en-4-ynohydroxamic acid, trapoxin A (--cyclic tetrapeptide (cyclo-(L-phenylalanyl-L-phenylalanyl-D- pipecolinyl-L-2-amino-8-oxo-9,10-epoxy-d ecanoyl)), depsipeptide, cyclic tetrapeptide (H. Mori et al, PCT Application WO 00/08048 (Feb.
  • apicidin cyclic tetrapeptide [cyclo(N ⁇ O-methyl-L-tryptophanyl-L-isoleucinyl- D-pipecoliny l-L-2-amino-8 ⁇ oxodecanoyl)], apicidin Ia, apicidin Ib, apicidin Ic, apicidin Ha, and apicidin lib, HC-toxin, cyclic tetrapeptide, cyclic tetrapeptide (WO 98/48825); and chlamydocin; hydro xamic acid-based hybrid polar compounds such as salicylihydroxamic acid, suberoylanilide hydroxamic acid, azelaic bishydroxamic acid, azelaic-1 -hydro xamate-9-anilide, M- carboxycinnamic acid bishydroxamide, 6-(3-chlorophenylureido)carpoic
  • histone deacetylase inhibitors are selected from the group consisting of butyrate salts, isovalerate, valerate, 4- phenylbutyrate, sodiumphenyl butyrate, propionate, butrymide, isobutyramide, phenylacetate, 3-bromopropionate, valproic acid, tributyrin and mixtures thereof.
  • the histone deacetylase inhibitor is a butyric acid prodrug.
  • the histone deacetylase inhibitor is tributyrin.
  • the butyric acid prodrug, tributyrin is a hydrophobic neutral short-chain fatty acid triglyceride containing three butyrate moieties esterified to glycerol. It has been approved as a food additive in the United States. It has been reported that tributyrin and its metabolite butyric acid inhibit proliferation, stimulate differentiation and induces apoptosis in a variety of tumour cell lines. Clinical trials with tributyrin and butyrate derivatives in cancer patients have already been started (Edelman et al. Cancer Chemother. Pharmacol. 2003. 51; 439-444. Conley et al. Clinical Cancer Research. 1998. 4; 629-634).
  • tributyrin a butyric acid derivative
  • tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell.
  • tributyrin is applied in a concentration range between about 3.4 to about 102 mM per milliliter of the composition, more preferably between 34 to 102 mM per milliliter of the composition.
  • the one or more active agents can be administered as the free acid or base or as a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making the acid-addition or base-addition salts thereof.
  • Example of pharmaceutically acceptable salts include but are not limited to mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, tolunesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic salts.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids
  • organic acids such as acetic, propionic, succinic, glycolic, ste
  • the pharmaceutically acceptable salts of the compounds can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the active agent(s) may exist as one or more stereoisomers.
  • stereoisomers refers to compounds made up of the same atoms bonded by the same bonds but having different spatial structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomers refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • optical isomer is equivalent to the term “enantiomer”.
  • racemate “racemic mixture” or “racemic modification” refer to a mixture of equal parts of enantiomers.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • enantiomeric enrichment refers to the increase in the amount of one enantiomer as compared to the other. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., “Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization of diastereomeric salts/derivatives or preparative chiral chromatography.
  • the matrices described herein are formed by chemical interactions between one or more precursor components which result in the formation of a three-dimensional network.
  • the type of chemical interactions taking place between the precursor components are either ionic interactions or the formation of covalent bonds.
  • Preferred is the formation of covalent bonds between the precursor components.
  • the matrix is formed of proteins, preferably proteins naturally present in the patient into which the matrix is to be implanted.
  • a particularly preferred matrix made of proteins is a fibrin matrix, although matrices made from other proteins, such as collagen and gelatin can also be used. Polysaccharides and glycoproteins may also be used as a matrix.
  • the matrix is formed of synthetic polymers.
  • synthetic matrices are obtained by crosslinking two precursor components via a Michael type addition reaction as disclosed in PCT application No.PCT/USOO/02608 (WO 00/44808) to Hubbell.
  • matrices can be formed from functionalized polyethylene glycols precursors to form a three- dimensional matrix.
  • the matrix is a fibrin matrix.
  • Fibrin is a natural material which has been used for several biomedical applications. Fibrin gels have been used as sealants due to their ability to bind to a variety of different tissues and their natural role in wound healing. Some specific applications of fibrin include as a sealant for vascular graft attachment, heart valve attachment, bone positioning in fractures and tendon repair. Additionally, these gels have been used as drug delivery devices, and for neuronal regeneration as well as material for cell in-growth matrices (see U.S. Patent No. 6,331,422 to Hubbell et ai.y
  • fibrinogen The process by which fibrinogen is polymerized into fibrin has also been characterized. Initially, a protease cleaves the dimeric fibrinogen molecule at the two symmetric sites. There are several possible proteases than can cleave fibrinogen, including thrombin, peptidase, and protease III, and each one cleaves the protein at a different site. Once the fibrinogen is cleaved, a self- polymerization step occurs in which the fibrinogen monomers come together and form a non-covalently crosslinked polymer gel. This self-assembly happens because binding sites become exposed after protease cleavage occurs.
  • Factor XIIIa a transglutaminase activated from Factor XIII by thrombin proteolysis, can be used covalently crosslink to the fibrinogen chains to form a polymeric network.
  • Other transglutaminases exist and may also be involved in covalent crosslinking and grafting to the fibrin network.
  • ⁇ 2-plasmin inhibitor acts by crosslinking to ⁇ chain of fibrin through the action of Factor XIIIa. By attaching itself to the gel, a high concentration of inhibitor can be localized to the gel. The inhibitor then acts by preventing the binding of plasminogen to fibrin and inactivating plasmin.
  • the ⁇ 2-plasmin inhibitor contains a glutamine substrate.
  • the composition capable of forming a fibrin matrix contains two precursor components in addition to at least one histone deacetylase inhibitor.
  • the first precursor component solution contains thrombin, preferably in a concentration range between about 15 to about 250 LU. thrombin per milliliter of precursor component solution, more preferably between about 50 to about 100 LU. thrombin per milliliter of precursor component solution, most preferably between about 70 to about 80 LU. thrombin per milliliter of precursor component solution.
  • the second precursor component solution contains fibrinogen, preferably in a concentration range between about 10 to about 130 mg fibrinogen per milliliter of precursor component solution, more preferably between about 30 to about 120 mg fibrinogen per milliliter of precursor component solution, more preferably from between about 50 to about 110 mg fibrinogen per milliliter of precursor component solution, most preferably between about 60 to about 90 mg fibrinogen per milliliter of precursor component solution.
  • a calcium ion source may be present in at least one of the precursor component solutions and preferably in the first precursor component solution.
  • the calcium ion source is preferably CaCl 2 * 2H 2 O, preferably in a concentration range between about 1 to about 10 mg per ml of precursor component solution, more preferably between about 4 to about 7 mg per ml of precursor component solution, most preferably between about 5 to about 6 mg per ml of precursor component solution.
  • An enzyme capable of catalyzing the matrix formation such as Factor XIIIa, may be added to at least one of the precursor solution.
  • Factor XIIIa is present in the fibrinogen precursor component in a concentration range between about 0.5 to about 100 LU. per milliliter of precursor component solution, more preferably between about 1 to about 60 LU. per milliliter of precursor component solution, most preferably between about 1 to about 10 LU. per milliliter of precursor component solution.
  • the matrix is a synthetic matrix.
  • Crosslinking reactions for forming synthetic matrices for application in the body include (i) free-radical polymerization between two or more synthetic precursor components containing unsaturated double bonds, as described in Hern et al., J. Biomed. Mater. Res. 39:266-276 (1998), (ii) nucleophilic substitution reactions, for example, between a synthetic precursor component including an amine group and a synthetic precursor component including a succinimidyl group as disclosed in U.S. Patent No.
  • Michael type addition reactions are described in WO 00/44808 to Hubbell et al., the content of which is incorporated herein by reference. Michael type addition reactions allow for in situ crosslinking of at least a first and a second precursor component under physiological conditions in a self-selective manner, even in the presence of sensitive biological materials.
  • one of the precursor components has a functionality of at least two, and at least one of the other precursor components has functionality greater than two, the system will self-selectively react to form a cross-linked three dimensional biomaterial.
  • the nucleophilic groups are preferably thiol-groups, amino-groups or hydroxyl-groups.
  • Thiol groups are substantially more reactive than unprotonated amine groups.
  • a thiol group is used as the functional group of the first precursor component, a conjugate structure that is selective in its reactivity to the thiol relative to amines is highly desirable.
  • Suitable first and second precursor components include, peptides, polyoxyalkylenes, poly(vinyl alcohol), poly(ethylene-co-vinyl alcohol), poly(acrylic acid), poly(ethylene-co-acrylic acid), poly(ethyloxazoline), poly(vinyl pyrrolidone), poly( ethylene -co-vinyl pyrrolidone), poly(maleic acid), poly(ethylene-co-maleic acid), poly(acrylamide), and poly(ethylene oxide)-co- poly(propylene oxide) block copolymers and derivatives thereof.
  • a particularly preferred precursor component is polyethylene glycol and its derivatives.
  • Polyethylene glycol (PEG) provides a convenient building block.
  • a strong nucleophile such as a thiol
  • a conjugated structure such as an acrylate or a vinylsulfone.
  • a PEG component can be reacted with a non- PEG component, and the molecular weight or hydrophilicity of either component can be controlled to manipulate the mechanical characteristics, the permeability, and the water content of the resulting biomaterial.
  • the synthetic matrices are operationally simple to prepare.
  • two liquid precursors are mixed; one precursor contains a precursor component with nucleophilic groups and the other precursor component contains the electrophilic groups.
  • Physiological saline solutions can serve as the solvent.
  • the gelation can be carried out in vivo or in vitro, in direct contact with tissue, without untoward toxicity.
  • polymers other than PEG may be used, either telechelically modified or modified on their side groups or side chains.
  • the matrices described herein, either natural matrices or synthetic matrices, allow for local administration or topical administration of the active agent, allowing the histone deacetylase inhibitor to be released over time at the site where adhesions could occur. Histone deacetylase inhibitors are thus readily available where it has to produce its effects. Additionally, the matrices may also provide a physical barrier to the formation of adhesions by hindering cell migration through the matrix while allowing wound healing at the site of implantation.
  • one or more histone deacetylase inhibitors are entrapped in a matrix and the drug is delivered at the desired location with the desirable release rate.
  • both natural and synthetic matrices are formed by aqueous solutions of precursor components and some histone deacetylase inhibitors have a limited solubility in water at room temperature and atmospheric pressure. Therefore, in order to load the matrix with the active agent and in order to tailor its release profile from the matrix, a carrier can be used depending on the type of drug.
  • one or more carriers are used to solubilise or disperse histone deacetylase inhibitors that are non water soluble or have limited water solubility at room temperature and atmospheric pressure, in an aqueous medium.
  • the carriers are preferably biocompatible and do not induce inflammation.
  • the carrier is an oil-in-water emulsion (O/W emulsion).
  • O/W emulsion oil-in-water emulsion
  • an emulsion is produced from an oil phase, one or more emulsifiers/stabilizers and an aqueous phase (e.g. water).
  • emulsif ⁇ ers examples include, but are not limited to, egg-lecithin, soya lecithin, phospholipids of egg or soya, Tween® 80, sodium glycocholate and sodium lauryl sulphate.
  • stabilization can be carried out by the addition of substances which have the effect of increasing stability by mechanisms other than emulsifiers, e.g. by steric stabilization or by increasing the zeta potential.
  • stabilizers include, but are not limited to, block co-polymers such as poloxamers (e.g. Poloxamer 188 and 407) and poloxamines (e.g.
  • Poloxamine 908 polyvinyl pyrrolidone, polyvinyl alcohol, gelatine, polysaccharides such as hyaluronic acid and chitosan and their derivatives, polyacrylic acid and its derivatives, polycarbophil, cellulose derivatives (e. g. methyl-, hydroxypropyl-and carboxymethyl cellulose), sugar esters such as saccharose monostearate and antiflocculants such as sodium citrate.
  • Emulsifiers and stabilizers can be used individually or in mixtures. Typical concentrations are from about 0.1% to 20% by weight of the composition, especially 0.5% to 10% by weight of the composition. All amounts used herein are wt. %, based on the total weight of the dispersion, unless otherwise stated.
  • the emulsion contains a non-aqueous phase, or oil phase, which contains a therapeutically effective amount of one or more active agents, such as one or more histone deacetylase inhibitors dispersed in a continuous phase containing water.
  • active agents such as one or more histone deacetylase inhibitors dispersed in a continuous phase containing water.
  • constituents of the oil phase of the emulsions include, but are not limited to, soya oil; safflower oil (thistle oil); long-chain triglycerides such as, for example esters of glycerol containing fatty acids having from 14 to 20 carbon atoms; medium-chain triglycerides such as, for example esters of glycerol containing fatty acids having from 6 to 12 carbon atoms; miglyols, fish oils and oils with an increased constituent of unsaturated fatty acids; acetylated partial glycerides such as in Stesolid; and combinations thereof.
  • emulsifiers and stabilizers can be used for stabilization of the dispersions.
  • One or more emulsifiers/stabilizers may already be contained in the emulsion used to produce the dispersion.
  • the addition of further emulsifiers and stabilizers can be advantageous in the production of the dispersion.
  • constituents of the aqueous phase or continuous phase of the O/W emulsion include, but are not limited to, water, mixtures of water with other water-miscible organic liquids or solvents, and liquid polyethylene glycols (PEG, especially PEG 400 and 600).
  • PEG liquid polyethylene glycols
  • the carrier forms an oil-in-water emulsion, the emulsion comprising a dispersed oil component containing a therapeutically effective amount of one or more histone deacetylase inhibitors dispersed in a continuous phase containing water.
  • the oil component of the emulsion is selected from the group consisting of soybean oil, safflower oil, corn oil, medium chain triglyceride, glycerol, egg lecithin phospholipids and mixtures thereof.
  • the carrier contains soybean oil, medium chain triglycerides, glycerol, egg lecithin phospholipids, ⁇ -tocopherol, sodium oleate and water.
  • medium chain triglycerides are a mixture of caprylic and capric acid.
  • Preferred medium chain triglycerides comprise about 60% of caprylic acid and about 40% of capric acid.
  • These preferred carriers are commercially available under the tradenames LIPOFUNDIN®, INTRALIP ID®, LIPOVENOES®, ABBOLIPID®, DELTALIPID® AND SALVILIPID®.
  • Carriers are not limited to oil-in-water emulsion as it will be obvious to the one skill in the art to replace emulsions or microemulsions with microparticles, microcapsules, microspheres, nanoparticles, nanocapsules, nanospheres, liposomes, micelles, water-in-oil (W/O) emulsions, and the like.
  • Exemplary carriers may include one or more of the following: pharmaceutically acceptable oils, low melting waxes, fats, lipids and any other pharmaceutically acceptable substance that are lipophilic (e.g., substantially insoluble in water) and are biodegradable and/or eliminated from the patient's body by natural processes.
  • the carrier is albumin.
  • the carrier is serum albumin and even more preferably the carrier is human serum albumin.
  • Some histone deacetylase inhibitors, such as tributyrin, are hydrophobic and liquid at room temperature and at atmospheric pressure. When put into water and after mixing, a non-stable emulsion is obtained which quickly partition into two separate phases.
  • Albumin is able to bind fatty acids and triglycerides, such as tributyrin.
  • the protein serves as a stabilizing agent to suspend the lipid or fat within a larger aqueous phase.
  • the amount of albumin is in range of between about 0.1 to 1 mg per milliliter of matrix of the precursor components forming the matrix.
  • the droplet size obtained by homogenizing the mixture is in a range of between 1 to 1000 ⁇ m, preferably in a range of between 0.5 to 200 ⁇ m
  • the carrier is entrapped in a matrix that protects it from rapid clearance, but does not impair its ability to slowly release its contents.
  • the carrier may also have a beneficial effect on the stability of the matrix, particularly matrices prepared from naturally occurring materials, such as fibrin matrices. This may be explained by the carrier present in the pores of the matrix preventing infiltration of the matrix by degradation enzymes such as plasmin
  • compositions described herein are formed from precursor component solutions and contain at least one active agent, such as one or more histone deacetylase inhibitors.
  • the histone deacetylase inhibitor is tributyrin, then the at least one histone deacetylase inhibitor is present in a concentration range of between about 3.4 and about 102 mM per milliliter of matrix of the precursor components forming the matrix, preferably between about 34 to about 102 mM per milliliter of matrix of the precursor components forming the matrix.
  • the matrix is a fibrin matrix and the at least one histone deacetylase inhibitor is tributyrin. In another preferred embodiment, the matrix is a synthetic matrix and the histone deacetylase inhibitor is tributyrin.
  • the matrices are formed from precursor component solutions and contain at least one histone deacetylase inhibitor solubilised or dispersed in a carrier.
  • the histone deacetylase inhibitor is tributyrin, then the at least one histone deacetylase inhibitor is present in a concentration range of between about 3.4 and about 102 mM per milliliter of matrix or precursor components forming the matrix, preferably between about 34 to about 102 mM per milliliter of matrix or precursor components forming the matrix.
  • the matrix is fibrin matrix or a synthetic matrix
  • the histone deacetylase inhibitor is tributyrin
  • the carrier is an oil-in- water emulsion wherein the emulsion contains an oil component containing a therapeutically effective amount of at least one histone deacetylase inhibitor, and a continuous phase containing water.
  • the oil component of the emulsion is selected from the group consisting of soybean oil, saffiower oil, corn oil, medium chain triglyceride, glycerol, egg lecithin phospholipids and mixtures thereof.
  • the carrier contains soybean oil, medium chain triglycerides, glycerol, egg lecithin phospholipids, ⁇ -tocopherol, sodium oleate and water.
  • Preferred medium chain triglycerides include mixtures of caprylic and capric acid.
  • Preferred medium chain triglycerides contain about 60% of caprylic acid and about 40% of capric acid.
  • the carrier is in a concentration range of between about 0.04% and about 0.4 % by weight of the total weight of the matrix or precursor components forming the matrix.
  • the matrix is fibrin matrix or a synthetic matrix
  • the histone deacetylase inhibitor is tributyrin
  • the carrier is albumin.
  • the carrier is serum albumin and more preferably human serum albumin.
  • the carrier is in a concentration range of between about 0.1 to about 1 mg per milliliter of matrix of the precursor components forming the matrix.
  • the histone deacetylase inhibitor is incorporated physically within the matrix during gelation.
  • the histone deacetylase inhibitor may be first mixed and homogenized with the thrombin precursor component,
  • the thrombin precursor component contains a carrier before mixing and homogenizing with the histone deacetylase inhibitor.
  • the carrier present in the thrombin precursor component are albumin or more preferably human serum albumin.
  • the fibrinogen component to the thrombin precursor component containing the histone deacetylase inhibitor will lead to polymerization of the fibrinogen into a crosslinked fibrin matrix wherein the histone deacetylase inhibitor is physically entrapped in the matrix.
  • the matrix is a synthetic matrix
  • the histone deacetylase inhibitor can be incorporated in either one of the precursor components.
  • the histone deacetylase inhibitor is first solubilised or dispersed in the carrier and the carrier containing the histone deacetylase inhibitor is then mixed with the thrombin precursor component.
  • the fibrinogen precursor component with the thrombin component containing the histone deacetylase inhibitor solubilised or dispersed in a carrier
  • the histone deacetylase inhibitor solubilised or dispersed in the carrier can be incorporated in either one of the precursor solution.
  • a method for preparing a composition for preventing adhesion containing a matrix containing at least one histone deacetylase inhibitor is provided.
  • the method includes at least the steps of a) providing a first precursor component b) providing at least a second precursor component capable of forming a three-dimensional matrix when combined with the first precursor component of step a) c) providing a histone deacetylase inhibitor d) mixing components provided in steps a), b) and c) to form a supplemented matrix.
  • the first precursor component contains thrombin and may further contain a calcium ion source and a carrier.
  • the carrier is albumin, more preferably serum albumin and even more preferably human serum albumin.
  • the second precursor component contains fibrinogen and may further contains a calcium ion source like CaCl2*2H2 ⁇ and factor XIIIa.
  • a carrier may be used to solubilise and disperse the histone deacetylase inhibitor prior to its incorporation into the matrix.
  • Histone deacetylase inhibitors are releasably incorporated into the matrix.
  • the solubilisation or dispersion of tributyrin in a carrier significantly alters the release profile of the drug from the matrix.
  • tributyrin When tributyrin is first dispersed in a carrier, which is an oil-in -water emulsion, and then incorporated in the fibrin matrix, tributyrin shows an even longer release profile over time than if incorporated without a carrier. Without any carrier, 50% of tributyrin is released after 1.5 days. In contrast, when tributyrin is entrapped into the fibrin matrix in the presence of a carrier, only 20% of the drug is release after 6 days.
  • FIG. 2 shows the release profiles of tributyrin solubilised in a carrier and entrapped in two different fibrin matrices.
  • Fibrin matrix No. 1 was formed using a higher concentration of Factor XIII than fibrin matrix No. 2.
  • the tributyrin release profile from fibrin matrix No. 1 shows that only 20% of tributyrin is released after 6 days. In contrast, 50% percent of tributyrin is released from fibrin matrix No.2 after 1.5 days and the entire amount of tributyrin is released after 6 days.
  • the supplemented matrices described herein may be formed in situ at the desired location upon mixing of the separated precursor components. Alternatively, the matrices may be preformed and then implanted at the desired location. Depending on the indication, the supplemented matrices can be applied or injected at different stages of gelation. Supplemented matrices may be applied by pouring, injecting or spraying. In order to prevent leakage, the precursor component solutions can be mixed to initiate gelation and applied after a certain period of time. This is done to prevent leakage of a still liquid matrix into the blood circulation.
  • the supplemented matrix may be injected into the body at different stages of gelation and can gel in situ in or on the body.
  • the supplemented matrix can be formed outside the body and then applied in a preformed shape.
  • the precursor components should be separated prior to application of the mixture to the body to prevent combination or contact with each other under conditions that allow polymerization or gelation of the precursor components.
  • a kit which separates the compositions from each other may be used.
  • the compositions form a three dimensional network supplemented with a histone deacetylase inhibitor.
  • gelling can occur almost instantaneously after mixing.
  • Treatment with the compositions, medications and methods described herein is intended for any site in which adhesions form or may form.
  • These include prevention of primary, and especially secondary, adhesions located in the abdominal cavity, including intestine to intestine, and intestine to peritoneum; in the pelvic cavity, including prevention of adhesion of the uterus, ovaries or fallopian tubes to other structures including each other and the pelvic wall; preventing adhesions in tendons and their support structures, including tendon to pulley or to synovium; preventing adhesions in the repair of nerve sheaths; preventing adhesions following spine or brain surgery by applying the compositions of the present invention to the dura-matter; in the pericardium; in treatment of joints for inflammation and to prevent pannus formation; and in any situation in which formation of adhesions impair function or cause pain.
  • the histone deacetylase inhibitor is used for the manufacture of a medicament for prevention of adhesions occuring in the abdominal cavity, in the pelvic cavity or following spinal or brain surgery.
  • the compositions may be used in other conditions in which unwanted tissue proliferation occurs, such as restenosis of arteries, repair of keloid or hypertrophic scars, hypertrophy which obstructs ducts, such as benign prostatic hypertrophy, and endometriosis.
  • the composition contains a histone deacetylase inhibitor, a fibrin matrix and optionally a carrier.
  • the histone deacetylase inhibitor when used in its therapeutic window, will induce cell differentiation and thus will prevent adhesions formation without impairing the wound healing process.
  • the fibrin matrix used herein has two main purposes. It will first provide a histone deacetylase inhibitor delivery system wherein the drug will be present and released over time at the site where adhesions may occur. Second, the fibrin matrix may provide a physical barrier to adhesion formation depending on factor XIII to fibrinogen concentration. The higher the factor XIII concentration, the denser fibrin network is obtained. Cell infiltration of the fibrin matrix depends to a large extent on the matrix network density.
  • One method of administering the supplemented matrix to and/or into areas of adhesion requires at least one liquid precursor component capable of forming a matrix at physiological temperatures and at least one histone deacetylase inhibitor and applying the precursor component and histone deacetylase inhibitor to and/or into the area of adhesion.
  • the composition can be administered in the form a gel, a hydrogel, a film, a paste, a cream, a spray, an ointment, a wrap or a bandage.
  • the compositions described herein allow for local delivery of a histone deacetylase inhibitor at the site of surgery.
  • the above methods are used to administer the compositions described herein by a route selected from intraarticular, intraperitoneal, topical, intravenous, ocular, or to the resection margin of tumors.
  • Precursor component solutions used in forming the supplemented matrices may be instilled by pouring, spraying or by devices such as infusion catheters, funnel like devices, syringes or mixing tips.
  • the kit contains a first precursor component, a second precursor component capable of forming a three-dimensional matrix when combined with the first precursor component and at least one histone deacetylase inhibitor.
  • the histone deacetylase inhibitor is solubilised or dispersed in a carrier.
  • the kits may also contain instructions for combining the different components as well as one or more devices for mixing and/or applying the precursor components such as syringes, pipettes, pipette bulbs, vials, and the like.
  • the kit contains a two way syringe device.
  • the precursor components may be in the form of a solid, such as a dry powder or may in solution, such as in a buffer. If the precursor components are in the form of a solid, the kit may contain buffer solutions and instructions for preparing solutions of the precursor components.
  • the first precursor component in the kit contains thrombin and the second precursor component contains fibrinogen which, when combined together, form a fibrin matrix.
  • Fibrinogen is dissolved (optionally aprotinin to increase stability) in a buffer solution at physiological pH (in a range from pH 6.5 to 8.0, preferably from pH 7.0 to 7.5) and is stored separately from a solution of thrombin in a calcium chloride buffer (e.g. concentration range of from 40 to 50 mM).
  • the buffer solution for the fibrinogen can be a histidine buffer solution at a preferred concentration of 50 mM including additionally NaCl at a preferred concentration of 150 mM or TRIS buffer saline (preferably at a concentration of 33mM).
  • the histone deacetylase inhibitor may be present in either the fibrinogen or the thrombin precursor component solution.
  • the thrombin precursor component solution contains the histone deacetylase inhibitor.
  • the thrombin precursor component solution contains the histone deacetylase inhibitor and a carrier.
  • both fibrinogen and thrombin are stored separately in lyophilized form. Either of the two can contain the histone deacetylase inhibitor.
  • the tris or histidine buffer is added to the fibrinogen.
  • the lyophilized thrombin is dissolved in the calcium chloride solution. Subsequently, the fibrinogen and the thrombin solutions are placed in separate containers/ vials/syringe bodies and mixed by a two way connecting device, such as a two-way syringe.
  • the containers/vials/syringe bodies are bipartite devices, having two chambers separated by an adjustable partition which is perpendicular to the syringe body wall.
  • One of the chambers contains the lyophilized fibrinogen or thrombin, while the other chamber contains an appropriate buffer solution.
  • the partition moves and releases the buffer into the fibrinogen chamber to dissolve the fibrinogen.
  • both bipartite syringe bodies are attached to a two-way connecting device and the contents are mixed by squeezing them through the injection needle attached to the connecting device.
  • the connecting device contains a static mixer to improve mixing of the contents.
  • Lyophilized Fibrinogen from Tissucol (Baxter AG) was reconstituted with aprotinin buffer (2mL) under aseptic conditions according to the manufacturer's recommendations to give a final of 70-110 mg/mL fibrinogen and 1.67 U/mL aprotinin. Neat Fibrinogen solution was used throughout.
  • Thrombin protein concentrate from Tissucol was dissolved in thrombin dilution buffer (2mL) to an activity of 500 IU/ml.
  • the concentration of Human Serum Albumin (HSA) present in the thrombin protein concentrate was 3.7 mg/mL.
  • a mixture of tributyrin (2% w/v, i.e. 68 mM) and thrombin precursor component (50 IU/ml) was extruded through a 23G needle to form an even dispersion of tributyrin-HSA complex throughout the aqueous solution.
  • the tributyrin-HSA complex did not contain any of the thrombin component as determined by the thrombin activity assay.
  • Lyophilized Fibrinogen from Tissucol (Baxter AG) was reconstituted with aprotinin buffer (2mL) under aseptic conditions according to the manufacturer's recommendations to give a final of 70-110 mg/mL fibrinogen and 1.67 U/mL aprotinin. Neat Fibrinogen solution was used throughout.
  • Human Serum Albumin (20%) (Baxter AG) was diluted in thrombin dilution buffer to a concentration of 0.37%.
  • a mixture of tributyrin (2%) and human serum albumin (0.37%) was extruded through a 23G needle to form an even dispersion of tributyrin-protein complex throughout the aqueous solution.
  • the size of the droplets of the emulsion was in a range of between 1 to 200 ⁇ m.
  • the activities of both tributyrin was unaffected by the extrusion procedure as determined by bioassay.
  • the stable homogenate resulted in sedimentation of tributyrin-protein complex over time which was readily resuspended following gentle inversion.
  • Thrombin protein concentrate from Tissucol (Baxter AG) was dissolved in thrombin dilution buffer (2 mL) to an activity of 500 IU/ml. This was then diluted 10 fold in the tributyrin-Human Serum Albumin emulsion mixture resulting in a final thrombin concentration of 50IU/mL.
  • tributyrin mixture and fibrin precursor component were filled separately and in identical quantity into syringes. They were closed by stoppers and assembled to the Duploject applicator (Baxter AG). Units were stored under sterile conditions at -15 to - 2O 0 C until needed. On the day of the experiment, the syringes were removed from storage and placed at 37 0 C until completely thawed. At the time of use, simultaneous application of both preparations was accomplished through the use of an adjustable joining piece and application needle. The generation of the fibrin gel resulted in a final 1:2 dilution of each component.
  • Example 2 Preparation of fibrin matrix containing tributyrin solubilized or dispersed in a carrier
  • thrombin dilution buffer (20 mM Na3-Citrate, 50 mM Niacinamide, 100 mM L-Histidine, 150 mM NaCl, pH 7.3 ⁇ 0.1 adjusted with 1 N HCl) according to instructions from the manufacturer in order to prepare a 75-115 mg/mL fibrinogen precursor solution.
  • Thrombin protein concentrate from Tissucol (Baxter AG) was dissolved as above to an activity of 500 IU/ml in sterile-filtrated thrombin dilution buffer (40 mM CaC12, 75 mM NaCl, pH 7.3 ⁇ 0.1 adjusted with NaOH).
  • a mixture of 10% tributyrin and 4% of a carrier (MCT/LCT Lipofundin; B. Braun Medical AG, Germany) was first vigorously vortexed in the thrombin dilution buffer at room temperature to stabilize the oil/water emulsion.
  • the emulsion was then mixed with the thrombin precursor component solution by gentle inversions to obtain a final concentration of 2% by weight (68 mM) tributyrin, 0.8% by weight carrier and 400 IU/ml of thrombin in thrombin dilution buffer.
  • an emulsion containing 20% by weight tributyrin and 8% by weight carrier was processed with 570 IU/ml of thrombin to a final of 6% by weight (204 mM) tributyrin, 2.4% by weight carrier and 400 IU/ml of thrombin in thrombin dilution buffer for administrating a higher dose of tributyrin.
  • thrombin precursor component containing tributyrin and fibrinogen precursor component were filled separately and in identical quantity into syringes.
  • the syringes were sealed with stoppers and assembled to an applicator system, such as Duploject (Baxter AG) or FibriJet (Micro medics).
  • the materials were stored at -15°C to -20 0 C until use.
  • the medicated barrier material was thawed at room temperature for at least 30 minutes and used within 4 hours.
  • the assembly was connected with a gas-assisted spray applicator designed for a 1: 1 ratio static mixing. Material was sprayed at a distance of 10 cm and 1 bar to an extent of 0.13-0.26 ml/cm 2 .
  • the fibrinogen precursor component and the thrombin precursor component are mixed crosslinking occurs.
  • the generated fibrin matrix solidifies very quickly (e.g., typically within a few seconds or so), an incubation period of at least 30 seconds is recommended to complete the polymerization process.
  • the first precursor component solution 235 mg of polyethylene glycol) tetrasulfhydryl (“PEG-SH-10") (mol. wt. 1OkDa) are dissolved in 1 mL of 10 mM acetate buffer (pH 5). Buffer was prepared by mixing a 10 mM acetic acid solution and a 10 mM sodium acetate buffer solution to achieve pH 5. To this precursor solution, tributyrin is added at a concentration of 68 mM. For the preparation of the second precursor component solution, 315 mg of TETRONIC®-tetraacrylate (mol wt. 15 kDa) was dissolved in 1 mL of a 1OmM acetate buffer pH 5.
  • PEG-SH-10 polyethylene glycol) tetrasulfhydryl
  • Buffer was prepared by mixing a 10 mM acetic acid solution and a 10 mM sodium acetate buffer solution to achieve pH 5.
  • the amount of polyethylene glycol) tetrasulfhydryl (“PEG-SH-10") is chosen in order to obtain a 1 : 1 ratio between the number of acrylate and thiol functional groups present in the corresponding pharmaceutical compositions.
  • the first and second precursor component solutions were filled into two distinct syringes that were connected with a coupler.
  • the first and second precursor component solutions were mixed by transferring the material contained in one syringe to the other syringe (Typically, the solutions are pushed back and forward 10 times). Although the mixture remains stable for approximately 10-20 minutes after its preparation, ideally the composition should be used within about 5 minutes after its preparation.
  • the biomaterial was formed in situ at the desired site, by delivering to the defect site the mixture comprising the first and second precursor component and the activator (0.2 mL of a 50 mM borate buffer pH 9.8.
  • Buffer was prepared by mixing a 100 mM boric acid buffer and a 50 mM sodium tetraborate decahydrate buffer to achieve pH 9.8) using a two component device equipped either with a spreader tip or a sprayer tip.
  • the biomaterial was formed in less than 1 minute after delivery of the content of the two component device.
  • sample MABs were formed by mixing 50 ⁇ L of a thrombin component (5 UI/mL) with 50 ⁇ L of a fibrinogen component ( ⁇ 100 mg/mL) to make cylindrical or slab-form gels of 100 ⁇ L.
  • the thrombin component of group A contained C14-labeled TB (68 mM) (i.e., without carrier) while that of group B contained C14-labeled TB (68 mM) as well as 0.8% Lipofundin (Braun Medical AG) as carrier.
  • the fibrinogen components for Group A and B in this first series were made from a Tissucol fibrin sealant kit (Baxter) (Fibrin Matrix No. 1 in Figure 2).
  • fibrinogen made from Beriplast fibrin sealant kit (ZLB) Fibrin Matrix No. 2 in Figure 2 was used in combination with group B of the thrombin component.
  • Fibrinogen component made from the Beriplast fibrin sealant kit differs from that of the Tissucol fibrin sealant kit in Factor XIII concentration and buffer-salt compositions, which influence the final fibrin matrix structure and cross-linking density.
  • the graph in Figure 1 shows that a higher percentage of radioactivity in retained in fibrin in the compositions without a carrier than for the composition which contains a carrier.
  • the graph in Figure 2 shows that the percentage of radioactivity retained in the fibrin matrix was higher for the Tissucol fibrin matrix than for the Beroplast fibrin matrix.
  • Example 4B Release of tributyrin from fibrin matrices
  • sample MABs were formed by mixing 50 ⁇ L of a thrombin component (50 UI/mL) with 50 ⁇ L of a fibrinogen component ( ⁇ 100 mg/mL) to make gels of 100 ⁇ L.
  • the thrombin component of group A contained tributyrin (68 mM) while that of group B contained tributyrin (68 mM) as well as 0.37% human Serum Albumin (Baxter) as carrier to form a homogenized mixture (prepared as described in example IB).
  • the fibrinogen components for Group A and B in this first series were made from a Tissucol fibrin sealant kit (Baxter).
  • the Tissucol fibrin sealant kit was replaced with Tisseel fibrin sealant VHSD kit (Baxter) and the in vitro studies repeated with the group B.
  • the sample MABs were then placed into 500 ⁇ L buffer (Hepes-based Ringer Solution, pH 7.3) and incubated at 37°C. Samples MAB gels without tributyrin served as blank controls. The buffer was exchanged at designated time points and analyzed for tributyrin and butyric acid at different time points up to two days.
  • the results shown in figures 4A, 5 A and 6A demonstrate that the homogenization of tributyrin with Human Serum Albumin does not significantly influence the release of tributyrin or butyric acid from Tissucol fibrin sealant as compared to tributyrin mixed by vortexing.
  • the overall amount of homogenized tributyrin remaining in the Tisseel fibrin sealant was similar to that of the Tissucol fibrin sealant after 2 days, although the amount of tributyrin being converted to butyric acid was found to be greatly reduced in the Tisseel fibrin sealant ( Figure 4B, 5B and 6B).
  • Example 5 Antiproliferative effects of tributyrin on fibroblast cells
  • tributyrin carrier/emulsifier In vitro studies were conducted to elucidate the influence of the tributyrin carrier/emulsifier on the cellular anti-proliferative characteristics of tributyrin as determined by WST-I proliferation assay. Briefly, human fibroblasts (5000/well) were incubated with different concentrations of tributyrin in 96 well plates for 3 days. Group A consisted of tributyrin vortexed in thrombin dilution buffer as previously described and then mixed with Human Serum Albumin (0.5% final). Group B consisted of tributyrin homogenized with Human Serum Albumin (0.5% final) in thrombin dilution buffer. Both groups were incubated with cells in serial dilutions of tributyrin ranging from 0 - 17mM.
  • Figure 7 shows the effect of the different tributyrin formulations on cell proliferation.
  • the homogenized formulation was shown to be significantly more effective at inhibiting cell proliferation than the vortexed formulation at concentrations of tributyrin ranging from 1.06 - 17mM.
  • Example 6 Prevention of adhesion in rabbit with a fibrin matrix supplemented with tributyrin solubilised or dispersed in a carrier
  • a rabbit sidewall model was used to measure the efficacy of the tributyrin-medicated fibrin matrix in the prevention of adhesion formation at the site of surgery.
  • Animals were anesthetized with a mixture of 55 mg/kg Ketamine hydrochloride and 5 mg/kg Rompum intramuscularly. Following preparation for sterile surgery, a midline laparotomy was performed. The cecum and bowel were exteriorized and digital pressure was exerted to create subserosal hemorrhages over all surfaces.
  • the damaged intestine was then lightly abraded with 10 x 10 cm 4-ply sterile gauze until punctuate bleeding was observed. The cecum and bowel were then returned to their normal anatomic position. A 5 x 3 cm area of peritoneum and transversus abdominous muscle was removed on the right lateral abdominal wall before the test item was applied. The incision was closed in two layers with 3-0 Vicryl sutures.
  • Terminated animals were evaluated at day 21 for general observation, and the abdomen was examined for the appearance and area of adhesion formation.
  • the tenacity of the adhesions was scored (number of adhesions and the tenacity; e.g., mild/dissectible, moderate/non-dissectible and dense/non- dissectible/tears organ).
  • the difference in adhesion formation between the control and treated groups was analyzed by Student's t-test and the incidence with Fisher's exact test.
  • the area involved in adhesions was evaluated by one way analysis of variance followed by Tukey's test and incident with Chi square.
  • the tenacity scores were ranked by order analysis followed by analysis of variance.
  • the excision site treated with a fibrin matrix supplemented with 34 mM of tributyrin dispersed in a carrier prior to the incorporation in the matrix significantly decreased both the area involved in adhesions (26 ⁇ 12.5%) and the tenacity of adhesions.
  • the excision site treated with neat FB alone showed little reduction in the area involved in adhesion (44 ⁇ 18%).
  • Example 7 Prevention of adhesion in rat with a fibrin matrix supplemented with tributyrin A rat hemilaminectomy model was used to evaluate the effectiveness of the Medicated Adhesion Barrier (MAB) in preventing epidural adhesions. Anesthesia was pre-empted using ketamine hydrochloride (50mg/kg s.c.) and maintained using isofiurane (2.5-3%)/oxygen (300 ml/min). For analgesia, Buprenorphine (0.1 mg/kg s.c.) was administered post operatively 5 hr after surgery and twice per day thereafter for 2 days.
  • MAB Medicated Adhesion Barrier
  • Buprenorphine (0.6mg / 120ml) was included in the drinking water for a further 24 hr. Animals were prepared for aseptic surgery. The thoracolumbal spine was approached dorsally with a 2cm incision and the left articular facets and the left vertebral dorsal arch of the lumbar vertebra Ll and L2 were exposed. The left hemilaminectomy was performed using an ocular magnification device and synovectomy micro rangeurs. The size of the bony opening was 4x3 mm, exposing the spinal nerve at the left ventral vertebral floor. Strong bleeding was controlled by gentle pressing with cotton gauze.
  • the treatment groups approximately 50 ⁇ l of the first and second precursor component solutions were applied (as prepared in example 1 ) to the hemilaminectomy site with fibrin matrices containing different tributyrin concentration (0 mM, 3.4 mM, 10 mM and 34 mM). Following gelation, the fascia was sutured with 5-0 Prolene and the skin closed using skin staples. The duration of the experiment was 4 weeks, after which time the animals were sacrificed using pentobarbiturate i.p. (150mg/kg) by a qualified veterinary surgeon and spinal segments with the vertebra Ll and L2 processed for histology.
  • a sheep laminectomy model was used to evaluate the effectiveness of the Medicated Adhesion Barrier (MAB) in preventing epidural adhesions.
  • MAB Medicated Adhesion Barrier
  • sheep Upon arrival at the test facility, sheep were placed in the appropriate pastures of the large animal research barn. They were dewormed and ear tagged for identification. Physical examination was performed and any animals with signs of respiratory disease had venous blood submitted for a complete blood count (CBC).
  • Cefazolin sodium 1 g was given intravenously to each sheep at induction, midway through the surgery and during closure.
  • the dorsal thoracolumbar area was prepared for aseptic surgery with multiple scrubs of povidone-iodine alternated with isopropyl alcohol.
  • the area was draped and local anesthesia (Lidocaine) infiltrated along the site of the intended approach to Tl 3 and L2 and spinous processes.
  • a 20 cm skin incision was made and the paraspinal muscles dissected off the spinous processes and laminae using electrocautery.
  • the dorsal spinous processes were removed from T 13 and L2 by drilling through the base and later these structures were removed with Rongeurs.
  • the wound was lavaged with normal physiological saline.
  • the articular facet joints were left intact.
  • Fibrin matrices containing different tributyrin concentration (0 mM, 10 mM, 34 mM and 102mM) were prepared as described in example 1 B and were applied over the exposed dura site. The control sites were left untreated. A waiting time of 3-5 minutes was allowed before closing the wound.
  • the dense dorsal spinous fascia was reapposed using 0 Maxon suture, in a continuous simple stitch, while the subcutaneous tissue was closed with 2/0 absorbable suture (simple continuous stitch) and skin with 2/0 monofilament non-absorbable suture. Operative time for each animal was about 50 minutes.
  • Procaine penicillin 3 million units, was given subcutaneously, once daily to each sheep for 3 days post-operatively.
  • the sheep were transferred from the operating table to a Sheep JeepTM or a Ewe HaulTM and while still under general anesthesia, taken to the radiology suite where dorsoventral and lateral radiographs of the fusion sites were obtained.
  • radiology suite where dorsoventral and lateral radiographs of the fusion sites were obtained.
  • Following radiographic evaluation while still in the Sheep JeepTM or Ewe Haul TM, they were observed until the swallowing reflex returned. At that point they were extubated and taken to the "Sheep Shuttle " where they were propped in sternal recumbency.
  • the end of the day all animals that were operated upon that day were moved to the research barn at the VTH.
  • the sheep were housed indoors for 2 weeks and then later (if all incisions were dry with no drainage) outdoors (with access to a three-sided shelter) for the rest of the convalescence period and allowed to exercise at will. Postoperative analgesia was provided. At 3 months, sheep were humanely euthanized and MRI analysis performed. Tissues from the cranial operative sites were retrieved and the laminectomy sites evaluated for scar tenacity. The remaining caudal operative sites were sent for histological analysis and evaluated for adhesion formation. Paraffin wax sections were prepared from various positions along the laminectomy defect site, including caudal, middle and cranial.

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Abstract

La formation d'adhérences, qui est un processus dans lequel des tissus ou des organes adjacents se lient les uns aux autres, peut être provoquée par des infections, des maladies inflammatoires, des procédures chirurgicales ou un traumatisme. A la suite d'une chirurgie abdominale, la fréquence de formation d'adhérences peut être aussi élevée que 90 %. La douleur, un inconfort, une immobilisation et un retard de la cicatrisation sont des complications courantes dues à la formation d'adhérences; en outre, selon les tissus impliqués, les adhérences peuvent provoquer des troubles divers. Dans l'œil, l'adhérence de l'iris au cristallin peut mener à un glaucome. Dans les intestins, les adhérences peuvent provoquer une obstruction intestinale partielle ou complète qui menace la vie. Les adhérences intra-utérines sont connues comme le syndrome d'Asherman. Les adhérences pelviennes peuvent conduire à la stérilité et à des problèmes de la reproduction. Les problèmes associés aux adhérences requièrent souvent une autre procédure opératoire afin d'éliminer les adhérences. Celle-ci pourrait présenter le désavantage majeur de conduire à la formation de nouvelles adhérences. Une large diversité de traitements d'appoint a été expérimentée pour réduire ou prévenir les adhérences post-chirurgicales. Toutefois, la plupart de ces traitements montrent des résultats irréguliers. Dans une tentative de réduction de la réaction inflammatoire dans le site lésé après l'intervention chirurgicale, l'utilisation de corticostéroïdes, d'AINS, d'antagonistes de l'histamine et de bloqueurs des canaux calciques a été expérimentée. Plus récemment, des matériaux barrières ont été suggérés pour la prévention d'adhérences post-chirurgicales. Ceux-ci comprennent, mais ne sont pas limités à, Hyskon®, la solution de Ringer au lactate, Interceed® (cellulose régénérée oxydée), Polaxamer 407® (polymère dépendant de la température), Gore-Tex® (polytétrafluoréthylène expansé) et SepraFilm® (film dérivé de l'acide hyaluronique).
PCT/EP2008/055363 2007-05-01 2008-04-30 Composition, procédés et kits destinés à la prévention d'adhérences WO2008132233A1 (fr)

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WO2013129719A1 (fr) * 2012-02-28 2013-09-06 주식회사 시지바이오 Composition de polymère antiadhésive pouvant servir de support à un facteur de croissance
WO2016084097A1 (fr) * 2014-11-13 2016-06-02 Hemarus Therapeutics Ltd. Procédé de production de fibrinogène et de thrombine
WO2018214087A1 (fr) * 2017-05-25 2018-11-29 苏州睿研纳米医学科技有限公司 Revêtement d'adhésion de matrice extracellulaire anti-biologique et procédé de préparation associé et utilisation associée
KR102810380B1 (ko) 2022-11-23 2025-05-22 주식회사 티앤알바이오팹 조직 재생 촉진형 유착 방지 피복재 조성물

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013129719A1 (fr) * 2012-02-28 2013-09-06 주식회사 시지바이오 Composition de polymère antiadhésive pouvant servir de support à un facteur de croissance
KR101330652B1 (ko) 2012-02-28 2013-11-18 (주)시지바이오 성장인자 담지 가능한 유착방지용 고분자 조성물
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WO2016084097A1 (fr) * 2014-11-13 2016-06-02 Hemarus Therapeutics Ltd. Procédé de production de fibrinogène et de thrombine
WO2018214087A1 (fr) * 2017-05-25 2018-11-29 苏州睿研纳米医学科技有限公司 Revêtement d'adhésion de matrice extracellulaire anti-biologique et procédé de préparation associé et utilisation associée
KR102810380B1 (ko) 2022-11-23 2025-05-22 주식회사 티앤알바이오팹 조직 재생 촉진형 유착 방지 피복재 조성물

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