Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/37—Digestive system
  • A61K35/407—Liver; Hepatocytes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1816—Erythropoietin [EPO]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the invention relates to microcapsules comprising liver cells and erythropoietin, methods for preparing said microcapsules and methods for treating a patient comprising applying said microcapsules to the patient.
• liver of a healthy subject is able to regenerate itself by repairing or replacing injured or ill tissue, unfortunately once a certain amount of liver cells has died or has been severely damaged through disease or injuries, the whole organ may fail. Such a failure, be it an acute or chronic failure, may cause disease and death.
• the therapy of liver diseases encompasses conventional means, such as the administration of drugs. However, it is also the state of the art to transplant livers or parts thereof. Furthermore, it is widely known to transplant liver cell populations in patients, such as described for instance in WO 2004/009766 A2.
• Haque et al. (Biotechnology Letters 27 (5) (2005), 317-322)) describe in vitro studies of alginate-chitosan microcapsules as an alternative to liver cell transplants for the treatment of liver failure.
• Chandrasekaran et al. (Tissue Engineering 12 (7), (2006)) disclose hepatic progenitor cells embedded in electrostatically produced beads.
• liver diseases in particular means which provide a high viability and physiological activity of the liver cells in the target body.
• microcapsules comprising a capsule shell, preferably a biocompatible capsule shell, encapsulating a suspension of a therapeutically effective amount of liver cells in physical contact to a liver cell stimulating amount of erythropoietin.
• the present invention provides microcapsules comprising a capsule shell and a core, wherein the capsule shell encapsulates in the core a suspension of a therapeutically effective amount of liver cells and a liver cell stimulating amount of erythropoietin, in particular wherein the erythropoietin (in the following termed EPO) and the liver cells are in physical contact to each other so as to provide a stimulating effect of the EPO to the liver cells.
• EPO erythropoietin
• the present invention foresees to provide microcapsules comprising a capsule shell, preferably made from a biocompatible capsule shell material, and a core being enveloped by said capsule shell.
• the core contains a suspension of a therapeutically effective amount of liver cells in physical contact to a liver cell stimulating amount of erythropoietin.
• the core contains a matrix, preferably made from a biocompatible matrix material, wherein the suspension of the therapeutically effective amount of liver cells is embedded in said matrix in physical contact to a liver cell stimulating amount of erythropoietin.
• the material of the matrix is the same as the capsule shell material.
• the biocompatible matrix material may be another material than the capsule shell material.
• the present invention provides the teaching to encapsulate both erythropoietin and liver cells together in a biocompatible capsule shell such that the erythropoietin is in physical contact to the liver cells so as to exert at least one of its biological functions on the liver cells, in particular in stimulating the liver cells.
• liver cells are encapsulated in the capsule shell and therefore do not elicit any adverse reaction, in particular allergic or immunological reaction, in the patient, in which the microcapsule is preferably transplanted. Furthermore, the close contact of the erythropoietin to the liver cell stimulates said liver cells to perform their biological function so as to provide the patient with the biological functions of a liver.
• the liver cells are contained in the microcapsule in such a concentration so as to be in physical contact to each other providing an even more pronounced effect when stimulated by the erythropoietin.
• the invention foresees in a particularly preferred embodiment that the liver cells contained in the microcapsules are in physical contact to each other and are in physical contact to the erythropoietin.
• liver cells are in physical contact to erythropoietin” means that erythropoietin is able to exert at least one of its biological functions on the liver cell, in particular is able to reach and being reversibly or irreversibly bound by the receptors for erythropoietin present on the liver cell.
• liver cells being in physical contact to each other means that the liver cells are present in the microcapsule of the present invention in such a close vicinity to each other that the cells touch each other and provide a stable environment closely resembling the natural physiological situation in a liver.
• the term “stimulating the liver cells” means that the erythropoietin increases the biological functionality of the liver cells, preferably in the patient in which the microcapsule is transplanted, increases the viability of the liver cells, increases their storage stability and/or increases their potential to successfully perform their biological function once being transplanted in the subject.
• biocompatibility means that the material, in particular the capsule shell material and/or the matrix material is able to keep the integrated liver cells viable and allow the interaction between the erythropoietin and the liver cells.
• biocompatible means that the material allows, preferably a long-term, implantation in a patient while still retaining the function of the embedded liver cells without eliciting any undesirable local or systemic effect in the subject, in particular allergic and immunological reactions.
• biocompatible means that the material is able to perform as a substrate supporting the liver cell activity including the solicitation of molecular and mechanical similar system between the liver cells and the EPO, preferably in order to optimize liver regeneration without eliciting any undesirable effects in the cells and the subject.
• erythropoietin designates a glycoprotein hormone that controls erythropoieses or blood cell production, preferably a substance that, in appropriately dosage, controls the growth, differentiation and maturation of stem cells via erythroblasts to erythrocytes.
• erythropoietin both encompasses the wild type erythropoietin, in particular the human erythropoietin, and derivatives therefrom.
• derivatives of erythropoietin are recombinant erythropoietin proteins which are characterized by at least one amino acid deviation, in particular deletion, addition or substitution of one more amino acid compared to the wild type EPO, and/or erythropoietin proteins with a different glycosylation pattern compared to the wild type erythropoietin.
• erythropoietin derivatives are also fusion proteins or truncated proteins of wild type erythropoietin or derivatives thereof.
• a derivative of erythropoietin is also a wild type erythropoietin having a different glycosylation pattern compared to the wild type glycosylation pattern.
• derivatives also those derivatives of erythropoietin that, while retaining the basic erythropoietin structure, are obtained by substitution of one or more atoms or molecular groups or residues, especially by substitution of sugar chains such as ethylene glycol, and/or whose amino acid sequences differ from that of the naturally occurring human or animal erythropoietin protein in at least one position but essentially have a high degree of homology at the amino acid level and comparable biological activity.
• Erythropoietin derivatives which can be employed, for example, in the present invention are known from WO 94/25055, EP 0148605 B1 or WO 95/05465.
• “Homology” means especially a sequence identity of at least 80%, preferably at least 85% and particularly preferably at least more than 90%, 95%, 97% and 99%.
• the term “homology” known by the person skilled in the art thus refers to the degree of relationship between two or more polypeptide molecules. This is determined by the agreement between the sequences. Such agreement can mean either identical agreement or else a conservative exchange of amino acids.
• the term “derivative” also includes fusion proteins, in which functional domains of another protein are present on the N-terminal part or on the C-terminal part.
• this other protein may be, for example, GM-CSF, VEGF, PIGF, a statin or another factor that has a stimulating effect on endothelial progenitor cells.
• the other protein may also be a factor that has a stimulating effect on liver cells.
• erythropoietin derivative and native or wild type erythropoietin may arise, for example, through mutations such as deletions, substitutions, insertions, additions, base exchanges and/or recombinations of the nucleotide sequences coding for the erythropoietin amino acid sequences.
• differences can also be naturally occurring sequence variations, such as sequences from another organism or sequences that have mutated naturally, or mutations introduced selectively into the nucleic acid sequences coding for erythropoietin, using common means known in the art, such as chemical agents and/or physical agents.
• the term “derivative” also includes mutated erythropoietin molecules, or in other words erythropoietin muteins.
• peptide or protein analogs of erythropoietin may also be used.
• the term “analogs” includes compounds that do not have any amino acid sequence identical to the erythropoietin amino acid sequence but have a three-dimensional structure greatly resembling that of erythropoietin, so that they have comparable biological activity.
• Erythropoietin analogs may be, for example, compounds that contain, in a suitable conformation, the amino acid residues responsible for binding of erythropoietin to its receptors, and that are therefore able to simulate the essential surface properties of the erythropoietin binding region. Compounds of this type are described, for example, in Wrighton et al., Science, 273 (1996), 458.
• the EPO used according to the invention can be produced in various ways, for example by isolation from human urine or from the urine or plasma (including serum) of patients suffering from aplastic anemia (Miyake et al., J.B.C. 252 (1977), 5558).
• human EPO can also be obtained from tissue cultures of human renal cancer cells (JA Unexamined Application 55790/1979), from human lymphoblast cells, which have the ability to produce human EPO (JA Unexamined Application 40411/1982), and from a hybridoma culture obtained by cell fusion of a human cell line.
• EPO can also be produced by methods of gene technology, using suitable DNA or RNA coding for the appropriate amino acid sequence of EPO to produce the desired protein by genetic engineering, for example in a bacterium, in a yeast, or in a plant, animal or human cell line. Such methods are described, for example, in EP 0148605 B2 or EP 0205564 B2 and EP 0411678 B1.
• derivatives of erythropoietin are in a preferred embodiment functional and clinically proven EPO derivatives, preferably selected from the group consisting of Epoetin, also termed Procrit, Epogen, Eprex or NeoRecormon, Epoetin delta, also termed Dynepo, Darbepoetin, also called Aranesp, PDpoetin, CERA (continuous erythropoietin receptor antagonist) and methoxy polyethylene glycol-epoetin beta, also termed Mircera.
• Epoetin also termed Procrit
• Epogen Epogen
• Eprex or NeoRecormon Epoetin delta
• Dynepo Dbepoetin
• PDpoetin also called Aranesp
• PDpoetin also called Aranesp
• CERA continuous erythropoietin receptor antagonist
• methoxy polyethylene glycol-epoetin beta also terme
• a microcapsule is a, preferably spherical, bead made from a biocompatible capsule shell material which contains embedded therein the therapeutically effective amount of liver cells in physical contact to a liver cell stimulating amount of erythropoietin.
• a microcapsule is preferably a sphere, preferably with a diameter from 140 ⁇ m to 10 mm, preferably 50 ⁇ m to 1 mm, preferably 60 ⁇ m to 800 ⁇ m, preferably 100 to 700 ⁇ m.
• the microcapsules of the present invention consist of the liver cells, the erythropoietin and the biocompatible capsule shell material.
• a coating of the microcapsule and/or a biocompatible matrix in the core of the microcapsule is foreseen.
• the present invention relates to microcapsules comprising a therapeutically effective amount of liver cells encapsulated in a biocompatible matrix material in physical contact to a liver cell stimulating amount of erythropoietin.
• the liver cells are embedded in the capsule shell in form of a suspension, preferably in a cell culture suspension.
• the liver cell suspension is preferably in form of liver cells contained in a cell culture medium or in a physiologically acceptable aqueous solution.
• the liver cell suspension is preferably a suspension of liver cells in a cell culture medium.
• the liver cells are embedded in the matrix contained in the shell in form of a suspension, preferably in a cell culture suspension, preferably in form of liver cells contained in a cell culture medium or in a physiologically acceptable aqueous solution.
• the present invention relates to microcapsules, wherein the liver cells are selected from the group consisting of hepatic precursor cells, hepatic stem cells, hepatoblasts and hepatocytes.
• the present invention relates to microcapsules, wherein the liver cells are obtained from adult liver, embryogenic liver, fetal liver, neonatal liver or liver cell cultures.
• the liver cells are living liver cells.
• the liver cells may be obtained from a living or a dead, in particular a recently deceased, donor.
• the present invention relates to microcapsules, wherein the liver cells are human liver cells, non-human primate liver cells, pig liver cells, dog liver cells, cat liver cells, rabbit liver cells, mouse liver cells or rat liver cells.
• the present invention relates to microcapsules, wherein the microcapsules have an average diameter from 100 to 700 ⁇ m, preferably from 200, 300, 400, 500, 600 or 650 to 700 ⁇ m.
• the present invention relates to microcapsules, wherein the therapeutically effective amount of liver cells is 10 4 to 10 8 , preferably 10 5 to 10 7 liver cells/ml suspension.
• the present invention relates to microcapsules, wherein the liver cells have an average diameter of 8 to 14 ⁇ m, preferably 9 to 12 ⁇ m.
• the present invention relates to microcapsules, wherein the liver cell stimulating amount of erythropoietin is 10 ⁇ 7 to 10 ⁇ 3 , preferably 10 ⁇ 7 to 10 ⁇ 5 and preferably 10 ⁇ 6 to 10 ⁇ 5 U/ml suspension.
• the present invention relates to microcapsules, wherein the EPO is wild type erythropoietin or recombinant erythropoietin.
• the present invention relates to microcapsules, wherein the capsule shell material is selected from the group consisting of alginate, alginate-chitosan (AC), alginate-poly-L-lysine (APA), thermogelation-polymer and PEG-hydrogel.
• the capsule shell material is selected from the group consisting of alginate, alginate-chitosan (AC), alginate-poly-L-lysine (APA), thermogelation-polymer and PEG-hydrogel.
• the present invention relates to microcapsules, wherein the matrix material is selected from the group consisting of alginate, alginate-chitosan (AC), alginate-poly-L-lysine (APA), thermogelation-polymer and PEG-hydrogel.
• the matrix material is selected from the group consisting of alginate, alginate-chitosan (AC), alginate-poly-L-lysine (APA), thermogelation-polymer and PEG-hydrogel.
• the present invention relates to microcapsules, wherein in addition to the liver cells at least one further cell type is present in the microcapsule.
• the at least one further cell type present in the microcapsule is selected from the group consisting of liver stellate cells, biliary cells, hemopoietic cells, monocytes, macrophage lineage cells, lymphocytes and endothelial cells.
• the microcapsule comprises in addition to the liver cells and the EPO at least one further growth factor, preferably selected from the group consisting of HGH (human growth factor), VEGF (vascular endothelial growth factor), CSF (colony stimulating factor), thrombopoietin, SCF complex (Skpcollien, F-box containing complex), SDF (stromal cell-derived factor-1), NGF (nerve growth factor), PIGF (phosphatidyl inositol glycan anchor biosynthesis, class F), HMG coreductase inhibitor, ACE (angiotensin converting enzyme) inhibitor, AT-1-inhibitor and an NO donor.
• HGH human growth factor
• VEGF vascular endothelial growth factor
• CSF colony stimulating factor
• thrombopoietin thrombopoietin
• SCF complex Skpcollien, F-box containing complex
• SDF stromal cell-derived factor-1
• NGF nerve growth factor
• the present invention relates to microcapsules, wherein the microcapsules are coated.
• the coating is a polymer coating, a sugar coating, a sugar alcohol coating and/or a fat or wax coating.
• the present invention relates to a method, wherein the microcapsules obtained in step c) are cryopreserved.
• the present invention relates to a method for the prophylactic or therapeutic treatment of a liver disease in a subject in need thereof comprising administering the microcapsules according to the present invention to the subject in need thereof.
• the present invention relates to a method, wherein the liver disease is hepatitis, cirrhosis, inborn errors of metabolism, acute liver failure, acute liver infections, acute chemical toxicity, chronic liver failure, cholangiocitis, biliary cirrhosis, Alagille syndrome, alpha-1-antitrypsin deficiency, autoimmune hepatitis, biliary atresia, cancer of the liver, cystic disease of the liver, fatty liver, galactosemia, gallstones, Gilbert's syndrome, hemochromatosis, hepatitis A, hepatitis B, hepatitis C and other hepatitis viral infections, poryphyria, primary sclerosing cholangitis, Reye's syndrome, sarcoidosis, tyrosinemia, type 1 glycogen storage disease or Wilson's disease.
• the liver disease is hepatitis, cirrhosis, inborn errors of metabolism, acute liver failure,
• the present invention relates to a method, wherein the administration is effected by introduction of the microcapsules under the liver capsule, into the spleen, into the liver, into the liver pulp or into the spleenic artery or portal vein.
• the present invention relates to a method for introducing liver cells into a subject comprising administering the microcapsules according to the present invention into the subject.
• the administration is effected by introduction into the subject in need thereof, wherein the administration is a topical, enteral or parenteral administration.
• the topical administration is an epicutaneous, inhalational, vaginal or internasal administration.
• the enteral administration is by mouth, by gastric feeding tube or rectally.
• the parenteral administration is by injection or infusion, preferably intervenous, intraarterial, intramuscular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal or intravesical administration.
• the parenteral administration is transdermal, transmucosal or inhalational.
• the present invention relates to a method for cultivating liver cells in a culture medium, preferably in vitro, comprising culturing microcapsules according to the present invention in a suitable culture medium and under conditions suitable for maintaining or increasing viability of the liver cells.

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