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WO1998034645A1 - Composition destinee a etre administree par voie intranasale, sublinguale ou vaginale - Google Patents

Composition destinee a etre administree par voie intranasale, sublinguale ou vaginale Download PDF

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Publication number
WO1998034645A1
WO1998034645A1 PCT/EP1998/000650 EP9800650W WO9834645A1 WO 1998034645 A1 WO1998034645 A1 WO 1998034645A1 EP 9800650 W EP9800650 W EP 9800650W WO 9834645 A1 WO9834645 A1 WO 9834645A1
Authority
WO
WIPO (PCT)
Prior art keywords
administration
protein
immunoglobuiin
composition according
insulin
Prior art date
Application number
PCT/EP1998/000650
Other languages
English (en)
Inventor
Vilma Rossi
Mario Pinza
Original Assignee
Angelini Ricerche S.P.A. Societa' Consortile
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angelini Ricerche S.P.A. Societa' Consortile filed Critical Angelini Ricerche S.P.A. Societa' Consortile
Priority to AU63953/98A priority Critical patent/AU6395398A/en
Publication of WO1998034645A1 publication Critical patent/WO1998034645A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin

Definitions

  • the present invention relates to a composition for therapeutic or diagnostic use, suitable for administration by the intranasal, sublingual or vaginal route and which comprises a protein-antibody complex.
  • the present invention refers to a composition of protein, peptides and polypeptides for administration by the intranasal, sublingual or vaginal route. It is known that many pathologies can be treated with proteins, peptides or polypeptides [hereinafter referred to collectively as protein(s)].
  • the muciparous cells secrete mucus which forms a protective supra-epithelial layer and constitutes a first barrier to the passage of substances through the mucosa.
  • the columnar cells are in the majority, have apical microviili and may be ciliated or non-ciliated.
  • the ciliated cells beat the cilia at a frequency of approximately 15 beats/sec, pushing the mucus towards the throat, thus removing dust particles, bacteria, pollen and allergens trapped in the mucus (mucociliary clearance). Due to this clearance and drainage, dwell time of the various substances/particles in the nose is fairly short, approximately 3-20 minutes in the human (Duchateau G.S.M.J.E.
  • the intranasal administration is not invasive, is generally well tolerated and is easy to self-manage; - unlike what happens after oral administration, the substance administered does not have to pass through the digestive system of the gastrointestinal tract or undergo hepatic metabolization;
  • the available area of nasal mucosa for absorption is relatively large and easily accessible; and - given that dwell time of the substance in the nose is short, the haematic concentration peak is quickly reached and this can be time by time controlled.
  • bioavailability is over 40% for peptides consisting of 3-6 amino acids (AA), fluctuates around 10-15% for polypeptides consisting of 9-27 AA, drops to less than 1 % for polypeptides having higher molecular weight (for example, for insulin - 51 AA - bioavailability is practically zero), although extremely high differences are found, for the same peptides, from species to species, or even from individual to individual of the same species.
  • AA 3-6 amino acids
  • a first object of the present invention therefore is a composition for therapeutic or diagnostic use which is capable of administration by the intranasal, vaginal and sublingual route, characterised in that it comprises a protein-antibody complex and at least one pharmaceutically acceptable ingredient.
  • hormones which control metabolic function and growth are ACTH (adrenocorticotropic hormone); amyline and the peptides associated with diabetes; enterostatin (capable of reducing fat absorption); glucagon and related peptides, peptides similar to glucagon, for example GLP-1 which controls glucose levels in type II diabetes and inhibits appetite in fasted rats; CCK (cholecystokynin) and related peptides, insulin, peptides similar to insulin; pancreastatin, which inhibits insulin secretion and causes increased glucose levels during intragastric administration of glucose; somatomedin C; calcitonins and their precursors, calcitonin gene-related peptides (CGRPs); parathyroid hormone and related proteins; thyroglobulin; gastrin and related peptides; proteinkinase- related peptides.
  • ACTH asdrenocorticotropic hormone
  • amyline and the peptides associated with diabetes enterostatin
  • hormones and growth factors are: insulin-like growth factors; the growth hormone (6-13) which potentiates the action of insulin; epithelial cell growth factors (EGF), nerve cell growth factors (NGF), hepatocyte growth factors (LGF), megakaryocyte growth factors (MGDF), blood platelet growth factors (PDGF), fibroblast growth factors (FGF), factors which stimulate granulocytes (GSF), transformation growth factors (TGF), erythrotropoietin, stem cell stimulating factors; glial cell- derived neurotrophic factors (GDNF) and brain cell-derived neurotrophic factors (BDNF).
  • EGF epithelial cell growth factors
  • NGF nerve cell growth factors
  • LGF hepatocyte growth factors
  • MGDF megakaryocyte growth factors
  • PDGF blood platelet growth factors
  • FGF fibroblast growth factors
  • TGF transformation growth factors
  • stem cell stimulating factors stem cell stimulating factors
  • GDNF glial cell- derived neurotrophic factors
  • BDNF brain cell-derived neurotrophic factors
  • Typical factors controlling coagulation are: fibrin-related peptides and fibronectin fragments; peptides possessing an antithrombotic action (lysyl- ⁇ -ketocarbonyl derivatives).
  • Typical examples of proteins with an antimicrobial activity are: caecoprin; dermaseptin (a powerful antifungal agent); magainin.
  • the antibody in turn is an immunoglobuiin selected from the group comprising the IgM, IgA and IgG categories and fragments thereof.
  • the immunoglobuiin may be specific or aspecific. Preferably, it is specific for the complexed protein. Even more preferably, the immunoglobuiin is of human origin, obtained by extraction and purification or by biological techniques such as, for example, the recombining DNA method.
  • the immunoglobuiin fragments are, preferably, of the Fc or Fab type.
  • the protein-immunoglobulin or protein-fragment complex comprises from 1 to 15,000 protein moles for each immunoglobuiin mole or for each immunoglobuiin fragment. Preferably, it comprises from 1 to 5,000, and even more preferably from 1 to 500 protein moles for each immunoglobuiin mole or immunoglobuiin fragment mole.
  • compositions according to the present invention are preferably prepared in suitable dosage forms for intranasal, sublingual or vaginal administration and comprise an effective dose of at least a protein-antibody complex and at least one pharmaceutically acceptable inert ingredient.
  • suitable dosage forms are powders and solutions in suitable metering devices for spray or nebulised administration by the intranasal route, and liposome-based formulations, creams, gels, pessaries and suppositories for the vaginal route, and tablets for the sublingual route.
  • the pharmaceutical composition according to the present invention may contain other pharmacologically active ingredients whose concomitant administration is useful.
  • the quantity of protein-antibody complex in the pharmaceutical composition according to the present invention may vary within a wide range dependent on known factors such as, for example, the type of disease to be treated, the severity of the disease, the patient's body weight, the number of daily administrations and the effectiveness of the preselected complex. Nevertheless, the optimum quantity may be easy and routinely determined by a person skilled in the art, in relation to the posology usually used for each specific protein in already known pharmaceutical compositions.
  • the dosage forms of the pharmaceutical composition according to the present invention may be prepared according to well known methods of pharmaceutical chemistry which include mixing, granulation, dissolution, sterilisation and the like.
  • the following examples are intended to illustrate the present invention, without limiting it in any way.
  • EXAMPLE 1 Intranasal Insulin Male New Zealand White rabbits, weighing approximately 2.5 kg (Charles River) were used; the animals were housed in individual cages, with free access to food and water.
  • a 5 ml syringe was used containing 4 ml of air and, instead of the needle, a Gilson tip was fitted (200 ⁇ l tipac). Quantities of 200 ⁇ l of solution per nostril were used for the administration; these were rapidly insufflated together with the air contained in a syringe (named "nasinga").
  • administration of insulin + aspecific IgAs complex causes a significant reduction of basal glycaemia (-12%; p ⁇ 0.05) 30' after administration.
  • administration of insulin + anti-insulin IgG complex is significantly more active (p ⁇ 0.001) than insulin alone 30' after administration and the action is also maintained after 90' and 180'.
  • administration of insulin + aspecific IgAs complex is significantly more active (p ⁇ 0.001 ) in comparison with insulin alone 30' after administration.
  • the animals were fasted for 18 hours prior to the experiment and basal glycaemia was tested immediately prior to administration of the preparations under evaluation.
  • a 1 ml syringe was used, containing 200 ⁇ l of a solution of insulin, either alone or in association with anti-insulin IgG and 500 ⁇ l of air.
  • a probe with rounded end was used, of the type used for intragastric administrations.
  • the experiment was carried out on 2 different days, by the same methods, until a total of 4 rabbits per treatment was attained.
  • the pharmacodynamic action of insulin was assessed by determination of glycaemia at time 0, 30' and 60' after administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composition à usage thérapeutique ou diagnostique adaptée à l'administration par voie intranasale, sublinguale ou vaginale. Cette composition comprend un complexe protéine-anticorps et au moins un ingrédient pharmaceutiquement acceptable.
PCT/EP1998/000650 1997-02-05 1998-02-04 Composition destinee a etre administree par voie intranasale, sublinguale ou vaginale WO1998034645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU63953/98A AU6395398A (en) 1997-02-05 1998-02-04 A composition for administration by the intranasal, sublingual or vaginal route

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT97MI000217A IT1289608B1 (it) 1997-02-05 1997-02-05 Composizione per uso terapeutico o diagnostico somministrabile per via intranasale,sublinguale o vaginale
ITMI97A000217 1997-02-05

Publications (1)

Publication Number Publication Date
WO1998034645A1 true WO1998034645A1 (fr) 1998-08-13

Family

ID=11375858

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/000650 WO1998034645A1 (fr) 1997-02-05 1998-02-04 Composition destinee a etre administree par voie intranasale, sublinguale ou vaginale

Country Status (3)

Country Link
AU (1) AU6395398A (fr)
IT (1) IT1289608B1 (fr)
WO (1) WO1998034645A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999004813A1 (fr) * 1997-07-24 1999-02-04 Brigham & Women's Hospital, Inc. Transport trans-epithelial d'agents therapeutiques specifique de recepteur
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
WO2000033814A3 (fr) * 1998-12-09 2000-11-30 Chiron Corp Technique d'apport d'agents au systeme nerveux central
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
EP1487992A2 (fr) * 2002-03-15 2004-12-22 The Brigham And Women's Hospital, Inc. Apport par les voies aeriennes centrales pour l'administration systemique de medicaments
US7273618B2 (en) 1998-12-09 2007-09-25 Chiron Corporation Method for administering agents to the central nervous system
US20130136744A1 (en) * 2002-11-08 2013-05-30 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
US9243065B2 (en) 2002-11-08 2016-01-26 Ablynx N.V. Polypeptide constructs including VHH directed against EGFR for intracellular delivery
US9371381B2 (en) 2002-11-08 2016-06-21 Ablynx, N.V. Single domain antibodies directed against tumor necrosis factor-alpha and uses therefor
US9732147B2 (en) 2005-02-23 2017-08-15 Janssen Biotech, Inc. Method for delivering alpha-melanocyte stimulating hormone mimetibody composition comprising propylene glycol for intranasal administration to the central nervous system

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305967A2 (fr) * 1987-09-02 1989-03-08 Ciba-Geigy Ag Conjugués d'interféron alpha avec immunoglobulines
WO1990002135A1 (fr) * 1988-08-26 1990-03-08 Robin Ewart Offord Derives de proteines et procede pour leur preparation
WO1991007418A1 (fr) * 1989-11-13 1991-05-30 Xoma Corporation Anticorps a10 chimerique souris-humain avec specificite envers un antigene de cellule tumorale humaine
WO1994014475A1 (fr) * 1992-12-21 1994-07-07 Tanox Biosystems, Inc. ANTICORPS MONOCLONAUX D'IgA SPECIFIQUES DE L'ALLERGENE ET PRODUITS APPARENTES POUR LE TRAITEMENT DES ALLERGIES
WO1995013831A1 (fr) * 1993-11-17 1995-05-26 The Schepens Eye Research Institute, Inc. Anticorps dirige contre l'epithelium superficiel oculaire et vaginal
WO1996022024A1 (fr) * 1995-01-17 1996-07-25 Brigham And Women's Hospital, Inc. Transport transepithelial specifique de recepteurs d'immunogenes
WO1997015296A1 (fr) * 1995-10-23 1997-05-01 Theratech, Inc. Apport buccal de peptides insulinotropiques du type glucagon
WO1997032572A2 (fr) * 1996-03-04 1997-09-12 The Penn State Research Foundation Materiaux et procedes permettant d'accroitre la penetration intracellulaire

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0305967A2 (fr) * 1987-09-02 1989-03-08 Ciba-Geigy Ag Conjugués d'interféron alpha avec immunoglobulines
WO1990002135A1 (fr) * 1988-08-26 1990-03-08 Robin Ewart Offord Derives de proteines et procede pour leur preparation
WO1991007418A1 (fr) * 1989-11-13 1991-05-30 Xoma Corporation Anticorps a10 chimerique souris-humain avec specificite envers un antigene de cellule tumorale humaine
WO1994014475A1 (fr) * 1992-12-21 1994-07-07 Tanox Biosystems, Inc. ANTICORPS MONOCLONAUX D'IgA SPECIFIQUES DE L'ALLERGENE ET PRODUITS APPARENTES POUR LE TRAITEMENT DES ALLERGIES
WO1995013831A1 (fr) * 1993-11-17 1995-05-26 The Schepens Eye Research Institute, Inc. Anticorps dirige contre l'epithelium superficiel oculaire et vaginal
WO1996022024A1 (fr) * 1995-01-17 1996-07-25 Brigham And Women's Hospital, Inc. Transport transepithelial specifique de recepteurs d'immunogenes
WO1997015296A1 (fr) * 1995-10-23 1997-05-01 Theratech, Inc. Apport buccal de peptides insulinotropiques du type glucagon
WO1997032572A2 (fr) * 1996-03-04 1997-09-12 The Penn State Research Foundation Materiaux et procedes permettant d'accroitre la penetration intracellulaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OIEN, NANCEE L. ET AL: "Induction of local and systemic immunity against human respiratory syncytial virus using a chimeric FG glycoprotein and cholera toxin B subunit", VACCINE (1994), 12(8), 731-5 CODEN: VACCDE;ISSN: 0264-410X, 1994, XP002050972 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067129B2 (en) 1995-01-17 2006-06-27 The Brigham And Woman's Hospital, Inc. Receptor specific transepithelial transport in therapeutics
US6086875A (en) * 1995-01-17 2000-07-11 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of immunogens
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US7547436B2 (en) 1995-01-17 2009-06-16 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US7060274B2 (en) 1995-01-17 2006-06-13 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
US6030613A (en) * 1995-01-17 2000-02-29 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
EP1616574A1 (fr) * 1997-07-24 2006-01-18 The Brigham And Women's Hospital, Inc. Transport trans-épithélial d'agents thérapeutiques spécifique de récepteur
WO1999004813A1 (fr) * 1997-07-24 1999-02-04 Brigham & Women's Hospital, Inc. Transport trans-epithelial d'agents therapeutiques specifique de recepteur
US7273618B2 (en) 1998-12-09 2007-09-25 Chiron Corporation Method for administering agents to the central nervous system
WO2000033814A3 (fr) * 1998-12-09 2000-11-30 Chiron Corp Technique d'apport d'agents au systeme nerveux central
EP1487992A4 (fr) * 2002-03-15 2007-10-31 Brigham & Womens Hospital Apport par les voies aeriennes centrales pour l'administration systemique de medicaments
EP1487992A2 (fr) * 2002-03-15 2004-12-22 The Brigham And Women's Hospital, Inc. Apport par les voies aeriennes centrales pour l'administration systemique de medicaments
US20130136744A1 (en) * 2002-11-08 2013-05-30 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
US9243065B2 (en) 2002-11-08 2016-01-26 Ablynx N.V. Polypeptide constructs including VHH directed against EGFR for intracellular delivery
US9320792B2 (en) * 2002-11-08 2016-04-26 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
US9371381B2 (en) 2002-11-08 2016-06-21 Ablynx, N.V. Single domain antibodies directed against tumor necrosis factor-alpha and uses therefor
US9725522B2 (en) 2002-11-08 2017-08-08 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
US9732147B2 (en) 2005-02-23 2017-08-15 Janssen Biotech, Inc. Method for delivering alpha-melanocyte stimulating hormone mimetibody composition comprising propylene glycol for intranasal administration to the central nervous system

Also Published As

Publication number Publication date
AU6395398A (en) 1998-08-26
ITMI970217A1 (it) 1998-08-05
IT1289608B1 (it) 1998-10-15

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