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WO2004000266A1 - Methode d'administration d'interferon par voie orale transmucosale - Google Patents

Methode d'administration d'interferon par voie orale transmucosale Download PDF

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Publication number
WO2004000266A1
WO2004000266A1 PCT/RU2002/000300 RU0200300W WO2004000266A1 WO 2004000266 A1 WO2004000266 A1 WO 2004000266A1 RU 0200300 W RU0200300 W RU 0200300W WO 2004000266 A1 WO2004000266 A1 WO 2004000266A1
Authority
WO
WIPO (PCT)
Prior art keywords
interferon
mammal
aerosol
oral
alpha
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/RU2002/000300
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English (en)
Inventor
Yuriy Vasilievich Tyagotin
Evgeny Nikolaevich Sventytsky
Igor Anatolievich Pomytkin
Pavel Vasilievich Veteletsky
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Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to PCT/RU2002/000300 priority Critical patent/WO2004000266A1/fr
Priority to AU2002330801A priority patent/AU2002330801A1/en
Publication of WO2004000266A1 publication Critical patent/WO2004000266A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha

Definitions

  • the present invention relates to a method for oral transmucosal delivery of interferon.
  • Interferons are naturally occurring proteins with antiviral, antiproliferative and immunoregulatory activity.
  • the following definition for interferon has been accepted by international committee assembled to devise a system for the orderly nomenclature of interferons: "To qualify as an interferon a factor must be a protein which exerts virus nonspecific, antiviral activity at least in homologous cells through cellular metabolic processes involving synthesis of both RNA and protein.”
  • Four distinct classes of interferons are known to exist in humans. Pestka et al., Ann. Rev. Biochem.. 56: 727 (1987): Emanuel and Pestka, J. Biol. Chem.
  • the three main human interferons are known as IFN-alpha, IFN-beta and IFN-gamma.
  • the IFN-alpha family represents the predominant class of human IFNs.
  • Intramuscular administration is a predominant route of interferon delivery to a systemic circulation of mammals.
  • the present invention provides a method for oral transmucosal delivery of interferon comprising the steps of: (a) providing an interferon formulation comprising a therapeutically effective amount of interferon, (b) administering said interferon formulation in form of aerosol consisting of solid particles or liquid droplets with mass median aerodynamic diameter from 4 to 150 ⁇ m sublingually into a mammal's oral cavity, and (c) delivering said interferon by absorption through a mammal's oral mucosal tissue.
  • a particular advantage of the present invention is that the level of interferon in systemic circulation achieved in a mammal with an amount of interferon when administered into a mammal's oral cavity in form of aerosol is greater than the level achievable with the same amount of interferon administered into a mammal's oral cavity in non-aerosol form and under otherwise equal conditions. Accordingly, it is now possible through the practice of this invention to achieve certain desired therapeutic effects using less amount of interferon than was heretofore possible.
  • the desired therapeutic effects achievable through the practice of this invention include all known in the art therapeutic effects of interferon. Such effects include, but are not limited to, antiviral, antiproliferative, antitumor, antibacterial, and immunoregulatory action of interferon in mammals. Therefore, in practicing this invention, it is possible to minimize potential adverse effects, which may be associated with larger, therapeutic doses of the interferon and still achieve the therapeutic effect.
  • aerosol means a colloidal system consisting of very finely divided solid particles or liquid droplets dispersed in and surrounded by a gas.
  • the present invention is not limited in any way to a specific device for aerosol preparation but is applicable to all such devices now known or subsequently developed.
  • the therapeutically effective amount of interferon is within the skill of those who practice in the art having the benefit of the disclosure herein.
  • interferon will be present in method of the invention in amounts within its normal or less dosage unit and daily regimen ranges as detailed in medical literature.
  • the dosage range will be from about 100 IU to about 5x10 6 IU interferon per mammal.
  • mammals are administered about 3x10 6 IU human recombinant interferon-alpha per mammal per day.
  • the present invention is not limited in any way to specific interferon but is applicable to all such interferon now known or subsequently discovered or developed. Nonetheless, a preferred interferon for use in the method of this invention is human recombinant interferon-alpha.
  • the interferon formulation may be formulated with various pharmaceutically acceptable carriers or diluents in the form of liquid aerosols, solid aerosols, or sprays.
  • Such carriers can include solid diluents, sterile aqueous media, non-toxic organic solvents, and etc.
  • the interferon formulation may be formulated with various pharmaceutical ingredients known from the art. These ingredients may include, but are not limited to, buffering agents (such as phosphate buffer, carbonate buffer, tris buffer, tartrate buffer, borate buffer, acetate buffer, or maleate buffer), colorants, flavorants, coating agents, suspending agents, sweetening agents, anti-fungal preservatives, antimicrobial preservatives, clarifying agents, antioxidants, surfactants, and tonicity agents.
  • buffering agents such as phosphate buffer, carbonate buffer, tris buffer, tartrate buffer, borate buffer, acetate buffer, or maleate buffer
  • colorants such as phosphate buffer, carbonate buffer, tris buffer, tartrate buffer, borate buffer, acetate buffer, or maleate buffer
  • colorants such as phosphate buffer, carbonate buffer, tris buffer, tartrate buffer, borate buffer, acetate buffer, or maleate buffer
  • colorants such as phosphate buffer, carbonate buffer, tris buffer, tartrate buffer, borate buffer,
  • Such absorption promoters may include, but are not limited to, as lecithin, fatty acids, chitosan, salicylates, amino acids, emulsifiers like polyoxyethylene alkyl esters and sodium lauryl sulfate, caproic acid, lactic acid, malic acid, citric acid, pyrrolidonecarboxylic acid, N-alkylpyrrolidones, benzalkonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, cyclodextrins, dextran sulfate, lauric acid, lysophosphatidylcholine, menthol, methoxysalicylate, methyl oleate, polyoxyethylene, polysorbate, sodium glycocholate, sodium glycodeoxycholate, sodium taurocholate, sulfoxides, various alkyl glycosides, etc.
  • the following examples are presented to demonstrate the invention. The examples are illustrative only and
  • This example shows that sublingual administration of interferon in form of aerosol resulted in improved transmucosal delivery of interferon.
  • mice were subdivided into three groups. Mice in the first group (control 1) received sublingually solution of 2.5 ⁇ g (0.5 ⁇ 10 6 IU) rhlFN-alpha dissolved in 0.1 ml of saline (pH 7.2). Mice in the second group (control 2) received intramuscularly 2.5 ⁇ g (0.5x10 6 IU) of rhlFN-alpha dissolved in 0.1 ml of saline (pH 7.2).
  • This example shows that sublingual administration of interferon formulation comprising interferon and an absorption promoter in form of aerosol resulted in improved transmucosal delivery of interferon.
  • mice were subdivided into two groups. Mice in the first group (control) received sublingually solution of 2.5 ⁇ g (0.5 ⁇ l0 6 IU) rhlFN-alpha dissolved in 0.1 ml of saline (pH 7.2) with addition of 0.01 mg soy lecithin as the absorption promoter.
  • mice in the second group received sublingually interferon formulation comprising 2.5 ⁇ g (0.5x10 6 IU) rhlFN-alpha in form of liquid aerosol by the following method: parent solution of 2.5 ⁇ g (0.5x10 6 IU) rhlFN-alpha was prepared by dissolution of 2.5 ⁇ g (0.5x10 6 IU) rhlFN-alpha in 0.1 ml of saline (pH 7.2) with addition of 0.01 mg soy lecithin as the absorption promoter, this solution was sprayed by nebulizer to form liquid aerosol consisting of liquid droplets with mass median aerodynamic diameter from 8 to 150 ⁇ m, and this aerosol was administered to field under tongue in mouse's oral cavity. Absorption of rhlFN-alpha through oral mucosa into systemic circulation was assayed in the course of time with human interferon alpha ELISA.
  • interferon formulation comprising interferon and an absorption promoter in liquid aerosol form
  • improved transmucosal delivery of interferon into systemic circulation which delivery is significantly much greater as compared to administration of the same amounts of interferon and the absorption promoter in liquid sublingual non-aerosol form and under otherwise equal conditions (control).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une méthode d'administration d'interféron par voie orale transmucosale qui consiste à : (a) fournir une formulation d'interféron qui contient une dose thérapeutiquement efficace d'interféron, (b) administrer à un mammifère, en prise sublinguale, ladite formulation d'interféron en aérosol constitué de particules solides ou de gouttelettes liquides ayant un diamètre aérodynamique moyen compris entre 4 et 150 µm, et (c) administrer ledit interféron par absorption par le tissu muqueux oral du mammifère. L'avantage particulier de l'invention réside dans le fait que le niveau d'interféron atteint dans la circulation systémique d'un mammifère avec une certaine dose d'interféron administrée en aérosol dans la cavité orale est supérieur au niveau atteint avec la même dose d'interféron administrée sous une forme non aérosol dans la cavité orale d'un mammifère et dans les mêmes conditions.
PCT/RU2002/000300 2002-06-20 2002-06-20 Methode d'administration d'interferon par voie orale transmucosale Ceased WO2004000266A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/RU2002/000300 WO2004000266A1 (fr) 2002-06-20 2002-06-20 Methode d'administration d'interferon par voie orale transmucosale
AU2002330801A AU2002330801A1 (en) 2002-06-20 2002-06-20 Method for oral transmucosal delivery of interferon

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/RU2002/000300 WO2004000266A1 (fr) 2002-06-20 2002-06-20 Methode d'administration d'interferon par voie orale transmucosale

Publications (1)

Publication Number Publication Date
WO2004000266A1 true WO2004000266A1 (fr) 2003-12-31

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PCT/RU2002/000300 Ceased WO2004000266A1 (fr) 2002-06-20 2002-06-20 Methode d'administration d'interferon par voie orale transmucosale

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AU (1) AU2002330801A1 (fr)
WO (1) WO2004000266A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103396A1 (fr) * 2003-05-08 2004-12-02 Nastech Pharmaceutical Inc. Compositions permettant une distribution mucosale amelioree de l'interferon alpha
WO2016169571A1 (fr) * 2015-04-20 2016-10-27 Ghaleb Haider Abbas Produit pharmaceutique pour le traitement et la prophylaxie des infections microbiennes/virales
US20210228687A1 (en) * 2018-06-01 2021-07-29 Ilc Therapeutics Ltd Compositions and methods relating to the treatment of diseases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017371A (en) * 1988-01-06 1991-05-21 Amarillo Cell Culture Company, Incorporated Method for reducing side effects of cancer therapy
WO1992010207A1 (fr) * 1990-12-14 1992-06-25 Schering Corporation Administration orale d'interferon alpha pour traiter les tumeurs malignes des poumons
WO1997025862A1 (fr) * 1996-01-19 1997-07-24 Mcgill University Composition et methode de pretraitement de l'hepatite
WO2001049260A2 (fr) * 1999-12-30 2001-07-12 Intermune, Inc. Aerosol a gouttelettes liquides de $g(g)-ifn et procede associe

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5017371A (en) * 1988-01-06 1991-05-21 Amarillo Cell Culture Company, Incorporated Method for reducing side effects of cancer therapy
WO1992010207A1 (fr) * 1990-12-14 1992-06-25 Schering Corporation Administration orale d'interferon alpha pour traiter les tumeurs malignes des poumons
WO1997025862A1 (fr) * 1996-01-19 1997-07-24 Mcgill University Composition et methode de pretraitement de l'hepatite
WO2001049260A2 (fr) * 1999-12-30 2001-07-12 Intermune, Inc. Aerosol a gouttelettes liquides de $g(g)-ifn et procede associe
US20010043906A1 (en) * 1999-12-30 2001-11-22 Vlasselaer Peter Van gamma-IFN liquid-droplet aerosol and method

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HARRIS D ET AL: "DRUG DELIVERY VIA THE MUCOUS MEMBRANES OF THE ORAL CAVITY", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 81, no. 1, 1992, pages 1 - 10, XP000247003, ISSN: 0022-3549 *
LECCIONES J A ET AL: "A pilot double-blind, randomized, and placebo-controlled study of orally administered IFN-alpha-n1 (Ins) in pediatric patients with measles.", JOURNAL OF INTERFERON & CYTOKINE RESEARCH: THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY FOR INTERFERON AND CYTOKINE RESEARCH. UNITED STATES SEP 1998, vol. 18, no. 9, September 1998 (1998-09-01), pages 647 - 652, XP001135200, ISSN: 1079-9907 *
RUSSELL I J ET AL: "Lymphocyte markers and natural killer cell activity in fibromyalgia syndrome: effects of low-dose, sublingual use of human interferon-alpha.", JOURNAL OF INTERFERON & CYTOKINE RESEARCH: THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY FOR INTERFERON AND CYTOKINE RESEARCH. UNITED STATES AUG 1999, vol. 19, no. 8, August 1999 (1999-08-01), pages 969 - 978, XP001145919, ISSN: 1079-9907 *
SENEL SEVDA ET AL: "Delivery of bioactive peptides and proteins across oral (buccal) mucosa.", CURRENT PHARMACEUTICAL BIOTECHNOLOGY, vol. 2, no. 2, June 2001 (2001-06-01), June, 2001, pages 175 - 186, XP001135244, ISSN: 1389-2010 *
VEUILLEZ F ET AL: "Factors and strategies for improving buccal absorption of peptides", EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, ELSEVIER SCIENCE PUBLISHERS B.V., AMSTERDAM, NL, vol. 51, no. 2, March 2001 (2001-03-01), pages 93 - 109, XP004257246, ISSN: 0939-6411 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103396A1 (fr) * 2003-05-08 2004-12-02 Nastech Pharmaceutical Inc. Compositions permettant une distribution mucosale amelioree de l'interferon alpha
WO2016169571A1 (fr) * 2015-04-20 2016-10-27 Ghaleb Haider Abbas Produit pharmaceutique pour le traitement et la prophylaxie des infections microbiennes/virales
US20210228687A1 (en) * 2018-06-01 2021-07-29 Ilc Therapeutics Ltd Compositions and methods relating to the treatment of diseases

Also Published As

Publication number Publication date
AU2002330801A1 (en) 2004-01-06

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