WO1992010207A1 - Administration orale d'interferon alpha pour traiter les tumeurs malignes des poumons - Google Patents

Administration orale d'interferon alpha pour traiter les tumeurs malignes des poumons Download PDF

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Publication number
WO1992010207A1
WO1992010207A1 PCT/US1991/009084 US9109084W WO9210207A1 WO 1992010207 A1 WO1992010207 A1 WO 1992010207A1 US 9109084 W US9109084 W US 9109084W WO 9210207 A1 WO9210207 A1 WO 9210207A1
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WO
WIPO (PCT)
Prior art keywords
treating
preventing
alpha interferon
interferon
pharmaceutical composition
Prior art date
Application number
PCT/US1991/009084
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English (en)
Inventor
Robert J. Spiegel
Francis M. Cuss
Original Assignee
Schering Corporation
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 Schering Corporation filed Critical Schering Corporation
Priority to JP4502377A priority Critical patent/JPH06503570A/ja
Publication of WO1992010207A1 publication Critical patent/WO1992010207A1/fr

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Classifications

    • 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
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to pharmaceutical compositions comprising human alpha interferon (hIFN- ⁇ ) as an active ingredient to treat lung malignancies in mammals.
  • the invention also relates to the use of hIFN- ⁇ for making medicaments for treating lung malignancies in mammals as well as to methods of treating lung malignancies, generally referred to as lung cancer, by administering by oral inhalation to a mammal in need of such treating an amount of human alpha in recombinant DNA human alpha interferon (rhIFN- ⁇ ) effective for such treating.
  • Human alpha interferon (hlFN- ⁇ ) is a naturally occurring mixture of at least eleven compounds including those designated alpha-1 interferon and alpha-2 interferon.
  • alpha interferon species or components are known and are usually designated by a numeral and letter after the Greek letter alpha.
  • Human alpha-1 interferon is one species contemplated for use in this invention as are the species designated human alpha- '2 interferons.
  • recombinant DNA human alpha-2 interferons are designated Interferon Alpha-2a, which can be made as disclosed in Rubenstein, Biochem. Biophys. Acta (1982), 695, 5-16, and Interferon Alfa-2b.
  • Interferon Alfa-2b is the preferred species for use in this invention and is a recombinant DNA human alpha interferon (hereinafter ThlFN- ⁇ *) .
  • ThlFN- ⁇ * a recombinant DNA human alpha interferon
  • Another suitable rhIFN- ⁇ included in the acope of this invention is recombinant DNA human interferon alpha-2a.
  • Human interferon alfa-2b can be produced in bacteria and other microorganisms using recombinant DNA techniques including those disclosed in Nagata et al. Nature, (1980) 284, 316-329; European Patent 32,134 and U.S. Patent No. 4,289,690.
  • Various alpha interferon species are disclosed in U.S. patent 4,503,035.
  • IFN- ⁇ intralesionally to treat condylomate acuminata.
  • Several groups of investigators have documented that parenterally administered IFN- ⁇ does not accumulate in the nasopharyngeal, oropharyngeal, or airway mucosa or in the lung parenchyma in sufficient concentrations or for long enough time periods to be effective against respiratory virus infections.
  • hlFN- ⁇ * ⁇ non- recombinant human leukocyte alpha-interferon
  • hlFN- ⁇ * ⁇ non- recombinant human leukocyte alpha-interferon
  • Nebulized hlFN- ⁇ inhibits viral replication in mice (Please give Reference) .
  • the instillation of hlFN- ⁇ into the bronchi of perfused rabbit lungs has resulted in measurable serum concentrations [V. Bocci et al., Antiviral Res. (1984) Vol. 4, 211-220].
  • interferon- ⁇ (hlFN- ⁇ ) given both intranasally and intraorally at a dose of 700- 1600 units/day was effective in the treatment of influenza, respiratory syncytial viral bronchiolitis, and asthmatic bronchitis (Jia-xiong, et al, Chin Med J. 100:162-166, 1987).
  • hlFN- ⁇ has been inhaled by patients with advanced non-small cell lung cancer at doses up to 120 million International Units ("IU") .
  • IU International Units
  • Kinnula et al. discloses in the J. Interferon Res. (1989), Vol 9, 419-23 that inhaled hlFN- ⁇ resulted in serum concentration and side effects (e.g. fever, headache, influenza-like symptoms and nausea) similar to those disclosed after systemic hlFN- ⁇ administration as well as reversible airflow obstruction but no activity against the lung cancer was observed.
  • Inhaled hlFN- ⁇ has also been administered to patients suffering from bronchoalveolar carcinoma but no activity on the bronchoalveolar carcinoma has been demonstrated [V. Kinnula et al. J. Interferon Res, (1988) Vol 8, Suppl. 1 pll5]
  • the present invention provides a pharmaceutical composition for treating or preventing a lung malignancy in a mammal which composition comprises an effective amount of recombinant DNA human alpha interferon.
  • the present invention also provides a use of recombinant DNA human alpha interferon for the manufacture of a medicament for treating or preventing a lung malignancy in a mammal.
  • This invention also provides a method of treating a lung malignancy in a mammal afflicted with such malignancy which comprises administering via oral inhalation to such a mammal an amount of recombinant human DNA alpha interferon effective for such treating.
  • This invention also provides a method of preventing a lung malignancy in a mammal susceptible to lung malignany - e.g. heavy smokers of any tobacco products especially cigars and cigarettes, which comprises administering via oral inhalation to such a mammal ' an amount of recombinant DNA human alpha interferon effective for such preventing.
  • lung malignancy means at least one of squamous cell carcinoma, large cell carcinoma, small cell carcinoma, alveolar cell carcinoma, bronchoalveolar carcinoma, adenocarcinoma, bronchogenic carcinoma-in-situ, metastatic carcinoma, or sarcoma from primary tumors outside the lung or airways.
  • the effectiveness of the interferon therapy of this invention can be shown clinically in mammals, e.g. human beings afflicted with a lung malignancy or suspectible to a lung malignancy due to the smoking tobacco products, especially cigarettes and/or cigars using patients with the following entry criteria:
  • the recombinant DNA human alpha interferon (rhIFN- ⁇ ) administered via oral inhalation in accordance with this invention may be used as monotherapy or as adjunctive therapy with other treatments e.g., chemotherapy or immunotherapy to treat lung malignancy and prevent, inhibit and/or cure the pulmonary metastatic spread of one or more of the types of lung malignancies listed hereinabove.
  • treatments e.g., chemotherapy or immunotherapy to treat lung malignancy and prevent, inhibit and/or cure the pulmonary metastatic spread of one or more of the types of lung malignancies listed hereinabove.
  • the list of conventional chemotherapeutic agents useful in combination with alpha interferon is disclosed by S. Wadler et al in Cancer Research (1990), Vol 50 pp 5472-3486.
  • the recombinant DNA human alpha interferon (“rhlFN- ⁇ *) is administered by oral inhalation in accordance with this invention as a pharmaceutical composition containing rhIFN- ⁇ which may be dissolved or dispersed in a pharmaceutically acceptable carrier suitable for use in a nebulizer and/or a metered dose inhaler.
  • pharmaceutically acceptable carriers include, for example, water, saline, ethanol and the like which form a rhIFN-o solution or suspension suitable for administration via oral inhalation in accordance with this invention.
  • the rhIFN- ⁇ pharmaceutical composition useful in this invention may also contain minor amounts of non-toxic auxiliary substances such as melting agents, emulsifying agents, preservatives, stabilizers, and pH buffering agents.
  • auxiliary substances such as melting agents, emulsifying agents, preservatives, stabilizers, and pH buffering agents.
  • the preparation of these pharmaceutical compositions is well known to those skilled in the art; see for example Remington's Pharmaceutical Sciences Mack Publishing Co., Easton PA 15th Edition (1975) .
  • a preferred rhIFN- ⁇ pharmaceutical composition for use in accordance with this invention is the Intron® A brand of interferon available as a solution from Schering-Plough Corporation, Kenilworth, New.Jersey.
  • This commercially available Intron A rhIFN- ⁇ composition contains glycine, di- and mono- basic sodium phosphate as a buffer and serum albumin.
  • Other preferred rhIFN- ⁇ pharmaceutical compositions include any sterile isotonic aqueous solution, e.g. physicological phosphate-buffered saline at pH 7.3 which may also contain pharmaceutically acceptable non-toxic auxiliary agents such as stabilizers and/or a surfactants and the desired amount of rhIFN- ⁇ .
  • the concentration of rhIFN- ⁇ in the pharmaceutical composition may be adjusted by dilution with 0.9% saline solution before administration via oral inhalation.
  • nebulizers and metered dose inhalers are well known. See for example Remington, ibid, at chapter 99, pages 1910-1912.
  • Useful nebulizers include the Spira Electro 4 nebulizer, manufactured by Hameenlinman Ty ⁇ leskus, Hameenlinna, Finland, whose use is disclosed by Kinnula et al. in the J. of Interferon Research (1989) Vol. 9 at p420.
  • Useful metered dose inhalers as well as drug delivery systems that help deliver oral aerosolized medications from metered dose inhalers to the lungs include INHAL-AID and INSPIREASE drug delivery systems available from Schering-Plough Corporation, Kenilworth, New Jersey, U.S.A, for as well as those disclosed in the Physicians Desk Reference, 1990 Edition, for use with bronchodilators.
  • the output of the nebulizer or metered dose inhaler for use in this invention should consistently and reliably produce particles and/or droplets having a mass median aerodynamic diameter (M.M.A.D.) above about 0.5 microns, preferably having a M.M.A.D.
  • inhaled particles and/or droplets containing rhIFN- ⁇ having a M.M.A.D in the range of above about 0.5 to less than about 8 microns are suitable for deposition on the peripheral airways and lungs and thus maximize the beneficial effects of inhaled rhIFN- ⁇ .
  • Droplets and particles having a M.M.A.D. greater than 8 microns become impacted in the upper airways; and those having a M.M.A.D. less than about 0.5 microns tend to behave like a gas and are exhaled.
  • droplets and/or particles of rhIFN- ⁇ having the preferred M.M.A.D. have a high surface energy and tend to agglomerate.
  • a surfactant preferably a non-volatile liquid soluble in the propellant used in nebulizers or metered dose inhalers is desirable to lessen such agglomeration.
  • the effective amount of rhIFN- ⁇ for treating and/or preventing a lung malignancy in accordance with this invention is a dosage range of rhIFN- ⁇ of about l x 10 6 international units (IU) to about 1 x 10 11 IU, preferably about 1 x 10 6 IU to about 5 x 10 10 IU, and more preferably about 1 x 10 6 IU to about 2 x 10 10 IU.
  • the rhINF- ⁇ maybe administered daily in single or divided doses.
  • the amount of rhIFN- ⁇ administered and the treatment regimen used will, of course, be dependent on the age, sex and medical history of the patent being treated, the severity of the specific lung malignancy and the tolerance of patient to the treatment regimen as evidenced by local toxicity (e.g. nasal irritation and/or bleeding) and by systemic side effects (e.g. fever, malaire pan ⁇ ytopenia, CNS depression, gastrointestinal irritation and elevated liver enzymes) .
  • local toxicity e.g. nasal irritation and/or bleeding
  • systemic side effects e.g. fever, malaire pan ⁇ ytopenia, CNS depression, gastrointestinal irritation and elevated liver enzymes
  • Study Design Prior to ' enrollment, all patients are throughly examined and their disease clinically staged using chest x-rays, computerized tomography, EKG, hematologic and blood chemistries. Clotting studies including total fibrinogen determination, PTT, PT, TT, and fibrin degradation products are conducted. Karnofsky performance status, pulmonary function including peak expiratory flow (PEF) , forced expiratory volume in one second (FEV ⁇ ) , and forced vital capacity (FVC) are measured. Subjective and objective symptoms including the number and severity of coughing bouts, shortness of breath, pain and coughing-up of blood as well as body temperature, blood pressure, and heart rate are measured.
  • PEF peak expiratory flow
  • FEV ⁇ forced expiratory volume in one second
  • FVC forced vital capacity
  • Serum rhIFN- ⁇ concentrations are determined by use of commercially available immunoradiometric assays (Abbott Diagnotic ' s and Centocor, respectively) or by vesicular stomatitis virus (VSV) plaque reduction in HEp2 cultures. Measurement are performed before inhalation and 2hr, 5hr, lOhr, 15hr and 24 hr after inhalation.
  • VSV vesicular stomatitis virus
  • Each patient is vigorously monitored for early signs of toxicity as well as radiographic evidence of clinical effectiveness throughout the treatment course . and on a regular basis thereafter.
  • Methods of evaluation include frequent physician examination, a regular schedule for performance of laboratory procedures including hematologic and serum chemistries pulmonary function and clotting studies.
  • Radiographic studies include chest x-rays and CT scans as appropriate.
  • •Toxicity is graded in accordance with the Work Health Organization's recommendations for grading of acute and subacute toxicity. Performance status is graded from zero to four with complete disability being defined as four.
  • Tumor response is determined by means of serial radiographic studies. Areas of referenced tumors are determined by multiplication of the longest diameter by the greatest perpendicular diameter.
  • Complete response would be then defined as the disappearance of all measurable disease determined by observation separated by at least four weeks with the appearance of no new lesions within the radiation portal.
  • Partial response is a 50% decrease in the referenced tumor mass and stable disease would be defined as a less than 50% decrease in tumor size, or less than 25% increase. A tumor growth larger than 25% is considered progressive disease.
  • Symptoms and objective side effects of rhIFN- ⁇ therapy including changes in body temperature, airflow obstructure and flu-like symptom are also measured.
  • a reduction in tumor growth and/or lung malignancy by administering by oral inhalation rhIFN- ⁇ to patients in need of such administer is expected.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention se rapporte à une composition pharmaceutique servant au traitement ou à la prévention des tumeurs malignes des poumons chez les mammifères et comprenant un interféron alpha humain d'ADN de recombinaison (rhIFN-α), à l'utilisation du rhIFN-α dans la fabrication d'un médicament servant au traitement ou à la prévention des tumeurs malignes des poumons chez les mammifères, ainsi qu'à un procédé de traitement ou de prévention des tumeurs malignes des poumons chez les mammifères, qui consiste à administrer par inhalation orale à un mammifère atteint d'une tumeur maligne des poumons une quantité efficace de rhIFN-α à l'aide d'un ébuliseur ou d'un inhalateur doseur.
PCT/US1991/009084 1990-12-14 1991-12-11 Administration orale d'interferon alpha pour traiter les tumeurs malignes des poumons WO1992010207A1 (fr)

Priority Applications (1)

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JP4502377A JPH06503570A (ja) 1990-12-14 1991-12-11 肺の悪性腫瘍類を治療するためのアルファーインターフェロンの経口投与

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US62824090A 1990-12-14 1990-12-14
US628,240 1990-12-14

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JP (1) JPH06503570A (fr)
AU (1) AU9139091A (fr)
CA (1) CA2098393A1 (fr)
EE (1) EE9400337A (fr)
IE (1) IE914326A1 (fr)
IL (1) IL100332A0 (fr)
MX (1) MX9102512A (fr)
PT (1) PT99784A (fr)
WO (1) WO1992010207A1 (fr)
ZA (1) ZA919769B (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0679718A2 (fr) * 1994-04-09 1995-11-02 F. Hoffmann-La Roche AG Procédé pour la production d'interferon-alpha
US5696163A (en) * 1992-06-23 1997-12-09 Scotia Holdings Plc Method of stabilizing polyunsaturates
EP0898478A1 (fr) * 1996-05-09 1999-03-03 Pharma Pacific Pty. Ltd. Stimulation des mecanismes de defense d'hotes contre les tumeurs
EP0906119A1 (fr) * 1996-05-09 1999-04-07 Pharma Pacific Pty. Ltd. Procede de traitement
US5997858A (en) * 1996-05-09 1999-12-07 Pharma Pacific Pty Ltd. Stimulation of host defense mechanisms against tumors
US6207145B1 (en) 1997-05-09 2001-03-27 Pharma Pacific Pty Ltd. Therapeutic applications of high dose interferon
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof
WO2004000266A1 (fr) * 2002-06-20 2003-12-31 Yuriy Vasilievich Tyagotin Methode d'administration d'interferon par voie orale transmucosale

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Publication number Priority date Publication date Assignee Title
EP0077063A1 (fr) * 1981-10-13 1983-04-20 Exovir, Inc. Compositions contenant de l'interféron et application de ces compositions dans le traitement des infections herpétiques, lésions prémalignes de la peau, malignités de la peau et psoriasis
EP0372809A1 (fr) * 1988-12-01 1990-06-13 Schering Corporation Médicament pour le traitement intralésionnel de carcinomes cellulaires squameux avec de l'interféron alpha humain recombinant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0077063A1 (fr) * 1981-10-13 1983-04-20 Exovir, Inc. Compositions contenant de l'interféron et application de ces compositions dans le traitement des infections herpétiques, lésions prémalignes de la peau, malignités de la peau et psoriasis
EP0372809A1 (fr) * 1988-12-01 1990-06-13 Schering Corporation Médicament pour le traitement intralésionnel de carcinomes cellulaires squameux avec de l'interféron alpha humain recombinant

Non-Patent Citations (8)

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Title
Derwent's abstract, No. 88-262 741/37, SU 1 377 113, publ. week 8837 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 04920443, Medline Acc.No. 83153443, Jones D.H. et al: "Human lymphoblastoid interferon in the treatment of small cell lung cancer", Br J cancer Mar 1983, 47 (3) p361-6 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 05666357, Medline Acc.No. 85282357, Grunberg S.M. et al: "Phase II study of reombinant alpha interferon in the treatment of advanced non-small cell lung carcinoma", Cancer Treat Rep Sep 1985, 69 (9) p1031-2 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 05998255, Medline Acc.No. 86299255, Ravine T.J. et al: "Treatment with human recombinant leukocyte interferons inhibits in vitro invasive ability of human lung carcinoma cells", Clin Exp Metastasis Jul-Sep 1986, 4 (3) p191-203 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 06185262, Medline Acc.No. 87159262, Fidler I.J. et al: "Direct antiproli- ferative effects of recombinant human interferon- -alpha B/D hybride on human tumor cell line", Cancer Res Apr 15 1987, 47 (8) p2020-7 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 07147980, Medline Acc.No. 90054980, Kardamakis D. et al: "Recombinant human interferon alpha-2b enhances the radiosensitivity of small cell lung cancer in vitro", Anticancer Res Jul-Aug 1989, 9 (4) p1041-4 *
Dialog Information Services, file 155, Medline 66-92, Dialog Acc.No. 07459116, Medline Acc.No. 90366116, Kinnula V. et al: "Effect of inhaled natural interferon-alpha on diffuse bronchioal- veolar carcinoma", Eur J Cancer 1990, 26 (6) p740-1 *
Dialog Information Sevices, file 155, Medline 66-92, Dialog Acc.No. 07026016, Medline Acc.No. 89328016, Kinnula V. et al: "Pharmacokinetics and toxicity of inhaled human interferon-alpfha in patients with lung cancer", J Interferon Res Aug 1989, 9 (4) p 419-23 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5696163A (en) * 1992-06-23 1997-12-09 Scotia Holdings Plc Method of stabilizing polyunsaturates
EP0679718A2 (fr) * 1994-04-09 1995-11-02 F. Hoffmann-La Roche AG Procédé pour la production d'interferon-alpha
EP0679718A3 (fr) * 1994-04-09 1996-08-21 Hoffmann La Roche Procédé pour la production d'interferon-alpha.
EP1104809A1 (fr) * 1994-04-09 2001-06-06 F. Hoffmann-La Roche Ag Procédé pour la production d'interferon-alpha
US6005075A (en) * 1994-04-09 1999-12-21 Hoffmann-La Roche Inc. Method for producing alpha-interferon
EP0906119A4 (fr) * 1996-05-09 1999-10-20 Pharma Pacific Pty Ltd Procede de traitement
EP0898478A4 (fr) * 1996-05-09 1999-05-26 Pharma Pacific Pty Ltd Stimulation des mecanismes de defense d'hotes contre les tumeurs
US5997858A (en) * 1996-05-09 1999-12-07 Pharma Pacific Pty Ltd. Stimulation of host defense mechanisms against tumors
EP0906119A1 (fr) * 1996-05-09 1999-04-07 Pharma Pacific Pty. Ltd. Procede de traitement
EP0898478A1 (fr) * 1996-05-09 1999-03-03 Pharma Pacific Pty. Ltd. Stimulation des mecanismes de defense d'hotes contre les tumeurs
US6361769B1 (en) 1996-05-09 2002-03-26 Pharma Pacific Pty Ltd Stimulation of host defense mechanisms against viral challenges
US6207145B1 (en) 1997-05-09 2001-03-27 Pharma Pacific Pty Ltd. Therapeutic applications of high dose interferon
US6660258B1 (en) 1997-05-09 2003-12-09 Pharma Pacific Pty Ltd Oromucosal cytokine compositions and uses thereof
WO2004000266A1 (fr) * 2002-06-20 2003-12-31 Yuriy Vasilievich Tyagotin Methode d'administration d'interferon par voie orale transmucosale

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AU9139091A (en) 1992-07-08
IL100332A0 (en) 1992-09-06
JPH06503570A (ja) 1994-04-21
PT99784A (pt) 1992-12-31
EP0563177A1 (fr) 1993-10-06
EE9400337A (et) 1996-02-15
MX9102512A (es) 1992-06-01
IE914326A1 (en) 1992-06-17
CA2098393A1 (fr) 1992-06-15
ZA919769B (en) 1992-09-30

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