[go: up one dir, main page]

EP1007083A1 - Stabilisation d'interferons dans une solution aqueuse en vue de la fabrication de pastilles que l'on administre par voie sublinguale - Google Patents

Stabilisation d'interferons dans une solution aqueuse en vue de la fabrication de pastilles que l'on administre par voie sublinguale

Info

Publication number
EP1007083A1
EP1007083A1 EP97919595A EP97919595A EP1007083A1 EP 1007083 A1 EP1007083 A1 EP 1007083A1 EP 97919595 A EP97919595 A EP 97919595A EP 97919595 A EP97919595 A EP 97919595A EP 1007083 A1 EP1007083 A1 EP 1007083A1
Authority
EP
European Patent Office
Prior art keywords
interferons
interferon
arabic gum
stabilised
tablets
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.)
Withdrawn
Application number
EP97919595A
Other languages
German (de)
English (en)
Inventor
Peter R. Rothschild
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
FERONPATENT Ltd
Original Assignee
FERONPATENT Ltd
FERONPATENT Ltd
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 FERONPATENT Ltd, FERONPATENT Ltd filed Critical FERONPATENT Ltd
Publication of EP1007083A1 publication Critical patent/EP1007083A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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]
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the invention concerns the stabilisation of interferons in aqueous solution for application in the manufacturing of sublingually administered tablets in low dosage for the preventing and treating of interferon sensitive viral infections in humans and for functioning as an immunomodulator.
  • Interferons belong to a group of glycoprotein and proteins and are derived from leukocytes, lymphoblastoid and fibroblast cells during the activation of immune responses in humans and other vertebrate animals or by recombinant DNA methods. Interferon is classified into alfa, beta and gamma designations which correspond to leukocyte, fibroblast and type II interferons, respectively.
  • interferon For the sake of clarity, the various kinds of interferon would simply be referred to as "interferon" in the following description.
  • PCT Patent Application WO 88/03441 is dealing with interferon therapy and may be considered as a good reference text to which one could report to become familiar with interferon and its use.
  • interferon may be used in contact with oral or pharyngeal mucosa, for instance in a lozenge as a solid unitary dosage adapted to be dissolved in saliva when placed in the mouth.
  • interferon which is commonly available in lyophilised form for application are highly hydrophobic and have to be stabilised in order to be kept, and used in low dosages. This is a key feature that seems to have been overlooked in the PCT Application cited above.
  • An object of the present invention is therefore to provide stabilised interferon for allopathic use and a method to stabilise interferon in order for this substance to be used in low dosages.
  • Another object of the invention is to use a viscous molecule having the general formula (C 5 H 10 O 5 ) n as a stabilising agent for stabilising interferon in tablets.
  • the method comprises adding a compound of the general formula (C 5 H ⁇ oO 5 )n., to an aqueous solution of lyophilised interferons.
  • arabic gum is a preferred compound.
  • Another object of the invention is a pre-stabilised interferon and -a method to pre-stabilise interferon by using albumin. This method comprises adding albumin as a previous pre-stabilising agent to an aqueous solution of lyophilised interferons.
  • Another object of the invention is to use such stabilised interferons in low dosages in a tablet or a pastille or granules which will be made in contact with saliva in a patient's mouth in order to enter the oral submucous lymphatic plexi.
  • the present invention thus relates to a method of stabilising interferons in aqueous solution with a compound of the general formula (C 5 H 10 O 5 ) n such as arabic gum for the manufacture of sublingually administrated tablets in low concentrations.
  • (C 5 H 10 O 5 ) n for instance arabic gum, will be used together with albumine as a pre-stabilisation agent and, in a preferred embodiment, various phosphates.
  • Such stabilised interferon may be kept in solution under room temperature without the use of refrigeration up to 6 months to treat interferon sensitive viral infections and cancers.
  • Said compound has to be used when preparing the tablets from the base material, and can be used as well earlier when preparing the base material to be transformed subsequently into tablets. In other words, this compound may be utilised twice successively during the manufacturing of the drug in its final form.
  • This method of stabilisation can be applied to any kind of interferon like alfa, beta or gamma interferons derived from bovine and humans, or by recombinant DNA methods.
  • interferons human alfa-interferon is preferred.
  • the invention relates also to a method for the preparation of an drug comprising an low amount of interferons , for instance from 1 I.U. to 2000 I.U. per 100 mg tablet, in which said tablet contains an excipient comprising a compound of general formula (CsH ⁇ Os),, , such as arabic gum.
  • an excipient comprising a compound of general formula (CsH ⁇ Os),, , such as arabic gum.
  • This tablet may also contain lactose and starch and is used to stimulate the therapeutic response in human patients by making contact with saliva in the patient's mouth.
  • Interferon is a macromolecule which cannot pass through mucosae in general and mouth mucosa in particular. It will act by stimulating the immune system, by oral contact. Therefore, interferon contained in the tablets are likely not to enter the blood or lymphatic system of the patient.
  • the tablets should preferably not be swallow as the interferon is likely to be destroyed in the stomach or the intestines and to become of no use.
  • This tablet can be administrated sublingually for the prevention and treatment of various diseases such as hepatitis B+C, viral tumours and cancers, aids (HIV) and other viral infections sensitive to interferon treatment
  • various diseases such as hepatitis B+C, viral tumours and cancers, aids (HIV) and other viral infections sensitive to interferon treatment
  • a tablet of 100 mg comprising between 100 to 300 I.U. of stabilised human alfa- interferon will be administrated one to four times a day.
  • a base material is prepared by dissolving lyophilised interferon in bidistilled water in the presence of lactose and by adding successively lyophilised albumin, sodium monohydrophosphate, sodium dihydrosulfate and (C 5 H 10 O 5 )n, for instance arabic gum.
  • the solution of base material obtained is then sprayed on granules of excipient containing (C 5 H 10 O 5 ) n , for instance arabic gum, lactose and starch, and the mixture is vacuum dried and finally compressed into tablets.
  • excipient containing (C 5 H 10 O 5 ) n , for instance arabic gum, lactose and starch
  • Example 1 This example is given for illustrative purpose only.
  • the clinical trial results of the invention are based on the application of human alfa-interferon in low concentration of 200 I.U. per 100 mg tablet, as expressed before dilution steps.
  • Example 1
  • the invention is carried out in two stages which are as follows :
  • Base stock of 30 million I.U. of lyophilised high purity human alfa- interferon is thoroughly mixed with 20 ml of double distilled water, 20 g of lactose, 600 ⁇ g of lyophilised HP albumin, 150 ⁇ g of sodium monohydrophosphate, 150 ⁇ g of sodium dihydrophosphate and 20 g of arabic gum to form the base material.
  • the base material must be free of alcohol, and all ingredients are either of high purity or pharmaceutical grade.
  • the excipient is prepared by mixing thoroughly 3000 g of arabic gum (20%); 4500 g of lactose (30%); and 7500g of wheat or rice starch, all pharmaceutical grade which become granular in texture.
  • the final stock solution (base material) is then sprayed on the granules of the excipient with a regular spray nozzle with sterilised, filtered air under one atmosphere pressure during less than 60 minutes while the entire mixture is being stirred by standard mixing procedures. Losses of stock solution vary between 5% and 50% depending on the equipment used. Tablets of 100 mg each containing 200 I.U. of stabilised human alfa-interferon are made by standard methods and vacuum dried at temperatures between 8 a C and 20 S C before packaging into blister packs.
  • the tablets are to be used by patients sublingually to promote and enhance the immune response of the body for the treatment of viral infections sensitive to interferon.
  • the excipient is prepared by mixing thoroughly 3000 g of arabic gum (20%); 4500 g of lactose (30%); and 7500g of Magnolia starch, all pharmaceutical grade which become granular in texture.
  • the final stock solution is then sprayed on the granules of the excipient with a regular spray nozzle with sterilised, filtered air under one atmosphere pressure during less than 60 minutes while the entire mixture is being stirred by standard mixing procedures. Losses of stock solution vary between 5% and 50% depending on the equipment used.
  • Tablets of 100 mg each containing 200 I.U. of stabilised human alfa- interferon are made by standard methods and vacuum dried at temperatures between 8 a C and 20 a C before packaging into blister packs.
  • the tablets are to be used by patients sublingually to promote and enhance the immune response of the body for the treatment of viral infections sensitive to interferon.
  • a treatment using the tablets of example 2 was given sublingally for 10 weeks at a daily dose of 200 I.U. to patients seropositive to HIV-1, 8 % of them being asymptomatic.
  • Excipient arabic gum, lactose, and starch for instance 20% arabic gum, 30% lactose, and 50% starch i

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Cette invention concerne des interférons naturels ou recombinants qui sont stabilisés à l'aide d'eau bidistillée, de lactose, d'albumine, de monohydrophosphates et de bihydrophosphates de sodium ou de (C5H10O5)n, tel que de la gomme arabique. La matière ainsi obtenue est vaporisée sur un excipient comprenant 20 % de gomme arabique, 30 % de lactose et 50 % d'amidon, ceci de manière à produire des pastilles de 100 mg chacune qui contiennent 200 I.U. d'alpha-interféron d'origine humaine. La solution obtenue en fin du processus est vaporisée sur un excipient comprenant 20 % de gomme arabique, 30 % de lactose et 50 % d'amidon, ceci de manière à produire des pastilles de 100 mg chacune qui contiennent 200 I.U. d'alpha-interféron d'origine humaine. Ces pastilles sont administrées au patient par voie sublinguale et permettent de traiter des infections virales sensibles à l'interféron telles que le SIDA.
EP97919595A 1997-05-09 1997-05-09 Stabilisation d'interferons dans une solution aqueuse en vue de la fabrication de pastilles que l'on administre par voie sublinguale Withdrawn EP1007083A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB1997/000530 WO1998051328A1 (fr) 1997-05-09 1997-05-09 Stabilisation d'interferons dans une solution aqueuse en vue de la fabrication de pastilles que l'on administre par voie sublinguale

Publications (1)

Publication Number Publication Date
EP1007083A1 true EP1007083A1 (fr) 2000-06-14

Family

ID=11004562

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97919595A Withdrawn EP1007083A1 (fr) 1997-05-09 1997-05-09 Stabilisation d'interferons dans une solution aqueuse en vue de la fabrication de pastilles que l'on administre par voie sublinguale

Country Status (4)

Country Link
EP (1) EP1007083A1 (fr)
JP (1) JP2001526662A (fr)
AU (1) AU730020B2 (fr)
WO (1) WO1998051328A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0950663B1 (fr) * 1997-08-01 2007-11-07 Toray Industries, Inc. Stabilisation de proteines utiles et compositions a base de proteines utiles
FR2834894B1 (fr) * 2002-01-21 2004-02-27 Servier Lab Composition pharmaceutique orodispersible de piribedil
FR2834896B1 (fr) * 2002-01-23 2004-02-27 Servier Lab Composition pharmaceutique orodispersible d'ivabradine
WO2019229480A1 (fr) * 2018-06-01 2019-12-05 Alfacyte Limited Compositions et méthodes associées au traitement de maladies

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0123291A2 (fr) * 1983-04-20 1984-10-31 Kyowa Hakko Kogyo Co., Ltd. Méthode de stabilisation d'interféron
DE3484374D1 (de) * 1983-08-04 1991-05-08 Green Cross Corp Gamma-interferonzusammensetzung.
JPS60258125A (ja) * 1984-06-06 1985-12-20 Hayashibara Biochem Lab Inc 蛋白性生理活性物質を含有する水溶性乾燥物
ZA878295B (en) * 1986-11-06 1988-05-03 Amarillo Cell Culture Co. Inc. Treatment of immuno-resistant disease
CA2024046A1 (fr) * 1989-09-28 1991-03-29 Alberto Ferro Interferons stabilises
US5215741A (en) * 1990-10-30 1993-06-01 Amarillo Cell Culture Company, Incorporated Method for prevention of parasite infections
EP0920329B1 (fr) * 1996-05-09 2002-09-25 Feronpatent Limited Stabilisation des interferons dans une solution aqueuse par de la gomme arabique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9851328A1 *

Also Published As

Publication number Publication date
AU730020B2 (en) 2001-02-22
JP2001526662A (ja) 2001-12-18
AU2401097A (en) 1998-12-08
WO1998051328A1 (fr) 1998-11-19

Similar Documents

Publication Publication Date Title
RO122011B1 (ro) Compoziţii farmaceutice cu dispersare rapidă
WO1997037643A1 (fr) Procede et produit pour le traitement de l'arthrite
US20230001128A1 (en) Aerosolization systems, methods, and apparatuses
AP1168A (en) Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets.
JP2802488B2 (ja) 経鼻吸収用生理活性ペプチド組成物
JPH07118166A (ja) インシュリン組成物
CN107412747B (zh) 一种含有乳铁蛋白和唾液酸的复方制剂
JPH07118164A (ja) 経鼻吸収薬物用キャリヤおよび生理活性ペプチド組成物
AU730020B2 (en) Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets
CA2382887A1 (fr) Compositions immunostimulantes
EP1366768B1 (fr) Compositions à usage thérapeutique comprenant de la vitamine C, un sel métallique fournissant des ions Ca, de l'insuline, un extract de camomille, de la vitamine B et une antihistamine
EP0242553A1 (fr) Utilisation d'allantoine et de soufre dans la préparation d'un médicament pour le traitement de maladies odontostomatologiques
US7465711B2 (en) Treatment of cancers of lymphocytic cells with product R
US5268169A (en) Treatment method of ovarian cancer using interferon gamma
JP2001520657A (ja) Ｈｉｖ感染用コンビネーションセラピー
US20020107184A1 (en) Method for treating melanoma
WO2022167925A1 (fr) Association ou composition comprenant de la lactoferrine stabilisée
CN1078468C (zh) 叶绿素铜钠盐用于制造抗胃粘膜损伤的组合物的用途
RU2234939C1 (ru) Лекарственный препарат сублингвальных таблеток, содержащий интерферон-альфа, и способ его получения
RU2141819C1 (ru) Мазь с интерфероном человеческим лейкоцитарным "интерон"
RU2291690C2 (ru) Фармацевтическая противогерпетическая композиция
RU2163121C1 (ru) Средство от простуды
RU2144832C1 (ru) Противовирусное, противомикробное и противокандидозное средство
CN1663610A (zh) 溶菌酶新制剂
RU2175554C2 (ru) Оральный препарат интерферона в виде таблеток

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19991007

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: FERONPATENT LIMITED

17Q First examination report despatched

Effective date: 20000901

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

R18D Application deemed to be withdrawn (corrected)

Effective date: 20020302