WO1998051328A1 - Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets - Google Patents
Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets Download PDFInfo
- Publication number
- WO1998051328A1 WO1998051328A1 PCT/IB1997/000530 IB9700530W WO9851328A1 WO 1998051328 A1 WO1998051328 A1 WO 1998051328A1 IB 9700530 W IB9700530 W IB 9700530W WO 9851328 A1 WO9851328 A1 WO 9851328A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- interferons
- interferon
- arabic gum
- stabilised
- tablets
- Prior art date
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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Virology (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1997/000530 WO1998051328A1 (en) | 1997-05-09 | 1997-05-09 | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
APAP/P/1999/001682A AP1168A (en) | 1996-05-09 | 1997-05-09 | Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets. |
JP54895898A JP2001526662A (en) | 1997-05-09 | 1997-05-09 | Stabilization of interferon in aqueous solution for the production of sublingual tablets |
EP97919595A EP1007083A1 (en) | 1997-05-09 | 1997-05-09 | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
AU24010/97A AU730020B2 (en) | 1997-05-09 | 1997-05-09 | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1997/000530 WO1998051328A1 (en) | 1997-05-09 | 1997-05-09 | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998051328A1 true WO1998051328A1 (en) | 1998-11-19 |
Family
ID=11004562
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB1997/000530 WO1998051328A1 (en) | 1996-05-09 | 1997-05-09 | Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1007083A1 (en) |
JP (1) | JP2001526662A (en) |
AU (1) | AU730020B2 (en) |
WO (1) | WO1998051328A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0950663A1 (en) * | 1997-08-01 | 1999-10-20 | Toray Industries, Inc. | Method for stabilizing useful proteins and useful protein compositions |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2834894B1 (en) * | 2002-01-21 | 2004-02-27 | Servier Lab | ORIBISPERSIBLE PHARMACEUTICAL COMPOSITION OF PIRIBEDIL |
FR2834896B1 (en) * | 2002-01-23 | 2004-02-27 | Servier Lab | ORODISPERSIBLE PHARMACEUTICAL COMPOSITION OF IVABRADINE |
US20210228687A1 (en) * | 2018-06-01 | 2021-07-29 | Ilc Therapeutics Ltd | Compositions and methods relating to the treatment of diseases |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0123291A2 (en) * | 1983-04-20 | 1984-10-31 | Kyowa Hakko Kogyo Co., Ltd. | Method for stabilizing interferon |
EP0133767A2 (en) * | 1983-08-04 | 1985-03-06 | The Green Cross Corporation | Gamma interferon composition |
DE3520228A1 (en) * | 1984-06-06 | 1985-12-12 | Hayashibara Biochem Lab | WATER-SOLUBLE BIOACTIVE DRY SOLIDS COMPOSITION, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
WO1988003411A1 (en) * | 1986-11-06 | 1988-05-19 | Amarillo Cell Culture Company, Inc. | Improved interferon therapy |
EP0420049A1 (en) * | 1989-09-28 | 1991-04-03 | F. Hoffmann-La Roche Ag | Stabilized leucocyte-interferon |
US5215741A (en) * | 1990-10-30 | 1993-06-01 | Amarillo Cell Culture Company, Incorporated | Method for prevention of parasite infections |
WO1997041885A1 (en) * | 1996-05-09 | 1997-11-13 | Feronpatent Limited | Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets |
-
1997
- 1997-05-09 EP EP97919595A patent/EP1007083A1/en not_active Withdrawn
- 1997-05-09 JP JP54895898A patent/JP2001526662A/en not_active Ceased
- 1997-05-09 AU AU24010/97A patent/AU730020B2/en not_active Ceased
- 1997-05-09 WO PCT/IB1997/000530 patent/WO1998051328A1/en not_active Application Discontinuation
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0123291A2 (en) * | 1983-04-20 | 1984-10-31 | Kyowa Hakko Kogyo Co., Ltd. | Method for stabilizing interferon |
EP0133767A2 (en) * | 1983-08-04 | 1985-03-06 | The Green Cross Corporation | Gamma interferon composition |
DE3520228A1 (en) * | 1984-06-06 | 1985-12-12 | Hayashibara Biochem Lab | WATER-SOLUBLE BIOACTIVE DRY SOLIDS COMPOSITION, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME |
WO1988003411A1 (en) * | 1986-11-06 | 1988-05-19 | Amarillo Cell Culture Company, Inc. | Improved interferon therapy |
EP0420049A1 (en) * | 1989-09-28 | 1991-04-03 | F. Hoffmann-La Roche Ag | Stabilized leucocyte-interferon |
US5215741A (en) * | 1990-10-30 | 1993-06-01 | Amarillo Cell Culture Company, Incorporated | Method for prevention of parasite infections |
WO1997041885A1 (en) * | 1996-05-09 | 1997-11-13 | Feronpatent Limited | Stabilization of interferons in aqueous solution for manufacture of sublingually administered tablets |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0950663A1 (en) * | 1997-08-01 | 1999-10-20 | Toray Industries, Inc. | Method for stabilizing useful proteins and useful protein compositions |
US6391296B1 (en) | 1997-08-01 | 2002-05-21 | Toray Industries, Inc. | Method of stabilizing useful protein and useful protein compositions |
EP0950663A4 (en) * | 1997-08-01 | 2003-03-19 | Toray Industries | Method for stabilizing useful proteins and useful protein compositions |
Also Published As
Publication number | Publication date |
---|---|
AU730020B2 (en) | 2001-02-22 |
AU2401097A (en) | 1998-12-08 |
EP1007083A1 (en) | 2000-06-14 |
JP2001526662A (en) | 2001-12-18 |
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