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AU730020B2 - 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 PDF

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Publication number
AU730020B2
AU730020B2 AU24010/97A AU2401097A AU730020B2 AU 730020 B2 AU730020 B2 AU 730020B2 AU 24010/97 A AU24010/97 A AU 24010/97A AU 2401097 A AU2401097 A AU 2401097A AU 730020 B2 AU730020 B2 AU 730020B2
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Australia
Prior art keywords
interferons
interferon
arabic gum
stabilised
aqueous solution
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Ceased
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AU24010/97A
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AU2401097A (en
Inventor
Peter R. Rothschild
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FERONPATENT Ltd
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FERONPATENT Ltd
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Publication of AU2401097A publication Critical patent/AU2401097A/en
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Anticipated expiration legal-status Critical
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    • 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

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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)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Peptides Or Proteins (AREA)

Description

WO 98/51328 ?PC-1" 89740530 1 STABILISATION OF INTERFERONS IN AQUEOUS SOLUTION FOR MANUFACTURE OF SUBUNGUALLY ADMINISTERED
TABLETS
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.
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 88/034/1 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. In this PCT Application, 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.
However, 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 (CsH 1 0
O
s )n as a stabilising agent for stabilising interferon in tablets.
The method comprises adding a compound of the general formula (CsHoOs)n.. to an aqueous solution of lyophilised interferons.
Among the compounds having the general formula (CsHioO),, arabic gum is a preferred compound.
WO 98/51328 PCT/IB97/00530 2 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 (CsH 10 Os)n such as arabic gum for the manufacture of sublingually administrated tablets in low concentrations.
In this case (CsH 10
O
s 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. Among 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 (CsHioOs)n 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.
WO 98/51328 PCT/IB97/00530 3 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 For example a tablet of 100 mg comprising between 100 to 300 I.U. of stabilised human alfainterferon will be administrated one to four times a day.
The optimum results are obtained when the interferon used has been put into contact with albumin and already compound of general formula (CsHo 1 0 0)n, especially arabic gum.
For the foregoing, it is clear that the compound of the general formula
(C
5
H
0 oOs)n provides an adhesive surface for the interferon molecules.
The preparation of tablets containing interferons in allopathic low dose may be divided in two steps. In a first step, 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 (CsH 10 Os)n, for instance arabic gum..
In a second step, the solution of base material obtained is then sprayed on granules of excipient containing (CsH 10 0s)n, for instance arabic gum, lactose and starch, and the mixture is vacuum dried and finally compressed into tablets.
A typical method of preparing tablets is given on the enclosed Table, which is an example with corresponding typical weights, volumes and proportions to be used.
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.
WO 98/51328 PCT/IB97/00530 4 Example 1 The invention is carried out in two stages which are as follows I Stabilisation of Interferon Base stock of 30 million I.U. of lyophilised high purity human alfainterferon is thoroughly mixed with 20 ml of double distilled water, 20 g of lactose, 600 gg of lyophilised HP albumin, 150 [tg 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.
II Preparation of the Excipient and Application The excipient is prepared by mixing thoroughly 3000 g of arabic gum 4500 g of lactose 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 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°C and 201C before packaging into blister packs.
The entire process must be carried out in strict conformity to the pharmaceutical norms.
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.
Example 2 g of lactose, 600 lig of lyophilised high purity (HP) albumin, 150 [ig of sodium monohydrophosphate, 150 ig of sodium dihydrophosphate are added to million I.U. lyophilised high purity human alfa-interferon of natural origin dissolved in 20 ml of distilled water.
WO 98/51328 PCT/IB97/00530 This material in then dissolved in three times under stirring in an aqueous solution containing propylene glycol to make an overall 25 albumin solution, with careful rinsing with distilled water between each disolution and recovery of the rinsing products. Stirring is continued at 60 RPM for 30 minutes to give the final solution.
The excipient is prepared by mixing thoroughly 3000 g of arabic gum 4500 g of lactose and 7500g of mais 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 depending on the equipment used.
Tablets of 100 mg each containing 200 I.U. of stabilised human alfainterferon are made by standard methods and vacuum dried at temperatures between 89C and 20QC before packaging into blister packs.
The entire process must be carried out in strict conformity to the pharmaceutical norms.
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 weeks at a daily dose of 200 I.U. to patients seropositive to HIV-1, 8 of them being asymptomatic.
All clinical symptoms commonly linked to HIV-1 infection scaled down radically after the 10 weeks of therapy, down to 0 for some patients. Karnofsky performance scores of the patients increased from an average of 60 at start of study to 100 at the end of treatment.
of the patients had seroconversion as measured by clinical trials.
CD4+ and CD8+ lymphocytes counts showed significant increase after 10 weeks of therapy.
WO 98/51328 PCT/IB97/00530 6 These results suggest that the low dose oral alfa-interferon is of benefit to seropositive patients.
By contrast, and as published in AIDS (1992), 6, 563-569, a traditional low-dose oral interferon with no arabic gum in its formulation and with no prestabilisation step during its preparation showed no significant change in a group of patients, in no aspect; and all patients remained HIV-1 -antibody-positive.
WO 98/51328 PCT/IB97/00530 7 Table STARTING MATERIAL 30 x 10 I.U. lyophilised HP human alfa-lnterferon 4 to 25 ml bidistilled water to 25 g pharmaceutical grade lactose 1 400 to 800 ig lyophilised HP albumin 100 to 200 Vg Na 2
HPO
4 100 to 200 g NAH 2
PO
4 15 to 25 g (CsHo 1 0 5 )n BASE MATERIAL Spray onto granules of 10 to 20 kg of excipient to compress 150 000 tablets of 10 mg each Excipient: arabic gum, lactose, and starch .2 for instance 20% arabic gum, 30% lactose, and 50% starch 4- Vacuum dry at temperatures between +89C and +252C Compress tablets under pressure
TABLETS
S Throughout the specification and claims, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense.
S 'Z7

Claims (9)

1. Stabilised interferons for sublingual administration in low concentrations, characterised in that the stabilising agent is arabic gum.
2. Stabilised interferons according to claim 1, wherein interferons are alfa-, beta- or gamma-interferon derived from bovine and humans or by recombinant DNA methods, in particular human alfa-interferon.
3. Stabilised interferons according to claims 1 or 2, further comprising albumin as a pre- stabilising agent.
4. A method of stabilising interferons in aqueous solution which comprises adding an arabic gum to an aqueous solution of lyophilised interferons.
A method according to claim 4, which comprises adding albumin as a previous pre- stabilising agent to an aqueous solution of lyophilised interferons.
6. An drug in tablet form comprising low amounts of stabilised interferons according to any of claims 1 to 3 and an excipient comprising an arabic gum.
7. An drug according to claim 6 containing low amounts of interferons from 1 I.U. to 2000 I.U. per 100 mg tablet, and an excipient comprising arabic gum, lactose, and starch.
8. A tablet of 100 mg comprising 100 to 300 I.U. of stabilised human alfa-interferon according to any of claims 1 to 3 administered sublingually one to four times a day for the prevention and treatment of hepatitis-B+C, viral induced tumours and cancers, HIV and other viral infections sensitive to interferon treatment.
9. A method for preparing tablets according claim 8 which comprises diluting in low concentration a stabilised interferon according to any of claims 1 to 3, and spraying onto an excipient containing an arabic gum, vacuum drying and compressing into tablets. A method for preparing tablets according to claim 9 comprising a) adding successively albumin and an arabic gum to an aqueous solution of lyophilised interferon, b) spraying this final solution onto an excipient containing arabic gum followed by vacuum drying and compressing into tablets. AMF~r ,~ET
AU24010/97A 1997-05-09 1997-05-09 Stabilisation of interferons in aqueous solution for manufacture of sublingually administered tablets Ceased AU730020B2 (en)

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 (2)

Publication Number Publication Date
AU2401097A AU2401097A (en) 1998-12-08
AU730020B2 true AU730020B2 (en) 2001-02-22

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JP (1) JP2001526662A (en)
AU (1) AU730020B2 (en)
WO (1) WO1998051328A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69838667T2 (en) 1997-08-01 2008-10-30 Toray Industries, Inc. PROCESS FOR STABILIZING USEFUL PROTEINS AND USEFUL PROTEIN AGENTS
RU2187331C1 (en) * 2000-12-18 2002-08-20 Гапонюк Петр Яковлевич Medicinal preparation
RU2204410C1 (en) * 2001-08-23 2003-05-20 Государственное унитарное предприятие "Иммунопрепарат" Antiviral agent
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
RU2277904C2 (en) * 2004-05-05 2006-06-20 Евгений Владимирович Воробейчиков Interferon-containing aerosol composition "nikofen"
RU2277932C2 (en) * 2004-09-24 2006-06-20 Седа Суреновна Григорян Sucking pill containing human interferon and/or interferon inductor possessing antiviral activity
EP3801599A1 (en) * 2018-06-01 2021-04-14 ILC Therapeutics Ltd Compositions and methods relating to the treatment of diseases

Family Cites Families (7)

* Cited by examiner, † Cited by third party
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
EP0133767B1 (en) * 1983-08-04 1991-04-03 The Green Cross Corporation Gamma interferon composition
JPS60258125A (en) * 1984-06-06 1985-12-20 Hayashibara Biochem Lab Inc Water-soluble dried material containing proteinic physiologically active substance
ZA878295B (en) * 1986-11-06 1988-05-03 Amarillo Cell Culture Co. Inc. Treatment of immuno-resistant disease
CA2024046A1 (en) * 1989-09-28 1991-03-29 Alberto Ferro Stabilized leukocyte-interferons
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

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WO1998051328A1 (en) 1998-11-19
AU2401097A (en) 1998-12-08
EP1007083A1 (en) 2000-06-14

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