WO1993020108A1 - Use of certain interferons for the treatment of disorders related to a misproportion of gamma-interferon producing t helper type 1 cells and interleukin-4 producing t helper type 2 cells - Google Patents

Use of certain interferons for the treatment of disorders related to a misproportion of gamma-interferon producing t helper type 1 cells and interleukin-4 producing t helper type 2 cells Download PDF

Info

Publication number
WO1993020108A1
WO1993020108A1 PCT/EP1993/000744 EP9300744W WO9320108A1 WO 1993020108 A1 WO1993020108 A1 WO 1993020108A1 EP 9300744 W EP9300744 W EP 9300744W WO 9320108 A1 WO9320108 A1 WO 9320108A1
Authority
WO
WIPO (PCT)
Prior art keywords
ifn
cells
producing
treatment
helper type
Prior art date
Application number
PCT/EP1993/000744
Other languages
English (en)
French (fr)
Inventor
Volker Brinkmann
Christoph Heusser
Sefik Alkan
Thomas Geiger
Original Assignee
Ciba-Geigy Ag
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 Ciba-Geigy Ag filed Critical Ciba-Geigy Ag
Publication of WO1993020108A1 publication Critical patent/WO1993020108A1/en

Links

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

Definitions

  • IFN- ⁇ Human alpha-interferon
  • IFN- ⁇ Human alpha-interferon
  • IFN- ⁇ is belonging to a family of polypeptides secreted by a large variety of eukaryotic cells upon activation.
  • IFN- ⁇ is coded for by a gene family comprising at least 15 non-allelic genes.
  • the primary translation product of IFN- ⁇ comprises 189 amino acids (except IFN- ⁇ 2: 188 amino acids), from which a signal peptide of 23 amino acids is removed by post-translational modification.
  • the amino acid sequence homology among IFN- ⁇ subtypes is 80-85 .
  • the present invention relates to the use of certain human interferons (for the manufacture of a pharmaceutical composition) for the treatment of disorders where a disturbed ratio of gamma-interferon (IFN- ⁇ ) producing T helper type 1 cells and interleukin-4 (IL-4) producing T helper type 2 cells in mammals including man is of pathogenic importance.
  • IFN- ⁇ gamma-interferon
  • IL-4 interleukin-4
  • a "disturbed ratio" of IFN- ⁇ producing T helper type 1 (THl) cells and IL-4 producing T helper type 2 (TH2) cells means that the ratio is smaller than normal, i.e. that the number of IFN- ⁇ producing T helper type 1 cells is decreased and/or the number of IL-4 producing T helper type 2 cells is increased.
  • disorders which are associated with a decreased production of IFN- ⁇ and an increased production of IL-4 are, for example: allergic (including atopic) disorders, e.g. atopic dermatitis, hyper IgE syndrome; asthma, e.g. atopic (intrinsic) or extrinsic asthma; hypereosinophilia, allergic rhinitis or hay-fever.
  • a decreased IFN- ⁇ production has been observed with facultative intracellular bacterial infections and some parasitic diseases.
  • Diseases caused by facultative intracellular bacteria include, for example: tuberculosis (Mycobacterium tuberculosis), brucellosis (Brucella abortus) and leprosy (Mycobacterium leprae).
  • Parasitic disorders include, for example: malaria (Plasmodia), Chagas disease (Trypanosoma cruzi), toxoplasmosis (Toxoplasma gondii) and sleeping sickness (Trypanosomes).
  • malaria Plasmodia
  • Chagas disease Trypanosoma cruzi
  • toxoplasmosis Toxoplasma gondii
  • sleeping sickness Trypanosomes.
  • EP-B-76489 inter alia the two human lymphoblastoid interferons LyIFN- ⁇ -2 and LyIFN- ⁇ -3 arc disclosed. These two interferons are also mentioned in US patent 4885 166.
  • US patent 4885 166 further discloses, inter alia, the IFN hybrid B 1 D 2 B 3 B 4 .
  • the IFN hybrid 6 ⁇ 6 3 6 4 is designated as "IFN BDBB".
  • LyIFN- ⁇ -2 has the following sequence: see SEQ ID No. 1.
  • LyIFN- ⁇ -3 has the following sequence: see SEQ ID No. 2.
  • IFN BDBB has the following sequence: see SEQ ID No.3.
  • administration of LyIFN- ⁇ -2 or IFN BDBB to mammals suffering from disorders which are associated with a disturbed ratio in the production of IFN- ⁇ and IL-4 may increase IFN- ⁇ production and thus bring back the IFN- ⁇ /E -4 ratio to normal and ameliorate and/or cure the disorders connected therewith.
  • the invention relates to the use of LyIFN- ⁇ -2 or IFN BDBB (for the manufacture of a pharmaceutical composition) for the treatment of disorders which are associated with a disturbed ratio of IFN- ⁇ producing T helper type 1 cells and IL-4 producing T helper type 2 cells in mammals including man.
  • One embodiment of the invention concerns the use of IFN BDBB, and another embodiment of the invention concerns the use of LyIFN- ⁇ -2.
  • the beneficial effects of said two interferons are determined, for example, by means of the following experimental methods.
  • the closely related LyIFN- ⁇ -3 is also included into the test methods:
  • Human PBMC (2xl0 6 /ml) are stimulated for 24h by anti-CD3 antibody coated to the culture plates (coating 24 h with anti-human CD3 antibody OKT3, 50 ⁇ g/ml). Cultures are performed in the presence of IL-2 (50U/ml), IL-4 (50ng/ml), and various concentrations of test compound. IFN- ⁇ is determined in culture supernatants after 24 hours, or the number of single IFN- ⁇ or IL-4 producing cells is determined in spot ELISAs after 24 h.
  • Human PBMC (2 x 10 6 /ml) are stimulated for 24h by plate bound anti-CD3 antibody in the presence of IL-2 (50U/ml), IL-4 (50ng/ml), and various concentrations of test compound.
  • IFN- ⁇ is determined in culture supernatants by ELISA: 96 well microtiter plates (Costar) are coated with mouse anti-human-IFN- ⁇ MAb 23.9 (l ⁇ g ml). All plates are blocked with 2% BSA in PBS containing 0.05% NaN 3 (1 h, 37°C, 150 ⁇ l well). After washing with PBS, test samples or control human IFN- ⁇ are added in blocking buffer (lOO ⁇ l well) and incubated for 16 h at RT.
  • mouse-anti-human IFN- ⁇ MAb 76.18 is added (0.2 ⁇ g lO0 ⁇ l/well, 2 h 37°C). Plates are washed and incubated with goat-anti- mouse Ig coupled to alkaline phosphatase (Tago, Burlingame, CA; O.l ⁇ g/lOO ⁇ l/well). Plates are washed and phosphatase substrat added (0.1mg/150 ⁇ l, Sigma).
  • LyIFN- ⁇ -2 increases IFN- ⁇ production by a factor of 19 and IFN BDBB even by a factor of 22, whereas LyIFN- ⁇ -3 induces a 6-fold increase only, in each case at a concentration of 10 ng/ml.
  • Human PBMC (5xl0 6 ⁇ nl) are stimulated for 24 h by anti-CD3 antibody coated to the culture plates (coating 24 h with anti-human CD3 antibody OKT3, 50 ⁇ g/ml). Cultures are performed in the presence of IL-2 (50U/ml), IL-4 (lOOng ml), and the test compound at a concentration of 10 ng ml.
  • IL-4 and IFN- ⁇ mRNA is determined as follows: Preactivated cells are lysed with 600 ⁇ l of guanidinium thiocyanate buffer (4M guanidinium thiocyanate, 25mM sodium citrate, pH7, 0.5% sacrosyl, 0.1M mercaptoethanol) and the cellular RNA is isolated by 2 cycles of acidic phenol extractions. The RNA pellet is dissolved in diethylpyrocarbonate-treated water and the concentration is determined by measuring the OD 26 o m M.
  • guanidinium thiocyanate buffer 4M guanidinium thiocyanate, 25mM sodium citrate, pH7, 0.5% sacrosyl, 0.1M mercaptoethanol
  • PCR amplifications are performed with the Gene Amp PCR it (Peridn-Elmer Cetus, Norwalk, USA) and commercially available primers for IL-4, IFN- ⁇ , and beta-Aktin (Clontech, Palo Alto, USA) according to the manufacturer's instructions. Briefly, 100 ng of total RNA are reverse-transcribed with 5U of reverse transcriptase at 42°C for 20 min, using as primers the specific PCR primers. Amplifications are performed for 30 cycles (1 min 60°C, 1 min 72°C, 1 min 94°C) using a thermal reactor from Hybaid®, Middlesex, UK. The amplified DNA is separated on a 1 % agarose gel together with DNA size markers.
  • the gel is stained with ethidium bromide and the bands are visualized by UV transillumination at 366 nM.
  • the relative intensities of the bands are determined by scanning the polaroid picture of the gel with a video densitometer (Bio Rad, Richmond, USA) in the reflection mode.
  • the values obtained with IL-4 and IFN- ⁇ are standardized with respect to beta actin RNA levels, to correct for variations in RNA amount.
  • LyIFN- ⁇ -2 increases IFN- ⁇ mRNA expression by anti-CD3 stimulated T cells more than 3-fold.
  • ELISA spot plates (96 well plates, Costar) are coated with mouse-anti-human-IL-4 MAb 8F12 or with mouse anti-human-IFN- ⁇ MAb 23.9 (l ⁇ g/ml).
  • PBMC ar activated for 24h with plate bound anti-CD3 (50 ⁇ g ml) in the presence of IL-4 (lOOng/ml) and IL-2 (50U/ml), washed and added in appropriate dilutions (IL-4: 2xl0 5 /100 ⁇ l; IFN- ⁇ : 2xl0 4 /100 ⁇ l) into the coated ELISA spot plates.
  • ELISA spot plates are centrifuged (3 min 40 x g) and incubated for 3h at 37°C. Cells are removed and developing antibodies added to the plates (IL-4: biotin-labelled mouse-anti-human IL-4 MAb 3H4; 0.2 ⁇ g 100 ⁇ l well, 2h 37°C, IFN- ⁇ : biotin-labelled mouse-anti-human IFN- ⁇ MAb 76.18; 0.2 ⁇ g/100 ⁇ l/well, 2h 37°C). Plates are washed, and avidin-AP added (Zymed, 0.2 ⁇ g/100 ⁇ l well, 2h 37°C).
  • LyIFN- ⁇ -2 as well as IFN BDBB increase the number of IFN- ⁇ producing cells about 6-fold, whereas LyIFN- ⁇ -3 only induces a 2-3 fold increase.
  • IL-4 producing cells are about 20-fold lower within PBMC, and it is important to note that they are not increased in the presence of LyIFN- ⁇ -2, IFN BDBB and LyIFN- ⁇ -3.
  • IFN- ⁇ increases the amount of IFN- ⁇ produced by THl cells. i contrast thereto, a slight and non-significant suppressive effect on the secretion of IL-4 is observed under the applied culture conditions.
  • human PBMC (10 6 /ml) are stimulated 24h by anti-CD3 antibody coated to the culture plates (coating 24 h with anti-human CD3 antibody OKT3, 50 ⁇ g/ml) in the presence or absence of either IFN- ⁇ (10 and lOOng/ml) or IL-4 (10 and lOOng ml), and the IL-4 and IFN- ⁇ secreting cells are determined as described above.
  • the data show that, surprisingly, addition of IFN- ⁇ to the cultures reduces the number of IL-4 producing TH2 cells about 3-fold, but increases the number of IFN- ⁇ producing THl cells about 3-fold, and changes the ratio of TH2 vs THl cells from 1:10 to 1:100. Therefore, the IL-4 production by TH2 cells is under the tight control of IFN- ⁇ produced by THl cells. An increase of the IFN- ⁇ production by IFN- ⁇ in vivo may therefore lead to a reduced IL-4 production and decreased IL-4 mediated immune responses.
  • IFN- ⁇ is able to suppress IL-4 production and to increase the number of IFN- ⁇ producing T cells.
  • IL-4 is able to block IFN- ⁇ production by THl cells.
  • similar cultures are performed in the presence of IL-4 (1 and lOng ml), or neutralizing antibodies to IL-4 (8F12, 1 and lO ⁇ g/ml). After 24 h, secreted IFN- ⁇ in culture supernatants is determined by ELISA [see under (2) above].
  • LyIFN- ⁇ -2 and IFN BDBB are interferons used according to the present invention.
  • LyIFN- ⁇ -2 and IFN BDBB make it possible for the first time to envisage long term treatment of diseases which are not as severe as those classically being treated with IFN- ⁇ , such as neoplastic diseases.
  • disorders which are associated with a disturbed ratio in the production of IFN- ⁇ and IL-4, for example atopic dermatitis, asthma or allergic rhinitis, can now be treated in the long term with LyIFN- ⁇ -2 and IFN BDBB without causing unacceptable side effects.
  • IFN BDBB With IFN BDBB, two Phase II trials have been performed in patients with malignant disease.
  • LyIFN- ⁇ -2 and IFN BDBB are preferably used in the form of pharmaceutical preparations that contain a therapeutically effective amount of the active ingredient optionally together with or in admixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for administration.
  • compositions for enteral such as oral administration
  • compositions for parenteral administration such as intravenous or subcutaneous administration
  • compositions for local administration such as intravenous or subcutaneous administration
  • compositions for local administration such as intravenous or subcutaneous administration
  • compositions for local administration such as intravenous or subcutaneous administration
  • compositions for administration by inhalation to mammals, in particular humans, the compositions comprising the pharmacologically active interferon on its own or together with customary pharmaceutical excipients.
  • the present pharmaceutical preparations which may, if desired, contain further pharmacologically valuable substances, are produced in a manner known per se, for example by means of conventional dissolving of lyophilising processes, and contain from approximately 0.1 % to 100 %, especially from approximately 1 % to approximately 50 %, and in the case of lyophilisates up to 100 %, of the active ingredient It is worthy of note that the.two interferons used according to the invention can be lyophilised and redissolved without any loss of activity.
  • the particular mode of administration and the dosage will be selected by the attending physician taking into account the particulars of the patient, the disease and the disease state involved.
  • the dosage of the active ingredient may depend on various factors, such as effectiveness and duration of action of the active ingredient severity of the disease to be treated and its symptoms, respectively, mode of administration, warm-blooded species, and/or sex, age, weight and individual condition of the warm-blooded animal.
  • the approximate daily dosage normally to be recommended for a warm-blooded animal weighing approximately 75 kg is from approximately 10 4 to approximately 10 8 units, especially from approximately 10 5 to approximately 10 7 units, which is optionally taken in several, optionally equal, partial doses. But also weekly regimens, for example 10 5 to 10 7 units once, twice or thrice weekly, come into consideration.
  • compositions for enteral and parenteral administration are, for example, those in dosage unit forms, such as drag ⁇ es, tablets or capsules and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
  • pharmaceutical preparations for oral administration can be obtained by combining the active ingredient with solid carriers, where appropriate granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, into tablets or drage cores.
  • Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, corn, wheat rice or potato starch, gelatin, tragacanth, methyl- cellulose and or polyvinylpyrrolidone and, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, using, for example
  • Adjuncts are especially flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and or polyethylene glycol.
  • Drage cores are provided with suitable coatings that may be resistant to gastric juices, there being used, inter alia, concentrated'sugar solutions that optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures or, to produce coatings that are resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colouring substances or pigments may be added to the tablets or drage coatings, for example for the purpose of identification or to indicate different doses of active in 'gere*
  • dry-filled capsules made of gelatin, and also soft sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of a granulate, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it being possible also for stabilisers to be added.
  • Parenteral formulations are especially injectable fluids that are effective in various manners, such as intravenously, intramuscularly, intraperitoneally, intranasally, intradermally or subcutaneously.
  • Such fluids are preferably isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations which contain the active ingredient alone or together with a pharmaceutically acceptable carrier.
  • the pharmaceutical preparations may be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers.
  • compositions for local administration are, for example, for the topical treatment of the skin, lotions, creams and ointments, that is to say liquid or semi-solid oil-in-water or water-in-oil emulsions, fatty ointments which are anhydrous, pastes, that is to say creams and ointments with secretion-absorbing powder constituents, gels which are aqueous, of low water-content or anhydrous and consist of swellable, gel-forming materials, foams, that is to say liquid oil-in-water emulsions in aerosol form which are administered from pressurised containers, and tinctures which have an aqueous-ethanolic base, it being possible that these compositions in each case contain other customary pharmaceutical excipients, such as preservatives.
  • Suitable for the local treatment of the eyes are, for example, eye drops which comprise the active ingredient in sterile aqueous or oily solution, and eye dintments which are also preferably manufactured in sterile form.
  • Suitable for the local treatment of the nose are, for example, sprays, similar to those described below for the treatment of the respiratory tract, coarse powders which are administered by rapid inhalation through the nostrils, and especially nose drops which comprise the active ingredient in aqueous or oily solution.
  • Suitable for the local treatment of the buccal cavity are, for example, lozenges and pastilles which comprise the active ingredient in an inert mass formed, for example, of sugar and gum arabic or tragacanth, to which flavourings may be added.
  • the pharmaceutical compositions for local admini ⁇ stration are prepared in a manner known per se by mixing the active ingredient with the pharmaceutical excipients, for example by dissolving or suspending the active ingredient in the base material or in a portion thereof, if necessary.
  • the active ingredient is, as a rule, dissolved therein before the emulsification; in order to prepare suspensions in which the active ingredient is suspended in the emulsion, the active ingredient is mixed with a portion of the base material after the emulsification and then added to the remainder of the formulation.
  • compositions for administration by inhalation are, for example, aerosols which are administered in the form of sprays or powders (powder aerosols).
  • Aerosols administered in the form of sprays are solutions, suspensions or emulsions of the active ingredient in a suitable, pharmaceutically acceptable liquid phase, such as in ethanol or water or a corresponding mixture, which may, as necessary, also comprise other pharmaceutical excipients, such as non-ionic or anionic surface-active agents, emulsifiers and stabilisers, and/or active ingredients of otiier kinds, and which comprise a propellant for example an inert gas, such as butane, under elevated pressure or especially a readily volatile liquid, preferably a liquid that boils under normal pressure below customary room temperature (for example at from approximately -30°C to approximately +10°C), such as an at least partially fluorinated polyhalogenated lower alkane, or a fluorinated lower alkane, e.g.
  • a corresponding pharmaceutical composition is introduced, together with the propellant into suitable containers, such as flacons or pressurised bottles, which are provided with a suitable spray device, for example a valve.
  • the valve is preferably constructed in the form of a metering valve which on operation releases a predetermined amount of the contents of the container, corresponding to a predetermined dose of the active ingre'dient
  • appropriate amounts of the pharmaceutical composition and of the propellant to be introduced separately into the containers and to be mixed with one another only at that stage.
  • active ingredient is to be understood as being either LyIFN- ⁇ -2 or IFN BDBB.
  • Example 1 100 vials each containing 3.33.10 6 units of IFN BDBB for parenteral administration are manufactured as follows:
  • IFN BDBB having a specific activity of 1.67 «10 8 units/mg on human WISH cells
  • the resulting solution is passed through a bacteriological filter and the filtered solution is subdivided under aseptic conditions into 100 vials each containing 3.33* 10 6 units of IFN BDBB.
  • the vials which are suitable for parenteral administration are preferably stored in the cold, for example between -20°C and +4°C.
  • vials containing 6.67* 10 6 or 1.33* 10 7 units may be prepared by using 4 or 8 mg, respectively, of IFN BDBB.
  • vials containing LyIFN- ⁇ -2 (specific activity 1.85»10 8 units/mg) can be prepared.
  • Example 2 100 g of an ointment comprising 0.005 % by weight of LyIFN- ⁇ -2 are manufactured as follows:
  • LyIFN- ⁇ -2 0.005 g 1
  • vaseline 4 5.00 g paraffin oil 19.60 g cetyl alcohol 5.00 g beeswax 5.00 g sorbitan sesquioleate 5.00 g p-hydroxybenzoic acid ester 0.20 g water, demineralised 20.195 g
  • LyIFN- ⁇ -2 has a specific activity of 1.85»10 8 units/mg on human WISH cells, 0.005 g of LyIFN- ⁇ -2 correspond to 9.25* 10 8 units.
  • 100 g of an ointment containing 3.7 «10 9 units may be prepared by using 0.020 g of LyIFN- ⁇ -2 (and 20.180 g of demineralised water).
  • the fatty substances and emulsifiers are melted together.
  • the preservative and the active ingredient are dissolved in water, and the solution is emulsified in the fatty melt at elevated temperature and then cooled.
  • an ointment containing IFN BDBB (specific activity 1.67»10 8 units/mg) can be prepared.
  • Example 3 An approximately 0.02 % aqueous solution, suitable for inhalation, of the active ingredient is manufactured as follows:
  • the active ingredient is dissolved in approximately 60 ml of freshly distilled water, and the stabiliser (disodium salt of ethylenediaminetetraacetic acid) and the preservative (benzalkonium chloride) are added. When all the components have completely dissolved, the resulting solution is made up to 100 ml and introduced into small pressurised bottles. The small bottles are sealed in gas-tight manner. The propellant is added, as required, in gaseous form under pressure or in liquid form.
  • an approximately 0.002 % aqueous solution, suitable for inhalation may be prepared by using 2 mg of the active ingredient
  • Example 4 Tablets each comprising 1 x 10 6 units of active ingredient are manufactured as follows:
  • composition (10.000 tablets) active ingredient 10 10 units lactose 500.0 g potato starch 352.0 g gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silica (highly disperse) 20.0 g ethanol q.s.
  • the active ingredient is mixed with the lactose and 292 g of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silica are admixed and the mixture is compressed to give tablets each of weight 145 mg and active ingredient content 50 mg, which, if desired, can be provided with breaking notches for finer adjustment of the dosage.
  • the active ingredient, the lactose and 40 g of the cornflour are mixed.
  • the mixture is moistened with a paste, prepared from 15 g of cornflour and water (with warming), and is granulated.
  • the granules are dried, and the remainder of the cornflour, the talc and the calcium stearate are mixed with the granules.
  • the mixture is compressed to give tablets (weight: 280 mg each) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the film-coated tablets: 283 mg each).
  • Example 6 Hard gelatin capsules each comprising 1 x 10 5 units of active ingredient are manufactured as follows:
  • composition 1000 capsules
  • active ingredient 10 8 units lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate 2.0 g magnesium stearate 8.0 g
  • the sodium lauryl sulfate is sieved into the lyophilised active ingredient through a sieve having a mesh width of 0.2 mm. Both components are intimately mixed.
  • the lactose is then first sieved in through a sieve having a mesh width of 0.6 mm and subsequently the microcrystalline cellulose through a sieve having a mesh width of 0.9 mm.
  • the four components are then intimately mixed for 10 minutes.
  • the magnesium stearate is sieved in through a sieve having a mesh width of 0.8 mm. After further mixing (3 minutes), 390 mg each of the formulation obtained is filled into hard gelatin capsules of size O.
  • Example 7 An injection or infusion solution, comprising 5 x 10 6 units of active ingredient per ampoule at 2.5 ml each, is manufactured as follows:
  • composition 1000 ampoules
  • active ingredient 5 x 10 9 units sodium chloride 22.5 g phosphate buffer solution (pH: 7.4) 300.0 g demineralised water ad 2500.0 ml
  • the active ingredient and the sodium chloride are dissolved in 1000 ml of demineralised water.
  • the solution is filtered through a microfilter (0.22 ⁇ m).
  • the filtrate is treated with the phosphate buffer solution, and the mixture is made up to 2500 ml with demineralised water.
  • To prepare unit dose forms 2.5 ml of the mixture each time are filled into glass ampoules, which then each contain 5 mg of active ingredient.
  • Gin Lys Ala Gin Ala lie Ser Val Leu His Glu Met lie Gin Gin Thr 50 55 60
  • Leu Leu Asp Glu Phe Tyr lie Glu Leu Asp Gin Gin Leu Asn Asp Leu

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/EP1993/000744 1992-04-07 1993-03-26 Use of certain interferons for the treatment of disorders related to a misproportion of gamma-interferon producing t helper type 1 cells and interleukin-4 producing t helper type 2 cells WO1993020108A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP92810266.4 1992-04-07
EP92810266 1992-04-07

Publications (1)

Publication Number Publication Date
WO1993020108A1 true WO1993020108A1 (en) 1993-10-14

Family

ID=8211905

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/000744 WO1993020108A1 (en) 1992-04-07 1993-03-26 Use of certain interferons for the treatment of disorders related to a misproportion of gamma-interferon producing t helper type 1 cells and interleukin-4 producing t helper type 2 cells

Country Status (5)

Country Link
AU (1) AU3889893A (enrdf_load_stackoverflow)
IL (1) IL105316A0 (enrdf_load_stackoverflow)
TW (1) TW218846B (enrdf_load_stackoverflow)
WO (1) WO1993020108A1 (enrdf_load_stackoverflow)
ZA (1) ZA932441B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0761228A3 (en) * 1995-09-07 1997-06-25 Suntory Ltd Composition containing gamma interferon for the treatment of prurigo

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076489A2 (de) * 1981-10-03 1983-04-13 Ciba-Geigy Ag Desoxyribonucleinsäuren, rekombinante Desoxyribonucleinsäuren, sie enthaltende Wirte, Polypeptide und Verfahren zu ihrer Herstellung
EP0177910A2 (de) * 1984-10-05 1986-04-16 BIOFERON Biochemische Substanzen GmbH & Co i.K. Verwendung von Interferon-gamma (IFN-gamma) enthaltenden Präparationen zur systemischen Behandlung von verschiedenen Erkrankungen des Menschen in niedriger Dosierung
EP0205404A2 (en) * 1985-06-11 1986-12-17 Ciba-Geigy Ag Hybrid interferons
WO1987001288A1 (en) * 1985-09-09 1987-03-12 Biogen N.V. Process for treatment of allergies
EP0329609A2 (en) * 1988-02-13 1989-08-23 Ciba-Geigy Ag Antiviral combination
US4915941A (en) * 1986-12-11 1990-04-10 New York University Method for preventing the development or decreasing the extent of malarial parasitemia

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0076489A2 (de) * 1981-10-03 1983-04-13 Ciba-Geigy Ag Desoxyribonucleinsäuren, rekombinante Desoxyribonucleinsäuren, sie enthaltende Wirte, Polypeptide und Verfahren zu ihrer Herstellung
EP0177910A2 (de) * 1984-10-05 1986-04-16 BIOFERON Biochemische Substanzen GmbH & Co i.K. Verwendung von Interferon-gamma (IFN-gamma) enthaltenden Präparationen zur systemischen Behandlung von verschiedenen Erkrankungen des Menschen in niedriger Dosierung
EP0205404A2 (en) * 1985-06-11 1986-12-17 Ciba-Geigy Ag Hybrid interferons
WO1987001288A1 (en) * 1985-09-09 1987-03-12 Biogen N.V. Process for treatment of allergies
US4915941A (en) * 1986-12-11 1990-04-10 New York University Method for preventing the development or decreasing the extent of malarial parasitemia
EP0329609A2 (en) * 1988-02-13 1989-08-23 Ciba-Geigy Ag Antiviral combination

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0761228A3 (en) * 1995-09-07 1997-06-25 Suntory Ltd Composition containing gamma interferon for the treatment of prurigo
US5972365A (en) * 1995-09-07 1999-10-26 Suntory Limited Remedy for prurigo

Also Published As

Publication number Publication date
IL105316A0 (en) 1993-08-18
ZA932441B (en) 1993-10-20
TW218846B (enrdf_load_stackoverflow) 1994-01-11
AU3889893A (en) 1993-11-08

Similar Documents

Publication Publication Date Title
EP1025124B1 (en) Low-toxicity human interferon-alpha analogues
US10273284B2 (en) Cytokine-based fusion proteins for treatment of immune disorders
EP0694307B1 (en) Atopic disease remedy
KR100223255B1 (ko) 개량된 알파 인터페론 조성물 및 인간 말초혈 백혈구로 부터의 제조 방법
EP1272515B1 (en) Immunoregulator
US7083782B2 (en) Method of treatment using interferon-tau
DE69805844T2 (de) Ifnnar/ifn komplex
US20040247565A1 (en) Method of treatment using interferon-tau
US8313730B2 (en) Treatment of celiac disease with IgA
CA2187336A1 (en) Pharmaceutical formulations for treating japanese cedar pollen allergy
US8119104B2 (en) Treatment of celiac disease with IgA
CA2632024A1 (en) Treatment of multiple sclerosis using interferon-tau
EA015924B1 (ru) Лечение вич
CA1290687C (en) Process for treatment of allergies
WO1993020108A1 (en) Use of certain interferons for the treatment of disorders related to a misproportion of gamma-interferon producing t helper type 1 cells and interleukin-4 producing t helper type 2 cells
Crockett et al. Side effects and toxicity of interferon in the treatment of recurrent respiratory papillomatosis
US20060078942A1 (en) Method of treatment using interferon-tau
CA2543485A1 (en) Use of interferon-tau in medicine
JP2003525040A (ja) 治療用ペプチド
US7235232B2 (en) Interferon alpha hybrids
WO2000006735A1 (en) Interferon alpha hybrids
US7754687B2 (en) Methods of inhibiting viral infection
US20060257363A1 (en) Treatment using an interferon
EP4137209A1 (en) Application of tff2 protein and ifn-? protein combination in treatment of a novel coronavirus infection
US20050118138A1 (en) Method of treatment using interferon-tau

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CZ FI HU JP KP KR LK MG MN MW NO NZ PL RO RU SD SK UA US VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)

Free format text: PL

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA