WO2020021574A1 - Compositions pharmaceutiques et procédés - Google Patents

Compositions pharmaceutiques et procédés Download PDF

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Publication number
WO2020021574A1
WO2020021574A1 PCT/IN2019/050546 IN2019050546W WO2020021574A1 WO 2020021574 A1 WO2020021574 A1 WO 2020021574A1 IN 2019050546 W IN2019050546 W IN 2019050546W WO 2020021574 A1 WO2020021574 A1 WO 2020021574A1
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WO
WIPO (PCT)
Prior art keywords
interleukin
cytokines
modulating
subject
compound
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.)
Ceased
Application number
PCT/IN2019/050546
Other languages
English (en)
Inventor
Ganesh Vishwanath SANGLE
Mohan Yashwant PATIL
Nitin Janardhanrao DESHMUKH
Sushant Ankushrao SHENGULE
Mahesh Vithalbhai Patel
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.)
Wockhardt Ltd
Original Assignee
Wockhardt 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 Wockhardt Ltd filed Critical Wockhardt Ltd
Publication of WO2020021574A1 publication Critical patent/WO2020021574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/5412—IL-6

Definitions

  • the invention relates to pharmaceutical compositions and their use in modulating one or more cytokines.
  • Cytokines are important biological molecules that are involved in several biological functions. Cytokines are small proteins, and particularly play important role in the immune system. Cytokines may include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors. The modulation of cytokines, for example by increasing or decreasing their levels, can help in achieving outcome of many intended treatments (e.g. infections, allergies, inflammation).
  • compositions for modulating one or more cytokines comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • a method for modulating one or more cytokines in a subject comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a method for modulating one or more cytokines in a subject comprising administering to the subject a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • the inventors have surprisingly discovered that certain compounds exhibit ability to modulate cytokines.
  • pharmaceutically acceptable salt refers to one or more salts of a given compound which possesses the desired pharmacological activity of the free compound and which are neither biologically nor otherwise undesirable.
  • pharmaceutically acceptable salts refer to and include those salts that are suitable for use in contact with the tissues of human and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. (J. Pharmaceutical Sciences, 66: 1-19 (1977)), incorporated herein by reference in its entirety, describes various pharmaceutically acceptable salts in details.
  • treat refers to administering a medicament, including a pharmaceutical composition, or one or more pharmaceutically active ingredients, for prophylactic and/or therapeutic purposes.
  • pharmaceutically effective amount or “therapeutically effective amount” or“effective amount” as used herein refers to an amount, which has a therapeutic effect or is the amount required to produce a therapeutic effect in a subject.
  • the compounds and/or pharmaceutical compositions according to the invention are used in amounts that are effective in providing the desired therapeutic effect or result.
  • administration includes delivery of a composition or one or more pharmaceutically active ingredients to a subject, including for example, by any appropriate methods, which serves to deliver the composition or its active ingredients or other pharmaceutically active ingredients to the desired site of action.
  • the method of administration may vary depending on various factors, such as for example, the components of the pharmaceutical composition, nature of the pharmaceutically active or inert ingredients, the desired site of action, age and physical condition of the subject and a like.
  • Some non limiting examples of ways to administer a composition or a pharmaceutically active ingredient to a subject according to this invention includes oral, intravenous, topical, intra-respiratory, intra-peritoneal, intra-mu scular, parenteral, sublingual, transdermal, intranasal, aerosol, intra-ocular, intra-tracheal, intra- rectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
  • “pharmaceutically inert ingredient” or“carrier” or “excipient” refers to a compound or material used to facilitate administration of a compound, including for example, to increase the solubility of the compound.
  • Typical, non limiting examples of solid carriers include, starch, lactose, dicalcium phosphate, sucrose, and kaolin and so on.
  • Typical, non-limiting examples of liquid carriers include sterile water, saline, buffers, non-ionic surfactants, and edible oils such as oil, peanut and sesame oils and so on.
  • various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, for example, in the Merck Index (Merck & Company, Rahway, N.J.).
  • subject refers to a vertebrate or invertebrate, including a mammal.
  • subject includes human, animal, a bird, a fish, or an amphibian.
  • Typical, non-limiting examples of a“subject” includes humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
  • modulating or “modulation” of cytokines refers to and includes increasing or decreasing level of cytokines.
  • modulating also refers to and includes stimulating cytokines.
  • compositions for modulating one or more cytokines comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof:
  • the pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in modulating one or more cytokines in a subject.
  • the cytokine is one or more of Tumor necrosis factor-a (TNF-a), Interleukin- 1 (IL-l), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin- 10 (IL-10), Interleukin- 1b (IL- 1 b), Interferon-g (IFN-g), and Granulocyte-macrophage colony stimulating factor (GM-CSF).
  • TNF-a Tumor necrosis factor-a
  • IL-l Interleukin-6
  • IL-8 Interleukin-8
  • IL-10 Interleukin- 10
  • IFN-g Interferon-g
  • GM-CSF Granulocyte-macrophage colony stimulating factor
  • the pharmaceutical compositions according to the invention may include one or more pharmaceutically acceptable carriers or excipients or a like.
  • Typical, non-limiting examples of such carriers or excipients include mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatine, sucrose, magnesium carbonate, wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, lubricants, stabilizing agents, binding agents and a like.
  • compositions according to this invention can exist in various forms.
  • the pharmaceutical composition is in the form of a powder or a solution.
  • the pharmaceutical compositions according to the invention are in the form of a powder that can be reconstituted by addition of a compatible reconstitution diluent prior to parenteral administration.
  • a compatible reconstitution diluent includes water.
  • the pharmaceutical compositions according to the invention are in the form of a frozen composition that can be diluted with a compatible diluent prior to parenteral administration.
  • compositions according to the invention are in the form ready to use for parenteral administration.
  • compositions or the active ingredients according to the present invention may be formulated into a variety of dosage forms.
  • dosage forms include solid, semi-solid, liquid and aerosol dosage forms; such as tablets, capsules, powders, solutions, suspensions, suppositories, aerosols, granules, emulsions, syrups, elixirs and a like.
  • the pharmaceutical composition and/or other pharmaceutically active ingredients disclosed herein may be administered by any appropriate method, which serves to deliver the composition or its constituents or the active ingredients to the desired site.
  • the method of administration can vary depending on various factors, such as for example, the components of the pharmaceutical composition, nature of the active ingredients, age and physical condition of the subject.
  • Some non-limiting examples of administering the composition to a subject according to this invention include oral, intravenous, topical, intra-respiratory, intra-peritoneal, intra-mu scular, parenteral, sublingual, transdermal, intranasal, aerosol, intraocular, intra-tracheal, intra-rectal, vaginal, gene gun, dermal patch, eye drop, ear drop or mouthwash.
  • compositions according to the invention can be formulated into various dosage forms wherein the active ingredients and/or excipients may be present either together (e.g. as an admixture) or as separate components.
  • the various ingredients in the composition are formulated as a mixture, such composition can be delivered by administering such a mixture.
  • the composition or dosage form wherein the ingredients do not come as a mixture, but come as separate components, such composition/dosage form may be administered in several ways. In one possible way, the ingredients may be mixed in the desired proportions and the mixture is then administered as required. Alternatively, the components or the ingredients (active or inert) may be separately administered (simultaneously or one after the other) in appropriate proportion so as to achieve the same or equivalent therapeutic level or effect as would have been achieved by administration of the equivalent mixture.
  • methods for modulating one or more cytokines in a subject comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the active ingredients disclosed herein may be administered to a subject in several ways depending on the requirements.
  • the active ingredients are admixed in appropriate amounts and then the admixture is administered to a subject.
  • the active ingredients are administered separately.
  • the invention further provides for combining separate pharmaceutical compositions in kit form.
  • the kit may comprise one or more separate pharmaceutical compositions, each comprising one or more active ingredients. Each of such separate compositions may be present in a separate container such as a bottle, vial, syringes, boxes, bags, and the like.
  • the kit comprises directions for the administration of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) ore are administered at different dosage intervals.
  • the active ingredients are administered separately, they may be administered simultaneously or sequentially.
  • test compounds in modulating one or more cytokines was evaluated using a whole blood cytokine secretion assay, using the following general procedure.
  • Peripheral venous blood was collected with consent from healthy adult volunteers between 25 to 40 years of age and stored in tubes containing heparin. All volunteers confirmed that they did not take any concomitant medication within the last 2 weeks prior to the start of study and also that they had no known hypersensitivity to any antibacterial drugs. All blood collections were in accordance to protocols approved by the Institutional Review Board of Wockhardt Ltd, India. Written informed consent was obtained from study participants. Lipopolysaccharide (Sigma, USA) was used as stimulating agent for immune cells. Quantikine ELISA human cytokine kits were purchased from, R & D Systems, Inc, USA. Test compounds were prepared using literature procedures.
  • the supernatants were analysed for IL-6 and TNF-a sandwich immunoassay using a BioTek 96 well Plate Reader.
  • the assay was performed according to the manufacturer’s instructions (R & D Systems, Inc, USA) and analysed with the BioTek 96 well Plate Reader software.
  • the sensitivity of TNF- a method was 1.6 pg/mL and the assay could accurately detect cytokines in the range of 15.6 - 1,000 pg/ml.
  • the sensitivity of IL-6 method was 0.7 pg/mL and the assay could accurately detect cytokines in the range of 3.13 - 200 pg/ml.
  • cytokine concentrations of samples treated with test compounds were expressed as a percentage compared to cytokine concentrations induced by LPS alone, which were defined as 100%.
  • Linear mixed models which take into account the possible dependence among measurements from the same sample under different drug concentrations, were employed to analyse drug concentration response data for each cytokine, stimulation condition and antibacterial agent independently. Data were expressed as means ⁇ standard error of mean (SEM). The results were analysed via a one-way ANOVA with Graph pad Prism 5 software, and Tukey’s post hoc test was used to compare the differences between groups.
  • Compound of Formula (I) and Telithromycin showed concentration-dependent inhibition of LPS-stimulated IL-6 release with 44% and 33% inhibition at highest concentration, respectively.
  • Compound of Formula (I) showed statistically non- significant higher inhibition of IL-6 release compared to Telithromycin at all the tested concentrations. Azithromycin and Clarithromycin did not show any effect on LPS-stimulated IL-6 release. Thus, Compound of Formula (I) was found to be more potent modulator when compared to Telithromycin, Azithromycin and Clarithromycin.
  • Compound of Formula (I) and Telithromycin showed concentration-dependent inhibition of LPS- stimulated TNF-a release with 64 and 52% inhibition at highest concentration, respectively.
  • Compound of Formula (I) showed statistically non-significant higher inhibition of TNF-a release compared to Telithromycin at all the tested concentrations. Azithromycin and Clarithromycin did not show any effect on LPS -stimulated TNF-a release.
  • Compound of Formula (I) was found to be more potent modulator when compared to Telithromycin, Azithromycin and Clarithromycin.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci : formule (I) pour moduler une ou plusieurs cytokines telles que : le facteur de nécrose tumorale α (TNF-α), l'interleukine-1 (IL-1), l'interleukine-6 (IL-6), l'interleukine-8 (IL-8), l'interleukine-10 (IL-10), l'interleukine-1β (IL-1β), l'interféron-g (IFN-g), et un facteur de stimulation de colonies de granulocytes-macrophages (GM-CSF), et des procédés de modulation d'une ou de plusieurs cytokines et leur utilisation pour moduler une ou plusieurs cytokines.
PCT/IN2019/050546 2018-07-27 2019-07-25 Compositions pharmaceutiques et procédés Ceased WO2020021574A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201821028332 2018-07-27
IN201821028332 2018-07-27

Publications (1)

Publication Number Publication Date
WO2020021574A1 true WO2020021574A1 (fr) 2020-01-30

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Application Number Title Priority Date Filing Date
PCT/IN2019/050546 Ceased WO2020021574A1 (fr) 2018-07-27 2019-07-25 Compositions pharmaceutiques et procédés

Country Status (1)

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WO (1) WO2020021574A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037983A1 (en) * 2003-03-11 2005-02-17 Timothy Dinan Compositions and methods for the treatment of depression and other affective disorders
WO2006090067A1 (fr) * 2005-02-25 2006-08-31 Aventis Pharma S.A. Composition pharmaceutique solide comprenant de la telithromycine
WO2008072034A1 (fr) * 2006-12-12 2008-06-19 Zambon S.P.A. Composés macrolides dotés d'une activité anti-inflammatoire
US20100209357A1 (en) * 2006-08-10 2010-08-19 Levitt Roy C Localized Therapy of Lower Airways Inflammatory Disorders with Proinflammatory Cytokine Inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050037983A1 (en) * 2003-03-11 2005-02-17 Timothy Dinan Compositions and methods for the treatment of depression and other affective disorders
WO2006090067A1 (fr) * 2005-02-25 2006-08-31 Aventis Pharma S.A. Composition pharmaceutique solide comprenant de la telithromycine
US20100209357A1 (en) * 2006-08-10 2010-08-19 Levitt Roy C Localized Therapy of Lower Airways Inflammatory Disorders with Proinflammatory Cytokine Inhibitors
WO2008072034A1 (fr) * 2006-12-12 2008-06-19 Zambon S.P.A. Composés macrolides dotés d'une activité anti-inflammatoire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KRISTINA LOTTER ET AL.: "In vivo efficacy of telithromycin on cytokine and nitric oxide formation in lipopolysaccharide-induced acute systemic inflammation in mice", JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, vol. 58, no. 3, October 2006 (2006-10-01), pages 615 - 21, XP055681399 *

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