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WO2019132847A1 - Formulation de pulvérisation à base d'anticorps immunoglobine y ayant des caractéristiques de traitement et de protection pour toutes les souches du virus de la grippe a - Google Patents

Formulation de pulvérisation à base d'anticorps immunoglobine y ayant des caractéristiques de traitement et de protection pour toutes les souches du virus de la grippe a Download PDF

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Publication number
WO2019132847A1
WO2019132847A1 PCT/TR2018/050923 TR2018050923W WO2019132847A1 WO 2019132847 A1 WO2019132847 A1 WO 2019132847A1 TR 2018050923 W TR2018050923 W TR 2018050923W WO 2019132847 A1 WO2019132847 A1 WO 2019132847A1
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WO
WIPO (PCT)
Prior art keywords
plga
influenza
production method
virus
solution
Prior art date
Application number
PCT/TR2018/050923
Other languages
English (en)
Inventor
Yasemin BUDAMA KILINC
Gokce UNAL
Original Assignee
Yildiz Teknik Universitesi
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
Priority claimed from TR2018/19897A external-priority patent/TR201819897A2/tr
Application filed by Yildiz Teknik Universitesi filed Critical Yildiz Teknik Universitesi
Priority to EP18852724.6A priority Critical patent/EP3731831A1/fr
Publication of WO2019132847A1 publication Critical patent/WO2019132847A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/23—Immunoglobulins specific features characterized by taxonomic origin from birds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a spray formulation which provides treatment and protection against influenza virus infections and the production method of said formulation.
  • the present invention particularly relates to obtaining nano-biotechnologic agent (lgY@PLGA) as a result of encapsulating with poly(lactic-co-glycolic-acid) (PLGA) which is a polymer which does not show toxic effect in the metabolism, in order to prevent specific immuno-globulin Y antibodies from fragmenting before reaching their targets in the body and in order to provide specific immuno-globulin Y antibodies to bind to the external region (M2e) of the M2 protein of the influenza A virus which is substantially well-protected and in order to provide deactivation of the viruses, and relates to application of said nano-biotechnologic agent (lgY@PLGA) in spray form.
  • PLGA poly(lactic-co-glycolic-acid)
  • Influenza is a disease which develops in an acute manner due to influenza A, B and C viruses and which is observed as local and seasonal epidemics, and in general, when viewed in a global manner, there are basically two influenza forms, namely, the seasonal epidemics induced by influenza A and B viruses and the epidemics where influenza A is actor and which occur without any reason in an independent manner from time and location.
  • Respiration system is the most important system affected by influenza.
  • the basic symptoms of influenza are fever, asthenia, head ache, joint pain and lack of appetite. Besides these symptoms, the other indications which occur together with the disease are throat ache, dry cough and nasal flow. After the first symptom of the disease, body temperature may increase to 41 °C within 24 hours and this value is the most important physical indication.
  • influenza A When the viruses, which are the actors of disease, are examined, there are basically 3 virus types. These virus types are influenza A, influenza B and influenza C. All these virus types belong to orthomyxoviridae family. Influenza A and B are seasonal disease actors and influenza C is the reason of the disease with less severe symptoms. This classification is realized according to the difference of nucleo-capsid and matrix proteins, the disease making capacity of viruses, the viral proteins and the number of gene segments.
  • Influenza A viruses are separated into sub-types based on antigenic characteristics of the two surface glyco-proteins like hema-glutinin (HA) and neuroaminidase (NA). For each gene segment virus, a functional protein having vital importance is coded. These are polymerase B2 protein (PB2), polymerase B1 protein (PB1 ), polymerase A protein (PA), HA, nucleo- capsid protein (NP), NA, matrix protein (M) and non-structural protein (NSP).
  • PB2 protein polymerase B2 protein
  • PB1 polymerase B1 protein
  • PA polymerase A protein
  • NP nucleo- capsid protein
  • NA matrix protein
  • NSP non-structural protein
  • the sub-types of said virus like H1 N1 , H3N2 and H2N2 are placed to human population in a stable manner.
  • HA is an important surface protein which protects influenza A virus against neutralizing antibodies and this big piece which comprises at least 5 antigenic domains is bonded to the lipid membrane in a tight manner and is presented to the outer surface of the membrane.
  • NA is a glico-protein like HA which exists on the virus surface. NA is a molecule which is needed for penetration of the virus to the mucin layer of the respiration epithelium and presented as a piece at the outer surface of the cell.
  • Influenza A is a single-chain, negative segment and enveloped RNA virus. Influenza A virus has pleomorphic view and its average diameter is between 80 and 120 nm. The replication cycle of influenza A virus is very rapid and leads to occurrence of the disease in a substantially rapid manner.
  • influenza A virus is infected by means of respiration way secretions formed by coughing or sneezing. The virus is infected from human to human via two different ways, namely, via air and via contact. In infecting via air, influenza A viruses are spread as aerosol in the form of very thin droplets in a manner able to reach very far distances. In infections with direct contact, the infected secretions are infected via direct contact of mucosa membranes of other individuals. This may be in the form of penetration through the mouth, nose and even eyelids. Any little contact may even lead to infection. In indirect contact, infection occurs in cases of contact to the locations where the infected individuals touch and in cases where cleaning is not cared.
  • Influenza can be a fatal disease when precaution is not taken and it is known that between years 1917-1918, the influenza A epidemic, named as Spanish influenza, created pandemic and led to death of nearly 50 millions of people in the world.
  • H1 N1 sub-type created pandemic and led to death of 284000 people in the world and indirectly led to labor loss and led to economical loss.
  • H3N2 sub-type is more virulent when compared with H1 N1 . Therefore, in a probable pandemic, H3N2 has the potential to lead to the death of bigger number of people in the world and to lead to economical loss.
  • inoculation In the present art, it is defended that the basic precaution for protection from this disease is inoculation; however, since influenza A virus continuously changes in form, up to now, it has not been yet possible to develop an inoculation formulation which is effective for protection from this virus.
  • the application area of inoculation methods is limited since inoculation methods need annual application and since inoculation methods can only be effective in a specific section of the target population and moreover since influenza A virus continuously changes in form. Every year it is estimated which strains of the influenza A virus will be in circulation in the next surveyance period and inoculation formulations are revised and developed.
  • Anti-viral therapy is the treatment method applied after the occurrence of the disease and applied after early diagnosis is made. Anti-viral therapy becomes possible with the help of agents which block M2 ion channels, which are targeted at HA and which inhibit polymerase complex and which can be bonded to the nucleo-protein. M2 channel blockers like amantadine and rimantadine and NA inhibitors like oseltamivir and zanamivir can be used as anti-viral agents.
  • influenza strains may develop resistance against M2 channel blockers like amantadine and rimantadine because of the pointwise mutations which may occur in M2 genes like S31 N and V27A (2, 3).
  • M2 channel blockers like amantadine and rimantadine
  • H1 , H2 and H5 form group 1 and H3 and H7 form group 2 (5).
  • influenza A and B viruses have single-chain RNA, the presence of agents which can inhibit the viral polymerase complex is substantially important for the treatment procedure.
  • the polymerase complex is separated into three sub-units like PA, PB1 and PB2.
  • the polymerase heterodimer structure of influenza A, B and C (8, 9, 10) is clarified by means of various crystallographic analyses.
  • Today, the agents which aim at the complex can be more easily developed with the help of this analysis.
  • Favipiravir T-705
  • T-705 is a RNA virus inhibitor with wide spectrum reported firstly in year 2002. In year 2014, it has been accepted for influenza treatment in Japan. In US and in Europe, the clinic test step is continued (5).
  • the activity mechanism of the medicine is explained by means of viral RNA polymerase which recognizes favipiravir-ribozil-5’-triposphate (T-705-RTP) as purine nucleotide erroneously.
  • T-705-RTP favipiravir-ribozil-5’-triposphate
  • PB2 PB1 polymerase
  • PA endo-nuclease inhibitors are also continued to be researched.
  • the agents which can be bonded to viral NP are the other chemicals used in development of new treatment methods and new medicines (5).
  • nucleosine which has been developed for this purpose, shows substantially good activity in rat models, it can be inactive against some influenza strains. This problem is tried to be overcome by means of usage of pharmacological agents like curcumin and naproxen (1 1 , 12).
  • the present invention relates to spray formulation based on immuno-globulin Y antibodies having treatment and protection characteristic for all strains of influenza A virus, for eliminating the above mentioned disadvantages and for bringing new advantages to the related technical field.
  • the primary object of the present invention is to obtain nano-biotechnologic agent (lgY@PLGA) by means of encapsulating poly(lactic-co-glycolic acid) which is a polymer which does not show toxic effect in the metabolism, in order to prevent specific immuno globulin Y antibodies from fragmenting before reaching their targets in the body and in order to provide deactivation of viruses by means of bonding to the external region (M2e) of substantially well-protected M2 protein of the influenza A virus and produced synthetically.
  • lgY@PLGA nano-biotechnologic agent
  • the object of the present invention is to present an efficient and innovative treatment approach.
  • the object of the present invention is to provide a formulation which provides treatment and protection against influenza A virus infections.
  • the present invention relates to specific immuno-globulin Y antibodies (lgY@PLGA) encapsulated with poly(lactic-co-glycolic acid) (PLGA) which provides treatment and protection against infections of influenza A virus in humans, and relates to spray form nano-biotechnologic formulations comprising said antibodies.
  • lgY@PLGA specific immuno-globulin Y antibodies
  • PLGA poly(lactic-co-glycolic acid)
  • the present invention relates to production method of nano-biotechnologic agent (lgY@PLGA) which provides treatment and protection against infections of influenza A virus in humans, said method is characterized by comprising the process steps of:
  • the organic solvent used in step a) is selected from a group comprising ethanol, methanol, propanol, isopropanol, dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), hexane, asetonitrile, benzene, toluene, ethylacetate, dichloro methane.
  • dichloro-methane is used as organic solvent.
  • PLGA concentration is between 65 mg/ml and 90 mg/ml, preferably 70 mg/ml and 85 mg/ml, particularly preferably 72 mg/ml and 83 mg.
  • the concentration of IgY antibody is between 0.70 mI/ml and 1.5 mI/ml, preferably 0.8 mI/ml and 1 .2 mI/ml, particularly preferably 0.83 mI/ml and 1.1 mI/ml.
  • step c) after the 1 st and 2 nd solutions are mixed, they are sonicated in ultrasonic homogenizer for 1 -10 minutes, preferably between 2-8 minutes, particularly preferably between 3-6 minutes.
  • step c) after the 1 st and 2 nd solutions are mixed, the sonication process in ultrasonic homogenizer is realized with amplitude of 80- 90%, preferably with amplitude of 87%.
  • step d) the aqueous solution of poly(vinyl alcohol) is used.
  • Poly(vinyl alcohol) solution can preferably have concentration of 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%.
  • the sonication process realized in step D) is realized for 1 -10 minutes, preferably for 2-8 minutes, particularly preferably for 3-6 minutes.
  • the centrifuge process is preferably realized at room temperature, preferably, at 24, 25, 26, 27, 28, 29, 30°C; for duration of 20-35 minutes, for instance for 20, 25, 30, 35 minutes; at 500-1000 rpm, for instance, at 5000, 6000, 7000, 8000, 9000 or 10000 rpm.
  • the present invention relates to obtaining nano-biotechnologic agent (lgY@PLGA) as a result of encapsulating with poly(lactic-co-glycolic-acid) (PLGA) which is a polymer which does not show toxic effect in the metabolism, in order to prevent immuno-globulin Y antibodies, produced specifically for the peptide epitope of the influenza A virus, from fragmenting before reaching their targets in the body and in order to provide specific immuno-globulin Y antibodies to bind to the external region (M2e) of the M2 protein of the influenza A virus which is substantially well-protected and in order to provide deactivation of the viruses.
  • PLGA poly(lactic-co-glycolic-acid)
  • the formulation which will be prepared by dispersing the subject matter nano- biotechnologic agent (lgY@PLGA) in a solution comprising a muco-adhesive polymer for various application methods (intranasal, oral, spray for the hands and surface), can be applied in spray form in order to provide treatment and protection in human against influenza A virus infections.
  • an application of the present invention relates to usage of IgY antibody (lgY@PLGA), encapsulated with the subject matter poly(lactic-co-glycolic acid) (PLGA), in the treatment of influenza A virus infections.
  • IgY antibody lgY@PLGA
  • PLGA poly(lactic-co-glycolic acid)
  • Another preferred application of the present invention relates to usage of IgY antibody (lgY@PLGA), encapsulated with the subject matter poly(lactic-co-glycolic acid) (PLGA), in preparation of a medicine which is suitable for use in the treatment of influenza A virus infections.
  • IgY antibody lgY@PLGA
  • PLGA poly(lactic-co-glycolic acid)
  • compositions comprising IgY antibody (lgY@PLGA) encapsulated with the subject matter poly(lactic-co- glycolic acid) (PLGA).
  • the pharmaceutical compositions comprising IgY antibody (lgY@PLGA) encapsulated with the subject matter poly(lactic-co-glycolic acid) (PLGA) comprises at least one auxiliary substance in addition to lgY@PLGA.
  • auxiliary substance or substances which can be used in the subject matter pharmaceutical compositions, can be selected from diluents, binders, dispensors, sliders, buffer couples, sweeteners, coloring agents, suspensing agents, emulsifying agents, dissolving agents, pharmaceutically acceptable polymers which can be used by the person skilled in the known state of the art within his/her information.
  • the subject matter pharmaceutical compositions are in the pharmaceutical dosage form which is preferably suitable for oral usage, the subject matter compositions can be in the form of for instance: capsule, tablet, sachet, effervescent tablet, oral spray, oral suspension, emulsion, aerosol.
  • the subject matter pharmaceutical compositions are particularly preferably in spray form.
  • the dosage range where the subject matter lgY@PLGA antibody can be used is determined according to the needs of the patient, the phase of the disease and the active substance to be used. The determination of the dose which is suitable for a specific condition is known by the authorized persons in the known state of the art.
  • the specification moreover covers the applications comprising the abovementioned characteristics/elements or other applications consisting of the abovementioned characteristics/elements.
  • nano-biotechnologic agent comprises two main process steps, namely, synthesis and test steps.
  • Production method of nano-biotechnologic agent which provides treatment and protection in humans against influenza A virus infections (synthesis step):
  • PVA poly(vinyl alcohol)
  • the effect of the synthesized lgY@PLGA on the virus is measured by means of neutralization test.
  • MDCK Madin-Darby canine kidney
  • Both specific IgY and lgY@PLGA are separately applied onto the cells at three different concentrations (0.1 mg/ml, 0.5 mg/ml and 1 mg/ml) onto the external region (M2e) of the well-protected M2 protein of the influenza A virus,
  • 10% formaldehyde solution is prepared.
  • the liquid in micro-plate is removed and it is waited for 20 minutes at room temperature with the prepared formaldehyde solution and fixed. After the fixation process, dyeing is realized to the micro-plate wells by means of 0.35% crystal violet and the formed plaques are counted.
  • influenza A in the positive control group shows an effective cytopathic effect on MDCK cells.
  • negative control group no plaque formation has been observed as expected. It has been observed that the increasing doses affect plaque formation in an inverse proportional manner on the MDCK cells.
  • PRNT80 neutralizing antibody titre
  • IgY antibodies are bonded to the well-protected external region (M2e) of the M2 protein of influenza A and provide neutralization of the virus.
  • M2e well-protected external region
  • PLGA poly(lactic-co-glycolic acid)
  • PLGA poly(lactic-co-glycolic acid)
  • Influenza A virus where lgY@PLGA, obtained by means of the subject matter method, is bonded in the neutralization test has been produced in a synthetic manner.
  • our invention which is a formulation which is to be dispersed and prepared in a solution formed by muco-adhesive polymer for various application methods (intranasal, oral, spray for hands and surfaces), comprises an effective and innovative treatment approach against influenza.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pulmonology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne l'obtention d'un agent nano-biotechnologique (lgY@PLGA) suite à l'encapsulation avec du poly (acide lactique-co-glycolique) (PLGA) qui est un polymère qui ne présente pas d'effet toxique dans le métabolisme, afin d'empêcher des anticorps immunoglobuline Y spécifiques de se fragmenter avant d'atteindre leurs cibles dans le corps et afin de fournir des anticorps immunoglobuline Y spécifiques à se lier à la région externe (M2e) de la protéine M2 du virus de la grippe A qui est sensiblement bien protégé et afin d'assurer la désactivation des virus, et concerne l'application dudit agent nano-biotechnologique (lgY@PLGA) sous forme de spray.
PCT/TR2018/050923 2017-12-28 2018-12-28 Formulation de pulvérisation à base d'anticorps immunoglobine y ayant des caractéristiques de traitement et de protection pour toutes les souches du virus de la grippe a WO2019132847A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP18852724.6A EP3731831A1 (fr) 2017-12-28 2018-12-28 Formulation de pulvérisation à base d'anticorps immunoglobine y ayant des caractéristiques de traitement et de protection pour toutes les souches du virus de la grippe a

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
TR201722694 2017-12-28
TR2017/22694 2017-12-28
TR2018/19897 2018-12-20
TR2018/19897A TR201819897A2 (tr) 2018-12-20 2018-12-20 İnfluenza a vi̇rüsünün tüm suşlari i̇çi̇n tedavi̇ ve koruma özelli̇ği̇ne sahi̇p i̇mmunoglobuli̇n y anti̇korlarina dayali sprey formülasyonu

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WO2019132847A1 true WO2019132847A1 (fr) 2019-07-04

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PCT/TR2018/050923 WO2019132847A1 (fr) 2017-12-28 2018-12-28 Formulation de pulvérisation à base d'anticorps immunoglobine y ayant des caractéristiques de traitement et de protection pour toutes les souches du virus de la grippe a

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EP (1) EP3731831A1 (fr)
WO (1) WO2019132847A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010028072A2 (fr) * 2008-09-02 2010-03-11 Huan Nguyen Anticorps aviaires spécifiques du virus de la grippe et procédés technologiquement simples de fabrication et d'utilisation de ceux-ci

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010028072A2 (fr) * 2008-09-02 2010-03-11 Huan Nguyen Anticorps aviaires spécifiques du virus de la grippe et procédés technologiquement simples de fabrication et d'utilisation de ceux-ci

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANNE-MARIE TORCHÉ ET AL: "PLGA Microspheres Phagocytosis by Pig Alveolar Macrophages: Influence of Polyvinyl alcohol) Concentration, Nature of Loaded-Protein and Copolymer Nature", JOURNAL OF DRUG TARGETING, vol. 7, no. 5, 26 January 1999 (1999-01-26), GB, pages 343 - 354, XP055579239, ISSN: 1061-186X, DOI: 10.3109/10611869909085517 *
JAIN R A ED - GOODMAN STUAT ET AL: "The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices", BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 21, no. 23, 1 December 2000 (2000-12-01), pages 2475 - 2490, XP004216917, ISSN: 0142-9612, DOI: 10.1016/S0142-9612(00)00115-0 *
TORCHE A M ET AL: "Immune responses after local administration of IgY loaded-PLGA microspheres in gut-associated lymphoid tissue in pigs", VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY, ELSEVIER BV, AMSTERDAM, NL, vol. 109, no. 3-4, 15 February 2006 (2006-02-15), pages 209 - 217, XP024999006, ISSN: 0165-2427, [retrieved on 20060215], DOI: 10.1016/J.VETIMM.2005.08.016 *

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