Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
  • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• • 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
  • A61K38/193—Colony stimulating factors [CSF]
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • 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
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
• • 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
  • A61P31/04—Antibacterial agents
• • 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
  • A61P31/10—Antimycotics
• • 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

Definitions

• the present invention relates to a liquid formulation comprising recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) for inhalation.
• rhGM-CSF granulocyte macrophage colony stimulating factor
• GM-CSF In addition to having a function of growth stimulation and differentiation on hemopoetic precursor cells, GM-CSF also was discovered as having a variety of effects on cells of the immune system expressing the GM-CSF receptor (for review see: Hamilton JA. Trends Immunol. 2002;23(8):403-408; de Groot RP et al. Cell Signal. 1998; 10(9):619-628).
• Granulocyte-macrophage colony stimulating factor inhalation therapy has been disclosed for treating patients suffering from autoimmune pulmonary alveolar proteinosis (aPAP) (Tazawa R et al. N Engl J Med. 2019;381(10):923-932) non- tuberculous mycobacterial (NTM) infection (Scott JP et al. Eur Respir J. 2018;51(4):1702127), acute radiation syndrome (Singh VK et al. Cytokine. 2015;71(1):22-37), acute respiratory distress syndrome (Herold S et al. Am J Respir Crit Care Med. 2014;189(5):609-611) and cystic fibrosis (Heslet L et al. J Inflamm Res.
• aPAP autoimmune pulmonary alveolar proteinosis
• NTM non- tuberculous mycobacterial
• Nebulizers are a very suitable method of treatment for lung infestations of fungi or bacteria as they fill the air with a very fine mist of respirable droplets capable of depositing in all regions of the lung.
• protein formulation as a liquid for inhalation therapy is a highly complex process as it requires the product to be ready for addition to a nebulizer and remain stable during aerosol generation.
• the formulation must maintain stability upon long term storage, minimize the effect of nebulization on the integrity of the protein and have appropriate tonicity for pulmonary delivery.
• a fine balance between stability, tolerability in the lungs, including potential toxicity, and isotonicity is key to achieve an efficient formulation of protein for inhalation therapy.
• a liquid formulation of GM-CSF (LEUKINE®) has previously been disclosed for i.v. administration (US2002141970A1).
• US2002141970A1 suggest addition of a chelating agent as an excipient to increase stability of the compound.
• the formulation of drug solution for nebulization is designed to optimize drug solubility and stability; small changes in formulation may also affect inhaled mass, particle size distribution, and treatment time.
• Nebulization carries an inherent risk of destabilizing proteins.
• the main reason for protein instability upon nebulization is unfolding and aggregation at the air-liquid interface, and thus the use of GM-CSF for nebulization requires a stable liquid formulation, which is ready for use for inhalation and does not result in significant changes upon nebulization. Summary
• the present invention discloses a stable liquid formulation of rhGM-CSF, which is ready for use for inhalation and does not experience relevant instability upon nebulization.
• the combination of a sugar alcohol or a sugar, albumin and polyethylene glycol (PEG) and water provides a highly stable liquid formulation of rhGM-CSF.
• liquid formulation described above is for use as a medicament for nebulization.
• liquid formulation of rhGM-CSF is for use in the treatment of aPAP or NTM infection.
• a method for pulmonary delivery of recombinant rhGM-CSF comprising nebulizing rhGM-CSF, a sugar alcohol, albumin and PEG is disclosed.
• Figure 1 Impact of Mannitol on % rhGM-CSF remaining after 3 months at 40°C.
• mannitol concentration was evaluated at accelerated conditions over 3 months.
• concentration of mannitol was found to influence drug stability.
• Higher concentrations (50 mg/mL ) of mannitol improved stability of rhGM-CSF.
• the y-axis is % rhGM-CSF content remaining compared to TO.
• Figure 2 Impact of rhGM-CSF level within groupings of mannitol cone, on % GM- CSF remaining after 3 months at 40°C
• rhGM-CSF concentration was also evaluated at accelerated conditions over 3 months.
• concentration of rhGM-CSF was found to influence drug stability.
• Higher concentrations of rhGM-CSF (400 pg/mL) at specific mannitol concentrations improved stability of rhGM-CSF in the liquid formulation.
• the y-axis is % rhGM-CSF content remaining compared to TO.
• Figure 3 Impact of rHA and PEG 4000 on rhGM-CSF impurity formation.
• Figure 4 18 Month performance stability of rhGM-CSF complex formulation.
• Figure 5 3 months stability of low rHA concentration formulation.
• the present invention relates to a liquid formulation of recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF)for use in administration by inhalation, wherein the liquid formulation comprises rhGM-CSF, a sugar alcohol or a sugar, albumin and water.
• rhGM-CSF human granulocyte macrophage colony stimulating factor
• rhGM-CSF is molgramostim (SEQ ID NO: 1), sargramostim (SEQ ID NO: 2) or regramostim.
• the liquid formulation of rhGM-CSF includes a sugar alcohol selected from the group consisting of mannitol or sorbitol.
• the liquid formulation of rhGM-CSF includes albumin.
• said albumin is HSA.
• said albumin is recombinant human albumin (rHA).
• the liquid formulation of rhGM-CSF further comprises PEG .
• PEGs include, but are not limited to PEG 1000, PEG 1550,
• the concentration of rhGM-CSF in the disclosed liquid formulation is in the range of 150-500 pg/mL. In another embodiment of the present invention the concentration of rhGM-CSF in the disclosed liquid formulation is in the range of 200- 300pg/mL .
• the present disclosure shows that increasing the concentration of rhGM- CSF in the presence of the sugar alcohol mannitol stabilizes the liquid formulation (figure 2).
• an embodiment of the present invention discloses a liquid formulation of rhGM-CSF, wherein the concentration of sugar alcohol or sugar is at least 25 mg/mL .
• the concentration of sugar alcohol is in the range 45-100 mg/mL .
• the concentration of sugar alcohol is in the range 45-55 mg/mL .
• increasing the concentration of the sugar alcohol mannitol improves stability of rhGM-CSF.
• the stabilizing effect of mannitol is observed at a concentration of the sugar alcohol of 25 mg/mL . This effect is significantly increased at a concentration of 50 mg/mL .
• the liquid formulation of rhGM-CSF comprises PEG for example in a concentration of max 50, such as max 40, such as max 30, such as max 20 such as max 10 such as max 1 mg/mL .
• the concentration of PEG is in the concentration range 0.05-0.5 mg/mL such as 0.05-0.3 mg/mL such as 0.05-0.2 mg/mL .
• the liquid formulation of rhGM-CSF comprises PEG in the concentration range 0.05-0.15 mg/mL .
• the concentration of rhGM-CSF is 150-500 pg/mL
• the concentration of mannitol is 45-100 mg/ml
• the concentration of recombinant human albumin is 0.5-1.5 mg/ml
• the concentration of PEG-4000 is 0.05-0.15 mg/mL .
• Buffers are added to a formulation to adjust and stabilize pH and optimize drug solubility and stability. For drugs for inhalation it is desirable that the product pH be close to physiological pH.
• the liquid formulation of rhGM-CSF further comprises a buffer.
• said buffer comprises citric acid monohydrate and Na2HP04.
• the osmolality of the formulation is a key parameter for a liquid formulation to be suitable for inhalation.
• the liquid formulation is essentially isotonic.
• the osmolality of the formulation is from 250 to 375 mOsm/L, preferably from 325 to 335 mOsm/L.
• a liquid formulation of rhGM-CSF, wherein the % of rhGM-CSF remaining after 3 months storage at 40°C is more than 60% is disclosed.
• a liquid formulation of rhGM-CSF, wherein the level of impurity formation after 6 months at 25°C is less than 5% is disclosed.
• the present invention further discloses in one embodiment, a method for pulmonary delivery of rhGM-CSF comprising nebulizing rhGM-CSF, a sugar alcohol, albumin and a PEG.
• the liquid formulation of rhGM-CSF presented herein is especially well suited for nebulization.
• Data in the present disclosure demonstrates that the potency of molgramostim for a liquid formulation comprising rhGM-CSF, a sugar alcohol or a sugar, albumin, PEG and water retains 99.4% of the biological potency of rhGM-CSF upon nebulization.
• rhGM-CSF remains largely intact after the nebulization process.
• little or no change in performance stability is found upon nebulization of the liquid formulation presented herein at time points up to 18 months.
• at least 90% such as at least 95% such as at least 98% such as at least 99% biologic potency of rhGM-CSF is retained after nebulization.
• the formulation is storage stable for at least 18 months at 25°C.
• the liquid formulation is for use in pulmonary administration.
• a formulation must be aerosolized into small, respirable droplets, where are large fraction are less than 5 pm in diameter.
• the formulation must maintain stability during the aerosolization process, where high levels of mechanical energy and increased area of air-liquid interface can lead to protein denaturation and/or aggregation.
• Formulations should also include excipients that are safe for administration to the lungs, and in a suitable range of pH and tonicity.
• the liquid formulation of rhGM-CSF is for use in the treatment of a lung infection.
• the liquid formulation of rhGM-CSF is for use in the treatment of bacterial, viral or fungal infection in the lungs.
• the bacterial infection is selected from the group consisting of: Streptococcus pneumoniae, Haemophilus species, Staphylococcus aureus and Mycobacterium tuberculosis.
• the viral infection is selected from the group consisting of bronchitis, pneumonia, and bronchiolitis.
• the fungal infection is selected from the group consisting of: Aspergillus, Cryptococcus, Pneumocystis, and endemic fungi.
• the liquid formulation of rhGM-CSF is for use in the treatment of autoimmune pulmonary alveolar proteinosis (aPAP) or non-tuberculous mycobacterial (NTM) infection, tuberculosis, ARDS, influenza infection, coronavirus infection, acute and chronic radiation syndrome, bronchial asthma, COPD, pulmonary fibrosis, lung cancer and respiratory inflammatory disorders.
• the formulation may also be used prophylactically to stimulate an immunological response and protect against pulmonary infection.
• a liquid formulation of rhGM-CSF is disclosed for use as a medicament for nebulization.
• a liquid formulation of rhGM-CSF is disclosed for use in the treatment of aPAP or NTM infection.
• a method of treating a medical condition comprising administering a liquid formulation of rhGM-CSF by nebulization to a person in need thereof.
• a method of treating aPAP or NTM infection comprising administering a liquid formulation of rhGM-CSF to a person in need thereof is provided.
• APAP is a rare autoimmune lung disorder. It is the most common form (90% of the cases) of pulmonary alveolar proteinosis (PAP). Most cases affect adults between the ages of 20-50 years. Some people may not show symptoms, while others may have progressive difficulty breathing and shortness of breath upon exertion. Other signs and symptoms may include a dry, chronic cough; fatigue; weight loss; chest pain; and a general feeling of ill health. In rare cases, coughing up of blood, rounding and swelling of the tips of the fingers, and cyanosis may be present. Autoimmune PAP is caused by an immune system malfunction, due to IgG antibodies that block the GM-CSF effect.
• GM-CSF regulates clearance of surfactant (a mix of protein and fat) by alveolar macrophages.
• surfactant a mix of protein and fat
• the standard treatment is a procedure called lung lavage
• NTM are mycobacterial, which do not cause tuberculosis or leprosy (also known as Hansen's disease). NTM do cause pulmonary diseases that resemble tuberculosis. The most common clinical manifestation of NTM disease is lung disease, but lymphatic, skin/soft tissue, and disseminated disease are also important. Pulmonary disease caused by NTM is most often seen in post-menopausal women and patients with underlying lung disease such as cystic fibrosis, bronchiectasis, and prior tuberculosis. It is not uncommon for alpha 1-antitrypsin deficiency, Marfan syndrome and primary ciliary dyskinesia patients to have pulmonary NTM colonization and/or infection. Pulmonary NTM can also be found in individuals with AIDS and malignant disease.
• Clinical symptoms vary in scope and intensity but commonly include chronic cough, often with purulent sputum. Hemoptysis may also be present. Systemic symptoms include malaise, fatigue, and weight loss in advanced disease. The diagnosis of M. abscessus pulmonary infection requires the presence of symptoms, radiologic abnormalities, and microbiologic cultures.
• an inhaler comprising the liquid formulation of rhGM-CSF according to the present disclosure.
• the inhaler is a nebulizer.
• Types of nebulizers include jet nebulizers, ultrasonic and vibrating mesh.
• Other embodiments include soft- mist inhalers, surface acoustic wave atomization and capillary aerosol generators,
• the present invention discloses a method for delivering rhGM-CSF to the lungs comprising nebulization of a liquid formulation of rhGM-CSF, wherein the liquid formulation comprises rhGM-CSF, a sugar alcohol or a sugar, albumin and water; whereby said rhGM-CSF is delivered to the lungs.
• a nebulizer comprising the liquid formulation of rhGM-CSF for use in the treatment of aPAP or NTM infection. This includes jet nebulizers, ultrasonic and vibrating mesh nebulizers. Examples
• RP-HPLC Reverse-Phase High Pressure Chromatography
• SE-HPLC Size Exclusion High Pressure Chromatography
• molgramostim Three formulation parameters of molgramostim were varied according to the table below (table 1). 1. Mannitol level (0 to 50 mg/mL ): buffer cone was also adjusted simultaneously so that the formulation would remain isotonic.
• Stabilizer (1 of 4 options): rHA and PEG, rHA alone, no stabilizer and tween 80 alone
• the complex formulation was prepared on a weight basis according to the description below. Sterile filtration was only done on the final formulated product. The content of the final formulated product is according to the table below.
• the rHSA was removed from 2-8°C storage and allow to equilibrate to room temperature.
• the required amounts of mannitol, PEG 4000, citric acid monohydrate, disodium hydrogen phosphate (anhydrous), and rHSA were pre-weighed in appropriate containers.
• a clean beaker/bottle and stir bar was placed on a top loading balance and the weight of the beaker and stir bar was recorded and tared. Approximately 800 g of Water for Injection (WFI) was added to the beaker.
• WFI Water for Injection
• the rhGM-CSF was thawed for 24h ⁇ 4h at 2-8°C. If the bulk material is not thawed within this timeframe, thawing is continued at room temperature by gentle turning of the bottle. The bottle should not be shaken and foaming should be avoided.
• the required amount of rhGM-CSF was pre-weighed into an appropriately sized container. A clean bottle and stir bar were placed on a top loading balance. The weight of the beaker and stir bar was recorded and tared. Approximately 800 g of Citrate/Phosphate/rHA Buffer was added to the beaker and then the pre-weighed amount of rhGM-CSF was also added to the beaker.
• the rhGM-CSF container was rinsed with Citrate/Phosphate/HSA Buffer and the rinse was transferred to the beaker.
• the beaker was then placed on a stir plate and the mixture was gently stirred for approximately 5 min while avoiding foaming. The mixture was checked for complete homogeneity.
• Citrate/Phosphate/HSA Buffer was added to reach a final weight of 1000 g followed by gently stirring for approximately 10 min while avoiding foaming.
• the formulated product was filtered using Millipore Stericup filter units (PVDF membrane (Durapore), very low protein binding, pore size 0.22 pm) and the formulated product was stored at 2-8°C, protected from light.
• Molgramostim Simple Formulation PVDF membrane (Durapore), very low protein binding, pore size 0.22 pm
• the simple rhGM-CSF formulation is prepared on a volumetric basis because the density of the simple formulation buffer is unknown.
• concentrations and amounts per vial of the ingredients in the final formulated product is shown in the table below.
• mannitol, citric acid monohydrate, disodium hydrogen phosphate (anhydrous) was pre-weighed in appropriate containers. Approximately 800 mL of Water for Injection (WFI) was added to a beaker with a stir bar. Citric acid monohydrate, disodium hydrogen phosphate (anhydrous), and mannitol was added to the WFI. The mixture was stirred until all solids were dissolved. The required amount of rhGM-CSF was added to the beaker and the rhGM-CSF container was rinsed with WFI and the rinse was transferred to the beaker. The beaker was placed on a stir plate and the mixture was gently stirred for approximately 5 min while foaming was avoided. Check for complete homogeneity.
• WFI Water for Injection
• the contents of the beaker was transferred to a 1 L volumetric flask.
• the beaker was rinsed with WFI and the rinse was transferred to the volumetric flask. Care should be taken not to generate foam during the transfer.
• WFI was added to the volumetric flask to QS to 1 L and the contents were mixed by gentle inversion of the flask.
• the formulated product was filtered using Millipore Stericup filter units (PVDF membrane (Durapore), very low protein binding, pore size 0.22 pm). The final formulated product is stored at 2-8°C, protected from light.
• the stability of the rhGM-CSF complex formulation following nebulization was evaluated by comparing un-nebulized formulation with condensed nebulized formulation and comparing detected impurities and protein aggregates.
• Aerosol generated by a vibrating mesh was collected directly after nebulization by collecting in a polypropylene tube positioned against the mesh.
• DD Delived dose under simulated breathing (according to USP ⁇ 1601 >, adult)
• FPF Fine particle fraction (droplets less than 5 pm)
• MMAD

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pulmonology (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Otolaryngology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Molecular Biology (AREA)
• Zoology (AREA)
• Gastroenterology & Hepatology (AREA)
• Immunology (AREA)
• Dispersion Chemistry (AREA)
• Inorganic Chemistry (AREA)
• Biochemistry (AREA)
• Virology (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (13)

Applications Claiming Priority (4)

Publications (1)

Family

ID=74871418

Family Applications (1)

Country Status (12)

Families Citing this family (1)

Citations (6)

• 2021
  • 2021-03-17 KR KR1020227035847A patent/KR102874958B1/ko active Active
  • 2021-03-17 JP JP2022548034A patent/JP7631358B2/ja active Active
  • 2021-03-17 BR BR112022018501A patent/BR112022018501A2/pt unknown
  • 2021-03-17 CA CA3168421A patent/CA3168421A1/en active Pending
  • 2021-03-17 CN CN202180022141.1A patent/CN115297844A/zh active Pending
  • 2021-03-17 MX MX2022011498A patent/MX2022011498A/es unknown
  • 2021-03-17 WO PCT/EP2021/056851 patent/WO2021185921A1/en not_active Ceased
  • 2021-03-17 IL IL295406A patent/IL295406A/en unknown
  • 2021-03-17 EP EP21711594.8A patent/EP4121000A1/en active Pending
  • 2021-03-17 AU AU2021237761A patent/AU2021237761B2/en active Active
  • 2021-03-17 US US17/906,599 patent/US20230201307A1/en active Pending
• 2022
  • 2022-08-11 ZA ZA2022/09002A patent/ZA202209002B/en unknown
• 2025
  • 2025-02-04 JP JP2025017042A patent/JP2025090573A/ja active Pending

Patent Citations (6)

Non-Patent Citations (13)

Also Published As

Similar Documents

Legal Events