WO2023203586A1 - Composition pharmaceutique inhalable comprenant de l'anakinra protéique pour le traitement d'une inflammation de fibrose kystique - Google Patents

Composition pharmaceutique inhalable comprenant de l'anakinra protéique pour le traitement d'une inflammation de fibrose kystique Download PDF

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WO2023203586A1
WO2023203586A1 PCT/IT2023/050105 IT2023050105W WO2023203586A1 WO 2023203586 A1 WO2023203586 A1 WO 2023203586A1 IT 2023050105 W IT2023050105 W IT 2023050105W WO 2023203586 A1 WO2023203586 A1 WO 2023203586A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
mannitol
anakinra
sucrose
trehalose
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PCT/IT2023/050105
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English (en)
Inventor
Stefano GIOVAGNOLI
Marilena PARIANO
Matteo PUCCETTI
Maurizio Ricci
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Università degli Studi di Perugia
Fondazione Per La Ricerca Sulla Fibrosi Cistica - Onlus
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Publication of WO2023203586A1 publication Critical patent/WO2023203586A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K38/20—Interleukins [IL]
    • A61K38/2006—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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

Definitions

  • Cystic fibrosis is an autosomal recessive pathology that affects multiple organs, including the respiratory, gastrointestinal, and genital tracts (1 ), and is more common in the Caucasian population, with a frequency of about 1 out of 2500. It is caused by mutations in the gene encoding for the transmembrane conductance regulator (CFTR) and more than 2000 variants have been identified. The most frequent mutation is the deletion of the phenylalanine residue at position 508, which causes the misfolding and degradation of CFTR before the protein can reach the plasma membrane for its functional activity. CFTR is a chloride/bicarbonate channel that regulates the ion equilibrium of surface fluid. It has been demonstrated that cells which express the most common CFTR mutant variant are defective in autophagy and accumulate polyubiquitinated proteins and similar structures (2).
  • TRIKAFTA a combination of two correctors (tezacaftor and elexacaftor) and a potentiator (ivacaftor) has received FDA approval for the treatment of the most common mutation, Phe508del. Notwithstanding the significant impact of these molecules in the treatment of CF patients, at least in the case of Phe508del carriers, it is not clear whether an improvement in the inflammatory response and autophagy also falls within their range of action. Therefore, inflammation appears as an independent factor of morbidity and the search for anti-inflammatory drugs remains an interesting area of research in the field of CF.
  • Anakinra is a recombinant, non-glycosylated form of the endogenous IL-1 receptor antagonist (IL-1 Ra), from which it differs because of the presence of an extra methionine at the amino terminus.
  • IL-1 Ra endogenous IL-1 receptor antagonist
  • Anakinra exerts its effects by inhibiting the binding of IL-1 (3 to IL-1 R1 (12).
  • IL-1 Ra In addition to a secreted protein, three non-secreted intracellular isoforms of IL-1 Ra have been described in humans and in mouse tissues (15). Whilst it is known that extracellular IL-1 Ra inhibits the activity of IL-1 by binding to IL-1 Rl, it has been observed that intracellular IL-1 Ra1 also has antiinflammatory properties (16).
  • the prior art document WO2021/113334 A1 describes the use of a liquid pharmaceutical composition comprising anakinra and excipients comprising a sugar selected from among lactose, mannitol, sucrose and sorbitol and amino acids such as histidine, proline, hydroxyproline and glycine.
  • document D1 describes an anakinra-based liquid composition for aerosol comprising a filler such as, for example, mannitol, and a tonicity modifier such as, for example, hydroxyproline, proline or combinations thereof (D1 , para. 211 ).
  • the composition can contain a buffer, such as, for example, histidine (D1 , par. 200), and further amino acids such as glycine (D1 , para. 261 ).
  • document D1 describes liquid anakinra compositions and suggests making powder formulations of anakinra.
  • anakinra can be advantageously administered by inhalation in a suitable pharmaceutical form so that the active ingredient is effective in the treatment of pathological inflammation in patients with CF.
  • a pharmaceutical composition comprising anakinra in dry powder form for inhalational use has been developed for the treatment of pathological inflammation in patients with CF.
  • a pharmaceutical composition in dry powder form, suitable for administration by inhalation which comprises an amount of the protein anakinra that is effective for this route of administration and wherein, at the same time, the stability of the protein itself is preserved.
  • a spray drying process suitable for obtaining the advantageous properties of the composition according to the present invention has also been developed.
  • the choice of excipients and of the preparation process conditions is capable of ensuring the stability of the protein both in the processing phase and during storage.
  • the preparation according to the present invention is intended to overcome the limitations of the present subcutaneous administration by enabling direct administration to the lungs. A reduction of the dosage and of systemic side effects and a considerable increase in compliance are the greatest advantages of the preparation according to the present invention, also by virtue of the elimination of the discomfort associated with the conventional method of administration.
  • a pharmaceutical composition comprising the protein anakinra, as the active ingredient, in combination with one or more pharmaceutically acceptable excipients, said pharmaceutical composition being in a dry powder form suitable for administration by inhalation, wherein said one or more excipients comprise or consist of one or more sugars selected from among mannitol, sucrose, trehalose, or lactose and one or more amino acids selected from among leucine, trileucine, lysine, tryptophan, arginine, aspartic acid, threonine, or phenylalanine.
  • the amino acid is leucine and/or trileucine, since these amino acids improve the yield of the process for producing the composition of the invention and the respirability thereof.
  • the leucine can be D-leucine or L-leucine, preferably the leucine is D- leucine.
  • the trileucine can be present in the composition in an amount by weight ranging from 1 to 10%, preferably from 4 to 8%, relative to the total weight of the composition.
  • one or more excipients consist of means that the excipients, and hence the composition of the invention, do not comprise other types of excipients besides said one or more sugars and said one or more amino acids.
  • said one or more excipients can comprise the amino acid leucine. Therefore, according to this embodiment, when the term “comprise” is considered, it means that the excipients of the pharmaceutical composition comprise, among the amino acids, only leucine, but they could comprise, in addition to sugar, other types of excipients. Again in this embodiment, when the term “consist of” or “consists of” is considered, it means that the excipients of the composition consist of the amino acid leucine and one or more sugars among those listed above, whereas they do not comprise other types of excipients.
  • said one or more amino acids can consist of the amino acid leucine and/or the amino acid trileucine, preferably the amino acid leucine.
  • said one or more excipients can comprise or consist of one of the following mixtures of said one or more sugars and said one or more amino acids: mannitol and leucine, trehalose and leucine, sucrose and leucine or mannitol, trehalose, sucrose, and leucine, mannitol and trileucine, trehalose and trileucine, sucrose, and trileucine, mannitol, trehalose, sucrose and trileucine.
  • the term “comprise” when the term “comprise” is considered, it means that the excipients of the pharmaceutical composition comprise the sugars specifically mentioned, and no other sugars, in combination with the amino acid leucine or the amino acid trileucine, and not in combination with another of the amino acids of the invention; however, the excipients could comprise other types of excipients.
  • the term “consist of” or “consists of” when the term “consist of” or “consists of” is considered, it means that the excipients of the composition consist of the above-mentioned mixtures of specific sugars with the amino acid leucine or trileucine and do not comprise other types of excipients.
  • said one or more excipients can further comprise a lipid selected from among dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, cholesterol, magnesium or potassium stearate, or mixtures of said lipids.
  • said one or more excipients can further comprise a hydrophilic polymer selected from among chitosan, polyethylene glycol, polyethylenepolypropylene glycol, or mixtures of said hydrophilic polymers.
  • the protein anakinra is present in the pharmaceutical composition in an amount that can range from 1 % to 40% by weight relative to the weight of the pharmaceutical composition, preferably from 10% to 30%, even more preferably from 15% to 25%.
  • the dry powder of the composition according to the present invention is characterised by particles with an average volume size that can range from 1 to 40 microns, preferably from 5 to 20 microns, even more preferably from 8 to 15 microns.
  • the present invention further relates to a pharmaceutical composition as defined above for use in the prevention or treatment of inflammation, wherein said pharmaceutical composition or protein anakinra is administered by inhalation.
  • the pharmaceutical composition as defined above can be advantageously used, by inhalation, in the prevention or treatment of inflammation in a patient with cystic fibrosis.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the protein anakinra, as the active ingredient, in combination with one or more pharmaceutically acceptable excipients, said pharmaceutical composition being in a dry powder form suitable for administration by inhalation, wherein said one or more excipients comprise or consist of the amino acid leucine, for example D-leucine, and do not comprise sugars.
  • the present invention further relates to a process for preparing the composition as defined above, said process comprising: a) preparing an aqueous solution of anakinra and one or more pharmaceutically acceptable excipients, wherein said one or more excipients comprise or consist of a sugar selected from among mannitol, sucrose and trehalose, or lactose and an amino acid selected from among leucine, trileucine, lysine, tryptophan, arginine, aspartic acid, threonine, or phenylalanine; b) subjecting the solution to spray drying, wherein the temperature ranges from 120 to 180°C, preferably from 120 to 160°C, even more preferably from 135 to 145°C; the feed rate ranges from 1 to 10 mL/min, preferably from 2 to 8 mL/min, even more preferably from 2 to 4 mL/min; the airflow speed ranges from 200 to 400 L/hour, preferably from 250 to 350 L/hour,
  • the trileucine can be present in the composition in an amount by weight ranging from 1 to 10 %, preferably from 4 to 8 %, relative to the total weight of the composition.
  • said one or more excipients can comprise a single sugar selected from among mannitol, trehalose or sucrose, or a mixture of said sugars selected from among mannitol and sucrose, mannitol and trehalose or mannitol, trehalose and sucrose. Therefore, according to the present invention, said one or more sugars can consist of a single sugar selected from among mannitol, trehalose or sucrose or a mixture of said sugars selected from among mannitol and sucrose, mannitol and trehalose or mannitol, trehalose and sucrose.
  • said one or more excipients can comprise or consist of one of the following mixtures of said one sugar and said one amino acid: mannitol and leucine, trehalose and leucine, sucrose and leucine or mannitol, trehalose, sucrose and leucine, mannitol and trileucine, trehalose and trileucine, sucrose and trileucine, mannitol, trehalose, sucrose, and trileucine.
  • the present invention also relates to a process for preparing the composition as defined above, said process comprising: a) preparing an aqueous solution of anakinra and one or more pharmaceutically acceptable excipients, wherein said one or more excipients comprise or consist of the amino acid leucine, such as, for example, D-leucine, and do not comprise sugars; b) subjecting the solution to spray drying, wherein the temperature ranges from 120 to 180°C, preferably from 120 to 160°C, even more preferably from 135 to 145°C; the feed rate ranges from 1 to 10 mL/min, preferably from 2 to 8 mL/min, even more preferably from 2 to 4 mL/min; the airflow speed ranges from 200 to 400 L/hour, preferably from 250 to 350 L/hour, even more preferably from 290 to 310 L/hour.
  • the temperature ranges from 120 to 180°C, preferably from 120 to 160°C, even more preferably from 135 to 145°C
  • the present invention relates to a kit for the administration by inhalation of a pharmaceutical composition according to the present invention as defined above, wherein said kit comprises: a) a device for administration by dry powder inhalation; and b) a pharmaceutical composition as defined above.
  • FIG. 6 shows the aerodynamic evaluation of the batch with the different amino acids listed in Table 4.
  • the test was carried out using a Twin- Stage Glass Impinger (TSGI).
  • TSGI Twin- Stage Glass Impinger
  • the samples were loaded into a size 3 Quali-V® hard capsule made of hydroxypropyl methylcellulose.
  • the DPI used was the RS01 7 model (Aereolizer®).
  • the conditions were fixed following European Pharmacopeia guidelines (apparatus A) (5 s of suction time, at a suction speed of 60 ⁇ 5 L/min).
  • Appatus A 5 s of suction time, at a suction speed of 60 ⁇ 5 L/min.
  • the amount of protein deposited on the capsule, on the inhaler, on the throat and on every stage of the TSGI was evaluated as reported in the methods section.
  • the results were expressed as a mean of three determinations and the error as S.D.
  • the measured parameters are the emitted fraction (ED) and the respirable fractions expressed as a percentage of the nominal dose (RFN) and percentage of the dose emitted (RFE).
  • ED emitted fraction
  • RFE percentage of the dose emitted
  • EXAMPLE 1 Preparation of anakinra in inhalable forma and study of its effectiveness against inflammation in cystic fibrosis
  • the dry powder formulation of anakinra was prepared using a Mini Spray dryer, model B-290 (Buchi, Switzerland) and employing mannitol and D-Leucine as excipients.
  • the solution of anakinra, mannitol and leucine was prepared in water by solubilising first the excipients, namely 80 mg of mannitol and 40 mg of leucine, and then 40 mg of protein, thereby obtaining a total amount of 160 mg of preparation.
  • the spray drying was carried out in the co-current mode, with a spray dryer provided with a 2-fluid nozzle with a 0.7 mm nozzle tip and 1 .5 mm diameter nozzle cap.
  • the spray drying operating parameters are: inlet temperature 140°C, air flow rate 301 L/hour, feed rate 2.4 mL/min and aspirator capacity of 20 m 3 /hour. Briefly, mannitol and leucine were dispersed in water and allowed to solubilise under magnetic stirring before the aqueous solution of anakinra was added; the complete protein solution was immediately processed. The dried powders obtained were recovered using a high-performance cyclone (Buchi, Switzerland).
  • the yield (%w/w) of the spray drying process was determined as follows:
  • the morphology of the particles and the surface characteristics of the dry powders of anakinra were evaluated by scanning electron microscopy (SEM) using an FEG LEO 1525 microscope (LEO Electron Microscopy Inc., NY). The potential tension of acceleration was maintained at 1 keV.
  • the samples were placed on aluminium stubs covered with double-sided carbon tape.
  • the stubs were coated with chromium prior to analysis by means of a high-resolution sputter coater (Quorum Technologies, East Essex, United Kingdom). The coating was applied at 20 mA for 20 s.
  • the particle size analysis was carried out with the Single Particle Optical Sensing technique.
  • a PSS Accusizer C770 equipped with an automatic dilution system PSS, Santa Barbara, CA
  • the measurements were performed in triplicate in the gravity mode using n-hexane as the dispersion medium.
  • the samples were prepared by dispersing an amount of powder in n-hexane and sonicating for several seconds to allow a homogeneous dispersion of the particles in the solvent.
  • the size was expressed as the volume mean diameter (VMD) and the error as S.D.
  • VMD volume mean diameter
  • a dry powder insufflator model DP-4M (Penn-Century Inc., Wyndmoor, PA, USA), was used to aerosolise and administer a precise dose of dry powder to the mouse lungs.
  • the device performance was evaluated to ensure an adequate and reproducible emission of powder.
  • the chamber was filled with 2.5 mg of powder to be delivered with a single puff.
  • the device was actuated by a volume of air of 0.2 mL. After every use, the residual anakinra was recovered from the device, which was then washed with ethanol and dried for 3 minutes.
  • DD delivered dose
  • the aerodynamic behaviour of the dry powders of anakinra was evaluated using a Twin-Stage Glass Impinger (TSGI) (Disa, Milan, Italy). The stages were loaded with 7 mL (stage 1 ) and 30 mL (stage 2) of an aqueous solution. Twenty mg of powder were manually loaded into a size 3 Quali-V® hard capsule made of hydroxypropyl methylcellulose (HPMC) (Qualicaps®, Alcobendas, Spain), which was placed in the capsule compartment of the dry powder inhalation device. The DPI used in this study was model RS01 7 (Plastiape, Lecco, Italy), used commercially for Aereolizer®. The capsule was weighed before and after every activation.
  • TSGI Twin-Stage Glass Impinger
  • EF Emitted fraction of proteins (stages 1 and 2) x Nominal dose > 100 Eq. 4
  • RFN% Amount of protein stage 2 x Nominal dose x 100
  • RFE% Amount of protein stage 2 x Emitted dose x 100
  • the human monocytic cell line THP-1 (ATCC Number: TIB-202) was maintained at 37 ° C in 5% CO2 in RPMI 1640 supplemented with 10% heat- inactivated FBS, L-glutamine, 100 units/mL of penicillin and 0.1 mg/mL of streptomycin.
  • the cells were seeded in a 12-well plate at a density of 5 x 10 5 cells/mL and incubated for 24 hours prior to the treatments.
  • the cells were treated with a final concentration of 10 pg/mL of standard anakinra or formulation 30 minutes before stimulation with 50 pg/mL of human recombinant IL-10 (research and development systems) and collected at different times (2, 6 and 24 hours).
  • RT-PCR analysis was carried out using the CFX96 Touch Real-Time PCR detection system and an iTaq Universal SYBR Green Supermix (Bio-Rad). The cells were lysed, the total RNA was isolated with TRIZOL Reagent (Thermo Fisher Scientific) and cDNAs were synthesised using a PrimeScript RT Reagent Kit with gDNA Eraser (Takara), according to the manufacturer’s instructions. The amplification efficiencies were validated and normalised to GAPDH. Each data point was examined to verify its integrity by analysing the amplification graph.
  • mice homozygous for F508del-CFTR which had been crossed for 12 generations with the strain C57BL/6, or in the FVB/129 outbred background (CftrtmlEUR mice, F508del, abbreviated CftrF508del) were obtained from Bob Scholte, Erasmus Medical Center Rotterdam, the Netherlands.
  • the mice were housed in a controlled environment at the animal breeding department of the University of Perugia. For infection, the mice were anaesthetised in a plastic cage by inhalation of 3% isoflurane (Forane, Abbott) in oxygen prior to intranasal instillation of 2 x 10 7 conidia of A.
  • mice were treated with 10 mg/kg of anakinra, as Kineret (Kineret IP) and the standard protein administered intraperitoneally (Anakinra IP), every day for one week starting from the day of infection, or administered into the lung by pulmonary insufflation (Anakinra PI) once 3 days after the infection. Seven days after the infection, the mice were monitored for fungal growth as described (11 ), lung histopathology on sections embedded in paraffin and stained with periodic acid- Schiff (PAS), the recruitment of neutrophils (PMN) in the bronchoalveolar lavage fluid, and the gene expression of inflammatory cytokines by RT-PCR. The images were acquired by means of an Olympus DP71 high-resolution microscope. The experiments on mice were carried out in accordance with authorisation no. 1021/2020-PR issued by the Italian Health Ministry as per Legislative Decree 26/2014.
  • anakinra was administered once at two dosages corresponding to 10 mg/kg and 5 mg/kg (200-100 pg/mouse), intraperitoneally (Anakinra IP) or by insufflation (Anakinra PI), at day 3 after the infection. Seven days after the infection, the mice were monitored as described above. Furthermore, peripheral neutropenia was studied by analysing peripheral blood smears of C57BL/6 mice treated with the different doses of anakinra.
  • RNA extraction and quantitative RT-PCR RNA extraction and quantitative RT-PCR (qRT-PCR).
  • the cDNA synthesis kit (BioRad, Milan, Italy) was used for reverse transcription according to the manufacturer’s protocol.
  • RT-PCR amplification (PCR using the CFX96 TouchTM Real-Time PCR Detection System) was carried out using the SYBR Green QPCR master mix (Agilent Technologies, Milan, Italy) under the following conditions: 45 cycles at 95°C for 1 min, appropriate annealing temperature for 1 min and 72°C for 30 s. All the reactions were repeated independently at least three times to guarantee the reproducibility of the results. Statistical analysis.
  • the dry powders of anakinra obtained showed a typical collapsed, irregular shape with a rough surface (Fig. 1 ). These characteristics support a potential respirability for the particles.
  • the size distribution also showed to be compatible with a potential respirability, with a DMV slightly greater than 10 pm and a homogeneous population (Fig. 1 , Table 1 ).
  • the dry powder ofanakinra preserves activity in vitro.
  • the insufflated dry powder ofanakinra protects against lung pathology in mouse cystic fibrosis.
  • the therapeutic effectiveness of the formulations was evaluated in relation to Kineret and standard anakinra administered IP daily for 7 days.
  • CF mice were infected with A. fumigatus and a single dose of the dry powder of anakinra was insufflated 3 days after the infection.
  • the single pulmonary insufflation reduced the growth and spread of the infection in a generally more efficient manner than the systemic daily administration of Kineret and the standard protein.
  • PMN recruitment was equal to or less than in the case of IP administration and the lung histopathology improved, as also confirmed by a significant reduction in the expression of inflammatory cytokines and chemokines.
  • the insufflated dry powder of anakinra allows for a reduction in the dose and prevention of peripheral neutropenia.

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Abstract

La présente invention concerne une composition pharmaceutique inhalable comprenant de l'anakinra protéique pour le traitement d'une inflammation de fibrose kystique, et qui est capable de préserver la stabilité du principe actif et de fournir une dose efficace de celui-ci par inhalation.
PCT/IT2023/050105 2022-04-21 2023-04-19 Composition pharmaceutique inhalable comprenant de l'anakinra protéique pour le traitement d'une inflammation de fibrose kystique WO2023203586A1 (fr)

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IT102022000007844A IT202200007844A1 (it) 2022-04-21 2022-04-21 Composizione farmaceutica inalabile comprendente la proteina anakinra per il trattamento dell’infiammazione nella fibrosi cistica
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118416033A (zh) * 2024-04-30 2024-08-02 杭州畅溪制药有限公司 阿普斯特吸入粉雾剂及其制备方法和应用

Citations (2)

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Publication number Priority date Publication date Assignee Title
AU2019203630B2 (en) * 2006-08-10 2021-05-20 Onspira Therapeutics, Inc. Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors
WO2021113334A1 (fr) * 2019-12-02 2021-06-10 Altavant Sciences Gmbh Traitement des voies respiratoires inférieures

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2019203630B2 (en) * 2006-08-10 2021-05-20 Onspira Therapeutics, Inc. Localized therapy of lower airways inflammatory disorders with proinflammatory cytokine inhibitors
WO2021113334A1 (fr) * 2019-12-02 2021-06-10 Altavant Sciences Gmbh Traitement des voies respiratoires inférieures

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"The Proceedings of the 16th Italian Convention of Investigators in Cystic Fibrosis", MULTIDISCIPLINARY RESPIRATORY MEDICINE, BIOMED CENTRAL LTD, LONDON, UK, vol. 14, no. 1, 6 February 2019 (2019-02-06), pages 1 - 15, XP021270913, DOI: 10.1186/S40248-018-0164-1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118416033A (zh) * 2024-04-30 2024-08-02 杭州畅溪制药有限公司 阿普斯特吸入粉雾剂及其制备方法和应用

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