WO2022224030A1 - Formulation d'inhalation de poudre sèche (dpi) - Google Patents

Formulation d'inhalation de poudre sèche (dpi) Download PDF

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Publication number
WO2022224030A1
WO2022224030A1 PCT/IB2021/056290 IB2021056290W WO2022224030A1 WO 2022224030 A1 WO2022224030 A1 WO 2022224030A1 IB 2021056290 W IB2021056290 W IB 2021056290W WO 2022224030 A1 WO2022224030 A1 WO 2022224030A1
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formulation
favipiravir
lactose
dry powder
range
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PCT/IB2021/056290
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English (en)
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Sriram Padmanabhan
Vinod Ramachandra Jadhav
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Sava Healthcare Ltd
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Publication of WO2022224030A1 publication Critical patent/WO2022224030A1/fr

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    • 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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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

Definitions

  • the present disclosure relates to a dry powder inhalation (DPI) formulation.
  • DPI dry powder inhalation
  • D10 refers to the portion of particles with diameters below the specified value is 10%.
  • D50 refers to the portion of particles with diameters smaller and larger than a specified value are 50%. Also known as the median diameter.
  • D90 refers to the portion of particles with diameters below the specified value is 90%.
  • MMAD mass median aerodynamic diameter
  • FPF Frine-particle fraction
  • Vero cells refer to mammalian cell lines derived from the kidney of an African green monkey extensively used in virology studies and other applications.
  • First pass metabolism refers to a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation.
  • Favipiravir is a broad-spectrum antiviral drug found to be active against various influenza viruses including seasonal strains A (H1N1), A (H3N2), influenza B, A (HlNl)pdm09, avian influenza virus A (H5N1) isolated from humans, A (H1N1), and A (H1N2) isolated from swine, A (H2N2), A (H4N2), and A (H7N2). Besides, it also inhibits the Ebola virus, bunyavirus, filovirus, West Nile virus, yellow fever virus, foot-and-mouth disease virus, and Lassa virus.
  • the drug inhibits the RNA-dependent RNA polymerase (RdRP) of 72 influenza and many other RNA viruses.
  • Favipiravir acts by inhibiting this viral RNA dependent RNA polymerase (RdRp) enzyme, an enzyme impeding replication of RNA viruses and allowing facile insertion of Favipiravir into viral RNA while sparing human DNA.
  • RdRp viral RNA dependent RNA polymerase
  • Favipiravir was preferred based on the available safety and efficacy details. The data suggest a high dose of Favipiravir was required to inhibit SARS- CoV-2 infection in Vero cells. The recommended dose for clinical use in the majority of the countries is 1800 mg bid on day 1, followed by 800 mg bid on days 2-14. It was observed that the high oral dosage leading to poor compliance of the patients. Further, it is also observed ethnic variations in the pharmacokinetic profile of the drug.
  • Favipiravir In an in vivo study, upon administration of single and multiple doses of Favipiravir lower concentration was observed in the lungs than in plasma. Further, a high dose of Favipiravir in animal models leads to mutations in the viral genomes (large number of G A and C U mutations). The mean number of mutations increased with an increase in the dosage of Favipiravir.
  • favipiravir is also associated with adverse reactions that include mild to moderate diarrhea, an asymptomatic increase of blood uric acid and transaminases, a decrease in the neutrophil counts, and increased levels of liver enzymes like AFT and AST.
  • Favipiravir administered at high dose of 1,000 mg-kg _1 -d _1 in the hamster transmission model markedly blocked viral infection of sentinel hamsters that were in direct contact with infected hamsters.
  • Favipiravir can be administered as a prophylactic before the onset of COVID symptoms, however administration of high doses can lead to adverse effects.
  • An object of the present disclosure is to provide a dry powder inhalation (DPI) formulation.
  • Another object of the present disclosure is to provide a dry powder inhalation formulation of Favipiravir.
  • An object of the present disclosure is to provide a dry powder inhalation formulation that avoids the first-pass metabolism.
  • Another object of the present disclosure is to provide a dry powder inhalation formulation that exerts equivalent/enhanced efficacy at a reduced dose.
  • Still another object of the present disclosure is to provide a simple process for the preparation of a dry powder inhalation formulation.
  • the present disclosure relates to a dry powder inhalation (DPI) formulation and a process for its preparation.
  • DPI dry powder inhalation
  • the dry powder inhalation formulation comprises a micronized favipiravir having a particle size in the range of 1 pm to 6 pm; first lactose having a particle size in the range of 19 pm to 93 pm; second lactose having a particle size in the range of 1 pm to 60 pm, and optionally at least one excipient.
  • the weight ratio of the first lactose to the second lactose is in the range of 6:1 to 10:1.
  • the process for the preparation of dry powder inhalation formulation comprises blending of first lactose and second lactose to obtain a lactose mixture.
  • the lactose mixture was sifted through 80 mesh to obtain a homogeneous lactose mixture.
  • the homogeneous lactose mixture is divided into two portions i.e. a first portion (-75%) and a second portion (-25%).
  • Additives such as magnesium stearate and citric acid are mixed with the first portion and blended to obtain a first resultant mixture.
  • a predetermined amount of Favipiravir is mixed with the second portion to obtain a mixture and the mixture is sifted through 80 mesh to obtain a second resultant mixture.
  • the first resultant mixture and the second resultant mixture are blended at a speed in the range of 15 rpm to 30 rpm for 20 minutes to 40 minutes to obtain the dry powder inhalation (DPI) formulation.
  • the so obtained dry powder inhalation (DPI) formulation is loaded into size 3 HPMC capsules by using a capsule filler.
  • Figure 1A illustrates a HPLC chromatogram of diluent (water: methanol, 1:1)
  • Figure IB illustrates a HPLC chromatogram of the standard solution of Favipiravir lOOppm
  • Figure 1C illustrates a HPLC chromatogram of 100 ppm solution of Favipiravir 10 mg dry powder inhalation (DPI) formulation of the present disclosure stored for 3 months at 40 °C/75%RH;
  • Figure ID illustrates a HPLC chromatogram of 100 ppm solution of Favipiravir 10 mg dry powder inhalation (DPI) formulation of the present disclosure stored for 3 months at 2-8 °C;
  • Figure IE illustrates a HPLC chromatogram of 100 ppm solution of Favipiravir 20 mg dry powder inhalation (DPI) formulation of the present disclosure stored for 3 months at 40 °C/75%RH;
  • Figure IF illustrates a HPLC chromatogram of 100 ppm solution of Favipiravir 20 mg dry powder inhalation (DPI) formulation stored for 3 months at 2-8 °C;
  • Figure 2A illustrates a graph depicting cumulative (% undersize) particle size distribution of dry powder inhalation (DPI) formulation of Favipiravir 10 mg of the present disclosure stored for 3 months at 40 °C/75%RH;
  • DPI dry powder inhalation
  • Figure 2B illustrates a graph depicting drug deposition of dry powder inhalation (DPI) formulation of Favipiravir 10 mg of the present disclosure stored for 3 months at 40 °C/75%RH
  • Figure 2C illustrates a graph depicting cumulative (% undersize) particle size distribution of dry powder inhalation (DPI) formulation of Favipiravir 20 mg of the present disclosure stored for 3 months at 40 °C/75%RH
  • DPI dry powder inhalation
  • Figure 2D illustrates a graph depicting drug deposition of dry powder inhalation (DPI) formulation of Favipiravir 20 mg of the present disclosure stored for 3 months at 40 °C/75%RH.
  • DPI dry powder inhalation
  • Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details, are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
  • the recommended oral dose of favipiravir for clinical use is 1800 mg bid on day 1 , followed by 800 mg bid on days 2 to 14. It is observed that due to high oral dosage, poor compliance of the patients is observed. Moreover, the oral administration of favipiravir is associated with adverse reactions that include mild to moderate diarrhea, an asymptomatic increase of blood uric acid and transaminases, a decrease in the neutrophil counts, and an increased level of liver enzymes like ALT and AST.
  • the present disclosure provided a dry powder inhalation (DPI) formulation and a process for its preparation.
  • DPI dry powder inhalation
  • the dry powder inhalation (DPI) formulation comprises:
  • the microni ed favipiravir is in an amount in the range of 35 wt% to 85 wt% with respect to the total weight of the formulation.
  • the first lactose is in an amount in the range of 17 wt% to 55 wt% with respect to the total weight of the formulation.
  • the mean particle size (dlO) of the first lactose is in the range of 19 pm to 43 pm.
  • the mean particle size (d50) of the first lactose is in the range of 53 pm to 66 pm.
  • the mean particle size (d90) of the first lactose is in the range of 75 pm to 93 pm.
  • the second lactose is in an amount in the range of 1 wt% to 8 wt% with respect to the total weight of the formulation.
  • the mean particle size (dlO) of the second lactose is in the range of 1 pm to 6 pm.
  • the mean particle size (d50) of the second lactose is in the range of 10 pm to 30 pm.
  • the mean particle size (d90) of the second lactose is in the range of 50 pm to 60 pm.
  • the weight ratio of the first lactose to the second lactose is in the range of 6:1 to 10:1. In an exemplary embodiment of the present disclosure, the weight ratio of first lactose to second lactose is 9:1.
  • the MMAD of the dry powder inhalation is in the range of 1 pm to 4 pm.
  • the excipient is in an amount in the range of 1 wt% to 7 wt% with respect to the total weight of the formulation.
  • the excipient is selected from citric acid, magnesium stearate, and a combination thereof.
  • the first lactose and second lactose are blended to obtain the lactose mixture.
  • the first lactose mixture is sifted through 80 mesh in controlled temperature and humidity conditions to obtain a homogeneous lactose mixture.
  • the homogeneous lactose mixture is divided into two portions i.e. first portion (-75%) and the second portion (-25%).
  • additives magnesium stearate and citric acid are mixed with the first portion and blended to obtain the first resultant mixture.
  • a third step separately Favipiravir is mixed with the second portion, the mixture is sifted through 80 mesh to obtain the second resultant mixture.
  • the first resultant mixture and the second resultant mixture are blended at a speed of 15 rpm to 30 rpm for a period of 20 minutes to 40 minutes to obtain the dry powder inhalation (DPI) formulation.
  • DPI dry powder inhalation
  • the so obtained dry powder inhalation (DPI) formulation is loaded into size 3 HPMC (Hydroxypropyl methylcellulose) capsules using a capsule filler.
  • the present disclosure provides the dry powder inhalation formulation that avoids the first- pass metabolism.
  • the formulation of the present disclosure is therapeutically effective at a reduced dose and also observed increased patient compliance. Further, the dry powder inhalation formulation of the present disclosure has been evaluated for its toxicity on rats. It is observed that the No Observed Effect Level (NOEL) of Favipiravir is >2.13 mg a.i./kg b.wt. when administered through inhalation for up to 2 weeks.
  • NOEL No Observed Effect Level
  • Favipiravir The compatibility of Favipiravir (API) has been evaluated with different carriers i.e., lactose and mannitol.
  • the favipiravir and carrier were mixed in equal proportions in the ratio of 1 : 1 to obtain API-Carrier mixture and evaluated in packed conditions (amber coloured glass vials (10 ml) with a rubber closure and flip off seal) and open conditions.
  • the formulations were subjected to accelerated stability studies.
  • the ratio of favipiravir (API) and carrier, stability conditions, and impurity profile of API-Carrier mixture are illustrated below in Tables 1-3.
  • Table 1 Ratio of favipiravir (API) to carrier
  • Table 2 Stability conditions of API-Carrier mixture
  • Table 3 Impurity profile of API-Carrier mixture
  • first lactose (respitose SV003) and 1.35 gm of second lactose (respitose ML006) were mixed using double lined polybags and sifted using 80 mesh to obtain a homogeneous lactose mixture.
  • the homogeneous lactose mixture was divided into two portions i.e. first portion (-75%) and a second portion (-25%).
  • 1.25_gm of magnesium stearate and 0.25 gm of citric acid were added to the first portion and blended to obtain the first resultant mixture.
  • Favipiravir particle size of 6 microns was mixed with the second portion to obtain the mixture, the mixture was sifted through 80 mesh to obtain the second resultant mixture.
  • the first resultant mixture and the second resultant mixture mixtures are transferred to a double cone blender and blended at a speed of 15 rpm for a period of 20 minutes to obtain the dry powder inhalation (DPI) formulation of Favipiravir (Formulation
  • the dry powder inhalation formulations were prepared in the similar manner as disclosed in Example 2, varying the concentration of ingredients according to the formulations as illustrated in Table 4.
  • Example 4 In-vitro Lung Deposition Study
  • Aerodynamic Particle Size Distribution (APSD), Delivered dose, are the Critical Quality Attributes for the in vitro characterization of Orally inhaled drug products (OINDPs).
  • the APSD of an aerosol determines the portion of DPI particles that deposit in the body especially in the lower respiratory tract.
  • the particles in the range of 1 to 5 microns reach the lower respiratory tract are considered effective, particles with larger than 5 microns will remain in the upper respiratory tract and are likely to impact the oropharynx and be swallowed, particles smaller than 1 micron will be cleared by lungs clearance mechanism.
  • APSD emitted from each dose of the dry powder inhalation formulation of the present disclosure was evaluated using Next Generation Impactor (NGI) instrument.
  • NTI Next Generation Impactor
  • the instrument was loaded with 100 mg of the dry powder formulation, the flow rate through the instrument during testing was regulated at 83 L/minute.
  • the dry powder inhalation formulation collected in the filter was analyzed for fine particle fraction and MMAD. The procedure was repeated for the various formulations (Favipiravir 10 mg and 20 mg), the results as illustrated in Tables 5 and 6.
  • the toxicity of the dry powder inhalation formulation of the present disclosure was evaluated in Wistar rats to determine the No Observed Effect Level (NOEL).
  • NOEL No Observed Effect Level
  • the study animals (24) (6 rats/sex/group) were divided into two groups, control (GI) administered with only air, intervention (GII) was administered Favipiravir at a dose of 2.13 mg/kg body weight once daily for 14 days.
  • the Favipiravir was loaded in the rotating brush generator and dust was generated.
  • the Favipiravir DPI was loaded, in a cylindrical powder reservoir of the aerosol generator system, positioned below the cylindrical bmsh.
  • the airflow rate through the dust generator was maintained approximately at 26 litres per minute for GII and 39 litres per minute for GI. Rats belonging to GI and GII were exposed for 15 minutes.
  • the mean delivered doses were 2.13 mg a.i./kg b. wt. for Favipiravir (mean measured value).
  • the mass median aerodynamic diameter (MMAD) of Favipiravir aerosols was found within a range of 3.54 and 3.93 pm with a geometric standard deviation (GSD) within a range of 1.59 and 1.62.
  • the animals were observed daily for clinical signs, morbidity, and mortality.
  • the body weight is recorded at regular intervals on day 1 (before treatment), day 4, day 8, and day 15.
  • the feed consumption was calculated on day 4, day 8, and day 15.
  • the rats were euthanized using thiopentone sodium overdose, followed by pathological examination.
  • the pathological examination includes external abnormalities, followed by euthanization organs were removed intact, examined, and weighed.
  • the organ weights of the left lung, liver, kidneys, spleen, adrenals, heart, testes, epididymides, ovaries, uterus with cervix, thymus, and brain were recorded. Further, the broncho-alveolar lavage (BAL) of the right lung was analysed.
  • BAL broncho-alveolar lavage
  • MMAD mass median aerodynamic diameter
  • Rats were observed twice each day in the duration of the experimental period for morbidity and mortality (before and after exposure on treatment days, and morning and evening on non-treatment days). Observations include evaluation of skin and fur, eyes, mucous membranes, respiratory and circulatory effects, autonomic and central nervous system effects, somatomotor activity and behaviour pattern, and observation of tremor, convulsions, salivation, diarrhoea, lethargy, sleep, and coma. In addition, rats were observed for the detailed clinical signs once daily along with the above observations. Rats were also observed for clinical signs at the end of exposure and one hour post exposure. ii. Body Weight The individual body weight for each rat was recorded on the day of randomization
  • Table 8 Body Weight (g) of Individual Rat (Group GII)
  • the feed consumption of animals was calculated on day 4, day 8, and day 15.
  • the weekly feed consumption for each rat was calculated throughout the study using the below formula.
  • Table 11 Feed Consumption (g/rat/day) of Individual Rat (Group GI)
  • Table 12 Feed Consumption (g/rat/day) of Individual Rat (Group GII)
  • the broncho-alveolar lavage was obtained from the right lung after euthanized by barbiturate overdose followed by exsanguination at scheduled sacrifices (day 15). The lavage was analysed for cellular contents, the details are illustrated below in Table 15;
  • the rats were euthanized by barbiturate overdose, organs were removed intact, examined, and weighed. Organ weights of left lungs, liver, kidneys, spleen, adrenals, heart, testes, epididymides, thymus, ovaries, uterus with cervix, and brain were taken. All organs were preserved in 10% neutral buffered formalin solution except testes which was preserved in Modified Davidson’s fixative. The organ weights of treated groups (GII) were compared well with the control group (GI), the results are illustrated below in Table 16.
  • the dry powder inhalation (DPI) formulation of Favipiravir in capsules of the present disclosure was subjected to 3 months accelerated stability testing at 40 °C/75%RH and 2-8 °C.
  • the content of Favipiravir in the capsules after 3 months of accelerated stability testing was evaluated by HPLC chromatography. The chromatographic conditions are provided below,
  • Buffer solution The buffer solution was prepared by dissolving 1 mL of orthophosphoric acid in 1000 mL of water, mixed well, and filtered through a 0.45 pm filter.
  • the mobile phase was prepared by mixing buffer solution and acetonitrile in the ratio of 75:25 % v/v.
  • Diluent The diluent was prepared by mixing water and methanol in the ratio of 1:1 % v/v. The chromatogram of diluent was illustrated in Fig. 1A.
  • Standard solution 25 mg of Favipiravir was mixed with 35 mL of diluent and sonicated to dissolve, cooled to room temperature and diluted to 50 mL with diluent to obtain a solution. Further, 5 ml of the solution is diluted to 25 ml with diluent to obtain a standard solution containing 100 ppm of Favipiravir. The chromatogram of the standard solution was illustrated in Fig. IB.
  • Sample preparation (Favipiravir lOmg capsules): Collect dry powder inhalation (DPI) formulation from 20 capsules and the average weight of the content was calculated.
  • the contents of the capsule i.e. 25 mg of dry powder inhalation formulation (equivalent to about 10 mg of Favipiravir) was mixed with 70 mL of diluent and sonicated for 15 minutes to obtain a sonicated DPI solution.
  • the sonicated DPI solution was cooled and diluted to 100 mL with diluent and mix well to obtain a DPI solution.
  • the DPI solution was filtered through a 0.45 pm nylon filter to obtain a filtered DPI solution.
  • the first 5mL of the filtered DPI solution was discarded and the remaining filtered DPI solution (100 ppm solution) was used for evaluation.
  • Sample preparation (Favipiravir 20 mg capsules): Collect dry powder inhalation (DPI) formulation from 20 capsules and the average weight of the content was calculated.
  • the contents of the capsule i.e. 25 mg of sample (equivalent to about 20 mg of Favipiravir) was mixed with 140 mL of diluent and sonicated for 15 minutes to obtain a sonicated DPI solution.
  • the sonicated DPI solution was cooled and diluted to 200 mL with diluent and mix well to obtain a DPI solution.
  • the DPI solution was filtered through a 0.45 pm nylon filter to obtain a filtered DPI solution.
  • the first 5mL of the filtered DPI solution was discarding and the remaining filtered DPI solution (100 ppm solution) was used for evaluation.
  • the standard solution was subjected to chromatography and peak response was recorded.
  • the % RSD of the area of the analyte of five replicate standard injections should not be more than 2.0%, the column efficiency should not be less than 2000 theoretical plates, and the tailing factor should not be more than 2.0.
  • the Favipiravir content was evaluated by separately injecting an equal volume of the diluent, standard, and sample solutions into the chromatograph, recorded the chromatograms, and measured the responses for the analyte peak, in standard and sample, and determining the amount of Favipiravir in % assay by the following formulae.
  • Wt. std. Weight of standard in mg
  • Wt. sp Weight of sample in mg
  • Avg.wt. Average content weight of sample powder in mg
  • chromatograms of dry powder inhalation (DPI) formulation of Favipiravir 10 mg stored for 3 months at 40 °C/75%RH and 2-8 °C were illustrated in Fig. 1C and ID respectively.
  • chromatograms of dry powder inhalation (DPI) formulation of Favipiravir 20 mg stored for 3 months at 40 °C/75%RH and 2-8 °C were illustrated in Fig. IE and IF respectively.
  • dry powder inhalation (DPI) formulation of Favipiravir 10 mg stored for 3 months at 40 °C/75%RH was evaluated for Aerodynamic Particle Size Distribution (APSD).
  • the APSD from each dose of the dry powder inhalation formulation of the present disclosure was evaluated using Next Generation Impactor (NGI) instrument.
  • NTI Next Generation Impactor
  • the instrument was loaded with content of the 10 mg capsule of the dry powder formulation, the flow rate through the instrument during testing was regulated at 83 L/minute.
  • the procedure was repeated for Favipiravir 20 mg.
  • the dry powder inhalation formulation collected in the filter was analyzed for Favipiravir content in lungs, fine particle fraction, MMAD, and geometric standard deviation (GSD), results are provided below in Table 18.
  • the cumulative (% undersize) particle size distribution, drug deposition for Favipiravir 10 mg and Favipiravir 20 mg was illustrated in Fig. 2 A, 2B, 2C, and 2D respectively.
  • DPI dry powder inhalation

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Abstract

La présente invention concerne une formulation d'inhalation de poudre sèche (DPI) et un procédé pour sa préparation. La formulation d'inhalation de poudre sèche comprend du favipiravir micronisé, un premier lactose, un second lactose et éventuellement au moins un excipient. La formulation de poudre sèche de la présente invention augmente la biodisponibilité du favipiravir, améliore l'observance du patient et réduit les effets secondaires.
PCT/IB2021/056290 2021-04-20 2021-07-13 Formulation d'inhalation de poudre sèche (dpi) WO2022224030A1 (fr)

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US20230310544A1 (en) * 2022-03-31 2023-10-05 Alexandre Vasilievich Ivachtchenko ANTI-RNA VIRAL PHARMACEUTICAL COMBINATION THERAPY WITH APROTININ + anti-RNA DRUG

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SAHAKIJPIJARN SAWITTREE ET AL., INTERNATIONAL JOURNAL OF PHARMACEUTICS: X, vol. 3, no. 2021, 27 February 2021 (2021-02-27), pages 100073 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230310544A1 (en) * 2022-03-31 2023-10-05 Alexandre Vasilievich Ivachtchenko ANTI-RNA VIRAL PHARMACEUTICAL COMBINATION THERAPY WITH APROTININ + anti-RNA DRUG

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