WO2023242262A1 - Method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material - Google Patents

Method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material Download PDF

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Publication number
WO2023242262A1
WO2023242262A1 PCT/EP2023/065952 EP2023065952W WO2023242262A1 WO 2023242262 A1 WO2023242262 A1 WO 2023242262A1 EP 2023065952 W EP2023065952 W EP 2023065952W WO 2023242262 A1 WO2023242262 A1 WO 2023242262A1
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Prior art keywords
aerosol
micro
distribution chamber
receptacle
biocompatible material
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PCT/EP2023/065952
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French (fr)
Inventor
Jesús SANTAMARÍA RAMIRO
María Pilar LOBERA GONZÁLEZ
Beatriz ARAUZO GIMENO
Francisco BALAS NIETO
Alberto CLEMENTE CORNAGO
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Universidad De Zaragoza
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0086—Inhalation chambers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/82—Internal energy supply devices
    • A61M2205/8218—Gas operated
    • A61M2205/8225—Gas operated using incorporated gas cartridges for the driving gas

Definitions

  • the present invention lies within the technical field of aerosol generation technologies. More specifically, the invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material, especially, from micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
  • Aerosol therapy is a technique for the administration of drugs or biocompatible substances in aerosol form by inhalation through nebulizers, metered dose inhalers (MDIs), or dry powder inhalers (DPIs), being “aerosol” understood as a suspension of solid micro/nanoparticles or liquid droplets in a gas, typically air. Aerosol therapy is commonly used in the treatment of various respiratory tract infections, such as pneumonia, and lung diseases (bronchitis, allergies, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, lung cancer, etc.), although it has also been effective as therapy against pain or diabetes.
  • drugs that can be supplied by this technique are antibiotics, antifungals, anti-inflammatories, antioxidants, antivirals, bronchodilators, corticosteroids, mucolytics and even vaccines.
  • inhalable aerosols from dry powder formulations remains a challenge.
  • main problems to be solved in DPIs are: production of short-lived, pulsed aerosols with highly polydisperse particle size distributions due to powder agglomerations; low flexibility regarding the nature of the powder formulations (until now, aerosolization has been limited to polymeric, lipid, hybrid and inorganic nanocarriers); complex device construction and/or handling; drug-carrier detachment; not suitable for young children or breath-dependent patients, as they might not have sufficient inspiratory volume to stimulate the powder dispersion.
  • the present invention proposes a solution to some of the technical problems mentioned above, by means of a novel method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material, especially, from micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
  • a first object of the present invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol of a dry-powered biocompatible material, wherein said method comprise the operation of an aerosol generator device comprising: a gas reservoir, adapted for storing a compressed gas at a pressure P1 ; a receptacle connected to the gas reservoir through a first shut-off valve, wherein said receptacle is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber connected to the first outlet means and pressurized at a pressure P2, wherein said aerosol distribution chamber comprises second outlet means;
  • said method comprises performing the following steps: a) introducing a dry-powered biocompatible material into the receptacle; b) introducing a gas flow into the gas reservoir; c) comprising and storing said gas in the gas reservoir at a pressure P1; d) releasing the compressed gas from the gas reservoir into the receptacle by opening the first shut-off valve for a period of time lower than 1.5 seconds, generating an aerosol of said material and causing said aerosol to reach the aerosol distribution chamber through the first outlet means; e) storing the aerosol in the aerosol distribution chamber at a pressure P2, maintaining a pressure ratio P1/P2 between 1.2 and 8; and, f) releasing the aerosol stored in the pressurized aerosol distribution chamber through the second outlet means.
  • inhalable micro- or nanoparticulate aerosol will be understood as an aerosol containing monodisperse particles with a diameter lower than 5 pm, preferably lower than 1 pm, and more preferably, lower than 100 nm.
  • the dry-powered biocompatible material introduced into the receptacle in step a) comprises micro- or nanoparticles of a polymer- based biocompatible material, of an active ingredient, or any combination thereof.
  • said method further comprises a step of connecting the second outlet means to: an inhaler device, preferably, to a face mask and, more preferably, to a Venturitype mask, before step f); or to an aerosol container, including a bag, a spray can, a bottle, or any other option technically possible, before step f).
  • an inhaler device preferably, to a face mask and, more preferably, to a Venturitype mask, before step f
  • an aerosol container including a bag, a spray can, a bottle, or any other option technically possible, before step f).
  • said method comprises performing step f) continuously.
  • “continuously” will be understood as without a pause or interruption for at least 5 minutes.
  • said method comprises an additional step of arranging the first outlet means at least partially inside the aerosol distribution chamber before step a).
  • the gas introduced into the gas reservoir in step b) comprises air.
  • the method comprises repeating steps a) to d) at least once to obtain an aerosol with higher particle concentration.
  • the method further comprises: filtering or drying the gas entering and/or exiting the gas reservoir and/or the aerosol distribution chamber; and/or monitoring the properties of the gas entering the gas reservoir and/or the aerosol entering the aerosol distribution chamber; and/or monitoring the properties of the aerosol exiting the aerosol distribution chamber.
  • said method further comprises the following steps: closing a second shut-off valve arranged between the receptacle and the aerosol distribution chamber before step a); and, opening said second shut-off valve after completing step a).
  • a second object of the invention relates to the use of an aerosol generator device, wherein said aerosol generator device comprises: a gas reservoir, adapted for storing a compressed gas at a pressure P1 ; a receptacle connected to the gas reservoir through a first shut-off valve, wherein said receptacle is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber connected to the first outlet means and pressurized at a pressure P2, wherein said aerosol distribution chamber comprises second outlet means; for the micro- or nanoparticulate dispersion of a dry-powered biocompatible material in a gas with a grade of dispersion of at least 95%.
  • said dry-powered biocompatible material comprises micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
  • Figure 1a shows a device for the generation of micro or nanoparticulate aerosols from dry- powdered biocompatible materials whose operation is included in the method of the present invention according to one of its preferred embodiments.
  • Figure 1b shows a detail view of the interior of the aerosol distribution chamber of the device.
  • Figure 1c shows another device design whose operation is included in the method of the present invention according to another of its preferred embodiments, wherein an aerosol container is connected to the second outlet means.
  • Figure 2 shows the results of generating an aerosol of ciprofloxacin-loaded chitosan nanoparticles (average size: 716.9 ⁇ 412.8 nm) following the method of the present invention in one of its preferred embodiments.
  • Figure 2a corresponds to a scanning electron microscopy (SEM) image of the sample before being aerosolized
  • Figures 2b and 2c after aerosolization following the method of the invention.
  • Figures 2d-2f show Transmission Electron Microscopy (TEM) ciprofloxacin-loaded chitosan nanoparticles after aerosolization.
  • Figure 2g shows the size distribution curve of the aerosol. The black curve represents the fitting of the experimental data according to a log-normal distribution.
  • Figure 3 shows the results of generating an aerosol of pure azithromycin microparticles (average size: 2.5 ⁇ 1.0 pm) following the method of the present invention in one of its preferred embodiments.
  • Figure 3a corresponds to a SEM image of the sample before being aerosolized
  • Figures 3b and 3c after aerosolization following the method of the invention.
  • Figures 3d-3f show TEM azithromycin nanoparticles after aerosolization.
  • Figure 3g shows the size distribution curve of the aerosol. The black curve represents the fitting of the experimental data according to a log-normal distribution.
  • Figure 4 shows the evolution of the concentration of particles with time in the generated aerosol from pure azithromycin microparticles following the method of the invention according to one of its preferred embodiments.
  • one object of the present invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol of a dry-powdered biocompatible material.
  • Said method comprises the operation of an aerosol generator device comprising: a gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) connected to the gas reservoir (1) through a first shut-off valve (3), wherein said receptacle (2) is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5) connected to the first outlet means (4) and pressurized at a pressure P2, wherein said aerosol distribution chamber (5) comprises second outlet means (6).
  • said method comprises performing the following steps: a) introducing a dry-powered biocompatible material into the receptacle (2), preferably, micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof (for example, active ingredient-loaded polymer-based biocompatible micro- or nanoparticles); b) introducing a gas flow into the gas reservoir (1), preferably an air flow; c) comprising and storing said gas in the gas reservoir (1) at a pressure P1; d) releasing the compressed gas from the gas reservoir (1) into the receptacle (2) by opening the first shut-off valve (3) for a period of time lower than 1.5 seconds, generating an aerosol of said material and causing said aerosol to reach the aerosol distribution chamber (5) through the first outlet means (4); e) storing the aerosol in the aerosol distribution chamber (5) at a pressure P2, maintaining a pressure ratio P1/P2 between 1.2 and 8; and, f) releasing the aerosol stored in the pressurized aerosol
  • the method of the invention is independent of patient’s inspiratory flow.
  • a continuous aerosol flow with a stable particle concentration and optimal particle size to reach the lower airways can be created.
  • particle size is lower than 1 pm, and more preferably, lower than 100 nm.
  • continuous aerosol flow will be understood as an aerosol flow produced following the method of the invention without a pause or interruption for at least 5 minutes.
  • the method of the invention allows the generation of controlled inhalable aerosol doses, either to be administered directly to a patient or to be stored in an aerosol container for later therapeutic uses.
  • the method of the invention further comprises a step of connecting the second outlet means (6) to an inhaler device (7), preferably, to a face mask and, more preferably, to a Venturi-type mask, before step f).
  • said method comprises an additional step of connecting the second outlet means (6) to an aerosol container (8) before step f).
  • the aerosol container (8) can comprise a bag, a spray can, a bottle, or any other option technically possible.
  • said method comprises an additional step of arranging the first outlet means (4) at least partially inside the aerosol distribution chamber (5) before step a) (Fig. 1b).
  • the first outlet means (4) and/or the second outlet means (6) can comprise an outlet hole, a nozzle, a pipe, or any other option technically possible.
  • the method comprises repeating steps a) to d) at least once to obtain an aerosol with higher particle concentration.
  • the method of the invention can comprise: filtering or drying the gas entering and/or exiting the gas reservoir (1) and/or the aerosol distribution chamber (5); and/or monitoring the properties of the gas entering the gas reservoir (1) and/or the aerosol entering the aerosol distribution chamber (5); and/or monitoring the properties of the aerosol exiting the aerosol distribution chamber (5).
  • said method further comprises the following steps: closing a second shut-off valve (3’) arranged between the receptacle (2) and the aerosol distribution chamber (5) before step a); and, opening said second shut-off valve (3’) after completing step a).
  • a second object of the invention relates to the use of an aerosol generator device, wherein said aerosol generator device comprises: a gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) connected to the gas reservoir (1) through a first shut-off valve (3), wherein said receptacle (2) is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5) connected to the first outlet means (4) and pressurized at a pressure P2, wherein said aerosol distribution chamber (5) comprises second outlet means (6); for the micro- or nanoparticulate dispersion of a dry-powered biocompatible material in a gas with a grade of dispersion of at least 95%.
  • said dry-powered biocompatible material comprises micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof. Examples of realization -based biocompatible material
  • This first example shows the result of the aerosolization of ciprofloxacin-loaded chitosan nanoparticles following the method of the invention.
  • a mass of 15 ⁇ 2 mg of ciprofloxacin- loaded chitosan nanoparticles (average size: 2.5 ⁇ 1.0 pm; Figure 3a) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 2 is maintained between the reservoir (1) and the aerosol distribution chamber (5).
  • a nozzle which comprises a main body with an inlet hole and an outlet hole is used as first outlet means (4), wherein said main body further comprises three cylindrical internal cavities connected to each other and substantially aligned along the longitudinal axis of the main body. The dimensions of said internal cavities are the following:
  • Inlet cavity diameter 12.7 mm; length 15 mm;
  • Outlet cavity diameter 1.6 mm; length 10 mm;
  • Passage cavity diameter 2 mm; length 5 mm.
  • Figures 2b and 2c shows ciprofloxacin-loaded chitosan nanoparticles after aerosolization and arranged on a polycarbonate filter by Scanning Electron Microscopy (SEM) and, in Figures 2d-2f, by Transmission Electron Microscopy (TEM) on a copper grid.
  • Figure 2g shows the particle size distribution of the aerosol obtained by means of an optical particle counter (two consecutive measurements were made, “Scan 1” and “Scan 2”, being the black curve the fitting of the experimental data according to a log-normal distribution).
  • the geometric mean diameter (GMD) is 29.7 ⁇ 1.8 nm. active ingredient
  • This second example shows the result of the aerosolization of pure azithromycin microparticles following the method of the invention.
  • a mass of 15 ⁇ 2 mg of azithromycin microparticles (average size: 2.5 ⁇ 1.0 pm; Figure 3a) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 2 is maintained between the reservoir (1) and the aerosol distribution chamber (5).
  • the same nozzle (4) as in Example 1 is used.
  • Figures 3b and 3c show SEM images of azithromycin particles after aerosolization arranged on a polycarbonate filter and, in Figures 3d-3f, TEM images on a copper grid.
  • the size distribution curve of the aerosol generated by this system is shown in Figure 3g, obtaining a GMD of 50.9 ⁇ 1.8 nm.
  • Example 3 Generation of a continuous nanoparticulate aerosol from a pure dry-powered active ingredient suitable to be administered through an inhaler device
  • This third example shows the generation of a continuous nanoparticulate aerosol from pure azithromycin with a high concentration of said drug following the method of the invention suitable to be administered through an inhaler device (7).
  • a mass of 20 mg of azithromycin microparticles (average size: 2.5 ⁇ 1.0 pm) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 5 is maintained between the reservoir (1) and the aerosol distribution chamber (5).
  • Example 4 Releasing of a nanoparticulate aerosol from a pure dry-powered active ingredient to an aerosol container
  • This forth example shows the generation of a nanoparticulate aerosol from pure azithromycin following the method of the invention, releasing said aerosol to an aerosol container (8) connected to the second outlet means (6) (Fig. 1c).
  • a mass of 15 mg of azithromycin microparticles (average size: 2.5 ⁇ 1.0 pm) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 5 is maintained between the reservoir (1) and the aerosol distribution chamber (5).
  • steps a) to d) are repeated three times.
  • the mean concentration of particles with a size between 0.3 - 10 pm was -1 ,690 #/cm 3 .

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Abstract

The present invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material, preferably, from micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof. The rapid actuation of the first shut-off valve together with the maintenance of the pressure ratio P1/P2 in the specified range allow increasing air turbulence and particle collisions, and thus enhances powder deagglomeration. Therefore, controlled inhalable aerosol doses as well as continuous aerosol flows with stable particle concentration and optimal particle size to reach the lower airways can be created independently of patient's inspiratory flow.

Description

DESCRIPTION
METHOD FOR GENERATING AN INHALABLE MICRO- OR NANOPARTICULATE AEROSOL FROM A DRY-POWDERED BIOCOMPATIBLE MATERIAL
FIELD OF THE INVENTION
The present invention lies within the technical field of aerosol generation technologies. More specifically, the invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material, especially, from micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
BACKGROUND OF THE INVENTION
Aerosol therapy is a technique for the administration of drugs or biocompatible substances in aerosol form by inhalation through nebulizers, metered dose inhalers (MDIs), or dry powder inhalers (DPIs), being “aerosol” understood as a suspension of solid micro/nanoparticles or liquid droplets in a gas, typically air. Aerosol therapy is commonly used in the treatment of various respiratory tract infections, such as pneumonia, and lung diseases (bronchitis, allergies, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, lung cancer, etc.), although it has also been effective as therapy against pain or diabetes. Among the drugs that can be supplied by this technique are antibiotics, antifungals, anti-inflammatories, antioxidants, antivirals, bronchodilators, corticosteroids, mucolytics and even vaccines.
The main advantages of aerosol therapy over oral or parenteral drug administration are greater drug bioavailability and the supply of a lower dose of active ingredient, which reduces the possibility of side effects. However, this requires not only a drug formulation suitable for being dispersed in aerosol form, but also user-friendly inhaler devices that produce stable monodisperse micro- or nanoparticulate aerosols over time and guarantee dose-reproducibility. It is generally accepted that a particle size range between 0.02 and 5 pm will allow pulmonary drug absorption [Smith, H (1994). Human respiratory tract model for radiological protection. ICRP Publ. 66],
In this context, the generation of inhalable aerosols from dry powder formulations remains a challenge. Among the main problems to be solved in DPIs are: production of short-lived, pulsed aerosols with highly polydisperse particle size distributions due to powder agglomerations; low flexibility regarding the nature of the powder formulations (until now, aerosolization has been limited to polymeric, lipid, hybrid and inorganic nanocarriers); complex device construction and/or handling; drug-carrier detachment; not suitable for young children or breath-dependent patients, as they might not have sufficient inspiratory volume to stimulate the powder dispersion.
The present invention proposes a solution to some of the technical problems mentioned above, by means of a novel method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material, especially, from micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
BRIEF DESCRIPTION OF THE INVENTION
A first object of the present invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol of a dry-powered biocompatible material, wherein said method comprise the operation of an aerosol generator device comprising: a gas reservoir, adapted for storing a compressed gas at a pressure P1 ; a receptacle connected to the gas reservoir through a first shut-off valve, wherein said receptacle is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber connected to the first outlet means and pressurized at a pressure P2, wherein said aerosol distribution chamber comprises second outlet means;
Advantageously in the invention, said method comprises performing the following steps: a) introducing a dry-powered biocompatible material into the receptacle; b) introducing a gas flow into the gas reservoir; c) comprising and storing said gas in the gas reservoir at a pressure P1; d) releasing the compressed gas from the gas reservoir into the receptacle by opening the first shut-off valve for a period of time lower than 1.5 seconds, generating an aerosol of said material and causing said aerosol to reach the aerosol distribution chamber through the first outlet means; e) storing the aerosol in the aerosol distribution chamber at a pressure P2, maintaining a pressure ratio P1/P2 between 1.2 and 8; and, f) releasing the aerosol stored in the pressurized aerosol distribution chamber through the second outlet means.
Within the scope of interpretation of the present invention, the expression “inhalable micro- or nanoparticulate aerosol” will be understood as an aerosol containing monodisperse particles with a diameter lower than 5 pm, preferably lower than 1 pm, and more preferably, lower than 100 nm.
In a preferred embodiment of the invention, the dry-powered biocompatible material introduced into the receptacle in step a) comprises micro- or nanoparticles of a polymer- based biocompatible material, of an active ingredient, or any combination thereof.
In another preferred embodiment of the invention, said method further comprises a step of connecting the second outlet means to: an inhaler device, preferably, to a face mask and, more preferably, to a Venturitype mask, before step f); or to an aerosol container, including a bag, a spray can, a bottle, or any other option technically possible, before step f).
In yet another preferred embodiment of the invention, said method comprises performing step f) continuously. Within the scope of interpretation of the present invention, “continuously” will be understood as without a pause or interruption for at least 5 minutes.
In yet another preferred embodiment of the invention, said method comprises an additional step of arranging the first outlet means at least partially inside the aerosol distribution chamber before step a).
In yet another preferred embodiment of the invention, the gas introduced into the gas reservoir in step b) comprises air. In yet another preferred embodiment of the invention, the method comprises repeating steps a) to d) at least once to obtain an aerosol with higher particle concentration.
In yet another preferred embodiment of the invention, the method further comprises: filtering or drying the gas entering and/or exiting the gas reservoir and/or the aerosol distribution chamber; and/or monitoring the properties of the gas entering the gas reservoir and/or the aerosol entering the aerosol distribution chamber; and/or monitoring the properties of the aerosol exiting the aerosol distribution chamber.
In yet another preferred embodiment of the invention, said method further comprises the following steps: closing a second shut-off valve arranged between the receptacle and the aerosol distribution chamber before step a); and, opening said second shut-off valve after completing step a).
This allows isolating the aerosol distribution chamber from the receptacle when the latter must be refilled, so that the aerosol stored in the aerosol distribution chamber can continue to be released through the second outlet means.
A second object of the invention relates to the use of an aerosol generator device, wherein said aerosol generator device comprises: a gas reservoir, adapted for storing a compressed gas at a pressure P1 ; a receptacle connected to the gas reservoir through a first shut-off valve, wherein said receptacle is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber connected to the first outlet means and pressurized at a pressure P2, wherein said aerosol distribution chamber comprises second outlet means; for the micro- or nanoparticulate dispersion of a dry-powered biocompatible material in a gas with a grade of dispersion of at least 95%. Preferably, said dry-powered biocompatible material comprises micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof. DESCRIPTION OF THE FIGURES
Figure 1a shows a device for the generation of micro or nanoparticulate aerosols from dry- powdered biocompatible materials whose operation is included in the method of the present invention according to one of its preferred embodiments. Figure 1b shows a detail view of the interior of the aerosol distribution chamber of the device. Figure 1c shows another device design whose operation is included in the method of the present invention according to another of its preferred embodiments, wherein an aerosol container is connected to the second outlet means.
Figure 2 shows the results of generating an aerosol of ciprofloxacin-loaded chitosan nanoparticles (average size: 716.9 ± 412.8 nm) following the method of the present invention in one of its preferred embodiments. Specifically, Figure 2a corresponds to a scanning electron microscopy (SEM) image of the sample before being aerosolized, and Figures 2b and 2c, after aerosolization following the method of the invention. Figures 2d-2f show Transmission Electron Microscopy (TEM) ciprofloxacin-loaded chitosan nanoparticles after aerosolization. Figure 2g shows the size distribution curve of the aerosol. The black curve represents the fitting of the experimental data according to a log-normal distribution.
Figure 3 shows the results of generating an aerosol of pure azithromycin microparticles (average size: 2.5 ± 1.0 pm) following the method of the present invention in one of its preferred embodiments. Specifically, Figure 3a corresponds to a SEM image of the sample before being aerosolized, and Figures 3b and 3c, after aerosolization following the method of the invention. Figures 3d-3f show TEM azithromycin nanoparticles after aerosolization. Figure 3g shows the size distribution curve of the aerosol. The black curve represents the fitting of the experimental data according to a log-normal distribution.
Figure 4 shows the evolution of the concentration of particles with time in the generated aerosol from pure azithromycin microparticles following the method of the invention according to one of its preferred embodiments.
NUMERICAL REFERENCES USED IN THE DRAWINGS
In order to provide a better understanding of the technical features of the invention, the referred Figures 1-4 are accompanied of a series of numerical references which, with an illustrative and non-limiting character, are hereby represented:
Figure imgf000007_0001
DETAILED DESCRIPTION OF THE INVENTION
As described in preceding paragraphs, one object of the present invention relates to a method for generating an inhalable micro- or nanoparticulate aerosol of a dry-powdered biocompatible material. Said method comprises the operation of an aerosol generator device comprising: a gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) connected to the gas reservoir (1) through a first shut-off valve (3), wherein said receptacle (2) is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5) connected to the first outlet means (4) and pressurized at a pressure P2, wherein said aerosol distribution chamber (5) comprises second outlet means (6).
Advantageously, said method comprises performing the following steps: a) introducing a dry-powered biocompatible material into the receptacle (2), preferably, micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof (for example, active ingredient-loaded polymer-based biocompatible micro- or nanoparticles); b) introducing a gas flow into the gas reservoir (1), preferably an air flow; c) comprising and storing said gas in the gas reservoir (1) at a pressure P1; d) releasing the compressed gas from the gas reservoir (1) into the receptacle (2) by opening the first shut-off valve (3) for a period of time lower than 1.5 seconds, generating an aerosol of said material and causing said aerosol to reach the aerosol distribution chamber (5) through the first outlet means (4); e) storing the aerosol in the aerosol distribution chamber (5) at a pressure P2, maintaining a pressure ratio P1/P2 between 1.2 and 8; and, f) releasing the aerosol stored in the pressurized aerosol distribution chamber (5) through the second outlet means (6).
The rapid actuation of the first shut-off valve (3) together with the maintenance of the pressure ratio P1/P2 between said interval allow increasing air turbulence and particle collisions, and thus enhances powder deagglomeration. This means that neither excipients nor nanocarriers are necessary. By overcoming this limitation, targeted therapy can be performed, even to alveoli.
The method of the invention is independent of patient’s inspiratory flow. A continuous aerosol flow with a stable particle concentration and optimal particle size to reach the lower airways can be created. Preferably, particle size is lower than 1 pm, and more preferably, lower than 100 nm. Within the scope of interpretation of the present invention, the expression “continuous aerosol flow” will be understood as an aerosol flow produced following the method of the invention without a pause or interruption for at least 5 minutes.
The method of the invention allows the generation of controlled inhalable aerosol doses, either to be administered directly to a patient or to be stored in an aerosol container for later therapeutic uses. In the first case, the method of the invention further comprises a step of connecting the second outlet means (6) to an inhaler device (7), preferably, to a face mask and, more preferably, to a Venturi-type mask, before step f). Alternatively, said method comprises an additional step of connecting the second outlet means (6) to an aerosol container (8) before step f). The aerosol container (8) can comprise a bag, a spray can, a bottle, or any other option technically possible.
In another preferred embodiment of the invention, said method comprises an additional step of arranging the first outlet means (4) at least partially inside the aerosol distribution chamber (5) before step a) (Fig. 1b).
In different realizations of the invention, the first outlet means (4) and/or the second outlet means (6) can comprise an outlet hole, a nozzle, a pipe, or any other option technically possible. In yet another preferred embodiment of the invention, the method comprises repeating steps a) to d) at least once to obtain an aerosol with higher particle concentration.
Additionally, the method of the invention can comprise: filtering or drying the gas entering and/or exiting the gas reservoir (1) and/or the aerosol distribution chamber (5); and/or monitoring the properties of the gas entering the gas reservoir (1) and/or the aerosol entering the aerosol distribution chamber (5); and/or monitoring the properties of the aerosol exiting the aerosol distribution chamber (5).
In yet another preferred embodiment of the invention, said method further comprises the following steps: closing a second shut-off valve (3’) arranged between the receptacle (2) and the aerosol distribution chamber (5) before step a); and, opening said second shut-off valve (3’) after completing step a).
This allows isolating the aerosol distribution chamber (5) from the receptacle (2) when the latter must be refilled, so that the aerosol stored in the aerosol distribution chamber (5) can continue to be released through the second outlet means (6).
A second object of the invention relates to the use of an aerosol generator device, wherein said aerosol generator device comprises: a gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) connected to the gas reservoir (1) through a first shut-off valve (3), wherein said receptacle (2) is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5) connected to the first outlet means (4) and pressurized at a pressure P2, wherein said aerosol distribution chamber (5) comprises second outlet means (6); for the micro- or nanoparticulate dispersion of a dry-powered biocompatible material in a gas with a grade of dispersion of at least 95%. Preferably, said dry-powered biocompatible material comprises micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof. Examples of realization
Figure imgf000010_0001
-based biocompatible material
This first example shows the result of the aerosolization of ciprofloxacin-loaded chitosan nanoparticles following the method of the invention. A mass of 15 ± 2 mg of ciprofloxacin- loaded chitosan nanoparticles (average size: 2.5 ± 1.0 pm; Figure 3a) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 2 is maintained between the reservoir (1) and the aerosol distribution chamber (5). A nozzle which comprises a main body with an inlet hole and an outlet hole is used as first outlet means (4), wherein said main body further comprises three cylindrical internal cavities connected to each other and substantially aligned along the longitudinal axis of the main body. The dimensions of said internal cavities are the following:
Inlet cavity: diameter 12.7 mm; length 15 mm;
Outlet cavity: diameter 1.6 mm; length 10 mm;
Passage cavity: diameter 2 mm; length 5 mm.
Figures 2b and 2c shows ciprofloxacin-loaded chitosan nanoparticles after aerosolization and arranged on a polycarbonate filter by Scanning Electron Microscopy (SEM) and, in Figures 2d-2f, by Transmission Electron Microscopy (TEM) on a copper grid. Figure 2g shows the particle size distribution of the aerosol obtained by means of an optical particle counter (two consecutive measurements were made, “Scan 1” and “Scan 2”, being the black curve the fitting of the experimental data according to a log-normal distribution). The geometric mean diameter (GMD) is 29.7 ± 1.8 nm.
Figure imgf000010_0002
active ingredient
This second example shows the result of the aerosolization of pure azithromycin microparticles following the method of the invention. A mass of 15 ± 2 mg of azithromycin microparticles (average size: 2.5 ± 1.0 pm; Figure 3a) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 2 is maintained between the reservoir (1) and the aerosol distribution chamber (5). The same nozzle (4) as in Example 1 is used.
Figures 3b and 3c show SEM images of azithromycin particles after aerosolization arranged on a polycarbonate filter and, in Figures 3d-3f, TEM images on a copper grid. The size distribution curve of the aerosol generated by this system is shown in Figure 3g, obtaining a GMD of 50.9 ± 1.8 nm.
Example 3: Generation of a continuous nanoparticulate aerosol from a pure dry-powered active ingredient suitable to be administered through an inhaler device
This third example shows the generation of a continuous nanoparticulate aerosol from pure azithromycin with a high concentration of said drug following the method of the invention suitable to be administered through an inhaler device (7).
A mass of 20 mg of azithromycin microparticles (average size: 2.5 ± 1.0 pm) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 5 is maintained between the reservoir (1) and the aerosol distribution chamber (5).
Two replications of this experiment were performed. In both cases, a continuous short-lived inhalable aerosol stream (~ 6 minutes) was obtained with a particle concentration of -55,000 #/cm3 and a particle size between 0.3 and 10 pm, which demonstrates the suitability of said aerosol to be administered through an inhaler device (7) (Fig. 4). The replicates of this test show the reproducibility of the method of the invention.
Example 4: Releasing of a nanoparticulate aerosol from a pure dry-powered active ingredient to an aerosol container
This forth example shows the generation of a nanoparticulate aerosol from pure azithromycin following the method of the invention, releasing said aerosol to an aerosol container (8) connected to the second outlet means (6) (Fig. 1c).
A mass of 15 mg of azithromycin microparticles (average size: 2.5 ± 1.0 pm) is introduced in the receptacle (2) and a pressure ratio P1/P2 of 5 is maintained between the reservoir (1) and the aerosol distribution chamber (5). To obtain a high concentration of particles inside the aerosol distribution chamber prior release to the aerosol container (8) and an aerosol volume representative of the mean volume of lung inhalation, steps a) to d) are repeated three times. The mean concentration of particles with a size between 0.3 - 10 pm was -1 ,690 #/cm3.

Claims

CLAIMS Method for generating an inhalable micro- or nanoparticulate aerosol of a dry-powered biocompatible material, said method comprising the operation of an aerosol generator device comprising: a gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) connected to the gas reservoir (1) through a first shut-off valve (3), wherein said receptacle (2) is adapted for receiving a micro- or nanoparticulate material and comprises first outlet means (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5) connected to the first outlet means (4) and pressurized at a pressure P2, wherein said aerosol distribution chamber (5) comprises second outlet means (6); wherein said method is characterized in that it comprises performing the following steps: a) introducing a dry-powered biocompatible material into the receptacle (2); b) introducing a gas flow into the gas reservoir (1); c) comprising and storing said gas in the gas reservoir (1) at a pressure P1 ; d) releasing the compressed gas from the gas reservoir (1) into the receptacle
(2) by opening the first shut-off valve
(3) for a period of time lower than 1.5 seconds, generating an aerosol of said material and causing said aerosol to reach the aerosol distribution chamber (5) through the first outlet means (4); e) storing the aerosol in the aerosol distribution chamber (5) at a pressure P2, maintaining a pressure ratio P1/P2 between 1.2 and 8; and, f) releasing the aerosol stored in the pressurized aerosol distribution chamber (5) through the second outlet means (6). Method according to the preceding claim, wherein the dry-powered biocompatible material introduced into the receptacle (2) in step a) comprises micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof. Method according to any of the preceding claims, further comprising a step of connecting the second outlet means (6) to an inhaler device (7) or to an aerosol container (8) before step f).
4. Method according to the preceding claim, wherein the inhaler device (7) comprises a face mask.
5. Method according to claim 3, wherein the aerosol container (8) comprises a bag, a spray can, a bottle, or any combination thereof.
6. Method according to any of the preceding claims, wherein step f) is performed continuously.
7. Method according to any of the preceding claims, wherein said method comprises an additional step of arranging the first outlet means (4) at least partially inside the aerosol distribution chamber (5) before step a).
8. Method according to any of the preceding claims, wherein the gas introduced into the reservoir (1) in step b) comprises air.
9. Method according to any of the preceding claims, wherein said method comprises repeating step a) to d) at least once.
10. Method according to any of the preceding claims, further comprising: filtering or drying the gas entering and/or exiting the compressed gas reservoir (1) and/or the aerosol distribution chamber (5); and/or monitoring the properties of the gas entering the compressed gas reservoir (1) and/or the aerosol entering the aerosol distribution chamber (5); and/or monitoring the properties of the aerosol exiting the aerosol distribution chamber (5).
11 . Method according to any of the preceding claims, further comprising: closing a second shut-off valve (3’) arranged between the receptacle and the aerosol distribution chamber before step a); and, opening said second shut-off valve (3’) after completing step a).
12. Use of an aerosol generator device, wherein said aerosol generator device comprises: a compressed gas reservoir (1), adapted for storing a compressed gas at a pressure P1 ; a receptacle (2) adapted for receiving a micro- or nanoparticulate material, wherein the receptacle (2) comprises an outlet hole or a nozzle (4) for releasing an aerosol of said micro- or nanoparticulate material; and, an aerosol distribution chamber (5), pressurized at a pressure P2 and connected to or containing the material receptacle (2); for the micro- or nanoparticulate dispersion of a dry-powered biocompatible material in a gas with a grade of dispersion of at least 95%. Use of an aerosol generator device according to the preceding claim for the dispersion of micro- or nanoparticles of a polymer-based biocompatible material, of an active ingredient, or any combination thereof.
PCT/EP2023/065952 2022-06-15 2023-06-14 Method for generating an inhalable micro- or nanoparticulate aerosol from a dry-powdered biocompatible material WO2023242262A1 (en)

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Citations (5)

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WO1997037708A1 (en) * 1996-04-09 1997-10-16 Vivorx Pharmaceuticals, Inc. Dry powder inhaler
US20040050966A1 (en) * 2000-09-25 2004-03-18 Piper Samuel David Shock wave aerosolization apparatus and method
WO2005060480A2 (en) * 2003-12-04 2005-07-07 Praxair Technology Inc. Portable gas operating inhaler
US20150122257A1 (en) * 2012-05-09 2015-05-07 Robert Gerhard Winkler Atomizer
WO2018213834A1 (en) * 2017-05-19 2018-11-22 Pneuma Respiratory, Inc. Dry powder delivery device and methods of use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037708A1 (en) * 1996-04-09 1997-10-16 Vivorx Pharmaceuticals, Inc. Dry powder inhaler
US20040050966A1 (en) * 2000-09-25 2004-03-18 Piper Samuel David Shock wave aerosolization apparatus and method
WO2005060480A2 (en) * 2003-12-04 2005-07-07 Praxair Technology Inc. Portable gas operating inhaler
US20150122257A1 (en) * 2012-05-09 2015-05-07 Robert Gerhard Winkler Atomizer
WO2018213834A1 (en) * 2017-05-19 2018-11-22 Pneuma Respiratory, Inc. Dry powder delivery device and methods of use

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