WO2020163416A1 - Devices and methods for tobramycin inhalation treatment - Google Patents

Devices and methods for tobramycin inhalation treatment Download PDF

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Publication number
WO2020163416A1
WO2020163416A1 PCT/US2020/016695 US2020016695W WO2020163416A1 WO 2020163416 A1 WO2020163416 A1 WO 2020163416A1 US 2020016695 W US2020016695 W US 2020016695W WO 2020163416 A1 WO2020163416 A1 WO 2020163416A1
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WIPO (PCT)
Prior art keywords
patient
tobramycin
composition
flow
mouthpiece
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Application number
PCT/US2020/016695
Other languages
French (fr)
Inventor
Jennifer MEERBURG
Eleni-Rosalina ANDRINOPOULOU
Aukje BOS
Hwain SHIN
Marcel VAN STRATEN
Kamal HAMED
Paul MASTORIDIS
Harm TIDDENS
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Mylan Inc
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Publication of WO2020163416A1 publication Critical patent/WO2020163416A1/en

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins

Definitions

  • kits and methods for administration of powdered or nebulized compositions and, in non-limiting embodiments or aspects, devices and methods for administration of powdered or nebulized tobramycin providing increased drug availability in small airways of the lungs.
  • Cystic fibrosis is an inherited disorder that causes significant damage of organ systems, including, notably, the respiratory system and the lungs. CF causes the normally thin layer of mucus in the lungs to become more viscous, which can cause blockage in lung airways. Critically, this altered lung environment makes it difficult for the body’s immune system to effectively clear pathogens, rendering the lungs hospitable for infections. In particular, individuals with CF become susceptible to chronic infections by Pseudomonas aeruginosa, which is the leading cause of morbidity and mortality in individuals with CF.
  • Aminoglycosides such as tobramycin
  • tobramycin are a class of potent bactericidal agents. Their main mechanism of action is on the bacterial ribosome, which in turn inhibits protein synthesis.
  • Inhaled (powder or nebulized solution) tobramycin is the treatment of choice for P. aeruginosa infections in individuals with CF.
  • delivery of sufficient levels e.g at or above the minimum inhibitory concentration (MIC) of tobramycin to the small airways, which is critical to effectively fight P. aeruginosa infections in individuals with CF, is inconsistent, and there is a lack of devices and methods in the field for improving such delivery.
  • a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis including the step of administering to a respiratory tract of the patient an effective amount of a nebulized composition including tobramycin, wherein the nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
  • Also provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis including the step of administering to a respiratory tract of the patient an effective amount of an aerosolized composition including tobramycin, wherein the aerosolized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
  • Also provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, including the step of administering to a respiratory tract of the patient an effective amount of a particulate composition including tobramycin, calcium chloride, and distearoyl phosphatidyl choline, wherein the particulate composition has a mass median diameter of 20 microns or less and a mass median aerodynamic diameter of 10 microns or less, wherein the particulate composition is administered to the patient at a flow rate of less than or equal to 80 liters per minute for at least three seconds, such that a concentration of tobramycin in at least one peripheral airway of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
  • kits including a handheld aerosolization apparatus having a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow; a mouthpiece having a perforated member and an aerosolized pharmaceutical formulation outlet, the mouthpiece being connectable to the housing to define a capsule chamber, the mouthpiece further having a shield which covers at least one air inlet, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and a puncturing mechanism disposed within the housing for creating one or more openings in the capsule; at least one blister pack including a plurality of capsules having a powdered composition including tobramycin therein; and instructions for the user to actuate the apparatus to release the powdered composition and to inhale the powdered composition at a rate of less than or equal to 80 liters per minute for at least three seconds.
  • kits including a plurality of ampules, each ampule of the plurality of ampules having a solution of tobramycin and saline therein; and instructions that instruct a user to nebulize the solution with a nebulizer; and inhale, through a mouthpiece of the nebulizer, the nebulized solution at a rate of 15 liters per minute for at least three seconds.
  • Also provided herein is a method of training a patient to self-administer an aerosolized or nebulized composition including tobramycin, the method including the steps of: providing an aerosolization apparatus or a nebulizer, having a flow sensor; measuring, with the flow sensor, flow through the aerosolization apparatus or nebulizer during an inhalation phase of the patient’s respiration to obtain a measured flow value; comparing the measured flow value to a target flow value; and providing feedback to the patient when the measured flow value exceeds the target flow value.
  • Clause 1 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of a nebulized composition comprising tobramycin, wherein the nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
  • Clause 2 The method of clause 1, wherein the nebulized composition comprises tobramycin and saline.
  • Clause 3 The method of clause 1 or clause 2, wherein the nebulized composition is administered to the patient at a flow rate of 15 liters per minute.
  • Clause 4 The method of any of clauses 1-3, wherein the nebulized composition is administered to the patient for at least four seconds.
  • Clause 5 The method of any of clauses 1-4, wherein at least about 5 milliliters of the nebulized composition is delivered to the patient’s respiratory tract.
  • Clause 6 The method of any of clauses 1-5, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
  • Clause 7 The method of any of clauses 1-6, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 1000 micrograms per milliliter.
  • Clause 8 The method of any of clauses 1-7, wherein the nebulized composition includes tobramycin particles having a mass median diameter of 20 microns or less.
  • Clause 9 The method of any of clauses 1-8, wherein the nebulized composition includes tobramycin particles having a mass median aerodynamic diameter of 10 microns or less.
  • Clause 10 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of any of clauses 1-9.
  • Clause 11 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of an aerosolized composition comprising tobramycin, wherein the aerosolized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
  • Clause 12 The method of clause 11, wherein the aerosolized composition is administered to the patient at a flow rate of 80 liters per minute or less.
  • Clause 13 The method of clause 11 or clause 12, wherein the aerosolized composition is administered to the patient for at least four seconds.
  • Clause 14 The method of any of clauses 11-13, wherein at least about 5 milliliters of the aerosolized composition is delivered to the patient’s respiratory tract.
  • Clause 15 The method of any of clauses 11-14, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
  • Clause 16 The method of any of clauses 11-15, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
  • Clause 17 The method of any of clauses 11-16, wherein the aerosolized composition includes particulate tobramycin having a mass median diameter of 20 microns or less.
  • Clause 18 The method of any of clauses 11-17, wherein the aerosolized composition includes particulate tobramycin having a mass median aerodynamic diameter of 10 microns or less.
  • Clause 19 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of any of clauses 11-18.
  • Clause 20 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of a particulate composition comprising tobramycin, calcium chloride, and distearoyl phosphatidyl choline, wherein the particulate composition has a mass median diameter of 20 microns or less and a mass median aerodynamic diameter of 10 microns or less, wherein the particulate composition is administered to the patient at a flow rate of less than or equal to 80 liters per minute for at least three seconds, such that a concentration of tobramycin in at least one peripheral airway of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
  • Clause 21 A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of
  • a kit comprising: a handheld aerosolization apparatus comprising: a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow; a mouthpiece comprising a perforated member and an aerosolized pharmaceutical formulation outlet, the mouthpiece being connectable to the housing to define a capsule chamber, the mouthpiece further comprising a shield which covers at least one air inlet, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and a puncturing mechanism disposed within the housing for creating one or more openings in the capsule; at least one blister pack comprising: a plurality of capsules comprising a powdered composition comprising tobramycin; and instructions for the user to actuate the apparatus to release the powdered composition and to inhale the powdered composition at a rate of less than or equal to 80 liters per minute for at least three seconds.
  • Clause 23 The kit of clause 22, wherein the mouthpiece of the apparatus is configured to limit a flow therethrough to 80 liters per minute or less.
  • Clause 24 The kit of clause 22 or clause 23, wherein the handheld aerosolization apparatus further comprises a flow sensor configured to measure flow through the mouthpiece.
  • a kit comprising: a plurality of ampules, each ampule of the plurality of ampules comprising a solution comprising tobramycin and saline; and instructions that instruct a user to: nebulize the solution with a nebulizer; and inhale, through a mouthpiece of the nebulizer, the nebulized solution at a rate of 15 liters per minute for at least three seconds.
  • Clause 26 The kit of clause 25, further comprising a nebulizer comprising: a housing having a proximal end, a distal end, and a sidewall therebetween defining a lumen, the lumen configured to receive the solution; a compressed gas inlet at the proximal end of the housing; a cap assembly configured to be removably connected to the distal end of the housing, the cap assembly comprising a cap and a stem extending from the cap and configured to be received in the lumen; an outlet comprising an opening in the sidewall; and a mouthpiece configured to be removably connected to the outlet.
  • a nebulizer comprising: a housing having a proximal end, a distal end, and a sidewall therebetween defining a lumen, the lumen configured to receive the solution; a compressed gas inlet at the proximal end of the housing; a cap assembly configured to be removably connected to the distal end of the housing, the cap assembly comprising a cap
  • Clause 27 The kit of claim clause 25 or clause 26, wherein the mouthpiece is configured to limit a flow therethrough to 15 liters per minute.
  • Clause 28 The kit of any of clauses 25-27, wherein the nebulizer further comprises a flow sensor configured to measure flow through the mouthpiece.
  • Clause 29 A method of training a patient to self-administer an aerosolized or nebulized composition comprising tobramycin, the method comprising the steps of: providing an aerosolization apparatus or a nebulizer, comprising a flow sensor; measuring, with the flow sensor, flow through the aerosolization apparatus or the nebulizer during an inhalation phase of the patient’ s respiration to obtain a measured flow value; comparing the measured flow value to a target flow value; and providing feedback to the patient when the measured flow value exceeds the target flow value.
  • Clause 30 The method of clause 29, wherein the target flow value is 100 liters per minute.
  • Clause 31 The method of clause 29 or clause 30, wherein the target flow value is 80 liters per minute.
  • Clause 32 The method of any of clauses 29-30, wherein the target flow value is 15 liters per minute.
  • Figures 1A-1E are schematic side views (FIGS. 1A-1D) and a cross-sectional view (FIG. IE) of an aerosolization device according to non-limiting embodiments or aspects;
  • Figures 2A and 2B are schematic side views of a nebulizer according to non-limiting embodiments or aspects
  • FIG. 3 is an overview of how the flows of the three groups (child, adult female, and adult male) were applied on computed tomography (CT) models.
  • CT computed tomography
  • TIP tobramycin inhalation powder
  • TIS mean inhalation of tobramycin inhalation solution
  • Every flow was used as input on three different CT models, resulting in a total of 144 simulations with computational fluid dynamics (CDM) modeling;
  • Figures 4A-4C show inspiratory flow curves for uninstructed (FIG. 4A), instructed fast (FIG. 4B), and instructed slow (FIG. 4C) inhalations.
  • Figure 5 shows three-dimensional airway models constructed from computed tomography (CT) scans of a child (upper row), adult female (middle row), and adult male (lower row).
  • CT computed tomography
  • TIP tobramycin inhalation powder
  • TIS tobramycin inhalation solution
  • Colors represent tobramycin concentration in pg/mL (White is the highest possible concentration, whereas dark blue represents the lowest concentration);
  • Figures 6A and 6B are box-and-whisker plots of the concentration of tobramycin in pg/mL in the large airways (FIG. 6A) and in the small airways (FIG. 6B).
  • the x-axis represents the flow types (uninstructed TIP, instructed fast TIP, instructed slow TIP, and TIS inhalation).
  • the bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile.
  • the whiskers represent either 1.5 times the 25th or 75th percentile value, or the minimum and maximum values.
  • the circles outside of the T-bars are outliers.
  • the dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL).
  • * p ⁇ 0.05 using generalized estimating equation models;
  • Figure 7 is a box-and-whisker plot of the concentration of tobramycin in pg/mL in the extrathoracic and central airways (dark versus light box).
  • the x-axis represents the flow types (uninstructed TIP, instructed fast TIP, instructed slow TIP, and TIS inhalation).
  • the bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile.
  • the whiskers represent either 1.5 times the 25th or 75th percentile value, or the minimum and maximum values.
  • the circles outside of the T-bars are outliers.
  • the dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL).
  • * p ⁇ 0.05 using generalized estimating equation models; and
  • Figures 8A-8D are box-and-whisker plots of the concentration of tobramycin in pg/mL per lung lobe for TIP in the large and small airways (FIGS. 8A-8B) and for TIS in the large and small airways (FIGS. 8C-8D).
  • the x-axis represents different lung lobes.
  • the bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile.
  • the whiskers represent either 1.5 times the 25th or 75th percentile value or the minimum and maximum values.
  • the circles outside of the T-bars are outliers.
  • the dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL)
  • the term“patient” is any mammal, including humans, and a“human patient” is any human.
  • the term“small airways” of the lungs refers to one or more peripheral airways of the lung.
  • “small airways” of the lungs refers to airways having a diameter of less than or equal to 1-2 mm.
  • the infection is an infection in the lungs caused by Pseudomonas aeruginosa.
  • the infection is a chronic P. aeruginosa infection.
  • the patient is a patient that has cystic fibrosis.
  • the antibiotic is an aminoglycoside antibiotic.
  • the antibiotic is tobramycin (0-3-amino-3-deoxy-a-D- glucopyranosyl-(l-4)-0-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(l-6)]-2- deoxy-L-streptamine).
  • the antibiotic is administered to the lungs of the patient.
  • the antibiotic is administered to the small airways of the lungs.
  • Aminoglycoside antibiotics such as tobramycin
  • FIGS. 1A-1E show schematic (FIGS. 1A-1D) and cross-sectional (FIG. IE) views of a device for delivery of a powdered composition by aerosolization.
  • FIGS. 2A and 2B show schematic views of a device for delivery of a solution by nebulization. The devices useful for the various administration regimens will be discussed in turn with the respective methods.
  • FIGS. 1A-1E shown are schematic (FIGS. 1A-1D) and cross- sectional (FIG. IE) views of a non-limiting embodiment or aspect of a device 100 for delivery of an aerosolized powdered composition of an antibiotic, such as tobramycin, to the respiratory tract of a patient.
  • an antibiotic such as tobramycin
  • FIGS. 1A-1E shown are schematic (FIGS. 1A-1D) and cross- sectional (FIG. IE) views of a non-limiting embodiment or aspect of a device 100 for delivery of an aerosolized powdered composition of an antibiotic, such as tobramycin, to the respiratory tract of a patient.
  • an antibiotic such as tobramycin
  • Device 100 can include housing 105, including housing body 205, having sidewalls 165 defining a chamber 110 having one or more air inlets 115 and one or more air outlets 120 arranged between one or more partitions 150.
  • one or more inlets 115 are at least two air inlets.
  • one or more air outlets 120 include at least one outlet through which an aerosolized composition can pass.
  • Chamber 110 can be sized to receive one or more capsules 125 containing an aerosolizable composition, such as tobramycin.
  • air inlets 115, chamber 110, and/or partitions 150 are configured and/or dimensioned to create a swirling airflow within chamber 110.
  • swirling airflow provides sufficient force to release a powdered composition from capsule 125, optionally without the need for a puncturing mechanism.
  • Non- limiting embodiments or aspects including a puncturing mechanism are described below with reference to FIG. IE.
  • mouthpiece 140 can be provided near one or more outlets 120. Mouthpiece 140 may be sized and shaped to be received in a patient's mouth or nose so that the patient may inhale the aerosolizable composition through opening 145 in mouthpiece 140 that is in communication with one or more outlets 120. In non-limiting embodiments or aspects, air flowing through one or more inlets 115 enters chamber 110, aerosolizes the composition, which flows through one or more outlets 120 and opening 145 in mouthpiece 140 to be delivered to the patient’s respiratory tract during inhalation.
  • air or another gas e.g., from a source of compressed air
  • inlets 115 to aerosolize the composition.
  • mouthpiece 140 includes at least one perforated member.
  • device 100 can include an air inlet shield 170 to prevent a patient from covering one or more air inlets 115 (e.g., with a finger or other portion of the patient’s hand) during an inhalation procedure.
  • Air inlet shield 170 can include covering portion 175.
  • mouthpiece 140 can include endpiece 210, which may be removed from housing 105 to allow a patient to insert a capsule 125 in the chamber 110 which is formed when housing 105 and the mouthpiece 140 are connected together.
  • device 100 including endpiece 210 and air inlet shielding member 170, includes a plurality of covering portions 175 (only one shown in the view of FIG. IB) and two open portions 180 between covering portions 175.
  • covering portions 175 are diametrically opposed about air inlet shielding member 170.
  • air inlet shielding member 170 includes three, four, or more covering portions 175 separated by open portions 180
  • the patient grasps device 100 by contacting the covering portions 175 and would, therefore, not block one or more air inlets 115.
  • space is provided between covering portion 175 and the outer surface of one or more inlets 115 under covering portion 175 in order to create a manifold airflow portion below covering portion 175.
  • FIGS. 1C-1D Non-limiting embodiments or aspects of device 100 including endpiece 210 and air inlet shielding member 170 are shown in FIGS. 1C-1D. These illustrated non-limiting embodiments or aspects include different arrangements for covering portions 175 and open portions 180 associated with air inlet shielding member 170.
  • a series of longitudinal open portions 180 is provided in the non-limiting embodiment or aspect shown in FIG. 1C.
  • one or more circumferentially extending open portions 180 are provided.
  • an open portion 180 can also extend circumferentially around base 185 of and under endpiece 210
  • capsule 125 can be punctured by puncture mechanism 250.
  • puncture mechanism 250 includes an actuatable plunger 255 connected to or engageable at a distal end thereof with puncture member 265.
  • Puncturing mechanism 250 can further include a seating member 280 which contacts plunger 255 and/or puncture member 265 and is slidable relative to plunger 255 and puncture member 265.
  • a user applies a force to plunger 255 (e.g., by pressing against an end surface 290 of plunger 255 with a finger or thumb). The force causes plunger 255 to slide within housing body 205.
  • a frictional contact between plunger 255 and a rear section 295 of seating member 280 causes seating member 280 to slide within housing body 205 of housing 105 until a forward seating surface 300 of seating member 280 contacts capsule 125.
  • Forward seating surface 300 which may be shaped to generally match the shape of capsule 125, secures capsule 125 between seating member 280 and partition 150.
  • force e.g., by removing a finger or thumb
  • biasing member e.g., spring
  • biasing member 310 urges puncturing mechanism 250 back to a rest position.
  • biasing member 310 may contact a shoulder 315 in housing body 205 and press a flange 320 on plunger 255 toward a rim 325 in housing body 205. Frictional engagement between plunger 255 and seating member 280 can also return seating member 280 to its retracted position when the plunger is returned to its retracted position.
  • Devices as illustrated in FIGS. 1A-1E can be used in a method of treating a P. aeruginosa infection in a patient having cystic fibrosis (CF). Accordingly, also provided herein are methods of treating a P. aeruginosa infection in the lungs of a patient with CF.
  • the method can include the step of administering an effective amount of an aerosolized composition including tobramycin to the respiratory tract of the patient at a flow rate of less than or equal to about 100 1pm, and/or for at least three seconds.
  • the term“effective amount” means at least the minimum effective concentration (MIC) of tobramycin for P. aeruginosa. In non-limiting embodiments or aspects, the MIC of tobramycin for P. aeruginosa is about 4 pg/mL.
  • Compositions including tobramycin as described herein can include one or more pharmaceutically-acceptable carriers or excipients.
  • the term“pharmaceutically-acceptable carrier or excipient” means an inactive substance that serves as a vehicle or medium for an active substance (e.g., tobramycin) and that can be introduced into the respiratory tract of a patient without significant toxicological effects. Suitable excipients for use in aerosolized compositions are known to those of skill in the art.
  • the composition includes tobramycin and calcium chloride and/or distearoyl phosphatidyl choline.
  • a device 100 suitable for administration of an aerosolized composition including tobramycin to the respiratory tract of the patient can be modified to limit air flow, for example by limiting air flow through one or more inlets 115, through one or more outlets 120, and/or through opening 145 in mouthpiece 140.
  • one or more inlets 115 are narrowed or obstructed to decrease the volume of air that can be introduced into chamber 110.
  • one or more outlets 120 and/or opening 145 in mouthpiece 140 is narrowed or obstructed to decrease the volume of air that can be withdrawn from chamber 110 and introduced into the patient’s respiratory tract.
  • mechanisms suitable for reducing airflow include use of porous membranes to cover inlets, outlets, and/or openings, reducing the number of openings (e.g., by blocking one or more inlets, outlets, and/or openings), venturis, and/or valves.
  • the aerosolized composition is administered to the respiratory tract of the patient at a flow rate of less than or equal to 80 1pm. In non limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract for at least four seconds.
  • device 100 can include a sensor for measuring flow through one or more outlets 120 and/or mouthpiece 140.
  • Suitable flow sensors are known to those of ordinary skill in the art, and include sensors that measure volume and/or mass, and include, without limitation, thermo-anemometer sensors, vane sensors, hot wire sensors, cold wire sensors, laminar flow sensors, and solid state sensors. Those of skill in the art will appreciate that suitable sensors are available commercially, for example, from Honeywell International, Inc. (Charlotte, NC, USA). Suitable flow sensors can be disposed within the device, e.g., in or adjacent to one or more outlets 120 and/or mouthpiece 140. For example, as shown in FIG.
  • a flow sensor 122 can be disposed in or adjacent to one or more outlets 120, to measure flow through one or more outlets 120.
  • a flow sensor may be disposed outside of device 100.
  • a flow sensor may be an external device that is attached to housing 105 and/or mouthpiece 140, between mouthpiece 140 and housing 105, and/or between mouthpiece 140 and a patient’s mouth.
  • a flow sensor can include one or more processors, memory storing programming instructions and/or a database of acceptable flow values, and/or one or more indicators (e.g., visual, audible, or tactile indicators).
  • a flow sensor useful with device 100 described herein can measure flow through one or more outlets 120 and/or mouthpiece 140.
  • a processor associated with the flow sensors can compare the measured flow value to one or more acceptable flow values stored in a memory associated with the flow sensor, and, if the measured flow differs from an acceptable flow value, the programming instructions, when executed by the processors, can cause the processor to instruct the indicator to alert a patient to either increase or decrease flow through one or more outlets 120 and/or mouthpiece 140 (e.g., by increasing or decreasing inhalation).
  • the processor causes the measured flow value to be stored in memory.
  • the patient and/or another individual can later access the measured value to determine whether the patient correctly utilized device 100, via communication between the sensor and a computing device (e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.) through a Universal Serial Bus connection, BLUETOOTH connection, or other wired or wireless connections known to those of skill in the art.
  • a computing device e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.
  • BLUETOOTH connection e.g., BLUETOOTH connection
  • a capsule 125 suitable for use in a device 100 as described herein can, in non-limiting embodiments or aspects, contain about 28 mg of a powdered, aerosolizable composition. In non-limiting embodiments or aspects, at least about 5 mL of aerosolized composition is delivered to the patient’s respiratory tract.
  • a MIC of tobramycin for P. aeruginosa can be about 4 pg/mL.
  • the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs during and/or following administration is at least about lOx MIC (e.g., at least about 40 pg/mL).
  • the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs during and/or following administration is at least about 50x MIC (e.g., at least about 200 pg/mL).
  • Characteristics of powdered, aerosolizable tobramycin compositions are provided in, for example, U.S. Patent No. 7,368,102, incorporated herein by reference in its entirety. Characteristics of tobramycin powder include geometric diameter, mass median diameter, and mass median aerodynamic diameter.
  • geometric diameter means a measure of geometric particle size, which can be determined using a laser diffraction analyzer.
  • mass median diameter means a measure of mean particle size of polydisperse particles, which can be determined by centrifugal sedimentation.
  • the term“mass median aerodynamic diameter” means a measure of the aerodynamic size of a dispersed particle.
  • the aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle.
  • the aerodynamic diameter encompasses particle shape, density, and physical size of a particle.
  • “mass median aerodynamic diameter” refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by Anderson cascade impaction.
  • the aerosolized composition delivered as described herein includes particulate tobramycin having a mass median diameter of about 20 microns or less. In non-limiting embodiments or aspects, the aerosolized composition delivered as described herein includes particulate tobramycin having a mass median aerodynamic diameter of about 10 microns or less.
  • the methods described herein for treating a P. aeruginosa infection in an individual having cystic fibrosis can be prescribed by a physician. Accordingly, provided herein is a method of treating a P. aeruginosa infection in a patient having cystic fibrosis including the step of prescribing to a patient a treatment regimen including administration of an aerosolized composition including tobramycin to the patient’s respiratory tract as described herein.
  • FIGS. 2A and 2B shown are schematic views of a non-limiting embodiment or aspect of a device 300 for delivery of a nebulized solution of an antibiotic, such as tobramycin, to the respiratory tract of a patient.
  • Device 300 can include housing 310 having a proximal end 320, a distal end 330, and sidewalls 325 therebetween defining a lumen (not shown) configured to hold a nebulizable solution, such as a solution of tobramycin.
  • lumen is defined by sidewalls 325 and proximal end 320 and is in the form of a nebulizer cup.
  • Device 300 can further include a cap assembly 340 including a nebulizer top 350 and valve cap 360.
  • Nebulizer top 350 can be reversibly engaged (e.g., by threaded interaction) with the distal end of housing 310.
  • Valve cap 360 can be reversibly engaged (e.g., by press or friction fit) with nebulizer top 350.
  • Nebulizer top 350 can include a stem 355.
  • Stem 355 can be arranged to reside within housing 310 lumen when the nebulizer top 350 is engaged with the distal end 330 of housing 310.
  • Device housing 310 can further include an outlet 370 in the sidewall 325. In non limiting embodiments or aspects, outlet 370 is arranged near distal end 330 of housing 310.
  • Device 300 can further include a mouthpiece 380. Mouthpiece 380 may be sized and shaped to be received in a patient's mouth so that the patient may inhale the aerosolizable composition through an opening in mouthpiece 380 that is in communication with outlet 370.
  • Device housing 310 can further include, at proximal end 320 thereof, air inlet 322. Air inlet 322 may be configured to be in communication with a source of air 400, e.g., a source of compressed air or a source of forced air. Source of air 400 drives the nebulizer, causing the solution within the lumen to be nebulized and delivered, via the mouthpiece 380, to the respiratory tract of a patient.
  • a source of air 400 e.g., a source of compressed air or a source of forced air.
  • Devices as illustrated in FIGS. 2A and 2B can be used in a method of treating a P. aeruginosa infection in a patient having cystic fibrosis.
  • the method can include the step of administering an effective amount of a nebulized composition including tobramycin to the respiratory tract of the patient at a flow rate of less than or equal to about 100 1pm and/or for at least three seconds.
  • a nebulized composition means to disperse a liquid composition in a mist of fine particles.
  • the effective amount e.g., at least MIC, at least lOx MIC, or at least 50x MIC of tobramycin is described elsewhere herein.
  • compositions including tobramycin as described herein can include one or more pharmaceutically-acceptable carriers or excipients. Suitable excipients for use in nebulized compositions are known to those of skill in the art. In non-limiting embodiments or aspects, the composition includes tobramycin and saline.
  • a device 300 suitable for administration of an aerosolized composition including tobramycin to the respiratory tract of the patient can be modified to limit air flow, for example by limiting air flow through inlet 322, through outlet 370, and/or through opening in mouthpiece 380.
  • Non-limiting examples of mechanisms suitable for reducing flow include use of porous membranes to cover inlets, outlets, and/or openings, reducing the number of openings (e.g., by blocking one or more inlets, outlets, and/or openings), venturis, and/or valves.
  • the aerosolized composition is administered to the respiratory tract of the patient at a flow rate of less than or equal to about 15 1pm. In non-limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract for at least four seconds.
  • device 300 can include a sensor for measuring flow through outlet 370 and/or mouthpiece 380.
  • Suitable flow sensors are known to those of ordinary skill in the art, and include sensors that measure volume and/or mass, and include, without limitation, thermo-anemometer sensors, vane sensors, hot wire sensors, cold wire sensors, laminar flow sensors, and solid state sensors. Those of skill in the art will appreciate that suitable sensors are available commercially, for example from Honeywell International, Inc. (Charlotte, NC, USA). Suitable flow sensors can be disposed within the device, e.g., in or adjacent to outlet 370 and/or mouthpiece 380. For example, as shown in FIG.
  • a flow sensor 372 can be disposed in or adjacent to outlet 370, to measure flow through outlet 370.
  • a flow sensor may be disposed outside of device 300.
  • a flow sensor may be an external device that is attached to housing 310 and/or mouthpiece 380, between mouthpiece 380 and housing 310, and/or between mouthpiece 380 and a patient’s mouth.
  • a flow sensor can include one or more processors, memory storing programming instructions and/or a database of acceptable flow values, and/or one or more indicators (e.g., visual, audible, or tactile indicators).
  • a flow sensor useful with device 300 described herein can measure flow through outlet 370 and/or mouthpiece 380.
  • a processor associated with the flow sensors can compare the measured flow value to one or more acceptable flow values stored in a memory associated with the flow sensor, and, if the measured flow differs from an acceptable flow value, the programming instructions, when executed by the processors, can cause the processor to instruct the indicator to alert a patient to either increase or decrease flow through outlet 370 and/or mouthpiece 380 (e.g., by increasing or decreasing inhalation).
  • the processor causes the measured flow value to be stored in memory.
  • the patient and/or another individual can later access the measured value to determine whether the patient correctly utilized device 300, via communication between the sensor and a computing device (e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.) through a Universal Serial Bus connection, BLUETOOTH connection, or other wired or wireless connections known to those of skill in the art.
  • a computing device e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.
  • BLUETOOTH connection e.g., BLUETOOTH connection
  • An ampule suitable for use in a device 300 as described herein can, in non-limiting embodiments or aspects, contain about 5 mL of a nebulizable solution. In non-limiting embodiments or aspects, at least about 5 mL of a nebulized composition is delivered to the patient’s respiratory tract.
  • a MIC of tobramycin for treating P. aeruginosa can be about 4 pg/mL.
  • the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs is at least about lOx MIC (e.g., at least about 40 pg/mL).
  • the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs is at least about 250x MIC (e.g., at least about 1000 pg/mL).
  • Characteristics of a nebulizable tobramycin solution are provided in, for example, U.S. Patent No. 7,368,102, incorporated herein by reference in its entirety. Characteristics of tobramycin solution include characteristics of the tobramycin itself (e.g., geometric diameter, mass median diameter, and mass median aerodynamic diameter), and characteristics of the tobramycin solution (e.g., pH). In non-limiting embodiments or aspects, the nebulizable composition delivered by the methods described herein includes particulate tobramycin having a mass median diameter of about 20 microns or less.
  • the nebulizable composition delivered by the methods described herein includes particulate tobramycin having a mass median aerodynamic diameter of about 10 microns or less.
  • a solution useful in the devices and methods described herein has a pH of about 6.0 and a concentration of 300 mg of tobramycin (free base) in 5 mL of saline (e.g., sodium chloride solution).
  • the methods described herein for treating a P. aeruginosa infection in an individual having cystic fibrosis can be prescribed by a physician. Accordingly, provided herein is a method of treating a P. aeruginosa infection in a patient having cystic fibrosis including the step of prescribing to a patient a treatment regimen including administration of a nebulized composition including tobramycin to the patient’s respiratory tract as described herein.
  • the method includes providing a patient with an aerosolization apparatus or a nebulizer having a flow sensor.
  • the patient can be provided with only one component of an aerosolization apparatus or nebulizer, such as a mouthpiece.
  • the method can further include a step of measuring, with the flow sensor, flow through the aerosolization apparatus or the nebulizer (or component thereol) during an inhalation phase of the patient’s respiration to obtain a measured flow value.
  • the method can further include a step of comparing the measured flow value to a target flow value.
  • the comparison is performed by a processor associated with the flow sensor.
  • the comparison is between the measured flow value and a target flow value stored in memory, for example in a database.
  • the method can further include a step of providing feedback to the patient when the measured flow value exceeds the target flow value.
  • the feedback is visual, audible, and/or tactile, and can include, for example and without limitation, audible feedback (e.g., providing beeps or other audible cues at differing rates depending on whether the patient’s inspiration should increase or decrease, and/or a verbal instruction to slow down or speed up), visual feedback (e.g., providing flashes of light at differing rates depending on whether the patient’s inspiration should increase or decrease), and/or tactile feedback (e.g., providing tactile pulses that are delivered at differing rates depending on whether the patient’s inspiration should increase or decrease).
  • a processor associated with the flow sensor provides instructions to an indicator, such as an LED device, speaker, and/or haptic device, to provide the desired feedback.
  • kits including devices as described herein, for performing the methods described herein.
  • a kit can include a handheld aerosolization device as described herein and shown for example in FIGS. 1A-1E, one or more capsules (e.g., a blister pack containing one or more capsules) of powdered tobramycin suitable for use with an aerosolization device, and instructions for a patient to actuate the handheld aerosolization device such that the aerosolized composition is delivered to the patient’s respiratory tract at a rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 1pm).
  • the capsule can include tobramycin and one or more pharmaceutically-acceptable excipients.
  • the instructions instruct the patient to inhale the aerosolized composition at a rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 lpm).
  • the handheld aerosolization device is configured (e.g., as described herein) to deliver aerosolized tobramycin at a flow rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm).
  • a kit can include one or more ampules of tobramycin solution (e.g., tobramycin and saline) and instructions for a patient to nebulize the solution such that the nebulized solution is delivered to the patient’s respiratory tract at a rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm, e.g., less than or equal to about 15 lpm).
  • tobramycin solution e.g., tobramycin and saline
  • the instructions instruct the patient to inhale the nebulized solution at a rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm, e.g., less than or equal to about 15 lpm).
  • a kit as described herein can also include a nebulizer as described herein and shown for example in FIGS. 2A and 2B.
  • the nebulizer is configured (e.g., as described herein) to deliver nebulized tobramycin at a flow rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 1pm, e.g., less than or equal to about 15 1pm).
  • the present study is an in silico study based on computational fluid dynamics (CFD) simulations with use of flow profiles from an observational study.
  • CFD computational fluid dynamics
  • TIP tobramycin inhalation powder
  • TIS tobramycin inhalation solution
  • Inclusion criteria for the observational study were a diagnosis of CF, age of six years and above, and maintenance treatment with TIP for at least one month.
  • Exclusion criteria were pulmonary exacerbation defined as the need for intravenous antibiotics at the time of the inspiratory flow registrations, and inability to follow instructions. Both children and adults from four Dutch CF centers were included: Amsterdam University Medical Center, Erasmus Medical Center (Rotterdam), Haga Teaching Hospital (The Hague), and University Medical Center Utrecht.
  • the inspiratory flows during inhalation of tobramycin with the T-326 inhaler were recorded.
  • Three inhalation maneuvers for each patient were measured during two study visits: an uninstructed, an instructed fast, and an instructed slow inhalation.
  • the uninstructed inhalation was measured after patients were asked to inhale TIP in the way they would normally do.
  • the instructed fast and slow inhalation were measured as follows: patients were asked (in random order) to inhale one TIP capsule as fast as possible, and to inhale another TIP capsule as slow as possible, but with enough force to let the capsule rattle in the T-326 inhaler.
  • inspiratory flows were recorded while inhaling 0.9% saline with a Porta-neb® compressor and PARI LC Plus® nebulizer during the second home visit.
  • the inspiratory flows during nebulization were measured in four recordings, of 15 seconds each. From these four recordings a mean inhalation curve was computed. Expiratory flows were not recorded, but computed using the recorded inhaled volume and total time between inhalations.
  • CFD modeling was used to simulate aerosol deposition in 3D computer lung models. This method has been extensively described elsewhere (De Backer et al., “Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation.” J Biomech. 2008, Vol. 41, pp. 106-113; De Backer et al.,“Validation of computational fluid dynamics in CT-based airway models with SPECT/CT.” Radiology 2010, Vol. 257, pp. 854-862). In short, the flow dynamics within lung models are determined to predict the course and velocity of the particles after they are virtually inj ected into the model.
  • the central and large airways were reconstructed from the chest CT scans.
  • the central airways are defined as the area from the trachea up to the lobar bronchi.
  • the large airways often referred to in the literature as the distal airways, are defined as the airways from the first segmental bronchi to airways with a diameter of +/- 1-2 mm that are still visible on chest CT scan.
  • the extrathoracic airways defined as the mouth and throat, including the larynx, until the trachea, were reconstructed. Since these are not imaged on chest CT, a representative adult extrathoracic airway model was selected. The model was then scaled down such that both the anteroposterior and lateral dimension of the scaled model’s trachea at the location of the sternum matched the lung model.
  • CT scans had to meet the following technical requirements: volumetric, spirometer-controlled; availability of both inspiratory and expiratory scans; and a maximum slice thickness of 1 mm or smaller. Furthermore, CT scans had to match the TIP- TIS study population as close as possible based on age, height, and gender. For this purpose, the study patients were divided into three subpopulations: children, female adults, and male adults. Average height of each subpopulation was calculated. The height of the patients for which CT scans were used differed by a maximum of 5% from the average height of the corresponding subpopulation.
  • CT scans from the Sophia database were obtained from patients younger than 18 years.
  • CT scans from adolescents after they were fully grown were selected, as determined by a flattened individual growth curve.
  • the differentiation between mild, moderate, and severe disease was based on the combination of these subscores.
  • the scans in thedale database were divided according to the three subpopulations (children, female adults, and male adults).
  • all CT scans were ranked according to the outcomes of the PRAGMA-CF scores for percentage disease.
  • the lowest tertile was defined as mild, the middle tertile as moderate, and the upper tertile as severe disease.
  • one CT scan within each tertile was selected for each subpopulation, resulting in the selection of nine CT scans.
  • the selected CT scans were reviewed by a pediatric pulmonologist to evaluate whether the disease severity corresponded to severity group. This evaluation confirmed that the selection represented a good spread of disease severity for each of the three subpopulations.
  • MMAD mass median aerodynamic diameter
  • Particle characteristics were available for three flow rates: 40, 60, and 85 L/min.
  • the mean flow rate of each simulated inhalation was calculated, and the particle characteristics (aerodynamic particle size distribution) of the flow that was closest to this mean flow were selected.
  • a single inhalation maneuver was simulated and the deposited mass scaled to the total of four capsule inhalation. It was assumed that the complete capsule dose of TIP would be released after an inhaled volume of 1.2 liter.
  • Exhaled drug drug that left the model during expiration phase
  • drug released by the nebulizer during expiration was considered lost to the environment.
  • the exhalation time of an individual patient had a large impact on the total amount of lost drug.
  • tobramycin concentrations throughout the bronchial tree the surface area of each reconstructed airway and of all the combined small airways was calculated. Concentrations of tobramycin in pg/mL were computed for the extrathoracic and central airways and for each lung lobe, with distinction between the large and the small airways. To assess the deposition with CFD, the following assumptions were made: First, it was assumed that particles were deposited once they touched the airway walls. Second, it was assumed that particles that were delivered beyond the reconstructed airway model were distributed evenly over the small airway surface area (determined by the Phalen model as described above). Third, it was assumed the thickness of the airway surface liquid to be constant to compute concentrations.
  • the ratio of deposited drug mass and airway surface liquid volume of each lung region is defined as its averaged drug concentration. These concentrations were computed for three different scenarios: a moderate thin (3 pm), in between (5 pm), and a thick layer (7 pm) of airway surface liquid. For the concentrations of deposited drug presented in this Example, the airway surface liquid thickness was 7 pm (worst case scenario). Concentrations for the other lining fluid layer scenarios can easily be calculated by dividing the outcomes by 7 pm and multiplying them by 3 pm or 5 pm.
  • tobramycin concentration for effective inhibition of Pa growth
  • a starting point a MIC of 4 pg/mL as described by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) was selected.
  • EUCAST European Committee on Antimicrobial Susceptibility Testing
  • an effective conservative tobramycin concentration was defined as ten times MIC, e.g., 40 pg/mL, as there are many factors such as mucus binding and mucociliary clearance that may negatively affect the activity of tobramycin (Bos et al.“The fate of inhaled antibiotics after deposition in cystic fibrosis: How to get drug to the bug?” J. Cystic Fibres. 2017, Vol. 16, pp. 13-23).
  • FIGS. 4A-4C show the inspiratory flow curves of the uninstructed, instructed fast, and instructed slow TIP inhalations. All patients performed an instructed fast inhalation that was faster than the uninstructed inhalation. Similarly, the instructed slow inhalation for all patients was slower than the uninstructed inhalation. Except for two situations, all patients were able to inhale more than the minimum volume of 1.2 L needed to inhale the full content of the capsule. One patient inhaled only 0.5 L through the T-326 inhaler with the instructed fast inhalation, and another patient inhaled only 0.7 L with the uninstructed inhalation. For the modeling of this maneuver, the inhaled dose of TIP was adjusted to 42% and 58% respectively.
  • FIG. 5 illustrates the computed tobramycin concentrations throughout the bronchial tree for uninstructed, instructed fast and instructed slow inhalations of TIP and the TIS inhalations for three single study subjects and for three of the nine CT models.
  • FIGS. 6A and 6B the box-and-whisker plots summarize the computed tobramycin concentrations in the large and small airways of all simulations for each flow type and device.
  • Large airway concentrations were up to 100-fold greater compared to small airway concentrations, which is a result of the much smaller airway surface in the large airways compared to the small airways.
  • Median (interquartile range) concentrations were 73,597 (41,587 - 126,353) pg/mL in the large airways and 1,038 (719 - 1,500) pg/mL in the small airways.
  • FIG. 7 the concentrations of tobramycin in the extrathoracic and central airways are shown.
  • Median (interquartile range) tobramycin concentrations were 226,721 (159,044 - 368,656) pg/mL in the extrathoracic airways and 44,378 (23,142 - 65,819) pg/mL in the central airways.
  • TIS inhalations resulted in significantly reduced concentrations in the extrathoracic airways and in significantly greater central, large, and small airway concentrations when compared with all TIP inhalations (all p ⁇ 0.001), except for instructed slow TIP inhalations, which resulted in similar small airway concentrations as TIS.
  • FIGS. 8A-8D show the deposition of tobramycin per lung lobe in the large and small airways for both TIP and TIS.
  • the tobramycin concentrations in both the large and small airways in all lung lobes were all well above the cut-off value for effective inhibition of 40 pg/mL, assuming an airway surface liquid layer of 7 pm.
  • the tobramycin concentration was 128 pg/mL, which is still more than triple the amount of the effective threshold concentration of 40 pg/mL.
  • the highest local concentration of tobramycin in the small airways was found in the left lower lobe of an adult male after inhalation of TIS.
  • the tobramycin concentration was 5,656 pg/mL, which is 141- fold greater than the effective threshold concentration.
  • the present study investigated the effect of inhalation maneuvers and different formulations of tobramycin on the deposition throughout the lung with CFD. Instructed slow inhalations of TIP result in greater tobramycin concentrations in the large and small airways compared to inhalations of TIP without instruction. Furthermore, inhalations with TIS results in greater large and small airway concentrations when compared to all TIP inhalations, except for the instructed slow TIP inhalations. For the slow TIP inhalations, the small airway concentrations were similar to those of TIS. All inhalations led to a concentration of tobramycin that was at least triple the amount of the effective clinical cut-off value of 40 pg/mL. Based on these results, it is feasible to instruct patients to achieve greater small airway deposition and/or to provide devices that allow this greater deposition. The conclusions are therefore directly relevant to daily clinical care.
  • Tobramycin concentrations are sufficiently high throughout the bronchial tree, using a clinical effective cut-off value of ten times MIC.
  • the present results were related to the data provided by EUCAST, e.g., a MIC of tobramycin for P. aeruginosa of 4 pg/mL.
  • the clinical cut-off was set at a value at ten times MIC, or 40 pg/mL. Nevertheless, the clinical cut-off value at ten times MIC does not necessarily mean that concentrations are high enough to be effective.
  • Bos et al. described in a review that the effectiveness of inhaled antibiotics is influenced by multiple factors. The binding of thick CF mucus to tobramycin molecules actuates various mechanisms that can lead to a decreased number and/or inactivation of these molecules. Therefore, the present in silico situation might be more positive than the in vivo situation.

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Abstract

Provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, including administering to a respiratory tract of the patient an effective amount of an aerosolized or nebulized composition comprising tobramycin, wherein the aerosolized or nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.

Description

DEVICES AND METHODS FOR TOBRAMYCIN INHALATION TREATMENT
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S. Provisional Patent Application Nos. 62/801,209 and 62/855,273, filed February 5, 2019 and May 31, 2019, the contents of which are incorporated herein by reference in their entirety.
BACKGROUND
Field of the Invention
[0002] Provided herein are devices and methods for administration of powdered or nebulized compositions, and, in non-limiting embodiments or aspects, devices and methods for administration of powdered or nebulized tobramycin providing increased drug availability in small airways of the lungs.
Description of Related Art
[0003] Cystic fibrosis (CF) is an inherited disorder that causes significant damage of organ systems, including, notably, the respiratory system and the lungs. CF causes the normally thin layer of mucus in the lungs to become more viscous, which can cause blockage in lung airways. Critically, this altered lung environment makes it difficult for the body’s immune system to effectively clear pathogens, rendering the lungs hospitable for infections. In particular, individuals with CF become susceptible to chronic infections by Pseudomonas aeruginosa, which is the leading cause of morbidity and mortality in individuals with CF.
[0004] Aminoglycosides, such as tobramycin, are a class of potent bactericidal agents. Their main mechanism of action is on the bacterial ribosome, which in turn inhibits protein synthesis. Inhaled (powder or nebulized solution) tobramycin is the treatment of choice for P. aeruginosa infections in individuals with CF. However, delivery of sufficient levels ( e.g at or above the minimum inhibitory concentration (MIC)) of tobramycin to the small airways, which is critical to effectively fight P. aeruginosa infections in individuals with CF, is inconsistent, and there is a lack of devices and methods in the field for improving such delivery.
[0005] Accordingly, a need exists in the art to ensure delivery of sufficient levels of tobramycin to the small airways of the lungs of individuals with CF.
SUMMARY
[0006] In view of the above-noted shortcomings in the art, provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, including the step of administering to a respiratory tract of the patient an effective amount of a nebulized composition including tobramycin, wherein the nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
[0007] Also provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis including the step of administering to a respiratory tract of the patient an effective amount of an aerosolized composition including tobramycin, wherein the aerosolized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
[0008] Also provided herein is a method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, including the step of administering to a respiratory tract of the patient an effective amount of a particulate composition including tobramycin, calcium chloride, and distearoyl phosphatidyl choline, wherein the particulate composition has a mass median diameter of 20 microns or less and a mass median aerodynamic diameter of 10 microns or less, wherein the particulate composition is administered to the patient at a flow rate of less than or equal to 80 liters per minute for at least three seconds, such that a concentration of tobramycin in at least one peripheral airway of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
[0009] Also provided herein is a kit including a handheld aerosolization apparatus having a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow; a mouthpiece having a perforated member and an aerosolized pharmaceutical formulation outlet, the mouthpiece being connectable to the housing to define a capsule chamber, the mouthpiece further having a shield which covers at least one air inlet, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and a puncturing mechanism disposed within the housing for creating one or more openings in the capsule; at least one blister pack including a plurality of capsules having a powdered composition including tobramycin therein; and instructions for the user to actuate the apparatus to release the powdered composition and to inhale the powdered composition at a rate of less than or equal to 80 liters per minute for at least three seconds.
[0010] Also provided herein is a kit including a plurality of ampules, each ampule of the plurality of ampules having a solution of tobramycin and saline therein; and instructions that instruct a user to nebulize the solution with a nebulizer; and inhale, through a mouthpiece of the nebulizer, the nebulized solution at a rate of 15 liters per minute for at least three seconds.
[0011] Also provided herein is a method of training a patient to self-administer an aerosolized or nebulized composition including tobramycin, the method including the steps of: providing an aerosolization apparatus or a nebulizer, having a flow sensor; measuring, with the flow sensor, flow through the aerosolization apparatus or nebulizer during an inhalation phase of the patient’s respiration to obtain a measured flow value; comparing the measured flow value to a target flow value; and providing feedback to the patient when the measured flow value exceeds the target flow value.
[0012] Further embodiments or aspects are set forth in the following numbered clauses:
[0013] Clause 1 : A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of a nebulized composition comprising tobramycin, wherein the nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
[0014] Clause 2: The method of clause 1, wherein the nebulized composition comprises tobramycin and saline.
[0015] Clause 3: The method of clause 1 or clause 2, wherein the nebulized composition is administered to the patient at a flow rate of 15 liters per minute.
[0016] Clause 4: The method of any of clauses 1-3, wherein the nebulized composition is administered to the patient for at least four seconds.
[0017] Clause 5: The method of any of clauses 1-4, wherein at least about 5 milliliters of the nebulized composition is delivered to the patient’s respiratory tract.
[0018] Clause 6: The method of any of clauses 1-5, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
[0019] Clause 7: The method of any of clauses 1-6, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 1000 micrograms per milliliter.
[0020] Clause 8: The method of any of clauses 1-7, wherein the nebulized composition includes tobramycin particles having a mass median diameter of 20 microns or less.
[0021] Clause 9: The method of any of clauses 1-8, wherein the nebulized composition includes tobramycin particles having a mass median aerodynamic diameter of 10 microns or less.
[0022] Clause 10: A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of any of clauses 1-9.
[0023] Clause 11 : A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of an aerosolized composition comprising tobramycin, wherein the aerosolized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
[0024] Clause 12: The method of clause 11, wherein the aerosolized composition is administered to the patient at a flow rate of 80 liters per minute or less.
[0025] Clause 13: The method of clause 11 or clause 12, wherein the aerosolized composition is administered to the patient for at least four seconds.
[0026] Clause 14: The method of any of clauses 11-13, wherein at least about 5 milliliters of the aerosolized composition is delivered to the patient’s respiratory tract.
[0027] Clause 15: The method of any of clauses 11-14, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
[0028] Clause 16: The method of any of clauses 11-15, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
[0029] Clause 17: The method of any of clauses 11-16, wherein the aerosolized composition includes particulate tobramycin having a mass median diameter of 20 microns or less.
[0030] Clause 18: The method of any of clauses 11-17, wherein the aerosolized composition includes particulate tobramycin having a mass median aerodynamic diameter of 10 microns or less.
[0031] Clause 19: A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of any of clauses 11-18.
[0032] Clause 20: A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising: administering to a respiratory tract of the patient an effective amount of a particulate composition comprising tobramycin, calcium chloride, and distearoyl phosphatidyl choline, wherein the particulate composition has a mass median diameter of 20 microns or less and a mass median aerodynamic diameter of 10 microns or less, wherein the particulate composition is administered to the patient at a flow rate of less than or equal to 80 liters per minute for at least three seconds, such that a concentration of tobramycin in at least one peripheral airway of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter. [0033] Clause 21: A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of clause 20.
[0034] Clause 22: A kit comprising: a handheld aerosolization apparatus comprising: a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow; a mouthpiece comprising a perforated member and an aerosolized pharmaceutical formulation outlet, the mouthpiece being connectable to the housing to define a capsule chamber, the mouthpiece further comprising a shield which covers at least one air inlet, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and a puncturing mechanism disposed within the housing for creating one or more openings in the capsule; at least one blister pack comprising: a plurality of capsules comprising a powdered composition comprising tobramycin; and instructions for the user to actuate the apparatus to release the powdered composition and to inhale the powdered composition at a rate of less than or equal to 80 liters per minute for at least three seconds.
[0035] Clause 23: The kit of clause 22, wherein the mouthpiece of the apparatus is configured to limit a flow therethrough to 80 liters per minute or less.
[0036] Clause 24: The kit of clause 22 or clause 23, wherein the handheld aerosolization apparatus further comprises a flow sensor configured to measure flow through the mouthpiece.
[0037] Clause 25: A kit comprising: a plurality of ampules, each ampule of the plurality of ampules comprising a solution comprising tobramycin and saline; and instructions that instruct a user to: nebulize the solution with a nebulizer; and inhale, through a mouthpiece of the nebulizer, the nebulized solution at a rate of 15 liters per minute for at least three seconds.
[0038] Clause 26: The kit of clause 25, further comprising a nebulizer comprising: a housing having a proximal end, a distal end, and a sidewall therebetween defining a lumen, the lumen configured to receive the solution; a compressed gas inlet at the proximal end of the housing; a cap assembly configured to be removably connected to the distal end of the housing, the cap assembly comprising a cap and a stem extending from the cap and configured to be received in the lumen; an outlet comprising an opening in the sidewall; and a mouthpiece configured to be removably connected to the outlet.
[0039] Clause 27: The kit of claim clause 25 or clause 26, wherein the mouthpiece is configured to limit a flow therethrough to 15 liters per minute.
[0040] Clause 28: The kit of any of clauses 25-27, wherein the nebulizer further comprises a flow sensor configured to measure flow through the mouthpiece. [0041] Clause 29: A method of training a patient to self-administer an aerosolized or nebulized composition comprising tobramycin, the method comprising the steps of: providing an aerosolization apparatus or a nebulizer, comprising a flow sensor; measuring, with the flow sensor, flow through the aerosolization apparatus or the nebulizer during an inhalation phase of the patient’ s respiration to obtain a measured flow value; comparing the measured flow value to a target flow value; and providing feedback to the patient when the measured flow value exceeds the target flow value.
[0042] Clause 30: The method of clause 29, wherein the target flow value is 100 liters per minute.
[0043] Clause 31 : The method of clause 29 or clause 30, wherein the target flow value is 80 liters per minute.
[0044] Clause 32: The method of any of clauses 29-30, wherein the target flow value is 15 liters per minute.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] Figures 1A-1E are schematic side views (FIGS. 1A-1D) and a cross-sectional view (FIG. IE) of an aerosolization device according to non-limiting embodiments or aspects;
[0046] Figures 2A and 2B are schematic side views of a nebulizer according to non-limiting embodiments or aspects;
[0047] Figure 3 is an overview of how the flows of the three groups (child, adult female, and adult male) were applied on computed tomography (CT) models. For every patient, an uninstructed, instructed fast, and instructed slow inhalation of tobramycin inhalation powder (TIP) was collected, and a mean inhalation of tobramycin inhalation solution (TIS) from 60 seconds of recording was collected. Every flow was used as input on three different CT models, resulting in a total of 144 simulations with computational fluid dynamics (CDM) modeling;
[0048] Figures 4A-4C show inspiratory flow curves for uninstructed (FIG. 4A), instructed fast (FIG. 4B), and instructed slow (FIG. 4C) inhalations. The x-axis represents the time in seconds and the y-axis represents the inspiratory flow in liter per minute (L/min). * = patient coughed during inhalation; # = irregular inhalation;
[0049] Figure 5 shows three-dimensional airway models constructed from computed tomography (CT) scans of a child (upper row), adult female (middle row), and adult male (lower row). The concentration is presented for each flow type: uninstructed, instructed fast and instructed slow inhalation of tobramycin inhalation powder (TIP) and the inhalations with tobramycin inhalation solution (TIS). Colors represent tobramycin concentration in pg/mL (White is the highest possible concentration, whereas dark blue represents the lowest concentration);
[0050] Figures 6A and 6B are box-and-whisker plots of the concentration of tobramycin in pg/mL in the large airways (FIG. 6A) and in the small airways (FIG. 6B). The x-axis represents the flow types (uninstructed TIP, instructed fast TIP, instructed slow TIP, and TIS inhalation). The bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile. The whiskers represent either 1.5 times the 25th or 75th percentile value, or the minimum and maximum values. The circles outside of the T-bars are outliers. The dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL). * =p < 0.05 using generalized estimating equation models;
[0051] Figure 7 is a box-and-whisker plot of the concentration of tobramycin in pg/mL in the extrathoracic and central airways (dark versus light box). The x-axis represents the flow types (uninstructed TIP, instructed fast TIP, instructed slow TIP, and TIS inhalation). The bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile. The whiskers represent either 1.5 times the 25th or 75th percentile value, or the minimum and maximum values. The circles outside of the T-bars are outliers. The dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL). * =p < 0.05 using generalized estimating equation models; and
[0052] Figures 8A-8D are box-and-whisker plots of the concentration of tobramycin in pg/mL per lung lobe for TIP in the large and small airways (FIGS. 8A-8B) and for TIS in the large and small airways (FIGS. 8C-8D). In lung models, due to technical reasons, the small airway region of the right upper and right middle lobe was combined. The x-axis represents different lung lobes. The bolt line in each box represents the median; the bottom and top lines of the box represent the 25th and 75th percentile. The whiskers represent either 1.5 times the 25th or 75th percentile value or the minimum and maximum values. The circles outside of the T-bars are outliers. The dotted line in both graphs represents the threshold value for effective dose of lOx MIC (e.g., 40 pg/mL)
DESCRIPTION
[0053] The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word "about". In this manner, slight variations (e.g., 10%) above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values, and any and all subranges between the minimum and maximum values. For definitions provided herein, those definitions refer to word forms, cognates and grammatical variants of those words or phrases.
[0054] The figures accompanying this application are representative in nature, and should not be construed as implying any particular scale or directionality, unless otherwise indicated. For purposes of the description hereinafter, the terms“upper”,“lower”,“right”,“left”,“vertical”, “horizontal”,“top”,“bottom”,“lateral”,“longitudinal” and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.
[0055] As used herein, the term“patient” is any mammal, including humans, and a“human patient” is any human.
[0056] As used herein, the term“small airways” of the lungs refers to one or more peripheral airways of the lung. In non-limiting embodiments or aspects,“small airways” of the lungs refers to airways having a diameter of less than or equal to 1-2 mm.
[0057] U.S. Patent Nos. 7,368,102; 7,442,388; 7,516,741; 7,559,325; 8,069,851; 8,349,294; and 8,715,623 are incorporated herein by reference in their entirety.
[0058] Provided herein are methods of treating an infection in a patient through administration of an antibiotic to the respiratory tract of the patient. In non-limiting embodiments or aspects, the infection is an infection in the lungs caused by Pseudomonas aeruginosa. In non-limiting embodiments or aspects, the infection is a chronic P. aeruginosa infection. In non-limiting embodiments or aspects, the patient is a patient that has cystic fibrosis. In non-limiting embodiments or aspects, the antibiotic is an aminoglycoside antibiotic. In non-limiting embodiments or aspects, the antibiotic is tobramycin (0-3-amino-3-deoxy-a-D- glucopyranosyl-(l-4)-0-[2,6-diamino-2,3,6-trideoxy-a-D-ribo-hexopyranosyl-(l-6)]-2- deoxy-L-streptamine). In non-limiting embodiments or aspects, the antibiotic is administered to the lungs of the patient. In non-limiting embodiments or aspects, the antibiotic is administered to the small airways of the lungs.
[0059] Aminoglycoside antibiotics, such as tobramycin, can be administered to the respiratory tract of a patient, for example the small airways of the lungs of the patient, using devices shown in FIGS. 1A-2B. FIGS. 1A-1E show schematic (FIGS. 1A-1D) and cross-sectional (FIG. IE) views of a device for delivery of a powdered composition by aerosolization. FIGS. 2A and 2B show schematic views of a device for delivery of a solution by nebulization. The devices useful for the various administration regimens will be discussed in turn with the respective methods.
[0060] With reference to FIGS. 1A-1E, shown are schematic (FIGS. 1A-1D) and cross- sectional (FIG. IE) views of a non-limiting embodiment or aspect of a device 100 for delivery of an aerosolized powdered composition of an antibiotic, such as tobramycin, to the respiratory tract of a patient. As used herein, the term“aerosolized” means the conversion of a substance into a fine spray or colloidal suspension, and the term“aerosol” means a liquid or particulate matter dispersed in air in the form of a mist. Device 100 can include housing 105, including housing body 205, having sidewalls 165 defining a chamber 110 having one or more air inlets 115 and one or more air outlets 120 arranged between one or more partitions 150. In non- limiting embodiments or aspects, one or more inlets 115 are at least two air inlets. In non- limiting embodiments or aspects, one or more air outlets 120 include at least one outlet through which an aerosolized composition can pass. Chamber 110 can be sized to receive one or more capsules 125 containing an aerosolizable composition, such as tobramycin. In non-limiting embodiments or aspects, air inlets 115, chamber 110, and/or partitions 150 are configured and/or dimensioned to create a swirling airflow within chamber 110. In non-limiting embodiments or aspects, swirling airflow provides sufficient force to release a powdered composition from capsule 125, optionally without the need for a puncturing mechanism. Non- limiting embodiments or aspects including a puncturing mechanism are described below with reference to FIG. IE.
[0061] With continuing reference to FIGS. 1A-1D, near one or more outlets 120, mouthpiece 140 can be provided. Mouthpiece 140 may be sized and shaped to be received in a patient's mouth or nose so that the patient may inhale the aerosolizable composition through opening 145 in mouthpiece 140 that is in communication with one or more outlets 120. In non-limiting embodiments or aspects, air flowing through one or more inlets 115 enters chamber 110, aerosolizes the composition, which flows through one or more outlets 120 and opening 145 in mouthpiece 140 to be delivered to the patient’s respiratory tract during inhalation. In non- limiting embodiments or aspects, air or another gas (e.g., from a source of compressed air) is introduced through one or more inlets 115 to aerosolize the composition. In non-limiting embodiments or aspects, mouthpiece 140 includes at least one perforated member.
[0062] In non-limiting embodiments or aspects, device 100 can include an air inlet shield 170 to prevent a patient from covering one or more air inlets 115 (e.g., with a finger or other portion of the patient’s hand) during an inhalation procedure. Air inlet shield 170 can include covering portion 175. [0063] In non-limiting embodiments or aspects, mouthpiece 140 can include endpiece 210, which may be removed from housing 105 to allow a patient to insert a capsule 125 in the chamber 110 which is formed when housing 105 and the mouthpiece 140 are connected together.
[0064] In non-limiting embodiments or aspects, device 100, including endpiece 210 and air inlet shielding member 170, includes a plurality of covering portions 175 (only one shown in the view of FIG. IB) and two open portions 180 between covering portions 175. In non limiting embodiments or aspects, covering portions 175 are diametrically opposed about air inlet shielding member 170. In non-limiting embodiments or aspects, air inlet shielding member 170 includes three, four, or more covering portions 175 separated by open portions 180
[0065] In the non-limiting embodiment illustrated in FIGS. 1A-1E, the patient grasps device 100 by contacting the covering portions 175 and would, therefore, not block one or more air inlets 115. In non-limiting embodiments or aspects, space is provided between covering portion 175 and the outer surface of one or more inlets 115 under covering portion 175 in order to create a manifold airflow portion below covering portion 175.
[0066] Non-limiting embodiments or aspects of device 100 including endpiece 210 and air inlet shielding member 170 are shown in FIGS. 1C-1D. These illustrated non-limiting embodiments or aspects include different arrangements for covering portions 175 and open portions 180 associated with air inlet shielding member 170. In the non-limiting embodiment or aspect shown in FIG. 1C, a series of longitudinal open portions 180 is provided. In the non limiting embodiment or aspect shown in FIG. 1C, one or more circumferentially extending open portions 180 are provided. In the non-limiting embodiment or aspect shown in FIG. ID, an open portion 180 can also extend circumferentially around base 185 of and under endpiece 210
[0067] With reference to FIG. IE, showing a cross-sectional view of a device useful for delivery of aerosolized compositions such as tobramycin, actuation for delivery can be described as follows. In non-limiting embodiments or aspects, capsule 125 can be punctured by puncture mechanism 250. In non-limiting embodiments or aspects, puncture mechanism 250 includes an actuatable plunger 255 connected to or engageable at a distal end thereof with puncture member 265.
[0068] Puncturing mechanism 250 can further include a seating member 280 which contacts plunger 255 and/or puncture member 265 and is slidable relative to plunger 255 and puncture member 265. To create the openings in capsule 125, a user applies a force to plunger 255 (e.g., by pressing against an end surface 290 of plunger 255 with a finger or thumb). The force causes plunger 255 to slide within housing body 205. A frictional contact between plunger 255 and a rear section 295 of seating member 280 causes seating member 280 to slide within housing body 205 of housing 105 until a forward seating surface 300 of seating member 280 contacts capsule 125. Forward seating surface 300, which may be shaped to generally match the shape of capsule 125, secures capsule 125 between seating member 280 and partition 150. Continued application of force causes plunger 255 and puncture member 265 to slide relative to seating member 280, to advance puncture member 265 through openings 305 in forward seating surface 300 and into capsule 125. Upon the removal of force (e.g., by removing a finger or thumb), biasing member (e.g., spring) 310 urges puncturing mechanism 250 back to a rest position. For example, biasing member 310 may contact a shoulder 315 in housing body 205 and press a flange 320 on plunger 255 toward a rim 325 in housing body 205. Frictional engagement between plunger 255 and seating member 280 can also return seating member 280 to its retracted position when the plunger is returned to its retracted position.
[0069] Devices as illustrated in FIGS. 1A-1E can be used in a method of treating a P. aeruginosa infection in a patient having cystic fibrosis (CF). Accordingly, also provided herein are methods of treating a P. aeruginosa infection in the lungs of a patient with CF. In non limiting embodiments or aspects, the method can include the step of administering an effective amount of an aerosolized composition including tobramycin to the respiratory tract of the patient at a flow rate of less than or equal to about 100 1pm, and/or for at least three seconds.
[0070] As used herein, the term“effective amount” means at least the minimum effective concentration (MIC) of tobramycin for P. aeruginosa. In non-limiting embodiments or aspects, the MIC of tobramycin for P. aeruginosa is about 4 pg/mL. Compositions including tobramycin as described herein can include one or more pharmaceutically-acceptable carriers or excipients. As used herein, the term“pharmaceutically-acceptable carrier or excipient” means an inactive substance that serves as a vehicle or medium for an active substance (e.g., tobramycin) and that can be introduced into the respiratory tract of a patient without significant toxicological effects. Suitable excipients for use in aerosolized compositions are known to those of skill in the art. In non-limiting embodiments or aspects, the composition includes tobramycin and calcium chloride and/or distearoyl phosphatidyl choline.
[0071] As described in the Example below, administration of tobramycin at low flow rates, e.g., by instructing a patient to inhale slowly (e.g., about 100 1pm or lower) can result in increased delivery of tobramycin to the small airways of the lungs. Accordingly, in non- limiting embodiments or aspects, a device 100 suitable for administration of an aerosolized composition including tobramycin to the respiratory tract of the patient can be modified to limit air flow, for example by limiting air flow through one or more inlets 115, through one or more outlets 120, and/or through opening 145 in mouthpiece 140. In non-limiting embodiments or aspects, one or more inlets 115 are narrowed or obstructed to decrease the volume of air that can be introduced into chamber 110. In non-limiting embodiments or aspects, one or more outlets 120 and/or opening 145 in mouthpiece 140 is narrowed or obstructed to decrease the volume of air that can be withdrawn from chamber 110 and introduced into the patient’s respiratory tract. Non-limiting examples of mechanisms suitable for reducing airflow include use of porous membranes to cover inlets, outlets, and/or openings, reducing the number of openings (e.g., by blocking one or more inlets, outlets, and/or openings), venturis, and/or valves.
[0072] In non-limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract of the patient at a flow rate of less than or equal to 80 1pm. In non limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract for at least four seconds.
[0073] In non-limiting embodiments or aspects, device 100 can include a sensor for measuring flow through one or more outlets 120 and/or mouthpiece 140. Suitable flow sensors are known to those of ordinary skill in the art, and include sensors that measure volume and/or mass, and include, without limitation, thermo-anemometer sensors, vane sensors, hot wire sensors, cold wire sensors, laminar flow sensors, and solid state sensors. Those of skill in the art will appreciate that suitable sensors are available commercially, for example, from Honeywell International, Inc. (Charlotte, NC, USA). Suitable flow sensors can be disposed within the device, e.g., in or adjacent to one or more outlets 120 and/or mouthpiece 140. For example, as shown in FIG. 1A, a flow sensor 122 can be disposed in or adjacent to one or more outlets 120, to measure flow through one or more outlets 120. In other non-limiting embodiments or aspects, a flow sensor may be disposed outside of device 100. For example, a flow sensor may be an external device that is attached to housing 105 and/or mouthpiece 140, between mouthpiece 140 and housing 105, and/or between mouthpiece 140 and a patient’s mouth. In non-limiting embodiments or aspects, a flow sensor can include one or more processors, memory storing programming instructions and/or a database of acceptable flow values, and/or one or more indicators (e.g., visual, audible, or tactile indicators).
[0074] In non-limiting embodiments or aspects, a flow sensor useful with device 100 described herein can measure flow through one or more outlets 120 and/or mouthpiece 140. A processor associated with the flow sensors can compare the measured flow value to one or more acceptable flow values stored in a memory associated with the flow sensor, and, if the measured flow differs from an acceptable flow value, the programming instructions, when executed by the processors, can cause the processor to instruct the indicator to alert a patient to either increase or decrease flow through one or more outlets 120 and/or mouthpiece 140 (e.g., by increasing or decreasing inhalation). In non-limiting embodiments or aspects, the processor causes the measured flow value to be stored in memory. In non-limiting embodiments or aspects, the patient and/or another individual, such as a healthcare professional, can later access the measured value to determine whether the patient correctly utilized device 100, via communication between the sensor and a computing device (e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.) through a Universal Serial Bus connection, BLUETOOTH connection, or other wired or wireless connections known to those of skill in the art.
[0075] A capsule 125 suitable for use in a device 100 as described herein can, in non-limiting embodiments or aspects, contain about 28 mg of a powdered, aerosolizable composition. In non-limiting embodiments or aspects, at least about 5 mL of aerosolized composition is delivered to the patient’s respiratory tract.
[0076] As described above, a MIC of tobramycin for P. aeruginosa can be about 4 pg/mL. In non-limiting embodiments or aspects, the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs during and/or following administration is at least about lOx MIC (e.g., at least about 40 pg/mL). In non-limiting embodiments or aspects, the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs during and/or following administration is at least about 50x MIC (e.g., at least about 200 pg/mL).
[0077] Characteristics of powdered, aerosolizable tobramycin compositions are provided in, for example, U.S. Patent No. 7,368,102, incorporated herein by reference in its entirety. Characteristics of tobramycin powder include geometric diameter, mass median diameter, and mass median aerodynamic diameter.
[0078] As used herein, the term“geometric diameter” means a measure of geometric particle size, which can be determined using a laser diffraction analyzer.
[0079] As used herein, the term“mass median diameter” means a measure of mean particle size of polydisperse particles, which can be determined by centrifugal sedimentation.
[0080] As used herein, the term“mass median aerodynamic diameter” means a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle shape, density, and physical size of a particle. As used herein,“mass median aerodynamic diameter” refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by Anderson cascade impaction.
[0081] In non-limiting embodiments or aspects, the aerosolized composition delivered as described herein includes particulate tobramycin having a mass median diameter of about 20 microns or less. In non-limiting embodiments or aspects, the aerosolized composition delivered as described herein includes particulate tobramycin having a mass median aerodynamic diameter of about 10 microns or less.
[0082] In non-limiting embodiments or aspects, the methods described herein for treating a P. aeruginosa infection in an individual having cystic fibrosis can be prescribed by a physician. Accordingly, provided herein is a method of treating a P. aeruginosa infection in a patient having cystic fibrosis including the step of prescribing to a patient a treatment regimen including administration of an aerosolized composition including tobramycin to the patient’s respiratory tract as described herein.
[0083] With reference to FIGS. 2A and 2B, shown are schematic views of a non-limiting embodiment or aspect of a device 300 for delivery of a nebulized solution of an antibiotic, such as tobramycin, to the respiratory tract of a patient. Device 300 can include housing 310 having a proximal end 320, a distal end 330, and sidewalls 325 therebetween defining a lumen (not shown) configured to hold a nebulizable solution, such as a solution of tobramycin. In non limiting embodiments or aspects, lumen is defined by sidewalls 325 and proximal end 320 and is in the form of a nebulizer cup. Device 300 can further include a cap assembly 340 including a nebulizer top 350 and valve cap 360. Nebulizer top 350 can be reversibly engaged (e.g., by threaded interaction) with the distal end of housing 310. Valve cap 360 can be reversibly engaged (e.g., by press or friction fit) with nebulizer top 350. Nebulizer top 350 can include a stem 355. Stem 355 can be arranged to reside within housing 310 lumen when the nebulizer top 350 is engaged with the distal end 330 of housing 310.
[0084] Device housing 310 can further include an outlet 370 in the sidewall 325. In non limiting embodiments or aspects, outlet 370 is arranged near distal end 330 of housing 310. Device 300 can further include a mouthpiece 380. Mouthpiece 380 may be sized and shaped to be received in a patient's mouth so that the patient may inhale the aerosolizable composition through an opening in mouthpiece 380 that is in communication with outlet 370. [0085] Device housing 310 can further include, at proximal end 320 thereof, air inlet 322. Air inlet 322 may be configured to be in communication with a source of air 400, e.g., a source of compressed air or a source of forced air. Source of air 400 drives the nebulizer, causing the solution within the lumen to be nebulized and delivered, via the mouthpiece 380, to the respiratory tract of a patient.
[0086] Devices as illustrated in FIGS. 2A and 2B can be used in a method of treating a P. aeruginosa infection in a patient having cystic fibrosis. The method can include the step of administering an effective amount of a nebulized composition including tobramycin to the respiratory tract of the patient at a flow rate of less than or equal to about 100 1pm and/or for at least three seconds. As used herein, the term“nebulized” means to disperse a liquid composition in a mist of fine particles. The effective amount, e.g., at least MIC, at least lOx MIC, or at least 50x MIC of tobramycin is described elsewhere herein. Compositions including tobramycin as described herein can include one or more pharmaceutically-acceptable carriers or excipients. Suitable excipients for use in nebulized compositions are known to those of skill in the art. In non-limiting embodiments or aspects, the composition includes tobramycin and saline.
[0087] As described in the Example below, administration of tobramycin at low flow rates, e.g., by instructing a patient to inhale slowly (e.g., about 100 1pm or lower) can result in increased delivery of tobramycin to the small airways of the lungs. Accordingly, in non- limiting embodiments or aspects, a device 300 suitable for administration of an aerosolized composition including tobramycin to the respiratory tract of the patient can be modified to limit air flow, for example by limiting air flow through inlet 322, through outlet 370, and/or through opening in mouthpiece 380. Non-limiting examples of mechanisms suitable for reducing flow are described above, and include use of porous membranes to cover inlets, outlets, and/or openings, reducing the number of openings (e.g., by blocking one or more inlets, outlets, and/or openings), venturis, and/or valves.
[0088] In non-limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract of the patient at a flow rate of less than or equal to about 15 1pm. In non-limiting embodiments or aspects, the aerosolized composition is administered to the respiratory tract for at least four seconds.
[0089] In non-limiting embodiments or aspects, device 300 can include a sensor for measuring flow through outlet 370 and/or mouthpiece 380. Suitable flow sensors are known to those of ordinary skill in the art, and include sensors that measure volume and/or mass, and include, without limitation, thermo-anemometer sensors, vane sensors, hot wire sensors, cold wire sensors, laminar flow sensors, and solid state sensors. Those of skill in the art will appreciate that suitable sensors are available commercially, for example from Honeywell International, Inc. (Charlotte, NC, USA). Suitable flow sensors can be disposed within the device, e.g., in or adjacent to outlet 370 and/or mouthpiece 380. For example, as shown in FIG. 2A, a flow sensor 372 can be disposed in or adjacent to outlet 370, to measure flow through outlet 370. In other non-limiting embodiments or aspects, a flow sensor may be disposed outside of device 300. For example, a flow sensor may be an external device that is attached to housing 310 and/or mouthpiece 380, between mouthpiece 380 and housing 310, and/or between mouthpiece 380 and a patient’s mouth. In non-limiting embodiments or aspects, a flow sensor can include one or more processors, memory storing programming instructions and/or a database of acceptable flow values, and/or one or more indicators (e.g., visual, audible, or tactile indicators).
[0090] In non-limiting embodiments or aspects, a flow sensor useful with device 300 described herein can measure flow through outlet 370 and/or mouthpiece 380. A processor associated with the flow sensors can compare the measured flow value to one or more acceptable flow values stored in a memory associated with the flow sensor, and, if the measured flow differs from an acceptable flow value, the programming instructions, when executed by the processors, can cause the processor to instruct the indicator to alert a patient to either increase or decrease flow through outlet 370 and/or mouthpiece 380 (e.g., by increasing or decreasing inhalation). In non-limiting embodiments or aspects, the processor causes the measured flow value to be stored in memory. In non-limiting embodiments or aspects, the patient and/or another individual, such as a healthcare professional, can later access the measured value to determine whether the patient correctly utilized device 300, via communication between the sensor and a computing device (e.g., a laptop computer, desktop computer, smartphone, tablet, smart watch, etc.) through a Universal Serial Bus connection, BLUETOOTH connection, or other wired or wireless connections known to those of skill in the art.
[0091] An ampule suitable for use in a device 300 as described herein can, in non-limiting embodiments or aspects, contain about 5 mL of a nebulizable solution. In non-limiting embodiments or aspects, at least about 5 mL of a nebulized composition is delivered to the patient’s respiratory tract.
[0092] As described above, a MIC of tobramycin for treating P. aeruginosa can be about 4 pg/mL. In non-limiting embodiments or aspects, the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs is at least about lOx MIC (e.g., at least about 40 pg/mL). In non-limiting embodiments or aspects, the methods described herein deliver a sufficient amount of tobramycin such that a concentration of tobramycin in the small airways of the patient’s lungs is at least about 250x MIC (e.g., at least about 1000 pg/mL).
[0093] Characteristics of a nebulizable tobramycin solution are provided in, for example, U.S. Patent No. 7,368,102, incorporated herein by reference in its entirety. Characteristics of tobramycin solution include characteristics of the tobramycin itself (e.g., geometric diameter, mass median diameter, and mass median aerodynamic diameter), and characteristics of the tobramycin solution (e.g., pH). In non-limiting embodiments or aspects, the nebulizable composition delivered by the methods described herein includes particulate tobramycin having a mass median diameter of about 20 microns or less. In non-limiting embodiments or aspects, the nebulizable composition delivered by the methods described herein includes particulate tobramycin having a mass median aerodynamic diameter of about 10 microns or less. In non limiting embodiments or aspects, a solution useful in the devices and methods described herein has a pH of about 6.0 and a concentration of 300 mg of tobramycin (free base) in 5 mL of saline (e.g., sodium chloride solution).
[0094] In non-limiting embodiments or aspects, the methods described herein for treating a P. aeruginosa infection in an individual having cystic fibrosis can be prescribed by a physician. Accordingly, provided herein is a method of treating a P. aeruginosa infection in a patient having cystic fibrosis including the step of prescribing to a patient a treatment regimen including administration of a nebulized composition including tobramycin to the patient’s respiratory tract as described herein.
[0095] Also provided herein are methods of training a patient to self-administer an aerosolized or nebulized tobramycin-containing composition in accordance with the present disclosure. In non-limiting embodiments or aspects, the method includes providing a patient with an aerosolization apparatus or a nebulizer having a flow sensor. In non-limiting embodiments, the patient can be provided with only one component of an aerosolization apparatus or nebulizer, such as a mouthpiece. The method can further include a step of measuring, with the flow sensor, flow through the aerosolization apparatus or the nebulizer (or component thereol) during an inhalation phase of the patient’s respiration to obtain a measured flow value. The method can further include a step of comparing the measured flow value to a target flow value. In non-limiting embodiments or aspects, the comparison is performed by a processor associated with the flow sensor. In non-limiting embodiments or aspects, the comparison is between the measured flow value and a target flow value stored in memory, for example in a database. The method can further include a step of providing feedback to the patient when the measured flow value exceeds the target flow value. In non-limiting embodiments or aspects, the feedback is visual, audible, and/or tactile, and can include, for example and without limitation, audible feedback (e.g., providing beeps or other audible cues at differing rates depending on whether the patient’s inspiration should increase or decrease, and/or a verbal instruction to slow down or speed up), visual feedback (e.g., providing flashes of light at differing rates depending on whether the patient’s inspiration should increase or decrease), and/or tactile feedback (e.g., providing tactile pulses that are delivered at differing rates depending on whether the patient’s inspiration should increase or decrease). In non-limiting embodiments or aspects, a processor associated with the flow sensor provides instructions to an indicator, such as an LED device, speaker, and/or haptic device, to provide the desired feedback.
[0096] Also provided herein are kits including devices as described herein, for performing the methods described herein. In non-limiting embodiments or aspects, a kit can include a handheld aerosolization device as described herein and shown for example in FIGS. 1A-1E, one or more capsules (e.g., a blister pack containing one or more capsules) of powdered tobramycin suitable for use with an aerosolization device, and instructions for a patient to actuate the handheld aerosolization device such that the aerosolized composition is delivered to the patient’s respiratory tract at a rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 1pm). In non-limiting embodiments or aspects, the capsule can include tobramycin and one or more pharmaceutically-acceptable excipients. In non-limiting embodiments or aspects, the instructions instruct the patient to inhale the aerosolized composition at a rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 lpm). In non-limiting embodiments or aspects, the handheld aerosolization device is configured (e.g., as described herein) to deliver aerosolized tobramycin at a flow rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm).
[0097] In non-limiting embodiments or aspects, a kit can include one or more ampules of tobramycin solution (e.g., tobramycin and saline) and instructions for a patient to nebulize the solution such that the nebulized solution is delivered to the patient’s respiratory tract at a rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm, e.g., less than or equal to about 15 lpm). In non-limiting embodiments or aspects, the instructions instruct the patient to inhale the nebulized solution at a rate of less than or equal to about 100 lpm (e.g., less than or equal to about 80 lpm, e.g., less than or equal to about 15 lpm). In non-limiting embodiments or aspects, a kit as described herein can also include a nebulizer as described herein and shown for example in FIGS. 2A and 2B. In non-limiting embodiments or aspects, the nebulizer is configured (e.g., as described herein) to deliver nebulized tobramycin at a flow rate of less than or equal to about 100 1pm (e.g., less than or equal to about 80 1pm, e.g., less than or equal to about 15 1pm).
Example
[0098] The present study is an in silico study based on computational fluid dynamics (CFD) simulations with use of flow profiles from an observational study.
[0099] For the computational investigation, the recorded inspiratory flows of the first 12 patients who were enrolled in a larger observational study of tobramycin inhalation powder (TIP) and tobramycin inhalation solution (TIS) were enrolled. Inclusion criteria for the observational study were a diagnosis of CF, age of six years and above, and maintenance treatment with TIP for at least one month. Exclusion criteria were pulmonary exacerbation defined as the need for intravenous antibiotics at the time of the inspiratory flow registrations, and inability to follow instructions. Both children and adults from four Dutch CF centers were included: Amsterdam University Medical Center, Erasmus Medical Center (Rotterdam), Haga Teaching Hospital (The Hague), and University Medical Center Utrecht.
Flow Recordings
[00100] The inspiratory flows were recorded at the patient’s home during two study visits using an inhalation profile recorder (The Technology Partnership, Cambridge, United Kingdom) as described before by Haynes et al. (“Inhalation of tobramycin using simulated cystic fibrosis patient profiles.” Pediatr Pulmonol. 2016, Vol. 51, pp. 1159-1167). In short, the inhalation profile recorder was adjusted to the T-326 inhaler or the PARI LC plus® nebulizer with an extra mouthpiece that fit closely. This mouthpiece was connected with a tube to a pressure gauge, which was connected to a transducer and a laptop. With this system, the pressure drop over the mouthpiece during inhalation was measured and plotted as flow- time curve (area under the curve representing the inhaled volume).
[00101] For TIP simulations, the inspiratory flows during inhalation of tobramycin with the T-326 inhaler were recorded. Three inhalation maneuvers for each patient were measured during two study visits: an uninstructed, an instructed fast, and an instructed slow inhalation. At the first study visit, the uninstructed inhalation was measured after patients were asked to inhale TIP in the way they would normally do. At the second study visit, the instructed fast and slow inhalation were measured as follows: patients were asked (in random order) to inhale one TIP capsule as fast as possible, and to inhale another TIP capsule as slow as possible, but with enough force to let the capsule rattle in the T-326 inhaler. [00102] For the TIS simulations, inspiratory flows were recorded while inhaling 0.9% saline with a Porta-neb® compressor and PARI LC Plus® nebulizer during the second home visit. The inspiratory flows during nebulization were measured in four recordings, of 15 seconds each. From these four recordings a mean inhalation curve was computed. Expiratory flows were not recorded, but computed using the recorded inhaled volume and total time between inhalations.
Computational Fluid Dynamics (CFD) Modeling of Aerosol Deposition
[00103] CFD modeling was used to simulate aerosol deposition in 3D computer lung models. This method has been extensively described elsewhere (De Backer et al., “Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation.” J Biomech. 2008, Vol. 41, pp. 106-113; De Backer et al.,“Validation of computational fluid dynamics in CT-based airway models with SPECT/CT.” Radiology 2010, Vol. 257, pp. 854-862). In short, the flow dynamics within lung models are determined to predict the course and velocity of the particles after they are virtually inj ected into the model. To assess the internal flow distribution, the differences between lobar volumes on expiratory and on inspiratory computed tomography (CT) scans were used. With this technique, local airway deposition of inhalation medication can be computed in patient specific models. The CFD model has been validated against single photon emission computed tomography (SPECT- CT) and has been used in CF (Bos et al.,“Patient-specific modeling of regional antibiotic concentration levels in airways of patients with cystic fibrosis: are we dosing high enough?” PLoS One 2015, 10:e0118454) and non - CF (asthma/chronic obstructive pulmonary disease) studies. CFD model simulations were performed in Fluent 14.0 (Ansys Inc, Canonsburg, PA). 3D Model Reconstruction
[00104] To execute CFD modeling, nine 3D lung models were reconstructed using chest CT scans from patients with CF. The process is extensively described elsewhere. Briefly, the following five steps were carried out:
[00105] First, nine CT scans of a dataset from Sophia Children’s hospital (n=187 patients) of routinely acquired biennial chest CT scans of patients with CF were obtained. The selection criteria of the CT scans are described in the next paragraph.
[00106] Second, the central and large airways were reconstructed from the chest CT scans. The central airways are defined as the area from the trachea up to the lobar bronchi. The large airways, often referred to in the literature as the distal airways, are defined as the airways from the first segmental bronchi to airways with a diameter of +/- 1-2 mm that are still visible on chest CT scan. [00107] Third, the extrathoracic airways, defined as the mouth and throat, including the larynx, until the trachea, were reconstructed. Since these are not imaged on chest CT, a representative adult extrathoracic airway model was selected. The model was then scaled down such that both the anteroposterior and lateral dimension of the scaled model’s trachea at the location of the sternum matched the lung model.
[00108] Fourth, CAD models of the T-326 inhaler or PARI LC plus® mouthpiece were connected to the mouth of the model.
[00109] Fifth, the small airways were defined for each lung lobe. Small airways, also referred to in literature as peripheral airways, are airways with a diameter smaller than +/- 1-2 mm. These airways are not visible on chest CT images and, therefore, cannot be reconstructed from a CT scan. Instead, their surfaces were determined by using Phalen’s description of the airway tree in infants, children, and adolescents, based on the patient’s height (Phalen el al. “Tracheobronchial deposition predictions for infants, children, and adolescents.” Ann. Occup. Hyg. 1998, Vol. 32, pp. 11-21).
Chest CT Selection
[00110] The selected CT scans had to meet the following technical requirements: volumetric, spirometer-controlled; availability of both inspiratory and expiratory scans; and a maximum slice thickness of 1 mm or smaller. Furthermore, CT scans had to match the TIP- TIS study population as close as possible based on age, height, and gender. For this purpose, the study patients were divided into three subpopulations: children, female adults, and male adults. Average height of each subpopulation was calculated. The height of the patients for which CT scans were used differed by a maximum of 5% from the average height of the corresponding subpopulation.
[00111] The CT scans from the Sophia database were obtained from patients younger than 18 years. For the female adult and male adult subpopulations, CT scans from adolescents after they were fully grown were selected, as determined by a flattened individual growth curve.
[00112] In addition to age, CT scans of patients with different disease severity were selected. Therefore, three lung models were reconstructed per subpopulation, each with a different lung disease severity category: mild, moderate, and severe.
[00113] To assess the severity of CF lung disease on CT scan, the validated Perth- Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) scoring method (Rosenow et al.“A quantitative structural lung disease computed tomography outcome in young children with cystic fibrosis.”Am. J. Respiratory and Crit. CareMed. 2015, Vol. 191, pp. 1158-1165), which is a morphometric method using a grid to score CT images for percentage of lung disease, was used. Using this score, the extent of bronchiectasis, mucus plugging, and airway wall thickening were computed. The differentiation between mild, moderate, and severe disease was based on the combination of these subscores. To select CT scans within each severity category, the scans in the Sophia database were divided according to the three subpopulations (children, female adults, and male adults). Next, all CT scans were ranked according to the outcomes of the PRAGMA-CF scores for percentage disease. The lowest tertile was defined as mild, the middle tertile as moderate, and the upper tertile as severe disease. Finally, one CT scan within each tertile was selected for each subpopulation, resulting in the selection of nine CT scans. In addition, the selected CT scans were reviewed by a pediatric pulmonologist to evaluate whether the disease severity corresponded to severity group. This evaluation confirmed that the selection represented a good spread of disease severity for each of the three subpopulations.
[00114] An overview showing how the flow profiles from the three subpopulations were applied on the CT models is presented in FIG. 3.
Aerosol Characteristics
[00115] For TIP, particle characteristics are dependent on flow rate. In general, when the flow rate through the T-326 inhaler increases, the mass median aerodynamic diameter (MMAD) of the generated particles decreases. Particle characteristics were available for three flow rates: 40, 60, and 85 L/min. The mean flow rate of each simulated inhalation was calculated, and the particle characteristics (aerodynamic particle size distribution) of the flow that was closest to this mean flow were selected. A single inhalation maneuver was simulated and the deposited mass scaled to the total of four capsule inhalation. It was assumed that the complete capsule dose of TIP would be released after an inhaled volume of 1.2 liter. Although it is required to inhale TIP twice, it was shown that most patients are able to empty the capsule in a single inhalation (Standaert el al.“Young cystic fibrosis patients can effectively use a novel high-payload capsule-based dry powder inhaler with tobramycin powder for inhalation (TPI).” Pediatric Pulmonol. 2004, Vol. 38, pg. 284). To strengthen the statistical models (all patients having the same amount of inhalations), only the first inhalation was simulated. If a patient was not able to inhale with a volume of 1.2 L, the dose of TIP injected into the model was adjusted relative to the inhaled fraction of 1.2 L. In the TIP simulations, exhalations were not accounted for, as the patient instructions list a breath holding of five seconds during which the medication is assumed to be deposited (Newhouse el al.“Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers.” Chest 2003, Vol. 280, pp. 360- 366). [00116] For TIS, the characteristics of nebulized droplets were considered to be flow independent. Aerosol characteristics that were measured at a flow rate of 15 L/min for all CFD computations were used. In each individual TIS simulation, TIS was continuously released until a full dose of 5 mL (300 mg of tobramycin) was nebulized, while inspirations were followed by expirations. Exhaled drug (drug that left the model during expiration phase) and drug released by the nebulizer during expiration was considered lost to the environment. For each patient, we used individual inhalation - exhalation ratios. Thus, the exhalation time of an individual patient had a large impact on the total amount of lost drug.
Tobramycin Concentration
[00117] To compute tobramycin concentrations throughout the bronchial tree, the surface area of each reconstructed airway and of all the combined small airways was calculated. Concentrations of tobramycin in pg/mL were computed for the extrathoracic and central airways and for each lung lobe, with distinction between the large and the small airways. To assess the deposition with CFD, the following assumptions were made: First, it was assumed that particles were deposited once they touched the airway walls. Second, it was assumed that particles that were delivered beyond the reconstructed airway model were distributed evenly over the small airway surface area (determined by the Phalen model as described above). Third, it was assumed the thickness of the airway surface liquid to be constant to compute concentrations. The ratio of deposited drug mass and airway surface liquid volume of each lung region is defined as its averaged drug concentration. These concentrations were computed for three different scenarios: a moderate thin (3 pm), in between (5 pm), and a thick layer (7 pm) of airway surface liquid. For the concentrations of deposited drug presented in this Example, the airway surface liquid thickness was 7 pm (worst case scenario). Concentrations for the other lining fluid layer scenarios can easily be calculated by dividing the outcomes by 7 pm and multiplying them by 3 pm or 5 pm.
Effective Tobramycin Concentration
[00118] To set the tobramycin concentration for effective inhibition of Pa growth, a starting point a MIC of 4 pg/mL as described by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) was selected. However, an effective conservative tobramycin concentration was defined as ten times MIC, e.g., 40 pg/mL, as there are many factors such as mucus binding and mucociliary clearance that may negatively affect the activity of tobramycin (Bos et al.“The fate of inhaled antibiotics after deposition in cystic fibrosis: How to get drug to the bug?” J. Cystic Fibres. 2017, Vol. 16, pp. 13-23).
Statistical Analysis [00119] Patient characteristics are tabulated using descriptive statistics, categorical data being presented as counts (n) and proportions (%). Continuous data are presented as median and interquartile ranges. The outcomes of the assessment are shown in box-and-whisker plots. To investigate differences in concentrations between different TIP inhalation maneuvers and differences in concentration between TIP and TIS, generalized estimating equation models for correlated data were used. These models account for multiple measurements within each patient. The reference conditions for the models were uninstructed TIP inhalations to assess differences within TIP, and TIS inhalations to assess differences between TIP and TIS. CT scan model and lung region were considered possible confounders. To check whether our results were biased by patients who did not receive a full dose of TIP because not all their inhaled volumes reached the needed 1.2 L to empty a capsule, sensitivity analyses were done without those patients. Results of testing are considered significant if the p-x alue is below 0.05. SPSS/PC statistics (SPSS Inc. Chicago, IL, USA) and statistical software package R, version 3.4.3 (free download) were used for the statistic calculations.
Ethics
[00120] Written informed consent for the use of de-identified data was obtained from the patients and/or their parents or guardians depending on their age. Approval for both the observational study and the Sophia database was obtained by the Institutional Review Board of Erasmus Medical Center, Rotterdam, the Netherlands (MEC-2015-329 and MEC-2013-078 respectively).
Results
[00121] The patient population selected from the clinical study consisted of four females (33%) and eight males (66%). Patients were divided into the three subpopulations as follows: child (n=2), adult female (n=3), and adult male (n=7). Patient demographics and lung function data are presented in Table 1 below:
Table 1
Figure imgf000025_0001
Figure imgf000026_0001
[00122] The patients inhaled TIP with a wide range of flows. FIGS. 4A-4C show the inspiratory flow curves of the uninstructed, instructed fast, and instructed slow TIP inhalations. All patients performed an instructed fast inhalation that was faster than the uninstructed inhalation. Similarly, the instructed slow inhalation for all patients was slower than the uninstructed inhalation. Except for two situations, all patients were able to inhale more than the minimum volume of 1.2 L needed to inhale the full content of the capsule. One patient inhaled only 0.5 L through the T-326 inhaler with the instructed fast inhalation, and another patient inhaled only 0.7 L with the uninstructed inhalation. For the modeling of this maneuver, the inhaled dose of TIP was adjusted to 42% and 58% respectively.
[00123] For TIS, mean inspiratory flow curves from the same population that were calculated for each individual ranged from 0.2 - 2.4 L.
[00124] FIG. 5 illustrates the computed tobramycin concentrations throughout the bronchial tree for uninstructed, instructed fast and instructed slow inhalations of TIP and the TIS inhalations for three single study subjects and for three of the nine CT models.
[00125] In FIGS. 6A and 6B, the box-and-whisker plots summarize the computed tobramycin concentrations in the large and small airways of all simulations for each flow type and device. Large airway concentrations were up to 100-fold greater compared to small airway concentrations, which is a result of the much smaller airway surface in the large airways compared to the small airways. Median (interquartile range) concentrations were 73,597 (41,587 - 126,353) pg/mL in the large airways and 1,038 (719 - 1,500) pg/mL in the small airways.
[00126] In FIG. 7, the concentrations of tobramycin in the extrathoracic and central airways are shown. Median (interquartile range) tobramycin concentrations were 226,721 (159,044 - 368,656) pg/mL in the extrathoracic airways and 44,378 (23,142 - 65,819) pg/mL in the central airways.
[00127] The complete results of the generalized estimating equation models are presented in Tables 2 and 3, below:
Table 2
Figure imgf000026_0002
Figure imgf000027_0001
Table 3
Figure imgf000027_0002
[00128] First, whether tobramycin concentrations differed between instructed inhalations of TIP, TIS inhalations, and uninstructed TIP inhalations was assessed (Table 2), with the latter being the reference in the generalized estimating equation model. Both instructed slow TIP inhalations and TIS inhalations resulted in significantly reduced extrathoracic airway concentrations (p = 0.024 and p < 0.001), and greater central (p = 0.047 and p < 0.001), large (p = 0.006 and p < 0.001), and small (both p < 0.001) airway concentrations when compared with uninstructed TIP inhalations. Instructed fast inhalations did not result in significantly different concentrations when compared to uninstructed inhalations for any airway region.
[00129] Second, whether tobramycin concentrations of all TIP inhalations differed significantly from that of TIS inhalations was assessed (Table 3), with TIS being the reference in the generalized estimating equation model. TIS inhalations resulted in significantly reduced concentrations in the extrathoracic airways and in significantly greater central, large, and small airway concentrations when compared with all TIP inhalations (all p < 0.001), except for instructed slow TIP inhalations, which resulted in similar small airway concentrations as TIS.
[00130] When redoing the analysis excluding the two patients who did not reach a volume of 1.2L in all their inhalations, the outcomes of the generalized estimates equation models did not show different significant results.
[00131] FIGS. 8A-8D show the deposition of tobramycin per lung lobe in the large and small airways for both TIP and TIS. The tobramycin concentrations in both the large and small airways in all lung lobes were all well above the cut-off value for effective inhibition of 40 pg/mL, assuming an airway surface liquid layer of 7 pm. Of the patients who received a complete dose of TIP, the lowest local concentration of tobramycin in our simulations was found in the small airways in the left upper lobe of an adult female after an uninstructed inhalation of TIP. The tobramycin concentration was 128 pg/mL, which is still more than triple the amount of the effective threshold concentration of 40 pg/mL. The highest local concentration of tobramycin in the small airways was found in the left lower lobe of an adult male after inhalation of TIS. The tobramycin concentration was 5,656 pg/mL, which is 141- fold greater than the effective threshold concentration.
Discussion
[00132] The present study investigated the effect of inhalation maneuvers and different formulations of tobramycin on the deposition throughout the lung with CFD. Instructed slow inhalations of TIP result in greater tobramycin concentrations in the large and small airways compared to inhalations of TIP without instruction. Furthermore, inhalations with TIS results in greater large and small airway concentrations when compared to all TIP inhalations, except for the instructed slow TIP inhalations. For the slow TIP inhalations, the small airway concentrations were similar to those of TIS. All inhalations led to a concentration of tobramycin that was at least triple the amount of the effective clinical cut-off value of 40 pg/mL. Based on these results, it is feasible to instruct patients to achieve greater small airway deposition and/or to provide devices that allow this greater deposition. The conclusions are therefore directly relevant to daily clinical care.
[00133] According to the results, the drug deposition of TIP is dependent on inspiratory flow rates. This finding contradicts the results of an earlier study that concluded that the T- 326 inhaler is flow-rate independent, when experimentally measuring total lung doses at the level of the trachea with in vitro mouth throat deposition models (Haynes el al.“Inhalation of tobramycin using simulated cystic fibrosis patient profiles.” Pediatric Pulmonol. 2016, Vol. 51, pp. 1159-1167). However, there were a few differences between the two studies. First, different throat models were used (no comparative studies between these models were performed). Furthermore, we assessed lung deposition for a larger number of flows: 36 flows as compared to 10 flows that were selected from 152 flows of 38 patients in the earlier study. In addition, the present flows showed a wider variation: peak inspiratory flows of 30 - 113 L/min were measured as compared to 49 - 88 L/min in the study of Haynes et al. Hence, the present results are likely to be representative of a more heterogeneous patient population.
[00134] Results reported here show greater tobramycin deposition in large and small airways by TIS, when compared to TIP inhalations. This finding contradicts results of a gamma scintigraphy study in healthy volunteers, in which more drug was delivered into the lungs with TIP than with TIS (Geller et al.“Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology.” J Aerosol Med Pulm Drug Deliv. 2011, Vol. 24, pp. 175-182; Challoner et al.“Gamma scintigraphy lung deposition comparison of TOBI in the Pasri LC Plus nebulizer and the Aerodose inhaler.” Am. J. Respir. Crit. Care Med. 2001, pg. 163). There are several differences between the two studies.
[00135] First, the gamma scintigraphy study was carried out with healthy volunteers whereas the current study was carried out with CF patients. Second, the inspiratory flows for the TIS simulations were based on mean inhalation recordings of 15 seconds and assumed consistent, periodic inhalation cycles during the use of the nebulizer for the complete treatment. When comparing the mass balances of tobramycin delivery with the Pari LC Plus® nebulizer observed by Newhouse with those from Lenney (Lenney et al.“Lung deposition of inhaled tobramycin with eFlow rapid/LC Plus jet nebulizer in healthy and cystic fibrosis subjects.” J. Cyst. Fibres. 2011, Vol. 10, pp. 9-14), the important relevance of the exhaled mass fraction on the much smaller lung deposition fraction can be detected. Even though device and extrathoracic losses are very similar in both publications, differences in patients or in their instruction can lead to different amounts of exhaled drug. As the computational modeling in this study did not account for exhalation once a drug particle reached the small airways, the amount deposited in these small airways and therefore the drug concentration might be overestimated for TIS. This modeling bias may explain the inconsistency with the results from scintigraphy studies and motivate further investigation on the sensitivity of nebulized therapies on variability of inhalation maneuver and its influence on deposited and exhaled fraction.
[00136] Uninstructed inhalations with TIP resulted in greater extrathoracic airway concentrations of tobramycin compared with TIS. This finding could be explained by the fact that the flows through the relatively small mouthpiece cross-section of the T-326 inhaler are much higher than when inhaling quietly through the relatively wide Pari LC Plus® nebulizer. This jet effect in combination with the higher inhalation rate results in greater velocity behind the mouthpiece for TIP compared with TIS. The consequences are higher inertial forces and increased deposition of the inhaled aerosol particles in the oral cavity, which was already observed in the clinical deposition studies using scintigraphy. This explains the difference in TIP and TIS concentrations in the extrathoracic airways observed by Konstan el al., who found greater sputum concentrations of tobramycin with use of TIP as compared to TIS (Konstan et al. “Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial.” . Cystic Fibres. 2011, Vol. 10, pp. 54-61). High concentrations in the upper airways might be disadvantageous as increased numbers of fungal organisms {Candida albicans and Aspergillus sp.) are found in patients who nebulized TIS (Cheer el al. “Inhaled tobramycin (TOBI): a review of its uses in the management of Pseudomonas aeruginosa infections in patients with cystic fibrosis.” Drugs 2003, Vol. 63, pp. 2501-2520). It is likely that greater extrathoracic airway concentrations of tobramycin might further increase this effect.
[00137] However, in silico studies require assumptions, which are potential confounders of the results. Accordingly, the following are possible limitations of the present study.
[00138] First, CFD analyses are validated with SPECT-CT scan studies with asthma patients using nebulized aerosol particles at lower flow rates (30 L/min) that might behave differently than TIP PulmoSphere™ particles. Due to the porous formulation of TIP, the particles have a low contact surface area, reducing cohesive forces among particles, which prevents agglomeration. Therefore, the models may have led to an underestimation of the true deposition of TIP. The present study did not include a SPECT-CT versus CFD validation study with CF patients using TIP PulmoSphere™ particles. That said, physical characteristics such as mass median aerodynamic diameter and its geometric standard deviation are the most decisive factors to predict aerosol behavior. By taking these characteristics of TIP into account, the present simulations are fit as closely as possible to in vivo situations.
[00139] Tobramycin concentrations are sufficiently high throughout the bronchial tree, using a clinical effective cut-off value of ten times MIC. The present results were related to the data provided by EUCAST, e.g., a MIC of tobramycin for P. aeruginosa of 4 pg/mL. Conservatively, the clinical cut-off was set at a value at ten times MIC, or 40 pg/mL. Nevertheless, the clinical cut-off value at ten times MIC does not necessarily mean that concentrations are high enough to be effective. Bos et al. described in a review that the effectiveness of inhaled antibiotics is influenced by multiple factors. The binding of thick CF mucus to tobramycin molecules actuates various mechanisms that can lead to a decreased number and/or inactivation of these molecules. Therefore, the present in silico situation might be more positive than the in vivo situation.
[00140] Furthermore, it was assumed that particles were distributed evenly over the small airways surface area. In reality, this distribution is uneven (Kleinstreuer el al.“Targeted drug-aerosol delivery in the human respiratory system.” Annu. Rev. Biomed. Eng. 2008, Vol. 10, pp. 195-220), as some airways may be partially or totally occluded by mucus, resulting in no or less tobramycin deposition to the periphery of those airways, while other airways are open enabling inhaled particles to pass. Hence, the present models of the small airways do not account for the possibility that some areas will not receive any tobramycin at all.
[00141] Patients are required to inhale TIP at least twice per capsule. However, of the 36 recorded inhalations with TIP, 34 (94%) were of a volume above the required 1.2 L to empty the content of a capsule. In the simulations, only one inhalation was simulated per occasion. Hence, the delivered dose was underestimated in the simulations because of the two patients who did not empty their capsule in one inhalation. However, when a sensitivity analysis excluding these patients was performed, the results were similar.
[00142] In conclusion, instructed slow inhalation of TIP resulted in greater concentrations of tobramycin in both the large and small airways compared to uninstructed inhalation as well as instructed fast inhalations. When patients are instructed to inhale TIP slowly, the deposition in the small airways is comparable to that of TIS. Importantly, all inhalation maneuvers with both TIP and TIS resulted in concentrations well above a concentration of ten times MIC for P. aeruginosa, even in the small airways. Careful and repeated instructions of patients regarding appropriate inhalation are important to target the small airways with an antibiotic deposition as high as possible.
[00143] Although the devices and methods have been described in detail for the purpose of illustration based on what is currently considered to be the most practical and preferred embodiments, it is to be understood that such detail is solely for that purpose and that the systems and methods are not limited to the disclosed embodiments, but on the contrary, is intended to cover modifications and equivalent arrangements that are within the spirit and scope of the appended claims. For example, it is to be understood that the present systems and methods contemplate that, to the extent possible, one or more features of any embodiment can be combined with one or more features of any other embodiment.

Claims

THE INVENTION CLAIMED IS
1. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising:
administering to a respiratory tract of the patient an effective amount of a nebulized composition comprising tobramycin,
wherein the nebulized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
2. The method of claim 1, wherein the nebulized composition comprises tobramycin and saline.
3. The method of claim 1, wherein the nebulized composition is administered to the patient at a flow rate of 15 liters per minute.
4. The method of claim 1, wherein the nebulized composition is administered to the patient for at least four seconds.
5. The method of claim 1, wherein at least about 5 milliliters of the nebulized composition is delivered to the patient’s respiratory tract.
6. The method of claim 1, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
7. The method of claim 6, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 1000 micrograms per milliliter.
8. The method of claim 1, wherein the nebulized composition includes tobramycin particles having a mass median diameter of 20 microns or less.
9. The method of claim 1, wherein the nebulized composition includes tobramycin particles having a mass median aerodynamic diameter of 10 microns or less.
10. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of claim 1.
11. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising:
administering to a respiratory tract of the patient an effective amount of an aerosolized composition comprising tobramycin,
wherein the aerosolized composition is administered to the patient at a flow rate of less than or equal to 100 liters per minute for at least three seconds.
12. The method of claim 11, wherein the aerosolized composition is administered to the patient at a flow rate of 80 liters per minute or less.
13. The method of claim 11, wherein the aerosolized composition is administered to the patient for at least four seconds.
14. The method of claim 11, wherein at least about 5 milliliters of the aerosolized composition is delivered to the patient’s respiratory tract.
15. The method of claim 11, wherein a concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 40 micrograms per milliliter.
16. The method of claim 15, wherein the concentration of tobramycin in peripheral airways of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
17. The method of claim 11, wherein the aerosolized composition includes particulate tobramycin having a mass median diameter of 20 microns or less.
18. The method of claim 11, wherein the aerosolized composition includes particulate tobramycin having a mass median aerodynamic diameter of 10 microns or less.
19. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of claim 11.
20. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising:
administering to a respiratory tract of the patient an effective amount of a particulate composition comprising tobramycin, calcium chloride, and distearoyl phosphatidyl choline, wherein the particulate composition has a mass median diameter of 20 microns or less and a mass median aerodynamic diameter of 10 microns or less,
wherein the particulate composition is administered to the patient at a flow rate of less than or equal to 80 liters per minute for at least three seconds, such that a concentration of tobramycin in at least one peripheral airway of the patient’s respiratory tract following administration is at least 200 micrograms per milliliter.
21. A method of treating a Pseudomonas aeruginosa infection in a patient having cystic fibrosis, comprising prescribing for the patient a regimen including performing the method of claim 20.
22. A kit comprising:
a handheld aerosolization apparatus comprising:
a housing having at least two air inlets, the inlets configured and dimensioned to produce a swirling airflow;
a mouthpiece comprising a perforated member and an aerosolized pharmaceutical formulation outlet, the mouthpiece being connectable to the housing to define a capsule chamber, the mouthpiece further comprising a shield which covers at least one air inlet, wherein the shield prevents blockage of at least one air inlet by a user grasping the apparatus; and
a puncturing mechanism disposed within the housing for creating one or more openings in the capsule;
at least one blister pack comprising:
a plurality of capsules comprising a powdered composition comprising tobramycin; and instructions for the user to actuate the apparatus to release the powdered composition and to inhale the powdered composition at a rate of less than or equal to 80 liters per minute for at least three seconds.
23. The kit of claim 22, wherein the mouthpiece of the apparatus is configured to limit a flow therethrough to 80 liters per minute or less.
24. The kit of claim 22, wherein the handheld aerosolization apparatus further comprises a flow sensor configured to measure flow through the mouthpiece.
25. A kit comprising:
a plurality of ampules, each ampule of the plurality of ampules comprising a solution comprising tobramycin and saline; and
instructions that instruct a user to:
nebulize the solution with a nebulizer; and
inhale, through a mouthpiece of the nebulizer, the nebulized solution at a rate of 15 liters per minute for at least three seconds.
26. The kit of claim 25, further comprising a nebulizer comprising:
a housing having a proximal end, a distal end, and a sidewall therebetween defining a lumen, the lumen configured to receive the solution;
a compressed gas inlet at the proximal end of the housing;
a cap assembly configured to be removably connected to the distal end of the housing, the cap assembly comprising a cap and a stem extending from the cap and configured to be received in the lumen;
an outlet comprising an opening in the sidewall; and
a mouthpiece configured to be removably connected to the outlet.
27. The kit of claim 26, wherein the mouthpiece is configured to limit a flow therethrough to 15 liters per minute.
28. The kit of claim 26, wherein the nebulizer further comprises a flow sensor configured to measure flow through the mouthpiece.
29. A method of training a patient to self-administer an aerosolized or nebulized composition comprising tobramycin, the method comprising the steps of:
providing an aerosolization apparatus or a nebulizer, comprising a flow sensor; measuring, with the flow sensor, flow through the aerosolization apparatus or nebulizer during an inhalation phase of the patient’s respiration to obtain a measured flow value;
comparing the measured flow value to a target flow value; and providing feedback to the patient when the measured flow value exceeds the target flow value.
30. The method of claim 29, wherein the target flow value is 100 liters per minute.
31. The method of claim 29, wherein the target flow value is 80 liters per minute.
32. The method of claim 29, wherein the target flow value is 15 liters per minute.
PCT/US2020/016695 2019-02-05 2020-02-05 Devices and methods for tobramycin inhalation treatment WO2020163416A1 (en)

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