Patent Application
20210077750
The present disclosure relates to a microstructured passage module and more particularly to a microstructured passage module for an aerosol generator.
Aerosolizer, also known as nebulizer or atomizer, is used to deliver medication to patients for inhalation. Particularly, liquid medicament is broken down into aerosol having fine particles/droplets for easier and more efficient inhalation and absorption. The particle size may be adjusted depending on different respiratory conditions, such as Chronic Obstructive Pulmonary Disease (COPD) or asthma, or depending on the requirement of the liquid medicament itself. The ability to receive the same precise amount of medication in each treatment is also very important for patients. In other words, a good aerosolizer should be able to deliver a precise dosage of medication having a fixed average particle size, a certain range of MMAD (Mass Median Aerodynamic Diameter), and at certain spray duration in every operation to reduce waste and risks of overdosing.
Referring to
As shown in
In another aspect, the nozzle 963 plays a pivotal role in whether the pressurized liquid medicament can be aerosolized into fine particles/droplets and exit the aerosolizer at a certain speed. As shown in
A typical nozzle used in an aerosolizer includes multiple elements with different geometric shapes. For example, some elements with a particular shape, e.g., elongated projections, are used as filters. Some other elements with a different shape, e.g., cylindrical projections, are used to structure a guiding system to control the liquid flow in the nozzle. In short, a nozzle used in the relevant art requires the combination and interaction of multiple elements having different structural and/or functional characteristics in order to achieve the desired aerosolization effect. However, due to the miniature size of the nozzle, fluid control therein is not easy. The structure, dimension and arrangement of the elements in the nozzle need to be carefully implemented to make the nozzle effective. As a result, the costs for the design and manufacture of the nozzle tends to be high.
The present disclosure aims to provide a nozzle structure with less complicated structure, design and arrangement. The resulting nozzle will improve the overall aerosolization quality and efficiency, while the cost for manufacturing such nozzle is reduced. Accordingly, patients can enjoy a more affordable treatment solution.
The present disclosure provides a microstructured passage module for an aerosol generator. The module includes a plate overlaid by a cover thus forming a compartment, an entrance for a liquid and an exit. The plate further includes a filtering structure. An exemplary filtering structure includes walls, pillars, protrusions, and combination thereof. In some embodiments, the plate includes a plurality of walls parallel to each other over its entire width so as to define a plurality of passages therebetween. The walls are arranged along a flow direction, which is substantially perpendicular to the entrance. In certain embodiments, a plurality of pillars protruding from the plate are evenly distributed in at least a section of the passages. In yet some other embodiments, the wall could be configured continuously or un-continuously. A column is disposed proximate to the exit and blocks a substantial part thereof, leaving longitudinal aisles for the liquid to leave via the exit. The liquid flows through the compartment from the entrance to the exit such that an aerosol is produced. A distance between two adjacent pillars is D and the longitudinal aisle has a width W. The D and the W are specifically configured such that the aerosol has a predetermined MMAD. In certain embodiments, the distance D and the width W are specifically configured to effectively deliver aerosolized drug to patient's lung. To achieve the foregoing, the aerosol must have an MMAD value less than 5.5 um and preferably between 4 um to 5.5 um. Further, for aerosol having MMAD less than 5.5 um, the spray duration is preferred to be approximately 1.6 seconds. Said combination increases the effectiveness of fine particles to be delivered into specific lung regions of a user, thus resulting in a more desirable treatment result. In certain embodiments, the microstructured passage module and the components thereof are specifically configured and arranged such that liquid medicament having certain characteristics can be aerosolized to have predetermined and consistent MMAD and spray duration, under certain liquid medicament conditions. The formulation of liquid medicament contains active pharmaceutical ingredients, stabilizer and preservatives. The active pharmaceutical ingredient may be selected singly or in combination from the group of betamimetics, anticholinergics, antiallergics, antihistamines, and/or steroids. Moreover, the liquid medicament is ethanol-free and may possess certain range of characteristics, such as viscosity and surface tension.
One or more embodiments are illustrated by way of example, and not by limitation, in the figures of the accompanying drawings, wherein elements are having the same reference numeral designations represent like elements throughout. The drawings are not to scale, unless otherwise disclosed.
The drawings are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. The dimensions and the relative dimensions do not necessarily correspond to actual reductions to practice of the invention. Any reference signs in the claims shall not be construed as limiting the scope. Like reference symbols in the various drawings indicate like elements.
The making and using of the embodiments of the disclosure are discussed in detail below. It should be appreciated, however, that the embodiments provide many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed are merely illustrative of specific ways to make and use the embodiments, and do not limit the scope of the disclosure.
Throughout the various views and illustrative embodiments, like reference numerals are used to designate like elements. Reference will now be made in detail to exemplary embodiments illustrated in the accompanying drawings. Wherever possible, the same reference numbers are used in the drawings and the description to refer to the same or like parts. In the drawings, the shape and thickness may be exaggerated for clarity and convenience. This description will be directed in particular to elements forming part of, or cooperating more directly with, an apparatus in accordance with the present disclosure. It is to be understood that elements not specifically shown or described may take various forms. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It should be appreciated that the following figures are not drawn to scale; rather, these figures are merely intended for illustration.
In the drawings, like reference numbers are used to designate like or similar elements throughout the various views, and illustrative embodiments of the present disclosure are shown and described. The figures are not necessarily drawn to scale, and in some instances the drawings have been exaggerated and/or simplified in places for illustrative purposes. One of ordinary skill in the art will appreciate the many possible applications and variations of the present disclosure based on the following illustrative embodiments of the present disclosure.
It will be understood that when an element is referred to as being “on” another element, it can be directly on the other element or intervening elements may be present. In contrast, when an element is referred to as being “directly on” another element, there are no intervening elements present.
It will be understood that singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, relative terms, such as “bottom” and “top,” may be used herein to describe one element's relationship to other elements as illustrated in the Figures.
It will be understood that elements described as “under” or “below” other elements would then be oriented “over” or “above” the other elements. The exemplary terms “under” or “below” can, therefore, encompass both an orientation of over and under.
The term “about,” as used herein, when referring to a measurable value such as an amount, a temporal duration, aerosol measurements, and the like, is meant to encompass variations of ±10% and more preferably ±5% from the specified value, as such variations are appropriate to achieve the intended purpose of the present disclosure.
Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will be further understood that terms; such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.
The microstructured passage module 1 is the pivotal component of the aerosolizer 90 where liquid medicament can be broken down into aerosol having fine particles/droplet. The microstructured passage module 1 of the aerosolizer 90 is a component having a microstructured filtering and guiding system, which consists of a plurality of microscale elements and a plurality of passages defined by such microscale elements. When pressured liquid medicament travels into the microstructured passage module 1 at a high speed, the microscale elements will partially block the flowing medicament and parse it into small particles. Furthermore, the configuration of the microscale elements and the passages therebetween will increase flow resistance, thereby reduce the liquid flow speed.
Furthermore, to increase effective aerosol deposition in lung, an ideal aerosol should have certain ranges of MMAD and spray duration. For example, the MMAD should be less than 5.5 um, and the spray duration is between about 1.2 and about 1.6 seconds. In some preferred embodiments, the MMAD is between about 4 um and 6 um; and the spray duration is between about 1.2 and about 1.6 seconds, and more preferably between about 1.4 and about 1.6 seconds. An aerosol having MMAD between about 4 um and 6 um is desirable for inhalation therapy. An aerosol having MMAD higher than such range makes it harder to reach the patient's lung. For example, the aerosol is more likely to be deposited at the throat. On the other hand, an MMAD lower than such range increases the chance of undesired aerosol dissemination. As a result, not enough aerosol reaches the patient's lung, and the therapy is considered ineffective. For spray duration, if that of the aerosol falls out the foregoing range, the inhalation efficiency of the patient will be affected. The chance of clogging or residue may increase, thereby affecting treatment. For example, undesired spray duration may negatively affect the amount of aerosolized medicament a patient inhales at a given time. The present disclosure provides a passage module 1 to better achieve the foregoing MMAD and spray duration. More details of the resulting aerosol will be discussed later.
FIB. 3B is a sectional view of the passage module 11 along the dotted line X-X′ as shown in
Referring to
The plate 10 may further include several components, such as a column 2, spacers 3, pillars 4 and walls 5. The arrangement of pillars 4, the spacers 3 and the walls 5 constitute a filtering structure for the microstructured passage module 1. The spacers 3, walls 5, pillars 4, and column 2 are adapted to project from the plate 10 in the direction transversely to the liquid flow direction In some embodiments, the spacers 3 are configured and arranged in a row proximate to the entrance 102, and a distance between two adjacent spacers 3 is about two times wider than the width of the passage 18. A cross-section of each spacer 3 is rectangular and the dimension of each spacer 3 is about 50 um width and about 200 um long. Generally, the spacers 3 is used as a preliminary filter for the liquid medicament entering the compartment and for dividing the liquid flow into separate passages 18.
In one embodiment, these components may be formed as integral parts of the plate 10 by etching the microstructured passage module 1. In certain embodiments, a depth of about 5-6 um of the plate 10 is etched so as to form such integral components. A depth may have a manufacturing tolerance about 1 um. Note that the manufacturing method of the plate 10 is not so limited. The plate 10 may be manufactured by other means known in the relevant art, such as molding, welding or printing. Further characteristic and the configuration of the integral components are further described below.
With reference to
Referring to both
In some embodiments, for the unfiltered liquid medicament entering the microstructured passage module 1, the space between two walls 5 are used as filters. For example, any particle with size larger than the width of the passage 18 will be blocked and therefore filtered. The walls 5 may further guide the direction of the liquid flow, such that liquids flow along the direction A-A′ more uniformly. Accordingly, turbulences may be reduced. In some embodiments, as shown in
As shown in
As shown in
Attention is now directed to Table 1 below. Table 1 shows a comparison of droplet size known as Mass Median Aerodynamics Diameter (MMAD) measured by Next Generation Impactor (NGI) Reference: USP 36 (601) Aerosols, Nasal Sprays, Metered-Dose Inhalers, AND Dry Powder Inhalers for aqueous solution.
In the present disclosure, the distance D and the width W are specifically configured for a pressurized aqueous liquid. The resulting aerosol has certain predetermined MMAD and spray duration.
The resulting (n=3) shown in Table 1, aerosol 50 has an MMAD less than about 5.5 um, and more preferably between about 4 um and 5.5 um. Moreover, the spray duration thereof is less than 1.6 seconds, particular between about 1.2 and 1.6 seconds and more preferably between about 1.4 and 1.6 seconds. Correspondingly, the spray velocity of the aerosol 50 exiting the exit 104 is between about 169 m/s and 175 m/s. Table 1 further shows a comparison of fine particle fraction (FPF) less than 5 micron for a pressurized aqueous solution. In one embodiment, the fraction of the droplets which are less than 5 micron in size is less than 50% and preferably between 35% to 45%.
To achieve the foregoing, the distance D and the width W needs to be specifically configured. In some embodiments, the width W is between about 7 um and 8 um and in combination with the distance D is between about 7 um and 8 um. Preferably, one of the width W and the distance D is less than 8 um, and/or another of the width W and the distance D is larger than 7 um. This is beneficial to generate a MMAD less than about 5.5 um and spray duration about 1.5 to 1.6 second. The forgoing leads to a desired particle size and soft mist for delivering drug to the lung of patient.
In other words, patients are capable of inhaling a fixed amount of aerosol having ideal particle size in every operation of the aerosolizer. However, the present disclosure should not be limited to the textual description. That is, any combination of the width W and the distance D within the range specified in Table 1 is within the scope of the present disclosure. In addition, the foregoing is capable of help producing aerosol having desirable MMAD and spray duration disclosed herein.
However, the liquid possesses certain characteristics and the selection thereof relates to the operation and desired result of the aerosolizer. Specifically, the aerosolizer delivers a less than 20 ul of liquid solution via an at least 50 bar of pressure source to generate a therapeutically effective propellant-free aerosol. To be considered as therapeutically effective, the aerosol must possess the characteristic disclosed herein. To achieve the foregoing, the liquid itself and the environment thereof must be controlled.
In certain embodiments, the formulation of the liquid contains no propellant gases. Furthermore, the formulation of liquid contains active pharmaceutical ingredients, stabilizer and preservatives. The active pharmaceutical ingredient may be selected singly or in combination from the group of betamimetics, anticholinergics, antiallergics, antihistamines, and/or steroids. For example, the active ingredient is selected singly or in combination form Albuterol Sulfate, Ipratropium Bromide, Tiotropium, Olodaterol, Budesonide, Formoterol, Fenoterol etc. The active pharmaceutical ingredient desirably has a concentration of 0.001 to 2 g/100 ml in a solution; A suitable stabilizer may be EDTA (ethylenediamine tetraacetic acid)) having a concentration of 0.001 to 1 mg/ml in a solution, particularly about less than 0.5 mg/ml and preferably about less than 0.25 mg/ml; A suitable preservative may be Benzalkonium Chloride. Moreover, the pH value of the formulation solution is adjusted to a specific range, and the formulation solution may include citric acid, and/or hydrochloric acid. In certain preferred embodiments, the ingredients of the liquid may be tiotropium bromide (or the like) of 0.22-0.23 mg/ml, Benzalkonium (or the like) of 0.08 mg/ml-0.12 mg/ml and EDTA (or the like) 0.08-0.12 of mg/ml. Moreover, the pH value is between 2.7-3.1. The acidic pH value may be used to stabilize the formation and achieve the delivery of desired dose level. Moreover, in a preferred embodiment, the liquid has a low viscosity, about 0.88 cP at room temperature. The surface tension of the liquid is between about 43 mN/m and 48 mN/m. In another embodiment, liquid is aerosolized to form a propellant-free aerosol for administering to the lungs of the patient.
As shown in
In addition to the foregoing, the combination of the specific structural design of the microstructured passage module 1 and the selection of liquid formation enables the aerosolizer to produce aerosol having predetermined MMAD and spray duration under an extended range of temperature. Attention is now directed to Table 2 below.
Table 2 shows the effect of different working temperatures for the specifically configured microstructure passage module 1 disclosed herein. It was found that the aerosolizer (n=3) can be operated at working temperature of about 4 to 25 degree Celsius. In one example, the storage container holding the drug is stored in a refrigerator, giving it a 4 degrees Celsius environment before the operation of the aerosolizer. As shown by Table 2, the present disclosure enables the aerosolizer to produce aerosol having similar characteristics at 4 degrees and 25 degrees Celsius. In other words, the present disclosure presents a specifically configured microstructured passage module 1 such that desirable aerosol can be produced in a stringent condition. Patients benefit from the foregoing because their aerosol inhalation treatment may be administered under more diversified circumstances. Further, in response to the extended operable temperature range, the aerosolizer becomes suitable for liquid medicament having certain liquid viscosity. In some embodiments, the viscosity of the drug solution is adjusted to about 0.5 cP to 3 cP. In certain preferred embodiments, the viscosity ranges from about 0.8 cP to 1.6 cP. Note that higher viscosity may affect the average particle size of the aerosol and aerosol spray duration, and it's preferred to keep the viscosity low. Moreover, the configuration of the microstructured passage module 1 of the present disclosure enables it suitable for liquid medicament having certain surface tension. In some embodiments, the surface tension of the drug solution is between about 20 to 70 mN/m and preferably between about 25 to 50 mN/m. The lower surface tension may provide a better spreadability of the drug. As a result, aerosol deposition on the lung surface may be improved. This will increase the effectiveness of the drug and thus the inhalation treatment.
Thus, with the above desired liquid formation. the preferred microstructured passage module 1 has the width W between about 6.7 um and 8.3 um, the distance D is between about 6.7 um and 8.3 um during the viscosity range of 0.5 to 3 cP (working temperature about 4-25 degree Celsius), resulting an MMAD of less than about 5.5 um and preferably between 4 to 5.5 um, a spraying duration of less than 1.6 second, and preferably between 1.4 to 1.6 second, and a fraction of the droplets which are less than 5 micron in size less than 50% and preferably between 25% to 40%. Under this setting, the aerosol inhalation treatment is the most effective.
In other words, the present disclosure presents a specifically configured microstructured passage module 1 such that desirable aerosol can be produced in a stringent environmental condition. Patients benefit from the foregoing because their aerosol inhalation treatment may be administered under more diversified circumstances.
Overall, the present disclosure provides a microstructured passage module 1 easier to manufacture because the design and arrangement microscaled components thereof are less complicated. The resulting device can deliver a more accurate doze of aerosol, having desired MMAD and spray duration, in each operation of the aerosolizer.
The present application claims priority to PCT Application No. PCT/CN2018/085665 filed on May 5, 2018, the entire content of which is incorporated by reference to this application.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2018/085665 | 5/4/2018 | WO | 00 |
