Instruments for collecting particles from inhalable formulations

Abstract

An apparatus for collecting aerosolized inhalable particles of an inhalable medicinal preparation, comprising: a dose collection portion having an air permeable filter (F), the filter (F) extending across the path of the aerosolized inhalable particles so as to retain particulate material in the aerosolized inhalable particles on the filter, the dose collection portion comprising: an upper filter support member (40) and a lower filter support member (50), the filter (F) being circumferentially retained between the upper filter support member and the lower filter support member (40; 50) to form a filter unit, a lower body (70) accommodating the filter unit, the lower body (70) comprising a recess (72), a quick release system (100) comprising a hook (102) movable between an open position and a closed position, wherein in the open position the hook (102) is able to enter the recess (72) around the filter unit, and in the closed position the hook (102) is able to grasp the filter unit, thereby allowing the filter unit to be removed from the lower body (70) without anyone touching the filter unit.

Description

Technical Field

[0001] The present invention relates to an apparatus for collecting particles of an inhalable formulation. Background Art

[0002] Orally inhalable formulations are widely used to administer drugs via the pulmonary route. Such drugs are often used to treat or prevent pulmonary disorders, the most common of which include, for example, asthma and chronic obstructive pulmonary disease. Also, where appropriate, drugs for systemic use can be administered by inhalation.

[0003] The efficacy and systemic exposure (lung bioavailability) of inhaled drugs depend on the deposition site and physicochemical properties of the pharmaceutical formulation. Drug particles deposited in the peripheral non-ciliary regions of the respiratory tract must dissolve before metabolism or transport across the lung membrane. Therefore, dissolution is a prerequisite for cellular uptake and / or absorption by the lung. Simulations have shown that dissolution rate is the main driving factor for drug retention in the lung. At present, however, there is no pharmacopoeial method to determine the in vitro dissolution rate of aerosols generated by inhaled products.

[0004] Dissolution testing is an important tool for determining the bioavailability of a variety of drugs. Standardized dissolution test methods can be used for solid dosage forms, such as tablets and capsules. These methods are widely used for quality control and to determine the correlation with the in vivo release curve. They are a particularly important tool, where it is necessary to prove the bioequivalence of different preparations, for example, to verify the bioequivalence of generic drugs to approved preparations. So far, however, there is no generally accepted method for estimating the dissolution behavior of inhaled active ingredient dosage forms. This hinders the development of reliable bioequivalent preparations. The lack of pharmacopoeial methods is particularly manifested as an obstacle to reliably and reusably proving the bioequivalence of new inhalable generic drugs to existing registered products, and therefore makes it more difficult to obtain authorization for inhalable drugs than for most oral or injectable pharmaceutical preparations. Studies have shown that there is a good correlation between in vivo measurements of total lung deposition and in vitro measurements of lung doses. Therefore, it is necessary to collect representative lung doses for dissolution studies (e.g., expelled doses, impactor-level mass, doses below a defined impactor level, etc.). For all reported filter collection systems, there is a slower dissolution rate as the collected mass of a given formulation increases by varying the number of actuations. This effect is thought to be due to the formation of in situ agglomerates on the filter after dose collection, which reduces drug exposure to the dissolution medium during dissolution given the smaller area / volume ratio. Since dissolution characteristics should be independent of collection method and number of actuations, the inconsistency in dissolution rates is thought to be due to an artifact of the collection process. The significant variations observed in dissolution behavior limit sensitivity and create challenges when comparing formulations of the same product with different fine particle masses.

[0005] In any dissolution method, two key steps are the collection of the respirable dose to be dissolved and the dissolution step to dissolve the collected dose. In order to provide a reliable prediction of the dose that will dissolve in vivo, the sample used in the dissolution step should reflect the dose that will actually be inhaled. In some known collection methods, the respirable dose is collected on a filter in an inertial impactor.

[0006] A reliable method for estimating the dissolution behavior of inhalation products would have a variety of applications. It could be applied in the context of quality control as a tool to evaluate the effects of material properties and processing on the dissolution of active ingredients. It would have general application in the collection and dissolution studies of aerosolized doses (e.g., expelled dose, impactor-grade mass, etc.). The most important potential application would be to provide in vitro-in vivo correlation (IVIVC) technology. IVIVC technology would have the potential to allow reliable assessments of the dissolution behavior of generic pulmonary drugs, such as those evaluated on the basis of showing comparability with existing authorized products, thereby reducing current barriers to satisfactory evaluation of generic forms of, for example, inhalable drugs.

[0007] In conventional impactors, inertial effects are used to separate powders, and particles can be separated according to their particle size due to the change in inertial behavior with particle size. Inertial separation techniques are advantageous because they allow physical separation according to particle size, thereby being able to determine the deposition location of the API between the particle sizes to be determined. This may be important because the effectiveness and distribution of API deposition in the lungs will be a function of their aerodynamic particle size. Impactors with multiple nozzles or jets have a series of stages, each consisting of a plate. Air carrying aerosolized powder is drawn into the impactor and flows sequentially through each stage. The number of nozzles increases with the number of stages, while the size and total nozzle area decrease with the number of stages. As the particles accelerate through the nozzles, they either remain entrained in the air flow, which is deflected at the outlet of the nozzle, or inertia causes them to separate from the deflected flow and impact the collection surface. As the flow direction changes, the aerosolized particles continue to move in the initial direction until they lose inertia. They then "relax" to the new flow direction (relaxation time). Placing the collecting surface perpendicular to the original flow results in particles that do not have enough relaxation time to impact. Small particles relax faster and therefore do not impact. By controlling the number of nozzles or jets, their diameter (W) and the impaction stage separation (S), the effective cut-off aerodynamic diameter can be controlled at different flow rates. Thus, particles with a given inertia level are collected while, at the same time, the rest of the sample passes to the next stage. Therefore, each stage of the impactor is associated with a cut-off diameter, a number that defines the size of the particles that remain on the collecting surface of that stage of the impactor device.

[0008] The main features of the impactor stage are the nozzle plate, the impact plate, and the stage wall through which the flowing and entrained particles are conveyed. The design and engineering of the nozzle plate are most critical for the collection parameters, which are the main design parameters, the number (N) of nozzles or orifices, and their diameter (W). Changing N and W allows the Reynolds number (Re) of the air flow to be controlled between set limits (typically, 500 < Re < 3000). The relationship between the Reynolds number and the impactor geometry in impactor-type devices is well understood by those skilled in the art (see, for example, Marple et al., Atmospheric Environment, 10, pp. 891 - 896, 1976).

[0009] In addition to stage 1 of a conventional impactor, where coarse separation of large, non - respirable particles is achieved, the nozzles of known impactors are sized and configured to create a pressure differential that causes acceleration of the air flow between a point immediately upstream of the nozzle and the region immediately downstream of the nozzle. This acceleration is important for generating the inertia required for the separation process at subsequent deflection points. For example, at stage 2 of a conventional impactor operating with an air flow of 60 L / min, the air flow through the nozzles can typically be accelerated to emerge as multiple air jets with an air flow velocity of approximately 890 cm / s.

[0010] Document WO2017051180A1 discloses an instrument that overcomes the drawbacks of traditional impactors. The instrument has a dose collection section that extends across the path and has an orifice that is opposite and upstream of a filter, and the orifice has an open area that is not less than 75% of the area of the filter to be deposited on. The larger orifice provides an unobstructed path for conveying the air flow onto the filter. Thus, the air flow in the filter unit (dose collection section) of the instrument of the present invention has a lower velocity, for example, from 30 cm / s to 250 cm / s, preferably from 60 cm / s to 100 cm / s. It appears that the combination of the lower flow velocity and the greater flow rate uniformity across the path, compared to the discrete high - velocity air jets present when leaving the nozzle in a typical impactor stage, enables more uniform deposition. This enables higher reliability and reproducibility in determining the dissolution characteristics of the deposited material, which vary less according to the amount of material deposited on the filter.

[0011] However, the instrument disclosed in WO2017051180A1 also has disadvantages. In particular, the instrument makes the removal of the loaded drug filter cumbersome, requiring a series of steps and a lot of manual operations (e.g., removing multiple "Allen key" screws to release the filter from the instrument, and using tweezers to remove the filter from the instrument and transfer it to the second support assembly for dissolution testing, etc.). Summary of the invention

[0012] The object of the present invention is to overcome the above-mentioned disadvantages.

[0013] In particular, the present invention seeks to minimize handling and facilitate the ability to transfer collected aerosolized samples to secondary instruments for testing (eg, dissolution testing, in vitro release testing, microscopic analysis, etc.) that is not in direct human contact.

[0014] It is also an object of the invention to provide such an instrument which is simple and inexpensive to manufacture and assemble and which is easy to use in a reliable manner.

[0015] Thus, the present invention provides an apparatus for collecting aerosolized inhalable particles of an inhalable pharmaceutical formulation, comprising: a dose collection portion having an air permeable filter, the filter extending across the path of the aerosolized inhalable particles so as to retain particulate material in the aerosolized inhalable particles on the filter, the dose collection portion comprising:

[0016] - an upper filter support member and a lower filter support member, the filter being circumferentially held between the upper filter support member and the lower filter support member to form a filter unit,

[0017] - a lower body accommodating the filter unit, the lower body having a top surface including a recess,

[0018] - a quick release system comprising a fixing device such as a hook movable between an open position and a closed position,

[0019] wherein in the open position the fixing means are able to enter the recess around the filter unit and in the closed position the fixing means are able to grip the filter unit, thus allowing the filter unit to be removed from the lower body without anyone touching the filter unit.

[0020] Advantageously, the quick release system further comprises a clamping base, an actuating lever and a spring, wherein actuation of the actuating lever is triggered by a thumb actuator.

[0021] Advantageously, the lower filter support member comprises an outer ring connected to an inner flange, the inner flange protruding radially inwardly from the lower surface of the outer ring, the inner flange having a peripheral inner edge defining a central opening, wherein the central opening has a central support structure connected to the peripheral inner edge by at least two radial ribs, thereby defining a plurality of holes.

[0022] Advantageously, said central support structure is hexagonal, each vertex of said hexagon being connected to said peripheral inner edge by a radial rib, thereby defining seven holes.

[0023] Advantageously, the upper filter support member comprises an upper ring and a lower ring, the lower ring extending axially downward from the upper ring, the upper ring and the lower ring having the same inner diameter, and the upper ring having an outer diameter greater than the outer diameter of the lower ring, wherein the outer edge of the filter is retained between the inner flange of the lower filter support member and the lower ring of the upper filter support member.

[0024] Advantageously, the lower filter support member comprises at least one, preferably three radial projections extending radially outwardly from the outer periphery of the outer ring.

[0025] Advantageously, the top surface of the lower body comprises a first recess adapted to cooperate with the radial projection of the lower filter support member to provide rotational alignment of the filter unit on the lower body.

[0026] Advantageously, the apparatus further comprises:

[0027] - an inlet for receiving an aerosolized dose of a medicinal preparation;

[0028] - a suction source for generating a pneumatic flow through the apparatus;

[0029] - a passage defining a path extending from the inlet to the suction source;

[0030] wherein the dose collection portion is located in the pathway and includes an inlet orifice, the filter is located opposite the orifice, and the orifice is sized and configured such that a clear area of ​​the orifice is not less than 75% of an area of ​​the filter over which the dose is to be collected;

[0031] wherein the suction source is in communication with the path downstream of the filter unit;

[0032] wherein the filter unit has a filter and a filter support, the filter support including one or more support members extending across a path on a surface of the filter opposite to the orifice for supporting a central area of ​​the filter, the filter support defining two or more apertures and blocking no more than 80% of the surface area of ​​the opposite surface.

[0033] Advantageously, the orifice is sized and configured such that it has an outlet area not less than 80%, preferably not less than 90% of the area of ​​the filter on which the dose is collected.

[0034] Advantageously, the filter is selected from the group consisting of a woven fabric, a nonwoven fabric, a mesh and a breathable membrane.

[0035] Advantageously, the filter comprises a fabric formed of glass microfibres, or a fabric formed of filaments of a polymeric material chosen from polycarbonate, polyester, polyolefin, polyamide, polyvinyl chloride and polyetheretherketone.

[0036] Advantageously, the filter comprises a metal mesh, such as a stainless steel mesh.

[0037] Advantageously, the filter has a pore size of no greater than 5 μm, preferably no greater than 3 μm.

[0038] Advantageously, the filter has a pore size of at least 1 μm.

[0039] Advantageously, the filter has an air permeability such that the filter produces a flow rate reduction of no more than 20%, preferably no more than 15%, more preferably no more than 10% relative to the absence of the filter.

[0040] definition:

[0041] "Inhalable pharmaceutical formulation" is understood to mean a formulation suitable for administration by inhalation to a human or animal patient, preferably a human patient, comprising one or more active ingredients effective for treating, preventing or diagnosing a disease or condition in a human or animal, especially a human, capable of pulmonary administration by inhalation. Inhalable formulations of the present invention include, but are not limited to, powders for dry powder inhalers, formulations for metered dose inhalers, and solutions or suspensions for nebulizer devices.

[0042] As used herein, a "powder formulation" refers to a formulation comprising a particulate solid, and in the context of the present specification, is preferably a dry powder formulation for a dry powder inhaler device or a formulation for a metered dose inhaler.

[0043] "Active ingredients" in this specification should be understood to include ingredients that are effective through any therapeutic route. For the avoidance of doubt, active ingredients for the purpose of this application include: therapeutically effective drugs that can be administered by the pulmonary route for local treatment, prevention or diagnostic methods implemented on the lungs; therapeutically effective drugs that can be administered by the pulmonary route for systemic treatment, prevention or diagnostic methods implemented on one or more other parts of the patient's body; and active ingredients that can be administered by the pulmonary route for local treatment, prevention or diagnostic methods implemented on the lungs by mechanical or physical routes, like pulmonary surfactant. Active ingredients for local action administered by the pulmonary route include, for example, drugs for the treatment of asthma, COPD, allergic rhinitis, cystic fibrosis and tuberculosis. Systemic drugs administered by the pulmonary route include, for example, insulin and small peptide therapeutics.

[0044] As used herein, "emitted dose" refers to the theoretical dose of active ingredient that is expelled when the inhalation device is activated. It can be equal to the theoretical total amount of aerosolized drug, but can be smaller if the theoretical dose is not fully aerosolized successfully.

[0045] As used herein, "particles" generally refer to solid particles, unless the context implies otherwise.

[0046] As used herein, "inhalable fraction" refers to the percentage (%) portion of particles that theoretically reach the lungs of a typical patient when a dose of a powder formulation is inhaled. Those skilled in the art typically understand this portion as a sub-portion of aerosolized particles of a powder formulation with an aerodynamic diameter less than 10 μm.

[0047] As used herein, "respirable dose" refers to the amount of released dose of the drug that theoretically reaches the lungs of a typical patient when a dose of an inhalable pharmaceutical formulation is inhaled. The respirable dose can be estimated with reasonable accuracy, which corresponds to the dose collected at or after stage 2 in a conventional impactor (e.g., MSP's next generation impactor), also commonly referred to as the impactor stage mass ("ISM").

[0048] As used herein, "fine particle dose" refers to the dose of aerosolized drug particles with an aerodynamic diameter of less than 5 μm. To determine the fine particle dose from the impactor, an interpolation or regression analysis of the impactor data is required to determine the dose associated with the aerodynamic cutoff of 5 μm diameter particles.

[0049] The “aerodynamic diameter” is defined as the density of 1000 kg / m 3The diameter of a sphere having the same settling velocity as the particle of interest. The aerodynamic diameter can be determined by any method commonly used by those skilled in the art. The aerodynamic diameter values ​​specified herein are measured using a cascade impactor. The flow rate or velocity described herein can be measured using any suitable flow meter, for example, a Copley DFM 2000 flow meter (Copley Scientific), which can be used to determine a standard or volume flow rate.

[0050] As used herein, "clear area" refers to a path or an orifice, which means that the path or orifice does not contain any structure within that area that would interrupt the pneumatic flow through the area of ​​the path or orifice, and a path or orifice having a given percentage clear area should be understood as the percentage of the area of ​​the orifice or the cross-section of the path that does not have any structure that, if set within the area of ​​the orifice or path area, would interrupt the pneumatic flow through that area of ​​the orifice or path. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Certain embodiments of the invention will now be described with reference to the accompanying drawings, given as non-limiting examples, in which:

[0052] Figure 1 is a schematic exploded perspective view of a dose collection device according to an advantageous embodiment of the present invention;

[0053] Figure 2 is through Figure 1 A cross-sectional view of a device;

[0054] Figure 3 yes Figure 2 A magnified view of detail D1;

[0055] Figure 4 is to accommodate Figure 3 a cross-sectional view of a dissolution container of a filter unit;

[0056] Figure 5 yes Figure 4 A magnified view of detail D2;

[0057] Figure 6 Shows Figure 5 An exploded perspective view of a filter unit;

[0058] Figure 7 shows a perspective view of a lower filter support member;

[0059] Figure 8 Shows Figure 5 A perspective view of an assembled filter unit;

[0060] Fig. 9 is through Figure 8A partial cross-sectional view of an assembled filter unit;

[0061] Fig.10 is a partial cross-sectional view through the lower body;

[0062] Fig.11 is a top view of the top surface of the lower body;

[0063] Fig.12 is a partial cross-sectional view of an upper body assembled on a lower body by a clamping device;

[0064] Fig.13 yes Fig.12 A magnified view of detail D3;

[0065] Fig.14 is a perspective view of a quick release system according to an advantageous embodiment of the present invention;

[0066] Fig.15 is through Fig.14 A cross-sectional view of a quick release system;

[0067] Figures 16 to 18 Shows the processing Fig.14 The quick release system has three consecutive steps;

[0068] Fig.19 Shown by using Fig.14 The quick release system will Figure 5 The filter unit is introduced into the dissolution vessel; and

[0069] Fig. 20 is with Fig.19 A similar view showing the release of the filter unit within the dissolution vessel. DETAILED DESCRIPTION

[0070] The present invention is an improvement of the instrument described in document WO2017051180A1, which is added herein as a reference. In the known instrument, a certain dose of atomized medicinal preparation is produced at the inlet of the instrument of the present invention, and a suction device extracts a pneumatic flow through the instrument from a downstream access point. The dose collection part is arranged in the path of the pneumatic flow through the instrument. A particularly advantageous application of the instrument relates to the preparations of dry powder inhalers and metered dose inhalers. The respirable part of the atomized inhalable medicinal preparation can be collected in the dose collection part. This enables accurate prediction of the amount of active ingredients of the preparation actually delivered to the lungs of a typical patient.

[0071] In the apparatus of WO2017051180A1, the orifice is sized and configured so that it has a free area of ​​not less than 75%, advantageously not less than 80%, for example not less than 90% of the area of ​​the filter on which the dose is to be collected. In contrast, in a standard impactor device, a major part of the path is blocked by a nozzle device having a plurality of nozzle jets, wherein the jets form only a small part of the cross-section of the nozzle device, as a result of which the pneumatic flow through the jets is accelerated and leaves the jets in the form of a plurality of parallel jets at a relatively high flow rate.

[0072] In the above-mentioned apparatus, the pneumatic flow is delivered through an orifice of which only a small portion not exceeding 25% of the area of ​​the orifice is obstructed, which enables the pneumatic flow to be delivered to the filter along a path that is either unobstructed or obstructed by no more than 25% by structures that would interrupt the flow of gas. Thus, in contrast to known impactors, the above-mentioned apparatus has a dose collection section in which the aerosol is delivered in a relatively uniform and relatively slow-moving flow, the entire flow being directed onto a collection filter. This flow pattern is in contrast to the nozzle (also called "jet") that accelerates the pneumatic flow in known impactors in order to achieve inertial separation.

[0073] In some embodiments, there may be a first removal device for removing particles having a particle size of 10 μm or larger and optionally one or more additional removal devices for removing one or more additional particle size fractions in the path upstream of the orifice of the dose collection portion. For example, the removal device for removing particles of a given particle size may be one or more stages of an impactor, in particular an inertial separation stage arranged to separate particles exceeding a specific aerodynamic diameter. Further, where there are more than one additional removal devices, those may include two or more impactor stages arranged in series, arranged to inertially separate successively smaller size fractions. Therefore, for the avoidance of doubt, the instrument of WO2017051180A1 may additionally include such a plurality of nozzle structures in a portion of the path upstream of the collection device, for example, in one or more inertial removal devices, the inertial removal device optionally being present to remove one or more particle size fractions from the aerosolized preparation before reaching the dose collection portion. The removal of particle size fractions within the respirable portion is generally considered to be potentially useful, for example, when attempting to replicate the respirable portion of a patient whose respiratory function is below that of an average adult patient, for example, a child, a neonate, or an adult with impaired respiratory function. Particularly suitable as a removal device are inertial removal devices. The inertial removal device used in the present invention may optionally include a deflection region in the path, whereby particles having a smaller than predetermined aerodynamic diameter are deflected with the pneumatic flow in the deflection region, and particles having an aerodynamic diameter greater than the predetermined aerodynamic diameter are discharged from the path by inertial effects. For example, there is a commercially available device called an "anatomical throat" that is suitable for removing larger particles. It has been demonstrated that such a device filters the inhaled dose so that the dose passing through the throat is very closely related to the dose found to enter the lungs in in vivo lung deposition studies. In some embodiments, one or more inertial separation units are provided in the path between the removal device and the dose collection unit for eliminating one or more additional particle size fractions from the pneumatic flow before the pneumatic flow reaches the dose collection unit.

[0074] The dose collecting portion comprises a filter unit downstream of the orifice, wherein the filter unit comprises said filter.

[0075] The flow characteristics necessary to achieve uniform deposition on the filter can be achieved by appropriately selecting the orifice area. Since the orifice area is typically circular in practice, the following discussion will be made with reference to a circular orifice. However, it should be understood that the configuration of the orifice does not have to be circular and can be any suitable configuration, for example, elliptical, square or rectangular, and the configuration of the filter is preferably selected to be similar or identical to the configuration of the hole. In practice, the orifice diameter is selected to be larger than the diameter of the nozzle in the nozzle plate typically used for the impactor device. For example, the diameter of the orifice may advantageously be at least 10 mm in diameter, advantageously at least 15 mm in diameter, and in particular at least 20 mm in diameter. In practice, the diameter of the orifice is generally preferably not more than 50 mm, for example, not more than 45 mm, and in particular not more than 40 mm.

[0076] In practice, it has been found to be advantageous to provide the orifice by a tapered member such that at the outlet the orifice diameter values ​​specified above are defined.The use of a tapered member has been found to reduce turbulence effects.

[0077] The unobstructed area of ​​the orifice through which the air flow is delivered to the filter is not less than 75% of the area of ​​the filter on which deposition occurs. The diameter of the filter is advantageously at least 10 mm, preferably at least 15 mm, for example, at least 20 mm. Advantageously, the diameter of the filter is no more than about 60 mm, more advantageously no more than about 50 mm, for example, no more than about 45 mm. It will be understood that in principle a larger filter size can be used. In this case, it will be understood that, in order to determine the relative size of the orifice and the filter, the area of ​​the filter used for this purpose is the area in which at least 90% (by weight) of the collected material is deposited.

[0078] The Reynolds number is the ratio of inertial forces to viscous forces and can predict the type of flow that will occur in a particular situation. In the design of the nozzles in the impactor, varying the number of nozzles and the width of the jet orifices enables the airflow to be controlled between set limits to maintain laminar flow. Typically, the number of jet orifices is selected to control the Reynolds number. To maintain laminar flow over a range of flow rates, the limits of Re (Reynolds number) should ideally be between 500 and 3000.

[0079] In practice, a circular orifice with a diameter of 2 to 5 cm, preferably 2.5 to 5 cm, more preferably 3 to 5 cm, for example 3 to 4.5 cm has been found to be suitable. Such dimensions have been particularly found to be advantageous when using a flow rate of 10 to 100 L / min, for example 15 to 100 L / min, in particular 15 to 70 L / min, for example 30 L / min or 60 L / min.

[0080] Advantageously, the path comprises a tapered portion leading to the orifice.

[0081] In one embodiment, the nozzle diameter has an inner diameter of 4.5 cm at the top of the nozzle portion and decreases to 3.9 cm at the opening. Reducing the diameter is advantageous because it reduces the appearance of sharp angles that may cause turbulence. Preferably, the filter, or at least the portion of the filter where deposition occurs, has a substantially planar structure.

[0082] The instrument of WO2017051180A1 includes a dose collection part, which includes a filter F as described above. The filter is arranged orthogonally to the flow direction of the pneumatic flow downstream of the orifice. As already mentioned, it is desired that at the point of collision with the filter, the condition is a relatively uniform and low-speed pneumatic flow. In fact, this can be achieved by appropriately selecting the size of the orifice and the interval between the orifice and the filter. Preferably, the diameter of the orifice is not less than 14mm. The distance between the orifice and the filter is advantageously no more than three times the diameter of the orifice, for example, up to twice the diameter of the orifice. In the case where the distance between the orifice and the filter is large, the interference caused by the deposition of material on the wall may adversely affect the collection efficiency, and in practice it may be desirable that the separation distance is significantly shorter than three times the diameter of the orifice. As an example, in some embodiments, the distance between the orifice and the filter can be up to 10cm, for example, from 1cm to 10cm. Preferably, the portion of the path extending from the orifice to the filter is straight and will not be or substantially will not be interrupted by any structure that will substantially interfere with the uniformity of the flow.

[0083] Advantageously, the filter F blocks at least a portion of the path at a point downstream of the orifice. In some embodiments, the filter blocks substantially the entire path.

[0084] Advantageously, the filter support comprises an elongate support member extending across a path on a surface of the filter opposite the apertures for supporting a central region of the filter, the filter support defining between two and ten apertures.

[0085] It has been found that providing a considerable area of ​​support structure below the filter adversely affects the deposition pattern of solids on the filter. It is believed that although the passage of air through the filter inevitably disrupts the uniformity of the flow to some extent, providing a support structure below the filter has a significant effect on the flow rate, so that the flow is disrupted upstream of the filter so as to form preferential islands of aggregate deposition at the point where the carrier air freely passes through the filter. For this reason, it is preferred that as much of the underside of the filter as possible, for example at least 75%, remain completely unobstructed, thereby avoiding any undue effect on the uniformity of the fluid when passing through the filter. A particular advantage of the instrument of the present invention is that the atomized particles are captured across the entire surface of the filter, rather than being deposited in a clearly defined position associated with the position of the jet port for delivery (as in some known instruments) or associated with a support structure that blocks the path below the filter.

[0086] The filter may be any filter suitable for retaining particles up to 5 μm, for example in the range of 0.45 μm to 5 μm. For example, filters with pore sizes up to 3 μm may be used.

[0087] Advantageously, the filter has such air permeability that the filter produces a flow rate reduction of no more than 20%, preferably no more than 15%, more preferably no more than 10% compared to the flow rate without the filter.Such a filter may, but need not, have a pore size of at least 1 μm.

[0088] For example, the filter can be selected from woven fabrics, nonwoven fabrics, nets and breathable membranes. In some embodiments, the filter includes a fabric formed by glass microfibers or by filaments of a polymeric material selected from polycarbonate, polyester, polyolefin, polyamide (e.g., nylon), acrylic resin, acrylic copolymer, polyvinyl chloride and polyetheretherketone. For example, suitable polyolefins include polyethylene, polypropylene and copolymers of ethylene and propylene with one or more other monomers. The filter can also include synthetic cellulose-based materials, for example, cellulose acetate, cellulose nitrate and mixed cellulose ester synthetic membranes.

[0089] Suitable glass microfibers include, for example, borosilicate glass, such as A / E type glass fiber filters commercially available from Pall Corporation in the United States, which have a nominal pore size of 1 μm. Examples of suitable polymer filters include acrylic propylene filters with a pore size of 3 μm or less, such as those with pore sizes of 0.2 μm, 0.45 μm, 0.8 μm, 1.2 μm, and 3 μm. Polymeric filters of polyamide or polyvinyl chloride with a nominal pore size of 3 μm or less are also widely available. This is also true for cellulose-based membranes.

[0090] In other embodiments, the filter comprises a metal mesh, for example a stainless steel mesh, which advantageously has a pore size of less than 3 μm.Other suitable materials include, for example, polymer membranes, provided they have a suitable level of gas permeability.

[0091] Advantageously, the collected particles are subjected to a dissolution test. Dissolution testing is widely practiced in the art, and it is a routine matter for those skilled in the art to select suitable dissolution media and methods for the particles collected from a given pharmaceutical preparation. One such test that can be conveniently used is a paddle-disc dissolution test (United States Pharmacopoeia Convention 2011, 711, Dissolution, paddle-disc apparatus). Commonly used dissolution media include, for example, phosphate buffered saline (PBS) solutions with or without surfactants (e.g., Tween 20, Tween 80, SDS, etc.). For example, the solution can be chemically analyzed by HPLC to determine the mass collected.

[0092] exist Figures 1 to 13 An advantageous embodiment of the dose collection part in the apparatus of the present invention is shown in FIG.

[0093] Figure 1 The dose collection device from Figure 1 From top to bottom, the filter housing 10 includes an upper adapter element 10, a first O-ring 20, an upper body 30, an upper filter support member 40, a lower filter support member 50, a second O-ring 60, a lower body 70 and a clamping device 80 for clamping the upper body and the lower body together to compress the second O-ring 60.

[0094] The upper body 30 comprises a funnel 31 defining an inlet aperture 32. The funnel 31 is tapered to reduce the presence of sharp edges which may cause turbulence, and is arranged to convey the fluid flow into a clear vertical path extending downwardly from the aperture 32 towards the filter collection means.

[0095] The filter F is supported by a filter unit including an upper filter support member 40 and a lower filter support member 50. Therefore, the filter F is circumferentially held between the upper support and the lower support.

[0096] The area of ​​the apertures 32 is similar to, but slightly smaller than, the exposed area of ​​the filter F upon which deposition occurs.

[0097] exist Figure 2 and Figure 3 In the embodiment of the present invention, a suction source (not shown) is in pneumatic communication with the filter on a side remote from the orifice and is used to draw air through a path including the orifice 32 and to draw suction on the filter F in a downward direction.

[0098] A flow controller (not shown) is associated with the suction source which maintains appropriate flow conditions.

[0099] The lower filter support member 50 is configured to have minimal contact with the filter F. Figures 6 to 9 A suitable filter unit is shown in .

[0100] The lower filter support member 50 includes an outer ring 57 connected to an inner flange 56 that projects radially inwardly from a lower surface of the outer ring 57 and has a peripheral inner edge 52 that defines a central opening.

[0101] The lower filter support member 50 includes at least one, preferably three radial projections 55 extending radially outwardly from the outer periphery of the outer ring 57 .

[0102] One function of the radial projections 55 is to properly align the filter unit at the correct depth within the dissolution vessel 90 for dissolution studies, such as Figure 4 and Figure 5 As shown. The dissolution vessel 90 is preferably a miniature Erweka dissolution apparatus. Advantageously, the radial projections 55 are tapered on their lower surfaces, which improves the positioning of the filter unit in the rounded bottom of the dissolution vessel 90, allowing the assembly to be quickly, accurately and repeatably positioned within the dissolution vessel 90. It also ensures that the filter unit remains vertically aligned with the paddle agitator during dissolution measurements and that the correct distance is maintained between the filter surface and the paddle.

[0103] Another function of the radial projection 55 is to provide rotational alignment with the lower body 70. This ensures that semi-automatic or automated equipment can correctly register the filter unit position. The outer ring 57 ensures coaxial alignment with the upper body 30 and the lower body 70, and the inner flange 56 enables sufficient contact surface for sealing the filter F.

[0104] like Figure 7 As shown, the central opening of the lower filter support member 50 may advantageously have a central hexagonal support structure 51, each vertex of the hexagon 51 being connected to the peripheral inner edge 52 by a corresponding radial rib 53, thereby defining seven holes 54. This hexagonal central structure 51 provides the maximum surface area while increasing the structural support of the filter F during atomization collection. Of course, this is just an example, and one can imagine any central support structure 51, whether polygonal or circular, for example, circular, and any number of radial ribs 53. The central support structure 51 and the radial ribs 53 can have a substantially triangular cross-sectional configuration, so that at their upper ends, they provide a narrow contact line with the filter F, while the bottom of the rib can be thicker for strength reasons.

[0105] The upper filter supporting member 40 includes an upper ring 41 and a lower ring 42 extending axially downward from the upper ring 41 , the upper and lower rings having the same inner diameter, and the upper ring 41 having an outer diameter greater than that of the lower ring 42 .

[0106] Therefore, the outer edge of the filter F is held between the inner flange 56 of the lower filter support member 50 and the lower ring 42 of the upper filter support member 40, as shown in FIG. Fig. 9 Best shown.

[0107] One function of the upper filter support member 40 is to provide a sealing element between the filter F and the lower filter support member 50 and to provide an appropriate weight to prevent the filter F from lifting or separating from the lower filter support member 50 during dissolution studies.

[0108] The lower ring 42 of the upper filter support member 40 can be made with a certain range of heights to accommodate different filter thicknesses. The height can also be changed to increase / reduce the compression force when the clamping device 80 is used to clamp the instrument.

[0109] The filter F suitable for the apparatus of the present invention is generally a filter with a nominal pore size in the range of 1 to 3 μm. Since the filter F is arranged in-line in the flow path in the apparatus of the present invention, it is preferred to select a suitable filter F with a sufficiently small pore size so that the filter captures substantially all, preferably not less than 90%, especially not less than 95% (by weight) of the solids entrained in the air flow, while the filter has a relatively small resistance to the air flow.

[0110] Studies have shown that filters with a pore size of 3 μm are fine enough to capture aerosol. Although a pore size of at least 1 μm is preferred, it is the air permeability of the filter that actually affects its suitability in the apparatus of the present invention, and filters with a pore size of less than 1 μm can be used, where they do not substantially increase the flow resistance, for example, resulting in a flow rate reduction of no more than 15%, preferably no more than 10%, relative to the absence of the filter.

[0111] The lower body 70 accommodates the filter unit on its top surface. Fig.10 and Fig.11 As shown, the top surface includes a second O-ring 60, which provides a main gas path seal of the instrument when clamped. The top surface also includes a first recess 71, which is adapted to cooperate with the radial protrusion 55 of the lower filter support member 50 to provide rotational alignment of the filter unit on the lower body 70. A second recess 72 is provided to allow the filter unit to be manually, semi-automatically or automatically extracted from the lower body 70 when the clamping device 80 is released.

[0112] Fig.12 and Fig.13The upper body 30 and the lower body 70 are shown assembled by the clamping device 80 . Fig.13 The dotted line L in shows the compressive force path. This ensures a controlled compressive load on the filter F when clamped. The applied forces are balanced to ensure that the filter structure is not damaged, while retaining and sealing the filter to the lower filter support member 50.

[0113] The clamping device 80 advantageously comprises two clamping halves which are rotatably connected to each other by a pin 81 and provided with a closing system. The closing system may comprise a threaded shaft 82 cooperating with a suitable nut 83. Other clamping devices, in particular other closing systems, may also be used.

[0114] The drug-laden filter F housed in the filter unit can be removed from the lower body manually, semi-automatically or automatically. This is facilitated by the second recess 72 in the lower body 70.

[0115] This loaded filter F can then be transferred to a second instrument for testing. Fig.19 and Fig. 20 The transfer to the dissolution vessel 90 is shown.

[0116] According to one aspect of the invention, the filter unit may be removed from the lower body 70 using a manually actuated quick release system 100, but this avoids any contact between a person and the filter unit.

[0117] Fig.14 and Fig.15 An example of a quick release system is shown in .

[0118] The quick release system 100 comprises a clamping base 101, a fixing device preferably formed by retaining hooks 102 (preferably three of them), an actuating lever 103, a link arm 104 and a main support 105. The actuation of the actuating lever 103 is triggered by a finger 106 and a thumb actuator 107. The system also comprises a cam tree 108, a locking pin 109 and a spring 110.

[0119] exist Figures 16 to 18 A series of diagrams are shown in which illustrate how the system is used in operation.

[0120] The quick release system 100 with the non-actuated thumb actuator 107, and thus the non-compressed spring 110 and the open hook 102, moves toward the filter unit located on the top surface of the lower body 70. The open hook 102 can enter the second recess 72 and be positioned around the filter unit. When the thumb actuator 107 is actuated, the actuation rod 103 moves downward, thereby compressing the spring 110 and moving the hook 102 radially inward to a closed position, in which they cooperate with the filter unit to hold the filter unit in the closed hook 102. The clamping base 101, which is basically formed of a thin plate, grasps the filter F to protect the filter F from the external environment.

[0121] Therefore, if Fig.19 and Fig. 20 As shown, the filter unit can be safely removed from the lower body and transferred to the dissolution container. When the actuation force on the thumb actuator 107 is released, the compression spring 110 can relax and allow the rod 103 to return to its rest position, thereby allowing the hook 102 to open and release the filter unit in the dissolution container 90.

[0122] In the foregoing description, reference is made to wholes or elements that have known, obvious or foreseeable equivalents, and these equivalents are incorporated herein as if set forth separately. Reference should be made to the claims for determining the true scope of the invention, which should be interpreted as including any such equivalents. The reader will also understand that wholes or features of the invention described as preferred, advantageous, convenient, etc. are optional and do not limit the scope of the independent claims. In addition, it should be understood that such optional wholes or features, although they may have benefits in some embodiments of the invention, may not be ideal in other embodiments and therefore may not exist.

Claims

1. A system comprising: - An apparatus for collecting aerosolized inhalable particles of an inhalable medicinal preparation, comprising: an inlet for receiving an aerosolized dose of a medicinal preparation; a suction source for generating a pneumatic flow through the apparatus; a channel defining a path extending from the inlet to the suction source; and a dose collection portion located in the path of the pneumatic flow through the apparatus, the dose collection portion having a filter (F) extending across the path of the aerosolized inhalable particles so as to retain particulate material in the aerosolized inhalable particles on the filter (F), the dose collection portion comprising: - an upper filter support member (40) and a lower filter support member (50), the filter (F) being circumferentially held between the upper filter support member and the lower filter support member to form a filter unit, - a lower body (70) accommodating the filter unit, the lower body (70) having a top surface including a recess (72) around the filter unit, - a quick release system (100) comprising a fixing device movable between an open position and a closed position, wherein in the open position the securing means are able to enter the recess (72) around the filter unit and in the closed position the securing means are able to grip the filter unit, thus allowing the filter unit to be removed from the lower body (70) without anyone touching the filter unit.

2. The system according to claim 1, wherein: The fixing means are formed by hooks.

3. The system according to claim 1, wherein: The quick release system (100) further comprises a clamping base (101), an actuating rod (103) and a spring (110), wherein the actuating rod (103) has a thumb actuator (107) to trigger actuation of the actuating rod.

4. The system according to any one of claims 1 to 3, wherein: The lower filter support member (50) comprises an outer ring (57) connected to an inner flange (56), the inner flange (56) protruding radially inwardly from a lower surface of the outer ring (57), the inner flange (56) having a peripheral inner edge (52) defining a central opening, wherein the central opening has a central support structure (51), the central support structure (51) being connected to the peripheral inner edge (52) by at least two radial ribs (53), thereby defining a plurality of holes (54).

5. The system according to claim 4, wherein: The central support structure (51) is hexagonal, each vertex of the hexagon is connected to the peripheral inner edge (52) by a radial rib (53), thereby defining seven holes (54).

6. The system according to claim 4, wherein: The upper filter support member (40) comprises an upper ring (41) and a lower ring (42), the lower ring (42) extending axially downward from the upper ring (41), the upper ring and the lower ring having the same inner diameter, and the upper ring (41) having an outer diameter greater than the outer diameter of the lower ring (42), wherein the outer edge of the filter (F) is held between the inner flange (56) of the lower filter support member (50) and the lower ring (42) of the upper filter support member (40).

7. The system according to claim 4, wherein: The lower filter support member (50) includes at least one radial projection (55) extending radially outward from an outer periphery of the outer ring (57).

8. The system according to claim 7, wherein: The lower filter support member (50) includes three radial projections (55) extending radially outward from the outer periphery of the outer ring (57).

9. The system according to claim 7, wherein: The top surface of the lower body (70) comprises a first recess (71) adapted to cooperate with the radial projection (55) of the lower filter support member (50) to provide rotational alignment of the filter unit on the lower body (70).

10. The system according to any one of claims 1 to 3, wherein: The dose collection portion comprises an aperture, the filter (F) being positioned opposite the aperture and the aperture being dimensioned such that a free-flowing area of ​​the aperture is not less than 75% of an area of ​​the filter on which the dose is to be collected; wherein the suction source is in communication with the path downstream of the filter unit; Wherein, the filter unit also has a filter support, which includes one or more support members extending across a path on the surface of the filter opposite to the orifice, for supporting the central area of ​​the filter, and the filter support defines two or more holes and blocks no more than 80% of the surface area of ​​the opposite surface.

11. The system according to claim 10, wherein: The orifice is dimensioned such that it has an outlet area that is no less than 80% of the area of ​​the filter on which the dose is to be collected.

12. The system according to claim 11, wherein: The outlet area is not less than 90% of the area of ​​the filter on which the dose is to be collected.

13. The system according to any one of claims 1 to 3, wherein: The filter (F) is selected from the group consisting of woven fabrics, non-woven fabrics, nets and breathable films.

14. The system according to claim 13, wherein: The filter (F) comprises a fabric formed of glass microfibers, a synthetic cellulose-based material, or a fabric formed of filaments of a polymeric material selected from polycarbonate, polyester, polyolefin, polyamide, polyvinyl chloride and polyetheretherketone.

15. The system of claim 13, wherein: The filter (F) comprises a metal mesh.

16. The system of claim 15, wherein: The metal mesh is a stainless steel mesh.

17. The system according to any one of claims 1 to 3, wherein: The filter (F) has a pore size of no greater than 5 μm.

18. The system according to claim 17, wherein: The filter (F) has a pore size of no greater than 3 μm.

19. The system according to any one of claims 1 to 3, wherein: The filter (F) has a pore size of at least 1 μm.

20. The system according to any one of claims 1 to 3, wherein: The filter (F) has an air permeability such that the filter produces a flow rate reduction of no more than 20% relative to the absence of the filter.

21. The system of claim 20, wherein: The air permeability is such that the filter produces no more than a 15% reduction in flow rate relative to the absence of the filter.

22. The system of claim 20, wherein: The air permeability is such that the filter produces no more than a 10% reduction in flow rate relative to the absence of the filter.

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