Patent Application
20180036497
The present invention describes a novel powder compartment for a single-use disposable pulmonary or nasal inhaler of simple construction, operation and low cost for the delivery of high dosages of pharmaceutical compounds.
Inhalers used for the delivery of pharmaceutical compounds have become widespread and include pressurized metered dose, nebulizers and powder-based inhalers. The latter category delivers the dose of medicinal powder using the energy generated by the patient's inspiratory effort and includes multi-use reservoir-based devices, re-usable devices supplied with unit-doses packaged in blisters, re-usable devices using unit-dose capsules loaded by the patient, and single-use disposable powder-based inhalers. The present invention is in this last category.
Powder-based inhalers have been used mainly for maintenance treatment of respiratory diseases such as asthma or the chronic obstructive pulmonary disease. However, single-use disposable devices have deserved considerable attention due to the need to treat situations were an infectious agent is being treated or is present in the mouth or airways and the elimination of the potential for inhaler contamination is thus required.
Furthermore, the effort to develop single-use disposable inhalers has also been fuelled by the growing interest in delivering to patients high payloads, in the range of 50 to 120 mg, of pharmaceutical compounds such as antibiotics, vaccines, proteins, peptides, insulin or other drugs systemically via the lung or nose through few, simple and intuitive interactions with the device. In such applications, pharmaceutical compounds that have been particle engineered by processing techniques such as spray drying or jet milling are normally characterized by high adhesion and cohesion properties resulting from low median particle size by volume, typically below 2 μm, in addition to low bulk density, typically in the range of 0.2 g/cm3-0.5 g/cm3.
Therefore, a major challenge is designing the mechanism for aerosolizing and dispersing large quantities, in the range of 50 to 120 mg, of highly cohesive and adhesive powders while minimizing the amount of powder retention in the device. In addition, a significant challenge is also the provision of deagglomeration mechanisms which ensure the break-up of such large quantities of highly agglomerated drug particles down to particles with an inhalable size of less than 5 μm while, simultaneously, preventing such large dose to be released in a very short period of time. Such sudden release may lead to the “powdery mouth” effect, throat irritation and large drug losses in the upper airways. The means for powerful aerosolisation and controlled powder deagglomeration and release is thus required by design.
Furthermore, the great majority of the patients requiring antibiotics, vaccines, proteins, peptides or other drugs in such applications are inhaler-naive and may not have any training in inhalation. It is thus required that the device be of extreme simplicity and intuitive to use. In addition, the developer of a disposable inhaler for high dosage drug delivery is also faced with the challenge of gaining competitive advantage through a reduction in the cost of the device, both through the use of the fewest number of components as possible and designing for fast assembly during high volume manufacturing.
There is abundant prior art in the field of single-use disposable inhalers, but a disposable inhaler solving all the above requirements has not been provided yet. The present application is particularly directed at the inventive improvement of the inhaler described in PT103481.
Previously, as described in PT103481 and illustrated in
Other single-use disposable inhalers are also already known in the prior art.
U.S. Pat. No. 5,797,392 discloses one of the simplest designs of a single-use disposable inhaler similar to a drinking straw. Although simple, the construction disclosed does not provide dispersion and deagglomeration mechanisms or features allowing the break-up of large quantities of highly cohesive drug particles and excipients down to the inhalable size while minimizing powder retention in the device.
U.S. Pat. No. 5,042,472, U.S. Pat. No. 5,239,991, U.S. Pat. No. 6,098,619 and WO pat. 2014/175815 disclose also other simple single-use and disposable devices apparently absent of major powder deagglomeration features and the constructions disclosed in the drawings are likely to cause the sudden release of powder leading to the undesirable “powdery mouth” and throat irritation effects.
U.S. Pat. No. 6,286,507, US pat. 2008/0190424 and US pat. 2009/0250058 disclose other single-use disposable inhaler constructions generally comprising a first body member including a powder compartment and a second body member which are closely fit to form an inhaler body with an outlet, where the two body member are separated by a strip or tape which exposes the powder compartment to air when pulled away from the inhaler body. However, the constructions presented rely on simple throughflows that are absent of flow patterns into the powder compartment thus preventing the application of powerful dispersion and deagglomeration forces on powders for its effective detachment from the compartment's walls, which is particularly important for the successful delivery of large payloads of cohesive powders.
U.S. Pat. No. 6,941,947 discloses another single-use dry powder inhaler having a dispersion chamber, a blister supported and adjacent to the dispersion chamber, a mouthpiece and a hinged cover. The opening movement of the hinged cover causes the blister to open and an airflow path is formed that extends under the blister and into the dispersion chamber. However, the drawings disclosed in this patent show also an apparent absence of powerful flow patterns for dispersion and deagglomeration of large payloads of powder, a construction comprising at least 4 unique components and a non-trivial assembly sequence, both adding to total manufacturing cost.
There is therefore the need for a single-use disposable device which achieves the functionalities of the disposable inhalers described above with effective aerosolisation and deagglomeration mechanisms for large payloads of very cohesive powers, in the range of 50 to 120 mg, that minimizes powder retention, that is simple and intuitive to use and that can be manufactured at a very low cost.
The present invention seeks to provides a novel powder compartment for a disposable inhaler that improves the construction disclosed in PT103481 for the dispersion and deagglomeration of large payloads, in the range of 50 to 120 mg, of inhalation powders characterized by high cohesive and adhesive properties, resulting from a low median particle size by volume, typically below 2 μm, while maintaining an inhaler that is simple and intuitive to use and that can be manufactured at a very low cost. Furthermore, the present invention seeks to provide a powder compartment for a disposable inhaler that minimizes the powder retention in the device during the dispersion of large powder payloads while retaining an improved deagglomeration performance leading to an improvement of the dose delivered to the patient's respiratory system.
When testing with a high payload, in the range of 80 to 100 mg, of inhalable amorphous composite particles composed of 80% trehalose and 20% leucine produced by spray drying, used as model drug particles representative of the typical high cohesive-adhesive behaviour found in powders for high dosage applications, we initially scaled up the existing construction disclosed in PT103481. This scale-up was made linearly in every dimension by 20% to increase the powder compartment capacity for accommodating such payloads of powders with typical bulk density in the range of 0.2 g/cm3-0.5 g/cm3. However, at a pressure drop of 4 kPa, the emitted mass from the device calculated from the mass of powder deposited at each stage of a cascade impactor was about 50%. It was clear that dispersive and aerosolisation characteristics of an enlarged construction as disclosed in PT103481 were not going to lead to an effective large dose disposable inhaler.
Subsequently, in order to increase the dispersive and aerosolisation power of the construction disclosed in PT103481, additional symmetrical air vents providing supplementary air flow to the powder compartment were introduced and the new construction was tested with the same payload of the model drug particles. At a pressure drop of 4 kPa, the emitted mass from the device calculated from the accumulated mass of powder deposited at each stage of a cascade impactor was increased to approximately 65% of the nominal or starting dose. This performance was still not adequate and it was clear that just an increase of flow rate passing through the powder compartment, provided by symmetrically disposed air vents was not going to lead to an effective large dose disposable inhaler.
The inventive solution was given by placing the air vents in a disposition that maximizes turbulence and aerosolization, in a new geometry. The powder compartment disclosed in PT103481 needed to be reinvented to create novel, effective dispersive and aerosolisation dynamics leading to low powder retention and a disposable inhaler capable of operating with large payloads of powders characterized by challenging cohesion-adhesion properties. To attain such purpose, the existing powder compartment which was provided with a an air slit at the bottom and a large outlet at the top, was constructed with additional lateral vents, forming pairs of lateral vents, placed at various heights of the powder compartment, with each vent forming the pair of vents offset relative to each other to provide a non-tangential admission of air. The new construction was tested with the same payload of the model drug particles representative of high dosage applications. At a pressure drop of 4 kPa, the emitted mass from the new device calculated from the mass of powder deposited at each stage of a cascade impactor was approximately 91% and powder retention within the compartment itself was observed to be residual. The results indicate that the novel design of the powder compartment provides a high rate of drug delivery of challenging powders characterized by low density and high cohesive-adhesive properties.
The table data indicates the improvement in performance in gravimetric emitted dose, expressed in percent of emitted dose, and the variability of performance expressed in terms of percent relative standard deviation.
The present invention accordingly provides a dry powder inhaler according to claim 1.
More particularly, the inhaler of the present invention comprises two plastic-injected components as in PT103481: a body and a cartridge. The body and cartridge are locked together after assembly to form an integral and functional inhaler.
As in PT103481, the inhaler body is provided with a mouthpiece or nosepiece, an opening shaped for receiving and holding in place a cartridge and an inhalation channel for providing fluid communication between the patient's mouth or nose when engaged with the mouthpiece or nosepiece and the assembled cartridge. One or more body side inlets are provided to admit air directly from the atmosphere to the inhalation channel. Optionally a body bottom opening is included in the bottom wall of the body opening shaped for receiving the cartridge, to allow the admission of air from the atmosphere into the cartridge powder compartment when the cartridge is moved into the inhalation position. One or more rails are also provided in the side walls of the body opening shaped for receiving the cartridge where one or more pins of the cartridge engage to provide the means for allowing the sliding movement of the cartridge relative to the body and limit its sliding travel.
As found in PT103481, the cartridge includes at least one powder compartment, preferably two, that are built or moulded therein, which are always isolated from each other and are of tapered cylindrical or near-cylindrical shape with rounded extremities absent of sharp angles, such as spherical, oval and the like to minimize powder retention during and after inhalation. The cartridge comprising the powder compartments is made movable when mounted in the body opening. This movement is allowed through the engagement of one or more cartridge pins with the rails provided in the body which allow the controlled sliding of the cartridge relative to the body. In addition, there is at least one compartment bottom slit for the admission of air that is of very small size, between 0.1 and 2 mm in width, preferably 1 mm or less in width, and is tapered in the direction of the compartment to create a funnel that blocks the flow of powder under gravity and other forces. Each powder compartment comprised also a compartment outlet, normally of the same or similar diameter as the compartment itself, to allow normal filling and automated high-speed filling of the powder and to allow fluid communication with the body inhalation channel through the body bottom inhalation channel inlet when the cartridge is moved into the inhalation position.
However, the inhaler of the present application includes new features not found in the inhaler described in PT103481 or in the prior art and they are now detailed.
In this new inhaler, the cartridge powder compartment further comprises at least two compartment vents for the admission of air, at least one of which is a lateral vent, preferably two or four forming pairs of lateral vents being present, where each of said pairs is included in opposite ends of the powder compartment and each vent forming the pair is offset relative to the other to provide a non-tangential admission of air, and being the lateral vents of very small size, between 0.1 and 2 mm in width, preferably 1 mm or less in width, to minimize powder leakage under vibration or other forces. The or each side vent preferably tapers inwards towards the inner surface of the compartment wall so as to funnel the air as it is drawn through the vent into the compartment, thereby increasing aerodynamic efficiency and facilitating manufacturing.
Furthermore, the new cartridge powder compartment comprises at least one compartment protruding rim or similar construction that provides close mechanical contact and interference with the top or bottom walls, or both, of the body opening shaped for mounting the cartridge, and at least one pair of compartment protruding rims or similar construction at the side inlets that provides close mechanical contact and interference with the side walls of the body opening shaped for mounting the cartridge, to ensure sealing of the powder compartment while allowing a low frictional sliding movement of the cartridge.
Two additional features are found in the inhaler of the present invention which are not present in the inhaler of PT103481. One is that the inhaler body of the present invention further comprises a bottom inhalation channel inlet, included in the top wall of the body opening shaped for receiving the cartridge, where said bottom inhalation channel inlet comprises a single orifice or multiple orifices of any shape or multiple orifices of any shape arranged to form a structured grid, that jointly provide a sharp geometric constriction in the fluid channel passage area where the geometric constriction area ranges between 0.3 and 0.99 of the cartridge powder compartment outlet cross section area, preferably between 0.8 and 0.98.
The other additional feature in this new inhaler is that the inhaler body includes one or more body side openings, included in the side walls of the body opening shaped for receiving the cartridge, to allow the admission of air from the atmosphere into the cartridge powder compartment when the cartridge is moved into the inhalation position.
The inhaler body and the cartridge can be made by injection-moulding of any suitable material for pharmaceutical use such as polyethylene (PE), polypropylene (PP), polysulfone (PSU), acrylonitrile butadiene styrene (ABS), polymethylmetacrilate (PMMA), polycarbonate (PC), polypropilene oxide (PPO), polybutylene terephthalate (PBT) polyethylene terephthalate (PET), liquid crystal polymer (LCP), polyethyleneimine (PEI), polyphenylenesulphide (PPS). Material selection should be made to maximize compatibility with the powder to be contained and delivered, minimize retention during inhalation and degradation during storage and allow transparency if possible.
During assembly, after filling the cartridge powder compartments with a unit dose of powder, the cartridge is inserted into the body through the opening shaped for mounting the cartridge. The powder compartment enters into the contact with the top, bottom and side walls of the body opening providing a close fit and sealing of the compartment. In addition, when the cartridge is mounted the pins engage with the body rails and allow the sliding movement into the cartridge storage position.
In the storage position, the powder compartments are offset relative to the inhalation channel provided in the body. Furthermore, the powder compartment bottom inlet slits are in contact with and fully blocked by the bottom wall of the body opening for mounting the cartridge. In addition, the powder compartment lateral vents are in contact with and fully blocked by the side walls of the body opening for mounting the cartridge. Therefore, the powder unit dose is effectively sealed inside its compartment and close contact with the opening bottom and side walls prevents the powder compartment contents from escaping. In its storage position, the inhaler is then ready for packaging, desirably in a foil or aluminium pouch, or pouch or packaging of any other suitable material and under low or equilibrium humidity conditions.
During use of the inhaler of the present invention, the patient removes it from its packaging and accesses the inhaler with the cartridge in the storage position. The patient then pushes into the cartridge to slide it into the inhalation position. At this position, the powder compartment bottom inlet slit becomes aligned with the air inlet provided in the bottom wall of the body opening for allowing air admission. Furthermore, at this position, the powder compartment lateral vents become aligned with the side openings/windows provided in the side walls of the body opening for allowing air admission. Also, at this position, the powder compartment outlet becomes aligned with the bottom inlet of the inhalation channel that is included in the top wall of the body opening.
When the cartridge has traveled into the inhalation position, the patient then inhales a first dose, according to the instructions for use, and airflow is created across the device. Air is first able travel through the body bottom air inlet and into the powder compartment through the compartment bottom inlet slit effectively inducing a turbulent jet to disperse the particles there contained.
In addition, air is also able to travel through the body side opening/window into the powder compartment through compartment lateral vents or through the pair of compartment lateral vents, which provide admission of supplementary air to allow an increase in the turbulence kinetic energy within the compartment that is available for dispersion and deagglomeration of the drug particles. Moreover, the non-tangential air admission through the compartment lateral vents induces a turbulent vortex that confines the bottom turbulent jet and generates a high velocity magnitude near to the compartment walls and thus provide the means to effectively reduce powder retention in the device during inhalation.
The turbulent and swirling air flow generated in the compartment thus allows the particles to be dispersed and travel through the powder compartment outlet and into the bottom inhalation channel inlet comprised in the body. There, the sudden cross sectional reduction that is constructed through the body inhalation channel inlet design allows further deagglomeration and break-up of the particle clusters through impaction on the surrounding inlet walls and through the generation of high shear forces and turbulence kinetic energy across the inlet passage itself.
The flow of air with entrained particles then enters the body inhalation channel and the supplementary air flow provided through the body side inlets induces additional channel turbulence leading to further dispersion and deagglomeration of the particles, for entrainment and final deposition in the intended site, in the lung or in the nasal cavity, depending on the application. If there is a second powder compartment comprised in the cartridge, the patient then moves it to the inhalation position and inhales a second time, repeating the maneuver as often as there are compartments. A benefit of all of these inlets and lateral vents is that inhalation may be complete with one single inhalation attempt.
In addition to providing the turbulent kinetic energy for powder dispersion and deagglomeration, the inlets, slits and vents provided in the powder compartment as well as those in the body allow the design of the inhaler resistance and aerodynamic profile which in turn determines the comfort experienced by the patient during inhalation.
This novel construction allows the dispersion and deagglomeration of large payloads of cohesive inhalation powders while minimizing powder retention and while maintaining an inhaler that is simple and intuitive and maintaining the part count to two unique components assembled through a single and simple assembly step, both contributing to low manufacturing cost and consequent economic advantage.
Based on these advantages, it is one inventive feature of the present application that the cartridge powder compartment of tapered cylindrical or near-cylindrical shape comprises at least one bottom inlet slit and at least one side/lateral vent, preferably two or four forming pairs of lateral vents, which are respectively blocked and sealed by the body opening bottom and side walls when the cartridge is in the storage position, and which become available for the admission of air into the compartment when the cartridge is aligned and placed into the inhalation position.
It is also an inventive feature of the present application that the cartridge powder compartment lateral vents are included in opposite sides of the powder compartment and each vent forming one pair is offset relative to the other to provide a diagonal, non-tangential admission of air, thus providing the means for the admission of supplementary air flow inducing a turbulent vortex in the compartment that increases the turbulent energy available for the dispersion and deagglomeration of drug particles there contained, and that increases the near-wall velocities in the compartment for the reduction of powder retention during inhalation.
It is also an inventive feature of the present application that the cartridge powder compartment lateral vents are of very small size, between 0.1 and 2 mm in width, preferably 1 mm or less in width, to increase air vent velocities for the application of high dispersive forces on particles there contained, and are further tapered towards the inner surface of the compartment to increase aerodynamic efficiency and allow manufacturing through standard injection moulding processes.
It is also an inventive feature of the present application that the cartridge powder compartment has at least one pair of compartment protruding rims or similar construction at the side inlets that provides close mechanical contact and interference with the side walls of the body opening shaped for mounting the cartridge, to ensure sealing of the powder compartment while allowing a low frictional sliding movement of the cartridge.
It is also an inventive feature of the present application that the body inhalation channel comprises a bottom inlet included in the top wall of the body opening shaped for receiving the cartridge where said bottom inhalation channel inlet comprises a single orifice or multiple orifices of any shape or multiple orifices of any shape arranged to form a structured grid, that jointly provide a sharp geometric constriction in the fluid channel passage area where the geometric constriction area ranges between 0.3 and 0.99 of the cartridge powder compartment outlet cross section area, preferably between 0.8 and 0.98, that allows further deagglomeration and break-up of the particle clusters dispersed within the powder compartment through impaction on the surrounding inlet walls and through the generation of high shear forces and turbulence kinetic energy across the inlet passage.
Referring to the drawings, numbered sequentially after the word “Fig.”, like numerals indicate like parts, and each of the embodiments is identified with series of numbers where the number of hundreds is the number of the embodiment (1xx to 8xx) and the equivalent feature in each of the embodiments has the same number xx.
Referring to
Referring next to
In
When the powder cartridge 803 is in the inhalation position and the patient's mouth or nose is engaged with a body mouthpiece 802, the patient's inspiratory effort creates a suction that forces the air to travel through the body bottom inlet 815 and the powder compartment bottom inlet slit 806 inducing a bottom turbulent jet and simultaneously through the body side opening windows 816 and the powder compartment lateral vent 809 inducing a turbulent vortex confining the bottom turbulent jet, which generates a turbulent and swirling air flow pattern 817 shown in
An inhaler embodiment according to the present invention has been tested in vitro to determine its aerodynamic profile as well as its powder dose delivery characteristics. The inhaler embodiment comprised a powder compartment according to the present invention that included one bottom inlet slit and four lateral vents with pairs of lateral vents in offset configuration as shown in
An experimental inhalation powder comprising inhalable amorphous spherical composite particles composed of 80% trehalose and 20% leucine was produced by spray drying. The composite particle spry dried powder was produced with a median particle size by volume (Dv50) of approximately 2 μm leading to high cohesiveness and adhesiveness properties. The particle size, cohesive and adhesive properties of the powder were representative of powders produced by spray drying for applications of high dosage drug delivery to the lungs.
The inhaler was hand filled with 80 mg of composite particle spray dried powder (40 mg per compartment), under controlled conditions of temperature and relative humidity (T<25° C. and % RH<30%), inside a glove box conditioned with nitrogen and using an appropriate analytical balance. The inhaler was then tested at a flow rate of 42 litres per minute and at a pressure drop of 4 kPa on an Andersen cascade impactor (Graseby Andersen. Smyrna, Ga.), actuated once to allow a volume of 4 litres of air to pass through the device, and the mass of powder deposited at each stage of the cascade impactor was quantified using gravimetric methods. From these data, the emitted mass and the fine particle mass were calculated, where the emitted mass was the sum of all masses collected from each of the impactor stages, including the inductor throat, and the fine particle mass was the mass of powder collected below the 5 μm cut-off point. High dispersive and aerosolisation efficiency leads to a high emitted mass from the inhaler. In addition, the higher the fine particle mass, the higher the delivered lung dose is expected to be. The results are summarized in the following table:
This data indicates that the inhaler embodiment according to the present invention is capable of effectively dispersing and delivering large doses, in the range of 50 to 120 mg, of an inhalation powder, under inspiratory effort conditions which are compatible with the ability of patients.
| Number | Date | Country | Kind |
|---|---|---|---|
| 108426 | Apr 2015 | PT | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/GB2016/051073 | 4/28/2016 | WO | 00 |
