Patent Application
20150136122
This application claims priority to United Kingdom Application No. 1210580.5, filed Jun. 14, 2012, which is incorporated herein in its entirety.
The present invention relates to metered dose dispensing valves and in particular to metered dose dispensing valves suitable for use with metered dose inhalers.
Asthma and other respiratory diseases have long been treated by the inhalation of appropriate medicament. Pulmonary inhalation is also becoming an attractive route of administration of medicaments that may be difficult to deliver orally such as proteins and peptides.
A widely used and convenient choice of pulmonary drug delivery has been the inhalation of medicament from an aerosol created by a pressurized metered dose inhaler (pMDI). As shown in
Typical commercial pMDI metering valves comprise seven or eight or even more components. An example is the 3M Spraymiser™ valve by 3M Company, St Paul, Minn., USA (
Besides cost issues, it has been observed that issues related to component alignment and guidance and complex dimensional tolerance stack-up factors may generate secondary potential issues with valve and pMDI performance, such as poor pressure-filling performance, high firing forces and/or inadequacies in stem return forces, as well as undesirable propellant leakage and moisture penetration rates.
The following documents disclose types of valve, some of which might be intended to be low cost and/or to have a limited number of components: GB 1054307 (Riker), GB 2361228 (Groeger), U.S. Pat. No. 3,019,947 (Gorman), EP 816 255 (Hildebrandt), GB 1115926 (Nadal), CH 428604 (Trautmann), GB 2300674 (Lacout), U.S. Pat. No. 3,521,859 (Gronemeyer), U.S. Pat. No. 3,642,180 (Lehmann), U.S. Pat. No. 3,862,741 (Steiman & Beres), U.S. Pat. No. 3,982,674 (Mildern), U.S. Pat. No. 4,471,893 (Knickerbocker), U.S. Pat. No. 4,477,001 (Galia), U.S. Pat. No. 4,852,807 (Stoody), U.S. Pat. No. 4,887,743 (Blake), U.S. Pat. No. 5,775,545 (Sullivan), WO 95/28620 (Keller), and WO 02/02435 (Corba). Note that not all these valves are metering valves.
Although a number of documents seemingly suggest low cost valves and/or valves with few components, presently there is no such valve with notable success on the market. Without wanting to be bound to a particular theory, it seems that the lack of success may be related to the fact that previously suggested valves show significant dissimilarities to industry-standard valves in the way that they interface with aerosol containers or actuator support blocks and/or perhaps in fact exhibit a higher level of complexity and/or lower levels of physical or operational robustness and/or provide poor valve performance (e.g. very variable dose volumes, high stem friction, high leakage rates, etc).
Accordingly there is an ongoing need and a demand for inexpensive pMDI valves of good quality and high reliability. It would be advantageous to overcome or mitigate issues in metering valves that can be made for very low cost, that can be pressure-filled, and that can interface in a conventional way to both the pMDI actuator and the typical aerosol container used in a pMDI (e.g. using a hollow male valve stem and a mechanically crimpable ferrule). In addition, it would be desirable to provide such a valve that would operate in the same way that conventional pMDI valves do: i.e. dispensing a metered dose of formulation along the valve stem bore when the stem is pushed inwardly (i.e. towards the aerosol container) along its longitudinal axis, and then resetting (with the stem moving back outwardly to its starting point) when the stem is released by the patient.
In one aspect of the present invention there is provided a metered dose dispensing valve for dispensing metered volumes of an aerosol formulation from an aerosol container, said valve comprising
a first valve body defining in part a metering chamber;
a valve stem passing axially through the metering chamber, movable relative to the chamber between non-dispensing and dispensing positions, and biased from its dispensing position towards its non-dispensing position by a compliant biasing member; and
a second valve body defining at least in part a pre-metering region, wherein the biasing member has at least one portion engaging the valve stem, thereby imparting a bias thereto, and at least one other portion being anchored to the second valve body; wherein, in use, the valve stem is moved axially against said bias from its non-dispensing position into its dispensing position and upon release the valve stem moves under the action of the bias from its dispensing position back to its non-dispensing position; and wherein said biasing member and second valve body are integrally provided in a single component.
Surprisingly we have found that by combining the compliant biasing member and the second valve body into an integral single component it is possible to provide a desirable metered dose dispensing valve for use in inhalation devices or for use in the provision of canisters (i.e. an aerosol container, filled or not yet filled with aerosol formulation, plus a valve) targeted for use in inhalation devices. Valves described herein are particularly desirable for dispensing metered volumes of pressurized aerosol formulations, and thus particularly suitable for use in pressurized metered dose inhalers or for use in the provision of canisters targeted for use in pressurized metered dose inhalers. In particular, the provision of such an integral single component allows one to avoid or minimize manufacturing costs and/or performance issues and/or dimensional tolerance issues associated with the assembly and alignment of a coil spring into a valve. In addition, valves described herein have a valve stem with axial travel distances to and from its dispensing and non-dispensing positions, wherein in its dispensing position a metered dose may be delivered and in its non-dispensing position the metering chamber may be refilled via the pre-metering region, said axial travel distances being very similar to those of industry-standard pMDI valves. Accordingly such valves are advantageously broadly similar to those of industry-standard valves, helping to make them readily compatible with existing actuators, aerosol containers and dose indicators, and making them acceptable to the industry as a stand-alone component offering.
Favorably, the valve operates similarly to industry-standard push-to-fire pMDI valves. Moreover, favorably the valve is configured and arranged such that, in use, when the valve stem is in its non-dispensing position, the pre-metering region is in communication either continuously or transiently with the contents of the aerosol container and the metering chamber is in communication at least transiently with the pre-metering region to allow substance to pass from the aerosol container to the metering chamber, and when the valve stem is in its dispensing position, the pre-metering region is isolated from the metering chamber and a communication path is provided between the metering chamber and the outside of the valve and aerosol container assembly, said path being either continuously or transiently open to allow substance to pass from the metering chamber to the outside of the valve and aerosol container assembly. The skilled person will understand that the terms ‘dispensing position’ and ‘non-dispensing position’ actually each refer to a range of spatial positions of the valve stem over its span of axial movement. The term ‘rest position’ refers to one specific non-dispensing position. The terms ‘continuously open’ and ‘transiently open’ in the context of the communication path may refer to both the case where the communication path is open continuously or transiently spatially or is open continuously or transiently temporally during valve stem operation.
Favorably the valve is designed to be similar to industry-standard push-to-actuate pMDI valves in that, in use, the valve stem is moved axially, e.g. by the user or a breath actuated mechanism, inwardly towards the aerosol container from its non-dispensing position to its dispensing position and upon release moves outwardly under the action of the bias from its dispensing position.
Favorably the second valve body, which is desirably formed with a cage or cage-like structure, acts among other things as a fixed support during valve operation for the biasing member that in turn acts to apply a bias to the valve stem. The compliant biasing member may favorably be a spring member. The term “spring” is generally understood to be an elastic object (e.g. member) used to store mechanical energy, whereby when the object is compressed or stretched, the force it exerts is proportional (or approximately proportional) to its change in length. Alternatively, a torsion spring could be used.
To further facilitate minimization of the overall number of components and/or any or all performance issues outlined above, desirably the valve stem is integrally provided together with the biasing member and second valve body in said single component. In other words, in such embodiments, the second valve body, biasing member and valve stem are integrally provided in a single component.
Integral single components including the second valve body, biasing member and, in more favorable embodiments, the valve stem, may favorably comprise a polymeric material, for example with one or more polymeric materials in a composite and/or including other materials such as fillers and/or reinforcing agents in one or more of the polymeric materials. Such components may be favorably molded, in particular via one-shot molding or two or more shot moldings. Alternatively such integral single component may favorably comprise metal and a polymeric material, for example when the compliant biasing member is made of or includes a metal sub-structure. Herein the single component may be desirably molded by insert molding in conjunction with one-shot or two or more shot polymeric molding (e.g. insert a metal spring into the appropriate portion of the component mold and then mold and as applicable over-mold the polymeric elements of the component). The use of metal per se or a substructure of metal (or other suitable materials) may facilitate avoidance or reduction of any tendency of the compliant biasing member to undergo stress relaxation or creep.
Favorably the valve further comprises an inner seal and an outer seal. The inner seal is generally located relative to the canister towards the interior, while the outer seal is generally located further away from the interior. The outer seal is favorably located at or near the open end of the first valve body away from the interior. The inner seal is favorably located at or near the open end of the first valve body towards the interior.
Favorably the valve stem comprises a dispensing passage, wherein the valve stem is movable relative to the inner and outer seals, such that,
in the non-dispensing position of the valve stem, the dispensing passage is isolated from the metering chamber, and a communication path is provided between the aerosol container and the metering chamber, said path being either continuously or transiently open to allow substance to pass from the aerosol container to the metering chamber, and
in the dispensing position of the valve stem, said communication path between the aerosol container and the metering chamber is closed and the dispensing passage is in communication, either continuously or transiently, with the metering chamber to allow substance to be dispensed from the metering chamber through the dispensing passage.
Both the inner and outer seals may be provided as separate components, or alternatively to facilitate minimization of manufacturing costs and/or any or all performance issues outlined above, the first valve body and the inner seal or the outer seal or both seals may be advantageously integrally provided in a single component. This second integral component may be composed of a polymeric material, for example with one or more polymeric materials in a composite and/or including other materials such as fillers and/or reinforcing agents in one or more of the polymeric materials. This second component may be molded, in particular molded via one-shot molding or two or more shot molding.
In alternative embodiments including inner and outer seals, the inner seal may provided as an integral member of the integral single component comprising the second valve body and biasing member (“first integral component”), while the first valve body and outer seal are either provided separately or are provided integrally in a single second component.
Valves described herein desirably further comprise a ferrule for securely attaching the valve onto the aerosol container. The ferrule may be provided as a separate component or alternatively to facilitate minimization of overall number of components, the ferrule may be provided as an integral part of the second integral component.
Valves described herein desirably further comprise a gasket seal. The gasket seal generally facilitates sealing between the valve and the aerosol container when the valve is mounted onto the aerosol container. The gasket seal may be provided as a separate component, e.g. in the form of a rubber or elastomeric ring, or alternatively to facilitate minimization of overall number of components, the gasket seal may be provided as an integral part of the first integral component or as an integral part of the second integral component or as an integral part of the ferrule. Typically, the gasket seal is in the form of an annular ring with a generally rectangular cross-sectional profile.
Another aspect of the present invention is the provision of a canister comprising an aerosol container and a valve described herein, in particular a canister filled with an aerosol formulation, more particularly a medicinal aerosol formulation, even more particularly a pressurized, medicinal aerosol formulation, and most particularly a pressurized, medicinal aerosol formulation comprising medicament and a propellant, said propellant comprising HFA 134a and/or HFA 227.
Another aspect of the present invention is the provision of a medicinal delivery device comprising a valve described herein or a canister described herein. Advantageously the device is an inhalation device, in particular a pressurized medicinal inhalation device.
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. Also further embodiments are described in dependent claims. In several places throughout the application, guidance is provided through lists of examples, which examples can be used individually and in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
The invention will now be described with reference to the accompanying drawings in which:
a, 10 and 11 represent illustrations of another exemplary metered dose dispensing valve in accordance to the invention described herein, being an isometric view of a sectioned valve and an end of an aerosol container (
In the description that follows, terms such as ‘top’, ‘bottom’, ‘above’, ‘below’, etc, refer only to features as shown in the Figures, and no restriction as to orientation of use, etc, is intended. Not all Figures are to the same scale.
It is to be understood that the present invention covers all combinations of particular, suitable, desirable, favorable, advantageous and preferred aspects of the invention described herein.
As discussed supra,
Metered dose dispensing valves for dispensing metered volumes of a pressurized aerosol formulation from an aerosol container described herein comprise a first valve body defining in part a metering chamber and a valve stem passing axially through the metering chamber, movable relative to the chamber between non-dispensing and dispensing positions, and biased from its dispensing position towards its non-dispensing position by a compliant biasing member. The volume of the metering chamber (and thus the dose metered upon actuation) may favorably be within the range 25 μl to 150 μl, and more particularly 50 μl to 65 μl (end points inclusive for both named ranges). Desirably the first valve body has two open ends through which the valve stem passes, wherein relative to an affixed aerosol container, the first end is located towards the interior of the container and the second end away from the interior of the container. In use, the valve stem is moved axially against said bias from its non-dispensing position into its dispensing position and upon release the valve stem moves outwardly under the action of the bias from its dispensing position back to its non-dispensing position.
This can be better understood for example in reference to an exemplary embodiment shown in the Figures. Making reference to the view and embodiment shown in
Metered dose dispensing valves for dispensing metered volumes of a pressurized aerosol formulation from an aerosol container described herein further comprise a second valve body defining at least in part a pre-metering region. The second valve body defines a space near the metering chamber to provide a pre-metering region such that the contents of the aerosol container will pass through the pre-metering region to the metering chamber, in particular the contents of the aerosol container will be fed directly and/or indirectly through the pre-metering region to the metering chamber. Advantageously the pre-metering region is located near the inner end of the metering chamber. In one of the exemplary embodiments to be discussed infra and shown in
As mentioned above, metered dose dispensing valves for dispensing metered volumes of a pressurized aerosol formulation from an aerosol container described herein comprise a compliant biasing member. The compliant biasing member and second valve body are integrally provided in a single component. As mentioned above, the compliant biasing member imparts a bias onto the valve stem biasing the valve stem towards its non-dispensing position. Typically the second valve body provides fixed support for the compliant biasing member. Accordingly the compliant biasing member has at least one portion engaging the valve stem and at least one other portion being anchored to the second valve body.
Valves described herein are favorably configured and arranged such that, in use, when the valve stem is in its non-dispensing position, the pre-metering region is in communication either continuously or transiently with the contents of the aerosol container and the metering chamber is in communication at least transiently with the pre-metering region to allow substance to pass from the aerosol container to the metering chamber, and when the valve stem is in its dispensing position, the pre-metering region is isolated from the metering chamber and a communication path is provided between the metering chamber and the outside of the valve and aerosol container assembly, said path being either continuously or transiently open to allow substance to pass from the metering chamber to the outside.
Once again by reference to the view and embodiment shown in
If the valve stem and compliant biasing member are not to be integrally formed, as is for example the case in the embodiment shown in
Advantageously compliant biasing members are spring members. Depending on the particular valve design, compliant biasing members may be compression or tension spring members. It is well known that compression springs become shortened (e.g. are compressed) when pressure is applied to them, generally offering resistance to a compressive force applied axially, while tension springs become extended (e.g. are stretched) when pressure is applied, generally offering resistance to an extensive force applied axially. Such spring members may have an overall cylindrical, frusto-conical, hourglass (convex), or barrel (concave) shape. They may have a conventional coil or helical, leaf, or stack spring configuration. Commercial pressured metered dose inhalers generally comprise a helical metal coil, cylindrical, compression spring, although other types of spring are known to be applied to aerosol valves in the patent literature, e.g. EP 1477234 and EP 1565270 both mention a stack spring for metering valves. Compliant biasing members may alternatively have less conventional spring configurations, such as C-springs.
Favorably, the single integral component comprising the second valve body, the compliant biasing member, and if applicable the valve stem may comprise a polymeric material, for example with one or more polymeric materials in a composite and/or including other materials such as fillers and/or reinforcing agents in one or more of the polymeric materials. Such components may be favorably molded, in particular via one-shot molding or two or more shot moldings. Alternatively such integral single component may favorably comprise metal and a polymeric material, for example when the compliant biasing member is made of metal (e.g. metal per se) or is reinforced with a metallic sub-structure. Herein the single component may be desirably molded by insert molding in conjunction with one-shot or two or more shot polymeric molding (e.g. insert a metal spring into the appropriate portion of the component mold and then mold, if applicable overmold, the polymeric elements of the component). Examples of suitable polymers for use to make such integral components include acetal (polyoxymethylene) polymers (such as Delrin™ (Dupont de Nemours & Company)), polyetherimide (e.g. ULTEM 1000), liquid crystalline polymer (LCP) or polyetheretherketone (PEEK). Other polymeric materials exhibiting low levels of creep include polyvinylidene difluoride (PVDF), polycarbonate, polyethersulphone (PES) and phenolic laminates. Preferably, food-grade or pharmaceutical-grade materials would be used, although standard industrial grades could be used for non-pharmaceutical applications. Suitable fillers and/or reinforcing agents include fibers, such as glass fibers or carbon fibers. In the event that the compliant biasing member is made of metal per se or is reinforced with a metallic sub-structure, suitable metals include stainless steel.
A cage or cage-like form for second valve bodies is advantageous in that such form is discontinuous and allows for large gaps and ready access of medicament formulation to the internal pre-metering region defined by such bodies as well as facilitating injection molding.
As stated supra, valves described herein favorably include an inner seal and an outer seal. Generally the outer seal is desirably located at or near the open end of the first valve body away from the interior, while the inner seal is favorably located at or near the open end of the first valve body towards the interior. The outer seal may be in sliding sealing engagement with the valve stem. Preferably the inner seal is in the form of a lip seal, which allows formation of a relatively low friction sliding seal with the valve stem component during valve operation. Such a seal is partially pressure-assisted during valve firing, in that the pressure difference that develops across it as the metering chamber empties helps to maintain a good seal while the stem (214) remains pushed in towards the aerosol container. Use of a lip seal type of inner seal also facilitates easy pressure-filling of the system. (Pressure filling, or previous air-blowing, can be used to ensure that the inner seal is in its correct as-shown orientation, e.g. if valve assembly turns it ‘inside out’.)
In alternative, “fast-fill, fast-empty” versions of the valves of the present invention, as opposed to “retention valve” versions, the inner seal may be provided as a face seal to operate in a manner analogous to the valves disclosed in WO04/022142 or WO04/022143, as shown later in the examples shown in
Valve stems typically comprise a dispensing passage, and desirably are movable relative to the inner and outer seals, such that, in use, in the non-dispensing position of the valve stem the dispensing passage is isolated from the metering chamber, and a communication path is provided between the aerosol container and the metering chamber, said path being either continuously or transiently open to allow substance to pass from the aerosol container to the metering chamber, and
in the dispensing position of the valve stem said communication path between the aerosol container and the metering chamber is isolated and the dispensing passage is in communication, either continuously or transiently, with the metering chamber to allow substance to be dispensed from the metering chamber through the dispensing passage.
Again referring to the view and embodiment in
Reference is now made to
Valves described herein may advantageously include the first valve body and the inner seal or the outer seal or both seals integrally provided in a single integral component (“second component”) to yet further minimize the overall number of components. Alternatively for valves using an inner seal that operates as a face seal, the inner seal may be provided as an integral member of the component comprising the compliant biasing member and second valve body (“first component”), while the first valve body and outer seal may be either provided separately or be provided integrally in a single second component. An example of such a valve will be discussed below.
In the exemplary embodiment shown in
Integral components comprising the first valve body and the inner seal and/or the outer seal are favorably composed of a polymeric material. Such integral components may be molded, in particular molded via one-shot molding or two or more shot molding. It will be noted that such integral components (e.g. that of the embodiment of
Valves described herein may include a ferrule. Ferrules are typically made by conventional deep-drawing from aluminum alloy strip metal, although alternative forms, such as injection molded plastics, could be used. In a deep-drawn form, the ferrule may comprise a skirt region for attachment onto the neck of the aerosol container by a conventional multi-jaw crimping process. Other processes could however be employed to affix and seal the ferrule to the aerosol container, for example rotary crimping, laser welding or ultrasonic welding. Alternatively, a screw-on attachment could be used, e.g. for an injection molded plastic ferrule.
Valves described herein may further comprise a gasket seal. Such a gasket seal may be provided separately, or once again to aid minimization of the overall number of components it may be provided either as an integral part of the second component, or as an integral part of the first component, or as an integral part of the ferrule.
For valves including a ferrule and a component comprising integrally the first valve body defining at least part of the metering chamber together with the inner seal and/or the outer seal, it is advantageous to size with care said integral component relative to the ferrule due to the intrinsic partially flexible nature of the integral component required for its sealing function. Also, it is advantageous to provide a close radial fit between part of (the inner wall of) the ferrule and part or all of the first valve body's radially outer wall, and to facilitate support of the first valve body in order to help ensure that it cannot flex radially outwardly enough to adversely affect control of the volume of the metering chamber. Accordingly, in such advantageous embodiments, the ferrule is formed such that a portion thereof defines an alcove-space and at least a portion (preferably a substantial portion) of the first valve body is located within the alcove-space such that at least a portion (preferably a substantial portion) of the radially outer wall of the first valve body is adjacent to the inner wall of the portion of the ferrule defining the alcove-space.
To help ensure a complete understanding of the exemplary embodiment shown in
The antechamber component (221) of the exemplary valve (202) provides multiple integral features and elements. In particular, it provides a valve stem (214) including a hollow male stem part (234) protruding through a piercing in the ferrule (211) and an inner stem part (235) having an internal stem passage (218); a compliant biasing member (215); and a second valve body (230) defining a cage enclosing a pre-metering region (223) and having a gasket rim (231) that gets fixedly located by the valve to vial crimping operation. The cage is discontinuous, with large gaps to allow ready access of medicament formulation to the inside regions (and to facilitate injection molding). For example, the cage (230) can preferably take the form of two curved walls on either side of the compliant biasing member spring (215). The spring (215) is in the form of a plastic stack spring, generally similar in principle to a multi-layered metal wave spring.
An internal passage (218) in the inner stem part (235) leads from the interior of the pre-metering region (223) to the metering chamber (212) via the filling side hole (228). The stem dispensing side hole (219) leads from the metering chamber (212) to the dispensing passage (209) provided as a bore of the protruding hollow male stem part (234) when the stem component (214) is pushed in towards the aerosol container (201; see
The metering chamber component (222) of the exemplary valve (202) provides multiple integral features and elements, such as a first valve body (213) defining at least in part the metering chamber plus the inner seal (216) and outer seal (217). The component also includes an integral, radially outwardly extending shelf member (236) in the form of a ring (closed or open, i.e. continuous or discontinuous) connected to the radially outer wall of the first valve body. This shelf member may desirably facilitate placement of the antechamber component and/or support of the metering chamber component within the ferrule (in particular near the shoulder of the ferrule) during assembly of the valve. For example, the shelf member can be dimensioned such as to abut the inner walls of the ferrule and thereby to align the antechamber component centrally within the ferrule. Use of a slight dimensional interference fit between the shelf member and the inner walls of the ferrule can serve to align and retain both the antechamber component and the metering chamber component within the ferrule prior to subsequent crimping onto an aerosol container.
The ferrule (211) of the exemplary valve (202) includes a ferrule skirt (226) allowing for crimping onto the canister (201; see
To assemble the exemplary valve (202) shown in
a, 10 and 11 illustrate aspects of a second exemplary valve in accordance to the present invention. In this valve, different designs are used for the ante-chamber component (221), the metering chamber component (222) and the ferrule (211), and in addition, no separate gasket seal is used. In regard to the first, as can be appreciated from
b illustrates a different variant of the valve shown in
The ante-chamber component (221) illustrated in
The ante-chamber component (221) illustrated in
The ante-chamber components (221) illustrated in
Taken together, the Figures and the illustrated exemplary embodiments show that metering valves in accordance to the invention are unique valves suitable for use in pMDIs that show simplicity and low component count (e.g. three or four components in these exemplary valve embodiments, versus typically eight components in many commercially available pMDI valves), whilst providing familiar conventional axial push-to-fire operation and desirably with conventional interfacing to the actuator (via a hollow male valve stem) and to the aerosol container (via a conventional crimp).
As will be apparent to one skilled in the art, it is favorable that compliant biasing members are designed not to impede flow of aerosol formulation as well as to provide appropriate functional parameters, e.g. suitable travels (i.e. distances of stem movement from rest to the firing point, from the firing point to the inwards movement end-point, from the inwards movement end-point back to the valve refill point, etc), adequate reset forces, adequate residual outward biasing force at the rest position, non-excessive firing forces, and a hard-stop feature capable of resisting an appropriate (e.g. 180 N) patient force without valve failure and without the valve ‘going continuous’. Desirably compliant biasing members are designed such that it is ensured that the aforementioned favorable parameters remain suitable over a desired range of storage and operation temperatures (e.g. 0° C. to 45° C.), e.g. by finite element analysis and/or by physical testing. For example, Finite Element Analysis (FEA) may be applied to the chosen design of biasing member with a 3-D mesh of about 0.2 mm element size, using well-known principles and methods of optimization described in the book “Finite Element Procedures” by K. J Bathe, published by Prentice Hall in 1996. The dimensions of the design, such as the thicknesses of any horizontal and vertical members and the diameter of any approximately cylindrical profile of the biasing member, may be modified until appropriate force versus distance results are obtained from the FEA. Thus typically where a compression force is applied, at a biasing member compression of 4 mm the force required is about 35 N, and when assembled into a valve the compression is about 1 mm corresponding to a force of about 7 or 8 N. It has been found that readily available FEA software accurately predicts force versus distance profiles for typical biasing members. This information can readily be used to tailor the design of compliant biasing member to provide an acceptable balance of forces, valve stem travel distances, materials stress levels, component costs, and the overall valve size envelope.
To aid in avoiding deposition of medicament and/or to enhance frictional properties for smooth operation, a part or all of the interior surfaces of the metering valve (e.g. part or all of the surfaces of the antechamber component and/or the metering chamber component) may be provided with a low energy surface coating. Example of such coatings include plasma coatings such as DLG (diamond-like glass) as disclosed in WO2009/061895 and WO2010/129753 and perfluoropolyether silane coatings optionally superimposed on a non-metallic, e.g. DLG, base coating as disclosed in WO2009/061891, WO2009/061907, WO2009/061902 and WO2010/129758. Other possible coatings include plasma polymerized fluorinated hydrocarbons, chemical or physical vapour deposited polymers, cold plasma polymerized siloxanes, e g dimethylsiloxane, diphenylsiloxane, hexamethyldisiloxane, tetramethyldisiloxane, silazanes, alkoxysilanes, Parylene N, fluoroparylene, Parylene C, Parylene D, fluoroacrylates, coatings of perfluoropolyethersilane, perfluoropolyetherphosphate and/or fluoroalkylsilane, where such coatings are deposited either by dipping, spraying or pouring, and causing or allowing the molecular attachment groups to cure, or by plasma deposition, vacuum deposited silica (about 500 nm thick) on steel component surfaces by a process known as the Silcosteel® process, and fluoroalkyl monolayer coatings as described in WO2007/112312.
As mentioned above, it is desirable to provide valves that can interface in a conventional way to typical aerosol aerosol containers used in pressurized metered dose inhalers. Such aerosol containers are typically made of a metal (e.g. aluminum or aluminum alloy or stainless steel). In such cases, typically it is advantageous to use mechanically crimpable ferrules (e.g. ferrules made of metal, such as aluminum or aluminum alloy). Aerosol containers may be made of other materials, such as glass, plastic or ceramics. Aerosol containers may be coated and/or the interior surfaces of the metering valve may be coated on part or all of their interior walls to reduce drug deposition, e.g. with any of the coatings listed in the previous paragraph. Alternatively, a coating may be selected from mixed fluoropolymer and nonfluoropolymer, where the fluoropolymer is e.g. polytetrafluoroethylene (PTFE), copolymerized ethylene tetrafluorethylene (ETFE), copolymerized perfluoroethylene propylene (FEP), perfluorinated polyalkoxyethylene-co-ethylene (PFA), polyvinylidene difluoride (PVDF), polymerized chlorinated ethylene tetrafluoroethylene (CETFE), and the non-fluoropolymer is e.g. a polymer selected from the following families of polymers: polyethersulphone (PES), polyamideimide (PAI), polyphenylenesulphide (PPS), polyamide, amine-formaldehyde thermosetting resin, benzoguanamine and/or polyethyleneglycol (PEG). Preferred options are PTFE-PES, FEP-PES and PFA-PEG. Aluminium aerosol containers may be anodized, and the anodized surface may help other coatings like PTFE or PFA to adhere more firmly to the container. The aerosol container may be coated with a fluoropolymer by electrostatic dry powder coating. Other coatings may include epoxy-phenolic or epoxyurea-formaldehyde linings (e.g. the epoxy/phenol formaldehyde resins described in WO95/17195).
In the event that a plastic aerosol container (e.g. a blow-molded or injection molded plastic container) is used rather than a conventional metal aerosol container, it may be desirable to use a plastic ferrule (e.g. an injection-molded ferrule) instead of a metal one. Here the plastic ferrule and aerosol container may be designed to allow the ferrule to clip or screw onto the aerosol container, or be equipped with co-operating surfaces for ultrasonic, laser or other thermal welding of the ferrule to the aerosol container. Alternatively, adhesives might be used to affix the valve onto the aerosol container.
It may be desirable to provide the ferrule as an integral element of the metering chamber component, to advantageously yet further reduce the number of components. The manufacture of such integral components may include single-shot molding or more advantageously at least two-shot molding, e.g. overmolding the other element(s) of the metering chamber component into a formed ferrule or alternatively overmolding a ferrule onto other formed element(s) of the metering chamber component. As can be appreciated from the exemplary embodiment shown in
The exemplary valve (202) illustrated in
In the previous exemplary embodiments the compliant biasing member is located at least in part (in particular, completely) within the pre-metering region. This is advantageous in that it allows for the production of compact valves with their compliant biasing members protected within their second valve bodies. The latter can be useful in terms of manufacturing, handling and transport of valves and/or individual components thereof. Nonetheless alternative designs are possible where the compliant biasing member may be located in part or completely outside the pre-metering region. This can be appreciated from the exemplary embodiment shown in
From the user's perspective, the valve operates likes a conventional push-to-fire valve. When the valve is actuated, the valve stem is moved axially and inwardly from its non-dispensing position (
The exemplary valves shown in
The compliant inner seal (216) is preferably formed by 2-shot moulding into an annular recess provided in the upper stem part (235). When the valve is assembled, the first integral component (221) is inserted by pushing the bottom tip of the stem into the aperture (the insertion aperture) in the radially inward ledge (246), then pushed firmly with the axial stop (229) against the outer seal (217). In the process, the compliant seal (216) deforms and also passes though the insertion aperture, opening out to resume its shape once it has passed through the insertion aperture. The frustoconical profile of the inner seal in the exemplary embodiment shown in
The exemplary valve shown in
It will be appreciated that an alternative form of the exemplary valve shown in
An alternative exemplary embodiment of the first valve body 213 is illustrated in
Although not illustrated, it will be appreciated that once a metering valve of one of the types described herein is affixed to an aerosol container, a valve and aerosol container assembly (a “canister”) is provided such that the inner walls of the aerosol container and the outer envelope of the metered dose valve located within the aerosol container define a formulation chamber in which medicinal aerosol formulation may be contained.
Canisters fitted with a metering valve described herein may be advantageously utilized as part of dispensers for the administration of medicament through oral, nasal, transmucosal (e.g. buccal, sublingual), vaginal, rectal, ocular or aural delivery. Canisters fitted with a metering valve described herein are particularly suited for delivering medicaments by inhalation to a patient. Accordingly, metering valves described herein and canisters fitted with such valves are particularly suitable for use in or as pressurized metered dose inhalers, respectively.
As indicated above, desirably valves described herein are used in standard pressurized metered dose inhalers, and thus it is favorable that the valves have appropriately dimensioned features to interface with the neck of a standard container (although atypical containers could be provided at the expense of new deep drawing tooling and new feed lines and transfer housings for the container making machine). The neck of a typical container has an opening of about 17 mm diameter comprising a rim and a neck, with a bead between the rim and the neck. Consequently, it would be favorable to provide valves such that the widest part of the valve that would be inserted into the container upon mounting the valve on the container to form a canister (in other words the widest insertable width) would be less than 17 mm in diameter. A gasket is typically included in the valve to seal against the rim, although as illustrated above other means for attachment may be used while maintaining the same outer profile of inhaler unit for use in typical actuators. The depth of the smallest, presently commercially used can is about 28 mm from rim to recessed base. Consequently, it would be favorable to provide valves such that that the longest part of the valve that would be inserted into the container upon mounting the valve on the container to form a canister (in other words the insertable depth of the valve) would be less than 28 mm.
Medicinal aerosol formulations may include any drug or combination of drugs that can be delivered by an aerosol (e.g. administered by inhalation) and such drug or drugs can be provided in suspension and/or solution in liquefied propellant, in particular liquefied HFA 134a and/or HFA 227. If desired or deemed necessary, medicinal aerosol formulations may comprise one or more other non-HFA 134a/HFA 227-propellant components, such as excipients, surfactants and suspending aids.
For manufacture of medicinal aerosol canisters filled with a formulation of drug or drugs in suspension, particulate drug in dry powder form may be and is often supplied in micronized form from the producer of the active ingredient. Micronization can be accomplished, e.g., by using a fluid energy mill driven by compressed air, such as shown in ‘Drug Delivery to the Respiratory Tract’ ed. D. Ganderton and T. Jones, publ. Ellis Horwood, Chichester (1987) pages 89-90, or by repeated stepwise millings or by use of a closed loop milling system.
The primary particle size of drug (e.g. the size upon completion of micronization) generally has a mass median particle diameter of 5 microns or less, and most suitably said mass median diameter is in the range 0.8 to 3 microns, with at least 90% by mass of the particles having diameters below 5 microns, which can be determined, for example, by using an Andersen Cascade Impactor.
Depending on the particular valve and/or filling system used, aerosol formulation may be filled into the aerosol container either by cold-filling (in which chilled formulation is filled into the aerosol container and subsequently the valve is fitted onto the aerosol container) or by pressure filling (in which the valve is fitted onto the aerosol container and then formulation is pressure filled through the valve into the aerosol container).
Suitable drugs include those for the treatment of respiratory disorders, e.g., bronchodilators, anti-inflammatories (e.g. corticosteroids), anti-allergics, anti-asthmatics, anti-histamines, and anti-cholinergic agents. Other drugs such as anorectics, anti-depressants, anti-hypertensive agents, anti-neoplastic agents, anti-tussives, anti-anginals, anti-infectives (e.g. antibacterials, antibiotics, anti-virals), anti-migraine drugs, anti-peptics, dopaminergic agents, analgesics, beta-adrenergic blocking agents, cardiovascular drugs, hypoglaecemics, immunomodulators, lung surfactants, prostaglandins, sympathomimetics, tranquilizers, steroids, vitamins, sex hormones, vaccines, therapeutic sense or anti-sense nucleic acids, and other therapeutic proteins and therapeutic peptides may also be employed for delivery by inhalation.
Exemplary drugs which may be employed for delivery by inhalation include but are not limited to: albuterol, terbutaline, pirbuterol, fenoterol, metaproterenol, isoproterenol, isoetharine, bitolterol, epinephrine, tulobuterol, bambuterol, reproterol, adrenaline, ipratropium, oxitropium, tiotropium, darotropium, glycopyrronium, aclidinium, umeclidinium, troventol, beclomethasone, betamethasone, flunisolide, budesonide, mometasone, ciclesonide, rofleponide, aminophylline, dyphylline, theophylline, cromolyn sodium, nedocromil sodium, ketotifen, azelastine, ergotamine, cyclosporine, salmeterol, fluticasone, formoterol, procaterol, indacaterol, olodaterol, carmoterol, milveterol, vilanterol, omalizumab, montelukast, zafirlukast, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, prednisone, methylprednisolone acetate, zileuton, insulin, atropine, prednisolone, benzphetamine, chlorphentermine, amitriptyline, imipramine, clonidine, actinomycin c, bromocriptine, buprenorphine, pentamidine, calcitonin, leuprolide, alpha-1-antitrypsin, interferons, propranolol, lacicortone, triamcinolone, dinoprost, xylometazoline, diazepam, lorazepam, folic acid, nicotinamide, clenbuterol, ethinyloestradiol, levonorgestrel, and pharmaceutically acceptable salts and esters thereof such as albuterol sulfate, formoterol fumarate, salmeterol xinafoate, vilanterol trifenatate, beclomethasone dipropionate, triamcinolone acetonide, fluticasone propionate, fluticasone furoate, tiotropium bromide, leuprolide acetate and mometasone furoate.
Further drugs that may also be delivered by inhalation include but are not limited to aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, fentanyl citrate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, diamorphine, trolamine salicylate, methadone hydrochloride, nalbuphine hydrochloride, nalorphine, tetrahydrocannabinol, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, meprobamate, ergotamine tartrate, propanolol hydrochloride, isometheptene mucate, dichloralphenazone, sumatriptan, rizatriptan, zolmitriptan, naratriptan, eletriptan, barbiturates (e.g., pentobarbital, pentobarbital sodium, secobarbital sodium), benzodiazapines (e.g., flurazepam hydrochloride, triazolam, tomazeparm, midazolam hydrochloride, lorazepam, buspirone hydrochloride, prazepam, chlordiazepoxide hydrochloride, oxazepam, clorazepate dipotassium, diazepam, temazepam), lidocaine, prilocaine, xylocaine, beta-adrenergic blockers, calcium channel blockers (e.g., nifedipine, diltiazem hydrochloride, and the like), nitrates (e.g., nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate), hydroxyzine pamoate, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, chlormezanone, haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothixene, fluphenazine hydrochloride, fluphenazine decanoate, fluphenazine enanthate, trifluoperazine hydrochloride, chlorpromazine hydrochloride, perphenazine, lithium citrate, prochlorperazine, lithium carbonate, bretylium tosylate, esmolol hydrochloride, verapamil hydrochloride, amiodarone, encainide hydrochloride, digoxin, digitoxin, mexiletine hydrochloride, disopyramide phosphate, procainamide hydrochloride, quinidine sulfate, quinidine gluconate, quinidine polygalacturonate, flecainide acetate, tocainide hydrochloride, lidocaine hydrochloride, phenylbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, indomethacin, meclofenamate sodium, gold sodium thiomalate, ketoprofen, auranofin, aurothioglucose, tolmetin sodium, colchicine, allopurinol, heparin, heparin sodium, warfarin sodium, urokinase, streptokinase, altoplase, aminocaproic acid, pentoxifylline, empirin, ascriptin, valproic acid, divalproate sodium, phenytoin, phenytoin sodium, clonazepam, primidone, phenobarbitol, phenobarbitol sodium, carbamazepine, amobarbital sodium, methsuximide, metharbital, mephobarbital, mephenytoin, phensuximide, paramethadione, ethotoin, phenacemide, secobarbitol sodium, clorazepate dipotassium, trimethadione, ethosuximide, doxepin hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride, phenelzine sulfate, desipramine hydrochloride, nortriptyline hydrochloride, tranylcypromine sulfate, fluoxetine hydrochloride, doxepin hydrochloride, imipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarboxazid, desipramine hydrochloride, trimipramine maleate, protriptyline hydrochloride, hydroxyzine hydrochloride, diphenhydramine hydrochloride, chlorpheniramine maleate, brompheniramine maleate, clemastine, azelastine, cyproheptadine hydrochloride, terfenadine citrate, clemastine, triprolidine hydrochloride, carbinoxamine maleate, diphenylpyraline hydrochloride, phenindamine tartrate, lamivudine, abacavir, acyclovir, gancyclovir, valganciclovir, cidofovir, foscarnet, azatadine maleate, tripelennamine hydrochloride, dexchlorpheniramine maleate, methdilazine hydrochloride, trimprazine tartrate, trimethaphan camsylate, phenoxybenzamine hydrochloride, pargyline hydrochloride, deserpidine, diazoxide, guanethidine monosulfate, minoxidil, rescinnamine, sodium nitroprusside, rauwolfia serpentina, alseroxylon, phentolamine mesylate, reserpine, calcitonin, parathyroid hormone, acitretin, amikacin sulfate, aztreonam, benzydamine, calcipotriol, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, ciprofloxacin hydrochloride, clindamycin hydrochloride, clindamycin palmitate, clindamycin phosphate, efalizumab, metronidazole, metronidazole hydrochloride, gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, tacrolimus, vancomycin hydrochloride, polymyxin B sulfate, colistimethate sodium, colistin sulfate, tetracycline, griseofulvin, keloconazole, interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, pentamidine e.g. pentamidine isoethionate, cephalosporins (e.g., cefazolin sodium, cephradine, cefaclor, cephapirin sodium, ceftizoxime sodium, cefoperazone sodium, cefotetan disodium, cefutoxime axotil, cefotaxime sodium, cefadroxil monohydrate, ceftazidime, cephalexin, cephalothin sodium, cephalexin hydrochloride monohydrate, cefamandole nafate, cefoxitin sodium, cefonicid sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefadroxil, cephradine, cefuroxime sodium, and the like), penicillins (e.g., ampicillin, amoxicillin, penicillin G benzathine, cyclacillin, ampicillin sodium, penicillin G potassium, penicillin V potassium, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride, cloxacillin sodium, ticarcillin disodium, azlocillin sodium, carbenicillin indanyl sodium, penicillin G potassium, penicillin G procaine, methicillin sodium, nafcillin sodium, and the like), erythromycins (e.g., erythromycin ethylsuccinate, erythromycin, erythromycin estolate, erythromycin lactobionate, erythromycin siearate, erythromycin ethylsuccinate, and the like), tetracyclines (e.g., tetracycline hydrochloride, doxycycline hyclate, minocycline hydrochloride, GM-CSF, ephedrine, pseudoephedrine, ammonium chloride, androgens (e.g., danazol, testosterone cypionate, fluoxymesterone, ethyltostosterone, testosterone enanihate, methyltestosterone, fluoxymesterone, testosterone cypionate), estrogens (e.g., estradiol, estropipate, conjugated estrogens), progestins (e.g., methoxyprogesterone acetate, norethindrone acetate), levothyroxine sodium, human insulin, purified beef insulin, purified pork insulin, glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide, rosiglitazone, pioglitazone, troglitazone, clofibrate, dextrothyroxine sodium, probucol, lovastatin, rosuvastatin, niacin, DNase, alginase, superoxide dismutase, lipase, calcitonion, alpha-1-antitrypsin, interferons, sense or anti-sense nucleic acids encoding any protein suitable for delivery by inhalation, erythropoietin, famotidine, cimetidine, ranitidine hydrochloride, omeprazole, esomeprazole, lanzoprazole, meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, promethazine hydrochloride, thiethylperazine, scopolamine, sildenafil, vardenafil, cilomilast, imiquimod or resiquimod Where appropriate, these drugs may be delivered in alternative salt forms.
Excipients may include for example, surfactants, co-solvent suspending aids, and/or particulate bulking agents.
Suitable surfactants include those disclosed in EP 372777, GB 837465 and GB 994734, each incorporated herein by reference. Span 85, oleic acid and/or lecithin are commonly used in medicinal aerosol formulations. Other suitable surfactants for use in medicinal aerosol formulations include HFA-soluble fluorocarbons such as those referred to in WO 91/11173, GB 2263064, each incorporated herein by reference, as well as polyethyleneoxide, polyoxyethylene-oxypropylene block copolymers such as members of the the Synperonic PE series (Croda International plc), polyoxypropylenes, polyoxyethylene-polyoxypropylene-ethylenediamine copolymers such as members of the Synperonic T series, castor oil ethoxylates such as Alakasurf CO-40, acetylated monoglycerides (e.g. Myvacet 9-40 or 9-45 from Farma International), polyvinyl pyrrolidone, polyvinylacetate, polyvinyl alcohol, polymers of acrylic acid, methacrylic acid and copolymers thereof, polyoxyethylene glyceryl trioleate (TagatTO), polyoxyethylene glyceryl monooleate (TagatO or TagatO2 from Degussa), diol-diacids such as those disclosed in WO 94/21228, incorporated herein by reference, oligolactic acid and derivatives thereof, such as those disclosed in WO 94/21229, incorporated herein by reference, functionalized PEGs such as those disclosed in WO 2003/059317, incorporated herein by reference, amide-ester excipients such as those disclosed in WO 2003/059331, incorporated herein by reference, propoxylated PEG (Antarox 31R1 from Solvay), polyoxyethylene glycerol esters such as those disclosed in U.S. Pat. No. 5,536,444, incorporated herein by reference, protective colloids such as those described in WO 95/15151, incorporated herein by reference, glyceryl triesters, capr(yl)ic diglyceryl succinates (e.g. Miglyol 829 from Condea Chemie GmbH), Vitamin E acetate, tocopherol (Vitamin E), polyglycolized polyglyceride (e.g. Labrafac Hydro WL 1219 from Gattefosse, Gennevilliers, France), polypropylene glycol, polyethylene glycol e.g. PEG300, aminoacids or derivatives such as disclosed in U.S. Pat. No. 6,136,294 incorporated herein by reference, and other surfactants in the same chemical family as the above but differing in chain length of alkyl or polyalkoxy groups.
Suitable co-solvents may include ethanol, propanol, isopropanol, and other alcohols, glycerol, polyethylene glycol 400, propylene glycol, decanol, sorbitol, mannitol, lactitol, maltitol, glycofurol, dipropylene glycol, propylene glycol diesters of medium chain fatty acids (e.g. Miglyol 840), triglyceride esters of medium chain fatty acids (e.g. Miglyol 810, 812), perfluorocyclobutane, perfluoropentane, perfluorodimethylcyclobutane, menthol, eucapyptus oil, propylene glycol monolaurate (Lauroglycol), diethylene glycol monoethyl ester (Transcutol), isopropyl myristate, saturated hydrocarbons in liquid form and essential oils. Ethanol is commonly used in medicinal aerosol formulations.
Suitable suspending aids may include lactose, glucose, sucrose, D(+)trehalose, as well as their various hydrates, anomers and/or enantiomers, other saccharides such as D-galactose, maltose, D(+)raffinose pentahydrate, sodium saccharin, polysaccharides such as starches, modified celluloses, dextrins, dextrans, DL-alanine, other aminoacids or derivatives such as disclosed in U.S. Pat. No. 6,136,294 incorporated herein by reference, ascorbic acid, sodium sulphate, cetyl pyridinium chloride or bromide other salts e.g. sodium chloride, calcium carbonate, sodium tartrate, calcium lactate, or other organic compounds e.g. urea or propyliodone.
| Number | Date | Country | Kind |
|---|---|---|---|
| 1210580.5 | Jun 2012 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US13/45549 | 6/13/2013 | WO | 00 |
