The present invention relates generally to improvements in the manufacture of valve components, in particular valve stems for pharmaceutical aerosol valves, in particular for metered dose dispensing valves. The present invention also relates to the provision of valve stems having desirable structural qualities and/or blockage resistance.
The use of aerosols to administer medicament has been known for several decades. Such aerosol formulations generally comprise medicament, one or more propellants, (e.g. chlorofluorocarbons and more recently hydrogen-containing fluorocarbons, such as propellant 134a (CF3CH2F) and propellant 227 (CF3CHFCF3)) and surfactant and/or a solvent, such as ethanol.
Pharmaceutical aerosols for inhalation, nasal, sublingual administration, generally comprise a container or vial of the aerosol formulation equipped with a metered dose dispensing valve. Although there are many different designs of metered dose valves, the majority comprises a metering chamber and a valve stem that slides through a diaphragm, also known as an outer stem gasket or seal, into the metering chamber. When the valve is in its non-dispensing position, the diaphragm maintains a closed seal around the valve stem. The valve stem includes a side port in communication within a passageway inside the valve stem. When the valve is actuated, the side port slides past the diaphragm and into the metering chamber, and the contents of the metering chamber pass through the side port and passageway, exiting the stem outlet.
The diameter of the side port can range from 0.1 to 0.8 mm, while the stem outlet diameter typically ranges from 0.8 to 3 mm. The central passageway typically has a diameter from 0.8 to 4 mm.
It will be appreciated that the aerosol valve as well as the aerosol formulation, each play an important part in obtaining optimum pharmaceutical properties from the product. For example, there should be no blockage of the valve, in particular the valve stem, which could impair or prevent medicament delivery.
Valve stems have conventionally been constructed by injection molding thermoplastics and by deep drawing metal. Metal valve stems may also be fabricated by machining and/or cold forging.
Deep drawn metal valve stems are hollow having a central bore from the closed end of the valve stem to the outlet end of stem, which acts the passageway. Typically the outlet end is curved inwardly restricting the size of the central bore at the outlet. The side port is generally formed by punching. This operation results in a circumferential projection or burr being formed around the side port within the valve stem. In some cases, the metal punched out to form the side port may not be completely removed leaving a large burr projecting inwardly into the valve stem. It has been observed, in particular for ethanol-containing medicinal aerosol formulations, that there is a tendency for drug to build up in areas where it cannot be readily dislodged, e.g. such projections or burrs around the side port. A large medicament build-up and/or any subsequent dislodgement thereof could cause complete blockage of the valve stem. Furthermore, the tendency for ethanol to evaporate is far higher at the openings to the atmosphere, e.g. the valve stem side port. Thus, there is a tendency for medicament build-up in these regions, which could lead to blockage of the side port.
It has been reported that although it is possible to insert a die prior to punching the side port in order to minimize the formation of the burr within the valve stem. This technique leaves a sharp edge around the side port on the inner as well as the outer surface of the valve stem. The sharp edge on the outer surface is prone to damaging the diaphragm seal associated with the valve stem. WO 99/55600 discloses metered dose valves having a machined and/or cold forged, preferably stainless steel, valve stem in which blockage problems are substantially reduced. The valve stems are preferably fabricated by machining and/or cold forging and then drilling with a drill bit the passageway including the outlet as well as the side port. To avoid the formation of burrs around the side port within the valve stem, it is described to preferably insert and remove the drill bit at least twice during the drilling operation.
Laser drilling of valves stems to provide the side port has been reported in The Aerosol Handbook (M. Johnsen, 2nd Edition, 1982, Wayne Dorland Co. p 164.) However, it is reported that by using laser beams, side ports as small as 0.13 mm have been made, but they are highly subject to clogging and other problems.
There is an ongoing need for a method for providing a side port in a valve stem, in particular allowing for the provision of a valve stem having desirable structural qualities and/or blockage resistance.
Surprisingly, we have found that by filling and sealing a fluid, such as water, into the passageway of the valve stem and then laser drilling a side port into the valve stem, a side port, and hence a valve stem having desirable structural qualities and/or blockage resistance can be provided.
It has been found that a number of defects occur during conventional laser drilling of valve stems. Backwall damage occurs due to impingement of excess laser beam on the backwall, when the laser beam breaks through the wall being drilled. Due to the accumulation of re-solidified material on the periphery of the orifice exit, dross forms around the side port within the valve stem. Furthermore, downwardly ejected melt can also lead to the deposition of particles on the interior surface of the valve stem, in particular on the backwall. In valve stems, these defects can provide undesirable surfaces for medicament build-up or attachment of loose medicament particles, and thus increasing the tendency of blockage in the valve stem. These defects may also enhance the possibility and/or onset of corrosion within metal valve stems.
It has been found that by filling a fluid into the valve stem passageway and sealing the stem outlet, to substantially prevent the fluid from escaping through the outlet (before and) during laser drilling of the side port, backwall damage as well as the formation of dross and deposited particles can be significantly reduced or substantially prevented. The reduction or substantial prevention of the damage seems to be the result from two aspects. First, by temporarily sealing the stem outlet, upon beam breakthrough, the fluid is initially held within the passageway (e.g. it is not simply pushed or blasted through the outlet) as a barrier, absorbing and diffusing excess laser beam and thus substantially preventing impingement of the laser on the backwall, as well as impeding the deposition of particles. Secondly, after beam breakthrough, at least a part of the fluid (vaporized and/or as fluid) and, if any assist gas used in the laser drilling process, assist gas are then forced to escape or are pushed out the newly laser-drilled hole, hindering the formation of dross accumulation at the hole exit and again deposition of particles.
The interior of valve stems thus laser drilled, exhibit desirable structural and/or blockage resistance qualities. In particular, the side port exit within the valve stem, which is free or substantially free of dross and does not exhibit a circumferential projection or a sharp edge, exhibits an advantageous minimum of potential seeding surface for medicament deposition or build-up and thus exhibits advantageous blockage resistance properties.
Accordingly, in one aspect of present invention there is provided a method for providing a hole into a valve component having an internal cavity, said method comprising the steps of filling and sealing a fluid within said cavity; and laser drilling the hole through the component into the internal cavity.
This method of laser drilling is desirably suitable for drilling a hole in any valve component having an internal cavity. However the method is particularly advantageous for providing a side port in a valve stem and in the manufacture of valve stems.
Another aspect of the present invention is the provision of a method of manufacturing a valve stem, said method comprising the steps:
Desirably laser drilling is performed in conjunction with an assist gas.
Methods according to the present invention are applicable for plastic or metal valve components or valve stems, respectively.
Valve components/stems thus laser-drilled may be suitably subjected to cleaning and/or finishing procedures conventionally used for such cleaning and/or finishing.
Alternatively or in addition thereto, valve components/stems thus laser-drilled may be subjected to an abrasive or chemical cleaning or finishing process to remove any spatter which may have formed on the outer surface of the respective component during laser-drilling, e.g. about the periphery of the hole entry, as a result of outwardly ejected melt. For metal valve components/valves, it has been found that when oxygen is preferentially used as an assist gas, any spatter and/or stray re-solidified particles are typically present in the form of a metal oxide and such oxide can be conveniently dissolved in an acid washing. Advantageously the use of such an acid washing as chemical cleaning process can also simultaneously bring about a desirable passivation of the metal surface.
Another aspect of the present invention is a valve stem obtainable according to a method described above.
An additional aspect of the present invention is a valve stem obtained according to a method described above.
In a further aspect, the invention provides a metered dose valve comprising such a valve stem. In yet another aspect, the invention provides a metered dose dispenser comprising such a valve stem.
The dependent claims define further embodiments of the invention.
The invention, its embodiments and further advantages will be described in the following with reference to the following drawings.
FIGS. 6(a) and (b) show SEM micrographs of a SS 305 valve stem obtained in accordance with a preferred method of the invention (in particular in accordance to Example 1).
FIGS. 7(a) and (b) show SEM micrographs of a SS 305 valve stem obtained after conventional laser-drilling (Example A).
FIGS. 10(a) and (b) show SEM micrographs of a SS 305 valve stem obtained after laser-drilling a work-piece filled with water but without sealing the outlet (Example B).
It is to be understood that the present invention covers all combinations of particular and preferred aspects of the invention described herein.
In its non-dispensing position, contents of the retention chamber or, if a retaining cup is not used, the formulation chamber, may enter the metering chamber (12) by passing through the groove (32) on the inner end (20) of the valve stem through the inlet aperture (30) of the metering chamber. When the valve stem is moved to its dispensing position (not shown) the groove (32) passes outside the tank seal (22) and thus the inner end of the valve stem completes a seal preventing flow of aerosol formulation into and out of the metering chamber through the filling end. In its dispensing position, the side port (34) of the valve stem passes through the diaphragm into the metering chamber. The side port (34) is in communication with a central outlet passageway (see
Referring to
Also in comparison to a side port obtained by conventional laser drilling, the undersides of side ports as well as valve stems obtained accordance methods of present invention show very desirable structural qualities.
Due to the desirable structural properties of the interior of valve stems laser drilled in accordance with methods of the invention, the valve stems are substantially free of seeding surfaces for the deposition or accumulation of medicament and hence show enhanced blockage resistance. Methods in accordance with the invention of filling and sealing within a cavity a fluid prior to laser drilling can be also advantageously used in providing a hole in other valve components having a cavity (besides valve stems). For example the method can be desirably used to provide aperture(s) in a retaining cup or a metering chamber.
Diameters for the laser-drilled hole or side port may suitably range from 0.1 to 1.1 mm: for side ports of valve stems, more particularly 0.3 to 0.8 mm and most particularly 0.35 to 0.75 mm, and for apertures in retaining cups and metering chambers, more particularly 0.6 to 1.0 mm and most particularly 0.75 to 0.95 mm.
Desirably laser drilling is performed in conjunction with an assist gas. Suitable assist gases include assist gases conventionally used in laser drilling, such as oxygen, argon, nitrogen, helium or air. For laser-drilling metal valve components/stems, oxygen as assist gas is preferred.
For ease in manufacturing and processing, the fluid is desirably a fluid at ambient temperature (e.g. about 22° C.). Preferably the fluid is a liquid or a liquid-based fluid (e.g. solutions, suspensions, gels, colloidal dispersions including foams, emulsions and sols); more preferably a liquid or liquid-based fluid having a dynamic viscosity less than 33000 mPa.s, preferably determined according to Standard Test Method ASTM D2196-99 (Test method A). Water and aqueous fluids are particularly suitable.
In methods of manufacturing plastic valve stems, the valve stem work-piece may be suitably provided by molding, in particular injection thermoplastic molding. More particularly, a valve stem blank having one or more exterior contours of the valve stem may be provided by molding, in particular by injection thermoplastic molding, while the passageway and outlet may be formed by drilling, in particular by laser drilling.
In methods of manufacturing metal, preferably stainless steel, valve stems, the valve stem work-piece may be suitably provided by machining and/or cold forging. More particularly, a valve stem blank having one or more exterior contours of the valve stem can be provided by machining and/or cold forging, while the passageway and outlet may be formed by drilling, in particular by laser drilling.
Alternatively, in the manufacturing of metal, preferably stainless steel, valve stems, the valve stem work-piece may be desirably provided by deep drawing. Preferably the work-piece is deep drawn having one or more exterior contours of the valve stem. For deep drawn valve stems, blockage resistance can be advantageously further enhanced by reducing dead volume within the valve stem, so that aerosol formulation only contacts and passes through the portion of the valve stem necessary to convey the formulation to the outlet (i.e. between the side port and the outlet of the valve stem). Desirably the manufacture of deep drawn valve stems include steps of: inserting into the passageway a plug, such that a portion of the interior of the passageway between the closed end of the valve stem and the side port is sealed off; and curling the outlet end of the stem inwardly. More desirably the plug is inserted, such that the interior of the valve stem from the closed end of the valve stem and substantially up to the side port is sealed off. The plug may be inserted either before or after laser drilling the side port, more particularly either before the passageway is filled or after the outlet is unsealed. The curling of the outlet end may also be performed either before or after laser drilling, more particular either before sealing the outlet or after unsealing the outlet, but in every case after the plug has been inserted.
Valve components/stems thus laser-drilled may be suitably subjected to cleaning and/or finishing procedures conventionally used for the cleaning and/or finishing, such as bright annealing, barreling or passivation for metal stems. Barreling is typically performed by tumbling a plurality of valve stems in a container with a water and detergent mixture; the detergent is typically a mixture of anionic and non-anionic surfactants and organic acids. In passivation, a metal (in particular stainless steel) valve stem is washed with acid to enhance the formation of a protective, passive metal (chromium) oxide film. Accordingly the valve stems are preferably treated with an acid solution of nitric acid (at 5 to 50% concentration) or citric acid (1 to 10% concentration) or other appropriate compound to remove surface contamination so as to enhance spontaneous passivation.
Alternatively or in addition thereto, valve components/stems thus laser-drilled may be subjected to an abrasive or chemical cleaning or finishing to remove any spatter or stray residual particles. Suitable abrasive cleaning or finishing may include buffing, shot-blasting or washing with acids. The latter two exemplary cleaning methods are particularly suitable for metal valve component/stems, and the use of acid washing as a cleaning method is particular advantageous when the laser drilling was performed in conjunction with oxygen assist gas. In shot blasting the outer surface is blasted, preferably spot blasted, with fine particles, such as alumina having a particle size of 10 to 100 μm, under high pressure, such as 3 to 5 bar for about 1 to 2 seconds. Desirably a metal pin or shaft may be inserted into the component/stem behind the laser-drilled hole to protect the backwall of the component/stem during the shot blasting.
Due to their desirable structural qualities, valve components/stems obtainable and provided according to the methods of the invention are particular suitable for use in metering valves, especially metering valves for the delivery of medicament, as well as metered dose dispensers, in particular medicinal metered dose dispensers, more particularly metered dose inhalers.
Materials Used
Valve Stem Work-Piece
All the following laser drilling experiments were performed with Stainless Steel valve stem work-pieces manufactured by deep drawing out of Stainless Steel Type 305 (“SS 305”) strip. The stems had an overall length of 24.4 mm, wall thickness 0.2 mm, an external flange between the open portion and the closed portion as well as an external groove. The central bore or passageway had an internal diameter of 2.4 mm at the position where the side port was to be drilled. Unless stated otherwise, the outlet end of the stem was curled inwardly and the outlet had a diameter of 1.6 mm. The internal volume of the stem was 85 microlitres. During the deep drawing process, the steel was coated with drawing oil (ADFORMAL™ EP 130 see below), which was not removed prior to laser drilling.
Tap Water
Gel: Aqua-Gel™ II Cable Pulling Lubricant, supplied by Ideal Industries Inc.
Deb™ hand-washing fluid, supplied by Deb limited.
Oil: Adformal™ EP130 extreme pressure metal forming oil, supplied by BP Lubricants and Special Products Limited.
Stainless steel shaft with a diameter of 2.2 mm
Plastic-coated wire with a diameter of 1.5 mm
Polytetrafluoroethylene (PTFE) sheet with a width of 2.2 mm
Blu-Tack™—a low tack adhesive putty manufactured by Bostik Limited, Leicester, UK.
Laser Drilling
An Electrox Scorpion 400 W pulsed Nd:YAG laser (supplied by Electrox, Letchworth, UK), emitting at 1.06 μm wavelength, was used to drill holes in the valve stem work-pieces.
A focusing lens with a focal length of 120 mm was used in all the experiments. The focal plane position was placed on the material surface with a nozzle-work-piece distance of 1.7 mm. The target hole size was 0.47 mm diameter. Experiments were carried out with the laser positioned vertically or horizontally, with the stem work-piece correspondingly positioned horizontally or vertically, respectively. It is to be appreciated that the positioning of the laser and work-piece does not have a material effect on the results of the laser drilling. However for the examples in which the stem work-piece was filled with a fluid it is convenient to have the stem work-piece positioned vertically with then the laser positioned horizontally.
In the examples in which the stem work-piece was filled with a fluid, the fluid was injected into the valve stem blank using a 10 ml syringe with a 1.27 mm diameter regular-bevel point needle. In the examples in which the stem opening was sealed, a compressible stem-constriction was pressed onto the stem-opening before and during laser drilling. The stem-constriction was created by placing a piece of Blu-Tack™ at the stem-opening and pressing physically with the index finger. In an automated process, the stem-constriction could be made from silicone rubber, such as used to make O-rings.
It was found in preliminary experiments that, to drill a hole in AISI 305 Stainless Steel stem work-pieces having a wall thickness 0.2 mm, a single or a double laser pulse was effective. However, a double pulse of 7 kW peak power was preferred because it produces more consistent holes. In the experiments that follow, a double pulse of 7 kW peak power, a pulse width of 0.3 ms, energy per pulse 2.1 J and pulse frequency of 20 Hz were used, unless otherwise stated. An assist gas, oxygen unless stated otherwise, at a pressure of 3 bar (42 liters per minute flow rate) unless indicated otherwise, was also used. A rectangular pulse shape was used.
Analysis
In order to analyze the laser-drilled valve stems a precision cutter was employed to section along the valve stems. After the stems were sectioned for a length of 17 mm, the stems were physically split open to reveal the underwall (underside) and backwall of the stems. On the underwall of the stems the extent of dross deposition around the hole exit was analyzed; while the backwall was analyzed for any damage as a result of the impingement of excess laser beam. Both samples were analysed for scattered particle deposition. Preliminary analysis was carried out with an optical microscope. Further analysis was then carried out using a scanning electron microscope (SEM).
FIGS. 7(a) and (b) show SEM micrographs of a SS 305 valve stem laser-drilled without the use of any barrier material. As can be seen from
In this example, tap water was filled into work-piece before laser-drilling. However no stem constriction was used. FIGS. 10(a) and (b) show SEM micrographs of a resulting SS 305 valve stem after laser drilling the side port. As can be seen from
FIGS. 6(a) and (b) show SEM micrographs of SS 305 valve stems obtained by laser-drilling work-pieces, whose outlet were sealed with a stem constriction after filling the work-piece with water (Example 1). Comparing the results with those of drilling without any barrier or with water but without sealing (Examples A and B), it can be seen that damage to the backwall as well as deposition of particles on the backwall were prevented. No discernible accumulation of dross around the periphery of the hole exit could be noted (as shown in
The results of these experiments as well as the results of examples C to E and examples 3-10 are summarized in the following table.
Using a 10 ml syringe fixed to a 1.27 mm diameter regular-bevel point needle, water was ‘pumped’ into the stems before and during laser drilling in order to continuously fill water into stems even when and after beam breakthrough occurs. The results, were similar to those of Examples A and B, an about 2 mm diameter spot backwall damage was noted together with a significantly amount of dross at the hole exit. Some particle deposition was noted.
Throughout the laser drilling a water jet spray was directed into the opening of the valve stem, using an airbrush, at approximately 20 psi. The nozzle of the airbrush was held at distance of 10 mm to the opening of the stem. The results, were similar to those of Examples A to C, an about 1 mm diameter spot backwall damage was noted together with a significantly amount of dross at the hole exit and some particle deposition.
Thus, local backwall damage and particle deposition were prevented completely using the stem constriction, thus providing a cleaner drilling than drilling with no such constriction. In addition, the underwall of the stem appeared to be substantially free from particle deposition and no discernible accumulation of dross around the periphery of the hole exit could be noted when using the stem constriction.
Use of different assist gas pressures of oxygen, i.e. lower pressures of 1 and 2 bars as well as higher pressures of 4 and 6 bar all gave optimal results, showing no significant difference to the results of Examples 1 and 2 performed with an assist gas pressure of 3 bar.
The use of a higher pulse frequency did not affect the results. Again the resulting valve stem was free or substantially free of backwall damage, particle deposition and dross accumulation.
The results for Examples 8 to 10 were similar to those of Examples 1 to 7, while the results of example E were similar to example B. Thus, the use of nitrogen or argon assist gas in conjunction with constricting the stem outlet also allows the production of valve stems whose interior showed desirable structural qualities, free or substantially free of backwall damage, particle deposition and dross accumulation at the hole exit.
Other fluids, such as gels, oils, solutions were examined as summarized in Table 3.
The results are these experiments are listed below:
The use of other fluids together with sealing the outlet with a stem constriction was equally effective, backwall damage, particle deposition, dross accumulation were either completely prevented or reduced considerably in comparison to results of the examples in which no stem constriction was applied.
Comparative H to J
Solids as barriers were examined as summarized in the following table. In each case the barrier was inserted into the cavity of the work-piece before drilling. For examples I and J, the outlet end of the stem work-piece was not curled, and thus the outlet had a diameter of about 2.4 mm in order to allow the insertion of the P TFE sheet and Stainless Steel (“SS”) shaft.
The results are summarized in Table 6.
Although in certain cases, the use of a solid barrier prevented backwall damage, in each case significant amounts of dross accumulation and particle deposition (in particular on the underwall) were noted for the resulting valve stems.
Number | Date | Country | Kind |
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0214990.4 | Jun 2002 | GB | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US03/14468 | 5/6/2003 | WO | 12/13/2004 |