Patent Application
20080023098
The invention, together with further objects and advantages thereof, may best be understood by referring to the following detailed description taken together with the accompanying drawings, in which:
a) illustrates an embodiment of the filling tool and (b) illustrates an enlarged view of a conical receptacle;
a) illustrates in principle a longitudinal section of an embodiment of the filling tool, (b) a cross section of the filling tool, (c) an enlarged view of cross section B and (d) an enlarged view of cross section A;
The present invention discloses a method and a device for exact metering and volumetric filling of finely divided dry powder medicament doses into preformed containers, where the doses and containers are adapted for administration by inhalation using a dry powder inhaler (DPI). The method according to the present invention is illustrated in a flow diagram in
In the context of the invention the term “container” is used generically and includes well-known designs such as blisters, capsules as well as bowls and pods, into which a metered quantity of dry powder medicament, a dose, may be deposited and sealed later to be made available in a DPI, which may deliver the dose as needed to a user inhaling through the DPI device. The term “receptacle” is used to describe a carefully made, truncated, conical cavity of very exact dimensions and volume—machined or otherwise made—into the outer surface of a filling tool, which may have more than one such cavity on its outer surfaces. From inside the tool access can be made to the smaller end of the conical cavity or cavities to allow fitting of filters and air supply nozzles, which will be described later.
Volumetric filling machines for dry powders in prior art are not easily adapted to metering and unloading of small doses, especially if the powder is finely divided presenting in the order of 90% by mass of particles with aerodynamic diameter between 1 and 5 μm. Gravitation in combination with impaction and vibration are popular prior art methods of first filling a receptacle and then unloading the powder collected in the receptacle into a selected container. Alternative methods and devices involving vacuum and air pressure to collect powder and fill it into targeted containers generally present better performance in terms of consistency and dose RSD compared to gravitation methods, especially when producing a dose of relatively small mass of powder particles less than 10 μm aerodynamic diameter. Excipients are commonly added to medicaments for different purposes, one of which is to dilute a potent medicament, another is to improve powder flowability.
A device according to the present invention is illustrated in
A filter is necessary when using air to attract or repel powder. A well-balanced suction force applied to a receptacle will attract available, nearby powder and will fill up the receptacle, such that the powder is compacted to a certain degree in the receptacle acting as a metering chamber. The filter at the bottom of the receptacle, i.e. at the second opening 12, stops powder from being sucked into the air system and thereby becoming lost in the filling process. The filter is also necessary when air pressure is used to push the load out of the receptacle during the unloading operation, because it will stop possible foreign particles in the air supply system from contaminating the powder in the load. The filter should not be of bag-type or be made of felt, because felt material may give off fibers, which may contaminate the powder load. Felt filters are usually rather thick and the fibers in the felt are not held in place by design; the felt is just a compressed collection of fibers, randomly arranged and held together by a bonding agent and a more or less loose fabric. In use the felt will let go of fibers, which may mix into the powder and follow the powder load into the container. The present invention preferably uses a woven, pre-stretched, surface-treated thin filter manufactured by W.L. Gore & Associates, Inc. of Newark Del., which by design cannot lose fibers to air passing through. A further advantage of the invention is that the filter is so thin that it is easily sealed to the air connection end of the metering receptacle. Instead of common prior art practice of squeezing the felt filter tight to the receptacle by mechanical high force deforming the thick felt, the stretched woven filter is held in place by an elastic seal, which seals the filter to the bottom end of the receptacle, preferably using an arrangement comprising a resilient, moderate spring force acting on the air nozzle on the other side of the seal, whereby the contact pressure is kept constant, thus maintaining a tight connection between the air nozzle and the air connection end of the receptacle. The seals should be non-fibrous and may be made of e.g. PTFE, PFA, EPDM, Neoprene or Nitril and similar, medically approved materials. A further advantage of the invention is that the woven filter requires much less differential pressure across it compared to a felt filter for a given flow and particle filtration, i.e. less energy is needed, which simplifies control of the filling and unloading operations.
Proper metering of the powder quantity in the receptacle is difficult but important and consistency between loads out of the same receptacle is of course also important and so is consistency between loads from different receptacles in the same tool, if there are more than one. A prior art felt filter is easily deformed when it is squeezed tight to the air connection end of a receptacle, e.g. by pushing an air nozzle with considerable force into the felt. The felt will bulge inwards and intrude into the bottom of the metering receptacle, thus reducing the actual volume in the receptacle, which in turn reduces the powder load sucked into the receptacle in the filling step and results in lower powder mass in the load to be transferred to a receiving container. The present invention solves this problem by using a pre-stretched, woven filter, which is not deformed by the moderate force needed to tighten the filter to the air connection end and it neither intrudes into the receptacle nor expands in the other direction, whereby the volume of the receptacle remains unaffected. Optionally a supporting wire netting may be used, if deemed necessary, to support the filter on one or both sides of the filter. The result is not only a reduced relative standard deviation (RSD) between subsequent loads from the same receptacle but also less RSD between loads from different receptacles. Of course a metered dose in a container may comprise more than one load, but this is by exception and not the normal procedure, because it takes longer time.
In a further aspect of the present invention a use of a mechanically strong but thin, cardboard-like, non-woven, non-compressible filter 106 makes it possible to use a larger surface filter area of the second opening 12 of receptacle 10, compared to prior art devices. This makes it possible to also increase the area of the first opening 11 of the receptacle and thereby increase the receptacle volume without increasing the height of the truncated cone constituting the receptacle. A big metering receptacle may be desirable for some dry powder medicaments, which are not so potent or where the powder formulation is of a type requiring a large metering volume, e.g. if the formulation is a mixture of active pharmacologic ingredient(s) and optional excipient(s), possibly presenting different particle size distributions, or composite powders. Because the non-woven filter is much less prone to bulging than other types of filters, such as bag-type or felt filters, when air-suction is applied during filling of the load in the receptacle, these may be filled and emptied many times in a production run without risk of exceeding set limits for the relative standard deviation (RSD) between load masses. Keeping the cone angle(s) of the receptacle at an optimum to facilitate emptying, but increasing the filter area leads to a wished for increase in receptacle volume. From a production point of view, a deposited load of small height, preferably not higher than about 2 mm, and large occupied area in a dose container, such as a blister, is preferred to a higher load occupying a smaller area in the container. A high load is more likely to collapse uncontrollably during the deposition of the load into the container or during transport of the container in the production line before sealing, which increases the risk of powder dust being spread where it is not wanted and which may affect the load mass. A small height of the deposited load is also preferred from a blister size aspect. Regardless of the type of blister, e.g. if made from aluminum foil or a thermo-plastic material, deep blister pockets are more difficult to make and are less economical, because the usable-area/volume relation becomes unfavourable. If necessary, the non-woven as well as any other filter type can be supported by a wire netting or a sintered filter on the air suction side to reduce the bulging effect, if the filter area is large. A similar type of wire netting or sintered filter can of course also be fitted to the other side of the filter, in order to reduce the bulging effect during ejection of the load, if advantageous or necessary. An advantage of the use of a non-woven filter in this way is that a big load from a large receptacle may represent a full, metered dose, which otherwise would have to consist of two or more loads, which would reduce the speed of production by at least a factor of two.
In yet another aspect, the non-woven filter presents generally the same flow resistance across the whole filter area, which gives an airflow per sqmm (mm2) value, which is roughly the same near the conical wall of the receptacle as in the middle of the total, exposed filter area. Compared to prior art, the woven filter facilitates a consistent filling as well as ejection of a load in the metering receptacle. Furthermore, the receptacle may be given a shape adapted to the dose container, such that the geometric form of the ejected load becomes well adapted to the dimensions of the dose container and the load may still present a considerable mass. The need for more loads than one to make up a dose in the same container may thus be eliminated.
Each receptacle is lined up with and connected to a nozzle, which in turn is connected to a supply of vacuum and compressed air through at least one fast acting on-off valve. For the sake of simplicity, the valve(s) may be common to all nozzles. Filling the receptacles is accomplished by making powder available to the receptacles, e.g. through a chute arrangement from a storage chamber, such as a trough or a hopper. Normally powder is fed by gravitation, optionally aided by addition of energy, e.g. by vibrating the trough. When the tool containing the receptacle(s) has brought at least one receptacle in position to be filled, by opening of at least one valve, suction is applied from a vacuum source to the respective air nozzle, which in turn sucks powder and compacts the load to a degree into the corresponding receptacle. The filter stops powder from entering the nozzle. After completing filling of some or all receptacles of the filling tool, the tool is cleaned from surplus powder and moved to a downward pointing position for unloading the load of at least one receptacle into a selected container. When a valve opens, a pulse of compressed air is led through at least one nozzle and filter to the at least one receptacle, where the air exerts a force on the powder load in the receptacle. The load will be ejected from the receptacle and will drop into a selected container, provided it is in correct position. If the tool contains a plurality of receptacles it is advantageous to control the channeling of compressed air to the receptacles to ensure that consistent, uniform air pulses are fed to all receptacles, e.g. by feeding pulses to receptacles one by one in turn. In doing so the risk of dropping air pressure during unloading is eliminated, which may otherwise cause problems if the air pulse is channeled simultaneously to all receptacles, since the individual loads are unlikely to leave their respective receptacles at exactly the same moment. This problem of synchronization may lead to higher powder retention in some receptacles, which are late in releasing their loads.
Surprisingly, it has been found that the retention of powder in the metering receptacle after unloading is less when using the woven or non-woven filter compared to the felt ditto. The reason for this is that because the felt filter of prior art becomes quite deformed and quite dense around the edges, where it is kept tight to the air connection end, pressurized air may only pass through with great difficulty near the inner wall of the receptacle during the ejection of the load. This phenomenon leads to a substantially reduced air stream near the receptacle inner wall with insufficient turbulence to clean out all of the powder adhering to the wall. However, even when the woven or non-woven filter is used instead of the felt filter the cone angle of the receptacle should not be too great, otherwise there is a risk that powder retention on the inner walls of the receptacle increases due to insufficient air turbulence near the wall.
Reducing powder retention on all surfaces that may come in contact with powder is a further aspect of the present invention. The material of the filling tool must be carefully selected to present extreme stability of form, good machining properties, good resistance to abrasion, high surface finish with low friction properties, if necessary achieved by coating. Suitable materials for the filling tool include for instance vacuum-arc-remelted (VAR) stainless steel, metals, alloys and glass. Suitable coating materials may be selected from thermoplastic materials, such as PTFE, PE, parylene and similar. The tool surfaces in contact with powder, e.g. the metering receptacles, should be polished or coated to a fineness modulus of less than Ra=0.25 μm, and preferably less than Ra=0.1 μm and the resulting surface should present as low dynamic friction coefficient as possible. A preferred embodiment of the filling tool uses a machined stainless steel body, which is ground in several steps and then optionally electro-polished, which results in a fineness of less than Ra=0.1 μm. The filling tool may then be metallurgically coated by vapour deposition of e.g. chromium nitride, coal/chrome-combination or graphitic coating. This will ensure a durable filling tool surface with very low friction, making it easy to remove sticking powder particles. Naturally, consideration must be paid to the type of medicament powder and powder formulation in deciding what materials to use for the filling tool, the appropriate grinding and polishing steps and type of coating, if needed.
Electrostatics is often a problem in handling of dry powders, especially finely divided powders. Fine particles are easily triboelectrically charged when transported, not only by contact with objects of the transportation system but also by flowing air. The problem is aggravated by the necessity of handling the powder in a dry atmosphere, typically below 20% relative humidity, in order not to affect the quality and properties of the powder. The powder particles may be electrically discharged by applying static elimination devices, e.g. from NRD LLC, Grand Island, N.Y., where needed to keep static charging of the powder, the filling tool and associated equipment to a minimum throughout the filling procedure. By doing so loss of particles due to particle-sticking and other interference from statics with the filling process are kept to a minimum. When an applied air pressure pulse unloads the powder load from the metering receptacle, the powder particles must pass an existing air gap before reaching a receiving container. By triboelectric charging, particles acquire a positive or negative charge to a higher or lesser extent. This electric charge makes them disposed by the influence of stray electric fields, existing in the air gap, to deflect in other directions than the expected inertial and gravitational track and thus settle onto other surface areas than the expected target area of the receiving container. To reduce spillage of this sort the present invention discloses the addition of a source of neutralizing charges, e.g. an ion source, to be positioned near the air gap between the tool incorporating metering receptacle(s) and the container(s). Electrically charged particles will then very quickly be neutralized by charges from the source and the loss of particles in transfer from receptacle to container due to electrostatics will be reduced.
When the powder load from the receptacle has been deposited in the container it may be necessary to spread the powder load more evenly over the available area inside the still open container, if the deposit has developed powder peaks. The peaks may interfere with a sealing cover, e.g. a foil to be applied on top of the container in order to seal the container in a next step. Spreading the powder may be accomplished in many ways, but preferably without means that presume contact between means and powder, e.g. scrapers. Preferred embodiments of spreading means include a vibrating or shock arrangement to jar the container, or ultrasonics to upset the powder so that powder peaks will collapse and not interfere with the seal being put onto the container in an ensuing step.
The present invention relates to consistent filling of dry powder doses of medicament into containers destined for insertion into a DPI, where the pre-metered doses are in a range 100 μg-50 mg and preferably in a range 100 μg-10 mg and most preferably in a range 100 μg-5 mg and presenting an RSD of 5% or less.
What has been said in the foregoing is by example only and many variations to the disclosed embodiments may be obvious to a person of ordinary skill in the art, without departing from the spirit and scope of the invention as defined in the appended claims.
