MXPA02004445A - Apparatus and method for dispensing small quantities of particles - Google Patents

Abstract

There is disclosed an apparatus and method which is capable of dispensing very small (typically less than 5 mg) quantities of particles to a high accuracy in a repeatable way and without undue wastage. Also, the need for advanced particle formulation is reduced. The apparatus comprises a closed loop control system which uses an electro mechanical actuator to deliver impact energy to a supply of particles initially held on a sieve in a hopper. The impact energy causes a small number of particles to fall through the sieve and onto a weight measuring balance. The weight obtained is scrutinised by a processor to see if further actuations are required. In preferred embodiments, the energy of actuation is varied in accordance with the rate of dispensation calculated by the processor. Also, a correction amount can be obtained to take account of the fact that the balance can take a considerable amount of time to settle to its final value.

Description

APPARATUS AND METHOD FOR DISTRIBUTING SMALL QUANTITIES OF PARTICLES FIELD OF THE INVENTION The present invention relates to devices and methods for distributing bulk particles, in particular, devices that are capable of distributing very small amounts (typically less than 5 mg of particles) in a precise and reproducible manner. The device can also be used to distribute weights in an exact manner, for example 100 mg. This invention can be applied to many types of particle distribution. Particularly this invention can be applied to pharmaceutical particle distribution applications, such as filling, with a predetermined dose of particles, dry powder inhalers, capsules and drug cartridges for use in gas driven injection systems.

BACKGROUND OF THE INVENTION In the patent of the United States of North America No. 5,630.7 *. 6 describes a method and device for accelerating p & drug particles through REF .: 138199 the skin, mucous surfaces and other layers. This device causes small particles to be dragged in a gas of very high velocity, accelerating them with enough force to penetrate the skin. The particles can be compounds and compositions of powdered drugs, or genetic material that can be attached to carrier particles (such as gold). Before the device is activated, the particles are retained between two diaphragms that can break. When the device is operated and the gas in the reservoir is released, the diaphragms break and the particles are entrained in the gas flow. Preferably the two rupturable diaphragms are constituted in the form of a removable and self-contained drug cartridge. This allows the same device to be used more than once by simply replacing the cartridge each time the device is used. This also allows the device to be supplied separately to the particles with the choice that the particles to be accelerated are produced after manufacture. For some applications it is required that the amount of particles initially contained in the cartridge be closely controlled. Although some drugs, such as lidocaine, are not very specific with respect to dose, other drugs such as insulin need to be administered in precisely controlled doses, also, some drugs are extremely potent in their pure form, which means that very small amounts should be used. Although this potency can be reduced by changing the drug formulation, this results in an increase in the total expense, since an additional step is required for the formulation in which the pure drug is mixed with an excipient. In addition, difficulties in the formulation can lead to an undesirable delay in the commercialization of the drug product. Also, some drugs and vaccines are very expensive, which means that for economic reasons the minimum amount must be used to produce the required effect.

For example, gold particles coated with DNA are expensive and some therapeutic compounds can cost tens of thousands of dollars per gram. As can be imagined, it is often essential that the cartridges are loaded accurately and reproducibly with known quantities of particles, for safety reasons. Ur overdose of certain drugs can have disastrous consequences, while a lower dose can result in the therapeutic agent not having the desired effect, with equally undesirable consequences. In addition, it is advantageous that the cartridges are dosed quickly to Ein that a large production of loaded cartridges can be achieved at a certain time. It is further preferred that any used apparatus meets the cleaning requirements associated with pharmaceutical production. Keeping all this in mind, the present invention addresses the problem of the great difficulty traditionally encountered in dosing very small quantities of particles in an exact and repeatable manner, and without undue depletion. Also, the previous dosage methods have not been very tolerant to the inhomogeneity in the formulation, shape and size of the particles that are used. The pharmaceutical products have been dosed conventionally using volumetric methods, which require the precise control of the parameters of the process when it is required to dose a specific mass of particles, there are many known methods that could be used to dose small amounts of particles. First of all, the vacuum method that will be described with reference to Figure 1 is known. Here, a small capillary tube 11 quje has a piston 12 of known displaced volume, is placed in a supply of particles 13 with the piston fully extended , that is, flush with the end of the capillary tube, see Figure la. Then the pistor retracts a certain distance (see Figure lb) and the particles are sucked into the space left by the piston in the capillary tube (see Figure lc). Then the piston extends to push the capillary tube particles towards the cartridge or other receptacle to be filled, see Figure ld. This method suffers from the disadvantage that although the volume of particles obtained can be controlled very well, the actual mass of particles depends on the density at that moment), air pockets and other anomalies can reduce the total mass delivered. In addition, the piston thrust action imparts forces on the particles, which can damage them, especially if they are fragile drug particles. This method suffers from the additional problem that in order to obtain an accurate dosage, free-flowing drug particles are required. In this case, a formulation of drug particles must be developed which results in a free flowing powder. If the powder does not flow freely, an inaccurate dosage may occur. A second method (not shown) involves the application of electrostatic printing technology for the distribution of particles, that is, using electrostatically charged particles that are manipulated by electric fields. This method suffers from the disadvantage that the particles must be charged electrostatically (which may be undesirable) and that the circuits Electronic devices required to manipulate the correct number of particles on a surface or to a container are complicated and expensive. Also, it is very difficult to control the electrostatic fields, such that they are not adversely influenced by external interference. An additional problem is that it is necessary to load the particles consistently and in this way changes in the shape and size of the particles should be avoided. The differences in the size of the particles have a drastic effect on the relative charge of the particle that can be achieved. This creates an additional workload in the formulation. A third method, shown in Figure 2, known as "scraper blade manipulation" involves compacting the particles in a receptacle of known volume (see Figure 2a) and then using a blade or other sharp blade to remove any excess particles that may be removed. stay above the top of the edges of the receptacle, see Figures 2b and 2c. As can be seen, a receptacle 21 is packed with particles 22 until it overflows. A blade 23 is used to remove excess particles above the upper edge of the receptacle 21, leaving a standard volume of particles 24. This method is undesirable because it exerts severe forces on the particles, not only during the compaction process but also when the blade to cut the top layer of particles. This method also suffers from the problem that many efforts must be made with the formulation of the drug particles so that they flow freely and are homogeneous.

Also, this method is not really appropriate for small-scale applications where it is required to accurately distribute less than 5 mg of particles. The present invention is an alternative to the techniques mentioned above. It has been found that it accurately distributes small numbers of particles in a repeatable form, with very little particle depletion. Also, the method does not require undue effort in the formulation of the drug particles. Virtually any particle, regardless of composition, and of any shape and size, can be dosed according to the present invention. In this way, the inverted conventional effort is obviated, obtaining a homogeneous and free-flowing drug particle formulation. In other words, the present invention allows pure or sparingly combined drug particles to be accurately dosed. According to a first aspect of the present invention there is provided an apparatus for distributing particles, comprising: a particle retainer for retaining a For the supply of particles to be distributed, the particle retainer has a plurality of openings for distributing the particles therethrough; an actuator for releasing particles, to cause, in response to a driving signal, that some art of the particle supply is distributed from the particle holder through the openings; and, a device for measuring the weight, for measuring the apparent weight of particles distributed from the particle retainer and for emitting a signal representing the measured weight. The plurality of openings serve to retain the particles, even when the openings have an average size greater than the average particle size. When the particle retainer has been mechanically agitated by the hardener for the release of particles, the particles are dislodged and pass through the openings. The openings are small enough to be "plugged" with particles in the steady state and there is a sufficient amount to ensure that an acceptable number of particles is dispensed after each actuation. Therefore the equipment provides an exact unrepeatable distribution mechanism, to distribute very high numbers of particles little ones. The speed of operation can be improved by adding a correction value to the apparent weight measured to take into account the effects of the non-instantaneous operation of the device for weight measurement. Accordingly, a second aspect of the present invention provides an apparatus for distributing particles, comprising: a particle retainer for retaining a supply of particles B or B to be distributed; an action for the release of particles, to cause, in response to a driving signal, that a certain part of the particle supply is distributed from the particle retainer; a device for measuring the weight, for measuring the apparent weight of particles distributed from the particle retainer and for emitting a signal representing the measured apparent weight; and, a processor functionally connected to the actuator for the release of particles and arranged to emit the driving signal thereto and functionally connected to the device for weight measurement and arranged to receive the signal of the measured apparent weight from it, the processor is arranged to estimate the actual weight of distributed particles, by adding a correction value to the apparent weight measured. The first aspect of the invention, like the second aspect, can use a processor that supplies an output drive signal to the actuator for the release of particles and receives a signal of the measured apparent weight from the device for measurement of the weight, A number of preferred features are associated both with the first aspect and with the according to or of the present invention. Accordingly, the processor of both the first and the second aspect can be arranged to provide a driving signal that engages a feature corresponding to the amount of particles to be distributed from the particle retainer. In this way, the number of particles distributed after each actuation of the actuator for the release of particles can be controlled by modulating the signal fed to the PPra actuator, the release of particles. This modulation may take the form, for example, of a variation of the amplitude, frequency or pulse width of a signal. The apparatus of the first or second modes can also be arranged to calculate the apparent speed with which the particles are distributed on the device for measuring the weight. This speed apparent can be used to calculate a correction to estimate the actual weight of particles on the device for weight measurement, at any particular time or additionally (or alternatively) can be used to control the power of the drive, such that a speed of d is achd. objective allocation. The processor of both the first and the second aspect can calculate the correction value by increasing the correction value by a stored standard weight value, each rez that the actuator is driven for the release of particles within a defined period of time. In this way, an actual weight value can be estimated that takes into account recent drives that have not been fully recorded by the device for weight measurement, for example, if the device for measuring the weight is modeled so that it has a delay of one second, the correction value is increased by the stored standard weight value for each drive that occurs within the last second. Preferably stored standard weight values are multiplied by a multiplicative factor and the correction value is increased by a multiplied standard weight, and the amount of multiplication is generally reduced with respect to the most distant drives in the past, the value used as the Increased weight The stored standard can be updated after each complete distribution cycle, calculating the average real mass supplied per drive, during the last distribution cycle. distribution cycle, the processor can be arranged to compare either the measured apparent weight or the actual, estimated, distributed weight with a weight of deferred particles, in order to decide if additional particle distribution is necessary, or if it can be stopped the cycle, if the correct mass of particles has been distributed. The predetermined particle weight is preferably represented as the weight of particles to be distributed, less a tolerance weight. This reduces the likelihood of overfilling. The apparatus of the first or second aspects may be arranged to track a target distribution speed, increasing by decreasing the drive energy when the measured distribution speed is lower or higher than a desired speed value, which may or may not be rotated consecutively or consecutively. Alternatively the speed of distribution can be reduced by pausing for a predetermined period of time, after actuation, such that the time between the taking of the weight measurements is increased, resulting in a decrease in the observed rate of distribution It is preferred to initially run a relatively high target distribution speed, and then change to a relatively smaller target distribution speed as it approaches the desired particle weight. This reduces the probability of exceeding the desired weight of particles. A preferable structure of the apparatus according to both the first aspect and the second aspect of the invention uses a hopper having openings that are provided with a screen through the cross section of the hopper. For pharmaceutical applications both the sieve and the sieve are preferably made of 316 stainless steel, although a one-piece plastic configuration is also useful. The apertures are preferably holes having a diameter (or other relevant dimension) of 50 to 800. μm, more preferably from 80 to 400 μm, even more preferably from 100 to 250 μm or even more preferably from 180 to 250 μm. The actuator for releasing particles is preferably an electromechanical actuator such as a solenoid which is arranged to distribute impact energy, substantially horizontally, next to the particle retainer. This is preferable to supplying impact energy to the top of the given retainer that access to the retainer is not prevented and it has been found that tapping on the side of the container provides more consistent results than tapping the top. To protect against airflows or pressure difference, a cover is preferably provided to cover the less a device for the measurement of the weight and the retainer of particles, and possibly also the actuator for the liberation of particles. Conventional vibration techniques suffer from the problem that they are difficult to control because the speed of particle distribution is not linearly related cor. the frequency or amplitude of the vibration. Once of that. As particles are flowing, a flow limit is established beyond which higher distribution speeds are difficult to achieve accurately. The present invention overcomes this by achieving that the particles do not flow as long as to reach the flow limit. The use of an actuator for the release of particles means that a substantially discrete force pulse can be applied to the particle retainer so that the particles are momentarily dislodged. This distribution method can be used to provide very accurate distribution up to very low weights, and it is also more controllable than continuous vibration techniques because the mass of the particles distributed after each drive are more linearly related to the drive force. The present invention also has the advantage that relatively no moving parts are associated with the parts in contact with the particles. Previous techniques have used bolts or screws that move to regulate the flow of particles. These can trap particles causing damage. The present invention also avoids the problem of mechanical damage that can occur when using parts that move relative to one another, and is easier to clean and receive maintenance. According to a third aspect of the present invention, there is provided a method for distributing particles in an exact form, which comprises the steps of: retaining a supply of particles to be distributed; causing a certain part of the particle supply to be distributed through a plurality of openings from its retained position to a position where its weight can be measured; measure the apparent weight of the distributed particles; and, use the apparent weight measured to control the distribution of particles.

The method of the third aspect of the invention allows the unrepeatable e --actactivity of a small number of particles. Additional accuracy can be obtained by estimating the actual weight of distributed particles, adding a correction value to the measured apparent weight. This relieves the effects of delay in obtaining a correct measurement of the weight, which is mainly due to delays that originate in the device for weight measurement, but also in the electronic components and due to the time it takes for the particles fall from the particle retainer to the cartridge. According to a fourth aspect of the present invention a method is provided for distributing particles in an exact form, which comprises the steps of: retaining a supply of particles to be distributed; cause that part of the particle supply is distributed from its retained position to a position where its weight can be measured; measure the apparent weight of the distributed particles; estimate the real weight of distributed particles by adding a. measured apparent weight, a correction value, to thereby reduce the effects of the delays in obtaining a correct weight measurement; use the measured apparent weight to control the distribution of particles. The method of the fourth aspect can be carried out using the apparatus of either the first or the second embodiment. In this way, each of the particles can be distributed through one of the plurality of openings formed in the particle reactor. A number of preferable steps of the method can be carried out together with the methods of the third or fourth aspect of the invention. The control d? Closed loop can be obtained by providing cyclically repeating method steps until a desired, predetermined particle weight has been distributed within a predetermined tolerance. This avoids the fact that a different mass of particles can be distributed following each actuation of the actuator for the release of particles. Preferentially, the apparent velocity with which the particles are distributed is calculated. This value can be used either to obtain a correction to the measured apparent weight or to provide a feedback in a control bucket that controls the rate of particle distribution (or both). The value of correction used to correct the Apparent apparent weight can be the calculated apparent velocity that is preferably multiplied by a time constant. Alternatively, the correction value can be obtained by adding a stored standard weight for each time the actuator is operated for a short period of time., of a certain defined duration. Each value of stored standard value used is preferably normalized by multiplying it by a multiplicative factor that varies between 0 and 1. This explains the oobbservervvaaction ofwhich they need to make further corrections if the actuator was operated very recently rather than in a relatively long time. .stant. There is no need to make a correction with respect} , to the drives carried out long in the past, given that the device for measuring the weight and other devices will have fully responded to those drives. After each distribution cycle, the standard weight value is preferably updated in order to correspond more closely to the average weight of particles, which was distributed in each actuation during the previous distribution cycle. The closed-loop control can be provided by comparing either the measured apparent weight or the estimated real weight, of distributed particles, with a predetermined stored weight, and providing a cycle the hopper, Preferably the sieve is positioned at the end of the hopper both are formed of 316 stainless steel. Alternatively the sieve and the hopper can be formed of plastic material or of an electroformed mesh and glass tube, respectively. The sieve openings are of such a size that they can become covered with the particle to be distributed in a stationary state, but can be easily uncovered for a short period of time with the application of external energy to the hopper ( which preferably is an elongated conduit] According to a sixth aspect of the present invention there is provided a processor that serves as the processor in the apparatus of the first or second aspect, or to carry out certain stages of the method of the third or fourth aspect, the processor comprises: signaling means for outputting an output signal of predetermined characteristic, an actuator for the release of particles; compacting means; signal input means for supplying the value of an input signal derived from an output signal from a device for weight measurement, to the comparison means; minor means for feeding a predetermined weight value stored therein, to the comparison means; the comparison means are arranged to compare the value of the input signal with the value of the predetermined weight, and to determine whether the input signal is greater than the value of the predetermined weight. The processor is preferably a personal computer that can be connected to a device for weight measurement and to the actuator for the release of particles. The personal computer is programmed to carry out the appropriate calculations in computer programs (software). In particular, the processor can be programmed to add a correction value to the signal received from the device for the measurement of the weight, in order to calculate an estimate of the real weight of the distributed particles. In fact, the processor may, in general, be programmed so as to carry out the various calculations described in relation to the methods of the third and fourth aspects of the invention described above. According to a seventh aspect of the invention there is provided a manufacturing station for manufacturing a particle cartridge, comprising: a collector for collecting an open and empty cartridge; a conveyor for moving the open and empty cartridge to a position in which its weight can be measured; In addition, an apparatus according to the first or second aspect of the invention for distributing particles to the open cartridge. The manufacturing station preferably further comprises a station for closing cartridges, closing a loaded cartridge to contain the distributed particles, and a second conveyor. to move the loaded cartridges to the cartridge closing station, The conveyor for this movement is preferably the same conveyor as the one used to move the cartridge open and empty. This conveyor can be in the form of a pivoted arm, having a locator for locating the cartridge at one end, or a rotating circular component having that locator placed on its circumference. This locator advantageously works to grip and release the cartridges. This promotes the automatic filling of cartridges and closing requiring minimal human intervention. The cartridges: they can be fed in an entrance lane and taken out in an exit lane. This allows a "queue" of cartridges to be provided on the inlet rail, such that a machine for the manufacture of cartridge bodies can be provided in series with the manufacturing station in order to simplify the depositing of cartridges on] an appropriate entry rail, for subsequent filling In accordance with a Eighth aspect of the present invention further provides a production line comprising: a plurality of manufacturing stations according to the seventh aspect of the present invention; an inlet lane for feeding open and empty cartridges, and, an exit lane for removing closed and loaded cartridges, wherein the plurality of respective means for moving the cartridges operate to take open and empty cartridges from the entry lane and to place the cartridges closed and loaded on the exit lane. According to a ninth aspect of the present invention there is provided a station for the distribution of particles, comprising: a plurality of apparatuses according to the first or second aspect of the invention; and, a loading hopper that can move between each particle retainer of each respective apparatus, to fill each particle retainer, with particles. According to a tenth aspect of the invention there is provided a method for estimating an actual weight of particles distributed on a device for weight measurement, which has a non-instantaneous reaction time, the method comprising: obtaining a measured apparent kerosene; and, adding a correction value to the measured apparent weight, the correction value is derived either from the value representing the rate of change of the measured apparent weight, or a value obtained by the sum of the heavy quantities of a value representing the average weight distributed in a drive The method of the tenth aspect is preferably carried out with computer programs (software) in a computer and is designed to allow an accurate calculation of the actual weight of the particles distributed, even when it is not available an exact weight of a scale that measures the weight of 2 particles; this significantly accelerates a particle distribution cycle in which p is distributed. rticulas, carrying out a number of discrete drives. According to a eleventh aspect of the invention, an estimation function is provided for use with the apparatus of the first or second aspect, the Reference to the accompanying drawings, in which: Figures 1 - 1d show, a side elevational view, in section, schematic, a series of drawings illustrating a way of dosing particles in accordance with a vacuum method of the prior art.; Figures 2a-2c show, a side elevational view, in cross section, schematic, a series of drawings showing a prior art method for dosing particles, known as "" 'scraper blade handling "; A side elevational view, partly in section, schematic, of the apparatus illustrating the general concept of the present invention: Figure 4 shows schematically, a side elevation view, partially in section, and in a simple form, an apparatus for In accordance with the present invention: Figure 5 is a flow chart exemplifying a first embodiment of a method in accordance with the present invention; Figure 6 [our graph of how the signal emitted by a balance varies typically with time; in response, the balance is instantly loaded with particles that have a weight R, Figure 7 shows a graph of how the signal emitted by a faster action scale typically varies over time in response to a balance that is instantaneously charged with a weight R of particles at time t = 0; Figure 8 is another flow chart exemplifying a second embodiment of a method in accordance with the present invention; Figure 9 is an idealized graph of how the signal emitted by a balance varies with time in response to the balance being instantaneously loaded with a mass of particles; Figure 10 is an additional graph of how the signal emitted by the balance ideally varies over time as the sphere is continuously loaded with discrete masses of particles; Figure 11 shows a flow diagram exemplifying a method according to the third embodiment of the invention; Figure 1. shows a response of the idealized balance as a firecracker of you; Figure 13 shows a graph of how a correction multiplier varies according to a third mode of the method of the present invention; Figure 14 is an additional graph of weight versus time, showing how it can be varied through of time the target distribution speed - Figure 15 is an additional flow diagram exemplifying a method similar to the second or third modes, but using the speed control distribution and in which a fixed reading is issued; Figure 16 is still an additional flow chart exemplifying a method similar to that of the first mode, but that μsa control of the speed of distribution; Figure 17 shows, in a schematic side elevation view, a preferred apparatus for use to carry out the method of the present invention; Figure 18 shows, in a perspective view from above, three devices according to the present invention arranged as a particle distribution station; Figure 19 shows, in a side elevational view, partly in section, a sample tube and the loading hopper of the apparatus of Figure 18; Figure 20 schematically shows, in a top plan view, a manufacturing device as provided by the present invention; The Figur; 21 is a cross-sectional view partly in section, along line A-A in Figure 20; Figure 22 schematically shows, in a perspective view from above, an exemplary embodiment of the invention for use in a large-scale production run; is a perspective view of a device for the distribution of particles, in accordance with the present invention, having a removable clamp and a pneumatic lifting / lowering device; Figure 24 is an exploded view of part of Figure 23; Figure 25 is a cross-sectional side view of the apparatus shown in Figure 23; Figure 26 is a graph showing how the apparent weight measured and the estimated real weight vary during a typical distribution cycle.

GENERAL ANALYSIS OF THE APPLIANCE A general analysis of the apparatus in accordance with the present invention is shown in Figure 3. As can be seen in this Figure, the apparatus has three main components. The first is a particle retainer 31 which serves to retain the particles 32 within its confines. 1 particle retainer is functionally connected to a control means 33 that is capable of sending signals 3i that cause the particle retainer to release some of the particles. The control means is also functionally connected to a device for measuring the weight 34. The device for weight measurement is constituted in order to receive particles that are released from the particle retainer 31 and to measure its accumulated weight. This weight measurement is passed to the controlling means 33 as a signal 36. A preferred apparatus is presented in greater detail in Figure 4. The particle retainer 31 is, as shown, constituted by a substantially frusto-conical hopper having a small diameter at its base (preferably from 1 to 3 mm, but could be up to 10 mm). At the lower end of the hopper is a sieve 46 which can be an electroformed mesh having holes of the order of 130 μm. The hole size is selected taking into account the nature of the particles to be distributed. For example, 130 μm is used to distribute gold particles coated with DNA, 250 μm is suitable for lidocaine particles (whose diameter is approximately 30 μm) and alprostadil requires a value between 200 and 300 μm. The optimum size of the hole sje typically obtains taking into account the particle size (La and other factors such as ease of flow of 1 powder formulation. An empirical trial and error method is used to fully optimize the hole size for a particular formulation. For pharmaceutical applications, the hopper and sieve are each made, preferably, of 316 stainless steel, and can also be separated from one another to aid in cleaning and disinfection (if necessary) between batches that change. As an additional alternative, an oxidizable steel hopper and screen or molded plastics could be used in one piece. When plastics are sanded, the hopper and sieve can simply be thrown between batches. The diameter of the hopper can be that of any suitable figure and can be selected taking into account the mass of particles to be distributed. An appropriate Dr val for lidocaine is, for example, 10 mm. The particles 32 are located in the hopper and, when the hopper is free of any external vibration, are able to settle stably in the hopper without falling through the mesh, although the average particle size (nominal diameter) is smaller than the diameter or other relevant dimension of the openings of the maya. This is achieved because the screen openings are plugged by particles in order to physically retain them within the hopper while the apparatus is in the stationary state. The corking is located around the sieve of the sieve neighborhood in such a way that the Clogging can be temporarily relieved by applying a vibration or other external movement to the hopper. The screen is not plugged to the extent that the particles do not flow through the screen, even if external energy is applied. To ensure this, additional equipment can be provided or attached to the hopper to ensure that the particles will remain substantially flowing. That equipment to fluidize standard particles in the art and its explanation will be omitted here. Another possibility is to treat the particles chemically to ensure their ease of flow. In practice, any standard fluidization technique can be used. The control means 33 is preferably composed of an electronic processor, more preferably a personal computer programmed in a language such as Visual BASIC or C ++. The processor is capable of transmitting a signal 35 to an actuation means 41 for releasing particles, which is preferably constituted by an electromechanical actuator such as a solenoid. The solenoid is shown in Figure 4 impacting the side of the hopper having a substantially vertical outer surface and this is the preferred arrangement. An alternative arrangement by which the actuator impacts the top of the hopper has been successfully tested but has been found to have two < * »* - disadvantages in terms of consistency of results (the repeatability in the mass of the particles distributed in response to the impacts of identical energy) and in terms of access to the hopper to fill it, the processor; 33 passes a signal 35 to the actuator 41 having a characteristic corresponding to the impact energy that the actuator will exert upon receiving the signal. For example, the signal may have a greater magnitude to achieve an impact of higher energy.

Preferably the signal is a rectangular voltage pulse modulated by the amplitude. The weight measurement device 34 may be a standard scale used to measure small quantities and may typically have a dynamic range of 60 g and an accuracy of 10. For example, a Mettier Toledo SAG285 (Registered Maica) balance is appropriate, instead of the previous balance, more accurate scales (such as a Sartorius MC5 (Registered Trade Mark)) can be used if the accuracy of the system as a whole is to be improved. Balances with a smaller dynamic range may be used, possibly specially manufactured scales, if it is desired to improve the speed of the system as a whole The weight measuring device 34 supplies a signal 36 to the processor 33 which is a function (for example, is proportional to a) of the weight applied to the balance.

The measured weight will typically be the sum of the weight of the particles 43 that have already been distributed from the particle retainer, and the weight of a cartridge 42 that is placed on the balance 34 in a position where it can substantially capture all of the particles. the particles 45 that leave the particle retainer 31. Figure 4 is shown in a schematic form only and it should be noted that a practical one should take measures to ensure that no particle 45 is able to leave the sieve 46 without falling into it. cartridge 42. This is generally achieved by co-locating the screen within the confines of the cartridge cavity, such that the particles have to have a vertically rising movement component in order to escape from the cartridge. word "cartridge" encompasses cartridge of the type mentioned in United States Patent No. 5,630,796, it is intended that the open also encompasses any form of containment apparatus. For example, the word cartridge also covers bags, capsules, ampoules for dry powder inhalers, cartridges for devices for the administration of drugs, capsules for the oral administration of drugs, etc. In fact, the word cartridge is intended to cover anything within which it is desirable to distribute particles. This can include a substrate made of excipients on which the particles can be distributed so that an additional substrate can be placed on top to "leave interspersed" the particles distributed between two substrates of the excipient, The complete package can be used as a tablet to be taken orally, which will be released by the particles distributed only when the excipient has been broken in the patient's stomach. The word cartridge is intended to cover also immediate containment devices in which the particle is weighed before being transferred to the desired site. For example, the particles could be weighed in a cartridge before being transferred (by tapping or any other suitable method) to an ampoule, substrate or any other receptacle. This has the advantage of allowing the transfer of particles to a final unit that is significantly heavier than the particle dose or that is too bulky to be weighed properly (eg a tape containing ampoules). An additional advantage of this arrangement is that it is compatible with a fast weighing form in which many cartridges (for example ten) are loaded simultaneously and a small number of these (for example three) are emptied into a final receptacle in a combination that provides the desired final weight. An accommodation 44 is provided actuator 41 which in the apparatus of Figure 4 serves to "tap" the particle retainer 31. This tapping is typically achieved by using a rectangular voltage pulse of fixed width to excite the actuator. In this mode the actuator is a solenoid but in general it could be represented by any appropriate device or system including motors, springs, etc. This tapping causes a small amount of the particles to be released and fall into the drug cartridge 42, placed on the device for measuring the weight 34. This amount tends to be proportional to the tapping energy, although there is some variation towards each side of the average. This can be a problem if a drive of some energy causes an unusually large amount of particles to be dislodged, but this problem can be alleviated by providing very low energy knocking during the final stages of a distribution cycle so that even an unusually large amount large particles dislodged, for the energy provided, do not increase the total weight of particles distributed, by more than twice the weight tolerance (the tolerance is defined as the weight of each side of the desired amount), for example a tolerance of 10 μg means ± 10 μg each: of the required amount). In general, a signal 36 of the device for the weight measurement that represents the weight of the particles released and the weight of the drug cartridge (although the weight measuring device may be calibrated (using a tare function) not to show the weight of the drug cartridge and only to show the weight of the particles released) it is supplied to the processor 33 which can carry out calculations using the measurement of the weight obtained. After carrying out a comparison to see if the weight of distributed particles is greater than or equal to a predetermined value stored in a memory of the processor 33. This predetermined value is preferably a value representing the desired weight of particles to be distributed minus the tolerance weight. If the weight of the distributed particles is not more than or equal to the predetermined value, insufficient particles have been distributed and the processor 33 sends a signal to the actuator 41 to perform another tapping on the particle retainer 31, thereby releasing another small amount of particles, Subsequently, another verification and comparison of the weight is carried out. This cycle is repeated until the desired particle weight has been reached or exceeded, which completes the process. The decribed apparatus can be used to perform a closed loop control of particle weight distributed. The processor 31 makes decisions regarding whether or not to drive the actuator 41 based on the signal 36 emanating from the device for measuring the weight 34. The processor can also control the amount of impact energy that the actuator 41 transmits to the retainer. particles 31. In this way, the cartridge can be dispensed with an accurately metered quantity of particles. The apparatus of the present invention is particularly advantageous for distributing small amounts of particles by mass. The amount to be dispensed could typically be less than 5 mg, and may preferably be in the following ranges (listed in descending order preferably): 0-4 mg; 0-3 mg; 0-2.5 mg; 0.2 mg; 0-1 mg; 0-0.5 mg. The ranges indicated above do not include the amount 0. Exemplary embodiments of methods in accordance with aspects of the present invention will now be described with reference to Figures 5 to 22. In general these methods can be carried out by the apparatus shown in the Figures 4 to 17 but they are not limited to it. In practice, any appropriate device can be used First Method Modality A method of dosing particles according to the first embodiment of the present invention is shown schematically by the flow chart of Figure 5. This embodiment represents one of the simplest forms of the invention. First, the processor 33 causes the actuator 41 to perform a controlled tapping on the particle retainer 31. The amount of tapping can be controlled by varying a characteristic. (such as, for example, the frequency or magnitude of the voltage or pulse width of the signal) of the signal 35 and the initial value used can be stored in a memory. However, the magnitude of the knocking does not need to be varied and the actuator performs a standard knock against the particle retainer each time. The "knocking" described herein may also consist of a series of knocks of predetermined magnitude and duration or on the contrary may take the form of a continuous or intermittent vibration. The knocking causes certain particles that are in the particle seal to be dislodged from their plugged position and pass through the openings in the maya 46, falling on a cartridge placed on the balance. The processor then checks the value of signal 36 to see what particle weight was distributed as a result of the tapping action. This weight W is then compared with a predetermined desired weight IVs and a measurement is made of how many more knocks are required. If more knocking is required, the cycle is repeated until the weight measured by the weight measurement device reaches an acceptable amount Typically, the predetermined weight value Ws stored in the memory will be slightly less than the desired final weight, for a value equal to the tolerance of the system. For example, if the weight to be distributed is 500 μg and the tolerance is -10 μg, the predetermined value Ws would be 490 μg. This is because the system only seeks to analyze if the measured weight is equal to or greater than the predetermined weight. If the predetermined weight is the minimum possible, there is less risk of overfilling the cartridge. The system does not allow poor filling (ie filling less than the predetermined weight) since the cycle stops only when it is satisfied or exceeds =. a predetermined value In practice, the balance can be programmed to output sampled weight values to the processor at regular intervals, for example approximately every quarter of a second, using a Mettier SAG285 balance or 10 times a second using a Sartorius balance.

The actual number of particles that leaves after each tapping, can be, however, 1 μg or even less. This depends on the relative size between the particles and the sieve as well as the energy of the drive.

Second Method Modality It has been found in practice that when standard balances are used, or a correct reading is obtained instantaneously. Although the particles fall from the particle retainer 31 very rapidly and rest in the drug cartridge 42 after a very short period of time (for example, less than 0.25 seconds), the balance may take a relatively longer time. stay still and get the correct weight measurement. Figure 6 shows the static impulse response of a Mettier SAG285 balance, which is a typical curve of how the balance responds to a sudden increase in the load applied at time t = 0. The applied particle weight (at t = 0) to the balance is WR. In response to this, the measurement signal emitted from the balance is a delay where nothing happens, followed by an approximation approximately exponential to the WR value that results in an S-shaped curve. of S represents the measurement that the balance emits and therefore represents the weight apparent particle on the balance at any time. This is the "apparent so measured". Therefore it can be seen that it takes many seconds for the measured apparent weight to reach the correct value. The exact shape of this curve depends on the design of the balance, For example (as shown in Figure 6) the rest time of the Mettier balance is approximately 4 seconds (which means that it reaches an exact stable weight in 4 seconds). If a lot of knocking is required, and it is necessary to wait 4 seconds between each tapping, then the time it takes to fill a cartridge for particles becomes prohively long. This can be solved to some degree by using a scale that stops to a stable weight et? a shorter time For example, the stabilization curve of a Sartorius MC5 scale is shown in Figure 7 and it can be seen from this figure that a stable weight is achieved in approximately 2.2 seconds. However, the problem of non-instantaneous response still exists and the improved method shown in Figure 8 has been developed to alleviate this situation. This modality is based on the observation that the final part of the curve of Figures 6 and 7 is approximated by a simple exponential curve C of the type shown in Figure 9. The method of Figure 8 is based on It is therefore useful for the processor 33 to store in a memory values representing the past weight measurements and values representing the time in which these measures were taken. The speed of weight increase dW / dt can then be calculated by calculating (W? -Wi) /. { t? -ti). Alternatively, well-known analog electronic methods can be used to differentiate the apparent-time weight curve. The impulse response of the balance will not in all cases be a true exponential curve. To take this into account, the selected value for the time constant T can be varied to provide the best fit. The choice of coefficient T is preferably obtained empirically and it has been found that it is usually in the vicinity of one second, being in the range of 0.5 to 2 seconds, or more preferably of 0. 8 to 1.2 seconds. During the execution of the method, the particle retainer 31 is subjected to tapping many times and the measurement of the instant weight at any time will be composed, in general, of many responses of individual impulses, small, distributed over time, It should be understood that, in general, these responses will be of different magnitudes since the amount of particles of change of the second modality, because the real stabilization curve has florma of S, which means that there are two positions that have the same gradient. In this way, the same amount of correction will be obtained in two positions, and this amount will not be correct for both positions. The method of the third modality does not have this problem. In addition, the method of the third modality allows the distribution cycle to be interrupted and to be restarted without any adverse effect. If the distribution cycle is interrupted D when the method of the second mode is used, an anomalous value is obtained for the distribution speed, which can result in an inaccurate distribution. The flow diagram for the third embodiment is presented in Figure 11 As can be seen, the method is very similar to the method of Figure 8 except that the apparent distribution rate for the correction value is not required. The third methodality of the method allows that the correction added to the measured apparent weight is determined by the recent history of knocks produced. In this way it is necessary that the used apparatus be able to record the time in which the actuator is actuated for the release of particles. In a simple way, the response of the balance could be modeled as a simple delay of time tj. This response is shown in Figure 12. As can be seen from Figure 12, when a HR mass is applied, nothing happens to the measurement of the weight emitted until time ti, when the correct weight measurement occurs. If the balance has that characteristic, then the method of the third mode would say that the correction value is equal to the weight WR multiplied by the number of drives that have occurred in the just elapsed time period, equal to ti. If in that way, if ti was equal to one second, and three drives occurred at the last second, then the correction value would be equal to 3WR. In this way, cue drives have occurred, but have not been recorded, they are taken into account when calculating the actual weight of particles on the scale at any time. The amount WR used in the calculation of the correction, is a weight almaclenado that is assumed equal to the weight that was distributed by a single drive. Of course, the actual weight distributed as a result of any individual actuation is unknown until it is measured. Therefore a small error will be introduced assuming that each drive is of a "standard" weight of particles. The above calculation can be summarized by the following equation: (8) t = now • ¡ Where C is the correction weight that is to be added to the measured apparent weight, now represents the current time, now -tp represents a time tp back, and WSt is a standard weight value. Therefore the correction value can be seen as the sum of each pounding that occurred in the time period from. { oh pray-tp) up. { now ) . Actually, the balance stabilization curve is not a pure delay and actually has the shape shown in Figures 6 or 7 for example. To take this into account, the "standard" tapping weight, mentioned above, may be subject to some adjustment before it is included in the calculation of the correction value. Since it will be evicient from Figure 7, if the actuator has performed only one drive, substantially all of the standard weight WSt will need to be added as a correction because the balance has not yet reacted to the drive. However, for more distant drives in the past, less than the standard weight needs to be added as a correction, because the scale will have reacted to some degree to the g ..a- »• - drive. As it could be imagined then, a standard weight normalization function can be obtained by simply moving the graph of Figure 7 around a horizontal axis in order to obtain a graph of how large the correction value will be with respect to the drives performed. at different times in the past. A linear approximation to that graph is presented in Figure 13. In this way, to take into account the curve of stabilization of the balance, in the form of S, a correction multiplier is defined that varies between 0 and 1. Each weight of Standard knock used to form the correction value is first multiplied by the appropriate correction multiplier M. The value of the correction multiplier is found from the graph in Figure 13. For example, if the action is operated between 0 and 0.35 seconds previously, then the correction multiplier M is 1. This does not mean that the standard tapping weight. { Wst) will be multiplied by 1. Resulting in the fact that the standard knocking weight Wst is added to the correction value with respect to the drives between 0 and 0.35 seconds back. For drives carried out between 0.35 and 1.35 seconds ago, the correction multiplier varies linearly between 1 and 0. In this way, a drive that occurred 0.85 seconds ago, will have a correction multiplier of 0.5 associated with it.

The method of the third modality requires that the "standard" weight be stored in memory and used as an approximation to the actual weight of particles that are distributed in any given beat. Changing environmental factors can dictate that the average real weight of particles distributed in the tapping changes with time. To take this into account, the stored "standard" weight can be updated at the end of a complete distribution cycle, to take these changes into account. This update is carried out in the present modality by dividing the total weight distributed in the last cycle, by the total number of taps used to distribute this weight in the last cycle. In this way, if the last cycle supplied 500 μg in 50 taps, then the stored "standard" weight would be adjusted to 10 μg. This value would then be used to calculate the actual distributed weight in the next distribution cycle. It should be noted that the graph of the correction multiplier shown in Figure 13 is optimized in an empirical way because it will not always correspond to the statistical stabilization curve of a balance? F displaced about a horizontal axis. This is due to. that the dynamic stabilization curve of a balance can vary with respect to the measured static stabilization curve. That is, the time of Rest can really be much less when the scale is being continuously loaded with particles, than what would be observed when the scale is at rest and is loaded with a particle impulse and allowed to rest. In this way, once the balance is in a dynamic read state > , the resting time is effectively reduced. This fact is represented in Figures 7 and 13 above where it can be observed that Figure 13 shows that drives more than 1.35 seconds before are not taken into account, while the static curve of the Figure 7 indicates that a drive 1.35 seconds behind, would require a correction multiplier of approximately 0.4.

Fourth Method Modality The fourth embodiment of the method comprises an additional calculation and adjustment of the operation parameters that can be used together with any of the methods described above for particle distribution. It has been found that the number of particles released by the particle retainer 31 contains some relation to the impact energy, with which the particle retainer 31 is tapped by the actuator 41. In this way, a stronger golp-strike causes usually that more particles are released, and a less loud pounding causes less particles to be released. This fact can be used advantageously when a dosage of particles with great accuracy is required, but large doses are required compared to the necessary tolerance. For example, if an accuracy in the dosage of 10 μg is required, for a dose of 500 μg, then the method of Figure 5 would require that approximately fifty 10 μg taps be carried out. This may represent an undesirably excessive time, even when the actual weight is estimated using a charge based on the measured rate of distribution or in the amount of recent knocks as described above in the second and third modes. In this way, the fourth mode provides an improved method by which stronger tapping is carried out near the beginning of the dosing process, and less strong tapping is carried out near the end. (when more accuracy is required). This is achieved through the pprreeddeetteerrmmiinnaacciiónn d uunnaa vvslocidad target distribution that serves to correspond to the actual distribution speed achieved in any given time. Figure 14 shows a plot of weight versus time, which shows a preferable configuration of how the target distribution speed changes with respect to time.

As can be seen, the target distribution velpcity reflects the fact that a high distribution speed is required at the beginning, but that a lower distribution speed is required as the distributed real weight reaches the target amount. The processor checks whether the value of the measured apparent weight (or the value of the estimated actual weight, if appropriate) has reached a predetermined value Wc. If so, the target distribution rate is reduced to a predetermined, smaller, different value, as shown in Figure 14. The ratio of 1 to desired amount with respect to Wc is usually kept constant and thus Wc can easily be obtained by multiplying the desired final weight by this ratio. As previously noted, the reduction in the target distribution speed has the effect of causing the actuator to tap less and therefore distribute less particles per unit time. Figure 15 shows a flow diagram similar to that of Figure 1, in which the feature described above, of the fourth embodiment, is combined with the method of the second embodiment. The main difference is that the calculated distribution speed. { dW / dt) is compared to the target velocity and the knocking force is conveniently adjusted (appropriately adjusting the characteristic of the signal supplied to the actuator for the release of particles). The calculated distribution speed is compared with the minimum and maximum values of the target distribution speed (minimum and maximum) if the calculated speed is too low, the knocking power in the next and subsequent cycles increases. If the calculated speed is too high, the knocking power in the next and subsequent cycles is reduced. In this way, initially, when a high target speed is set (setting high and low maximum values), the popping rate will increase until this target speed is achieved. The maximum and minimum values can be set to be identical, but in general they are different to allow a range of acceptable target speeds at any time. The maximum and minimum values can be set as identical but are generally different to allow a range of acceptable target speeds at any time. The selection of the value of the target velocity is generally determined by the absolute value of the estimated real weight, such that as the estimated real weight becomes irreducible, the set target speed decreases and therefore the knocking power also decreases. This allows an exact dosage to be achieved in a short time. Although Figure 14 shows what the target speeds might be, more velocities could be used or an objective velocity could be used with constant adjustment (for example, inversely proportional to the actual stowed weight). Although control based on estimated weights works well in practice, for regulatory reasons it is often necessary to match the exact final weight of particles in the cartridge before the cartridge is sealed.

In this way, an additional step is taken to take a reading at rest in this modality (Figure 15). This step is performed if the comparison based on estimated weights shows that enough particles have been distributed. A reading is taken at rest allowing the balance to rest for a sufficient time (for example, 2 or 3 seconds) in such a way that a true distributed particle weight is obtained. In practice, a certain number of consecutive samples can be taken (for example 30 for a scale Sartorius MC5), of the balance, and these can be compared to determine if a reading at rest has been achieved. For example, a reading at rest can be assumed when the value of each of the thirty samples varies less than a certain predetermined amount, for example 2 μg. If this reading of the resting weight, true, falls far below the required amount, then additional tapping can be given until the correct amount is obtained. Taking a reading at rest provides certainty that has distributed the exact mass of particles. It should be noted that a reading can be taken at rest, and usually it will be possible in the modalities of Figures 5 and 8 as such (this is not shown) and it is not limited to the modality of Figure 15. Likewise, the stage of taking A final resting reading can be emitted from the mode of Figure 15 if it is not necessary to know the actual final weight of the p-joints distributed with great accuracy. The need to estimate the real weight based on the correction of the value of. Measured apparent weight is reduced if a scale is used that quickly reaches its resting point. Thus, the method of Figure 16 can be carried out in such a way that an apparent distribution velocity is calculated only for the purpose of adjust the power of goal peteo, and not to estimate the real weight using the apparent distribution speed.

Preferred Apparatus Modality Figure 17 shows a particular embodiment of the apparatus, which is suitable for carrying out any of the above methods. Like reference numbers denote equal parts in Figure 4. As can be seen, in this embodiment, the actuator 41 is separated from the particle retainer 31 by a rod 120. This has a practical reason because the actuator 41 produces electric and magnetic fields which can interfere with the sensitive components of the device for weight measurement 34. The rod 120 serves to transmit the energy of horizbntal impact created by the actuator 41 beside the particle retainer 31 Also, in this embodiment, the particle retainer 31 and the actuator 41 are supported by a pivot 121 and a spring 122. This allows the lower end of the particle retainer be lifted and lowered in such a way that it can be accommodated within the cartridge cavity, thereby reducing any risk of particles not entering the cartridge. The particle retainer can be lifted to allow the entire cartridge to be replaced by a vacuum. The particle retainer 31 is mounted on elastomeric supports 123 such that the impact energy of the actuator is quickly damped after each tapping, such that there is no further movement in the screen. The supports 123 also prevent the impact energy from being transmitted to the balance.

Additional Apparatus Modalities If large numbers of filled cartridges are going to be produced, then it is desirable to implement manufacturing systems and production lines that can produce that large number of cartridges with minimal human intervention. It is also desirable that these systems and production lines are compatible with the clean area furnace in which it is often essential for the handling of drugs and genetic material. Figure 18 shows a station for dosing particles, comprising three distributing devices in accordance with the present invention. In addition, a loading hopper 130 is provided that can be moved along a rail 131 to fill the particle retainer 31 of the separate devices. In this embodiment each particle retainer would carry approximately a 30 minute particle capacity and the loading hopper 130 could operate to fill each particle retainer when it is empty. This minimizes the opportunity for stratification in the particle retainer 31. This also allows the particles to be handled only by the machine, so that there is less risk of contamination by humans. The loading hopper shown in Figure 18 is & Ji & . "J- shows in more detail in Figure 19. As can be seen, the particles 140 become pre-packaged in a sample tube 141, which can be inverted and mounted directly to the loading hopper 130. The loading hopper could comprise a retainer as such of particles similar to that of the dosing devices, such that a fixed dose of particles is distributed to each particle retainer in the production line. Of course much less accuracy is required and a much higher target distribution speed can be used. It is contemplated that the sample tube can be quickly and easily attached to the loading hopper and contain enough particles for many hours of production. Also, the loading hopper 130 could be manufactured in accordance with any known distribution technology, and is not limited to the distribution method of the present invention. Figure 20 shows a manufacturing station that is capable of receiving open cartridges and delivering correctly dosed and closed cartridges. This apparatus comprises means 150 for moving an open cartridge 42 on the device for measuring weight 34 and means for removing the cartridge of the device for weight measurement, once the cartridge has been filled. The apparatus also comprises a means 152 to close the cartridge once it is full. In this embodiment the means for moving the cartridge comprises a circular ring 150 that can rotate around its center, and having means of locating 151 (three in Figure 20) of cartridges, located around its circumference. Figure 21 shows a sectional side view along the line A-A in Figure 20. As can be seen, the locating means 151 supports the cartridge 42 under a ridge 181 on the cartridge. In the cartridge entry position, the cartridge moves towards one of the locating means, by the action of a conveyor. When the wheel rotates the cartridge is transferred to the dosing position at which point it is lifted and removed from the locating means 151 by an elevated surface 182 on the tray of the balance 134. The wheel is inverted afterwards by a small increase, so leave the cartridge on the scale without making contact with the locating medium. After the cartridge is filled, the wheel rotates again and the cartridge is transferred to the cartridge production position, where it is first sealed, and then removed from the wheel by the action of a second conveyor. Alternatively, the locating means 151 could operate to grasp and release a cartridge 42 according to the signals provided to it by the controller. central, This mode allows three tasks to be carried out simultaneously. While one locating medium is capturing a new cartridge, another is near a cartridge that is being dosed and the other is holding a cartridge that is being sealed. The manufacturing station described has the advantage that the cartridges are closed shortly after they are filled, which minimizes the risk of particle spillage and contamination. Also, it is possible to achieve a transfer cap between the removal of a full cartridge and to provide an empty cartridge to the balance, which minimizes the disturbance of the balance. The manufacturing station of Figure 20 can be combined with the loading hopper system of the Figure 18 in order to produce the production line presented in Figure 22. Here, only the operator is required to supply the number of open cartridges 47 to an inlet lane 160 of cartridges and the cartridges are dosed and closed automatically. The finished product is supplied to an exit lane 161. Therefore, the minimum intervention of an operator is required. The lanes 160, 161, of entry and exit of cartridges, could be combined with the apparatus of FIG. in order to provide a manufacturing station that has the function of loading cartridges with particles, but not necessarily that of sealing cartridges. The entry lane and the lane of Jida 161 may be composed, perhaps, of a basic conveyor system that carries the cartridges using a moving belt. Alternatively, if the cartridge configuration of Figure 21 is used, the conveyor could consist of two metal rails where the rim 182 of each cartridge rests. The cartridges could then serve to push one another along the lane, such that no specific means of movement is required. When the cartridges are not required to be closed in the same manufacturing station in which they were dosed, the entry and exit lanes could take a course that simply crosses the balance. An elevated portion on the scale (as already described) would then serve to lift the cartridge from the rail in order to allow accurate measurement of the weight.

Whichever form the conveyor takes, it is advantageously controlled by the same processor that is used to control the dispensing apparatus. In the apparatus of the present invention, the speed of distribution can be controlled over a wide range, by varying the frequency of the strokes, by the energetics of the impingement of the tapping and the size of the strokes. openings Any of these parameters may be varied in order to provide an appropriate device for the particular tip of particle to be distributed. The closed loop system described has the advantage that it is tolerant to the variability of the material as well as the variabilities of the process conditions. Overcome the fact that the distribution by knocking is not necessarily accurate. Also, the present invention has the advantage that there is a very low risk of causing damage to the particles. This is particularly advantageous when particles of o are distributed. ro coated with DNA. In addition there are no relatively mobile parts with respect to the physical elements of computation (hardware) and therefore there is less opportunity for particles to become trapped and damaged. Also, the simplicity of the device makes it compatible in a clean room environment which is often required when dosing pharmaceutical compounds. The particle retainer 31 of the present invention could be removed and disposed of, such that the separate particle retainer could be used for different drugs. This prevents the batch crossing problems that could occur if the same retainer is used with different types of particles.

Sometimes the particles can become compacted in the particle retainer 31 which leads to lower global rates of distribution and longer distribution times. To alleviate this, the particle retainer could be one that has two ends and can be inverted, with a screen at each end. At different points in time, dictated by the processor 33, the particle retainer may be inverted 180 ° so that the distribution continues through the other screen. This would prevent undue compaction of the particles in the retainer and ensure smooth and rapid distribution for as long as the particles are in the particle retainer. Alternatively stirring means or other breaking means could be used to break the compaction. Another way to solve this problem is to use a standard particle retainer that has a closed upper part, and sequentially invert it twice (ie by flipping it through 360 °). This would break the compaction and allow a faster distribution. The break could take you < = performed on a regular basis, for example every 10 minutes. Alternatively (or in addition to) standard fluidization techniques could be used to limit the compaction of particles. Due to the housing to isolate the device for weight measurement, from the effects of dragging, it has been found that the present invention works satisfactorily even in a lot of air movement, such < As the one found in the flow chambers sheet In this way the present invention can be effectively used in an area with laminar flow, when particularly clean conditions are required, Figures 23 to 25 show a perspective view of an additional modality of a device for the distribution of particles, which is similar to that presented in Figure 17. The hopper 31 is attached to the rod 120 by a clamp 230. As can be seen from Figure 24, the clamp 230 is attached to the rod by a bolt and engages a groove that is on the external surface of the hopper, in order to prevent movement in a vertical direction. The hopper 31 sits in a conical hole 242 at one end of the rod 120 and thereby prevents it from moving laterally with respect to the rod L20. As in the embodiment of Figure 17, a solenoid actuator 41 is located at the other end of the rod 120 so as to impart a force pulse substantially horizontal to the rod 120 and to the hopper 31 oak. The rod 120 is connected to a member 244 by two suspension arms 240. These brackets 240 are designed to be relatively flexible in the horizontal direction, such that the rod l? Or be able to translate horizontally with respect to the member 244. This movement is damped by the cushion cylinder 232 connected to one or both of the arms 240 and to the member 244. The member 244 is rotated around the pin 121 on a base plate. 246 that is motionless. This structure allows most of the dispensing apparatus comprising the member 244, the cylinder 232, the arms 2 0, the rod 120, the actuator A 1, the clamp 230 and the hopper 31 to rotate about the axis defined by the bolt 121. This allows the hopper to move substantially vertically in order to bring the screen 46 towards the cartridge 42 and outwardly thereof. The rise and fall are automatically achieved through a pneumatic actuator 234 positioned below the base plate 246. The actuator 234 causes an up / down member 236 to rise and fall such that a vertical force is transmitted to the member 244 through the connecting bolt 238. In this form, the member 244 can be rotated about the bolt 21 to raise and lower the hopper 31. As already mentioned, the hopper 31 is connected to the asking rod 120 a clamp 230 This clamp usually ensures that the hopper can not move relative to the rod 120. However it has been foundthat beneficial effects can be obtained when the clamp 230 is not used, such that the hopper simply sits in the hole 242 and is capable of being disturbed vertically. This clampless embodiment has been found to be particularly effective when it is desired to distribute particles that tend to adhere to each other or to the hopper or screen. For example, agarose beads tend to exhibit adhesiveness that often prevents them from being fully distributed. If the clamp is not used and the hopper 31 can move freely vertically (and / or can rotate) in the aperture 242, the agarose beads can be distributed. It is believed that the reason for this is that the actuator 41 provides a horizontal force that becomes, in part, a vertical force in the side walls of the hopper, possibly due to the tapered nature of these side walls. This vertical force causes the hopper to vibrate ertically which serves to fluidize the agarose beads, making them more easily distributed. This configuration has the additional advantage that the hopper 31 can rotate freely in the opening 242 and in general, the hopper 31 rotates when rod 120 is activated solely by actuator 41. It is believed that these rotations are due to asymmetries in the components, for example when the plane of opening 242 is not precisely horizontal. This rotation of the Hopper 31 serves to allow the driving force to be applied from a slightly different direction in each foraging drive such that each knock occurs at a different point on the circumference of the hopper. This helps to allow the particles to compress or adhere to each other Experimental Results Figure 26 shows a graph that has an ordinate that represents the weight in grams, and an abscissa that represents the time in seconds. The curve marked "1" represents the reading of the balance obtained during a distribution cycle (ie the apparent weight measured.) The curve marked with "2" represents the determined real weight, obtained by the addition of a correction value. the apparent weight measured The algorithm used to obtain the correction value was that of the third modality and the control of the speed of distribution was carried out in such a way that a lower velocity of distribution was obtained, as It will approximate the target weight of 0.00025 g The diamonds and squares each represent the sampling moments and it should be observed that a sample was taken at a time, after each knocking of the actuator Initially the balance takes longer to respond to the knocks of the actuator as can be seen from curve "1" of the apparent weight measured. At this time, most of the value of the determined real weight is composed of the component of the correction value. For example, after one second (and 10 knocks of the actuator), the balance indicates 6 μg but the actual weight of the particles on the balance can be predicted to be 50 μg. At this time, the correction value is 44 μg. μg. This correction value tends to remain relatively if the hopper is tapped at a very constant frequency and with a constant force (as with the present experiment). In this way the correction value tends to be about 50 μg for the first 4 seconds of distribution. As it approaches the target weight of 250 μg, the algorithm of the distribution speed control ensures that the actual distribution speed is reduced by tapping less frequently (5 times per second in this case). As a result, the required correction rate is reduced, which means that the actual weight determined is more accurate. After 6.2 seconds, the algorithm predicts that the target weight has been exceeded and that the hopper should no longer be tapped. Measurement samples of the weight are then taken at a rate of 30 times per second. These samples continue to be taken until it is found that the current sample and another taken a second before, differ by at least some predetermined amount (for example 2 μg). In effect, the balance lies at a relatively constant value after approximately 8 seconds and after 9 seconds the distribution is complete, the apparent weight measured "1" now represents the actual weight of particles on the balance. This final reading is stored in a memory and is considered as the real weight of the distributed particles. SSee lllleev performed experiments to distribute three different powdered compounds, using the correction algorithm in the third modality together with the control of the target distribution speed of the fourth modality. A Sartorius MC5 scale (the resting point for which it is presented in Figure 7) is used. The powder compounds and target distribution weights analyzed were lidocane (1 mg), BSA (0.5 mg) and Agarose (0.25 mg). The table below shows the average weight actually distributed (in ing) and the standard deviation of this average. The master table also showed that minimum and maximum weights were distributed in an experiment of 50 samples. As can be seen, the minimum and maximum values deviate from the average value by approximately 0.05 mg or less. The standard deviation is 2 or 3% of the average, which indicates a very good distribution repeatability. The board it also shows the time in seconds it takes to get the distribution. This is typically about 8 seconds for all types of dust. Interestingly, Agairosa, which has proved difficult to distribute using traditional methods, due to its poor flowability, was distributed with a standard deviation of only 9 μg. However, the time it takes to distribute the agarose is more varied, which shows a standard deviation of 15% of the average, compared to 8% for lidocaine or BSA Lidocaine BSA Agarose Weight of 1.00 0.50 0.25 dose mg mg mg objective Weight Weight Time (s; Weight Time (s) (mg) Time (s¡ (mg) (mg) Average 1.018 7.975 503 8.148 0.252 7.790 Desv. 0.026 0.637 0.012 0.643 0.009 1.201 Standard CV 2,537 7,985 2,432 7,889 3,517 15,419 Minimum 0.944 6.678 463 6.810 0.237 5.208 Medium 1.022 8.002 .506 8.269 0.251 7.876 Maximum 1,602 9,445 CD .528 9,323 0.276 10,313 It is understood that with respect to this date, the best method known to the applicant to carry out said invention is that which is clear from the present description of the invention.

Claims (2)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An apparatus for distributing particles, characterized in that it comprises a particle retainer for retaining a supply of the particles to be distributed, the particle retainer has a plurality of openings arranged to be plugged by the particles and to be selectively uncovered, to distribute the particles through them; an actuator for releasing particles, to cause, in response to a driving signal, the unclogging of the openings, in order to allow some of the supply of particles from the particle retainer to be distributed through those uncovered openings; and a weight measuring device for measuring the apparent weight of the particles distributed from the particle retainer and for emitting a signal representing the measured apparent weight.
2. 2. The apar; in accordance with the a processor operatively connected to the actuator for releasing particles, and arranged to emit the actuation signal thereto and operatively connected to the weight measuring device, and arranged to receive therefrom the signal of the measured apparent weight, the processor is arranged to estimating the actual weight of the particles distributed, by adding a correction value to the measured apparent weight, 5. The apparatus according to claim 5, characterized in that it also comprises a plurality of openings through which the particles. The apparatus according to any of claims 2 to 5, characterized in that the processor is arranged to provide a drive signal having a characteristic corresponding to the amount of particles to be distributed from the particle retainer , when the actuator for the particle release re-tibe the signal. The apparatus according to any of claims 2 to 6, characterized in that the processor comprises a chronometer and can be operated to calculate, from an output signal of that chronometer, and apparent weight measured, the apparent speed with which the .. t particles on the weight measuring device. 8. The apparatus according to claim 7, characterized in that the processor is arranged to use the calculated apparent velocity, to obtain the (a) correction value that is to be added to the measured apparent weight, in order to estimate the actual weight of the particles distributed. The apparatus according to claim 8, characterized in that the processor is arranged to multiply the calculated apparent velocity, through a constant time, to obtain the (a) correction value. 10. The apparatus according to any of claims 2 to 7, characterized in that the processor is arranged to calculate the (a) correction value to be edited to the apparent weight measured, in order to estimate the weight Real of the distributed particles, the calculation comprises: counting the number of times the actuator is activated for the release of particles, within a defined period of time; and adding a stored standard weight, to the correction value, for each drive. 11. The apparatus according to claim 10, characterized in that the processor is additionally arranged to multiply each stored standard weight, by a multiplicative factor of 1 or less, that standard standard weight is used in place of the standard weight, when the correction value is calculated. 12. The apparatus according to claim 11, characterized in that the multiplicative factor is determined according to the time during the defined period of time by which the actuator is actuated for the release of particles. 13. The apparatus according to claim 11 or 12, characterized in that the multiplicative factor is determined using a function that generally decreases linearly as time increases from the corresponding drive of the actuator for the release of particles. The apparatus according to any of claims 10 to 13, characterized in that the processor is arranged to update the stored standard weight after the desired mass of particles has been distributed. 15. The aparphate according to claim 14, characterized in that the update comprises obtaining a value for the average weight of the particles distributed, as a result of each actuation performed the last time the apparatus was used. to distribute particles. 16. The apparatus according to claim 15, characterized in that the value is obtained by dividing the total weight of distributed particles, among the number of drives, 17. The apparatus according to any of the claims from 8 to 16. , characterized in that the processor is arranged to compare the actual distributed weight, estimated). with a predetermined weight of particles, in order to decide whether the additional distribution of particles is necessary, 18. The apparatus according to claim 17, characterized in that the predetermined weight of particles comprises a desired weight of particles that is to be distributed, less a tolerance weight. 19. The apparatus according to any of claims 7 to 9, characterized in that the processor is arranged to provide the actuator for the release of particles, a signal to increase its drive power, when the calculated apparent speed is lower that a predetermined, desired speed value 20. The apparatus according to any of claims 7 to 9, characterized in that the processor is arranged to provide the actuator for particle release, a signal to reduce its drive energy, when the calculated apparent velocity is greater than a predetermined, desired velocity value. The apparatus D according to any of claims 7 through 9, characterized in that the processor is arranged to pause for a predetermined period of time, when the calculated apparent velocity is greater than a desired, predetermined velocity value. . 22. The apparatus according to any of claims 19 to 21, when they are indirectly dependent on claim 3 or 4, characterized in that the processor is arranged to reduce the predetermined, desired speed value when one enters the measured apparent weight and the value of the estimated actual weight is within a predetermined range of a predetermined particle weight. 23. The apparatus according to any of claims 1 to 5, or claims 2 to 3 or 6 to 22, when they are finally dependent on claim 1 or 5, when The particle retainer removes a hopper and the openings are provided with a sieve through the section cross section of the hopper, the screen is capable of supporting particles thereon, 24. The apparatus according to any one of claims 1 to 5, or to claims 2 to 3, or from 6 to 23, when they are finally dependent on claim 1 or 5, characterized in that the openings have a larger size than the average size of the particles to be distributed, the openings can be covered by the particles until the particle retainer 25 is disturbed. The apparatus D according to any of claims 1 or 5, or with claims 2 through 3, or 6 through 24, when they are finally dependent on the claims. 1 or 5, characterized in that the openings are holes having a diameter of 50 to 400 μm. 26. The apparatus according to any of the pre-pending claims, characterized in that the particle retainer comprises a hopper and a plastic screen molded in one piece. 27. The apparatus according to any of the preceding claims, characterized in that the particle retainer comprises a stainless steel hopper and a stainless steel screen. 28. The device according to any of claims 23, | 26 or 27, characterized in that the screen has a diameter of approximately 3 mm. 29. The apparatus according to any of the preceding claims, characterized in that the actuator for the release of particles comprises an electromechanical actuator arranged to supply impact energy to the particle retainer. The apairate according to claim 29, characterized in that the electromechanical actuator comprises a solenoid. 31. The apparatus according to any of the preceding claims, characterized in that it further comprises a closed housing to cover at least the weight measuring device and the particle retainer. 32. A method for distributing particles in an exact form, characterized * because it comprises the steps of: retaining a supply of particles that are to be distributed; the particles cover a plurality of openings causing said openings to become uncovered, such that the supply of particles is distributed through a plurality of openings, from their retained position to a position where their weight can be measured; measure the apparent weight of the particles 35. A method according to claim 35, characterized in that each of the particles is distributed through a plurality of openings. 36. A method according to any of claims 32 to 35, characterized in that the step of using the measured apparent weight comprises determining whether the measured apparent weight is equal to or greater than a predetermined weight of particles, and if not, repeat the steps of the method cyclically. 37. A method according to any of claims 33 to 35, characterized in that the step of using the measured apparent weight, estimated actual weight is equal to or greater than a predetermined particle weight, and if not, repeat cyclically the steps of the method. 38. A method according to claim 36 or 37, characterized in that the predetermined weight comprises a weight of particles to be distributed, less a tolerance weight. 39. A method according to any of claims 32 to 38, characterized in that the step of causing a certain part of the supply of particles to be distributed, comprises actuating an actuator for the release of particles A method according to claim 39, characterized in that it further comprises: timing the period of time between successive operations; and, calculating the apparent speed at which the particles are distributed to the weighing position, 41. A method according to claim 40, characterized in that it also comprises: estimating the real weight of distributed particles, adding e [1 apparent weight measured , at (a-) correction value, based on the calculated apparent velocity / 42. A method according to claim 41, characterized in that the correction value is obtained by multiplying the apparent velocity by a time constant. 43. A method according to claim 39 or 40, characterized in that the (a) correction value to be added to the measured apparent weight, at the end of estimating the real weight of distributed particles, is calculated by: count the number of drives within a defined period of time; and, add a stored standard weight, to a correction value, for each drive. 44. A method according to claim 43, characterized in that it also comprises: multiplying each stored standard weight, by a multiplicative factor of 1 or less, the multiplied standard weight is used in the standard weight, when the correction value is calculated . 45. A method according to claim 44, characterized in that it further comprises, before the multiplication step-: determining the multiplicative factor in accordance with the time during the defined period of time in which the aeration occurs. 46, A method according to claim 44 or 45, characterized in that the multiplicative factor is determined using a function that decreases, in general, linearly, for increased periods, from the corresponding acclimation. 47. A method according to any of claims 43 to 46, characterized in that it further comprises: updating the standard weight value, 48. A method according to claim 47, characterized in that the update comprises: obtaining a value for the average weight of distributed particles, as a result of each actuation performed the last time the apparatus was used to distribute particles 49. A method according to claim 48, characterized in that the value is obtained by dividing the total weight of distributed particles, by number of drives 50. A method according to any of claims 41 to 49, characterized in that it further comprises: comparing the estimated actual pfso, with a predetermined particle weight., in order to decide if additional particle distribution is required. 51. A method according to claim 50, characterized in that the predetermined particle weight comprises a weight of particles to be distributed, less a tolerance weight. 52. A method according to any of claims 40 to 42, characterized in that it further comprises: determining whether the calculated apparent speed, during the previous cycle, is less than a predetermined desired speed; and if the apparent calculated speed is lower that the desired, predetermined speed causes more particles to be distributed in the current cycle than those distributed in the cycle, 53. A method according to any of claims 40 to 42, characterized in that it also comprises: determining whether the calculated apparent speed, during the previous cycle, is greater than a predetermined desired speed; and, if the calculated apparent velocity is greater than the predetermined desired velocity, cause that in the current cycle less particles are distributed than those distributed in the previous cycle. 54. A method according to any of claims 40 to 42, characterized in that it further comprises: determining whether the apparent speed calculated, during the previous cycle, e greater than a predetermined desired speed; and, if the calculated apparent velocity is greater than the desired predetermined velocity, pause for a predetermined period of time. 55. A method according to any of claims 52 to 54, when dependent on claim 33 or 34, characterized because it further comprises: determining whether one between the measured apparent weight and the actual weight is: - stored, within a predetermined range, of a predetermined particle weight; if so, reduce the desired speed value, predetermined. 56. A method according to any of claims 39 to 55, characterized in that the step of actuating an actuator for releasing particles comprises vibrating the supply of particles. 57. A method according to any of claims 32 to 56, characterized in that less than 5 mg of particles are distributed, 58. A particle retainer serving for use in the apparatus according to any one of the claims of 1 to 31, or a particle retainer for retaining a supply of particles for use in the method of con fi rity with any of claims 3 to 57", the particle retainer is characterized in that it comprises: a Hopper, a sieve through the cross section of the hopper. 59. A particle retainer according to claim 58, characterized in that the screen is positioned at one end of the hopper. 60. A particle retainer according to claim 58 or 59, characterized in that the hopper is a glass tube and the tjamiz is an electroformed mesh. 61. A particle retainer according to claim 58 or 59, characterized in that the hopper and the screen are formed from a piece of plastic material, 62. A particle retainer according to claim 58 or 59, characterized in that the hopper and the sieve are formed of stainless steel. 63. A particle retainer according to any of claims 58 to 62, characterized in that the screen has holes whose diameter is in the range of 50 to 400 μm. .4. The processor for use as the processor in the apparatus according to any of claims 2 to 31, or to carry out some of the steps of the method of any of claims 32 to 57, the processor is characterized in that it comprises: means for outputting signals for emitting an output signal of predetermined characteristic, to an actuator for releasing particles; means of comparison; signal input means for supplying the value of an input signal derived from a signal output of a device by weight measurement, to the comparison means; and memory means for feeding a predetermined weight value stored thereon, to the comparison means; the comparison means are arranged to compare the value of the input signal with the predetermined weight value, and to determine if the input signal is greater than the val Dr of predetermined weight. 65. The processor according to claim 64, characterized in that it further comprises: calculation means programmed and arranged to receive a signal from the device for weight measurement, and to aidicionar a correction value to this signal, in order to calculate an estimate of the actual weight of the distributed particles, this estimate is fed to the signal input means 66. The processor according to claim 65, characterized in that the calculating means calculates the rate of change of the signal received from the device. for the measurement of weight, with respect to time, and use it to obtain the correction value. 67. The processor according to claim 65, characterized in that the calculation means executes the following: '. count the number of times that the actuator for the release of particles is activated within a predefined period of time; determining a multiplicative factor in accordance with time i, during the defined period of time, that the actuator is actuated for the release of particles; multiply a stored standard weight, by the multiplicative factor; and, add the stored standard weight, multiplied, for each drive, to obtain the correction value. The processor according to claim 66, characterized in that the characteristic of the output signal is increased if the calculated rate of change is less than a desired, predetermined value, and decreases if the calculated rate of change is greater than the desired value , default. 69. The processor according to any of claims 64 to 68, characterized in that it also comprises: sampling means to obtain samples successive of the signal signaled from the device for weight measurement; second comparison means for comparing a plurality of those mules back, in order to determine if a level of the input signal has been reached, the substantially stable, when the stored value is not greater than the input signal. 70. A computer program for carrying out the method according to any of claims 32 to 57, or for causing the processor, according to any of claims 64 to 69, to function, 71 A manufacturing station for manufacturing a particle cartridge, characterized in that it comprises: a collector for collecting an open and empty case; a conveyor: to move the cartridge open and empty, to a position in which its weight can be measured; an apparatus according to any one of claims 1 to 31, for distributing particles in the open cartridge in order to obtain a loaded cartridge. 72. A manufacturing station, according to claim 71, characterized in that further comprises: a station for closing cartridges, for closing a loaded cartridge, so as to contain therein the distributed particles; and, a second conveyor for moving a loaded cartridge towards the cartridge closing assembly. 73. A manufacturing station according to claim 72, characterized in that the conveyor for moving the cartridge open and empty, is the same conveyor as the second conveyor used to move the loaded cartridge 74. A manufacturing station according to claim 73, characterized in that the conveyor for moving the cartridge comprises a pivoted arm, wherein one end of that arm has a locator for locating the cartridge. 75. A manufacturing station according to claim 73, characterized in that the conveyor for moving said cartridge comprises a rotating circular component having a locator placed on its circumference to locate the cartridge. 76. A manufacturing station according to claim 74 or 75, characterized in that the locator can be made to operate to grip and release the cartridge. 77. A manufacturing station according to any of the claims 71 to 76, characterized in that it further comprises: a lane d: entrance to introduce the open cartridges and empty an exit lane to remove the loaded cartridges. 78. A production line, characterized in that it comprises: a plurality of manufacturing stations having the structure of any of claims 71 to 77; an entry lane for feeding open and empty cartridges and an exit lane for removing closed and loaded cartridges; wherein the plurality of respective conveyors, for moving the cartridges, can be operated to take open and empty cartridges from the entrance lane and place closed and loaded cartouches on the exit lane. 79. A production line according to claim 78, characterized in that it further comprises: a loading hopper, which can move between each particle retainer a of each manufacturing station 103 MMtotfl SUMMARY OF THE INVENTION In the present invention an apparatus and method is described which is capable of distributing very small amounts (typically less than 5 mg) of particles, with high accuracy, in a repeatable manner, and without undue depletion. The need for advanced particle formulation is also reduced. The apparatus comprises a closed loop control system that uses an electromechanical actuator to supply impact energy to a supply of particles initially contained on a screen in a hopper. The impact energy causes a small number of particles to fall through the sieve and onto a balance for weight measurement. The weight obtained is scrutinized by a processor to see if additional drives are required. In preferred embodiments, the drive energy is varied in accordance with the delivery rate calculated by the processor. Also, a correction amount can be obtained to take into account the fact that the balance may take a considerable time to stop at its final value.