ES2586429T3 - Powder filling process - Google Patents

Abstract

A method for filling a plurality of microdepressions on a main surface of a continuous sheet having said microdepressions having a depth of about 5 to 500 microns, but being less than the thickness of the continuous sheet, and an opening in the surface of the continuous sheet of approximately 10 to 500 microns in width, with finely divided powder, said process comprising: continuously supplying the continuous sheet to, and through, a powder filling stage; in the powder filling stage, filling said microdepressions with powder on the surface of the continuous sheet using a driven roller, wherein said roller is rotating about an axis generally transverse to said direction of continuous sheet movement, while the speed of the surface of the roller and the speed of the continuous sheet are different, and where the roller and the continuous sheet are located relative to each other, so that between the upper surface of the continuous sheet and the outer surface of the roller there is a seperation; and where the powder is supplied either on the continuous sheet upstream of the roller of the powder filling stage or on the roller of the powder filling stage.

Description

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DESCRIPTION

Field Powder Filling Process

The present invention relates to a process for filling finely divided powder into a plurality of microdepressions on the surface of a flexible continuous sheet, as well as to a method of manufacturing an elongated carrier with microdepressions containing finely divided powder. The filled continuous sheet and or the elongated carrier can be conveniently used in the administration of biologically active substances, in participating medications, by inhalation.

Background

Asthma and other respiratory diseases have been treated for a long time by inhaling an appropriate medication. For many years, the two most widely used and most convenient treatment possibilities have been the inhalation of a medication from a drug solution or suspension in a pressurized metered dose inhaler (pMDI), or the inhalation of a powdered drug , usually mixed with an excipient, from a dry powder inhaler (DPI). After the strong concern about the relationship between the reduction of the ozone layer and the emissions of chlorofluorocarbon (CFC), the use of these materials in pressure inhalers has fallen into disuse, increasing interest in IPR systems.

The majority of the DPIs use either bulk powder deposits or previously individual measured doses. However, there are problems associated with the precise measurement of a small measured amount (for example 500 milligrams or less) of powder both from the bulk deposit within an inhaler and within a capsule or vial. With many drugs, for example potent drugs, this introduces the need to add excipients, such as lactose powder, to significantly increase the amount of powder to be measured. Such excipients are, however, generally undesirable since they can represent subsequent dust breakdown problems and can cause dryness and other unwanted effects in the patient's mouth.

Dry powder inhalers in which predetermined doses of medication are dispensed from a sheet material that includes discrete microdepressions (having a depth of about 5 to 500 microns and a surface opening of the sheet material of about 10 to 500 microns wide) filled with medication, are described in US Patents 5,408,994, 5,437,271, 5,469,843, 5,482,032 and 5,655,523.

Various methods for powder coating on substrates are known. Some typical in consideration for use in drug administration applications are the electrostatic coating methods described in US Patents 4,197,289, 5,699,649, 5,960,609, 6,146,685, 6,319,541 and 6,652,903 and the United States patent application US2002 / 0085977. Such methods tend to be complex, slow and difficult to control.

Other methods for coating powders on moving continuous film substrates include fluidized bed methods, for example as described in US Patents 4,088,093 and 6,037,019, spray methods, (e.g. United States 4,288,521 and 5,897,746), suction methods (for example US Patent 4,313,972) magnetic methods (for example US Patent 4,470,350), and sprinkling methods (for example patents United States 4,209,553 and 5,415,717). A method of depositing suspended particles on a substrate for use in inhalation devices, which involves evaporation of the suspended agent, is described in US Patent 5,503,869. However, none of these different methods is well suited to the precise measurement of pharmaceutical powders in microdepressions on a continuous sheet surface.

Patent application WO 95/21768 describes a process for filling blister cavities with powder while mounted on a continuous sheet. An oscillating and rotating system is provided to break the aggregates in powder doses of 0.1 to 10 mg. Such large masses of powders are many times greater than the small amounts of powder that the tape-based inhalers with microdepressions described in the aforementioned patents are intended to be administered.

US 5,192,548 describes a method of coating a micronized drug in a closed loop of a sheet material that includes microdepressions on its upper side, in which the micronized drug is supplied on the sheet material, rollers help in the distribution of the Micronized drugs on the surface of the sheet material and curved slats work to spread the micronized drug on the surface of the sheet material. A roller is shown with a flattened part intended to help prevent the drug from accumulating behind it.

WO 95/21768 refers to a device for filling with high precision a finely divided powder medicine having a particle size smaller than 10 pm cavities that have a size corresponding to the volume of the powder to be filled, where said device comprises means of

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oscillation and rotation to break the aggregates formed in the finely divided powder medicine and to fill and compact it in said cavities.

WO 92/19198 describes a configuration for depositing particles in a continuous sheet in motion. The configuration includes a particle dispenser and a perforated tape that moves on the continuous sheet of material. The particle dispenser is intended to dispense the particles continuously in a uniform and wide flow whose width is equal to or greater than the width of the orifice pattern of the tape and the tape is separated a distance from the continuous sheet of material that It is at least large enough for the particles deposited on the continuous sheet of material to be housed between the tape and the continuous sheet.

Summary of the invention

There is still a need to provide processes for accurately and uniformly filling microdepressions with finely divided powder (in particular, biologically active substances, such as medicaments) and / or providing processes for the manufacture of elongated carriers that have substantially precisely filled microdepressions. and uniform with said finely divided powders, in particular operating such processes continuously and / or suitable for use on an industrial scale.

According to one aspect of the present invention there is provided a method for filling a plurality of microdepressions, on a main surface of a continuous sheet, with finely divided powder in which the continuous sheet is supplied continuously and through a filling stage. of powder containing a driven roller. In the powder filling stage, the powder that is supplied either on the continuous sheet upstream of the roller or on the roller of the powder filling stage, is introduced into the microdepressions of the continuous sheet using the driven roller, wherein said roller is rotatable about an axis generally transverse to the direction of movement of the continuous sheet, while the speed of the surface of the roller and the speed of the continuous sheet are different and where the roller and the continuous sheet are located in relation to each other, so that there is a gap between the upper surface of the continuous sheet and the outer surface of the roller.

Another aspect of the present invention is the provision of a method of manufacturing an elongated carrier of microdepressions containing finely divided powder, the process comprising the step of filling a plurality of microdepressions on a main surface of a continuous sheet as described above. and which also includes the step of removing excess dust not deposited within the microdepressions from the upper surface of the sheet and remaining in the surface areas between the depressions. Additionally, if desired, grooves can be formed in the continuous sheet with full microdepressions or cut to predetermined widths and / or predetermined lengths.

Surprisingly, by applying different speeds to the surface of the driven roller and the continuous sheet, and placing the roller and the continuous sheet relative to each other to provide a separation between the outer surface of the roller and the upper surface of the continuous sheet, during the operation of the powder supply process and filling of the outer surface of the roller a substantial dust cover is formed visually uniform (eg visually uniform in smoothness and thickness) and the continuous layer, which allows for desirable precision and filling uniform microdepressions. The formation of a stable, substantial dust cover on the roller is desirably facilitated through the application of a separation width of 1.25 mm or less. The application of a separation width of 0.2 mm or greater is desirable for a stable and smooth filling process. Stable processes of uniform powder filling in the depressions of the continuous moving sheet found for a fixed separation width, however an element of flexibility in the positioning of the roller and the continuous sheet has been found to be advantageous for the separation be variable in width. For example, to facilitate the prevention of the formation of high pressures in the roller, due to the accumulation of dust in the separation, the positioning of the roller and the continuous sheet may be arranged so that the separation is loaded to a predetermined minimum width , for example, through the use of springs, but at the same time allowing some variability in the separation width, for example, movement towards a greater separation width.

The formation of a stable, substantial dust cover on the roller is also desirable, facilitated by the rotation of the roller in the same direction as the movement of the continuous sheet. In addition, the provision of a roller surface speed that is greater than the speed has been found useful in maintaining a stable dust cover on the roller during filling. A surface speed for the roller that is 1.1 or more times greater than the continuous sheet speed has been found particularly useful.

Even to fill more easily, as well as to achieve improved process reliability and stability, it has been found desirable to supply the continuous sheet to the roller generally along a foreground and from the roller along a background, so that in the roller, the continuous sheet goes through a break, where the first plane and the second plane define an angle of less than 180 ° towards the roller (referred to in the following as "contact angle"). Although it is not desired that it be limited to a particular theone, it is believed that the provision of such a contact angle allows a partial wrap around the continuous sheet in the roller providing

a force component directly normal to the powder coating on the roller.

Due to the desirable precision and uniformity in the processes according to the invention, these processes are particularly suitable for filling continuous sheets and / or manufacturing elongated carriers with a biologically active substance. In addition, continuous filled sheets and / or elongated carriers as provided by the processes described herein, which include small quantities and well-controlled measures of a biologically active substance, can be advantageously used as such or as a part of the supply systems for the administration of such powders formed by a biologically active substance or substances.

According to a first embodiment of the present invention, a method is provided for filling a plurality of microdepressions on a main surface of a continuous sheet, said 10 microdepressions having a depth of about 5 to 500 microns, but being less than the thickness of the continuous sheet and an opening in the surface of the continuous sheet approximately 10 to 500 microns wide, with a finely divided powder, said process comprising: continuously filling the continuous sheet through a powder filling stage; in the powder filling stage, introducing the powder into the microdepressions on the surface of the continuous sheet using a driven roller, wherein said driven roller 15 is rotating around an axis generally transverse to said direction of movement, while the speed of The surface of the roller and the speed of the continuous sheet are different and where the roller and the continuous sheet are positioned relative to each other, such that there is a gap between the upper surface of the continuous sheet and the outer surface of the roller; and where the powder is supplied, either on the continuous sheet upstream of the roller of the powder filling stage, or on the roller of the powder filling stage.

According to a further embodiment of the present invention, there is provided a method of manufacturing an elongated carrier with microdepressions containing finely divided powder, said process comprising: providing a continuous laminate comprising a plurality of microdepressions on a main surface of the continuous sheet, said microdepressions having a depth of about 5 to 500 microns but being less than the thickness of the continuous sheet and an opening in the surface of the continuous sheet of about 10 to 500 microns in width, continuously supplying the sheet continues to, and through, a powder filling stage to the powder filling stage, depositing powder within said microdepressions on the surface of the continuous sheet using a driven roller, wherein said roller is rotating about an axis generally transverse to said direction of continuous sheet movement, while the v The surface quality of the roller and the speed of the continuous sheet are different and where the roller and the continuous sheet 30 are located relative to each other, so that between the upper surface of the continuous sheet and the outer surface of the roller there is a seperation; removing from said surface of the sheet the excess dust that has filled the microdepressions and that remains in the surface areas between the depressions continues; and optionally forming slits and / or cutting the continuous sheet to predetermined widths and / or lengths; and wherein the powder is supplied on the continuous sheet upstream of the roller of the powder filling stage or 35 to the roller of the powder filling stage.

The dependent claims define further embodiments of the invention.

Brief description of the drawings

The invention will be described in more detail below with reference to the accompanying drawings in which:

Figure 1 represents a schematic illustration of an exemplary device for filling microdepressions with a finely divided powder on a main surface of a continuous sheet using an exemplary process, in accordance with the invention.

Figure 2 represents a schematic illustration of the continuous sheet supply to, and from, the roller illustrated in Figure 1.

Detailed description

45 It is understood that the present invention covers all combinations of particular, suitable, desirable, favorable, advantageous and preferred aspects of the invention described herein.

Referring to Figure 1, which provides a schematic illustration of an exemplary device (1) for filling microdepressions of a continuous sheet with finely divided powder using an exemplary process according to the invention, the continuous sheet (8). ) is generally supplied continuously to, and 50 through, a powder filling stage (15). The continuous sheet (8) can be supplied from a roller (not shown).

The continuous sheets for use in the process described herein comprise a plurality of microdepressions on a main surface of the continuous sheet. The microdepressions may be suitably truncated cones, but alternatively they may have any suitable configuration to contain finely divided dust, including truncated pyramids, partial hemispheres, and tetrahedra or other geometric configurations as well as non-geometric configurations. Preferred depressions have a lateral wall angle of 15 ° -20 ° with the

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vertical when the main surface is horizontal. The plurality of depressions can be arranged in an irregular configuration, or alternatively the configuration of depressions can take any form or pattern and does not need to be regular (that is, the arrangement can be irregular in appearance). Desirably, the microdepressions are discrete.

The depressions generally have a depth of about 5 to 500 microns and an opening in the surface of the continuous sheet of about 10 to 500 microns in width. The depressions have a depth less than the thickness of the continuous sheet, so that the depressions do not form pores that extend across the entire thickness of the continuous sheet. In the case of discrete depressions having circular openings such as truncated cones or partial hemispheres, for example, the above-mentioned achura is, in fact, the diameter of the circular opening. Preferred depressions have a depth of about 5 to 150 microns and an opening (for example, diameter in the case of discrete truncated cones or partial or similar hemispheres) on the surface of the sheet material of about 50 to 200 microns. Depressions may be adequately separated in a range of about 20 to 2000 microns, more suitably in a range of about 300 to 2000 microns. Depressions can be suitably in a number between about 25 and 1000 per cm2 of continuous sheet. The volume of each depression and the separation or number of depressions will depend on the particular desired application of the resulting continuous full sheet and / or the elongated carrier in the case of biologically active substances (e.g., medications), the potency of the particular substance and the area of the sheet material intended to represent a single dose of the substance. Typically it is desirable that the continuous sheet material have a substantially uniform volume of depression per unit area when considered on a scale of the area of a single dose or other functional unit.

The depressions can be formed in a continuous sheet material by any suitable technique such as microprinting using a magnesium alloy plate with a photolithographic pattern or another micromachined plate. Other conventional techniques that can be used are the optical generation of images or the generation of images by laser.

Continuous sheets for use in the processes described herein are generally flexible. The continuous sheet can be a (single) layer material or a laminate that includes a bonded layer (for example laminated, bonded or extruded) on a support layer. The support layers may be formed by paper, be non-knitted, knitted, mesh or polymeric films, such as polyester films. Suitably, the continuous sheet, as a single material or as a layer thereof fixed to a support layer, may comprise a polymeric material (such as polyethylene, polypropylene, polyester, polytetrafluoroethylene or mixtures thereof, in particular polyethylene or Polypropylene). For filling with powders that are sensitive to moisture, it may be desirable to incorporate a drying material. Also, inorganic salts or well dispersed conductive materials can also be incorporated into the continuous sheet material to decrease any static load that can accumulate in the continuous sheet.

Generally, the continuous sheets formed, either by a single material or as a laminate, have a thickness of at least 25 microns. Continuous sheets having a thickness of at least 75 microns are more suitable and a thickness of at least 100 micas is most suitable. Continuous sheets having a thickness of at most 1000 sights are generally adequate, while continuous sheets having a thickness of at most 750 microns are more suitable, at most 500 microns even more suitable and at most 250 microns as appropriate. An example of suitable material for a continuous sheet of single material includes polypropylene, because the polypropylene has sufficient integrity and durability without the inclusion of a support layer. An example of a suitable laminated continuous sheet includes kraft paper coated with polyethylene.

Returning to Figure 1, the continuous sheet (8) can be supplied to a powder filling stage (50) where the finely divided powder (4) is supplied on the upper surface of the continuous sheet, said surface comprising a plurality of microdepressions (not shown). The movement of the sheet continues in the general direction indicated by the arrow (10) then causes the powder on the sheet to continue traveling with the sheet continuing to the powder filling stage (15) which includes a driven roller (12).

The powder delivery arrangement can be in any way suitable for delivering powder, either directly to the roller of the powder filling stage, or on the surface of the continuous sheet upstream of the roller of the powder filling stage. Figure 1 shows an exemplary representation of this last type of powder supply.

In a second type of powder supply, the powder can be provided, for example, on the upper surface of the continuous sheet upstream of a "nip", or separation of the roller, on the upstream side of the roller (for example, near the separation under the roller of the powder filling stage). Allowing an excess of dust to accumulate as a shock lift in the roller separation, the shock lift can act as a deposit, and ensure continuity and uniformity of the powder application process. Conveniently, the powder can be supplied to the roller separation by dropping it onto the continuous sheet moving upstream of the roller and its shock elevation. Alternatively, the powder can be supplied

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(for example, dropping it) directly on the dust shock elevation just upstream of the roller of the powder filling stage. Such dust supplies may be continuous, may be intermittent or change speed. Desirably, the powder feeder arrangement is selected so that during the powder delivery, large agglomerates (for example 2 mm or larger) are not formed, for example to prevent large agglomerates from reaching the separation of the roller which it could cause the obstruction of the dust inlet in the region of the separation of the roller and / or disturbances in filling. Screw feed configurations, vibrating screen arrangements, and quartered arrangements (powder sample dividers) are examples of powder feeding systems that may be suitable. Suitably, the continuous sheet is continuously supplied to, and through, the powder supply arrangement or stage. Conveniently, as shown in the schematic illustration of Figure 1, a vibrating hopper (2) with a screw feed arrangement (5) can be used to fill (drop) dust (4) onto the continuous sheet, as the sheet continues to nine, and through, the powder feed stage (50).

The powder supply does not need to be spread laterally across the width of the sheet, but it can be supplied to only a part of the width of the continuous sheet, for example it can be supplied to the central line of the continuous sheet. Once a sufficient amount of dust has accumulated as a shock elevation on the upper surface of the continuous sheet in the roller, the powder tends to spread it laterally. For a continuous sheet width of approximately 150 mm, a single supply is typically satisfactory. For continuous wider sheets, or if lateral segregation of the dust occurs within the dust shock elevation (for example if the thicker or finer particles of a particular powder substance have a tendency to move outside the edges of the sheet continues preferentially), then multiple supplies can be used through the continuous sheet. Alternatively, a single supply can be spread to produce a wide lateral spread of the powder on the upper surface of the continuous sheet, by means of a rotary or alternative quarterator or other suitable arrangement.

With regard to the alternative of supplying powder directly to the roller, here the powder can be supplied directly on the roller, typically through a moderate supply, so that the continuous powder layer on the roller is maintained at the same time That is answered. Alternatively, a wall arrangement upstream of the roller can be used to contain a powder deposit on the downstream side of the roller, from which the roller can collect and deliver (transport) the powder on itself to the separation of the water roller above, where it can be incorporated into the continuous cover layer to maintain and replenish the layer. Here again, it is desirable that the powder supply arrangement be selected so that it does not allow too much excess dust to disturb the layer in the roller or allow large agglomerates to be supplied to the roller and / or to the separation of the roller.

For both types of powder supply, it is desirable that the powder supply be performed, to provide a build-up of dust on the continuous sheet upstream of, and adjacent to, the roller (for example, in the separation of the roller). Such accumulation (for example in the form of a shock lift) can act as a dust deposit, replenishing the dust cover on the outer surface of the roller, and thus helping to ensure the continuity and uniformity of the powder filling process. . The processes described herein may desirably or additionally comprise automatic control means for connecting or disconnecting, or for modifying the speed of the powder supply. In addition, the powder supply may be desirably automatically controlled in response to a sensor or sensors, such as a sensor or sensors that detect the accumulation of dust (e.g., the presence and / or the amount of dust) on the roller. and / or the accumulation of dust (for example the presence and / or the amount of dust) on the continuous sheet upstream of the roller, for example in the elevation of shock. For example, a sensor or sensors (for example capacitive sensor (s) or opto-electronic reflective sensor (s) can be conveniently used to control the thickness of the powder coating layer on the rotation roller. Adjusting the sensitivity of such a sensor or sensors, the reduction of this coating layer can be detected before it becomes sufficiently non-uniform or reduced to provide an acceptable uniformity of the coating, so that the powder supply can be adjusted accordingly automatically to replenish the cover layer on the roller In combination with this or alternatively, it has been found advantageous to use a sensor or sensors (for example a capacitive sensor (s) or a transmission sensor (s) of opto-electronic type source / detector to detect the amount of dust accumulated upstream of the roller, for example in the elevation of shock, for example, an arrangement of torque thickness f Opto-electronic source / transmitter of transmittance type has proved highly advantageous for detecting the presence of such accumulation of several millimeters of dust in front of the leading edge of a 23 mm diameter roller. Such a sensor or sensors for the amount of dust accumulation is / are well suited to control the amount of dust and to provide automatic feedback to control the dust supply (for example, by connecting and disconnecting a powder feeder or by varying the speed of the powder supply, etc.). Generally, in processes in which the powder is supplied on the surface of the continuous sheet upstream of the roller, it is desirable that the feeder is located quite close to the roller, so that the time delays in the powder supply adjustment are minimized and therefore the control has adequate response.

The processes described here include a dust container on the continuous sheet and on the roller. For example, they can be conveniently achieved by arranging vertical plates or metal cradles on both sides of the continuous sheet of moving sheet material in order to laterally confine the powder. (The confinement

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vertical is, of course, provided by the continuous sheet itself and by gravity, and adequate longitudinal confinement is provided by the movement of the continuous sheet and by the nature of the process itself). Desirably, the vertical plates may be gently loaded against the edges of the continuous sheet, to allow for differences in the lateral rotation of the continuous sheet over time while avoiding significant bending of the continuous sheet. Conveniently, loaded rubber sheets can be used.

Turning again to Figure 1, which provides a schematic illustration of an exemplary process according to the invention, it can be seen that the driven roller (12) of the powder filling stage (15) is rotating about an axis generally transverse to the direction of movement of the continuous sheet. Desirably, the roller is rotating in the same direction as that of the general movement of the continuous sheet (as indicated by the arrow (10)) and therefore in the direction of the arrow (14). In addition, as can be seen in Figure 1, there is a narrow gap (16) between the outer surface of the roller (12) and the upper surface of the continuous sheet (8). In the exemplary embodiment of Figure 1, the application of a solid base plate (18) under and properly separated from the roller to form a passage (6) allows a positioning of the roller (12) and the continuous sheet (8 ) one in relation to the other, such that a separation (16) between the outer surface of the roller and the upper surface (towards the roller) of the continuous sheet is provided. In particular, in the exemplary embodiment of Figure 1, when the continuous sheet (8) crosses the passage (6) between the roller (12) and the base (18), the powder (4) on the continuous sheet it forms an accumulation (7) upstream of the roller (12) and the separation (16) is disposed between the outer surface of the roller and the upper surface of the continuous sheet. The positioning of the roller and the sheet continues relative to each other to provide a separation between the two can be achieved by other suitable means, such as replacing the base plate illustrated in Figure 1 with other types of base elements (for example , a series of non-driven rollers, tape configuration or a scraper blade or a second roller (which may or may not be driven)) opposite the driven roller of the powder filling stage, so that a passage for the continuous sheet between the roller and the base.

By providing a separation together with the application of a roller surface speed that is different, preferably greater, than the speed of the continuous sheet, during the operation of the process, a continuous and visually uniform layer of dust quickly accumulates in The outer surface of the roller. The presence of a continuous and visually uniform layer of dust on the roller, the formation of which is believed to be (although it is not desired that it be limited by any teona) caused by the shear action of the powder at different speeds of the roller surface and the continuous sheet in the presence of the separation between the two, allows desirably accurate and uniform packing of the powder in the depressions. The formation of this powder layer is also favorably facilitated by the rotation of the surface of the roller in the same general direction as the movement of the continuous sheet. Returning to the exemplary embodiment shown in Figure 1, it will be appreciated at the beginning of the filling, when the continuous sheet (8) and the powder (4) pass through the passage (6), that the continuous sheet will move away from the outer surface of the roller (12) towards the base plate (18) to provide a separation (16) between the roller and the continuous sheet, and (shortly after) once the continuous layer of powder (9) forms the surface Outside the roller, this layer of dust in turn maintains the separation between the roller and the continuous sheet.

The separation width generally tends to affect the thickness of the powder layer that forms on the rotating roller in the process. Typically, the thickness of the powder layer formed in the roller is similar to the separation width. It will be appreciated that for embodiments that employ a base in combination with the roller of the powder filling stage to provide a passage and, thus, the respective positioning of the continuous sheet and the roller, as described above or shown in As an exemplary embodiment of Figure 1, the separation width is typically the width of the passage minus the thickness of the continuous sheet. The selection of the particular separation width depends on a number of factors, such as the properties of the particular powder being filled, the dimensions and pattern of the microdepressions to be filled, and the thickness of the continuous sheet and its thickness variation. For example, micronized albuterol sulfate with a particle diameter of average mass of approximately 2 to 3 microns and with at least 95% of mass particles having a diameter of less than 5 microns has been successfully deposited in the microdepressions of a material 0.2 mm thick sheet using a separation width of 0.65 mm, while micronized lactose monohydrate of a similar particle size distribution has been successfully deposited in the same sheet material in 0.45 mm separations and 0.65 mm. Generally, it has been found that the formation of a stable, substantial, dust cover on the roller is desirably facilitated through the application of a separation width of 1.25 mm or less, more desirably 1.00 mm or smaller and most desirable 0.75 mm or less. To facilitate the maintenance of a stable dust cover on the roller together with a smooth continuous continuous process of supply and filling of the continuous sheet, the application of a separation width of 0.2 mm or greater is desirable, 0.3 or greater is more desirable and 0.4 mm or greater the most desirable. As mentioned above, the inclusion of an element of flexibility in the positioning of the roller and the continuous sheet has been found to be advantageous, so that the separation is variable in width. For example, to facilitate the prevention of the formation of high pressures in the roller, due to the accumulation of dust in the separation, the positioning of the roller and the continuous sheet can be arranged such that the separation is loaded towards the minimum width predetermined, for example through the use of springs, but at the same time allowing some variability in the separation width, by

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For example, the movement towards a greater separation width.

The formation of a stable, substantial powder cover on the roller is desirably further facilitated by the provision of a roller surface speed that is greater than the speed of the continuous sheet at the roller position. It has also been found that, in order to minimize the risk of blockage of dust in the separation (and the risk of subsequent process failure and possible breakage of the continuous sheet), the use of a roller surface speed that exceeds the Continuous sheet speed at a minimum factor of 1.1 (ie in a ratio of at least 1.1 to 1) is advantageous. It has been found that an optimal speed ratio regime depends on a number of factors, such as the speed of the continuous sheet, the diameter of the roller, the characteristics of the powder, the characteristics of the surface of the continuous sheet, and the separation width. For example, it has been observed that when the continuous sheet speed increases, the optimum ratio of the surface speed of the roller to the speed of the continuous sheet also increases. In general, a relationship between the roller surface speed and the continuous sheet surface speed of at least 1.1 to 1 is adequate, at least 2 to 1 is more suitable and at least 3 to 1 is the most appropriate. For the stability of the overall process it has been found that it is advantageous to apply a relationship between the roller surface speed and the continuous sheet speed of at least 10 to 1 or less, more suitably at least 7 to 1, and most suitable at minus 5 to 1.

Continuous sheet speeds of 3 meters per minute or greater are generally adequate, while for higher production rates and generally better process stability, continuous sheet speeds of at least 10 meters per minute, at least 15 per minute more are desirable. desirable, and at least 17 meters per minute the most desirable. Generally, a suitable maximum continuous sheet speed is 25 meters per minute. For continuous sheet speeds of about 20 to 25 meters per minute, generally the ratio between the roller surface speed and the continuous sheet speed is desirably at least 3: 1. To further improve the overall process and the reliability of the filling, it may be desirable to automatically couple the surface speed of the roller to the speed of the continuous sheet. For example, through such coupling the relationship between the optimum and / or desired speed and the surface speed of the roller and the continuous sheet speed can be maintained during changes in the continuous sheet speed and / or surface speed. of roller. To minimize any potential tendency to process clogging, for example through blockage of dust in the separation, desirably the continuous sheet speed is generally maintained without significant speed fluctuations (i.e., at most 10%, more adequately as much 7% and most suitable as much 3% speed fluctuation). It has been found that for a roller having a diameter of 20 mm or greater, the application of continuous sheet speeds of at least 10 meters per minute improves uniformity as well as the stability of the filling process.

Suitably, the roller is circular in section, in particular without any flattened parts. The roller can have a diameter of up to 150 mm. It has been found that smaller diameter rollers are advantageous to provide desirable geometries in the separation of the roller relative to the continuous sheet and thus the desirable shear forces for powder filling. Therefore, the desirable roller has a diameter of 60 mm or less, more desirably 40 mm or less, even more desirably 30 mm or less and most desirably 25 mm or less. To help minimize the centrifugal acceleration at any given roller surface speed (and thereby minimize the potential for dust particles to be driven from the roller surface as a result of such centrifugal acceleration), use has been found desirable. of a roller with a diameter of 8 mm or greater, more desirably 10 mm or greater, even more desirably 15 mm or greater, and most desirably 20 mm or greater.

The surface of the roller is adequately hard and sharp. The rollers can suitably comprise a metal surface, for example a solid metal roller or a roller provided with a metal surface. It has also been found desirable that the surface of the roller be generally smooth, for example, without encumbrances, and without being provided with any elevated structure. For example, it has been found that a solid and smooth stainless steel roller is particularly suitable for use in the process. Other materials, such as aluminum alloys, can be used for the roller.

As mentioned above, for even greater ease in filling as well as to make the process more reliable and stable, it has been found desirable to supply the continuous sheet to, and from, the roller, so that in the roller the continuous sheet go through a break so that there is a contact angle of less than 180 ° towards the roller. Here, the continuous sheet is desirably supplied generally along a first plane and from the roller generally along a second plane, the intersection of the first and second planes in the roller defining an angle less than 180 °, towards the roller Referring to the exemplary embodiment in Figure 1, it can be seen that the total continuous sheet movement is from left to right along a horizontal plane as indicated by the arrow (10), and towards the roller (12) the continuous sheet (8) is being supplied along the horizontal plane, while from the roller the continuous sheet is being supplied along a plane that has an upward inclination relative to the horizontal. This can best be seen in Figure 2 which provides a schematic drawing of only the continuous sheet feed (8) to, and from, the roller (12) of the exemplary embodiment of Figure 1. (For a Easy visualization, the roller is shown in dashed lines, although dust, base, etc. are not shown in the schematic drawing.). Here, the continuous sheet (8) is fed to the roller (12) along a designated plane

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as A and exits the roller along a designated second plane B, and the intersection of these pianos in the roller define a contact angle (a) towards the roller, the angle being approximately 173 ° in the exemplary embodiment .

Again, it is believed that the provision of such a contact angle of less than 180 ° allows a partial wrap around the continuous sheet in the roller providing a force component directly normal to the powder layer on the roller. Furthermore, it is believed that when the continuous sheet passes through a break in the roller, for example a contact angle of less than 180 °, more preferably 177 ° or less, most preferably 175 ° or less, then a force contributes to the filling process. by the tension of the continuous sheet, as a component of the tension of the continuous sheet normal to the dust cover layer on the roller, and that this improves the filling and the stability and reliability of the process. Smaller contact angles generally confer greater stability to the filling process. However, to minimize friction, component wear, and the risk of continuous sheet breakage, desirably, the contact angle is 150 ° or greater, more desirably 160 ° or greater, and the most desirable 170 ° or higher.

It is appreciated that provision of the desired contact angle can be achieved using other continuous sheet supply configurations to, and from, the roller other than those of Figures 1 and 2, which show the continuous sheet being fed to the roller along of a horizontal plane and moving away from the roller along a plane that has an upward inclination in relation to the horizontal. For example, the continuous sheet can be supplied to the roller along a plane that has a downward slope relative to the horizontal (for example in a difference of 4 ° with the horizontal) and supplied from the roller along the horizontal (that is, a difference of 0 ° with the horizontal) or along a plane that has an upward inclination relative to the horizontal (for example a difference of 8 ° with the horizontal) to provide an angle of less 180 ° towards the roller (for example a contact angle of 176 ° or 168 °, respectively). It is possible to supply the continuous sheet from the roller along a plane that has a downward inclination relative to the horizontal (for example, in a difference of 5 ° with the horizontal) when the continuous sheet is supplied to the roller at along a plane that has an inclination downwards with the horizontal at an appropriate inclination (for example in a difference of 15 ° with the horizontal) so that a contact angle of less than 180 ° is provided towards the roller (for example a 170 ° contact angle). Correspondingly, it is also possible to supply the continuous sheet to the roller along a plane that has an upward inclination with respect to the horizontal (for example in a difference of 5 ° with the horizontal), when the continuous sheet is supplied from the roller along a plane that has an upward inclination relative to the horizontal at an appropriate inclination (for example in a difference of 13 ° with the horizontal) so that a contact angle of less than 180 ° is provided towards the roller (for example a contact angle of 172 °).

It will be appreciated that for a powder material since it will be deposited in the microdepressions in a particular continuous sheet, some basic experimentation can be used to determine the appropriate combinations of the process variables such as the separation width, the continuous sheet speed , the surface speed of the roller and the diameter of the roller and, if applicable, the contact angle and the tension of the continuous sheet. For example, for filling with micronized albuterol sulfate powder with an average mass particle diameter of about 2 to 3 microns and with at least 95% of its mass particles having diameters below 5 microns in microdepressions discrete (50 microns deep and 140 microns wide on the upper surface) on a continuous sheet thickness of kraft paper coated with LPDE (low density polyethylene) 0.2 mm thick, using a continuous sheet speed 10 meters per minute together with a 23 mm diameter polished stainless steel roller that rotates with a surface speed of approximately 3.5 times the continuous sheet speed, a separation width of 0.65 mm and an angle of Approximately 171.5 ° contact with the sheet continues to be supplied to the roller horizontally, providing a stable and robust process with adequate precision and uniform filling of the microdepressions.

Aqrn processes suitably include an additional step of removing excess dust not deposited within the depressions from the surface of the sheet and remaining in surface areas between the depressions. Such removal can be achieved for example by using one or more scraper blades to scrape off the residual dust that remains on the surface of the continuous sheet between the depressions. Such scraper blades may be desirably made of metal (for example stainless steel), may be polymeric materials (for example polyethylene) and / or elastomeric materials (thermoplastic or thermosetting elastomeric). Conveniently they comprise flexible rubber sheets of thickness between 1 and 3 mm, supported at an angle to the continuous sheet in motion. An angle between 10 ° and 60 ° with respect to the continuous sheet may be preferable, more particularly between 40 ° and 50 °. Conveniently, the rubber sheets may be held between parallel nested plates, with a portion of their length protruding. A surface cleaning arrangement of rubber scraper blades that is in contact with the upper surface of the continuous moving sheet is shown in the exemplary embodiment of Figure 1. The continuous sheet (8) moves in the direction of the arrow (10) under the two scraper blades (20, 30). Each scraper blade surface cleaner (31), which can be a 1.5 mm thick nitrile rubber sheet and approximately a Shore A hardness of 70, is desirably secured between the nested plates (34, 36) . The plate towards the continuous sheet (34) generally has a bevel, to ensure that it cannot come into contact and damage the continuous sheet. The scraper blade surface cleaner (31) desirably protrudes approximately 3 mm to 6 mm past the end of the plate towards the continuous sheet (34) and approximately

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6 mm past the end of the other plate (36), the plates being at a 45 ° angle with respect to the continuous sheet, and its vertical height in relation to the continuous sheet being chosen to ensure good contact of the cleaning edge ( 32) of the scraper blade surface cleaner (31) with the continuous sheet while avoiding excessive frictional forces on the continuous sheet. However, it will be evident that many alternative configurations can be conceived. Vacuuming of the dust removed from around the edges (32) of the scraper blade surface cleaner (31) can be conveniently used to ensure that the process continues uniformly and consistently to remove excess dust. The collected dust can be recirculated from the front end of the process for the types of dust that are not degraded or altered by the passage through the process. As can be seen in Figure 1, it may be desirable to use a scraper blade (40) on the bottom surface of the continuous sheet to remove any dust that has been left on the bottom surface of the continuous sheet during processing. Two sheets above the continuous sheet, with one below it located between them, have been found to be particularly satisfactory. Their positions and heights can be chosen in a preferred manner to ensure a good contact of the continuous sheet with each one, while maintaining the curvature or deflection of the continuous sheet in a minimum, to avoid large frictional forces and other forces. Generally the full continuous sheet is continuously supplied to, and through the configuration or step of removing excess dust.

If desired and / or necessary, the processes may additionally comprise means for subsequently forming slits and / or cutting the continuous sheet filled with dust to desired widths and / or lengths, for example to provide a tape. Any one of a variety of such means can be employed, such as shear slit formation knives, or crushing slit formation knives or in particular rotating shear slit formation knives. It will be appreciated that such formation of slits and / or cuts can be carried out at the step (s) of the process in line after filling, and typically after removal of excess dust. Alternatively, such slit formation and / or cutting can be performed as a process step (s) outside the line, where for example, the full continuous sheet is stored in a large roll and is transferred to a separate unit for the formation of slits and / or cuts. In both cases, it is desirable that the full continuous sheet be supplied continuously to, and through, the configurations or stages of slit formation and / or cutting.

Preferably, the ratio between length and width is greater than 5: 1, more preferably greater than 10: 1 and most preferably between 100: 1 and 1000: 1. Preferably, the elongated carriers and / or ribbons will have a width of about 0.5 to 3 cm and more preferably about 1 to 2 cm. Continuous filled sheets and / or elongated carriers (for example, in the form of a tape may be arranged wound in a coil or arranged in a roll form.

The processes may also comprise means for controlling the ambient temperature or the relative humidity of the environment in which the application of dust takes place. This could be particularly relevant when moisture sensitive powders are applied to the continuous sheet. Suitably, the continuous sheet filling process could then be performed in a controlled temperature and relative humidity enclosure to accommodate the powder material being used. Such an enclosure could be sized to include only the powder supply and filling equipment, the continuous sheet being supplied to the enclosure through a narrow slit and out to the slit formation knives through another. It could demonstrate the file to fit the air handling and filtration apparatus in the enclosure, in order to protect the operators from the exposure to any harmful dust. In addition, means can be used to control the electrostatic face present in the continuous sheet or in the powder. For example, a deionizing fan, such as those available from 3M Corporation, may be arranged to blow on the continuous moving sheet before it reaches the point of powder supply.

The configurations used to transport the continuous sheet through the process, together with the arrangement of the driven roller of the powder filling stage as well as other structural elements (for example, the solid base and the scraper blades) are generally chosen and suitably to minimize variation in continuous sheet tension across the width of the continuous sheet. Also in the case where in the continuous sheet grooves are formed in elongated carriers, it is desirable to control the tension of such slit-forming carriers, in order to help maintain a uniform tension across the entire continuous sheet plus water above, for example at the point where the continuous sheet is being filled with dust. The means for controlling the tension of the continuous sheet are well known to those skilled in the art. In addition, the curving, bending or wrinkling that go laterally, of the continuous sheet, as well as the excessive continuous sheet edge vibration can be generally avoided by using appropriate configurations of the continuous sheet path and proper control of continuous blade rotation.

Finely divided powders are generally well retained within microdepressions (possibly by a combination of electrostatic attraction, Van der Waals forces, physical attraction and, depending on the configuration of the depression itself, mechanical bonding or welding) so that a layer Cover on the filled micro-depression is generally not necessary to ensure that the powder remains in the microdepressions. However, if desired and / or necessary for the extra protection of the process, it may include covering and / or sealing the surface of the continuous sheet with powder filled microdepressions. This can be achieved by attaching a suitable laminar material to the surface of the continuous sheet. Additionally or

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alternatively, the storage of the continuous sheet or the elongated carrier in a rolled state will affect the sealing of the upper part of the depressions through contact with the rear side of the continuous sheet or the elongated carrier itself on the next round of the roll .

The finely divided powders used in the processes and methods described herein generally have a particle diameter of average mass typically 10 microns or less. More suitably, said average mass diameter is 7 microns or less, even more adequately 5 microns or less, and most suitable, said average mass diameter is between 1 and 3 microns, with at least 90% by mass of particles that have diameters below 5 microns.

The powders may be micronized, for example, using a fluid energy grinding driven by compressed air, such as that shown in "Drug Delivery to the Respiratory Tract" ed. D. Ganderton and T. Jones, publ, Ellis Horwood, Chichester (1987) pages 89-90, or by repeated stage grinding or by using a closed loop grinding system.

The processes and methods described herein are particularly suitable in the filling of continuous laminate and / or the manufacture of elongated carriers filled with biologically active substances, such as drugs, agrochemicals, or cosmetic products. A biologically active substance may, for example, be a drug, a vitamin or a vaccine. The powders used may be a biologically active substance in itself (for example micronized drug particles) or it may be a carrier substance with a biologically active substance incorporated therein (for example, mixtures of micronized drug particles with volume agents of micronized lactose or other excipients, mixtures of more than one micronized drug, sprayed dry drug coated particles, or microcapsules).

In addition, the continuous filled sheets and / or elongated carriers provided by the processes and methods described herein, including small, well-controlled measured amounts of a biologically active substance can be used advantageously as such or as part of delivery systems for administration. of biologically active powder substances orally (for example, using a biodegradable and / or digestible continuous sheet material) or topically (for example provided as part of a medical or surgical tape, sheath, garment and / or bandage) or through transdermial, transnmucosal (eg buccal, sublingual) vaginal, rectal, ocular, auditory delivery for use with humans or animals.

Such prepared filled continuous sheets and / or elongated carriers are well suited for the application of measured amounts of biologically active powdered substances in the field of agriculture, for example growth regulators, pesticides, fungicides or other chemicals.

Continuous filled sheets or elongated carriers provided by the processes described herein are particularly suitable for administration of medicaments for inhalation by a patient. Continuous filled sheets and / or elongated carriers preferably will provide constant release of the medicament when exposed to the force used to spray the medicament. In a preferred embodiment of an aerosol device, the finely divided medicament (for example micronized) is sprayed in a state not agglomerated by the impact of the back side of the sheet material. Suitable devices for spraying the medicament are described in US Patent Nos. 5,408,994 and 5,619,984, incorporated herein by reference. Other suitable devices that employ non-impact means for spraying the medicament from continuous filled sheets and / or elongated carriers are described in US Patent No. 5,619,984. The filled continuous sheet and / or the elongated carrier will preferably have a tape form that is contained within a cassette and is advanced dose by dose as required by the patient.

Typically, an area of carrier or elongated tape 20 mm in length and 10 mm in achura for a single dose is suitable for use by a dry powder inhaler. Typically, such a dose area could be 200 to 2000 discrete microdepressions, each about 45 microns deep and about 150 microns in diameter. Advantageously, the rows of microdepressions along the longitudinal axis of the elongated carrier or tape are not positioned exactly parallel to the axis, but instead are positioned skewed at a small angle (for example 0.5 ° to 2 ° ) with it, in order to avoid the "quantization effects" caused by lateral variability in the slit formation positions. (The angle of bias can be chosen appropriate to the separation distance of the microdepressions and to the desired slit formation width, so that a total microdepression volume is present in each dose area (for example 20 mm x 10 mm) , regardless of where the slit formation occurs, laterally). For use in dry powder inhalers, preferably, the microdepressions are arranged by embossing by fusion of a layer of low density polyethylene (LDPE) using a roller of photolithographic pattern and engraving or machining with diamantare. Suitably, the aforementioned LDPE layer is arranged in a paper scrape or a laminated paper / LDPE backing (with the paper between the two layers of LDPE).

For administration by inhalation, such medications include any drug or combination of drugs that can be administered by inhalation, that is, a solid or that can be incorporated into a solid carrier. Suitable drugs include those for the treatment of respiratory disorders, for example, bronchodilators, corticosteroids, and drugs for asthma prophylaxis. Other drugs as agents

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anorectic, anti-depressant, anti-hypertensive, anti-neoplastic agents, anti-cholinergic agents, dopaminergic agents, narcotic analgesics, beta-adrenergic blocking agents, prostaglandins,

Sympathomimetics, steroid tranquilizers, vitamins, and sex hormones can be used for administration by inhalation. Similarly, anti-alginates, antibacterials, antibiotics, anti-inflammatories, anti-migraine drugs, anti-peptides, antiviral drugs, cardiovascular drugs, hypoglycemic drugs, immunomodulators, pulmonary surfactants, and vaccines can be used.

It is preferred for inhalation delivery that the medicament used has a potency that allows a single dose to be charged on the continuous sheet and / or the elongated carrier in an area of less than about 25 cm2 and preferably less than about 5 cm2. More preferred is a continuous sheet and / or elongated carrier that contains a drug in such a way and such that between 0.25 and 2.5 cm2, most preferably between 1.5 and 2.25 cm2, of continuous sheet and / or elongated carrier will contain a single dose when used in a device such as that described in US Patent No. 5,408,994 or 5,619,984. Differentially mentioned, since a continuous laminate and / or elongated carrier filled can conveniently carry between about 25 and 500 µg of powder per cm2, the potency of the medicament will preferably be such that a single dose can be carried in the above exposed 0.25 2.5 cm2 of continuous sheet and / or elongated carrier.

Exemplary drugs that can be used for inhalation delivery include but are not limited to: albuterol, terbutaline, fenoterol, metaproterenol, isoproterenol, isoetardin, bitolterol, epinephrine, tulobuterol, bambuterol, reproterol, adrenaline, ipratropium, oxytropia, tiotropium , beclomethasone, betamethasone, flunisolide, budesonide, mometasone, ciclesonide, rofleponide, aminophylline, diphilin, theophylline, sodium chromolin, nedocromil sodium, ketotifen, azelastin, ergotamine, cyclosporine, salmeterol, fluticacaterol, acetaminalcaterolone, prokalcaterolonea, monolitholterolone, acetaminalcaterolone, albuminase, testosterone , zarfilukast, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, prednisone, methylprednisolone acetate, zoleuton, insulin, atropine, prednisolone, benzfetamine, chlorphentermine, amitriptyline, imidrapin, bipreptin, bipreptin, bipreptin, bipretin pentamidine, calcitonin, leuprolide, alpha-1-antitrypsin, interferons, propra nolol, lacicortone, triamcinolone, dinoprost, xylometazoline, diazepam, lorazepam, folic acid, nicotinamide, clenbuterol, ethynyl estradiol, levonorgestrel, and pharmaceutically acceptable salts or esters thereof such as albuterol sulfate, formoterol hydrochloride diphlorate, formoterol hydrochloride Beclomethasone, triamcinolone acetonide, fluticasone propionate, tiotropium bromide, leuprolide acetate and mometasone furoate.

More drugs that can also be supplied by inhalation include but are not limited to aspirin, acetaminophen, ibuporphene, sodium naproxen, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsilate, meperidine hydrochloride, hydrochloride hydrochloride citrate hydroforphine fentanyl, oxycodone hydrochloride, coderna formate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, diamorphine, trolamine salicylate, methadone hydrochloride, methamphenochloride methanochloride butorphanol, salicicato choline, butalbital, phenyltoloxamine citrate, citrate diphenhydramine hydrochloride, cinnamedrine, meprobamate, ergotamine tartrate, propanolol hydrochloride, isometheptene mucate, dichloralphenazone, sumatriptan, rizatriptan, zolmitriptan, zolmitriptan, naratriptan, eletriptan, barbiturates (for example, pen tobarbital, sodium pentobarbital, secobarbital sodium), benzodiazapine (for example, flurazepam hydrochloride, triazolam, tomazeparm, midazilam hydrochloride, lorazepam, buspirone hydrochloride, prazepam, hydrochloride, oxordiapapopazezene dialozepazoeamide, cloazepazepazoeamideamide, cloazepazeze diazepaepazoleamide, chlorazepazepazoeamideamide, clovazepazepazoeamideamide, chlorazepazepazoamideamide, chlorazepazepazoleamide, chlorazepazepazoleamide, chlorapazepazoleamide, chlorazepazepazoleamide, chlorazepazepazoleamide, chlorazepazepazoleamide, chlorazepazezozoazoleamideamide, chlorazepazepoxyl diazepazoleamideamide , prilocarna, xilicama, beta-adrenergic blockers, calcium cove blockers (for example, nifedipine, diltiazem hydrochloride, and the like) nitrates (for example, nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate) hydroxyzine, hydroxyzine hydrochloride, alprazolam, droperidol, halazepam, clormezanone, haloperidol, loxapine succinate, loxapine hydrochloride, thioridazine, thioridazine hydrochloride, thiothiexenne, fluphenazine hydrochloride, fluoroazethazethanorazacenorazine, fluoroazethazethanorazine, fluoroazethazine oxychloroacetoleazethane, fluoroazethazethanorazine, fluoroazethazethanorazine, hydrofluorophazethanorazachlorine, oxychlorine chlorpromazine, perphenazine, lithium citrate, prochlorperazine , lithium carbonate, bretilium tosylate, esmobol hydrochloride, varapamil hydrochloride, amiodaradone, encainide hydrochloride, digoxin, digitoxin, mexyletin hydrochloride, disopyramide formate, procainamide hydrochloride, quinidine polycinidine, quinidine glucine , flecainide acetate, tocainide hydrochloride, lidocaine hydrochloride, penilbutazone, sulindac, penicillamine, salsalate, piroxicam, azathioprine, idomethacin, sodium meclofenamate, golden sodium thiomalate, ketoprofen, auranofin, aurothinopulin, sodictin-threopygine , sodium heparin, warfarin sodium, urokinase, streptokinase, altoplase, aminocaproic acid, pentoxifylline, empirin, ascriptin, valproic acid, sodium divalproate, phenytoin, sodium phenytoin, clonazepam, primidone, phenobarbitol, phenobarbitol, sodium methobarbitol, sodium methobarbitol, sodium , mefobarbital, mefenitoina, fensuximida, parametadiona, etotoina , Phenacemide, secobarbitol sodium, clorazepate dipotassium, trimethadione, ethosuximide, doxepin hydrochloride, amoxapine, trazodone hydrochloride, amitriptyline hydrochloride, maprotiline hydrochloride, phenelzine sulfate, hydrochloride desepramina hydrochloride, nortriptyline, tranylcypromine sulfate, hydrochloride fluoxetine, doxepine hydrochloride, imipramine hydrochloride, imipramine pamoate, nortriptyline, amitriptyline hydrochloride, isocarbozazide, desipramine hydrochloride, trimipramine maleate, protriptyline hydrochloride, hydroxychlorine malehydrochlorine hydrochloride hydrochloride clemastine, azelastine, cyproheptadine hydrochloride, terfenadine citrate, clemastine, triprolidine hydrochloride, carbinoxamine maleate, diphenyl spiraline hydrochloride, phenylamine tartrate, lamivudine, abacavir, acyclovir, ganciclovir, valgancvirate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, valgancrylate, atridolate, valgancrylate, valgancrylate, valgancrylate, atriatin, fordichlorohydrate na, hydrochloride

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tripelenamine, dexchlorpheniramine maleate, metdizaline hydrochloride, trimprazine tartrate, trimetafan camsylate, phenoxybenzamine hydrochloride, pargiline hydrochloride, deserpidine, diazoxide, guanetidine monosulfate, minoxidro, nitroprisamine, albuminase, phenolamine, albuminase reserpine, calcitonin, parathyroid hormone, acitretin, amikacin sulfate, aztreonam, benzidamine, calcipotriol, chloramphenicol, chloramphenicol palmitate, chloramphenicol sodium succinate, ciproflozacin hydrochloride, clindamycin palmitate, clindamycin hydrochloride, methylatronzole phosphate gentamicin sulfate, lincomycin hydrochloride, tobramycin sulfate, tacrolimus, vancomycin hydrochloride, polymyxin B sulfate, sodium colistimethate, colistin sulfate, tetracycline, griseofulvin, keloconazole, interferon gamma, zidovudine, hydrochloride acrylamide , by Isethionate example pentamidine, cephalosporins accessories (eg, cefazolin sodium, cephradine, cefaclor, cephapirin sodium, liothyronine sodium ceftizoxime, cefoperazone sodium, cefotetan disodium, axotil cefutoxime, cefotaxime, cefadroxil monohydrate, ceftazidime, cephalexin, sodium cephalotin, hydrochloride monohydrate cephalexin, cephamandol naphtate, cefoxitin sodium, cefonicide sodium, ceforanide, ceftriaxone sodium, ceftazidime, cefacroxil, cefradine, cefuroxime sodium and the like), penicillins (for example, ampicillin, amoxicillin, penicillin G benzinic ampicilla, malecinic ginazin, potassium benzathic acid, malecinic ampulin, ginazinic potassium, sodinic acid, malecinic acid , penicillin V potassium, piperacillin sodium, oxacillin sodium, bacampicillin hydrochloride, cloxacillin sodium, disodium ticarcillin, azlocillin sodium, carbecillin indanyl sodium, penicillone G potassium, penicillin G procaine, methicillin sodium, similar naphcillin, example naphcillin, naphthromine , erythromycin ethyl succinate, erythromycin stolate, lactobion Arythromycin aether, erythromycin siearate, erythromycin ethyl succinate, and the like), tetracyclines (e.g., tetracycline hydrochloride, doxycycline hyclate, minocycline hydrochloride, GM-CSF, ephedrine, pseudoephedrine, ammonium chloride, example Danazol, testosterone cypionate, fluoxymesterone, ethyl tostosterone, methyltestosterone enanihate, fluoxymesterone, testosterone cypionate), estrogens (for example, estradiol, stropipate, conjugated estrogens), progestins (for example, methoxyprogesterone acetate, norethindin acetate) , humada insulin, purified beef insulin purified thistle, glyburide, chlorpropamide, glipizide, tolbutamide, tolazamide, rosiglitazone, pioglitazone, troglitazone, clofibrate, SODIUM dextrothyroxine, probucol, lovastatin, rosuvastatin, niacin, DNase, anginasa, superoxide dismutase, lipase, calcitonion, alpha-1-antitrypsin, interferons, sense nucleic acid or anti-sense encoding any protein suitable for delivery by inhalation, erythropoietin, famotidine, cimatidine, ranitidine hydrochloride, omeprazole, esomeprazole, lanzoprazole, meclizine hydrochloride, nabilone, prochlorperazine, dimenhydrinate, hydrochloride of promtazinazine, velpentazine, cylethazine, cyclostromedinine, cyclostromedin, cyclostromedin, cyclostromedin, cyclostromedinine , imiquimod or resiquimod. When appropriate, these drugs can be supplied in the form of alternative salts.

The medicament may comprise one or more drugs, which have one or more particle forms, or may include one or more physiologically acceptable or inert excipients.

Claims (13)

5 10 fifteen twenty 25 30 35 40 Four. Five 1. A method for filling a plurality of microdepressions on a main surface of a continuous sheet having said microdepressions having a depth of about 5 to 500 microns, but being less than the thickness of the continuous sheet, and an opening in the surface of the sheet continuous of approximately 10 to 500 microns in width, with finely divided powder, said process comprising: continuously supply the continuous sheet to, and through, a powder filling stage; in the powder filling stage, filling said microdepressions with powder on the surface of the continuous sheet using a driven roller, wherein said roller is rotating about an axis generally transverse to said direction of continuous sheet movement, while the speed of the surface of the roller and the speed of the continuous sheet are different, and where the roller and the continuous sheet are located relative to each other, so that between the upper surface of the continuous sheet and the outer surface of the roller there is a seperation; Y where the powder is supplied either on the continuous sheet upstream of the roller of the powder filling stage or on the roller of the powder filling stage. 2. A method according to claim 1, further comprising the step of removing from said surface of the sheet the excess dust not deposited within the depressions and which remains in the surface areas between the depressions. 3. A method according to claim 1 or 2, further comprising the step (s) of forming slits and / or cutting the full continuous sheet at predetermined widths and / or lengths. 4. A method for manufacturing an elongated carrier with microdepressions containing finely divided powder, said process comprising: providing a continuous sheet comprising a plurality of microdepressions on a main surface of the continuous sheet, said microdepressions having a depth of about 5 to 500 microns, but being less than the thickness of the continuous sheet, and an opening in the surface of the continuous sheet approximately 10 to 500 microns wide, continuously supply the continuous sheet to, and through, the powder filling stage in the powder filling stage, filling the microdepressions on the surface of the continuous sheet with powder using a driven roller, wherein said roller is rotating about an axis generally transverse to said direction of continuous sheet movement, while the speed of surface of the roller and the speed of the continuous sheet are different, and where the roller and the continuous sheet are positioned relative to each other, so that between the upper surface of the continuous sheet and the outer surface of the roller there is a separation; removing from said surface of the continuous sheet in excess of dust that has not filled the microdepressions and that remains in the surface areas between the depressions; and optionally forming slits and / or cutting the continuous sheet at predetermined widths and / or lengths; Y where the powder is supplied, either on the continuous sheet upstream of the roller of the powder filling stage, or on the roller of the powder filling stage. 5. A method according to any preceding claim, in which the roller is rotating in the same direction as the movement of the continuous sheet. 6. A method according to any preceding claim, wherein the speed of the roller surface is greater than the speed of the continuous sheet. 7. A method according to claim 6, wherein the ratio between the surface speed of the roller and the speed of the continuous sheet is 1.1 to 1. 8. A method according to claim 6, wherein the ratio between the surface speed of the roller and the speed of the continuous sheet is at most 10 to 1. 9. A method according to any preceding claim, wherein the separation is 1.25 mm or less. 10. A method according to any preceding claim, wherein the continuous sheet is supplied to the roller generally along a foreground and supplied from the roller generally along a second plane, so that the continuous sheet crosses a break, where the first plane and the second plane define an angle of less than 180 ° towards the roller. 11. A method according to claim 10, wherein the first and second planes define an angle of 150 ° or greater towards the roller. 5 12. A method according to any preceding claim, wherein the powder is supplied on the continuous sheet upstream of the roller or in the roller of the powder filling stage, so that a collection of dust is provided on the continuous sheet upstream and adjacent to the roller. 13. A method according to any preceding claim, further comprising detecting the accumulation of dust in the roller and / or in the continuous sheet upstream of the roller and in response to said 10 detection automatically control the powder supply. 14. A method according to any preceding claim, wherein the powdered substance is a medicament suitable for administration by inhalation.