MXPA98000826A

MXPA98000826A - Inhaled device

Info

Publication number: MXPA98000826A
Application number: MXPA/A/1998/000826A
Authority: MX
Inventors: Hansson Henri; Asking Lars; Bacstrom Kjell; Jahnsson Magnus
Original assignee: Astra Ab
Priority date: 1995-08-10
Filing date: 1998-01-29
Publication date: 1998-04-01

Abstract

The present invention relates to an inhalation device comprising the means for breaking the aggregates of finely divided powdered medicaments having a particle size of less than 10æm, to provide a finely divided medicament having a large number of particles within the range Respiratory, for example having particle sizes less than 10æm, said means comprise at least a pair of surfaces in a gas / air flow path, the first surface of the pair provides an inlet surface of a constriction of the gas path / air, by which the gas / air velocity that passes along the flow path through the constriction is increased, and the second surface of the pair is located at or near the outlet of the constriction, and provides a impact surface so that in the use of aggregates or particles impact the surfaces, and with this the first and second surface ies are oriented to different angles in the longitudinal direction of the flow path

Description

DEVICE FOR INHALERS :A.M? O TECHNI C OF I NVENC ION The present invention relates to an inhalation device comprising means for breaking up aggregates of finely divided powdered medicament, having a particle size of less than 10 μm, to provide a finely divided medicament having a large amount of particles within it. of the respiratory range, for example having particle sizes less than 10 μm.

BACKGROUND OF THE INVENTION In inhalation therapy it is of the greatest importance that the diameter of the medicament particles to be inhaled, is less than 10 μm to ensure adequate penetration of the l 'particles within the bronchial region of the lungs. For particles that have a diameter less than 10 μm, the forces between particles are in the neighborhood greater than the force of gravity, and consequently the material is cohesive. Undefined agglomerates or s are randomly formed REF: 26622 when this drug is handled in finely divided powder, for example, during storage, transportation, sieving, sifting, mixing or milling. When using dry powder inhalers and especially dry powder inhalers powered by breath or breathing, it is therefore important that the inhalation device be provided with means, which break just before or during inhalation the agglomerates or aggregates formed from finely divided powder into primary particles having a particle size within the respiratory range of less than 10 μm, preferably less than 5 μm. If the particles are larger than 10 μm, they will not penetrate the bronchial region of the lungs, but will terminate the oro-laryngeal tract or, if swallowed, in the gastrointestinal tract where they could lead to unwanted side effects. The particles could be more easily retained in the device, which also leads to loss of the particles which will have a negative effect on the accuracy of the doses.

BACKGROUND OF THE INVENTION The means for breaking up the agglomerates / aggregates of powder created in finely divided powdered medicament, having a particle size less than 10 μm, are known in the prior art. An example of such a medium is described in European Patent No. EP-B-069 715. In this document, a rotary propeller-like device is provided in the air duct as the de-agglomeration means. Another example is described in European Patent EP-B-237 507, where a stationary deflector device is provided in the buccal piece and / or the air duct of the dry powder inhaler operated by respiration, which has a container for multiple doses. . These stationary baffle devices, during inhalation, will provide a disaggregation effect, since they are constructed to create a turbulent movement in the airflow that carries the substance. Due to this turbulent movement, the particles will collide on the walls of the air duct and the deflector device, and will collide with each other, and in this way will break into particles within the respiratory range.

In World Patent WO 92/04069, there is disclosed a disposable, dry inhaled powder inhaler for single use. This inhaler is provided with means for breaking the agglomerates / aggregates in the air duct. The deagglomeration media are also in this inhaler built to create a turbulent movement in the air flow during inhalation. This is achieved since all de-agglomeration means are constructed as flat surfaces oriented at approximately 30 ° relative to the longitudinal direction of the tubular housing of the inhaler. Tests have shown that the aforementioned disaggregation means do not give an optimal disaggregation effect. In some cases, retention in the inhaler could reach an unacceptable level. This could lead to different doses with different inhalations.

THE INVENTION Therefore, an objective of the present invention is to provide the unbundling means which optimize the disaggregation and which they minimize retention and resistance to flow at a typical rate of gas or air flow, which depends on the inhalation force of a patient. According to the present invention, there is provided an inhalation device comprising the means for breaking the aggregates, the device is characterized in that the means comprise at least one pair of surfaces in a gas / air flow path, the first surface of the torque provides an input surface of a constriction in the gas-air flow path, whereby the gas / air velocity passing along the flow path through the constriction is increased, and the second The surface of the pair is located at or near the exit of the construction, and provides an impact surface so that in use the aggregates or particles impact the second surface, whereby the first and second surfaces are oriented to different angles to the longitudinal direction of the flow path, and with this the first and second surfaces are oriented at different angles to the longitudinal direction of the flow path . The additional preferred embodiments and advantages are clear from dependent claims 2 to 11.

BRIEF DESCRIPTION OF THE DRAWINGS The device according to the present invention will now be described by way of example with reference to the accompanying drawings, wherein Figure 1 shows a preferred embodiment of the disaggregation means according to the present invention; Figure 2 shows the first disaggregation means according to the invention, as shown in Figure 1; Y Figure 3 shows the two bodies of the second disaggregation means according to the invention, as shown in figure 1.

DETAILED DESCRIPTION OF THE DRAWINGS It is generally known in the technology of powders that the breaking of the aggregates formed from the powdered substances can be achieved by giving the aggregates an acceleration before they make an impact with a surface, for example, the walls placed in the direction of aggregate movement. When this technology is applied to the materials for inhalation, the so-called disaggregation means are placed in the gas / air flow path of the inhalation device. Such disaggregation means can be provided as walls, as described in the aforementioned documents. Tests have shown that the breaking of the aggregates into primary particles is related to the positions and angles of the surfaces, as well as to the dimensions of the cross sections of the gas / air flow path of the inhaler to different positions. A preferred embodiment of the disaggregation means according to the present invention will be described with reference to figures 1, 2 and 3. The disaggregation means of the present invention are in the preferred embodiment designed to be placed in the flow path of gas / air from a unit dose dry powder inhaler, but the construction of the disaggregation means could easily be adapted to be placed in the gas / air flow path of any dry powder inhaler, having a dose which comprises aggregates of a powdered substance placed in a gas / air flow path 10, an air inlet 5 and an air outlet 6.

The air inlet 5 and the air outlet 6 are placed at a distance from one another, by which the gas / air flow during inhalation will pass in the gas / air flow path between the air inlet and the air inlet. air outlet, whereby the dose is raised so that it can be carried along with the gas in the gas / air flow. The description of the device is related to this mode, but this is only given as an example and for clarity purposes. In the preferred embodiment, several groups of oblique planar surfaces are provided along the gas / air flow path 10 in the inhaler. The dose 8 is placed in a reservoir (not shown) which could be a unit dose reservoir or a reservoir which could be filled again for the following inhalations. The oblique surfaces provide constrictions in the gas / air flow path, which will result in an acceleration of the gas / air inhalation flow and guidance during its passage through the gas / air flow path. The aggregates and / or particles will thereby be forced to collide on the walls and surfaces of the gas / air flow path.

In the preferred embodiments, the disaggregation means have substantially two different shapes and constructions. As shown in Figures 1 and 2, the first disaggregation means 20 and 30 are formed as wall pairs 21a, 21b and 31a, 31b, respectively, extending at an angle aa and a respectively to the main direction (Arrow A in the figures) of the gas / air flow, and the longitudinal central axis of symmetry of the gas / air flow path 10 and the device observed from the air inlet to the air outlet. Said longitudinal central axis is marked with X-X in figures 1-3. Preferably, said wall pairs extend from the edges of the housing on both sides of the gas / air flow path symmetrically, and are spaced apart to provide a passage for the gas / air flow and a restriction in the flow path of the gas flow. gas / air. The first pair of walls 21a, 21b are placed adjacent to the dose release area 8. Said wall pairs 21a, 21b and 31a, 31b are connected to a part 22a, 22b and 32a, 32b, respectively which is longitudinal in the main direction A of the gas / air flow. The longitudinal parts extend parallel to the direction main A of the gas / air flow and are separated to provide a passage for the gas / air flow. The other end of the longitudinal parts 22a, 22b and 32a, 32b are connected to a wall 23a, 23b and 33a, 33b, respectively, which together with the first wall and the longitudinal part of each disaggregation means form a quadrangle 20, 30 respectively. In Figures 1 and 2 a preferred embodiment of these first disaggregation means is shown. The angle and shape of the walls 23a ,. 23b and 33a, 33b are only of importance for the construction and geometry of the disaggregation means and the gas / air flow path, and are not important for the function of the device. The important feature for the function is the objective of minimizing the retention of the substance in the gas / air flow path. Therefore, any angle and / or shape of the walls that have this function, can be used. The second disaggregation means 40, 50 are formed as wall pairs 41a, 41b and 51a, 51b respectively. The two walls in each pair of walls are connected to each other and form a point or point 42, 52, respectively. The tip or point 42, 52 is provided in the center of the flow path 10 of gas / air, and coincides with the longitudinal axis of symmetry XX of the gas / air flow path and also with the main direction A of the gas / air flow observed from the air inlet 5 to the air outlet 6. In the preferred embodiment, the second disaggregation means 40, 50 are formed as quadrangles that are symmetrical about their longitudinal axis YY, as can be seen in figure 3. Said quadrangles will be formed with this so that the longitudinal axis of each quadrangle it will be parallel and in the preferred embodiment it will coincide with the longitudinal axis of symmetry XX of the gas / air flow path. The impact surfaces 41a, 41b and 51a, 51b of the disaggregation means are provided at angles ß and d, respectively, to the main direction A of the gas / air flow, and the longitudinal axis of symmetry XX of the flow path gas / air and the device observed from the air inlet 5 to the air outlet 6. The preferred embodiment of the second disaggregation means 40 and 50 are shown in Figure 3. The first and second disaggregation means 20, 30 and 40, 50 are placed in the gas / air flow path in a manner that will give rise to gas / air acceleration areas and the aggregates / particles thus as the guide with which the aggregates and particles are forced to collide on the walls of the disaggregation media. The form of the disaggregation means has been determined by tests, and the most optimal forms for the aforementioned purpose have shown that they are those represented in figure 1. The forms of the disaggregation means are also of importance for the retention of the substance in the gas / air flow path, as well as for the resistance of the gas / air flow of an inhaler in which the disaggregation means are provided. For example, if the unbundling means are formed as triangles with the tip of the triangles facing the direction of the air flow during inhalation, the back side of the media will have a generally flat surface placed perpendicular to the airflow of the air. inhalation. This will give rise to substantial retention. The tests have shown that the values of the angles aa, ab and especially the values of the angles β and d are of the highest importance for the proper functioning of the disaggregation means, and with this the operation of the inhaler. Several tests have been carried out with different substances, and the values of the angles have been determined from a optimization of the different parameters, which influences the operation of the gas / air flow during inhalation. With this it has been important to minimize the retention of substance and the flow resistance, as well as to maximize the disaggregation at a typical gas / air flow rate, which depends on the inhalation force of a patient. The first tests have shown that the angles a3 and b could be substantially from about 30 ° to the main direction of the gas / air flow observed from the air inlet to the air outlet, and to a longitudinal axis which is parallel to the longitudinal axis of the air. symmetry of the device. The choice of 30 ° for these angles is dependent on the minimization of the resistance to flow and retention of the substance, as well as the optimization of gas / air flow acceleration after entry into the first constriction of the gas / air flow path. The value of the angle ß is substantially about 45 ° to the main direction of the gas / air flow observed from the air inlet to the air outlet and to the longitudinal axis of the device. The value of the angle d is substantially about 60 ° to the main flow direction gas / air observed from the air inlet to the air outlet and to the longitudinal axis of the device. The choice of these values is based on the test results, a summary of which is shown below.

SUMMARY OF THE RESULTS FROM THE TESTS CARRIED OUT IN ORDER TO DETERMINE THE VALUES OPTIMAL OF THE ANGLES ß AND d: Several tests have been carried out in order to decide the optimal values of the angles of the second and third means of deagglomeration, for example, the angles ß and d. Below is a summary of the results from this test, in the tables. In all tests, the first angles aa and ou have been kept constant at 30 ° in order to provide a smooth entry for the air / gas flow in the air / gas flow path. The tests were carried out using substances that had different properties, and the substances used in each test are indicated in the table. In order to make it possible to compare the results from the different tests, it was introduced an index. This index is based on the following calculation: I = (F '+ (Re * C) * 10000 where I is the index, F is the fraction of fine particles, Re is the percentage retention of the total dose, and C is the resistance to inhalation (value C). By multiplying the result by 10000 an "easy to read" value was provided.

STUDY 1 TABLE 1 In this study a substance, terbutaline sulfate, was used, and the objective of the tests was to determine the relationship between the values of the ß and d angles.

As can be seen, test No. 2, with ß which is 45 ° and d which is 60 °, showed the highest Index. On the other hand, test No. 4, with ß which is 45 ° and d which is 21 °, showed the lowest index. This indicates that ß < d is more favorable than ß > d.

STUDY 2 In this test, three different substances were tested, terbutaline sulfate, budesonide, and formoterol, mixed with lactose. The objective of the tests was to determine if an optimal value of the angles in the range of 21 ° - 75 ° could be found. TABLE 2 Substance: terbutaline sulfate TABLE 3 Substance: budesonide TABLE 4 Substance: Formaterol mixed with lactose The results of these tests also showed that ß < d gave a better result than ß > d. The value of ß does not influence the result to a significant degree, but the result for ß = 45 ° and d = 45 ° was better than expected. In fact, this was the best thing for the substance formoterol mixed with lactose.

The results obtained in the first studies show that 45 ° seem to be the optimum for the ß angle.that.

STUDY 3 This study was carried out in order to determine the upper limit of the value of angle d. The substances used were conditioned and non-conditioned terbutaline sulfate.

TABLE 5 Substance: Terbutaline sulfate conditioning TABLE 6 Substance: non-conditioned terbutaline sulfate The results of thtests also showed that the best results are achieved with the values of the angles ß and d that are 45 ° and 60 °, respectively. The results of the tests described above gave the basis for the choice of the following values on the angles in the inhalation device according to the prt invention: a3 since they are 30 °, ß which is 45 ° and d which is 60 °.

The device according to the invention is simple to manufacture. This is preferably produced in two pieces, a substantially flat first part and a second part in which the air flow path with the constrictions and the unbundling portions is formed during a molding or cold forming process. The two parts are then connected to each other in a manner that provides an airtight seal between two parts. For this purpose, it could be used in heat or cold sealing, laser welding or ultrasonic welding, as well as any other suitable sealing method. The two parts of the device are preferably made of plastic material, but any other material in which the required air flow path can easily be formed can be used. The device could also be formed by two identical parts, which are sealed to one another. This is however a more complicated method. It is also possible to produce the device in one part, whereby injection molding or blow molding could be used.

MODIFICATIONS The device according to the invention as described above can of course be modified within the scope of the appended claims. Thus, in the preferred embodiment, the first and second deagglomeration means are formed as quadrangles having the described shape. However, it is clear that the form of the deagglomeration means can be varied. For example, the "back side" of the deagglomeration means can have any shape that preferably does not give rise to a significant reduction in gas / air flow velocity or substantial retention of the substance as mentioned above. The second means of deagglomeration could for example be formed as triangles or be V-shaped, whereby the upper part of the triangle or the tip of the V is placed in the center of the gas / air flow path of the device. The values of the angles aa, otb and ß, d could be changed although the tests performed show that the most optimal values of thangles are those as previously established.

Furthermore, it is easy for the person skilled in the art to realize that the means of disaggregation as described above and as claimed in the appended claims, could be modified to be used in any powder inhaler, in particular dry powder inhalers. .

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS 1. An inhalation device comprising means for breaking aggregates of finely divided powdered medicament, having a particle size of less than 10 μm, to provide a finely divided medicament having a large number of particles within the respiratory range, for example having particle sizes less than 10 μm, characterized in that the media comprises at least one pair of surfaces in a gas / air flow path, the first surface of the pair provides an inlet surface of a constriction in the gas flow path / air, by which the velocity of the gas / air passing through the flow path through the constriction is increased, and the second surface of the pair is located at or near the outlet of the constriction, and provides an impact surface so that in use the aggregates or particles collide with said surfaces, and with this the first and second surfaces are oriented at different angles to the longitudinal direction of the flow path.
2. A device according to claim 1, characterized in that they are present at least two pairs of said surfaces in series, so that aggregates of drug particles when the device is in use, impact impact surfaces located on or near the outlet of at least two constrictions, wherein the volume The gas / air between the two constrictions is accommodated such that the gas / air velocity along the flow path from the first constriction is reduced before the air gas velocity is further increased as a result of the passage through of the second constriction.
3. The device for inhalers according to claim 2, characterized in that the first disaggregation means are provided as pairs of surfaces or flat walls extending from the edges of the housing on both sides of the gas / air flow path and oriented towards an angle a ,, ar, respectively, in relation to the longitudinal direction of the housing, observed from the entrance of air towards the air outlet.
4. The device for confound inhalers with claim 3, characterized ? - > because the angle a-, ac is preferably substantially from 30 °. ? The device for inhalers according to claim 4, characterized in that the second disaggregation means are provided as pairs of surfaces or flat walls placed symmetrically around the longitudinal central axis of the housing, and oriented at angles ß and d respectively, with respect to the direction longitudinal of the housing observed from the air inlet towards the air outlet. c. The device for inhalers according to claim 5, characterized in that the angle ß is preferably substantially about 45 ° and because the angle d is preferably substantially about 60 °. 7. A device according to any of the preceding claims, characterized in that it is disposable and substantially elastically clastic material. 8. A device according to claim 7, characterized in that it is a dry powder inhaler containing at least one dose of a medicament for use in the treatment of a disease. 9. A device according to claim 7 or 8, characterized in that there is a reservoir for retaining a plurality of medicament doses. 10. A device according to any of claims 7, 8 or 9, characterized in that the medicament comprises an active ingredient and a carrier therefor.