Inhaler.

Inhalation device, - Inhaleringsanordning.

The present invention relates to an inhalation device by means of which a solid in particulate form, in particular a pharmacologically active substance, can be added to the air inhaled by the user of the inhaler.

Various such inhalers are known and one such is disclosed in German Patent 845385 (equivalent to UK Patent 654860) issued to a company called Abbott Laboratories. In the Tass Abbott device, a solid material in the form of a fine powder is arranged in a capsule with a strainer at the lower end. The capsule is adapted to be inserted into the device so that its lower end protrudes into a chamber which communicates with the air inlet through an inlet pipe bent approximately in the shape of a semicircle. The air outlet is formed by a mouthpiece or the like. A ball is placed in the inlet tube and during inhalation the inhaled air stream moves it towards the end of the inlet tube, causing the ball to strike the capsule and cause a small amount of solid material to fall through the capsule screen and join the air stream.

One major disadvantage of the device just described is that it is only suitable for dispensing a relatively large amount of material, and this means that the material in the capsule must contain a large amount of inert carrier in addition to the active ingredient. This means that many inhalations are required to transfer the amount of such solid material and it may take 5 to 10 minutes for the user to inhale a sufficient amount of air to obtain the required dose of active ingredient. In many cases, this is not acceptable, especially when inhalation is intended to alleviate diseases that require immediate treatment, such as asthma symptoms.

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In addition, due to its shape, the device described above is quite large and heavy and too large to be carried suitably in a bag or pocket, for example. In addition, the user is required to take too many steps to prepare the device for use, i.e. the capsule must be inserted into the device after removing the sieve closing cap (at which point there is a risk of losing solids through the sieve) and the device must be positioned correctly during inhalation.

At this stage, it should be mentioned that other known inhalers have some, though not all, of the disadvantages described above. In particular, all inhalers currently on the market are relatively large in size and, due to their high cost, are all intended for repeated use.

It is an object of the present invention to provide an inhalation device which can be made much smaller than known inhalation devices if desired and which is simple and inexpensive enough to be used only once and then disposed of and to provide a uniform and similar repetitive device. dose.

According to the present invention, there is provided an inhalation device for adding a solid in particulate form to user inhaled air, the device being characterized by a) a body having an inner surface defining an endless path, a suction channel for inhalable air which opens tangentially to the endless path, and an exhaust system for inhaled air, the system communicating with and centrally positioned with respect to the endless path, the air outlet system communicating with the air outlet, wherein inhalation by the user through the outlet causes airflow through the intake duct, the endless path and the air outlet to the outlet; is ranked

9 3 31 in an endless path to circulate it under the influence of an air stream, the solid being intended to contain a pharmacologically active substance which is arranged on said surface of the body or on the surface of the ball.

Said endless orbit is hereinafter referred to as an orbit and is preferably at least approximately circular when viewed from above. Likewise, the air outlet is preferably arranged so that the air exits the orbit in a centrifugal or centripetal direction. The advantages obtained in this way are explained below.

In one embodiment of the invention, the air inlet communicates with the orbit through an air intake duct that opens tangentially to the orbit. However, the air inlet may alternatively open directly into the orbit, in which case the air enters the orbit tangentially by itself. The significance of the air tangential orbital inlet is that it helps to ensure a laminar airflow in the orbit and this in turn is advantageous for providing easy rotation of the ball. If the air entered non-tangentially, turbulence would likely occur and a less effective driving force would be applied to the balloon.

Next, the operating principles of the device, as currently understood, will be explained. However, it is clear that the use of the device does not in any way depend on the correctness of the explanation now presented. The air is brought into the orbit preferably tangentially by suction to the air outlet. This causes the ball to rotate and this ball motion causes a spectrum of mutual movements between the fixed surface of the orbit and the surface of the ball rotating in all directions in space. These mutual movements apply compression and shear! abrasive forces on the material on the surface of the ball, on the surface of the orbit, or between the surfaces of the ball and the orbit, initiating a process of fracture or comminution.

This, in combination, involves an aerosol formation process in which finely ground particulate material is dispersed in the air leaving the orbit through the air inlet, preferably centrally.

At this stage, it is appropriate to note the advantageous effect obtained by causing the exhaust air to flow centrally. Particulate material passing around both the ball and the orbit is subjected to centrifugal forces, while air is forced to leave the orbit centrifugally. This causes a mixing effect between the air and the particles, with the air forcing a certain proportion of the solid particles with it. Furthermore, it can be seen that the opposing centrifugal and centrifugal forces acting on the particles cause a difference between smaller and larger particles, whereby smaller particles are more likely to leave with air flowing centrifugally and larger particles are not as easily entrained. Larger particles then tend to remain in orbit until they grind to a smaller size. One fairly obvious additional benefit of making the exhaust air flow centrally is that this reduces the size of the device and makes it easier to build.

The inhaler device according to the invention allows the administration of a small amount of active ingredients in precise doses.

For this reason, it is unnecessary to dilute the active substance and thus a rapid effect can be obtained in a short time.

The device does not require a separate cartridge or other container of active substance, nor does it require precise setting during use, which makes it simple and safe to handle. Thanks to its almost immediate effect, it is suitable for use in emergencies. The device can be built simply at low cost and from this

9 331 reasons it can be used once and then thrown away.

In addition, the design of the inhaler allows it to be manufactured in a very small size so that the user can carry the inhaler with him at any time.

Instead of one ball, two, three or even more balls can be placed in the orbit. The additional balls form additional friction zones, thus improving the removal of solids. This effect can be further enhanced by giving the balls different diameters.

The diameter of the ball used is preferably 2 to 4 mm, more preferably 3 to 5 mm and most preferably about 4 mm. When multiple balls are used, the above diameter means the diameter of the larger or largest ball.

The solid material to be inhaled is preferably applied in the form of a film to the surface of the ball and / or to the surface of the orbit. The surface of the ball and / or the surface of the orbit is preferably not smooth, in which case a larger amount of substance can be used, the substance can be applied more simply, the film finishes faster when the device is used and the substance is better dispersed in air during use.

In a preferred embodiment, the body of the inhaler consists of a support in which an orbit is formed, a tangential air inlet duct (if used) and an air outlet system centered with respect to the orbit, and a cover plate in which an air inlet and an air outlet are formed. In this embodiment, the air inlet and the air outlet are simply circular air openings in the cover plate. To ensure that microbiological contamination is kept to a minimum until the device is used, the cover plate is preferably itself covered with a pull-out film which closes the air inlet and the air outlet. In order to prevent solid material particles from adhering to the film in the region of the inlet and outlet of the cover plate, which particles may have detached from the surfaces of the ball or orbit during transport or handling, the film is preferably formed to repel such particles in the air inlet and outlet region. For this purpose, the film may be of coated metal, preferably coated aluminum, with the coating located on the side facing the air inlet and outlet. Alternatively, the film may be made entirely of metal, for example aluminum foil, or it may be a laminated film consisting of, for example, laminated paper and aluminum films, or it may be a film coated with a hydrophobic material such as poly tetra fluoroethylene.

The invention will now be further elucidated with reference to the accompanying drawings, in which:

Figure 1 is a schematic side sectional view of a first embodiment of a device according to the invention, the body of which is formed by a support and a cover plate. Figures 2 and 3 show from above a support and a cover plate of the device shown in Figure 1.

Figure 4 is an enlarged section along the line IV-IV in Figure 2.

Figure 5 is a side sectional sectional view of another embodiment of a device according to the invention.

Figures 6 and 7 show a top view of the support and cover plate of the device according to Figure 5.

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Figure 8 is a schematic sectional view of a prototype device according to the invention made for the purposes set out in the text and having a replaceable inner body.

Figures 9 and 10 show the inner body of Figure 8 from the side and from the top, respectively.

Figures 11 and 12 are diagrams of two possible shapes of the orbit of the inhaler that differ from the circular shape.

Figure 13 is a perspective view of another embodiment with a mouthpiece.

The inhaler shown in Figures 1 to 3 has a body consisting of a support 1 and a cover plate 2, the support 1 having a recess which forms an annular, circular orbit 3 for the ball 4 in the body. The support 1 further has a recess which forms an air intake duct 5 opening into the orbit 3. The duct 5 communicates with a circular air opening 6 in the cover plate 2, which opening forms the air inlet of the device. The support 1 is further provided with an air extraction system 7 which establishes a connection between the orbit 3 and the circular air opening 8 formed in the cover plate 2, the latter forming an air outlet of the inhaler. The pull-out membrane 9 sterically closes the inlet and outlet openings 6 and 8. It can be stated that the air intake duct 5 is not as deep as the orbit 3, so that the ball 4 can be sufficiently mechanically guided also in the area where the duct opens into the orbit. The inhalable active substance is preferably drawn as a film on the surface of the ball 4 and / or on the surface of the orbit 3, as will be explained in more detail below.

As shown in Fig. 4, the ball has a certain amount of clearance or clearance with respect to the surface of the track 3, this surface being formed partly by the inner surface of the support 1 and partly by a part of the inner surface of the cover plate 2. The amount of clearance determines the efficiency of the ball's air thrust and how much active substance the air leaving the orbit entrains. Due to the suction of air during the inhalation through the air outlet 8, the air enters the orbit through the suction duct 5 and drives the ball 4 forward. As already stated, due to the movement of the ball, compressive and frictional forces are generated between the surface of the ball and the surface of the orbit, which first detaches the active substance particles from either surface to which the substance is applied and then grinds or disperses these particles. In this way, the fine particles are distributed in the air leaving the orbit through the exhaust system 7 and further through the air outlet 8 to the user.

The centrifugal deaeration system 7 is formed inside the orbit 3 by the free space formed in the central region 10 between the support 1 and the cover plate 2. In the embodiment according to Figures 1-4, the air exhaust system 7 is simply an annular clearance of uniform cross-section, the outer diameter of which is the diameter D of the region 10 and the inner diameter of which is the diameter of the circular air outlet 8.

The ball thrust efficiency or efficiency can be improved by giving the above annular clearance a non-uniform cross-section so that the cross-section is smallest immediately after the point where the suction channel 4 protrudes into orbit (point a in Fig. 2) and increases steadily to its maximum immediately before ) before abruptly returning to the minimum (point c in Figure 2). Such a variation in the cross-section of the air extraction system 7 is easily achieved by the helical or notched structure of the central region 10 of the orbit 3, as will be explained in more detail below with reference to Figs.

In the embodiment shown in Figures 5 to 7, the central region 10 includes a truncated cone-shaped top with a cone angle of 120 °. The upper surface of the truncated cone-shaped part is flush with the upper surface of the boundary point between the support 1 and the cover plate 2. The diameter of the air outlet 8 corresponds to the inner diameter of the orbit 3, i.e. the diameter of the base of the truncated conical portion of the central region 10, thus creating an annular clearance between the lower edge of the air inlet 8 and the truncated conical surface of the central region 10. In the case of the embodiment according to Figures 1-4, the air exhaust system is formed by an annular clearance which is rotationally symmetrical, i.e. the cross-section of the annular clearance is the same at all points.

In a typical practical embodiment of the device shown in Figures 5-7, the inhaler has a length of 50 mm, a width of 22 mm and a height of 4.5 mm. The width of the orbit is 3.1 mm and the diameter of the glass ball used is 3 mm. The diameter of the air outlet 8 is 10 mm and the diameter of the air inlet 6 is 5 mm. Depending on the selected pressure difference and the selected ball tolerance or play, the ball rotation speed is 5-50 Hz, which corresponds to 300 3000 rpm. If the diameter of the ball is preferably 4 mm, the width of the orbit is preferably about 4.3 mm, the other dimensions already mentioned being substantially the same. The same measuring characteristics apply essentially to the embodiment according to Figures 1-4.

From the above dimensional analysis, it can be stated that the device according to the present invention can actually be made very small compared to

9 331 currently available inhalers.

Figure 8 shows a part of a prototype of an inhaler according to the invention formed of three aluminum elements. The three elements are a lower support body 1a and having a circular orbit 3a, an upper cover plate 2a and a circular air opening 8a forming an air outlet, and a replaceable inner body 11 having an upper end 11a forming the center of the orbit 3a. This prototype has been used to test different geometric shapes in the center of the orbit.

As can be seen from Fig. 8, the frustoconical portion 11b of the upper end 11a of the inner body 11 has a helical shape, so that the cross section of the annular clearance 7a forming the centrifugal deaeration system widens immediately from the minimum point immediately after the air intake to the maximum

Referring to Figures 9 and 10 showing the inner body from the side and from above, the manufacture of the above-mentioned helical shape by means of a main milling machine will now be briefly explained. The inner body 11 starts from the shape shown at the top of Fig. 9, which means that the upper end has a cylindrical lower part and a truncated cone-shaped part with a cone angle of 90 ° on it. The inner body 11 is then slowly rotated about its vertical axis and at the same time the milling is slowly moved forward towards the axis of rotation of the inner body. The cutter is a tool with a diameter of about 4-5 mm, and the axis of rotation of the cutter is shown by reference numeral 9 in the inner body.

As a result of the helical shape of the central region of the orbit, the cross-section of the annular air outlet is relatively small in the first pushing phase of the ball, which phase can be considered to extend about 120 ° immediately after the air intake duct opens into the orbit.

During this phase, little air is allowed to flow out of orbit. This is followed by a second phase in which the cross-section of the clearance progressively widens so that more and more air can escape from the annular track. It can be stated that there is no exact distribution point between these two phases because the width of the ring clearance is constantly increasing. During the first stage, an efficient thrust of the ball is achieved, whereby the aim is to achieve the highest possible rotational speed for the ball. During the second stage, the ball continues to push forward, but larger amounts of air disappear from the area in front of the ball and the air entrains the inhalable particulate material. The second step ensures that the desired amount of particulate material is inhaled with acceptably low suction.

It has been found that a slightly non-circular orbit can be useful because the intermittent acceleration effects of the ball tend to improve the release of the active substance from the surface of the ball and / or the surface of the orbit and further improve aerosol formation. These periodic acceleration forces can be obtained by using an elliptical orbit or by using a generally circular orbit with several

2

331 convex or concave notches, the number of which varies, for example, from two to four. In any case, the deviations from the circular shape should not be too great or otherwise the braking effect on the ball will be too great. For elliptical tracks, an ellipticity factor of about 1.25 has proven to be suitable.

Figures 11 and 12 are diagrams showing two examples of circular tracks with convex and concave recesses, respectively. Arrow 13 indicates the air intake orbit. The difference from the circular shape marked with the letter d can be about 1/25 of the diameter of the circular track.

The device of the invention can be used to perform inhalation either orally or nasally. To facilitate the use of the device, an outlet part in the form of a mouthpiece or a nose piece can be attached to the cover plate 2, as the case may be, in connection with the air outlet opening 8. Fig. 13 is a perspective view of a device according to the invention with a mouthpiece shown at 20. In other respects, the device of Fig. 13 is broadly the same as the device of Figs. 5-7, and for this reason, in Fig. 13, the same reference numerals are used as in the previously mentioned figures.

The body of the inhaler according to the invention, i.e. the support 1 and the cover plate 2, can be suitably made of, for example, ABS plastic material, the support being either an injection molded part of plastic granules or a deep-drawn casting formed of heated and molded plastic film. Injection molding is currently a better solution because this method achieves greater accuracy. Alternatively, the body of the inhaler may be formed of a metal, such as aluminum, whereby the desired shape is obtained by stamping or deep drawing.

The support and cover plate can be joined together by several methods depending on the materials used, in which case ultrasonic welding, anode fixing or gluing can be involved.

If gluing is used, the amount of glue, the adhesive application pattern and the contact pressure should be such as to prevent the glue from penetrating the ball web.

The ball can be glass, metal, plastic material, ceramic material, for example alumina.

For the reasons already mentioned, it is advantageous that the surface of the ball and / or the surface of the orbit is not smooth. When glass beads are used, the roughly ground surface gives the desired effect and allows good adhesion of the active substance by applying the substance to it by wetting it with a solution of the active substance and then evaporating the solvent. Next, the method of applying the active substance to the glass beads will be explained in more detail. Alternatively, the surface texture of the ball may be similar to that of a golf ball. If the surface of the orbit is not smooth and the active substance may also have been applied to the orbit, a glass ball can be used for acid treatment.

In addition to the possible surface roughening properties of the surface of the orbit, the surface of the orbit preferably has helical grooves formed therein which extend in the direction of movement of the bullet in the same way as the grooves of firearms. Contact of the ball with the helical track with grooves causes the ball to rotate or spin perpendicular to the direction of movement. This appears to be particularly advantageous for the dispersion of the active substance in air. The helical grooves may be formed in the orbit during the injection molding, deep drawing, stamping or any other process used to form the support.

The ball grinding and dispersing functions are better understood when looking at the dynamic behavior of a moving ball with reference to Figure 4.

1. Due to the centrifugal force, the ball is in rolling contact with the annular outer wall of the orbit 3 (see contact point B). This causes the ball to rotate about axis A.

2. Orbital surface of the helical grooves causing the simultaneous rotation of the ball, for example, the arrow direction about the axis C, which axis extends perpendicularly to the plane of the drawing.

3. The velocity gradient between the surface of the ball and the surface of the orbit increases continuously in the direction of the arrows L, which indicate the air flow towards the centrifugal exhaust system and which results in a good particle / air distribution due to the acceleration forces on the particles.

The inhaler device according to the invention is suitable for the administration of any pharmacologically active substance which can be inhaled and which is absorbed through the mucous membranes of the respiratory tract. The inhaler is specifically designed to treat asthma and bronchitis with substances such as salbutamol, beclomethasone dipropionate, terbutaline and sodium cromoglycate.

There are several ways to add the active ingredient to the inhaler and some of these will be mentioned below.

1. The active ingredient is dissolved in a solvent and the ball is dipped in it. Evaporation of the solvent leaves a film of solid active ingredient.

2. The active substance solution is added to the recess in the support, which forms an orbit. After drying, a film of active substance remains in the well.

After the device, including the ball, has been completely assembled, the active substance is added as a solution to the orbit and, after evaporation, the film formed by the active substance remains on the surface of the orbit and can also remain on the surface of the ball.

4. The substance is added in solid form to the device after assembly. In this case, the particulate matter simply settles on the surface of the orbit without adhering to it in the same way as when it is in the form of a film.

If the active substance is used as a solution and if the body of the inhaler is made of a plastic material, the possibility that the solvent used may cause an interaction between itself and the plastic material, for example by dissolving the plasticizer or plasticizer, must be taken into account. If this is to be expected, a metal coating can be applied to the body of the inhaler by evaporating the solvent to prevent it from attacking it.

Due to the rotation of the ball, the solid particles become finely divided or dispersed and their diameter on leaving the inhalation device is such that your particles become inhaled.^-a reaction ranging in size from 10 to 20 microns. The total amount of active substance removed from the inhalation device depends on the nature of the active substance itself and the dosage requirements. For example, for salbutamol, a typical dose is 200 to 400.

6

As already mentioned, a single inhaler can be equipped with more than one ball. For example, when the orbital width is 3.7 mm, ball pairs with a diameter of 3.5 and 3 mm can be used, and when the orbital width is 4.3 mm, a pair of 4.1 mm and 3.7 mm balls can be used. These dimensions are given as an example only and other dimensions may be used. In each case, the larger ball is the one to which the air applies the main thrust. The smaller ball will be driven forward mainly by hitting together with the larger ball. When two balls are used, both may contain the same active ingredient, but an alternative possibility is that each has a different active ingredient. For example, it is sometimes necessary to co-administer salbutamol and beclomethasone dipropionate, in which case one ball may be coated with one of these materials and the other ball may be coated with the other.

The following are some examples of compositions used to coat salbutamol on glass beads by the solvent method previously described. The mixtures are shown by weight.

<td colspan="4">cents.</td>

<td>Relationship 1</td><td></td><td></td><td></td>

<td>Glass Beads</td><td> 4</td><td>mm</td><td> 59,95</td>

<td>salbutamol</td><td></td><td></td><td> 0,08</td>

<td>ethanol</td><td></td><td></td><td> 39,97</td>

<td>Relationship 2</td><td></td><td></td><td></td>

<td>Glass Beads</td><td> 4</td><td>mm</td><td> 57,49</td>

<td>salbutamol</td><td></td><td></td><td> 0,08</td>

<td>ethanol</td><td></td><td></td><td> 42,43</td>

<td>Relationship 3</td><td></td><td></td><td></td>

<td>Glass Beads</td><td> 4</td><td>mm</td><td> 59,37</td>

<td>salbutamol</td><td></td><td></td><td> 0,08</td>

7

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<td>polyvinylpyrrolidone</td><td> 0,008</td>

<td>ethanol</td><td> 40,542</td>

Relationship 4

<td>Glass balls 4 mm</td><td> 98,96</td>

<td>salbutamol</td><td> 0,17</td>

<td>ethanol</td><td> 0,87</td>

Relationship 5

<td>Glass balls 3 mm</td><td> 95,34</td>

<td>salbutamol</td><td> 0,58</td>

<td>polyvinylpyrrolidone</td><td> 0,58</td>

<td>ethanol</td><td> 3,50</td>

Relationship 6

<td>Glass balls 4 mm</td><td> 82,22</td>

<td>salbutamol</td><td> 1 ,49</td>

<td>polyvinylpyrrolidone</td><td> 1 ,49</td>

<td>ethanol</td><td> 14,80</td>

Relationship 7

<td>Glass balls 4 mm</td><td> 53,91</td>

<td>salbutamol</td><td> 0,09</td>

<td>ethanol</td><td> 46,00</td>

Relationship 8

<td>Glass balls 4 mm</td><td> 95,71</td>

<td>salbutamol</td><td> 0,12</td>

<td>polyvinylpyrrolidone</td><td> 0,07</td>

<td>ethanol</td><td> 4,10</td>

Relationship 9

<td>Glass balls 3 mm</td><td> 91 ,95</td>

<td>salbutamol</td><td> 0,56</td>

<td>polyvinylpyrrolidone</td><td> 0,09</td>

<td>ethanol</td><td> 7,40</td>

ό 9 33'1

<td colspan="3">Relationship 10</td>

<td>Glass balls 4</td><td>mm</td><td> 59,91</td>

<td>salbutamol</td><td></td><td> 0,15</td>

<td>ethanol</td><td></td><td> 39,50</td>

<td>Distilled water</td><td></td><td> 0,40</td>

<td>glycerin</td><td></td><td> 0,04</td>

<td>Relationship 11</td><td colspan="2"></td>

<td>Glass balls 4</td><td>mm</td><td> 59,66</td>

<td>ethanol</td><td></td><td> 39,73</td>

<td>Distilled water</td><td></td><td> 0,40</td>

<td>glycerin</td><td></td><td> 0,06</td>

<td>salbutamol</td><td></td><td> 0,15</td>

<td>Relationship 12</td><td colspan="2"></td>

<td>Glass balls 4</td><td>mm</td><td> 57,31</td>

<td>salbutamol</td><td></td><td> 0,15</td>

<td>Xylitol</td><td></td><td> 1 ,73</td>

<td>Distilled water</td><td></td><td> 2,60</td>

<td>ethanol</td><td></td><td> 37,78</td>

<td>Distilled water</td><td></td><td> 0,38</td>

<td>glycerin</td><td></td><td> 0,05</td>

<td>Relationship 13</td><td colspan="2"></td>

<td>Glass balls 4</td><td>mm</td><td> 73,03</td>

<td>salbutamol</td><td></td><td> 0,18</td>

<td>Xylitol</td><td></td><td> 1 ,70</td>

<td>Distilled water</td><td></td><td> 2,64</td>

<td>ethanol</td><td></td><td> 22,00</td>

<td>Distilled water</td><td></td><td> 0,22</td>

<td>glycerin</td><td></td><td> 0,23</td>

Considerations

1. When mixtures 10 to 13 are used, glycerin acts as an adhesive to improve the adhesion of salbutamol to the beads.

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2. The xylitol contained in mixtures 12 and 13 also acts as an adhesive.

3. The distilled water mentioned in mixtures 10 and 11 and the second amount of distilled water mentioned in mixtures and 13 act as a plasticizer for salbutamol. The former distilled water in mixtures 12 and 13 acts as a solvent for xylitol.

4. When mixtures 1 to 11 were used, salbutamol alone or in combination with an adhesive was dissolved in ethanol and this solution was sprayed with a hand-held spray gun into rotating glass balls in a coating pan. The coated balls were dried at 40 ° C with a hot air blower. Using mixtures 12 and 13, a solution of xylitol and distilled water was sprayed into the balls before the solution of salbutamol and adhesive was fixed in the same manner.

The solvent used to apply the film formed by the active substance to the beads or orbit naturally depends on the nature of the active substance. For example, when the active ingredient is beclomethasone dipropionate, the solvent may be chloroform, methylene chloride, dichloroethane, acetone, methanol, ethyl acetate or methyl isobutyl ketone.