CA2227547A1

CA2227547A1 - Device in inhalers

Info

Publication number: CA2227547A1
Application number: CA002227547A
Authority: CA
Inventors: Kjell Backstrom; Lars Asking; Magnus Jahnsson; Henri Hansson
Original assignee: Individual
Current assignee: AstraZeneca AB
Priority date: 1995-08-10
Filing date: 1996-07-23
Publication date: 1997-02-20
Also published as: CZ38398A3; MX9800826A; PL324865A1; WO1997005917A1; BR9609880A; ID15911A; EE9800042A; IL122760A0; EP0902700A1; SK17198A3; AU6539196A; IS4661A; KR19990036287A; JPH11510411A; AR003078A1; HUP9802454A2; ZA966776B; SE9502799D0; AU703128B2; CN1192702A

Abstract

The present invention relates to an inhalation device comprising means for breaking down aggregates of finely divided powdered medicament having a particle size less than 10 µm to provide a finely divided medicament having a large amount of particles within the respiratory range, i.e. having particle sizes less than 10 µm, said means comprise at least one pair of surfaces in a gas/air flow path, the first surface of the pair providing an inlet surface of a constriction in the gas/air flow path whereby the speed of gas/air passing along the flow path through the constriction is increased, and the second surface of the pair is situated at or near the outlet of the constriction and provides an impact surface so that in use aggregates or particles impact said surfaces, and whereby said first and second surfaces are oriented at different angles to the longitudinal direction of the flow path.

Description

WO 97/05911 pcT~s~6~oas DEVICE IN INHALERS

Technical field of the invention s The present invention relates to an inhalation device comprising means for breaking down aggregates of finely divided powdered m~oAi~m~nt having a particle size less than 10 ~m to provide a finely divided m~ m~nt having a large amount of particles within the res~i,dlo.y range, i.e. having particle sizes less than 10 ~m.

o Back~round to the invention In inhalation therapy it is of utmost importance that the ~ meter of particles of the medicament to be inhaled is less than 10 ~Lm to ensure the adequate penetration of the particles into the bronchial region of the lungs.
IS
For particles having a ~ m~t~r less than 10 ~lm the inltlya licular forces are generally greater than the force of gravity and consequently the material is cohesive. Non-defined agglomerates or aggregates are formed at random when tnis finely divided powdered meAi~ment is h~n~ll~, for in~t~n~e during storage, conveying, sieving, sifting, mixing or grinding.

When using dry powder inhalers and especially breath-~c tll~t~l dry powder inh~l~rs it is therefore illl~JUl l~nl that the inhalation device is provided with means which break down just before or during inhalation the said agglon,.,l~es or aggregates formed from the fimely 2S divided powder into the primary particles having a particles size within the l~ tc, y range, of less than 10 ~Lm, preferably less than S llm.

If the particles are bigger than 10 ~m they will not pe.~ lale to the bronchial region of the lungs but will end up in the oro-laryngeal tract or, if swallowed, in the gastrointestin~l tract where they could lead to unwanted side-effects. Particles could more easily be retained in CA 02227~47 1998-01-20 the device which also leads to a loss of particles which will have a negative effect on the exactness of the doses.

Prior art Means for breaking down agglo~ al~3/ag~ ,gdles of powder created in finely divided powdered n ç~ m~nt~ having a particle size less than 10 ~m are known in the prior art.
One example of such means is described in EP-B-069 715. In this document a rotating, propeller-like device is provided in the air conduit as deagglomeration means. Another o example is describecl in EP-B-237 507, where a stationary deflector device is provided in the mouth-piece and/or the air conduit of a breath-actuated dry powder inhaler having a cont~inçr for multiple doses. These stationary deflector devices will, during inhalation, provide a deaggregating effect as they are constructed to create a turbulent movement in the air flow carrying the subst~nce Due to this turbulent movement the particles will impact on 15 the walls of the air conduit and the deflector devices and collide with each other and in this manner break down into particles within the re*)ildtoly range.

In WO 92/04069 a disposable breath-actuated dry powder inhaler for single use is disclosed.
This inhaler is provided with means for breaking down agglo. .~ tes /aggregates in the air 20 conduit. The deagglomerating means are also in this inhaler constructed to create a turbulent movement in the air flow during inhalation. This is achieved as all of the deagglo.,.~,.alil.g means are consllu-;~d as planar snrf~ces oriented about 30~ relative to the longitudinal direction of the tubular housing of the inhaler.

25 Tests have shown that the above mentioned deaggregation means do not give an op~illlLlln deag~..,gaLion effect. In some cases retention in the inhaler could reach an unacceptable level. This could lead to dirr~ t dosages with different inhalations.

CA 02227~47 1998-01-20 WO 97/05917 PCTfSE96f~1(196g The invention It is therefore an object of the present invention to provide deaggregation means which optimize the deaggregation and which ...i.~i...ise the retentiQn and the flow reci~t~n~e at a s typical gas or air flow rate which depends on the inhalation force of a patient.

According to the present invention there is provided an inhalation device comprising means for breaking down aggregates, the device being characterised in that said means comprise at least one pair of surfaces in a gas/air flow path, the first surface of the pair providing an inlet o surface of a constriction in the gas/air flow path whereby the speed of gas/air passing along the flow path through the constriction is increased, and the second surface of the pair is citu~teA at or near the outlet of the constriction and provides an impact surface so that in use aggregates or particles impact said second surface whereby said first and second surfaces are oriented at dirr~,-cl~ angles to the longit~l-lin~l direction of the flow path and whereby said first and second surfaces are oriented at different angles to the longitu~lin~l direction of the flow path.

Further preferred embo~lirn~ntc and adavantages are clear from the depending claims 2 to 11.

Brief descnption of the drawings The device according to the present invention will now be described by way of example with reference to the appended drawings, wherein Figure 1 shows a l~lcr~ d embodiment of the deaggregation means according to thepresent invention;

Figure 2 shows first deaggregation means according to the invention as shown in figure 1;
30 and CA 02227~47 1998-01-20 W 0 97/05917 PCT/SE96tO0969 Figure 3 shows the two bodies of the second deaggregation means according to theinvention as shown in figure 1.

s ~et~ A de,s~flylion of the drawings It is generally known in powder technology that the breakdown of aggregates formed from powdered substances can be achieved by giving aggregates an acceleration prior to impact with a surface, for example walls placed in the direction of the movement of the aggleg~les.
o When this technology is applied to inhalation materials so-called deaggregation means are placed in the gas/air flow path of the inh~l~tion device. Such deag~,gation means can be provided as walls, as described in the above mentioned documents.

Tests have shown that the breakdown of aggregates into primary particles is related to the positions and angles of said surfaces as well as the tlirnen~ions of the cross sections of gas/air flow path of the inhaler at dirfelent positions. A ylcr~ ,d embodiment of deaggregation means in accordance with the present invention will be described with reference to figures 1, 2 and 3.

The deaggregation means of the present invention are in the prcr~ d embodiment clesign~l to be placed in the gas/air flow path of a unit dose dry powder inhaler but the construction of the deaggregation means could easily be adapted to be placed in the gas/air flow path of any dry powder inhaler having a dose 8 which comprises aggregates of a powdered substance placed in an gas/air flow path 10, an air inlet 5 and an air outlet 6. Said air inlet 5 2S and air outlet 6 are positioned at a distance from each other, whereby the gas/air flow during inhalation will pass in said gas/air flow path between the air inlet and the air outlet thereby lifting the dose so that it-can be carried along by the gas in the gas/air flow. The description of the device is related to this embodiment but this is only given as an example and for the matter of clarity.

WO 97/05917 PCT~E96/00969 s In the preferred embodiment several sets of oblique planar surfaces are provided along the ~ gas/air flow path 10 in the inhaler. The dose 8 is placed in a m~g~7ine (not shown) which could be a unit dose m~g~7inç or a m~g~7ine which could be refilled for the following inhalations.
s Said oblique surfaces provide constrictions in the gas/air flow path which will result in an accel~,laLion of the inh~l~hon gas/air flow and guidance during its passage through the gas/air flow path. The aggregates and/or particles will thereby be forced to impact on the walls and surfaces of the gas/air flow path.

In the ~llef~ ,d embodiments the deaggregation means have substantially two dirr~ t forms and constructions.

As shown in Figures 1 and 2, the first deaggregation means 20 and 30 are formed as pairs of S walls 21a, 21b and 31a, 31b respectively extçn-ling with an angle a, and ab, rt,*,~Li~ely, to the main direction (Arrow A in the figures) of the gas/air flow and the longitl--lin~l centre axis of sylnllltLly of the gas/air flow path 10 and the device seen from the air inlet to the air outlet. Said longitll.1in~1 cenhre axis is marked with X-X in figures 1-3. Preferably said pairs of walls extend from the edges of the housing on both sides of the gas/air flow path symmetrically and are spaced apart so as to provide a passage for the gas/air flow and a restriction in the gas/air flow path. The first pair of walls 21a, 21b are placed ?~dj~cçnt the release area of the dose 8. Said pairs of walls 21a, 21b and 31a, 31b are COIUlC.,L~ to a part 22a, 22b and 32a, 32b respectively being longiLu.lil,al in the main direction A of the gas/air flow. Said longitu~lin~l parts extend parallel to the main direction A of the gas/air flow and 2s are spaced apart so as to provide a passage for the gas/air flow. The other end of said 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 longit~--iin~l part of each dea~ galion means form a quadrangle 20, 30 rt,s~c.,Li~ely. In figures 1 and 2 a preferred embodiment of these first deaggregation means are shown. The angle and form of the walls 23a, 23b and 33a, 33b are only of importance for the construction and geometry of the deaggregation means and the gas/air flow path and is not illl~o~ t for the function of the device. The important feature for the function is the aim to minimise the retention of cubst~n(~e in the gas/air flow path. Therefore any angle and/or forrn of said walls having this function can be used.
s The second deaggregation means 40, 50 are formed as pairs of walls 41a, 41b and 51a, 51b l~,;,~;~ively. The two walls in each pair of walls are co.n.~;l~ to each other and form a tip or point 42, 52 le~e~ ely. Said tip or point 42, 52 is provided in the centre of the gas/air flow path 10 and coincides with the longitudinal axis of syl,~mellr X-X of the gas/air flow o path and also with the main direction A of the gas/air flow seen from the air inlet 5 to the air outlet 6.

In the pl~,f~ ed embodirnent said second deaggregation means 40, 50 are formed as quadrangles being sy,,~ ical around their lon~ihlr~in~il axis Y-Y as can be seen in figures 3. Said quadrangles will thereby be formed so that the longihl*insl axis of each quadrangle will be parallel and in the ~lcÇell~,d embodiment coincide with the longitudinal axis of syllllllclly X-X of the gas/air flow path.

The impaction surface 41a, 41b and 51a, 51b of said deaggregation means are provided at angles ,B and o, rei,~Li~ely, to the main direction A of the gas/air flow and the longih-*in~l axis of syn~ elly X-X of the gas/air flow path and the device seen from the air inlet S to the air outlet 6. The preferred embodiment of the second deaggregation means 40 and 50 are shown in figu,re 3.

25 The first and second deaggregation means 20, 30 and 40, 50 are positioned in the gas/air flow path in a manner which give rise to acceleration areas for the gas/air flow and the aggregates/particles as well as guidance whereby the aggregates and particles are forced to impact on the walls of said deaggregation means.

The form of the deaggregation means has been determined by tests and the most optimal forms for the above mentioned purpose have shown to be the ones represented in figure 1.
The forms of the deaggregation means are also of importance for retention of substance in the gas/air flow path as well as for the gas/air flow recict~n~e of an inhaler in which the dea~alion means are provided. For example if the deag~,galion means are formed as triangles with the tip of the tri~ngles facing the direction of the air flow during inh~l~tion the backside of the means will have a generally flat surface positioned perpendicular to the inhalation air flow. This will give rise to substantial retention.

o The tests have shown that the values of the angles aa, ab and especially the values of the angles ~ and o are of utmost i.~ la~ce for good functioning of the deaggregation means and tnereby the functioning of the inhaler. Several tests have been done with dirr~,r~.~t substances and the values of the angles have been cl.~ t~ infA of an optimi7~tion of the different parameters which influen~es the performance of the gas/air flow during inhalation.
It has thereby been important to minimice retention of substance and the flow resistance as well as maximise the deaggregation at a typical gas/air flow rate which depends on the inh~l~tion force of a patient.

The earlier tests have shown that the aa and ab should be sllbst~nti~lly about 30~ to the main direction of the gas/air flow seen from the air inlet to the air outlet and to a lor gitl-~in~l axis being parallel to the longil...l;..~l axis of s~ y of the device. The choice of 30~ for these angles is dependent on minimicing the flow recict~nce and retention of substance as well as op*micing the accele~ation of the air/gas flow upon entry into the first constriction in the gas/air flow path.

The value of the angle 13 is subst~nti~lly about 4~~ to the main direction of the gas/air flow seen from the air inlet to the air outlet and to the longitll-lin~l axis of the device.

The value of the angle o is ~ubst~3nti~lly about 60~ to the main direction of the gas/air flow seen from the air inlet to the air outlet and to the longitll-~in~l axis of the device.

The choice of these values is based on test results, a ~U~ l~y of which is shown below.

Sumrnary of the results from tests carried out in order to dete~rnine the o~tinlulll values of the an~les ,B and o:
s Several tests have been carried out in order to decide the Op~ ulll values of the angles of the second and third deagglomeration means, i.e. the angles ~ and o. Below a ~ullllncuy of the results from these test are shown in tables.

o In all tests the first angles aa and ab have been kept constant at 30~ in order to provide a smooth entry for the air/gas flow into the air/gas flow path. Tests were carried out using s~lbst~nces having dir~rent plo~c.ties and the sl-t st~nces used in each test is in~lic~teA in the table.

15 In order to be able to compare the results from the dirr~ent tests an index was introduced.
Said index is based on the following calculation:

I = (F +(Re * C) )*10000 20 where I is the Index, F is the fraction of fine particles, Re is the retention in ~,rce.~ge of total dose, and C is the inh~l~tinn recict~nce (C-value). By multiplying the result with 10000 an "easy-to-read" value was provided.
=

Study 1.

Table 1 s In this study one substance - Terbnt~line~ulphate - was used and the aim of the tests was to determine the rel~tion~hip between the values of the angles ,B and S.

TestValue of Value Value Fraction ofRetention Inh~l~tic)n Index No. angles of angle of angle fine (% of resistance ( I ) aa~ ab 13 o particles total (C-value) (F) dose) 30~ 75~ 60~ 44 18 15395 70 2 30~ 45~ 60~ 44 15 14424 89 3 30~ 75~ 21~ 36 18 14765 70 4 30O 45O 21~ 35 14 12488 49 30~ 60~ 30~ 43 21 12825 69 As can be seen test no. 2 with ,13 being 45~ and S being 60~ showed the highest index. On the other hand test no. 4 with 13 being 45~ and S being 21 ~ showed the lowest index. This inriiç?~tes that ,B < S is more favourable then ,B > S.

Study 2.

In this test three different substances was tested Terbut~linçslllrh~te, Budesonide, and Formoterol mixed with Lactose. The aim of the tests was to determine whether an optimum value of the angles could be found in the range 21~ - 75~.

Table 2 Substance: Terbutalinesulphate TestValue of Value Value Fraction of Retention Tnh~l~tion Index No. angles of angle of anglefine (% of total rÇ~icpnre ( I ) aa, ab 13 o particles (F) dose) (C-value) 30~ 21~ 21~ 24 8 10630 71 2 30~ 75~ 21~ 24 11 11110 50 3 30~ 45~ 45~ 32 11 12420 76 4 30~ 21~ 75~ 37 12 13120 86 30~ 75~ 75~ 40 11 14000 107 s Table 3 Substance: Budesonide TestValue of Value Value Fraction of Retentior~ Tnh~l~tion Index No. angles of angle of anglefine (% of total resi.ct~nce ( I ) aa, ab l3 o particles (F) dose) (C-value) 30~ 21~ 21~ 17 12 10630 22 2 30~ 75~ 21~ 22 22 11110 20 3 30~ 45O 45~ 27 17 12420 364 30~ 21~ 75~ 37 28 13120 39 30~ 75~ 75~ 43 31 14000 42 Table 4 Substance: Forrnoterol mixed with Lactose Test Value of Value Value Fraction of Retention Tnh~l~ti~n Index No. angles of angle of angle fine (% of total reci~t~nre ( I ) aa~ ab ~ ~O particles (F) dose) (C-value) 30~ 21~ 21~ 31 16 10630 58 2 30~ 75~ 21~ 42 28 1 1 1 10 58 3 30~ 45~ 45~ 49 21 12420 90 4 30~ 21~ 75~ 51 27 13120 74 30~ 75~ 75~ 63 30 14000 86 s The result of these tests also showed that 13 < o gave a better result than ~ > o . The value of ~ does not influence the result to a signifil~nt extent but the result for 13 = 45~ and ;o =
45~ was beKer than expected. In fact this was the best one for the substance Formoterol rnixed with Lactose.

o The results obtained in the first two studies show that 45~ seem to be the o~ ,um for the angle ,B.

Study 3.

This study was carried out in order to de~ F the upper limit of the value of the angle ~.
The s~h~ es used was conditioned and unconditioned Terbut~lines~ hate CA 02227~47 1998-01-20 Table 5 Substance: conditioned Terbutalinesulphate Test Value of Value Value Fraction of Retention Tnh~l~ti-)n Index No. angles of angle of angle fine (% of total resistance ( I ) aa, ab ~ ~particles (F) dose) (C-value) 30~ 45~ 60~ 49 14 13342 129 4 30~ 45~ 80~ 50 22 15183 75 30~ 45~ 85~ 52 23 15482 76 s Table 6 Sll'ost~nce: unconditioned Terbutalinesulphate TestValue ofValue Value Fraction of Retention Tnh~l~tion Index No. anglesof angle of angle fine (% of total re~ict~nre. ( I ) aa, ab ¦~ o particles (F) dose) (C-value) 30~ 45~ 60~ 53 11 13342 191 2 30o 4So 750 49 12 15502 129 3 30O 45o goo 55 13 15872 147 The result of these tests also showed that the best results are achieved with the values of the o angles ~B and o being 45~ and 60~, respectively.

The results of the above described tests gave the basis for choosing the following values on the angles in the inhalation device according to the present invention:
aa and ab 'oeing 30~.13 being 45~ and o being 60~.

The device according to the invention is simple to produce. It is preferably produced in two pieces, a first substantially flat part and a second part in which the air flow path with the constrictions and the deaggregation parts is formed during a moulding or cold forming procedure. The two parts are then conne~ted to each other in ~ uler that provides a air s tight seal l~l~.~n the two parts. For this purpose heat- or cold-se~ling, laser-welding or ultra sonic welding could be used as well as any other suitable sealing method. The two parts of the device are preferably made of plastic m~teri~l but any other m~t~ori~l in which the required air flow path can be easily formed can be used. The device could also be formed by two identical parts which are se~lingly connected to each other. This is however o a more complicated method.

It is also possible to produce the device in one part whereby injection moulding 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.

20 Thus in the prcf~ ,d embodiment the first and second deagglomer~tion means are formed as quadrangles having the described form. It is however clear that the form of the deagglomeration means can be varied. For example, the "b~ ;de" of the ~ gglom~ration means can have any form which preferably does not give raise to a sig,~ canl re~lction in the speed of the gas/air flow or substantial retention of substance as mentioned above. The 25 second deagglomeration means could for example be formed as fri~ngles or being V-formed whereby the top of the triangle or the tip of the V is placed in the center of the gas/air flow path of the device.

CA 02227547 l998-0l-20 The values of angles a~" ab and 13. o could be changed although the performed tests show that the most optimate value of these angles are the ones as stated above.

Furtholl~lol~, it is easy for the man skilled in the art to realise that the deaggreagtion means s as described above and as cl~im~d in the appended claims can be moflifie~l to be used in any powder inhaler, in particular dry powder inh~lPrs

Claims

1. An inhalation device comprising means (20; 30; 40; 50) for breaking down aggregates of finely divided powdered medicament having a particle size less than 10 µm to provide a finely divided medicament having a large amount of particles within the respiratory range, i.e. having particle sizes less than 10 µm, c h a r a c t e r i s e d in that said means (20; 30; 40; 50) comprise at least one pair of surfaces in a gas/air flow path, the first surface of the pair providing an inlet surface of a constriction in the gas/air flow path whereby the speed of gas/air passing along the flow path through the constriction is increased, and the second surface of the pair is situated at or near the outlet of the constriction and provides an impact surface so that in use aggregates or particles impact said surfaces, and whereby said first and second surfaces are oriented at different angles to the longitudinal direction of the flow path.

2. A device as claimed in claim 1 wherein there is present at least two pairs of said surfaces (40, 50) in series so that aggregates or particles of medicaments i when the device is in use impact upon two impact surfaces situated at or near the outlet of at least two constrictions wherein the volume for the gas/air between the two constrictions is arranged such that the speed of the gas/air along the flow path from the first constriction is reduced before the speed of the gas/air is further increased as a result of passage through the second constriction.

3. Device in inhalers according to claim 2, c h a r a c t e r i s e d in that first deaggregation means (20, 30) are provided as pairs of planar surfaces or walls (21a, 21b; 31a, 31b) extending from the edges of the housing on both sides of the gas/air flow path and oriented at an angle .alpha..alpha.,.alpha.b respectively, relative to the longitudinal direction of the housing (1) seen from the air inlet (5) to the air outlet (6).

4. Device in inhalers according to claim 3, c h a r a c t e r i s e d in that the angle .alpha.a,.alpha.b is preferably substantially about 30°.

5. Device in inhalers according to claim 4, c h a r a c t e r i s e d in that second deaggregation means (40, 50) are provided as pairs of planar surfaces or walls (41a, 41b; 51a,51b) positioned symmetrically around thelongitudinal centre axis of the housing (1) and oriented at angles .beta. and .delta. respectively, relative to the longitudinal direction of the housing (1) seen from the air inlet (5) to the air outlet (6).

6. Device in inhalers according to claim 5, c h a r a c t e r i s e d in that the angle .beta. is preferably substantially about 45° and in that the angle .delta. is preferably substantially about 60°.

7. A device as claimed in any one of the preceding claims which is disposable and substantially made of plastics material.

8. A device as claimed in claim 7, which is a dry-powder inhaler containing at least one dose of a medicament for use in treatment of a disease.

9. A device as claimed in claim 7 or 8, wherein there is a magazine to hold a purality of doses of medicament.

10. A device as claimed in any of claims 7, 8 or 9, wherein the medicament comprises one active ingredient and a carrier therefor.