Patent Publication Number: US-7708014-B2

Title: Inhalation device for transpulmonary administration

Description:
TECHNICAL FIELD 
   The present invention relates to a self-inhaling type inhalation device for transpulmonary administration. 
   BACKGROUND OF THE INVENTION 
   Such inhalation devices are provided with a chamber for containing a pharmaceutical composition, and are configured in such a way that outside air is introduced to the chamber by the inhalation-induced pressure of a user (patient) to apply an air-generated impact to the pharmaceutical composition, thus pulverizing the pharmaceutical composition into fine particles so that the user (patient) can inhale the pulverized pharmaceutical composition into the lungs from the mouth-side flow path (disclosed in Japanese Unexamined Patent Application No. 1999-221280, for example). 
   Such an inhalation device disadvantageously places a burden on users (patients) who have reduced pulmonary capacity or children (patients) when generating the air impact with his/her inhalation-induced pressure. 
   This burden on the user can be reduced by providing an auxiliary flow path which directly reaches the mouth-side flow path of the mouthpiece, not via the chamber, so that he/she can inhale outside air which is not used for applying air impact to the pharmaceutical composition (hereinafter, referred to as auxiliary air). This auxiliary air also serves to efficiently deliver the generated fine particles to the lungs. 
   However, because fine particles easily coalesce/agglomerate, they tend to form coalesced or agglomerated masses due to disturbances in the air flow within the mouth-side flow path of the mouthpiece that are caused when the auxiliary air is mixed with air containing the pulverized pharmaceutical composition. Thus, some of the pulverized pharmaceutical composition does not reach the user&#39;s (patient&#39;s) lungs and adheres to his/her throat. 
   The pulverized pharmaceutical composition is partially dispersed in the form of agglomerated masses of fine particles when the air-generated impact applied to the pharmaceutical composition is insufficient. 
   In view of the above-described problems, the present invention provides an inhalation device for transpulmonary administration which can prevent agglomerated masses of fine particles of the pharmaceutical composition from entering the user&#39;s (patient&#39;s) mouth. 
   DISCLOSURE OF THE INVENTION 
   According to one aspect of the present invention, an inhalation device for transpulmonary administration comprises; a chamber for containing a pharmaceutical composition which is pulverized into fine particles by an air-generated impact for dispersal in air; an air inlet flow path for introducing to the chamber outside air to apply the air-generated impact to the pharmaceutical composition and for injecting the outside air toward the pharmaceutical composition; an inhalation flow path having a suction port located inside the chamber to inhale the pulverized pharmaceutical composition; a housing for accommodating the chamber, the air inlet flow path, and the inhalation flow path; a mouthpiece provided at one end of the housing, the mouthpiece being provided with a mouth-side flow path which communicates with the inhalation flow path, and an auxiliary flow path for directly inhaling the outside air which does not communicate with the inhalation flow path and the mouth-side flow path; wherein the inhalation device for transpulmonary administration is configured such that the air-generated impact is applied to the pharmaceutical composition by the outside air which flows into the chamber by inhalation-induced pressure generated when a user (patient) inhales air, and the pulverized pharmaceutical composition is introduced to the mouth-side flow path, and at the same time the outside air is directly introduced to the auxiliary flow path by the inhalation-induced pressure. 
   According to another aspect of the present invention, an inhalation device for transpulmonary administration comprises: a chamber for containing a pharmaceutical composition which is pulverized into fine particles by an air-generated impact for dispersal in air; an air inlet flow path for introducing to the chamber outside air to apply the air-generated impact to the pharmaceutical composition and for injecting the outside air toward the pharmaceutical composition; an inhalation flow path having a suction port located inside the chamber to inhale the pulverized pharmaceutical composition; a housing for accommodating the chamber, the air inlet flow path, and the inhalation flow path; a mouthpiece provided at one end of the housing, the mouthpiece being provided with a mouth-side flow path which communicates with the inhalation flow path and a divider having an orifice at least one of the mouth-side flow path or the inhalation flow path for reducing the diameter of the flow path by forming a step part; wherein the inhalation device for transpulmonary administration is configured such that the air-generated impact is applied to the pharmaceutical composition by the outside air which flows into the chamber by inhalation-induced pressure generated when a user (patient) inhales air so that the pulverized pharmaceutical composition is introduced to the inhalation flow path and the mouth-side flow path, and also passes through the orifice. 
   It is preferable that a plurality of dividers each having an orifice are provided at appropriately spaced intervals. 
   The mouthpiece has an auxiliary flow path for directly inhaling the outside air which does not communicate with the inhalation flow path and the mouth-side flow path and is preferable to have a configuration such that the pulverized pharmaceutical composition is introduced to the inhalation flow path and the mouth-side flow path, and at the same time the outside air is directly introduced to the auxiliary flow path by the inhalation-induced pressure. 
   According to another aspect of the present invention, an inhalation device for transpulmonary administration comprises: a chamber for containing a pharmaceutical composition which is pulverized into fine particles by air-generated impact for dispersal in air; an air inlet flow path for introducing to the chamber outside air to apply the air-generated impact to the pharmaceutical composition and for injecting the outside air toward the pharmaceutical composition; an inhalation flow path for inhaling the pulverized pharmaceutical composition; a housing for accommodating the chamber, the air inlet flow path, and the inhalation flow path; a mouthpiece provided at one end of the housing, the mouthpiece being provided with a mouth-side flow path which communicates with the inhalation flow path, and an auxiliary flow path for inhaling outside air which is not used for applying air impact to the pharmaceutical composition, and does not flow via the chamber, and furthermore allows the inhaled outside air to flow into the mouth-side flow path through an air outlet which opens into the mouth-side flow path; wherein the inhalation device for transpulmonary administration is configured such that the air outlet allows the outside air to flow in the air discharge direction of the mouth-side flow path and is formed in a ring shape along the inner circumferential wall surface of the mouth-side flow path; and the pharmaceutical composition is pulverized by the air impact generated by the outside air flowing into the chamber by inhalation-induced pressure that is generated when a user (patient) inhales air, and the pulverized pharmaceutical composition flows into the mouth-side flow path surrounded by the outside air flowing into the mouth-side flow path from the ring-shaped air outlet. 
   Preferably, the device is configured such that a divider has an orifice for reducing the diameter of the flow path is formed at the mouth-side flow path; and outside air containing the pulverized pharmaceutical composition passes through the orifice, and thereafter is surrounded by outside air flowing into the mouth-side flow path from the ring-shaped air outlet. 
   Preferably, the device is configured such that a flow-path length of the orifice is formed to be elongated to the air discharge direction of the mouth-side flow path 
   Further, it is preferable that the device comprises the chamber for containing a non-powder cake-like form which disperses in air by an air-generated impact and accommodating a vessel sealed by a sealing member; and an unsealing member for releasing the sealed condition provided by the sealing member; wherein the inhalation device for transpulmonary administration is configured such that the vessel is unsealed by the unsealing member to establish communication between the chamber and the inside of the vessel; and the air-generated impact is applied by the inhalation-induced pressure to the pharmaceutical composition contained in the vessel. 
   Still further it is preferable that the device is constituted to have a check valve to prevent the pulverized pharmaceutical composition from flowing to the outside from the air inlet flow path. 
   According to another embodiment of the present invention, an inhalation device comprises: a main body formed cylindrically; a mouthpiece provided at one end of the main body; a vessel provided at the other end of the main body, the vessel being for containing a pharmaceutical composition which is pulverized into fine particles by an air-generated impact for dispersal in air; an inhalation flow path formed of the inner side space of the main body, the mouth piece and the vessel, the inhalation flow path being for flowing outside air containing the fine particles of the pharmaceutical composition from the vessel-side toward the mouthpiece-side; an air inlet port for introducing the outside air to the inhalation flow path; and a divider for dividing the inhalation flow path, the divider having an orifice for reducing the diameter of the inhalation flow path and being located downstream of the air inlet port; wherein the inhalation flow path has such a capacity that an air-generated impact can be applied to the pharmaceutical composition by the outside air, which is fed from the air inlet port into the inhalation flow path located upstream of the divider by an air inhalation of user. 
   It is preferable that the inhalation device comprises: an air outlet which opens into the inhalation flow path; and an auxiliary flow path for feeding the outside air into the inhalation flow path through the air outlet by the air inhalation of user; wherein the air outlet is provided at such a position that the outside air flowing in from the air outlet is inhaled into the mouth of the user without passing through the orifice. 

   
     BRIEF DESCRIPTION OF DRAWINGS 
       FIG. 1  is a perspective view of an inhalation device according to the first embodiment of the present invention. 
       FIG. 2  is a longitudinal cross section of the inhalation device. 
       FIG. 3  ( a ) is an enlarged longitudinal cross section of the inhalation device. 
       FIG. 3  ( b ) is an enlarged horizontal cross section of the inhalation device. 
       FIG. 4  ( a ) is an enlarged elevation view of the mouthpiece. 
       FIG. 4  ( b ) is an enlarged longitudinal cross section of the mouthpiece. 
       FIG. 4  ( c ) is an enlarged horizontal cross section of the mouthpiece. 
       FIG. 4  ( d ) is an enlarged rear view of the mouthpiece. 
       FIG. 5  is a longitudinal cross section showing the operation of the inhalation device. 
       FIG. 6  is a longitudinal cross section showing the operation of the inhalation device. 
       FIG. 7  is a longitudinal cross section showing the operation of the inhalation device. 
       FIG. 8  is a longitudinal cross section showing the operation of the inhalation device. 
       FIG. 9  is a perspective view of an inhalation device according to the second embodiment of the present invention. 
       FIG. 10  is a longitudinal cross section of the inhalation device. 
       FIG. 11  ( a ) is an enlarged elevation view of the rear divided body that forms part of the mouthpiece of the inhalation device. 
       FIG. 11  ( b ) is an enlarged longitudinal cross section of the mouthpiece. 
       FIG. 11  ( c ) is an enlarged horizontal cross section of the mouthpiece. 
       FIG. 11  ( d ) is an enlarged rear view of the mouthpiece. 
       FIG. 12  ( a ) is an enlarged elevation view of the front divided body that forms part of the mouthpiece. 
       FIG. 12  ( b ) is an enlarged longitudinal cross section of the mouthpiece. 
       FIG. 12  ( c ) is an enlarged horizontal cross section of the mouthpiece. 
       FIG. 12  ( d ) is an enlarged rear view of the mouthpiece. 
       FIG. 13  is an elevation view showing an inhalation device according to the third embodiment of the present invention. 
       FIG. 14  is a cross section taken on line X-X of  FIG. 13 . 
       FIG. 15  is a cross section taken on line Y-Y of  FIG. 13 . 
       FIG. 16  is a cross section showing an inhalation device having an orifice formed at the front side only of the mouthpiece. 
       FIG. 17  ( a ) is a perspective view of an inhalation device according to the fourth embodiment of the present invention. 
       FIG. 17  ( b ) is a cross section showing the inhalation device. 
       FIG. 18  ( a ) is an elevation view of the mouthpiece. 
       FIG. 18  ( b ) is a cross section of the mouthpiece. 
       FIG. 18  ( c ) is a rear view of the mouthpiece. 
       FIG. 19  ( a ) is a plan view of a part of the main body. 
       FIG. 19  ( b ) is a cross section of the main body. 
       FIG. 19  ( c ) is a rear view of the main body. 
       FIG. 20  ( a ) is a cross section of the vessel. 
       FIG. 20  ( b ) is a cross section of the vessel having a greater depth. 
       FIG. 21  is a perspective view illustrating an inhalation device according to another embodiment of the present invention. 
       FIG. 22  is a perspective view illustrating a dry powder inhalation device according to another embodiment of the present invention. 
       FIG. 23  is a perspective view illustrating a dry powder inhalation device according to another embodiment when not in use. 
   

   BEST MODE FOR CARRYING OUT THE PRESENT INVENTION 
   Hereinafter, an inhalation device of the present invention will be described according to its embodiments with reference to drawings attached hereto.  FIGS. 1 through 8  show an inhalation device according to the first embodiment,  FIGS. 9 through 12  show an inhalation device according to the second embodiment, and  FIGS. 13 through 16  show an inhalation device according to the third embodiment. 
   Embodiment 1 
   The inhalation device in this embodiment comprises a needle part  3  (an example of an unsealing member) in which are formed an inhalation flow path  1  and an air inlet flow path  2 , a holder part  5  for containing a vessel  4  which contains one dose of pharmaceutical composition A and is sealed by a stopper  4   a  (an example of a sealing member), a chamber  6  for housing the vessel  4  of the holder part  5 , a guide part  7  for guiding the holder part  5  in the axial direction of the needle part  3 , and a holder operating part  15  for advancing and retreating the holder part  5  along the guide part  7 ; these are all housed in a tubular housing  9 . Moreover, a mouthpiece  10  is provided at a tip of the housing  9 . 
   The pharmaceutical composition A can be pulverized into fine particles having a particle size suitable for transpulmonary administration by an air-generated impact that flows into the vessel. The present embodiment employs a freeze-dried composition, which will be explained in more detail later. 
   As shown in  FIG. 5 , the housing  9  is provided with a housing main body  9 B in which is formed a removal/insertion port  9 A in which the holder part  5  is in a retreated position, and a lid  9 C that opens and closes the removal/insertion port  9 A. The lid  9 C is connected to the housing main body  9 B by a hinge  9 D, and a window  9 E for verifying whether the vessel  4  has been loaded is provided on the lid  9 C. 
   An inlet port  9 F for introducing outside air is provided on a wall of the housing  9 . The inlet port  9 F is equipped with a check valve  9 G for preventing the pulverized pharmaceutical composition A from flowing out. 
   A flange-shaped partition part  3 A is formed at the base end of the needle part  3 , and an end of the air inlet flow path  2  of the needle part  3  opens at an outer wall surface of the partition part  3 A through the inside of the partition part  3 A. Moreover, a peripheral wall part  3 B extends from an outer end part of the partition part  3 A to the front. An engagement hole  3 C is formed at the peripheral wall part  3 B. An engagement projection  3 D is formed at a part inserted into the front from the needle part  3 , and the inhalation flow path  1  opens at the tip portion through the engagement projection  3 D. 
   The needle part  3  is attached to the housing  9  by fitting the partition part  3 A of the needle part  3  into the tip part of the housing  9 . Furthermore, the axial direction of the housing  9  and the axial direction of the needle part  3  are aligned with each other. 
   The mouthpiece  10  is provided with a mouth-side flow path  11  and an auxiliary flow path  12 . More specifically, the mouthpiece  10  consists of the mouth-side flow path  11 , which communicates with the inhalation flow path  1  of the needle part  3  so as to introduce the pulverized pharmaceutical composition A, and the auxiliary flow path  12 , which does not communicate with the mouth-side flow path  11  so as to introduce outside air into the user&#39;s (patient&#39;s) mouth. 
   The mouth-side flow path  11  passes through the mouthpiece  10 . The front end and rear end of the mouth-side flow path  11  open at the front side and the rear side of the mouthpiece  10 , respectively, to form a front opening  11 A and a rear opening  11 B. An engagement concave portion  110  is formed at the rear opening  11 B. As shown in  FIG. 3 , a divider  13  having an orifice  13 A is provided in the mouth-side flow path  11 . The center of the orifice  13 A is positioned at the center of the axis of the mouth-side flow path  11  of the mouthpiece  10 . Suction port  1   a  is part of the inhalation flow path  1 . 
   The auxiliary flow path  12  is formed annularly around the mouth-side flow path  11  as shown in  FIG. 4 . At the rear end of the auxiliary flow path  12  is formed an auxiliary air inlet port  12 C which opens at the rear surface of the mouthpiece  10  so as to introduce outside air. The tip portion of the auxiliary flow path  12  is branched to form a plurality of inhaling branched paths  12 A. These branched paths  12 A open at the front surface of the mouthpiece  10  to form auxiliary openings  12 B. These auxiliary openings  12 B surround the front opening  11 A of the mouth-side flow path  11 . Thus, when a user has the mouthpiece  10  in his/her mouth, the front opening  11 A of the mouth-side flow path  11  and the auxiliary openings  12 B of the auxiliary flow path  12  are located in the user&#39;s mouth. 
   A pair of attachment portions  14  are vertically formed in the mouthpiece  10  extending toward the rear of the mouthpiece  10 , and engagement projections  14 A are formed in each attachment portion  14 . 
   The engagement projection  3 D of the needle part  3  is engaged with the engagement concave portion  11 C of the rear opening  11 B of the mouth-side flow path  11  of the mouthpiece  10  to communicate between the inhalation flow path  1  and the mouth-side flow path  11 . In addition, the pair of vertically provided attachment portions  14  are fitted into the peripheral wall part  3 B of the needle part  3  to engage the engagement projections  14 A of the attachment portions  14  with the engagement holes  3 C formed at the peripheral wall part  3 B of the needle part  3 , thus fixing the mouthpiece  10  to the needle part  3 . 
   The above-described configuration prevents communication between a main flow path, which allows the user to inhale the pulverized pharmaceutical composition A into his/her mouth by the inhalation flow path  1  of the needle part  3  and the mouth-side flow path  11  of the mouthpiece  10 , and a sub flow path, which allows the user to inhale auxiliary air introduced from the auxiliary air inlet port  12 C by the auxiliary flow path  12 . Therefore, the auxiliary air can flow directly into the user&#39;s mouth. 
   The holder operating part  15 , which is another one of the elements constituting the inhalation device, comprises a mechanism  15 A for moving the holder part  5  back and forth along the axial direction of the housing  9 , and an operating lever for operating the mechanism  15 A. The mechanism  15 A has a connector  15 B, one end of which is connected to the holder part  5  by a hinge  5 A, and the other end of which is connected to the lid  9 C by a hinge  91 A. The lid  9 C also serves as the above-mentioned operating lever. By opening and closing the lid  9 C, the holder part  5  is advanced and retreated along the guide part  7 . The holder part  5  is provided with a remover  16  for lifting the vessel  4  from the base thereof to remove the vessel  4 , and a lever  17  for lifting the vessel  4  is formed on the remover  16 . 
   The inhalation device is used as follows. Firstly, the lid  9 C is lifted to open the removal/insertion port  9 A of the housing  9  as shown in  FIG. 5 , whereby the holder part  5  is pulled backward to reach the removal/insertion port  9 A of the housing  9 . Next, the vessel  4  is attached to the holder part  5  with the stopper  4   a  facing forward. Next, the lid  9 C is pushed down to close the removal/insertion port  9 A of the housing  9  as shown in  FIG. 6 , whereby the holder part  5  is pushed toward the needle part  3  by the connector  15 B, and the stopper  4   a  of the vessel  4  is pierced by the tip of the needle part  3 , thus placing the inhalation flow path  1  and the air inlet flow path  2  of the needle part  3  in communication with the inside of the vessel  4 . 
   Subsequently, the user takes the mouthpiece  10  in his/her mouth and inhales air from the vessel  4  through both the mouth-side flow path  11  of the mouthpiece  10  via the inhalation flow path  1  of the needle part  3  by the user&#39;s (patient&#39;s) inhalation-induced pressure. During this process, the inside of the vessel  4  becomes subject to negative pressure and thus the check valve  9 G opens, and outside air flows into the vessel  4  through the air inlet flow path  2  of the needle part  3 . As a result, an air-generated impact is created in the vessel  4 , the pharmaceutical composition A is pulverized into fine particles, and the fine particles are delivered into the user&#39;s (patient&#39;s) lungs from the inhalation flow path  1  and the mouth-side flow path  11 . At the same time, the auxiliary air is directly inhaled into the user&#39;s (patient&#39;s) mouth from the auxiliary air inlet port via the auxiliary flow path  12 . As described above, the auxiliary air is not mixed with air containing the pulverized pharmaceutical composition A flowing through the inhalation flow path  1  and the mouth-side flow path  11 , which prevents the coalescence/agglomeration of fine particles due to the flow of the auxiliary air. By allowing inhalation of the auxiliary air, the inhalation device can thus reduce the burdens on a user (patient) having reduced pulmonary capacity or the burden on a child (patient). 
   Even if the pharmaceutical composition A were to be partially dispersed in the form of agglomerated masses because a user&#39;s (patient&#39;s) inhalation strength is weak, the agglomerated masses would be crushed against the divider  13  located at the periphery of the orifice  13 A in the mouth-side flow path  11  of the mouthpiece  10  and thus dispersed and pulverized into fine particles when the agglomerated masses pass through the orifice  13 A. The agglomerated masses formed when passing through the mouth-side flow path  11  are also dispersed through the divider  13 . 
   The check valve  9 G prevents the pulverized pharmaceutical composition A from flowing to the outside from the inlet port even when the user (patient) erroneously blows air into the vessel  4  from the mouth-side flow path  11  of the mouth piece  10 . 
   After transpulmonary administration is completed, the lid  9 C is lifted to pull the holder part  5  back up to the removal/insertion port  9 A of the housing  9  as shown in  FIG. 7 , and then the remover  16  is lifted by the lever  17  and the vessel  4  is removed from the holder part  5  as shown in  FIG. 8 . 
   When the inhalation device is not being used, the mouthpiece  10  is closed with a cap  18  as shown in  FIG. 1 . 
   As described above, the air flow rate of one inhalation by the user (patient) is generally in the range of 5 to 300 L/min. Considering the possible respiratory ability of the user (patient), the inhalation device of the present invention is set so that the volume of the vessel  4  is about 5 ml, the bore (diameter) of the air inlet flow path  2  is about 2 mm, the bore (diameter) of the inhalation flow path  1  is about 2 mm, and the bore (diameter) of the inhaling branched path is about 1 mm. 
   EMBODIMENT 2 
   An inhalation device of the present embodiment is provided with two dividers  13  and  131  that are formed along the mouth-side flow paths  11  and  111  of the mouthpiece  10  at appropriately spaced intervals as shown in  FIGS. 9 and 10 . The components constituting the device other than the mouthpiece  10  are the same or similar to those of the first embodiment, and thus the same or similar components are designated by the same numerals as in the first embodiment, and their detailed descriptions are omitted here. 
   A single orifice  13 A, the center of which is positioned at the center of the axis of the mouth-side flow path  11  of the mouthpiece  10 , is formed at the divider  13  in the front part of the mouthpiece. A plurality of orifices  13 A are provided at substantially equally spaced intervals at the divider  131  in the rear part of the mouthpiece, as shown in  FIG. 11 . 
   The mouthpiece  10  is comprised of two separable parts: a front part and a rear part. The divider  13  is formed in a front divided body  101  while the divider  131  is formed in a rear divided body  102 . 
   As shown in  FIG. 12 , the front divided body  101  is provided with a mouth-side flow path  11  and an auxiliary flow path  12  as in the mouthpiece  10  of the first embodiment. An engagement concave portion  11 C is formed at a rear opening  11 B of the mouth-side flow path  11 . An engagement concave portion  101 A is formed at an inner wall of the auxiliary flow path  12 . As shown in  FIG. 11 , the rear divided body  102  is configured by integrating an internal tube  102 A containing the mouth-side flow path  111  and an external tube  102 B. The external tube  102 B is provided with engagement projections  102 C and  102 D. 
   The tip of the internal tube  102 A of the rear divided body  102  is fitted to the engagement concave portion  101 C of the front divided body  101  and the engagement projection  102 D of the external tube  102 B is engaged with the engagement concave portion  101 A of the front divided body  101 . This establishes connection between the front and rear divided bodies  101  and  102 . The external tube  102 B of the rear divided body  102  is engaged with the peripheral wall part  3 B of the needle part  3 , the engagement projection  102 C of the external tube  102 B is engaged with the engagement hole  3 C of the peripheral wall part  3 B, and the internal tube  102 A is engaged with the engagement projection  3 D of the needle part  3 . The mouthpiece  10  is thus positioned at the tip of the housing  1 . 
   The inhalation device of the present embodiment is used in the same manner as described above. The auxiliary air is introduced from the auxiliary air inlet port  12 C of the front divided body  101  of the mouthpiece  10  as shown by an arrow in  FIG. 10 . 
   The dividers  13  and  131  are provided at two locations in the mouth-side flow path  11  of the mouthpiece  10 , thus allowing them to expedite the dispersal of agglomerated masses of fine particles of the pharmaceutical composition. Dividers may also be provided at three or more locations. 
   EMBODIMENT 3 
   As shown in  FIGS. 13 through 15 , the mouthpiece  10  is provided with an outer shell  10 A, a tubular internal member  10 C having a divider  10 B, and a dividing block  10 D. The composition of the inhalation device other than the mouthpiece  10  is the same as in the first embodiment, and their detailed descriptions are omitted here. 
   The mouthpiece  10  is assembled by fitting the internal member  10 C into the outer shell  10 A from the rear, and fitting the dividing block  10 D into the internal member  10 C from the rear. A plurality of spacers  101 C project along an outer circumferential surface of the internal member  10 C of the rear side at predetermined spaced intervals in the circumferential direction. A step part  101 A is formed at an inner circumferential surface of the outer shell  10 A throughout its length in the circumferential direction. The spacers  101 C are fitted into the step part  101 A of the outer shell  10 A, and thus a cylindrical space is formed between the outer shell  10 A and the internal member  10 C, to be served as an auxiliary flow path  12 . 
   A ring-shaped air outlet  12 D is formed at a tip part of the auxiliary flow path  12 . The air outlet  12 D is located in the midway of the mouth-side flow path  11  and allows the outside air to flow in the air discharge direction of the mouth-side flow path  11 . The auxiliary air introduced from the auxiliary air inlet port  12 C flows into the auxiliary flow path  12  through the spaces formed between the spacers  101 C, and flows into the mouth-side flow path  11  in a ring form from the air outlet  12 D through the auxiliary flow path  12 . 
   The divider  10 B and the dividing block  10 D of the internal member  10 C are provided with a plurality of orifices  10 E and  10 F, respectively which are provided at substantially uniformly spaced intervals. The dividers  10 B and the dividing block  10 D of the internal member  10 C are enlarged in thickness, which elongates the orifices  10 E and  10 F to the air discharge direction. The orifices  10 E and  10 F are not to be located forward of the air outlet  12 D. 
   The inhalation device of the present embodiment is used as follows. The inhalation flow path  1  and the air inlet flow path  2  of the needle part  3  are communicated with the inside of the vessel  4  as described in the above. A user (patient) takes the mouthpiece  10  in his/her mouth for inhalation, and thus the auxiliary air flows into the auxiliary flow path  12  from the auxiliary air inlet  12 C, and then flows out in a laminar flow from the air outlet  12 D into the mouth-side flow path  11 . The pharmaceutical composition is pulverized into fine particles by air impact generated by outside air flowing from the air inlet flow path  2  of the needle part  3 . The outside air containing fine particles of the pharmaceutical composition flows into the mouth-side flow path  11  from the inhalation flow path  1 , and passes through the orifices  10 E, and thereafter flows out from the front opening  11 A of the mouthpiece  10  with surrounded by the auxiliary air flowing out from the air outlet  12 D. Thus, the outside air containing fine particles of the pharmaceutical composition is prevented from disturbing, which can suppress dispersal of fine particles of the pharmaceutical composition. 
   The mouthpiece  10  is set so that the auxiliary air flows into the mouth-side flow path  11  from the air outlet  12 D before the outside air containing fine particles pass through the orifices  10 E. Thus, the outside air containing fine particles are surely surrounded by the auxiliary air in a laminar flow. 
   The auxiliary air avoids the outside air containing fine particles from contacting inner circumferential wall surface of the mouth-side flow path  11 , which prevents the fine particles of the pharmaceutical composition from adhering to the wall surface of the mouth-side flow path  11  or the like even if the mouthpiece  10  is formed of a material such as a plastic which is likely to have static electricity. 
     FIG. 16  shows an inhalation device having a plurality of orifices  10 E formed at the front side only of the mouthpiece  10 . 
   EMBODIMENT 4 
   As shown in  FIGS. 17 through 20 , the inhalation device is provided with a main body  100   a , a mouthpiece  100   b  and a vessel  100   c  for containing pharmaceutical composition A which is pulverized into fine particles by an air-generated impact for dispersal in air. 
   As shown in  FIG. 18 , the mouthpiece  100   b  is formed cylindrically, and a dividing part  100   e  inside the mouthpiece  100   b  is formed by a dividing member  100   d . A plurality of orifice  100   f  is provided on the disc-shaped dividing member  100   d , and notches  100   g  are formed at the outer circumferential surface of the dividing member  100   d . Due to the notch  100   g , an auxiliary flow path  100   h  for inhaling an auxiliary air into the mouthpiece  100   b  is formed between the mouthpiece  100   b  and the dividing member  100   d . An air inlet port  100   i  is provided at one end of the auxiliary flow path  100  and an air outlet  100   j  at the other end of the auxiliary flow path  100   h . As described in the above Embodiment 3, the air outlet  100   j  may be formed into a ring shape. 
   As shown in  FIG. 19 , the main body  100   a  is formed cylindrically, and a notch  100   m  for forming an air inlet port  100   k  is provided at the end of the main body  100   a.    
   As shown in  FIG. 20 , the vessel  100   c  is formed cylindrically and has a bottom part  100   p.    
   The inhalation device is assembled by attaching the mouthpiece  100   b  to one end of the main body  100   a  and by detachably attaching the vessel  100   c  to the other end of the main body  100   a . As shown in  FIGS. 20(   a ) and  20 ( b ), the depth of the vessel  100   c  may be changed as appropriate. 
   As shown in  FIG. 17 , the inhalation device is provided with an inhalation flow path  100   q  and a mouthpiece-side inhalation flow path  100   r  for inhaling the outside air containing fine particles of the pharmaceutical composition A, which are formed of the inner side space of the main body  100   a , the mouthpiece  100   b  and the vessel  100   c . The inhalation flow path  100   q  includes the inside space of the vessel  100   c.    
   The capacity of the inhalation flow path  100   q  and the inhalation flow path  100   r  taken altogether is in such an amount that the inhalation flow path  100   q  located upstream of the divider  100   e  is filled with the outside air which is allowed to flow from the air inlet port  100   k  by the inhaled air of a patient so that the air-generated impact can be applied to the pharmaceutical composition A. An example of the capacity is 3 to 100 ml. If necessary, the inhalation device can be downsized to almost the same size as, or smaller than, a cigarette. For example, the inhalation device may have a total length of 80 mm, an outside diameter of 10 mm, and an inside diameter of 8 mm. 
   The inhalation device of the present embodiment can be constituted only by joining the main body  100   a  in cylinder form, the mouthpiece  100   b  and the vessel  100   c  of the pharmaceutical composition A, and providing the air inlet port  100   k  of the outside air and the dividing part  100   e  having the orifice  100   f . Thus the inhalation device can be downsized to almost the same size as, or smaller than, a cigarette, and become less prone to being out of order due to its simple structure. 
   The pharmaceutical composition A is sealed in the vessel  100   c  by filing up an opening  100   s  of the vessel  100   c  with a sealant. At the use of the inhalation device, the vessel  100   c  is attached to the main body  100   a  after removing the sealant. The sealant may be made of aluminium, plastic and the like. 
   The inhalation device provided with the vessel  100   c  may be stored in a moisture-proof case or a moisture-proof bag and may be taken out therefrom at the time of use. A sealant is necessary in this case. 
   The inhalation device according to the invention is used as follows. The inhalation flow path  100   q  is filled with the outside air due to an air inhalation of patient, so that the pharmaceutical composition A can be pulverized by the air impact. The outside air containing the fine particles of the pharmaceutical composition A is inhaled into the user&#39;s mouth after passing through the orifice  100   f  and then the inhalation path  100   r  inside the mouthpiece  100   b . Agglomerated masses of the pharmaceutical composition A can be dispersed by passing through the orifice  100   f . Due to the inhaled air of patient, the auxiliary air flows into the mouthpiece  100   b  from the auxiliary flow path  100   h , thereby reducing the burden on the patient. 
     FIGS. 21 through 23  show examples of other embodiments. In the inhalation device shown in  FIG. 21 , an operating member  19  is arranged in such a way that it can be rotated in both forward and reverse circumferential directions of the housing  9  as shown by the arrows. The mechanism of the holder operating part, which is not shown in the drawing, is provided with a spiral groove and a follower that engages therewith; when the operating member  19  is rotated forward or reverse, this rotation is converted to a linear movement (back and forth movement) of the holder part  5  in the axial direction of the needle part  3 . The rotation angle of the operating member  19  is substantially 180°. The inhalation devices shown in  FIGS. 22 and 23  are rotatably provided with an annular operating member  19  at the housing  9 . The mechanism of the holder operating part, which is not shown in the drawing, comprises a feed screw; when the operating member  19  is rotated, this rotation is converted to linear movement of the holder part  5  in the axial direction of the needle part  3 . The holder part  5  can be withdrawn from the back of the housing  9 . The other composite parts such as the mouthpiece  10 , are the same as in the first embodiment. 
   Freeze-Dried Pharmaceutical Composition 
   A freeze-dried pharmaceutical composition is prepared in a non-powder dry form by pouring a solution containing a single effective dose of a drug into a vessel and then freeze-drying it as is. The non-powder-form freeze-dried pharmaceutical composition can be manufactured by a manufacturing method ordinarily used for freeze-dried preparations (freeze-dried pharmaceutical composition), such as an injection that is dissolved at the time of use by selecting a suitable composition (types and amounts of active ingredient and carrier used together with the active ingredient) such that the disintegration index of the freeze-dried pharmaceutical composition prepared is 0.015 or more, and the freeze-dried pharmaceutical composition can be made into fine particles down to a particle diameter suitable for transpulmonary administration by the impact of outside air introduced into the vessel. 
   The disintegration index in the present invention is a value particular to the freeze-dried pharmaceutical composition that can be obtained by measuring the composition according to the following method. 
   &lt;Disintegration Index&gt; 
   0.2 to 0.5 ml of a mixture containing target components that will constitute the freeze-dried composition is poured into a vessel having a trunk diameter of 18 mm or 23 mm, and is subjected to freeze-drying. Next, 1.0 ml of n-hexane is instilled gently down the wall of the vessel onto the non-powder-form freeze-dried pharmaceutical composition obtained. The mixture is agitated for about 10 seconds at 3,000 rpm, and is then put into a UV cell with an optical path length of 1 mm and an optical path width of 10 mm, and the turbidity is measured immediately at a measurement wavelength of 500 nm using a spectrophotometer. The measured turbidity is divided by the total amount (weight)) of the components constituting the freeze-dried pharmaceutical composition, and the value obtained is defined as the disintegration index. 
   Here, an example of the lower limit of the disintegration index of a freeze-dried pharmaceutical composition of the present invention can be given as the above-mentioned 0.015, preferably 0.02, more preferably 0.03, yet more preferably 0.04, still more preferably 0.05, and most preferably 0.1. Moreover, there is no particular restriction on the upper limit of the disintegration index of the freeze-dried pharmaceutical composition of the present invention, but an example can be given as 1.5, preferably 1, more preferably 0.9, yet more preferably 0.8, and still more preferably 0.7. The freeze-dried pharmaceutical composition of the present invention preferably has a disintegration index in a range including lower and upper limit selected as appropriate from the above, provided that the disintegration index is at least 0.015. Specific examples of the range of the disintegration index are 0.015 to 1.5, 0.02 to 1.0, 0.03 to 0.9, 0.04 to 0.8, 0.05 to 0.7 and 0.1 to 0.7. 
   Moreover, it is preferable to prepare the freeze-dried pharmaceutical composition of the present invention in a non-powder cake-like form through freeze-drying drying. In the present invention, ‘non-powder-form freeze-dried pharmaceutical composition’ means a dry solid obtained by freeze-drying a solution, and is generally called a ‘freeze-dried cake’. However, even if cracks appear in the cake, the cake breaks into a plurality of large lumps, or part of the cake breaks into a powder during the freeze-drying process or during subsequent handling, this cake is still included as a non-powder-form freeze-dried pharmaceutical composition that is the subject of the present invention, provided the effects of the present invention are not impaired. 
   As described above, the freeze-dried pharmaceutical composition of the present invention has a disintegration index of 0.015 or more and a non-powder cake-like form and becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more from an air-generated impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec based on the specific property particular to the freeze-dried pharmaceutical composition characterized by the above-described disintegration index. 
   A preferable freeze-dried pharmaceutical composition is such that, from the above air-generated impact, the mean particle diameter becomes 10 microns or less and preferably 5 microns or less or the proportion of effective particles (fine particle fraction) of 10% or more, preferably 20% or more, more preferably 25% or more, still more preferably 30% or more, and most preferably 35% or more. 
   As described above, the air-generated impact applied to the freeze-dried pharmaceutical composition is not limited, as long as it is generated by air having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec. Specific examples of an air-generated impact include an impact generated by air having a speed of 1 m/sec or more, preferably 2 m/sec or more, more preferably 5 m/sec or more and still more preferably 10 m/sec or more. Here, there is no restriction on the upper limit of the air speed, but it is generally 300 m/sec, preferably 250 m/sec, more preferably 200 m/sec and yet more preferably 150 m/sec. The air speed is not limited and can be selected to be in a range with any of the above-described lower and upper limits; specifically, however, the ranges of 1 to 300 m/sec, 1 to 250 m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200 m/sec or 10 to 150 m/sec can be mentioned. 
   Examples of air-generated impact include those generated by air having an air flow rate of generally 17 ml/sec or more, preferably 20 ml/sec or more and more preferably 25 ml/sec or more. There is no particular restriction on the upper limit of the air flow rate; however, the air flow rate is generally 900 L/min, preferably 15 L/sec, more preferably 5 L/sec, yet more preferably 4 L/sec, and most preferably 3 L/sec. More specifically, the air flow rate is not limited and can be selected to be in a range with any of the above-described lower and upper limits; specifically, however, examples of such a range include 17 ml/sec to 15 L/sec, 20 ml/sec to 10 L/sec, 20 ml/sec to 5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/sec and 25 ml/sec to 3 L/sec. 
   The inhalation device for transpulmonary administration of the present invention is configured as described above and provides various effects as described below. 
   As is evident from the above description, the inhalation device according to the present invention is provided with a mouthpiece having a mouth-side flow path communicating with an inhalation flow path, and an auxiliary flow path for directly inhaling outside air which does not communicate with the inhalation flow path and the mouth-side flow path, and is configured in such a way that outside air is directly introduced to the auxiliary flow path by the inhalation-induced pressure of a user (patient). Therefore, the auxiliary air does not collide with air containing the pulverized pharmaceutical composition, and thus the fine particles can be prevented from coalescing/agglomerating due to the flow of the auxiliary air. Auxiliary air containing no pharmaceutical composition is inhaled and thus, the air flow rate can be further increased. Therefore, the fine particles that are generated can be efficiently delivered to the lungs. 
   According to the inhalation device of the present invention, at least one of the mouth-side flow path or the inhalation flow path is provided with a divider having an orifice for reducing the diameter of the flow path by forming the step part. Thus, agglomerated masses of fine particles of the pharmaceutical composition passing through the mouth-side flow path of the mouthpiece can be dispersed. 
   Further, a plurality of dividers having an orifice are formed at appropriately spaced intervals, and thus agglomerated masses of the pharmaceutical composition can be further dispersed. 
   Moreover, fine particles can be prevented from coalescing/agglomerating due to the flow of the auxiliary air which occurs in the prior art, and further, agglomerated masses of fine particles of the pharmaceutical composition passing through the mouth-side flow path of the mouthpiece can be dispersed. Therefore, agglomerated masses of fine particles of the pharmaceutical composition can be prevented from entering the user&#39;s (patient&#39;s) mouth. 
   According to the inhalation device of the present invention, the pharmaceutical composition pulverized into fine particles by air-generated impact flows in the mouth-side flow path with surrounded by auxiliary air. Thus, the fine particles of the pharmaceutical composition are not dispersed by turbulent flow, and therefore fine particles of the pharmaceutical composition pass swiftly through the mouth-side flow path to reach the inside of lungs, which can avoid fine particles from adhering to throat. Moreover, the fine particles of the pharmaceutical composition can be prevented from adhering to the mouthpiece due to static electricity. 
   The outside air containing pulverized pharmaceutical composition pass through the orifice, and thereafter is surrounded by the auxiliary air. Thus, the auxiliary air is prevented from disturbing by the orifice. 
   Moreover, the flow-path length of the orifice is formed to be elongated to the air discharge direction of the mouth-side flow path. Therefore, the outside air containing the pharmaceutical composition in a turbulent flow is accelerated in the orifices to become a laminar flow. Thus, the outside air containing the pharmaceutical composition is easily surrounded by the auxiliary air. 
   Air containing the pulverized freeze-dried pharmaceutical composition is not mixed with the auxiliary air, and the divider car disperse agglomerated masses of fine particles of the pharmaceutical composition. 
   A check valve is provided for preventing the fine particles from flowing to the outside from the air inlet flow path even when the user (patient) mistakenly blows air instead of inhaling it.