TWI327073B - Dry powder inhale system for pulmonary administration - Google Patents

Description

丄 327073 坎, invention description [Technical Field of the Invention] The present invention relates to a novel έ4 sleeve powder inhalation 适于 suitable for pulmonary administration. More specifically, the present invention relates to a form suitable for transpulmonary two: 1 蜊 by micronization when used in a container 糸=dry composition, and can be directly inhaled and thrown in the form, Powder inhalation system. Further lung administration and drying. Further, the present invention relates to the following technique relating to the dry system for pulmonary administration. Specifically, such techniques are, for example, preparation of a cold-dried composition suitable for pulmonary administration of a particulate powder (dried by a lung to a formulation). The dry powder preparation for pulmonary administration: The method comprises the use of the above-mentioned cold-drying composition for inhalation or (4) blood administration, and the use of the freeze-dried composition when using a dry powder preparation for pulmonary administration. Further, the term "microparticles" as used in the present specification means that it is included in the form of a fine powder, a needle, a plate, or a fiber, as long as it has a fine shape. / [Prior Art] - Generally speaking, it is known that when the lung is administered, the effective particle size of the active ingredient contained in the pharmaceutical product can be made less than 1 micron and preferably 5, and the effective ingredient can be effectively raped. The ground reaches the lungs. Therefore, the current situation is: the prior inhalation of the lungs, in order to prepare the pharmaceutical raw materials in advance for the particle size to be administered by the lungs, and to prepare the particles by spray drying and jet milling, or The processing is carried out, and the bran is collected, and the department then fills it into the inhalation device to provide it. 315314 6 1327073 Specifically, 'Always Steps' a A 4-JL La i There are three types of dry powder-free inhalers known. (1) A preparation in which a powdery composition consisting only of drug particles is filled in a suitable container; (2) Gently granulating the drug particles into a larger particle size and filling the powdered composition into a crying; sputum, sputum, and the smuggled preparation; and (the drug particles and ratio The drug is micro-cluster. The excipient particles (lactose, etc.) of the heart ancestor are uniformly mixed and the powdery composition composed of the obtained mixed particles is filled in a suitable container (for example, refer to the patent of the patent) ;· 1 7 1 7 6 0, etc.). In these documents, δ contains: If these dry powder inhalants are administered into the respiratory tract, ', 円, then the following actions are not included. · (j) The drug particles in the composition will go to the children's snoring, and the children will be in the lower respiratory tract such as the trachea and bronchi. (2) The granulated drug fly rod is named, rock && When Jie Jie rolled Siam, it dissociated into particles, and the generated music particles will arrive and sink in the name. β children in the lower respiratory tract such as rolling officials and bronchial tubes; (3) the excipients are deposited in the mouth due to the head or throat 'only the drug particles reach and sink in the lower respiratory tract such as the trachea and bronchi. As mentioned above, the previous lungs are administered. The inhalation component is preliminarily prepared into a desired powder by using a dry powder inhaler, or the microparticles are processed by any combination method, filled in an inhalation device, and then administered through the lungs. ¥ S The micromolecular drug is micronized, and the spray drying method can be used (for example, JP-A No. 11-1 71760, Rong, Yuelu & _ a, this A-ji Temple) and jet-grinding method (for example, JP-A-2001-151673) No. bulletin, etc.) 箄 复 复 复 ) 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 寺 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复 复The method of micronizing the shovel, the shovel, the _ _, and the knives, and the method of atomizing the drug with low air impact is not known. On the other hand, regarding a polymer drug such as taiyue and protein, there is a known example of 315314 7 1327073. For example, a spray solution of a pharmaceutical stock solution containing an additive is spray-dried by a single bolus to have an average particle diameter of sw. In the method of the first step (spray, remove the particles below the micron' and fill it with the inhalation and the additive - such as W〇95/3 (four), etc., and then fill the V and then the cold; Grinding method, such as Zheng 91/16038, etc.). Double shot grinding is prepared by spray drying or jet milling as shown above. • Lung administration with dry powder inhalers, especially for peptides and protein i:: sub-drugs, is not necessarily ideal. For example: W095/31479 ^ ^, ^ 娆 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰 干扰Reduced activity. Also, for polymer drugs, as with low molecular music, it is impossible to understand the method of micronization by low air impact. Further, in the case of the spray drying method or the freeze drying/jet milling method, it is necessary to reclaim the fine powder from the spray drying device or the jet mill and fill it into a small portion. Therefore, with this operation, problems such as a decrease in the modulation yield due to recovery and filling loss, an increase in cost, and an incorporation of inclusions into the preparation are inevitably caused. Moreover, in a glance, it is difficult to accurately divide the powder into small portions under a small amount. Therefore, it is highly accurate for the spray drying method and the jet milling method which must be filled in a small amount in a powder state. The establishment of a micro-powder filling method is necessary for L. In fact, for example, in the U.S. Patent Gazette No., the system for the powder filling of the fine powder, the skirting method, and the method of the 315314 8 are detailed. [Summary of the Invention] The dry powder is inhaled to solve the problem that the above-mentioned previous lung administration can be used for slowing down the lungs. Specifically, the object of the present invention is to provide a two-in-one formulation system and a delivery system that are contained in a container, wherein the freeze-dried composition is micronized in the container into a particle size suitable for pulmonary administration. And inhaled directly. In order to achieve the discovery, the inventors will do as follows: the eight medicines and the in-depth study of the 'intentional non-page ingredients of the music active substance filled in the container and two, 乂, dry method to prepare the non-powder state The freeze-dried composition, the low-impact air impact, can be directly stored in the container, based on the knowledge, the inventors further studied and found that the container was kept in a non-powder state in the cold; The composition is combined with a device that has an air impact of ====(4), a means for introducing a specific velocity and a flow rate into the valley, and a means for discharging the micronized powder composition from the container. When used (especially when inhaled), the lyophilized non-powder formulation can be simply prepared into a particulate state suitable for administration via the lung, so that by direct inhalation of the microparticles, silicosis can be achieved. Further, the present inventors have found that the composition containing the pharmacologically active substance in the liquid state is not limited to the case where the added component (especially the active ingredient for effective wounding) is clearly dissolved in the solvent or is clearly mixed. Even though these additional ingredients are present in an undissolved or non-dissolved state, the freeze-dried composition suitable for pulmonaryly administered microparticles can be made by specific air impact. Therefore, the present inventors have confirmed that if the dry powder inhalation system is administered by the lung by the 315314 9 1327073, the problem of the dry administration of the powder: inhalation can be completely solved. ~ The above-mentioned "Phase also p according to the present invention, the sputum administration system, 进行 micro-chemicalization and then divided into small parts filled in the container: = = :::, can be applied to the lungs. Also, according to = , , , lung & and the use of dry powder inhalation system, because unlike the protein and peptides in the manufacturing step are the ingredients of the drug 9, and therefore do not have s "昱 + peptides must be exposed to High temperature This astringency causes a problem of reduced pharmacological activity for I. For peptides and proteins such as high-priced drugs, the lungs are administered from an economic point of view. The party is useful. Furthermore, if you follow the = dry powder ί inhalation system, you can get extremely high effective granules 2 = Η, lung Ϊ Ϊ) can efficiently deliver the drug to the lungs. The dry powder inhalation system for pulmonary administration according to the present invention is characterized in that the non-dissolved state composition liquid of the active ingredient is cooled; the cold form composition of the block form of the east end is used as a transpulmonary administration system; The cold-dried composition of the block form of the second and second forms is applied to the dry powder inhalation system of the present invention before drying the powder, and is sprayed or spray dried according to the first inhalation of the inhaler. The method can be obtained by previously granulating the granules to a desired size to be suitable for the application of the powdered preparation administered by the lungs to the dry powder inhalation device of the spleen, and a significantly higher ratio of effective particles can be obtained. Thus, the dry powder inhalation system of the present invention can be placed in a performance-to-performance pulmonary administration system. The present invention is based on the findings of the developer, and includes the following aspects. 315314 10 1327073 (Item 1) A composition for pulmonary administration, which comprises a composition comprising a non-dissolved additive component, which is lyophilized and has the following (i) to (iii) characteristics: (i) having a non-powder block form; (ii) a decay index of 〇.〇5 or more; and (iii) by withstanding an air velocity of up to 1% / 'sec And an air impact of an air flow rate of at least 17 ml/sec may be a particle having an average particle diameter of less than 10 μm or an effective particle ratio of 1% or more. (Item 2) The composition of the cold, the private, the lower, and the upper _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (3rd: Bay)_ A method for producing a dry powder preparation for transpulmonary administration, which is contained in a container of the following cold-drying composition of the trough, which can be used to impart the following air impact to the cold bath in the container. a device for drying a composition, introducing air having the air impact capability', thereby causing the above-mentioned cold-bed-dried composition to form a flat sentence: 仏I 10 μm or less or an effective particle ratio of 10% or more. The composition is prepared by freeze-drying a composition liquid containing an additive component in an undissolved state, and has the following (1) to (iii) (1) a non-powder block form ((1) a decay index of 0.05 or more, And () by means of an air impact having an air velocity of at least im/sec and an air flow rate of at least 17 ml/sec, the particles having an average particle diameter of 丨〇micron or an effective particle ratio of 10% or more can be obtained. (Personal) The method for producing a dry powder preparation for transpulmonary administration according to the third aspect of the invention, wherein the freeze-dried composition comprises a high-scoring drug as an active ingredient. The door knife (item 5) Item 3 A method for producing a dry powder preparation, which is obtained by using a dry powder inhalation device described in the following (A) or (B) as a device to micronize the freeze-dried composition: (A) for pulmonary administration a dry powder inhalation device which is a device for atomizing a freeze-dried composition which is contained in a container in a non-powder state and inhaling the obtained fine particles, and comprising: a needle portion having an air jet flow path, a needle portion of the discharge flow path, an air pressure feed means for conveying air in the air injection flow path of the needle portion, and a suction port communicating with the discharge flow path of the needle portion; and configured to: thread the needle portion a port plug for sealing the container to communicate the air ejection money and the discharge flow path with the inside of the container, and the air pressure is used to spray the helium gas into the container by the air jet flow path by the air jet The impact of the air causes the above-mentioned cold; the east dried composition to be micronized, and the obtained fine particles are discharged from the suction port through the discharge flow path; or (8) the dry powder inhaling device, which is to be in a non-powder state, θ In the case where the freeze-dried composition is micronized and the subject inhales the particles to be used, the present invention is characterized in that: the needle portion having the suction flow path has a needle portion having an air introduction flow path, and the suction plate of the disk a suction port that communicates with the flow path, and is configured as: 315314 12 1327073. The needle is inserted into the mouth of the container to seal the mouth of the container, and the air in the container is sucked from the suction port by the suction pressure of the user. At the same time, air is introduced into the container which has become a negative pressure through the air introduction flow path, and the freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are discharged from the suction port through the suction flow path. (Item) A dry powder inhalation system for pulmonary administration, which is used in combination with the following (1) and (2): (1) accommodating a container having a freeze-dried composition, which will contain a non-dissolved state The component liquid of the added component is prepared by freeze-drying, and has the following characteristics (1): (1) having a non-powder block form, (Π) decay index being 〇_05 or more, and (iii) borrowing An air impact capable of with an air velocity of at least im/sec and at least an air flow rate can be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (7) having the above-mentioned air impact can be imparted to the above A means of drying in a container and means for discharging the micronized powdered cold-rolled composition. (Item 7) The lungs are administered by dry powder according to item 6. The container is used in combination with the above device at the time of inhalation. (Item) The transpulmonary administration of the sixth aspect of the invention is as follows: The freeze-dried composition comprises: ...effective wounds [fj molecular medicine (item 9), as in item 6, the dry powder inhalation system for transpulmonary administration, in J15314 13 1327073, using the following (A) or (B) as a device: A) A dry powder inhalation device for pulmonary administration, which is a device for micronizing a freeze-dried composition contained in a container in a non-powder state and allowing a user to inhale the obtained microparticles, having: an air jet flow path a needle portion having a needle portion for discharging a flow path, an air pressure feed means for conveying air in the air injection flow path of the needle portion, and a suction port communicating with the discharge flow path of the needle portion; The needle portion is inserted into the mouth plug for sealing the container to communicate the air jet flow path and the discharge flow path with the inside of the container, and the air is sprayed into the container through the air jet flow path by the air pressure means. The impact of the jet air causes the freeze-dried composition to be micronized, and the obtained fine particles are discharged from the suction port through the discharge passage; or (B) j the dry powder inhalation device for lung administration, which is not The device for pulverizing and drying the freeze-dried composition in the container in the container and allowing the sample to be inhaled by the subject includes a needle portion having a suction flow path, a needle portion having an air introduction flow path, and the above a suction port that is connected to the suction passage; and is configured to:: the needle portion is inserted into the sealing chamber for sealing, and the air is passed through the air when the suction pressure is sucked into the container from the suction port. The inflow of the introduction flow path has been carried out: "The inside of the two devices is cooled by the inflow of air: ... The composition of the island is granulated by the micro-315314 1327073, and the obtained fine particles are discharged from the suction port through the suction flow path. (Item) A method of pulmonary administration comprising using a freeze-dried composition, wherein the composition of the additive component comprising an additive component in an undissolved state is prepared by cold drying; : (i) having a non-powdered block form, (Π) decay index of 〇'〇5 or more, and (out) borrowing; bearing an air impact with an air velocity of at least lm/sec and an air flow of at least Η(6), It may be an average particle diameter below 丨〇micron or an effective particle ratio of 10°/. The above particles; when used, by applying the above air impact to the freeze-dried composition, forming particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more, and then by inhaling the user The micronized powder is administered. (11) The method according to claim 10, wherein the cold-drying composition is contained in a container, and the micronized powder is prepared by means of a squatting device. The above-mentioned air impact imparts to the container, the means of drying, and forming, and means for discharging the micronized powdery freeze-dried composition from the container. (12) The method of transpulmonary administration according to the first aspect, wherein the frozen flocculating composition comprises a polymer drug as an active ingredient. (Item 13) The method of transpulmonary administration according to item U, wherein a dry powder inhalation device loaded in the fly (A) or (8) is used as the device: (A) I : t with dry powder The inhalation device is a device that will receive the pen in a non-powder state and is cooled in the present; the device that is micronized by the east drying composition and allows the user to suction 315314 15 like ϋ73, has:: air nozzle jet The needle portion of the road has a needle portion for discharging the flow path, and the air pressure feed hand for conveying air in the air body, the air, the body, the body, the body, and the melon road of the needle portion is connected to the discharge flow path of the needle portion. The suction port is configured to: insert the needle portion into the poor port. Flow path and discharge flow path disk: ratio one: "the port plug is used to spray air... 〃, the above-mentioned valley state is connected internally, and the air pressure is used to cause two + 喷射 to be sprayed into the container by the air jet flow path. The impact of the injected air causes the above-mentioned cold "dry composition to pass through;; and the particles that have been taken out are discharged from the suction port through the above-mentioned discharge flow path; or m (B) through the lung for dry powder ^ ^ ^ ^ ^ ^ w The sputum sputum system is housed in a non-powder state; the device for pulverizing the cold/east dry composition in the device and allowing the subject to inhale the obtained particles has: a needle portion having a suction flow path having an air guide a needle portion of the human flow path and a suction port that communicates with the suction flow path; and configured to suck the container from the suction port by the suction pressure of the subject in a state in which the needle is sealed by the needle The air inside is the same as that: the air is introduced into the flow path through the air into the negative pressure, and the cold-drying composition is atomized by the air impact of the flowing person, and the obtained particles pass through the suction flow. The road is discharged from the population. (p. 14) a lyophilized composition for use in an inhaled pulmonary administration, wherein the cold-washed dry composition is prepared by freeze-drying a composition comprising an undissolved component of 315314 16 1327073. And (1) has a non-powder block form, in particular. (ii) the decay index is 〇.〇5 or more, and (n〇 is subjected to an air velocity of at least im/sec and at least pm丨/sec. The air impact may be a fine particle having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more; and the freeze-dried composition may be powdered to be a fine particle having the above average particle diameter or effective particle ratio, and used. (Item B) The freeze-dried composition of Item 14 is administered by pulmonary administration, wherein the freeze-dried composition is contained in a container, and the micronized powder is used in preparation The above-mentioned air impact imparts a means for imparting a bundle drying composition in the crucible and a means for discharging the micronized powdery freeze-dried composition from the container. (Item 16)" 14 items of freezing Drying group The product is administered by transpulmonary administration, wherein the freeze-dried composition comprises a high molecular drug as an active ingredient. (Part 1) A freeze-dried composition is produced in an inhaled dry powder formulation for pulmonary administration Use, 纟中, the cold; East dry, the composition has the following characteristics: (1) The composition liquid containing the additive component in an undissolved state is prepared by cold-blown drying, - (11) has a non-powder block form, (ui) the decay index is 〇〇5 or more, and (lv) can be average particle size by withstanding an air impact having an air density of at least im/sec and an air flow of at least 17 m丨/sec 315314 17/073 Particles having a ratio of 10 μm or less or an effective particle ratio of 10% or more; and, at the time of use, the freeze-dried composition is micronized to have an average particle diameter of the above > or the above effective particle ratio. The freeze-dried composition of item 17 is used for the manufacture of a dry powder preparation for transpulmonary administration, and the composition of the lyophilized composition of the hexa-containing freeze-dried composition contains a polymer drug as an active ingredient. As the 17th The freeze-dried composition is used in the manufacture of a pulmonary-administered powder preparation. The cold-green dry composition is produced in Guyi, and the micronized powder is used to impart the above-mentioned void: impact to the container. Cold; East means of drying the composition and calm

::Extracting the hand of the micronized powdery cold to dry the composition to form β τ I (Item 20) A composition liquid containing an additive component in an insoluble state • I dry = manufactured for modulation of the lung The cold-blown composition used for dry powder preparations has the following characteristics: (0 has a non-powder block form, (1丨) decay index is 0.05 or more, and (4) borrows, receives, At least lm /, the air velocity and at least the air impact of the 轧一王轧流 ir, can be an average particle size of 1 or an effective particle ratio of 10% or more of the particles; ... clip ratio ^ and in use by the particles The use of the above-mentioned average particle diameter or the above-mentioned effective particles (Item 21) as in Item 20 of the group containing the insoluble state of the additive component 315314 18 1327073 liquid, wherein, the portion of the southern molecular drug. s Hai cold; The dry composition comprises, as an effective ingredient (Item 22), in the use of non-liquid forming, as in Item 20, the cold-drying ==: the group of added components and the aged powdered utensil container Inside the inside of the container, the means of drying the composition and can be::: impact The apparatus for imparting the granulated powdery cold-dried composition is prepared by the following: [Embodiment] The best energy of the invention is (1) cold-dried composition, the cold-kneading composition of the present invention, A non-powder dry state composition prepared by filling a container containing an additive component in an undissolved state in a liquid state and directly cooling it to a non-powder composition. It preferably contains one or several times. A freeze-dried composition prepared by lyophilizing an insoluble amount of an active ingredient (in an effective amount comprising a single dose of the active ingredient), which is prepared by lyophilization. Selecting and modulating the composition of the above composition liquid (the active ingredient, and the kind and amount of the carrier used together with the active ingredient) so that the non-powder composition obtained by the freeze-drying treatment has a decay index of 0.05 or more, and can be introduced by ( Influx) air impact (air impact, jet pressure) in the container, instantaneously or rapidly micronized into a lung suitable for the administration of the 'in the present invention, the so-called sorrow index, for cold; The dry composition 'is inherent in the freeze-dried composition measured according to the following method! 9 315314 1327073 Value: <decay index> In a container having a diameter of 018 mm or a diameter of 12 23, the liquid is filled with 0.2 to 5. 5 ml of the composition liquid (the composition liquid contains the components which are cooled to dry the electroformed product as a target) and is cooled; the east is dried. Then, in the obtained non-powdered lyophilized composition, The container wall was quietly dropped into n-hexane 丨nU. The mixture obtained by mixing it at 3 rpm for about 1 () seconds was put into the optical path length 1 position, and then (), followed by (4) chamber, and quickly measured with a spectrophotometer. Turbidity at a wavelength of 500 nm $ ^ . The obtained turbidity is divided by the total amount (weight) of the components constituting the freeze-dried composition, and the obtained value is defined as a decay index. The lower limit of the decay index of the cold/east dry composition of the present invention is 0.05, and the ideal order is 〇〇8 〇〇9 〇Η ", 〇·12 is preferred, and 013 is Further, the upper limit of the cold-dried composition of the present invention is not limited, but is preferably 15 和 and ..., 付., preferably 'the ideal order is 〇. 9, 〇. 8 〇7 〇·6', especially G·5 is optimal. The cold of the present invention; the east dry composition is preferably limited to 005 or more, and the desired m has the upper limit of 44 selected from the above-mentioned ones. The sorrow index within the range of values. The range of the decay index, and the body..." is 〇.〇5 to Μ, 0.08^.5, 〇〇...;, to .9'O.iO to. .8, to .7, 〇1 to 〇6 and. The dry composition of the present invention is a block form which can be dried by a dry powder. In the case of a non-competitive composition, it means that it will be effective as an eight-two S. 'The non-powdered cold-bundled dry-formed liquid is dried by lyophilization. 315314 20 iW7073 Solid' is usually referred to as freeze-dried, block production === drying step Or if it is broken into powdery, as long as it is not r: solid bulk, M and Min Ming are not powder-like cold; Donggan; = Ming; effect, are the non-powder block form of the hair Cold-drying, composition towel. The dry composition of the present invention is characterized in that the composition liquid containing the additive component containing the non-dissolving energy is subjected to a decay index of the frozen core to be characterized as The number and the non-powder block form, and the time of the cold pure composition represented by the above-mentioned sorrow index is tempered by the air impact with at least one air velocity and at least 17: the rolling flow rate. It is formed into fine particles having an average particle diameter of J 〇 micron and an effective particle ratio of 10% or more. The ideal cold-dried composition can form an average particle diameter of 10 μm or less by receiving the above air column. (preferably 5 micrometers or less) or particles having an effective particle ratio of A 1 G% or more (preferably 2 G% or more, more preferably 25/° or more, preferably 3 % by weight or more, particularly preferably 35% or more). Air impact of the dry composition, if by means of Shang oil "above the air speed and 17ml / se. There is no particular limitation on the impact of the air flow of the above air flow. Specifically, the above-described air impact is generated by, for example, an air velocity of 1 m/se C or more, preferably -2 m/sec or more, more preferably 5 m/secu, which is preferably 1 〇 m/sec or more. Shock. The upper limit of the air velocity is not particularly limited, but is usually 3 〇〇: /s:c ' is preferably 250 m/sec or more, more preferably 2 〇〇 m/sec or more, and most preferably 150 m. /sec or above. Further, the air velocity is not particularly limited as long as it is within the range consisting of the lower limit and the upper limit of the above-mentioned 315314 21 1327073. Specifically, 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, 1 to 200 m/sec, to 150 The range of m/sec. Further, the above-mentioned air impact is, for example, usually caused by an air flow rate of 17 ml/sec or more and a slave of 20 ml/sec or more and more preferably 25 ml/sec or more. The upper limit of the air flow rate is not particularly limited, and may be, for example, 900 L/min, preferably 15 L/sec, 1 〇 L/sec, 5 L/sec, 4 L/See, and 3 L/. Sec is the best. Specifically, the air flow rate is not particularly limited as long as it is within the range of the lower limit and the upper limit which are selected as described above. The range is, for example, 17 ml/sec to 15 L/sec, 2 〇mi/sec to Μ L/sec > 20 ml/sec 5 L/sec > 20 ml/sec J. 4 L/sec > 20 ml /sec to 3 L/Sec, 25 ml/sec to 3 L/sec. In the present invention, the active ingredient used in the present invention can be used as a technique: the composition of the dry powder inhaling agent has any pharmacological activity. • The substance: the following may also be referred to as a drug) There are no special restrictions on molecular drugs, low molecular drugs and high molecular drugs. Also high-fermented $, hormone and antibody 4 proteins (including Sheng liver and peptide) and DNA such as DNA and peptides and rna (including genes and cDN physiologically active ingredients.) < Also as a drug f « „. According to the situation, it can be two kinds of systemic therapy and topical therapy. % m is used as a low molecular drug, such as skin f cortisone, and ~ is anti-bey% (hydro-wind alcohol (prednisol〇) Ne), de-inflammation in 315314 22 1327073 (triamcinolone), dexamethasone (dexamethas〇ne), betamethasone, bec丨〇methas〇ne 'fluticasone ^ ^ Mometasone, budesonide, salbutam 1 (salbutam), salmeterol, pr〇cater〇i, buprenorphine hydr〇chloride Anti-biomass such as ap〇m〇rphine, taxol, and tobramycin. It is used as a molecular drug (physiologically active ingredient such as protein and nucleic acid), such as interferon. U,/5,7 ), interleukin (eg, interleukin) 2 '3, 4, 5, 6, 7, 8, 9, 10, η, 12, 13, 14, 15, 16, 17, 18, etc.), anti-interleukin-1α antibody, interleukin "receptor , interleukin receptor antagonist, interleukin-4 receptor 'anti-interleukin-2 antibody, anti-interleukin-heart receptor antibody, interleukin-4 antagonist, interleukin _6_ antagonism Agent, anti-interleukin-8 antibody, chemonectin receptor antagonist, anti-interleukin-7 receptor, anti-interleukin-7 antibody, anti-interleukin-5 antibody, interleukin-5 receptor , anti-interleukin -9 antibody, interleukin-9 receptor, anti-interleukin-1 〇 antibody, interleukin-1 〇 receptor, anti-interleukin-14 antibody, interleukin-14 receptor , anti-interleukin _丨5 antibody, interleukin-receptor, interleukin _18 receptor, anti-interleukin _18 antibody = erythropoietin (ΕΡΟ), erythropoietin derivative, particle ball community stimulation Factor (G-CSF), granule megaloblast cell/community stimulating factor (CSF), macrophage-community stimulating factor (M_CSF), calcitonin, insulin, and temsin derivatives (LisPro, NovoRapid, h〇E9〇 1, NN 3〇4, etc.), insulinotropic hormone, insulin-like growth factor, sucrose Somatostatin or its analog, vasopressin (vas〇pre = analog of 315314 23 1327073 or ..., stimulating powder-like enzymes, human corpus luteum "hormone release hormone, follicle stimulation" Hormone, bismuth, scorpion scorpion hormone, vascular endothelial growth factor, platelet-derived-proliferation factor, keratinocyte growth factor, epithelial cell growth factor, fibroblast growth factor, neurotrophic factor from the brain, hairy body Neurotrophic factor, tumor necrosis factor (TNF), TNF receptor, TNF inhibitor, transforming long-factor (TGF), hepatocyte growth factor (HGF), neurogenic: yue (GF) blood stem cell growth factor, enterprise Platelet proliferation factor, nalagidine peptide, blood coagulation factor, blood hepatocyte growth factor (s_Ca), FLT3 ligand, anti-platelet aggregation inhibitor monoclonal antibody, tissue fibrin/proenzyme/activating factor or Derivatives, super disproportionated oxidase, antisense medicine, immunosuppressive agents (such as cyclosporine, tacr〇Hms hydrate, etc.), cancer suppressor gene p53, Cytoplasmic membrane-regulated regulatory protein (CFTR) gene, RNA interferon (RNAi), bridging nucleic acid, alpha-antitrypsin, thrombopoietin (thr〇mb〇p〇ietin, butyl p〇), blood &; production of statins (metastasin), deoxyribonuclease (biliary, stimulating hormone, oxytocin, thyrotropin releasing hormone, bactericidal / permeability-enhancing protein (Βρι) and influenza vaccine, AIDS vaccine, round Vaccine vaccines such as malaria vaccines and tuberculosis vaccines such as Mtb72f. These active ingredients may be used alone or in combination of two or more. The above various peptides also include a natural polypeptide, a recombinant polypeptide, a chemically synthesized polypeptide, and the like. Further, these active ingredients can be used in their own free state or in a salt state. 315314 24 1327073 can also be used to keep it arbitrarily 1 8% related to the captive body, right to make the active ingredients (such as the package, take a 匕3 protein class and nucleic acid and other high scores early music and synthesis The low-molecular drug is not particularly limited as long as it is attached to the form (absorbent, inclusion, ion-bonding, etc.), such as a lipid membrane construct, a microcapsule, a cyclodextrin, or a dendrimer (dendri_, ' : micron spherules, nanocapsules, nanospheres, etc. Among them, lipid membrane structures include liposomes such as monolayer membrane liposomes and multilamellar liposomes, 〇/w type or w/o/w type ritual fluid, spherical Colloidal particles, fine-banded colloidal particles, and layered j-forms, etc. In addition, the "dendrimer" is generally a shape in which a chain of molecules is formed in a three-dimensional manner from the center to the rule of the molecule. Molecule. The dendrimer has a spherical structure, and has a space for ingesting the drug inside, and functions as a nanocapsule. In order to maintain the drug in the interior of the dendrimer, the following methods are known: Using the inside of dendrimers and drugs Interactions (hydrophobic interactions, electrostatic interactions, etc.), or 2) Formation of dense cell structures on the surface of dendrimers, physical capture of drugs, etc. (Reference: Nagano Kenji: Drug Delivery System, 17-6, 462 -470 (2 002)). Further, the Superfect used in the examples was formed from active dendrimers having a certain shape (Documents: Tang, MX, Redem.ann, CT· and Szoka, Jr. FC: In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate) Chem. 7, 703 (1 996)). These molecules are branched from the center, by having a positively charged amine group at the terminal and interacting with the acid group of the nucleic acid (negatively charged). In addition, SuperFect has the property of condensing 25 315314 1327073 DNA and RNA into a dense form in order to easily introduce DNA and RNA into cells. As a preferred holder, for example, liposome, dendrimer, retrovirus vector, adenovirus vector, adenovirus-associated virus, lentivirus (lentlVlrUS), herpes simplex virus vector, HVJ (Sendai virus) - liposomes (eg HVJ coat carrier sets, etc.). Among them, a lipid membrane construct and a cage such as a dendrimer are widely used because they can introduce a foreign gene into a cell. In the present invention, a liposome for gene introduction and a dendrimer for gene introduction are used in the same manner. Again, these are commercially available. Further, the particle diameter of the body (the average particle diameter of the geometry: measured by dynamic light scattering or field refracting and scattering) is not particularly limited as long as it is 10 μm or less. It is preferably 5 microns or less. For example, liposomes and emulsions, the particle size (the average particle size of the particles) is from 50 nm to several m, and the globular colloid has a particle size of 5 to 50 nm. Further, regarding the measurement method of the average particle diameter of the geometry, generally, for the particle size distribution of the particles in the field of several tens of nanometers, dynamic light scattering can be used to determine the particle size distribution of particles of several tens of micrometers or more, and Ray can be used. Any measurement method can be used for the measurement of the particle size distribution of particles in the field of several hundred nanometers and several micrometers by the measurement of the refracting and scattering method. Regarding the retention form of the active ingredient in these holders, there is no particular J, for example, in the case of a mussel membrane structure, for example, in the membrane of the lipid membrane structure, in the surface, in the interior, in the lipid layer, or on the surface of the lipid layer. Any form of attachment/existence. The method of forming the above-described holding form is, for example, a method in which a water-based solvent is added to a mixed dried product of a lipid membrane structure 315314 26 1327073 and an active ingredient (gene or the like), and then emulsified or suspended by an emulsifier such as a homogenizer; After a carrier such as a lipid membrane structure is dissolved in an organic solvent, the dried product obtained by distilling off the solvent is added to a water-based solvent containing a gene to emulsify it, and a carrier such as a lipid film structure which has been dispersed in an aqueous solvent In addition, a method of adding an aqueous solvent containing an active ingredient (gene or the like) in white, and a method of adding a dried product obtained by dispersing a carrier such as a lipid film structure to an aqueous solvent and then drying it to an aqueous solvent containing an active ingredient (gene or the like) (Refer to Unexamined 2〇〇ι_2592). b Further, in the case of controlling the size (particle size), a membrane type having the same pore diameter is used, a method of performing the extrusion at a high level, or a method using a pressurized granulator (refer to, for example, JP-A-6_238142) One of the characteristics of the cold-drying composition of the present invention is that a composition liquid containing an additive component in an insoluble state is prepared by cold-drying. The so-called non-dissolved state means that the added component is in the constituent liquid. The solvent may not be dissolved in a state of being dissolved or mixed in a clear state. The insoluble form is contained in a solvent in a state in which it can be detected by any means: Specifically, for example, in a solvent, it has a ruthenium 〇1 heart or more, compared with: 〇.05...上,更更01...上,更更更0.2...上, 〇 〇.5...the geometry of the average grain (using dynamic light scattering or lightning. The presence of the solid matter determined by the scattering method can be detected. If the object of the present invention can be achieved, the geometric mean particle size of the solid object (measured by the first scattering method or the laser refraction and scattering method) Upper limit There is no particular limitation 'but it is 20", preferably 15" or less, and more preferably ι 315314 27 1327073 // m. More specifically, the so-called "non-dissolved state" in the present invention is included in the solvent, geometry. The average particle size (measured by dynamic light scattering or laser refraction and scattering) is 0.01 to 20 // m, 0.05 to 15 # m, 〇.1 to 15 U. UJ iE-1 (J β 0.2 to 15 / The state in which the solid matter in the range of /m, 0.5 to 16 μ to 10 /zm, 0.2 to 10 "m*〇5 to 10#m exists in a state detectable by any means. The specific form of the insoluble state For example, the additive component is continuously dissolved in the solvent to be saturated or higher, and added to a state in which it is insoluble in the solvent, that is, a state in which the active component which is insoluble or poorly soluble in the solvent is suspended or turbid in the solvent. Further, in the method of specifically evaluating the non-dissolved state, the method of measuring the turbidity of the sample is a general method, but a method of measuring the particle size distribution of the insoluble matter by the particle size distribution measuring device can be used. The latter method, and physically, borrows Insoluble state that will be the object The composition liquid is diluted with a steamed crane water or a physiological saline solution to a concentration suitable for particle diameter measurement, and then charged into a chamber and stirred. Then, the particle size distribution is measured by a particle size distribution measurement method to determine the particle diameter of the particles present in the obtained diluent. Implementation. In, 1F, the so-called "non-dissolved state of the human knife" means not only the package, the tooth, the Ken, the body is in the undissolved state, but also the above-mentioned liposome, microcapsule, net paste _ The active ingredient held in the pyridinium support is in a state in which the dextrin, the dendrimer or the like is in a state of being preserved, but the retaining body such as a liposome is in an insoluble state, and the component is in a non-dissolved state: The active ingredient, ... the addition of the support or any other component of the non-dissolved state is formulated as a constituent liquid (described below), which is not particularly limited. Further, the solvent constituting the composition liquid at the same time as the additive component is not particularly limited, and may be, for example, a liquid, a culture medium or a buffer solution such as water or a physiological saline solution. Further, the solvent may contain an organic solvent, but the final preparation (freeze-dried composition for pulmonary administration) does not adversely affect the human body. The organic solvent is, for example, decyl alcohol, ethanol, isopropanol 'acetone, ethylene glycol or the like. The freeze-dried composition 'of the final preparation of the present invention' may be a combination of the above-mentioned effective ingredient or active ingredient and the support, or a suitable carrier, as long as the above-mentioned decay index of the final preparation is sufficient. When the carrier is added to the active ingredient, the type and amount of the carrier to be used may be such that the final freeze-dried composition prepared by freeze-drying the composition liquid containing the insoluble state of the active ingredient satisfies the following (1) to (iii) characteristics: (i) having a non-powdered block form, (Π) a decay index of 0.05 or more, and (in) by withstanding an air velocity of at least lm/sec and at least i7 mi/sec The air impact of the two gas jets may be fine particles having an average particle diameter of 1 μm or less or an effective particle ratio of 10% or more, and the effect of the present invention may be achieved without any particular limitation, and the prior freeze drying may be arbitrarily used. The carrier or desired amount used. As the carrier, specifically, a hydrophobic amino acid such as lysine, leucine, isoleucine or phenylalanine or a salt or guanamine thereof; glycine, guanamine a hydrophilic amino acid such as an acid, alanine, arginine or valine; or a salt or a guanamine; a derivative of an amino acid; a dipeptide having two or more of the same or different amino acids, Tripeptides or their salts or amines. 315314 29 1327073 One or two or more types are used in combination. Among them, it is used as an amino acid or a salt of a metal such as an alkali metal such as nano or slant, and a mineral acid such as a mineral acid such as phosphoric acid or hydrochloric acid or an organic acid such as a sulfonic acid. For example, it is L-leucine toluene hydrochloride. Further, as the carrier, an amino acid other than the ?-amino acid may be added, and the amino group is, for example, a-alanine, methic acid, tauronic acid or tauroic acid. Further, 'as other carriers, such as monosaccharides such as glucose; disaccharides such as curtain sugar, maltose, lactose and trehalose; sugar alcohols such as mannitol; oligosaccharides such as cyclodextrin; dextran 40 and poly Polysaccharides such as triglucose; polyhydric alcohols such as polyethylene glycol; and sodium fatty acid such as sodium citrate. Further, these carriers may be added singly or in combination of two or more. Wherein 'the carrier can be efficiently delivered to the lungs, and 5 is a hydrophobic amino acid such as isoleucine, valine, leucine or phenylalanine or a salt thereof or Indoleamine; alkalamine-proline-' leucine-phenylalanine and phenylpropylamine hydrazino-isoleucine and other hydrophobic dipeptides; and leucine-alkamine-based Hydrophobic tripeptides such as leucine, leucine, leucine, valine and the like. These may be added singly or in combination of two or more. Further, in the case of interferon-γ, it is preferable to remove the above-mentioned hydrophobic amino acid or its salt or guanamine, hydrophobic dipeptide and hydrophobic tripeptide from the viewpoints of fine powder and finalization and formulation stability. Further, a basic amino acid or a salt thereof or a guanamine, a basic dipeptide, and a basic tripeptide may be used in combination. Among them, those which are basic amino acids are, for example, arginine, lysine, histidine and salts thereof. Preferably, 3Ι53Ι4 30 is a combination of streptoalanine and hydrochloric acid, phenylalanine, leucine and arginine hydrochloride. The content ratio of the active ingredient (drug) of the lyophilized composition is preferably limited to, for example, π is 20 mg or less, preferably 丨〇 mg or less, more preferably 5 or less, and further Good 2mg or less, especially good - below. The addition ratio of the full load agent is not particularly limited as long as the final cold bead drying composition is set to the characteristics of 1 to (111). Although there is no limit to denier:: The standard is when the cold-beam drying composition is set to 1% by weight, the ratio is 0. 1 to less than i 〇 better, weight / °, with 1 to less than 100 weight . /〇为,旦. Less than 1% by weight is better, from 20 to less than 100

Weight 0/〇 is especially good. The king SJ iUU also has the characteristics of the present invention (1) to (iii) and: the composition: as long as it satisfies the effect of the present invention in the composition liquid before drying, 'the cold is stabilized and Prevention = Stabilization, drying of the active ingredients, 天, days V ·,, in the case of benefits, you can add white, the above ingredients! 2: In other words, these additives may contain human serum white eggs, such as Tong's side's tongue agent and buffer. Regarding the surfactant, the right is generally applied to the pharmaceutical 0 丨w surfactant, cationic: surface, and the surfactant, regardless of the anionic boundary, and the non-ionic surfactant. (For example, Tweeni!lK, a polyemulsified ethylene sorbitan fatty acid ester surfactant/surface active agent) and a non-ionic sorbitol liver oil meter, etc. (d), the composition of the knife and any component is cold; Dongganyi _ 'can be used to generally manufacture lyophilized preparation 315314 31 1327073 (freeze-dried composition) 'if dissolved type Note =. Although there is no limit, depending on the situation, the cold bath can be adjusted to freeze and dry quickly. Conditions, it is possible to rush the cold-dried composition of the present invention, by which the particles suitable for pulmonary administration can be formed. Therefore, the air-cooling composition is suitable for preparing a powder for pulmonary administration. The invention can be provided as a preparation for the preparation of a pulmonary preparation by a pulmonary preparation: a freeze-dried composition for preparing a preparation. ). Further, with the powder sample: 'The cold-dried composition of the present invention comprises the cold-drying composition for the specific application of the lungs as disclosed below, and the composition liquid containing the non-dissolved t-added component is subjected to a cold bundle. It is prepared by drying and has the following characteristics (1) to (iii): "(i) has a non-powder block form;

(ii) a decay index of 〇.〇5 or more; and (iv) an average particle size of less than 1 μm by withstanding an air velocity of at least lm/sec and at least a gas impact of at least J/M Or particles with an effective particle ratio of more than 1%. 102. The freeze-dried composition according to aspect 101, wherein the decay index is 〇.〇5 to 1.5. - 1〇3. The cold-dried composition of the sample, as described in paragraph 1〇1, wherein the air impact by an air flow having a velocity of at least 2 m/Sec and an air flow of at least 17 m" It is a fine particle having an average particle diameter of less than 丨〇micrometer or an effective particle ratio of 1% by weight or more. 315314 32 1327073 1 (Μ) The cold-bed drying composition as described in Item 1G1, wherein the air impact by the air velocity in the range of 1 to 3 and the air flow rate of at least Uml/sec can be # & τ & _ is a fine particle having an average particle diameter of less than 丨〇 micron or an effective particle ratio of 10% or more. 105. The cold-dried composition of the sample 101, wherein, by bearing at least lm The air velocity of /sec and the air impact of air flow of at least 20ml/sec can be particles with an average particle size below 10 microns or an effective particle ratio of more than 10%. 1 0 6. If the pattern is 1 〇 1 item $ Christine 4, person, A 4 . The cold and dry composition, which can be averaged by bearing an air impact with an air velocity of at least 1 m/sec and an air flow of at least 17 ml/sec to 15 Usec. Particles with diameters below 微) below micro water or with effective particle ratios above 1%. 1:7. The freeze-dried composition according to the aspect 101, which is capable of standing on a particle having a dry average particle diameter of 5 μm or less or an effective particle ratio of 20% or more by being subjected to an impact of air. It is a low-molecular drug that contains the following ingredients: .1〇9: As described in paragraph 1〇1 of the cold; East dry composition is an active ingredient protein and nucleic acid and other polymer drugs. 110. A cold-dried composition according to the aspect 1-9, which is an active ingredient, which is a nucleic acid which is maintained in a retainer state. (1) The cold-kneading composition as described in the aspect (10) is a low-molecular-weight drug and a carrier which are active ingredients, and the carrier is a group consisting of amino acids, dipeptides, tripeptides and saccharides. 315314 33

11 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A group consisting of a peptide, a tripeptide, and a saccharide 11 3. As a bad sample, the 1 u item is recorded by Ju Xiu, Zhan & For the right arsenic & 八, f freeze-dried composition, is a low-molecular drug that is used as a knife, and contains ώ ' ' ' ' ' ' carrier carrier is at least one from hydrophobic amino acids, hydrophobic species, gas A group of aqueous dipeptides. > 1 14. If the lyophilized composition contains 12 substances, the lyophilized composition contains the protein as an active ingredient, and the carrier is at least one selected from the group consisting of hydrophobic three. A group of peptides. Steep amine group Hydrophobic dipeptide and hydrophobicity 11 5 · As in the case of 1 〇 1 item. ,. The "East Dry Composition" is a water-soluble solution as described in item iG1; the East-dried composition contains the active ingredient in one dose. 117. The cold-dried composition as described in paragraph 1〇1, The composition liquid containing the additive component in a non-dissolved state is adjusted by cold-drying to have the following characteristics (1) to (iii): (i) having a non-powdered bulk form; (ii) a decay index of 〇.〇5 To 1.5; and (d) by subjecting an air velocity of 1 to 3 〇-range air velocity and air flow of 17 mI/sec to I5L/SeC, the average particle diameter is below 1 〇 micron or the effective particle ratio is 〇% The above particles. η 8. As in the case] The freeze-dried composition of the seventeenth item, wherein the air velocity is 315314 34 1327073, the gas velocity is 1 to 250 m/see. __ I sample 11 7 items of cold; Object, straight, air flow rate is 2〇ml/sec to 1〇1^”. ^ (2) A method for producing a dry powder preparation by pulmonary administration, and the present invention relates to a method for preparing a cold-dried composition in a container by being placed in a container in a non-powder state, and having a suitable composition A dry powder preparation having a particle size of 〇, and a dry powder prepared by a lung (4). The method can be carried out by using a dry powder in a non-powder state. The method of producing a dry powder preparation for pulmonary administration according to the present invention is as follows. The composition liquid containing the additive component in the undissolved state described in the above (1) is dried by cold beads to prepare an upper decay index. The non-tantal freeze-dried composition of the present invention is then subjected to an air impact having an air flow rate of at least a speed and a flow rate of at least 17 ml/see, whereby the powder can be cooled in a powder form; the east dry composition It is prepared to have an average particle diameter of 4 1 μm or less (more than #5 μm or less) or an effective particle ratio of ίο% or more (preferably 2 G% or more, more preferably 25% or more, and even more preferably 3 5 /. Particle form Dry powder preparation. The average particle size of the particles in the present month means the average particle size 15 used in the inhalant-related industry; specifically, it is not the geometric particle size, but the air Average particle size of mechanics (MMAD). The average particle size of the air force can be obtained by conventional methods. Specifically, the average particle size of aerodynamics is used, for example, by the installation of an artificial pulmonary air respirator 315314 35 1327073 Particle Size Distribution s (Amberst Process Instrument, Inc., USA), two-stage dust detector (GW Hallworth and DG)

Westmoreland: J. Pharm. Pharmacol., 39, 966-'US Patent Publication No. 6 1 53224), multi-stage hard dust tester, marble impactor, Anderson multi-stage impactor, etc. Moreover, B. Olsson et al. reported an increase in the transport of lungs with a ratio of particles with an average aerodynamic particle size below 5 " m (B. Olsson et al: Respiratory Drug _ Dehvety V' 273-281 (1996) The method for estimating the amount that can be transported to the lungs is, for example, an effective particle measured by a dry particle size distribution meter, a two-stage dust measuring device, a multi-stage hard dust measuring device, a marble grinding impactor or an Anderson multi-stage impactor. The production method of the present invention is preferably a freeze-dried composition in which a powder containing a component in an insoluble state is contained in a container, and a powder is formed by cold beam drying in this state. Then, by introducing air into the glutinous rice containing the product, the air-refining composition is applied to the freeze-dried composition. In this case, 'drying treatment and powder formulation treatment=using the same container It is implemented, so it will not be caused by being divided into small portions and being able to be dyed. Section, ::::: The impact of helium gas on the hand-applied device of the above-mentioned cold-dried composition i 'but The drying agent described in the following (3) is used as a method for producing a dry powder preparation, and the patient can be dried (four) in a self-made material (inhalation, in a container) The cold; East dry composition is prepared into a powder preparation suitable for particle size of 315314 36 1327073. Further, the method for producing a pulmonary dry powder preparation for use in the present invention comprises the following specific aspects: 20 1. The method for manufacturing the sputum by using the dry powder pulverized by the lung, and the preparation method comprises the method of adding the undissolved additive component to the home of the knives and lyophilizing the liquid. 'The freeze-dried composition having the following (1) to (iii), the human soil + Θ f raw is contained in a container: (丨) has a non-powder block form, (1)) the decay index is 〇.〇 5 to 1.5, and (by) having an air impact in an air flow having at least lm/sec# from θ and a flow rate of at least 17 ml/sec, may constitute an average particle diameter Particles below 10 microns or with an effective particle ratio above 1%; by using The drying composition of the above-mentioned container can be used to introduce the above-mentioned air impact device, and the air having the impact of 亥 W 丄 ° ° 空 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; The average particle diameter is below 〇 micron or the effective particle ratio is 丨〇% or more. 202.:: The method for producing lungs by the method of lung injection according to the item 201, and the effective component of the amount of the cold-ball-dried composition contained in the container. Cut 3 has 1 into 2 0 3 . 0 1 is gradually m ", J: and dry powder preparation ..., wherein the average particle size or effective particle ratio of the prepared particles is above 20%. Below the secondary water 204. If the remote sample 201 records The lung is administered (4) _ manufacturing method 'where 'the decay index of the freeze-dried composition; the known number of the agent is in the range of 0.05 to 315314 37 1327073 1.5. 205_ as shown in paragraph 201 of the lung administration The dry preparation method, wherein the cold; the east dry composition comprises a low molecular medicine of the final preparation. 1 2 as an active ingredient 206. The appearance of the lung production and dry manufacturing as described in the aspect 2 () The method 'where' the cold; the Donggan listener comprises a polymer drug such as a protein and a nucleic acid. Qian n 207. The method for producing a dry powder potential for pulmonary administration according to the aspect 2 (1) 'Where' the cold; the eastern dry composition contains nucleic acids that remain in the retaining state as effective. According to the 205 items of the lung-administered system - soil Hir Ganzi », the hole H of the powder preparation of the cold H; cold; East dry composition contains low molecular weight drug as an active ingredient and carrier 'the carrier a group consisting of at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides. = A dry powder preparation for pulmonary administration as described in paragraph 2G6, the freeze-dried composition containing as an active ingredient A polymer drug such as a protein or a nucleic acid, and a carrier containing β, ^β are at least one selected from the group consisting of an amino acid, a dipeptide, a tripeptide, and a saccharide. 38 1 1 0. If the evil sample is 2 0 8 The lungs are found in the lungs &, the lung cylinders/the tk method using dry powder preparations, wherein the freeze-dried 4 m-m composition is combined with a low knife and a carrier as an active ingredient. The carrier is a group consisting of a hydrophobic amine group ilL aqueous one peptide and a hydrophobic tripeptide. 2 2 1 1. As the aspect 2 0 9 items m system! + '戟之经肺叉 and the method of using a dry powder preparation', the cold-dried composition contains as an active ingredient 3 15314 1327073 Polymeric drugs such as proteins and nucleic acids, and carriers, which are selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic = peptides. The method for producing a dry powder medicinal preparation for transpulmonary administration by the lungs, wherein the cold/east dry composition is a water-soluble composition 2 1 3 . The method for producing a dry powder preparation for pulmonary administration according to the aspect 20 1 'A method of micronizing the ruthenium of Α1 in a container having a capacity of 0.2 to 50 ml. The invention relates to a method for manufacturing a dry and sputum aging preparation, wherein an air flow having an air velocity of at least 2 m/sec and an air flow of up to / w ml/sec is provided by using a freeze-dried product in the container. The air is subjected to an impact means, and the air having the impact is introduced into a container for accommodating the freeze-dried composition. 215. The method for producing a dry powder for pulmonary administration according to the aspect 201, wherein the air velocity having i to 300 m/sec is imparted to the composition of the cold east container in the container and at least The air flow of the air to generate a means of impact, and will have:::: air impact of the air to guide people to accept the cold "dry composition of the container and needle. Work 2 1 6. If the situation 2 0 1 item" Fp 彡 彡 彡 贞 贞 贞 贞 贞 贞 贞 贞 贞 经 经 经 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺 肺The air speed of the sec and the air of the wide air flow to generate a shock device, and the air with the two-gas impact is introduced into the cold; ^ The container of the raw material of the L-refining composition is entered into the 217.印番★α &, a method for the manufacture of a dry powder preparation 315314 39 1327073, which has a minimum of lm by using a cold-aged composition in the valley state /see air', air temperature and air flow of 17ml/sec to - air flow The apparatus for the means of impact and the air impinging on the air are introduced into a container for accommodating the cold and sterilized composition. 0 218. The aspect 2 (manufacturing method of the dry powder preparation for pulmonary administration according to item H) Here, the dry powder inhalation device of the aspect 301 or 302 described in (3) the dry powder inhalation device described later is used as a device, and the dry composition is atomized. '丨 丨 219. For the production of a dry powder preparation, the method of using a dry powder inhalation device of the item 309 described in Chapter (3) of the dry powder inhalation device is used as a device to atomize the cold-kneaded composition. 220. The method for producing a dry powder preparation for pulmonary administration according to the aspect 218 is to use the method described in section (3) of the dry powder inhalation device (the dry powder inhalation device of U) is cold. The method for producing a dry powder preparation of the east dry composition particles, wherein the amount of the mother air spray in the container is 5 to i〇〇mi. 221. The lung injection according to the aspect 218 Dry powder The manufacturing method is a method for producing a dry powder powder preparation in which a dry powder inhalation device is formed by using a dry powder inhalation device of the aspect 302 in the dry powder inhalation device described in the above (3). The flow rate to the suction port is 5 to 300 L/min. 222. The method of manufacturing the cold-dried lyophilized group of the 315314 40 1327073 knives of the dry powder preparation according to the aspect 201, including the method of 201 The special product having the following (丨) to (丨丨丨) prepared by adding the non-dissolved state to freeze-drying is contained in a container: (I) has a non-powder block form, and (II) has 0 , the decay index of 05 to 1.5, and (out) by the air impact with an air velocity of i to 300 m / sec and an air flow of η mi / sec to 15 L / sec, can become an average particle: at 1 〇 micron The following or particles having an effective particle ratio of 1% or more. By using the cold-blown composition for the above container, the above-mentioned air, impact device can be placed and the air having the air impact can be introduced. Forming the above freeze-dried composition The average particle size is below 丨〇micron or the effective particle ratio is at 10. / ❶ above the particles. 223 土如态# The 222 method for the administration of a dry powder preparation by the lungs, wherein the active ingredient contained in the container is administered in a dose of *. The composition of the bundle contains 1 2 = the method of transdermal administration of a dry powder preparation as described in Item 222, wherein the air velocity is i to 25 〇 _. ^ (1) The air flow rate of the finely-dried dry powder preparation as described in (10) (2), wherein the air flow rate is 2 〇ml/sec to 1 〇仏. (3) Dry powder inhalation device - Transmitting ...... When applying a dry powder preparation, the powder-inhalation device can not only be used in a non-powder state; the cold-drying preparation (cold-pure dry composition) in the container is widely used in the container: 315314 41 1327073: :::Second: The powder preparation is also available for the user to inhale the service. It can be used to: granules: two powder-like cold-cold dry group by micronization 〇i # A 6 #二乳冲挲And (2) the means by which η * — , , the fine substance can be administered by inhalation to the user at the same time, and the cold can be applied at the same time; The user is sighed and sighed. In addition, the above-mentioned π air impact is introduced into this - the slave can also be said to "have the above-mentioned:: the milk is introduced into the container containing the cold-dried composition", the above (2 The means can also be ★ Jia + ± ^ month will be in the valley state through the micronized private preparations discharged from the container ^ 4. ^ slave In the present invention, if it is provided with this (4), the means of any one of the previously known or future developers (1) may be used, specifically, by being able to be contained in a container. The drying composition is carried out by introducing air impinging on the air into the center of the container. Further, the means of (1) may be a means for imparting an air impact having an air velocity of at least i and an air flow of at least 17 ml/sec to the cold-dried composition in the container. By means of (7) or by means of this means, a dry powder preparation prepared in a form suitable for pulmonary administration can be administered to a user such as a patient. Further, the means (2) such as the working chamber and the flow path can be designed such that the composition can be further atomized or dispersed. The dry powder inhalation device comprises the spray type dry powder inhalation device disclosed in (a) below and the self-inhalation type dry powder inhalation device disclosed in (b). Active powder inhaler (a-1) a dry powder inhalation device which is housed in a non-powder state in a device of 315314 42 1327073: a freeze-dried composition for atomization and for inhalation, having air The needle portion of the jet flow path has a needle portion for discharging the flow path, an air (four) feeding means for conveying air in the air jet flow path of the needle portion, and a suction σ for communicating with the S Hai discharge flow path: The needle portion is inserted into the mouth for sealing the container, and the air jet flow path and the drain passage are communicated with the inside of the container, and the air is sent from the air jet flow path to the container π by the air pressure feeding means. The fine particles obtained by atomizing the freeze-dried composition by the impact of the jet air are discharged from the suction port through the discharge flow path. (a) The dry powder inhalation device according to (a-1), wherein the air pressure feeding means is a manual type, and includes a suction port provided with a suction valve and a bellows having a discharge port of a discharge valve The body is configured to close the suction valve, and by compressing the air box body and opening the discharge valve, the air in the air box body can be pressure-fed to the air injection flow path that communicates with the needle portion of the discharge port to In the state in which the discharge valve is closed and the suction valve is opened, the air box body is expanded by the elastic restoring force, and air is introduced into the wind box body. (a-3) The dry powder inhalation device according to the above aspect (a), wherein the air jet flow path and the discharge flow path are formed in a needle portion - (b) self-inhalation type (Passive p〇wdei·inhaier) (b-1) A dry powder inhalation device is a device for atomizing and cooling a cold/east dry composition which is contained in a container in a non-powder state, and 315314 43 1327073 a needle portion having a suction flow path, a needle portion having a suction port 丨L path communicating with the suction flow path, and a needle portion that is inserted into the needle portion to seal the container can be sucked by a user From the above-mentioned heart, the above-mentioned and the inlet are sucked into the container a, so that the air is rolled through the air guide, and the inside of the container is filled with a negative pressure by the inflow of air. The particles that are formed into the air are discharged from the suction port through the suction flow path. ', (b-2) as described in (bl), the sub-inhalation of the user, and the sub-inhalation of the user, consisting of the majority of the particles of the composition (b- 3) If (b_!) or (b_2) the dry (4) end suction suction flow path and the air introduction flow path are formed in one needle portion, the means for introducing air into the container (the means (1) above The means for introducing air from the outside is not required to specifically reduce air. The means for introducing air from the outside is not particularly limited. For example, the above-mentioned dry powder inhalation device introduces external air into the container. Means; in addition, in the case of drying the powder inhalation device by itself, the negative pressure in the user's inhalation can be used to naturally attract the outside air into the container. Further, in the case of the former spray-type dry powder inhalation device, the method of manually introducing the outside air into the container may be manual or automatic using any machine. '' 315314 44 The dry powder inhalation used in the present invention is a self-inhalation type, and can be introduced by means of h: set, regardless of the inside of the squirt type. . Inside and outside. The cold coffee preparation in the P open space is micronized. ^The non-powder state is contained in the capacity, and the 裒σ used for the material and shape will be I special "丨: to be used for the drying of the cold beads, for example, in the case of polyethylene, in terms of material , ^ , Λ The polyolefins such as vinyl are mainly used for plastics, broken glass and sho... etc. The shape is j-shaped, triangular prism (triangular cone), positive D can be the same shape, cup octagonal woman h (square Cone), hexagonal column (hexagonal cone), corner column (octagonal cone) and other polygonal columns (polygonal pyramid). In order to obtain the capacity of the container of the effect product efficiently, it is preferable to use 02 二谷广 drying group 25 刎, preferably i to 15 ml as a m ' to 0.2 to diameter), expect, ., soil, the diameter of the container (internal, to / 吏 (four) 2 to 1 〇 01 (10), from 2 to "coffee is better than 至 2 to 5 〇 mm. Bao people." and "in the container The amount of the lyophilized composition is preferably the amount of the active ingredient in the amount of the dose of the tablet or the amount of the dose of the dose of the dose of the dose of the amount of the active ingredient. More preferably, it includes the unit dosage (the number of times of spotting, the east drying effect component f. In addition, the specific amount of the cold, east dry composition, depending on the type and amount of the active ingredient contained in the cold and the product. f can be selected in the appropriate amount of people, there will be no special limit ^, from below, preferably A on 〇mg below. ^ is below 20.mg 'better than 1 〇 post below, especially good - again, by The air impact generated by the external air introduced into the container, 3153 J4 45 is the air flow from at least human times or several times and the air generated by it flows into the container = within the limit of the durability And the air speed is higher than the above, and the air flow rate is usually 5 to 3 () (). The human inhalation is 300 L/min, which is more detailed. In addition, in the spray type Dry powder, ., 0 to 2 〇〇 L / 1: The amount of under-air injection is 5 to just; ^ device, user can be better adjusted for filling in the volume / preferably 10 to 50 ml surface caused at least /: Yinu cold; East dry composition 〇f # ^ ^ msec air velocity generated by the air The name is better. The better air impact is at least the gas impact. It is better to estimate the air velocity generated by 5 丨V 2 m/SeC to be even better! 1η>5~The air impact caused by the air catch, ^" The air impact generated by the air velocity. The impact of the air velocity is as follows: a C ^ ^ ώ about 5 hp upper limit, preferably 250 m / sec generated air impact, more preferably 2 - air speed Air impact. & 150 (10) The air velocity generated by the hole is right by the air generator having the air velocity in the range of the lower limit 选 selected from any of the above-mentioned ones. 1 to 3〇〇m/sec ' 1 to 250 m/sec, 2 to 25 〇pa ' 5 to 250 lWSeC, 5 to 2 〇〇 m/sec, 10 to 2 〇〇 m/sec, 〇 to 丨 5〇 The impact of the air generated in the range of m/sec. The speed of the air imparted to the freeze-dried composition may be as follows: 'jet type drying 315314 46 1327073 shown in the following embodiment example 1 In the powder inhalation device, it is used to accumulate in the wind box body 1 The flow path 3 is forcibly introduced into the container to be filled in the container, and the second dry composition (block-like freeze-dried composition: hereinafter also referred to as "cold dry block to impart air impact, and the resulting particles are discharged from the flow path" The mechanism of the ' ί 4 discharge. This b' flows through the air jet flow path 3 y A by dividing the amount of air accumulated in the wind phase body 10 by dividing the air into the container Then, by dividing the air flow rate by the cross-sectional area of the flow path for introducing the air into the container, such as the air injection flow path 3, etc., the air velocity for imparting an impact to the freeze-dried composition 1 = Kanggan no block can be calculated. Air speed (cm/sec) = air flow rate (nU = cm3/sec) + cross-sectional area of the air introduction flow path (cm2) Specifically, for example, the hole diameter designed as the air injection flow path 3 is a must discharge path The hole control is a case of a spray type dry powder inhalation device which is divided into 18 claws m and accumulated in the air of the wind box body j of about 20 mi, and is about 2 〇m of air which is accumulated in the wind box body 10. When the amount was forcibly introduced into the cold-dried composition in the container from the air jet tearing path 3 in about 5 seconds, the air was about 40 ml/sec. If the value is divided by the cross-sectional area of the air introduction flow path (two gas injection flow path) (0,06 X 0,06 X 3.14 = 0. Oil 3 cm2), it will become 3540 cm/sec, that is, the air velocity is about 35 m/sec. In addition, in the self-inhalation type: the last inhalation device shown in the following Example 2 '3 and *, the air is introduced into the flow path] [the flow of air into the freeze-dried block is generated, and the resulting The mechanism that is slightly discharged from the suction flow path 16 is thus regulated by the holes of the air introduction flow path 17 and the suction flow path 6 to regulate the flow rate of the air flowing through the flow path. Therefore, the air velocity of the freeze-dried composition carried in the container 47 315314 1327073 can be measured by passing through the air into the air introduction channel 17 and dividing it by the air introduction channel 17 Calculated by the cross-sectional area of the nozzle. Air velocity (cm/sec) = air flow rate (ml = cm3/sec) + cross-sectional area of the air introduction flow path 17 (cm2) Specifically, the inhalation split containing the grain is installed in the European Pharmacy (European) Pharmacopoeia, Third Edition Supplement 2001, Pll3-II5), the device A (device A) (two-stage dust detector. manufactured by Copley, UK), using a flow meter (K〇FL〇c DP Μ - 3) The flow rate of air flowing through the air introduction flow path 1.7 is measured. For example, in a self-inhalation type dry powder inhalation device designed to have an air introduction flow path 17 having a hole diameter of 0 199 mm and a suction flow path of 0 丨.99 mm, L is 60 (k〇FLOC DPM- 3) The measured air flow rate through the air introduction flow path 17 is 17·7 L/min (that is, 295 ml/sec) 'empty' I speed can be divided by the air introduction flow path The cross-sectional area _ (0'0995χ 〇·〇995Χ 3.14 = 0.G311cm2) is obtained (9486 em/Sec, ie 95 m/sec). The cooling drying composition filling the inside of the container has a gas flow 罝' of, for example, at least ml/sec, f V, ....ml/sec. The flow rate of air is preferably at least 20 mi/sec ‘more preferably to the limit, and is not particularly limited, for example, L above the air flow rate L/sec, more preferably 〖0T 〇 L/min. The upper limit is preferably 15

Wee, especially good for 3 (8)' and more preferably 5 L/SeC, and even better selected for any of the four. Specifically, the air flow rate is not limited to 315314 48 1327073 as long as it is within the range from the upper and lower limits and the upper limit. The range is, for example, 17 ml/s L/sec' 20 ml/sec to 5 L/see to 3 L/sec, 25 ml/sec to 3 ec to 15 L/sec, 20 ml/sec to ι〇' 20 mi /sec to 4 L/sec, 2 such as /... L/sec. Eight orders of % r / T 1 used to close to the bottom of the container to the east:: into the sorrow 4 彳 has the empty spit outlet (preferably with fine pores? dry composition of the state from the flow path. _ Soil outlets. The means of spitting out air, such as the air gentleman's knives detailed in the examples, as a means of increasing the impact of air from the outside. In addition, the aperture of the spout of the machine is due to the aperture. .备蜱#Λ β ^ λ* The size of the valley state, etc., the preferred range is 曰, so there is no particular limitation, and the acre η can be from 0.3 to 10 mm, preferably from 0.5 to 5 mm, more preferably. 8$ <: inside. Mm 'extra good range of 1 to 4 mm to be contained in a non-powder state. The degree of micronization, for example, the average particle diameter is 丨〇m into the container by introducing air into the container, and the lyophilized composition in the container can be atomized into a particle size suitable for transpulmonary administration, 'Better 5" m below. Further, the dry powder inhaling device used in the present invention comprises the specific state disclosed below. The dry powder inhaling device for repeated administration of the lungs is air-blown, non-private. The composition is freeze-dried in the container and the subject is inhaled into the resulting microparticles. · 3〇1. A dry powder inhalation device for transpulmonary administration according to the aspect 300, which microtilizes the freeze-dried composition contained in a container in a non-powder state and obtains the microparticles for the subject Inhalation device with: 315314 49

丄JZ/U/J has a needle portion of the air jet flow path, and the air nozzle flow path of the needle portion conveys the air two-needle portion, and the suction port delivery means that communicates with the discharge flow path of the needle portion And the configuration is as follows: ' The needle portion is inserted into the mouth of the container for sealing the container, and the discharge is made to check the air jet flow segment. The air is sent by the air pressure to cause the air to be smashed by the air. The jet stream jets the impact of the jet air so that the upper Α, φ 妒 玫 玫 今 , , , , , , , , , , , , , , n n n n n n n n n n n n n n n n n n n n n n n n . 3 Aspect 3 (10) The transpulmonary administration is carried out by using a dry == non-powder state to be stored in a container to cool the composition and to take the particles into the subject for inhalation. The needle portion of the suction flow path has a needle portion having an air introduction flow path and a suction port through which the suction flow path communicates; and is configured to: ^ the needle portion is inserted into the state of sealing the mouth of the container, and is tested The suction pressure of the person is sucked into the air in the container from the suction 4 and the inlet,

%, the air is introduced through the air guide A ^ t ,, and the claw path flows into the container which has become a negative pressure = ' 'The cold is hit by the air of the flow person; the east dry rainbow is atomized, and the particles that are served are attracted by the above The flow path is discharged from the suction port. 3. U 301 § The Pulmonary Drying Inhalation Device for Pulmonary Injection is configured to spray the air into the container once, so that the freeze-dried group is micronized and discharged from the suction port. . 3 0 4 · As in the case of 3 0 1 item, Yin Xi Xi Cheng 8 Qi. As it is, the two lung technology and the dry powder inhalation device 315314 50 1327073, the lanthanum system is configured to spray the air into the above container, so that the freeze-dried composition is micronized into an average particle size of 1 〇胄The particle ratio S is 10% or more and is discharged from the above-mentioned suction port. =: The dry powder inhalation device for lung administration according to the aspect 3CH item:: is a form in which the air jet flow path and the discharge flow path needle portion are formed. The π 胤 态 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如 如...the dry composition, the lung injection according to the item, the dry powder inhalation device is configured to be micronized into a flat by the subject's absorbing body]] 4^_ + The attack and dryness is pulled at 1 〇 micron to be above 1〇%, and from the upper ^ entrance (four). The cut knot ratio is 3 0 8. If the pattern is 3〇2, it will attract the above-mentioned Shanghai: through the lungs The form in which the dry powder is sucked into the needle-loading portion. The μ and the air introduction flow path are formed in one piece, as shown in the following paragraphs, and the following structures are provided: *There are the following structures *±巾? a powder inhalation holding container for the end of the suction device: hitting to perform micronization: the container is to be received by the air to be sealed with the mouth seal; and the final block form of the freeze-dried composition, and the The inside of the container, the suction bow of the container is made by *:> Donggan 垛 composition air impact 'and means from the composition; % pulverized and micronized powder freeze-dried 315314 51 1327073 which has: needle portion It has a suction flow path for the above-mentioned volume and a cold side for the outer gas to be guided; The flow path is introduced into the suction port portion of the air introduction needle portion of the container into the suction port portion. The holding portion operation portion is formed into a bow in the axial direction and a guide portion, and the container is guided to the needle portion. Needle 卞, 隹: 保 (4) The above-mentioned holding part of the tip of the needle, or from the upper and the mouth of the bar is pushed back from the needle tip by the upper 4, the mechanism of the needle tip, to the mouth of Fen. The bolt is pulled away from the above-mentioned needle portion, and the force required to operate the body and the plug is small, and the force required for the plug is to support the needle portion and to provide the suction port portion. Keep the Ministry of Transportation (4) outside of H and W. The crucible and the suction channel formed in the port and the air introduction flow path and the volume 4 needle portion are positioned to be in the air introduction 2, and the cold shaft is dried by @^^阿·, In the state of force, by using the above-mentioned suction port of the subject and sucking air through the air into the weeping effect, the work wind of ώ π ... into the container, the above tolerance can be The inner 7 freeze-dried composition imparts an air impact. 310. The method of claim 309, wherein the outer casing is formed into a cylindrical shape, and the end, (4) outer casing core = is in front of the outer casing. Ρ 315 314 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 The gas introduction port is provided in a wall portion of the outer casing; and/or the holding portion is moved forward and backward in the axial direction of the casing by the holding portion operation portion. U. According to the aspect of the invention, the transpulmonary administration is carried out by inhalation of the dry powder, and the outer casing is formed by the outer casing body having the above-mentioned capacity: the mouth is formed at the position where the retaining portion retreats, and the hinge is formed. a lid that is coupled to the inlet and outlet of the outer casing body; and a closed portion that includes the lid on the lid, and the needle inlet of the lid hitting portion to the (four) portion of the inlet and outlet, and is pulled up When opening, the above-mentioned holding portion is from the needle portion of the needle portion, the body is returned to the mechanism portion, and the lid is also used as the mechanism portion. (4) The dry powder inhalation system for lung administration is dry group == :: The dry powder inhalation system is a system in which a combination of cold and medium, which is incorporated into a device, the composition of which is contained in a volume composition, which is in a non-powder state in which the air impact thief is cold and not pulverized. When the micron has a composition of two or four, a particle having an average particle diameter of 1% or more of the lung-spraying effect particle ratio can be formed in the container. According to the transpulmonary and dry powder inhalation system, the user Use (inhalation) to save 315314 53 πI Providing cooling to the dried composition, to prepare a self pulmonary and adapted to: dosage form 'i.e. the ratio or effective particle with an average particle diameter in microns square〗). A dry powder preparation consisting of U particles on a %, and can be self-administered (it is important to obtain a dry powder inhalation system for pulmonary administration by the treatment of I. "Composition of the composition, inhalation device And the container as the freeze-dried composition, preferably # # μ 1 + ^ t in the dissolved state, the added component is used to prepare the composition liquid containing non-.+ by freeze-drying, and has The characteristic cold-drying (IV) f I and eight (1) have a non-powder block form; (ii) the decay index is 〇.〇5 or more; and (in) by bearing a name of at least lm/sec, 6 曰 wind speed and air impact of at least 1 7ml / Sec work flow S, ^ L becomes particles with a mean particle size below 10 microns or an effective particle ratio of 1% or more. About the freeze-dried composition The group uses the right ··+. η, 立, 立 U and its modulation method, which can be used later in the above (1). The freeze-dried composition is contained in 啰1> The pirates are freeze-dried and sighed in the distance. They are contained in containers and better packaged. Fr rt θ 巧 巧 'East dry composition of the amount of flat and 1 soil EL with early cast (i fish-owed) on the disk θ, or several people (specifically 2 to 3 - people) And the amount of the active ingredient in summer, preferably the amount of the active ingredient of the package. It is contained in the early 4 and the amount (1 shot of the specific amount, depending on the composition of the dry composition of the cold; the addition of the dry composition) The amount is different from the inhalable amount; (4) and the addition of 佴W is not particularly limited, and the 315314 54 1327073 is usually 30 mg or less, and the sputum is more than 20 mg, more preferably 10 mg or less. It is less than 5 mg. There are the following two: face 'as a dry powder inhaler, preferably I use a dry gentleman with the following characteristics', 〇 + / know the end of the device: with (1) air impact盥手# (or air introduction means, month ah-, thousand & '(2) political granule discharge means (or inhaled fish fleet, by the above (1) air impact: mountain), powder state of cold to dry roasting : The machine "introduces (--) the container that contains the non-* sown from the rβ substance, and uses the introduction (inflow) of the two", ·, pressure) to lyophilize the composition. The granulation is further obtained by the above-mentioned (2) particle discharge means 'dissolving the particles of the means (1): the contents are taken out, and can be directly injected into the method =: inhaled 2 - for example, on The dry powder detailed in the chapter (3), that is, the appropriate transpulmonary administration of the present invention is at least used when it is used, and is used to contain the above-mentioned The container of the lyophilized dry-welded composition of the invention and the system of the above-mentioned system are also used in the system of the dry powder inhalation device. The dried granules of the present invention are used for accommodating the sputum and smuggling of the present invention. Use 刖, a container with a freeze-dried composition and a powder inhalation device. 35 u and the above-mentioned dry right, 3⁄4 The system of the present invention is inhaled by using the 窨 窨 从 从 播 播 播 播 播 播 : : : : : : : : : : 吸入 吸入 吸入 吸入 吸入 吸入 吸入 吸入 东 东 东 东 东 东 东 东 东 东 东+, A is now Liu < each benefit, ' °, freeze-dried composition is presented to the disk, b] πι / sec air speed and ... 'Wang Xi 1 hit, can be prepared and prepared: 'air flow The air is rushed into the wrong diameter of the lungs or can be effectively used 315314 55 1327073 for the ratio of the effective particles administered by inhalation through the lungs, regarding the particle size that can be administered by inhalation through the lungs, for example, early preparation The average particle size of aerodynamics, ΜΜΑ _ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Above, "," the effective granules are better than 30%, especially better than 35%. More than 25 /. Above, according to the system, the modulated lung can be administered (by inhalation) to use This °, the preparation directly with the dry powder inhalation system can be described as "suitable for the dream of the second" Mingzhi lung,.. 9 And a manufacturing system for a dry powder preparation for pulmonary delivery, and a system for administering the dried product to the user." The final preparation is administered by the lung, and the dry powder for pulmonary administration of the present invention is used. The inhalation system includes the specific forms disclosed below: Le, brother package 3 below 401. - type of dry powder for lung administration and (7) combination: ... into the system, the following (1) (1) contain the freeze-dried composition The composition of the freeze-dried composition will contain non-additional components in the state of the solution, and the liquid is prepared by freeze-drying and has the following characteristics (1) to (iii): 1) having a non-powder block form; (Π) a decay index of 〇·〇5 or more; and relying on, by an air impact having an air velocity of at least lm/sec and an air flow of at least the old (10), Particles having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (2) having a gas-capable (9) and a cold of the above-mentioned volume; East Drying Group 315314 56 1327073 means of forming and discharging micronized A device for the means of powdered cold-bundled composition. The dry powder inhalation system and the container in which the freeze-dried composition is contained in the lungs according to the above paragraph #4〇1, is a container for accommodating the freeze-dried composition containing the active ingredient in the sub-injection. For example, the dry lung inhalation system for transpulmonary administration according to Item 401 is used in combination with the above-mentioned container and the above-mentioned splitting form when inhaled. 钵,: 4·如## The dry powder for transpulmonary administration described in Item 401 In the second line of the system, the decay index of the composition of the east dry matter is as described in the article. The air impact system described in the dry lung inhalation system is described in the article. At least one: a velocity and an air flow of at least 17 ml/sec. In particular, if the lungs are administered by the lungs and the dry powder is inhaled, the air impact recorded in (4) is produced by the air velocity of at least 17 ml/see. Two milk, summer air production system, ^07. According to the 401 items of the lungs, the dry powder inhalation system is used, and the air impact system described in (m) is by the hollow space. At least 1 m/sec < gas velocity and air flow of at least 20 ml/sec* are produced. 08. Transplantation of lungs as described in the aspect of the art. The air shock described in (m) is produced by having a helium air velocity and a flow rate of 17 ml/seC to i5 L/sec*V mSec. The amount of air produced by two milks 315314 57 1327073 409. If the lungs are administered to the heart as described in paragraph 4〇1, the cold-dried composition has the ability to withstand air rushing 4 =

The average particle size is below 5 microns or the effective particle ratio is characteristic of the coffee grains. Work unit U 410. According to the aspect of the invention, the transpulmonary administration system is described in the above paragraph, wherein the cold-dried composition comprises as an effective ingredient: a two-two drug. His knife

Inhalation of the active ingredient of the protein with a dry powder, the inhalation of the active ingredient in the dry powder is maintained as 4 1 1. According to the aspect 40, the pulmonary administration system described in paragraph 1 1 wherein the freeze-dried composition comprises as a class and nucleic acid And other polymer drugs. 4 1 2 · The lung administration system as described in the aspect of the invention, wherein the freeze-dried composition contains nucleic acid as a state of maintenance. Three 4U. According to the aspect 410, the transpulmonary administration uses a dry powder system, wherein the freeze-dried composition comprises as a low component of the active ingredient: a drug and a carrier, the carrier being at least one selected from the group consisting of amines A group of peptides and saccharides composed of a base acid and a dipeptide knife. ' 414. According to the aspect 4U, the lung is administered by a dry powder inhalation system, wherein the cold; the east dry composition comprises an egg (a) as an active ingredient, a polymer drug such as a nucleic acid, and a carrier. The agent is at least one selected from the group consisting of amino acids, dipeptides, tripeptides and saccharides. 415. The dry powder inhalation system for transpulmonary administration according to the aspect 4, wherein the cold bead dry composition comprises a low hydrazine drug as an active ingredient and a carrier, the carrier being at least one selected from the group consisting of hydrophobicity Amino acid, 315314 58 1327073 Aqueous dipeptide and a group of hydrophobic tri-forms. = a dry powder inhalation system for transpulmonary administration according to the aspect 414, wherein the cold-dried composition comprises a southern molecule drug such as a protein or a nucleic acid as an active ingredient, and a carrier, wherein the carrier is At least one selected from the group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tri-form; wherein the lung is administered by a dry powder inhalation system, and the medium lyophilized composition is A water soluble composition. = According to the 401 item, the dry powder inhalation system for transpulmonary administration, /, the device uses the following 丨) and ii): i) via the lung, with dry powder for six crying, human, It is a device for inhaling the dry composition of the east of the non-powder state, and the obtained microparticles are supplied to the subject for inhalation, which has: 2 a needle portion of the air nozzle flow path, and a needle portion having a discharge flow path And an air pressure feed means for conveying air in the heart-empty nipple jet flow path, / a suction port through which the discharge flow path of the needle portion communicates; and configured as <

The needle portion is inserted into the supply + P path and the discharge flow path and the above-mentioned volume 2:; the air jet flow segment 4 is stolen and connected, and the air jet flow path is sprayed by the air jet flow path. In the above-mentioned container, the freeze-dried composition is atomized by the impact of η έ : λ , and the obtained fine particles are discharged from the suction port through the discharge flow path. η)Π:! A dry powder inhalation device is used to store the dried composition in a non-powder state by micronization and to obtain a microparticle for inhalation, which has: 315314 59 1327073 /, a needle portion having a suction path, and a suction portion having an air guide and the suction flow path; the needle phase is configured to: the suction pressure of the subject in the needle portion is sealed from the upper portion; +, B is sad, when the error is caused by the air in the container, through the inside of the container, by the inflow: two ^ particles that have become a container of negative pressure through the above:: = dry composition micronization The upper attack and drainage path are discharged from the suction port. 19. For example, in the case of 418, the lungs are administered by the Department of Health, in which the device (4) is administered by the lungs (4), and the device has the following components. The smashing of the smashing is carried out in a non-powder block shape, and 7 钇煸 composition, and the above freezing in the container Drying the above-mentioned container to attract air by air === air impact, and from the means of the composition; ❹化的粉状冷凌干 It has: Needle part, with a supply from the above 5! 0 knife bow 丨μ, + ·The suction of the human 彡丨F 1 , / β. The suction channel of the above-mentioned freeze-dried composition is attracted by the heart of the flow path (4) and the air guide for guiding the external air to the above-mentioned volume (4) and the suction (four) of the needle. The holding portion is guided to the needle portion holding portion operating portion, and has a guiding portion in the upper/two directions, and when the "grass is held in the holding portion 315314 60", the container is inserted into the needle tip, and From the second and the container of the container is used by the mechanism of the needle tip The mouth bolt is pulled away from the above portion to be formed into a usable body, and the mechanism, the needle portion is required to be inserted into the mouth of the container, the operation body is operated with a small force, and (4) the force is required If the needle portion is provided with a casing for providing the suction port portion, the guiding portion, and the holding portion operating portion; and the needle portion is inserted into the needle portion to facilitate the suction flow path of the needle portion and

Li Guang': the road is connected to the inside of the container, and when the freeze-drying group is clamped into the state of the front end of the air introduction flow path, the suction air is sucked into the container from the suction port by using the subject. Air and air are introduced into the container through the air introduction flow path to impart an air impact to the freeze-dried composition in the container. 420. The dry powder inhalation system for transpulmonary administration according to aspect 401, wherein the following (1) and (1) containers for lyophilizing the composition are contained, the freeze-dried composition system comprising non-dissolving The composition of the added component of the state is prepared by cold drying to have 'the characteristics of the following (1) to (iii): (i) having a non-powdered bulk form; (ii) having a decay index in the range of 0.05 to 1.5 And (iii) by subjecting an air impact having an air velocity of 1 to 300 m/sec and an air flow of i7 ml/sec to 15 L/sec, the average particle diameter is below 1 〇 micron or the effective particle ratio is 1 〇%. The above microparticles; and 315314 61 1327073 (2) are provided with means for imparting the above-mentioned air impingement to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition. ^ 421. According to the aspect 420, the transpulmonary administration uses a dry powder inhalation system, 'first, wherein the container for accommodating the freeze-dried composition is a freeze-dried composition for containing the active ingredient of the worker. Container. 422. The air velocity of the transpulmonary administration using the dry powder inhalation system as described in item 420 is 1 to 25 μm/sec. 423. According to paragraph 420, the lungs are administered with a dry powder inhalation system, and the air flow rate is 20 ml/sec to 1 〇L/sec. (5) Transpulmonary administration method Further, the present invention relates to a pulmonary administration method comprising the state of being prepared into a particle which can be administered through the lung when the (ly) lyophilized composition in a non-powder state is used (administered) And inhaling the dry powder preparation in the form of the microparticles. The method of pulmonary administration can be carried out by using a dry-pulling inhalation system for pulmonary administration according to the present invention as described in detail in (4), which system is intended to contain a non-dissolved state as detailed in containment (1). The container of the component of the present invention is prepared by freeze-drying the container of the freeze-dried composition of the present invention, and the dry powder inhalation system consisting of the dry powder inhalation device detailed in the chapter (3). The pulmonary administration method comprises the specific aspects disclosed below: Baxin 501. - A method of pulmonary administration, comprising using a freeze-dried composition, 62 315314 1327073 = to dry the composition will contain an additive component in an undissolved state. The composition liquid and the cold 4 are dried to be prepared, and have the following characteristics: (0 has a non-powder block form; (11) a decay index is 0 05 or more; and (Hi) by withstanding an air velocity of at least W And an air impact of at least Uml/sec air flow can be a particle having an average particle diameter below ι〇micron or an effective particle ratio of 10% or more; The east dry composition is equal to the average particle M 1G micron or the effective particle ratio is ι〇% and the micro pull 'and then by the user inhaling the micronized powder and cast 502 · as described in the 5G1 lung injection method Wherein, the frozen "composition contains the active ingredient of the sputum administration amount. 5. 〇 3. The method for the pulmonary administration according to the item 5G1, wherein the cold-drying composition is contained in the argon And the micronized powder is used for the preparation of the glutinous rice, the lyophilized composition can be given the above-mentioned air impact, and the powdered lyophilized powder can be pulled by the granules. The composition is prepared from the device of the means of discharging from the crying. .... 5 0 4. If the state is 5 〇 1 jgΛ

d The admin has a method of transpulmonary administration, wherein the decaying composition of the A-card dry composition and the number of _ / λ ^ 7 are in the range of 0.05 to i. 5 0 5. As in the case 5 (Π is 4 in mpt, the method of transpulmonary administration, in which air is generated at an air velocity of mw eight to 2 m/sec and air flow of ml/sec. 5 0 6 · As in the case of 5 (Π, 项 己 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载 载The air velocity of sec and the air flow rate of air flow of at least 17ml/sec S., 507. How to record the lung injection method of 503, in which (A) has a work A impact by at least The air velocity of the air and the air flow to >, 2 〇 ml/sec. 508. If the pattern is 503 jg 4 ^ ^ item 5, the method of lung administration, wherein, in (iii) The air impact system, (3) the air flow with an air velocity of at least 1 m/sec and m sec to 15 L/Sec. The lung administration method according to the state #5〇3, wherein the cold/ The east dry composition comprises a low molecular drug which is an active ingredient of & ^ horse. 510. The method according to 503, wherein the preparation of the lung is dry The substance comprises an oxygen-based 7-drug. The protein is an active ingredient of a protein and a nucleic acid, etc. 5 11. If the 503瑁4A ^ .^ item is a lung-administered method, wherein the cold nucleic acid is effective. The component is maintained in the state of the retaining body 512. If the composition is 5〇91^匕东 dry composition is included as: loading:: lung administration method,", the cold carrier is at least - selected t effective ...molecular drug and carrier, group k from amino acid, dipeptide, tripeptide and anthraquinone 5 1 3 · as in the case of 5 1 〇 - . _ Ά ^, the recorded transpulmonary administration method, wherein a group consisting of a protein and a nucleic acid such as an active ingredient of the carrier and a high-quality tripeptide and a saccharide: the agent is at least one selected from the group consisting of an amino acid, a dipeptide, and 315314 64 5 1 4. 5th dry composition comprises, as the carrier, a group consisting of at least one selected from the group consisting of tripeptides. The pulmonary administration method, wherein the cold active ingredient is a low molecular drug and a carrier, Hydrophobic amino acid, hydrophobic dipeptide, and hydrophobic 5, as described in paragraph 513 of the method of pulmonary administration, wherein the cold: And the product comprises a high-grade Thousand music and a carrier such as a protein and a nucleic acid as an active ingredient, 兮#士,&, 洌为至>, one selected from hydrophobic amino acids, myosin dipeptide And a group of hydrophobic tripeptides. 5 16. As the aspect; the east dry composition is the 503 method of pulmonary administration, wherein the cold water> gluten composition. 5 1 7. 503 1B, the pulmonary administration method is a method of administering microparticles into microparticles having an average particle diameter of 5 μm or less or an effective particle ratio of more or more. 5 1 8 . The method according to aspect 503, wherein the device is a dry powder inhalation device according to the item 3〇 j or 302 described in the chapter (3) of the dry powder inhalation device. 5 1 9. The method according to the aspect of the invention, wherein the device is a dry powder inhalation split of the shape item 3〇9 described in the chapter (3) of the dry powder inhalation device. 520. The pulmonary administration method according to the aspect 5, wherein the freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following characteristics: (1) ) has a non-powder block form; : and (ii) the decay index is in the range of 〇·〇5 to 1.5 315314 65 1327073 (d) by withstanding! The air impact at an air velocity of 300 m/sec and an air flow of the old (6) to 15 L/sec may be particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more; It is prepared by using a device having means for imparting the above-described air impingement to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition from the container. 521. The method according to aspect 520, wherein the air velocity is 1 to 25 〇m/sec.曰522, a method according to the aspect of the invention, wherein the air flow rate is from 20 ml/sec to l〇L/sec. (6) Cold/East dry ingredients are used in inhaled transpulmonary administration. Further, this is the use of a cold-dried composition in a non-powder state for inhaled transpulmonary administration. This use includes the following aspects: 〃 601. The freeze-dried composition is administered by inhalation via the lung, wherein the freeze-dried composition will contain the added component in an undissolved state, and the solution is cooled. / East dry and prepared, and has the following characteristics: (i) has a non-powder block form; (ii) decay index is 〇. 〇 5 or more; · and (mountain) with at least lm / sec The air velocity of the air velocity and the at least air flow rate may be particles having an average particle diameter below ι〇micron or an effective particle ratio of more than 1% by weight; the freeze-dried composition is powdered to have the above average particle diameter or has 315314 66 1327073 Particles of the effect particle ratio are used. 602. The freeze-dried composition according to aspect 601, which is administered by pulmonary administration, wherein the freeze-dried composition is an active ingredient containing j administration amount. 603. The freeze-dried composition according to aspect 601, which is used for pulmonary administration, wherein the freeze-dried composition is contained in a container, and the micronized powder is used in the container. The freeze-dried composition can be prepared by means of the above-described means of air impact and means for discharging the micronized powdery freeze-dried composition from the container. 7 04·If the chilled dry composition of the 603 item 6 is used in the administration of the lung, the decay index of the cold-drying composition is in the range of 〇 5 to 1.5. 6〇5. Use as described in paragraphs 6.3, wherein the freeze-dried air velocity of 2 m/sec and at least 17 strokes can form particles having an average particle diameter above 丨〇micron. The lyophilized composition is administered to the composition via the lungs by subjecting the air to have an air flow rate of at least ml/sec to the following or effective particle ratio at 丨〇0/〇606. * private β, and the freeze-dried composition is used in the administration of the lung, the towel, the freeze-dried composition is subjected to an air velocity of 1:3〇〇m/SeC and at least 1.... The air impact of the air flow of C can form particles having an average particle diameter of less than 1 〇 1 υ domain wood or an effective particle ratio of 10% or more. 607. If the lyophilized composition of the 603th record is used in the pulmonary administration, wherein the freeze-drying is performed, and the adult system is subjected to an air velocity of at least 3Ι53Ι4 67 1327073 and at least The air flow of the air flow of 2〇mi/sec forms an average particle size! Those below 0 microns or having effective particles above the above. The freeze-dried composition of the heart-shaped 603 brothers is administered in the lungs, and the medium freeze-drying composition is subjected to an air velocity of at least lm/sec and π ―, _ n ml/seC to 15 L/ The air flow of the sec air is impacted by the air, forming a particle with an average particle size above the post. The ratio of the effective particle or the effective particle is 609. If the state is 6〇3, it is recorded in the evening, and the free-drying composition is placed in the lung to form an average particle size of 5 micro or less =# Those who withstand the impact of air, the particles. , ^ or the effective particle ratio is above 20% 6 1 〇 · If the state of 6 〇 3 items describes the use of cold ling, loaded by ... "The composition of the drug in the lungs of low molecular drugs. 勹 has been "effective Ingredients 611. If the 603 items are used, the use of human society, JL, ^r A^ 7 / L dry composition in the lungs can be used to dry #4 cold 4 dry composition white matter and nucleic acids, etc. Polymer drugs. To be effective as an egg 612. If the 603 items are used in the cold, where is the frozen skin? Further, the adult is administered a nucleic acid which is maintained in a maintained state by the lung. ',,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, The carrier is at least one selected from the group consisting of an amine group v:r too low 315314 68 1327073 tripeptide and a saccharide. 614. If the cold-dried dry matter recorded in the 611th aspect is used in the lungs, the cold-dried composition contains the peptone and the nucleic acid-specific molecular drug and the carrier as active ingredients. The carrier is at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides. 6 1 5. If the lyophilized composition contained in the L-class 6 § 1:1 is used in the lung, the lyophilized composition contains the low-molecular drug as an active ingredient and the carrier. The agent is at least one selected from the group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tripeptide. 616. The cold-pure dry composition according to aspect 614 is used in a lung-dropping, wherein the cold-washed dry composition comprises two molecules of a protein such as a protein and a nucleic acid as an active ingredient, and a carrier. The carrier is at least one species: a group consisting of a hydrophobic amino acid, a hydrophobic dipeptide, and a hydrophobic tripeptide. 0 617. The cold-dried composition described in Section 603 is used in the lung. Wherein the cold-dried composition is a water-soluble composition. 618. If the cold and pure dry composition described in the 6G3 item is used in the lung, the device is used in the dry powder inhalation device of the above (3), and the sadness of the sample is 3 0 1 or 3 02 Dry powder inhalation device. 619•If the cold-bead-dried composition described in the aspect (10) is used in the lung, the 'where' device is used in the dry powder inhalation device of Chapter (3) above. Dry powder inhalation device. 620. The lyophilized composition according to the 603th item of sadness is used in the blood of the lung, and the composition of the cold stalk is contained in the non-dissolving form = 315314 69 1327073. And having the following characteristics: (1) having a non-powder block form; (ii) a decay index in the range of 0.05 to 1.5; and (111) by withstanding an air velocity of 1 to 300 m/sec and The air impact of the air flow rate from 17ml/sec to 15L/Sec can be a particle with an average particle diameter of less than micrometer or an effective particle ratio of 10% or more. The powder is cryogenically micronized, and the air impact can be used. The lyophilized composition described in the above-mentioned means for lyophilizing the composition and the means for discharging the micronized powder from the container, and the lyophilized composition described in Item 620, is injected into the lung The flow rate is 1 to 25 〇 m/sec. The freeze-dried composition described in the above paragraph 62 is administered by transpulmonary administration, wherein the air flow rate is from 20 ml/sec to 10 L/sec. The dry composition is manufactured by using a dry powder for inhaled transpulmonary administration. Furthermore, the use of the cold-dry dry in the non-powder state for the manufacture of inhaled transpulmonary sputum P "^ is contained in the preparation of the sputum-dried sputum. The use package 3 is not disclosed in the following: 701· freeze-dried composition is too much to be used in the main & inhaled lung-administered dry powder preparation, and the cold-cold dry composition has the following composition Characteristics: (1) The composition will contain non-dissolving energy, and the composition of the added component will be dried by cold drying. 315314 70 丄 / 073 (II) has a non-powder block form, (III) decay index 0.05 or more, and (d) by subjecting an air impact having an air velocity of at least 丨m/sec and an air flow of at least ι: = l/sec, the average particle diameter may be micro== or the effective particle ratio is 1%% The above microparticles; and, at the time of use, the freeze-dried composition is micronized to have the above average particle diameter or the above effective particle ratio. 7〇2. If sorrow, sample 701 is cold; use of east dry composition. 'The freeze-dried composition is contained! The sub-injection and the effective component of the dose:, the t-sample 7〇1 item of the freeze-dried composition in the manufacture of the lung finger: and the use of dry powder for the use of 丨 丨 + 一 , The clothing index of the object is in the range of 〇.〇5 to 1,5. 704. The lyophilized composition of aspect 701, wherein in the manufacture of transpulmonary: a dry mash composition, the lyophilized composition f = having an air velocity of at least 2 and at least an old air emulsion The air impact of the flow rate can form particles having an average particle diameter of 1 μm or less or an effective particle ratio of 1% or more. ^ 7〇5·如_7〇1 The cold-dried composition of my use is used in the manufacture of dried sputum preparations for the lungs. Among them, the cold; the eastern dry composition is straw! ! Ϊ́ί has an air velocity of 1 to 300 m/sec and at least 17 - a gas impact in the gas engine can form particles having an average particle diameter of less than 1 〇 micrometer or an effective particle ratio of 纟 10% or more. 706• The cold as described in paragraph 7〇1; the dry composition of the east is used in the manufacture of a dry powder preparation for transpulmonary administration, and the freeze-dried composition is 315314 1^27073 2 Luo and eight to J The air velocity of lm/sec and at least the air impact of the air flow can form particles with an average particle diameter below 10 μm or an effective particle ratio of 10% or more. The freeze-dried composition is used in the manufacture of a transpulmonary = dry (four) final formulation, wherein the cold-drying composition has an air velocity of at least lm/sec and an air flow of 17 ml/seC to L/sec. The air is impinged to form particles having an average particle diameter of 1 μm or less, or an effective particle ratio of !% or more. The freeze-dried composition described in 1971, in the manufacture of a pulmonary dry powder preparation, wherein The cold-dried composition is subjected to air impact and can form particles having an average particle diameter of 5 μm or less or an effective particle ratio of 20% or more. The freeze-dried composition described in the & && sample 7〇1 Manufacture of a pulmonary dry powder preparation for use The cold-dried composition is a low-molecular drug containing the active ingredient of the package 3. The freeze-dried composition of the L' sample 701 is used in the manufacture of a lung and a dry powder. The freeze-dried composition package 2 is effective, and a polymer drug such as a protein or a nucleic acid is used. The cold-dried composition described in the 7G1 item is used for the production of a lung-dried composition, wherein the freeze-dried composition is used. The bacteriological component is a nucleic acid which is maintained in a state of being in a retaining body. The lyophilized composition of 709 δ is used in the manufacture of a dry powder containing 2 dry powder preparation, wherein the cold-blooming composition has an effect component a low molecular drug and a carrier, the carrier being at least one of 315314 72 1327073 selected from the group consisting of diamine acids, dipeptides, tripeptides and saccharides. 3. Cold beam drying composition as described in & 71G In the manufacture of the lungs and the use of dry powder f, the lyophilized composition package::: protein components of nucleic acids and nucleic acids and other high-molecular drugs and planted groups are at least One selected from the group consisting of amino acids, dipeptides, Peptide and anthraquinone group π disc 2, such as the cold-dried composition described in Item 712, is produced in the lungs, and is used in a dry powder preparation. In which, the 'freeze-dried composition is packaged, white ^/文刀的低分子药物和载剂' The carrier is at least one of the group consisting of hydrophobic amino acids, hydrophobic dipeptides and hydrophobic tripeptides t ～ 713 圮 之 freeze-dried compositions In the manufacture of transpulmonary and dry powder preparations, the sword, nucleic acid and other high-molecular medicines and the group of J-types are at least one selected from the group consisting of hydrophobic amine hydrophobic tripeptides. ^Sexual peptide and m The cold-cold drying group described in Item 701 is administered with a dry powder to prepare a lung water-soluble composition. Wherein the cold-dried dry composition is 717. The use of a dry powder preparation for cold-supplied administration as described in Item 701 to produce a finely divided powder of the lung preparation has a dry powder ratio of the lung for administration. the above. The dry-dried composition described in the following paragraphs or the granules of the granules 718 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ In the container, and the micronized powder, a device having means for imparting the above-described air impact to the freeze-dried composition in the container and means for discharging the micronized powdery freeze-dried composition from the container Modulated. 7 1 9. The lyophilized composition according to the aspect 7 1 8 is used in the manufacture of a pulmonary injection and a dry powder preparation, wherein the occupation is carried out in the chapter (3) Drying_Powder inhalation device. A dry powder inhalation device of the form item 3〇1 or 3〇2. ^ 72 〇 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 9 dry powder is placed inhaled. 72 1 · The use of the freeze-dried composition according to the aspect 70 1 in the manufacture of a dry powder preparation for transpulmonary administration, wherein a cold-rubber composition having the following characteristics is used

(0) The composition liquid containing the additive component in an undissolved state is prepared by cold beam drying, L (II) has a non-powder block form; (III) The decay index is in the range of 0 〇 5 to 15 And (mountain) by an air impact with an air velocity of 1 to 300 m/sec and an air flow of i7mi/see to 15L/sec, the average particle size is below 1 〇 micron or the effective particle ratio is 丨〇 More than % of the particles. 7 2 2. The lyophilized composition described in paragraph 7 2 1 is used in the manufacture of 315314 74 1^27073 in combination with a dry powder formulation, wherein the air velocity is from 1 to 250 claws/ Sec 〇 723. The lyophilized composition according to the aspect 721 is used in the manufacture of transpulmonary and dry powder preparations, wherein the air flow rate is from 20 ml/sec to 1 〇L/sec. The use of a lyophilized composition for preparing a dry powder preparation for pulmonary administration is prepared by dissolving a composition liquid. Further, the present invention relates to a non-dissolving composition liquid for adding an ingredient in the preparation of a dry powder preparation for pulmonary administration The use of cold green dry ingredients is required. Method for preparing a component for preparing a freeze-dried composition, a method for preparing the same, a method for preparing a freeze-dried composition using the same, and a method for using the freeze-dried composition (dried powder for pulmonary administration) The preparation method of the preparation is as described above. ^ EXAMPLES The present invention is not limited to the following examples, and the examples of the invention are specifically described in the examples. Further, in the following examples, the dry composition (freeze-dried cake) is used. The fading evaluation was calculated by the method of dry powder which was micronized. <Calculation of Decay Index> The non-powdered freeze-dried index and effective particle ratio of the present invention (indicator for delivery to the lungs) were in accordance with the dried composition (freeze-dried cake), 〇ml-hexane. It is automatically dropped into the 1 315314 75 1327073 laboratory mixer NS-8 (manufactured by Pas () Lina Co., Ltd.) in a non-powdered cold P East which is prepared in a non-powder form at a 3 rpm. Wreak 〇 second. The obtained mixed solution was placed in the optical path length i, and the uv of the optical path width was 1 to the surface (manufactured by Shimadzu GLC Co., Ltd.), and the mixture was quickly measured by a spectrophotometer (UV 240 'Shimadzu Corporation) at the measurement wavelength. In addition, the value obtained by dividing the twist by the total prescription amount (the total amount (weight) of the active ingredient and the carrier) is taken as the decay index. <Calculation of effective particle ratio> The container filled with the prepared non-powder-shaped freeze-dried composition was attached to a dry-end inhalation device. The device A (two-stage dust detector) which is used in the Pharmacopoeia, Third Edition Supplement 2001, pll3-115) of the powder preparation obtained by using the device and imparting specific air impact. Directly discharged from the British c〇pley company. Thereafter, the solvent charged in the second stage and the second stage of the apparatus is separately recovered, and the second stage and the second part are quantified by a method suitable for measuring the active ingredient in the cold-rolled dry composition such as bioassay and HpLC. The active ingredients contained in each of the solvents and media [Lucas's report (10) with r ", called), 562.569 (1998)) and the report of Iida et al. (Ref. Pharmacy Journal 1 19 (1 0) 752-762 (1999))]. It can be expected that the part of the lung that is delivered to the second stage (the particle size of the aerodynamics recovered in this part is 6 4 #爪#)" usually reaches the second paragraph of it. The ratio of the effective ingredient is called the effective particle ratio (the amount of lungs that can be expected to be obtained, that is, the fine particle ratio), which is used as a benchmark for evaluating the applicability of the inhalation agent for pulmonary administration. In the examples and comparative examples, the weight of the active ingredient contained in each of the second and second stages is quantified, and the weight of the active ingredient in the second stage is 315,314,76,1,327,073 divided by the total weight of the active ingredient to be sprayed (the first The total weight of the active ingredients contained in paragraphs i and 2: hereinafter referred to as "the second paragraph") The value is used as the effective particle ratio Kyu, Q /,, more than ten sheep twist (/ °). In addition, in principle, in the case of using the two-stage dust measuring device (manufactured by British company c〇pley) in the European Pharmacopoeia, the suction flow of the square and the working gas is set to 6〇, so the following examples And the comparative example is also the same. Dry powder inhalation device (injection type 1) The spray type used in the present invention, an embodiment of the original umbrella main exhibition and the inhalation device is described with reference to Fig. 1. The dry powder inhalation device is in a container for glare The non-powder unit at the bottom of 1 or several times of freeze-dried composition 2 of human, human, ± k, ^ is micronized and delivered to the air organ of the lung organ. θ ', ' ^ The utility model has a suction member 7 provided with an air jet flow path 3 and a discharge flow path 4, a suction port 6 and a base end provided at the base end of the needle portion 5, surrounding the oblique fixing and needle-free 5 and the same female full cover 8 and the air pressure feeding means 9 which are held by the container 1. The air pressure feeding means 9, the owner * seven n - is a manual type and has a tubular wind box 10 in the wind phase body The suction inlet 12 with the pull-in valve 11 and the discharge port 1 4 with the discharge valve 13 are provided on the 10, and the η- 2 ^ ^ 14 is disposed on the base of the air jet pair path '3 of the needle portion 5 The joint port 15 formed on the end side is in communication with the air jet flow path 3. Moreover, the sorrow of sucking in the ϋΐ & _, Λ valve 11 is closed The hunting is performed by applying a compressive force to the wind phase body 1 收 to the 511. The threshold 13 will be opened, and the nipple discharge port 14 in the wind box body: 10 is discharged through the second rolling jet flow path 3. In the container 。. On the other hand, if the compression force is released, the elastic recovery force of the wind phase body 10 by the body 1 〇 * will be stretched out 'spit out i 3 盍 or closed and the suction valve 丨丨 opened , 315314 77 1327073 The air is then introduced into the wind box body 10. When the dry powder inhalation device is used, . . . 1 shows the container 1 into the cylindrical safety cover 8 so that the needle portion 5 L 8 The plug portion 1 a of the state 1 and the air jet flow path 3 and the discharge flow path 4 are connected to each other. The inner state of the valley state 1 is connected. In this case, if the air pressure is sent to the first phase of the body 1 The crucible is contracted to allow air to be discharged from the discharge port 14, which will be ejected from the front end of the needle portion 5 toward the freeze-drying portion of the container through the work beam channel 3 by the air impact 'freeze-dried composition 2, the particles are further broken, and are discharged from the suction port 6 of the air suction member 7 via the discharge flow path 4 of the needle portion 5. The user (patient) can be delivered to the lung organ of the patient by inhaling the material from the inhalation port 6 of the inspiratory member 7, and the particles of the freeze-dried composition 2 can be delivered to the patient's lung. Further, the present invention The material of the mouth plug used in the container is not particularly limited. For example, you can choose any material such as rubber, plastic or aluminum, which is usually used as a medicine for accommodating medicines and sputum 仏α-milk and compound containers. In the injection type suction device, the air injection amount is set to about 20 ♦ 刎, the capacity of the container is about 5 (6), the aperture (diameter) of the air injection flow path 3 is about 1.2 mm, and the diameter of the discharge flow path 4 is (diameter) is about 18 丨 (10). However, the diameter of the air jet flow path 3 and the discharge flow path 4 is not limited to a preferred range such as the size of the container, and is not particularly limited. The diameter may be from 0 to 3 mm, preferably from 3 to 3. Suitable for selection in the range of -7 mm, more preferably 5 mm. Further, by adjusting the compression speed of the wind box body 10, the air pressure feeding means 9 can withstand the discharge amount of the fine particles required for the suction and can be adjusted to make the freeze-dried composition 2 large by the air injection. Partially micronized. 78 315314 1327073 Embodiment of the dry powder inhalation device (self-inhalation type 实施 One embodiment of the self-inhalation type dry powder inhalation device used in the present invention (the 1) is illustrated by a 帛 2 diagram. The dry powder inhalation device shown in Fig. 2 The needle portion 5 having the suction flow path 16 and the air introduction flow path 丨7, the cylindrical safety cover 8, and the suction member 186 having the suction port 8 communicating with the suction flow path 丨6 are provided, and the suction member is provided. 1 9 is connected to the proximal end side of the suction flow path 丨 6 of the needle portion 5. When the dry powder inhalation device is used, the container is placed in the cylindrical safety cover 8 as shown in Fig. 2, and the needle portion 5 is inserted. The port plug u of the container is connected to the inside of the container port by the suction flow path 16 and the air introduction flow path 17. In this state, the air in the handcuff 1 is sucked from the suction port 18 via the suction flow path 16 by the suction pressure of the patient. At the same time, the outside air is introduced from the air introduction flow path 17 and thus becomes the inside of the barn 1 of the negative pressure. At this time, the freeze-dried composition 2 is atomized by the air impact acting on the freeze-dried composition 2, and is prepared. The particles are delivered to the patient from the suction port 8 via the suction flow path 6 Further, the dry powder inhalation device is set to be inhaled by the patient, and most of the freeze-dried composition 2 can be micronized and discharged from the suction port j 8. Further, although the patient sucks once The air flow rate of A is preferably 5 to 3 〇〇 l/min, and even 200 L/min, preferably 1 〇 to 1 〇 () L /, more preferably, the self-inhalation type dry powder inhalation device of the present invention The design can be appropriately changed according to the breathing ability of the patient to be used. The inhalation device ίτ' shown in Fig. 2 is set so that the capacity of the container is about i 〇 ml, the air introduction flow path 17 and the suction flow path according to the breathing ability of a certain patient. The aperture (diameter) of 16 is about i 5 mni, whereby the composition is set to be inhaled by the patient, and the freeze-dried composition 79 315314 1327073 can be completely micronized substantially without residue and discharged from the suction port 18. Your i__l dry powder inhalation device (self-inhalation type 2) One embodiment of the self-inhalation type dry powder inhalation device used in the present invention (the 2) is illustrated in Fig. 3. The dry powder inhaling device shown in Fig. 3 and the Spray dry powder shown in Figure 1 The suction device is in the same form when the air box body 1 for pumping air is removed from the connection port 15; and the discharge flow path 4 of the spray type dry powder inhalation device of the second drawing is equivalent to the suction flow path Lu 1 ό 'air The jet flow path 3 corresponds to the air introduction flow path 17, and the getter member 7 having the suction port 6 corresponds to the getter member 19 having the suction port 18. Therefore, when using the self-inhalation type dry powder inhaler, In the same manner as the dry powder inhaling device shown in Fig. 2, the air in the container 1 is sucked from the suction port 18 through the suction flow path 16 by the suction pressure of the patient, and the external air is introduced from the air introduction flow path 17 Thereby, in the container 1 of the negative pressure, the freeze-dried composition 2 is atomized by the air impact generated by the inflow of the air. Thereafter, the obtained microparticles are delivered from the inhalation port 18 to the lung organ of the patient. Further, if the above-mentioned patient has an inhaled air flow rate of 5 to 300 L/min, the inhalation device shown in Fig. 3 can be set to a container capacity of about 5 m in accordance with the breathing ability of the patient to be used. The aperture (diameter) of the flow path 17 is about 1 _ 2 mm 'and the aperture (diameter) of the suction flow path 16 is about 1.8 mm. Thereby, the majority of the freeze-dried composition 2 is micronized by one inhalation by the patient and discharged from the suction port 18. When the dry powder constituting such a self-inhalation type is sucked into the farm, the air suction means 9 such as the bellows body 10 can be detachably attached to the port 15, and the self-inhalation type inhaler can be changed to Spray type. By 315314 80 1327073 The same dry powder inhalation device can be used in any form suitable for the type of suction and spray. The dry powder inhalation device of the present invention can be inhaled or sprayed by itself! In either form, the freeze-dried composition may be formed so as to form fine particles having an average particle diameter of not more than 丨〇 micrometer (preferably 5 μm or less) and having substantially no residual scattering by selecting the size of the impact of the second gas. FORM TYPE _ _ _ dry powder inhalation device (self-inhalation type 3) An embodiment (3) of the self-inhalation type dry powder inhalation device used in the present invention will be described with reference to Figs. 4 to 丨〇. Further, Fig. 4 is a perspective view showing the dry powder inhaling device, and Fig. 5 is a cross-sectional view showing the dry powder inhaling device. Further, Fig. 6(a) is a partial cross-sectional view showing the needle portion 5 and the suction port 3' of the dry powder inhaling device, and Fig. 6(b) is a side view showing the needle portion 5. Further, Fig. 7 to Fig. 1 are sectional views showing the operation of each dry powder inhalation device. The dry powder inhalation device includes a needle portion 5 formed by the suction flow path 16 and the air introduction flow path 17 , a holding portion 22 for holding the container 1 , a storage chamber 20 for accommodating the container 1 via the holding portion 22 , and a holding portion for holding the container 1 The guide portion 23 provided in the storage chamber 20 in the axial direction of the guide needle portion 5 and the holding portion operating portion 24 that advances and retracts the holding portion 22 along the guide portion 23, and are housed in the cylindrical outer casing 21 in. Further, the mouthpiece 32 is provided at the front end of the casing 21. The mouthpiece 32 has a suction port 31 which communicates with the suction flow path 16 of the needle portion 5. As shown in Fig. 7, the outer casing 2 1, in particular, has a casing body 26 having an inlet and outlet 25 formed at a position where the holding portion 22 is retracted, and a cover of 315314 81 ^^/073 ^^/073 into 26 25 27. The cover 27 is coupled to the casing body by a hinge 21A. A window 28 for confirming the filling of the container 1 is provided on the cover 27. Into 32, an inlet port 29 for introducing an outside air is provided in a wall portion of the outer casing 21, and a check valve 30 is installed in the guide. Further, the mouthpiece mouthpiece 32 is attached to the front portion of the casing door, and the suction port 31 is closed by the lid 32a when the dry powder suction device is not used. The soil forms a flange-shaped partition wall portion 33 at the base end portion of the needle portion 5, and the air introduction: the end portion of the passage 17 passes through the partition wall portion 33 and opens to the outer circumference of the partition wall portion 33. Further, the peripheral wall portion 34 is separated from the partition wall portion. The outer periphery of the portion 33 faces the mouthpiece 32 and can be extended by:::31. The needle portion 5 is mounted in the outer casing 21 by inserting the partition wall portion 33 into the front end of the outer casing 21. The gentleman is wrong. The shaft of the outer casing 21 and the direction of the image are aligned with the axial direction of the needle 5. The ampule is placed in the holding portion 22 for the knee. The female thief 1 is pulled out from the bottom of the holding portion 22 and taken out. The body 35 is provided with a control lever 36 for picking up the card c. The pulling unit 1 is formed on the wire body 35. The operation unit 24 is provided with a mechanism portion 37 for reciprocating the holding portion 22 in the axial direction of the casing. a ^ ^ ', 乍 mechanism. Operation control lever of P 37. Mechanism unit 37. Having a connecting body 39. Lianshe Ά Jh A3. 4*. Body 3 9-end with a hinge 4 0,. On the holding portion 22, the other end of the connecting body 39, .97, μ is connected to the cover 27 by a hinge 41. The dice 27 is also used as the upper pa ga , and + as a fine control lever. wood Therefore, the holding portion can move the pen 2 π guide portion 23 forward and backward. The force of the force of the scorpion 27 is fi 〇# gp , , Λ ^ ^ Λ Μ is the arrow C of the 苐7 diagram, that is, The ΜΑ ΜΑ ΜΑ ΜΑ 该 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 41 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 The force required for the plug 1 of the device 1 is a small force operation cover (operation control lever) 2 7 〇 and 'as shown in Fig. 6, forming a second introduction path 42 for introducing air into the dry powder inhalation device in a supplementary manner » When the powdered freeze-dried composition is sucked by the suction nozzle 32, the outside air flows into the suction port 31 of the direct mouthpiece 32 via the second introduction path 42. Thereby, the patient or the child patient with low lung capacity can use the dry powder inhalation device without any burden. Further, the second introduction path 42 can be omitted. The second introduction path 42' is attached to the partition portion 33 of the needle portion 5 by the introduction groove 42a, and the introduction groove 42b is attached to the peripheral wall portion 34, and the mouthpiece 32 is fitted into the peripheral wall portion 34 of the needle portion 5, and It is formed by the mouthpiece 32 and the introduction groove 42& and 4 holes. A small gap 43 is formed between the mouthpiece 32 and the outer casing 2, and one end 44 of the second introduction path 42 is opened to the outside of the outer second introduction path through the gap 43 to the suction port 3 of the mouthpiece 32. Further, as shown in Fig. 6, the suction port 31 is provided with a wall 47 of the vent hole 46. Therefore, even if the air impact force of the freeze-dried composition 2 is reduced by the insufficient attraction or the like, the portion of the dry composition 2 is not the last portion, and the non-powder portion passes through the vent hole of the wall 47. It can be powdered. & Again, as shown in Fig. 6(4), before the air introduction path 17 of the needle portion 5, the mouth m is larger than the suction turbulence 1316 "front end. The i6a is closer to the freeze-dried composition 2 η ' as much as possible to suppress the flow rate of the air in the port barn 1 before the air introduction channel 17 is lowered, and the air 315314 83 1327073 can be effectively applied to the freeze-dried composition 2 . Further, since the port 16a of the suction channel 16 of the needle portion 5 is farther from the freeze-dried composition 2 than the port 17a before the air introduction channel 17, the month of attraction in the suction channel 16 of the needle portion 5' The freeze-dried composition 2 can be micronized as much as possible in the container 1. Therefore, the 'dry powder inhalation device' is used as follows. First, as shown in Fig. 7, the holding portion 22 is retracted to the inlet and outlet 25 of the outer casing 21 by pulling up the lid 27 and opening the inlet and outlet 25 of the outer casing 21. The container 1 is then mounted in the holding portion 22 in a manner that the oral inspection la is forward. Next, as shown in Fig. 8, the $ is used by closing the lid to close the inlet and outlet 2 of the outer casing 21. The body 39 presses the holding portion 22 in the direction of the needle portion 5, and the end portion of the needle portion 5 is inserted into the mouth plug 1 of each of the devices 1, so that the suction flow path 16 of the needle portion 5 and the gas introduction path 1 7 with the container! Internal connectivity. Next, by the patient

The suction pressure is 32 from the mouthpiece 32$ <59 2丨η A and the inlet 31 passes through the suction flow path 16 of the needle portion 5 and the air in the container 1, and the m hole becomes negative in the current 1 The pressure and the check valve 30 are opened, and the air is introduced into the container 1 through the air of the needle portion 5. The worker's rolling V inlet path U flows into the container 1. Air shock is generated in each ang 1 , cold; east granulation, 1 钇 钇 钇 2 2 2 2 2 2 2 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒 微粒The entrance and exit 25 de, the sputum π u κ P 22 sin near the outer casing 21 is used for control; ^ 36 is pulled up and taken out from the holding portion 22. The body 35 and the container 1 are otherwise provided, and even in the suction device 1 from the mouthpiece 32, the micronized cold-beam drying composition 21 blows air into the check valve 3 to block it. The discharge of 4 will be affected again, although the inhalation of the above-mentioned patients is usually in the range of 5 315 314 84 to 300 L / min. The ribs can be placed according to the patient's second 'but from the 4th to the 10th The inhalation shown, for example, the ability of the air to be introduced into the flow path, set to a container of about 5 channels of 16 caliber (heart) ^ σ # (diameter) is about 2.5 mm, suction flow inhalation, cold; Two 2.5mm. By this, the patient is discharged by one time. Most of the particles will be micronized and sucked from the mouth of the mouth without powder inhalation. Other embodiments of the inhaled type, such as the dry powder indicated in Fig. 11, are thrown into the device (self-inhalation type 4), such as *. It is not shown that it is arbitrarily set to the circumference of the outer 21, and it is fastened with the _ piece, and the mechanism part of the turning part has a spiral groove and is transformed into: a needle... The angle of rotation of the first 48 in the axial direction of the mouth P 5 is about 18 degrees. , spring sports. In addition, the operating body, the U-shaped figure and the 户 户 & quot 入 入 入 入 入 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状 环状In the slewing motion of 49, the _ section has a linear motion in the direction of the axis of the feed screw. The holding portion 2.2 is: 22 is converted to be freely taken out to the rear of the needle portion 5. The ^ becomes a gene that can be extracted from the outer casing 2 Positive lipid for introduction (invitrogen, five WokctAMiNE 2〇〇 < 4) 7 and pEGFp_c2 315314 85 1327073 (manufactured by Clontech) 24 for cytoplasmic culture were added to 〇ρτι_MEM I serum-free medium (Invitr) 〇gen company, Ig's minimum necessary & nutrient improvement medium) 丨2〇〇" 1 , and suspension mixing, forming a complex in the presence of the culture solution. The geometric average of the complex The diameter was measured by a dynamic 'light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.). Next, each suspension containing the composite was added and mixed in one container (1 tube). 18 mm) (number of samples: 1〇), its Each of the containers was preliminarily contained in an aqueous solution (5 mg/ml) of L-leucine dissolved in water, and then subjected to cold beam drying using a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYB0LD). 'For the obtained non-powdered freeze-dried composition (freeze-dried cake), the decay index was calculated. Next, the container containing the obtained non-powdered cold-bed dried composition (freeze-dried cake) was installed in the air designed to be air An injection type dry powder inhalation device having a diameter of 0 1.2 mm and a hole diameter of 0 1.8 mm in the discharge flow path 3 (having a bellows body 10 capable of supplying an air amount of about 2 μm, see Example 1 Fig. 1) The φ transposition can be carried out by introducing an air volume of about 20 ml from the inhalation device into the container (giving the impact of air having an air velocity of about 35 m/sec and an air flow of about 40 ml/sec). The non-powdered freeze-dried cake inside is micronized and instantaneously ejected from the container through the particle discharge flow path 4. The artificial lung type air respirator (Amhrst Process, USA) is installed.

Instrumentation, RW Niven: Pharmaceutical Technology, 72-78 (1993)) (measurement conditions, respiration rate: 60 L/min; respiration volume: 1 L; acceleration: 19) particle size distribution meter (aerogel analyzer (aerosizer) Amherest Process Instrument, RW Niven· 315314 86 1327073

Pharmaceutical Technology, 72-78 (1993)) was recovered, and the particle size distribution of the micronized particles was measured, and the aerodynamic mean particle diameter U m ± SD) was calculated therefrom. The geometric mean particle size of the particles present in the suspension in an undissolved state, and the decay index of each freeze-dried composition, and the aerodynamic mean particle diameter (//m ± SD) of the particles ejected from the device In Table j <Table 1> i frozen ι dry composition geometric mean particle size (μιη) a aerodynamic mean particle size (pm ± SD,

The leucine is decayed by the impact of an air velocity of about 35 m/sec and an air flow of about 40 ml/se::, as shown in Table 1, and is formed into an aerodynamic average. (IV) A particulate dry (four) final formulation administered via the lung. ^ If the sample is in a cold state before the east; the sample before the drying in the east is in a non-dissolving state, 'by the specific air specified in the present invention, the product is made suitable for the micronized dry powder administered by the lung. The sample before lyophilization is non-soluble: 'The dry powder inhalation system for pulmonary administration of the present invention is also applicable, ...: by the lungs. Also, by using the cancer inhibitor gene ρ53:? The through-regulatory protein (the cytoplasm of the capsule) can be used to introduce the gene 315314 87 1327073 or the antisense molecule into the body by pulmonary administration. The lung-administered dry powder inhalation system is considered to be effective for gene therapy. 'Example 2, Age-old Example 1 Lip0fect AMIN £ 2000 (InWtrogen) 72 for introduction of a gene into a 1% liposome //§ and 〇Ug〇_RNA 1〇"g (made by Otsuka Pharmaceutical Co., Ltd.) 1 #g, in the presence of OPTI-MEMI serum-free medium (Invitrogen, Inc., modified medium of the least necessary medium of Ig's), mixed % float to form a composite. The geometric mean particle size of the composite is dynamic. A light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.) was measured. Next, each suspension containing the composite was separately mixed and mixed in one container (bore diameter 0 18 mm), wherein Each container was previously added with an aqueous solution of L-leucine (5 mg/mi) prepared by dissolving l-leucine in water to prepare a sample for freeze-drying (Example 2). In the comparative example, an aqueous solution of dextran 40 (5 mg/mi) 4 〇〇 # i was used instead of the above aqueous leucine solution, and the samples for freeze-drying were prepared in the same manner (Comparative Example). Each sample was freeze-dried by a shed-type freeze dryer (ly〇vac gt_4, manufactured by LEYBOLD Co., Ltd.), and a decay index was calculated for the obtained non-powder freeze-dried composition (freeze-dried cake). Freeze-dried composition (cold; Donggan The container of the block is installed in a spray type dry powder inhalation device having a pore diameter of 2 mm and a pore diameter of 0 1.8 mm which is designed to be an air jet flow path 3 (having a wind supplyable amount of about 20 ml) The case 10 is referred to in the first embodiment and the first embodiment. 315314 88 1327073 As a result, it was confirmed that the freeze-dried composition of Example 2 was introduced into the container from the inhalation device by the amount of air of about 20 ml. The impact of the air at a speed of about 35 m/sec and an air flow of about 40 ml/sec, the non-powdered freeze-dried cake in the trough can be atomized and instantaneously ejected from the container through the particle discharge flow path 4. discharge. In the same manner as in Example ,, a particle size distribution meter (gas gel analysis) using an air breathing apparatus (manufactured by Amherst Prence Insuument Co., Ltd.) (measurement conditions, respiration rate: 60 L/min; respiratory volume: il; acceleration: 19) was used. Instrument (aer〇sizer): United States

Amherest Process Instrument Co., Ltd.)) The particle size distribution of the microgranulated particles was measured and recovered, and the aerodynamic average particle diameter (in m soil SD) was calculated therefrom. On the other hand, in the freeze-dried composition of Comparative Example 1, the seed shot produced by the air having an air of about 35 m/see and an air flow rate of about 4 Qmi/see was completely undispersed, and thus the average particle diameter of the line mechanics could not be determined. . ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Shown in Table 2:. 'The aerodynamic mean grain of the particles of the shot (a 315314 89 1327073 < Table 2 > cold east dry composition 茕 何学 flat decay index average particle size (μιη) aerodynamic mean particle size (pm ± SD, mmad) implementation Example 2) LipofectAMINE2 000 + 〇lig〇-RNA + leucine 1.19 0.165 1.633±1.496 Comparative Example 1) 1.19 LipofectAMINE 2 000 + Oligo-RNA+ Dextran 40 0.002 Completely non-dispersible cannot be determined as shown in Table 2 'Showing decay index In the non-powdered freeze-dried cake of Example 165 (Example 2), the sample before the freeze-drying was in an insoluble state (in which it was in a suspended state), in the same manner as in Example 藉, by an air velocity of about 35 m/ The sec and the air flow rate collapsed by an impact of air of about 4 〇mi/sec, and formed into a particulate dry powder preparation suitable for pulmonary administration with an aerodynamic average particle diameter of 5 μm or less. Relative to this, a non-powdered cold-baked dry-blocking block having a decay index of 〇〇〇2 (Comparative Example D, completely undispersed and micronized by the above-mentioned impact, is not suitable for preparation for drying by transpulmonary administration) Powder preparations. Examples 3 to 5 and Comparative Example 2 Supeifect (manufactured by Qlagen Co., Ltd.) 36 〇" g and QUgo RNA (manufactured by Otsuka Pharmaceutical Co., Ltd.) 5 for the introduction of the active dendrimer (positive polymer) for gene introduction (Example 3, Comparative Example 2) or plastid DNA: PEGFP-C2 (manufactured by Clontech Co., Ltd.), and Examples 4 and 5) were mixed and suspended in the presence of OPTI-MEM to form a complex. The geometric mean particle diameter of the 315314 90 1327073 composite was measured by a dynamic light scattering photometer (ELS-8000' manufactured by Otsuka Electronics Co., Ltd.) or a laser refracting and scattering type particle size distribution measuring apparatus (SALD-3000J, manufactured by Shimadzu Corporation). Next, 'the suspension containing these complexes is 1 000 // 1, as shown in Table 3, respectively, added to the pre-conditioned L_leucine solution (5 mg/ml) 40 0 //1 The container (the diameter of the tube must be 18 claws) (Examples 3 and 4) and the aqueous solution of the lactose solution (5 4 〇〇 "I container (tube diameter)" (for example 5) In each of the examples, one container was used to prepare a cold sample for the east drying. Further, with respect to the comparative example, 400 μ of an aqueous solution (mg/ml) of dextran 40 was used instead of the leucine of Example 3. The aqueous solution was prepared in the same manner as in the freeze-drying sample (Comparative Example 2). Then, it was obtained by cold-drying with a shed-type cold-drying machine (LYOVAC GT-4, = Β〇^5). : The composition (cold-rolled dry block) was used to calculate the decay index. Next, the obtained non-powder-like freeze-dried product was assembled in a container of the 吟 吟 Λ + + + + + + 冷冻It is also counted as the hole of the hole 4 of the work flow channel 3, 妒A r/】1 〇仏 is 12 mm, and the discharge type is '2', and the spray drying type of 0.8 mm is available for hollowing out the wood of the scorpion. Into the device (with J仏, .., work rolling 3: about 2〇nU wind box 1〇, Fig. 1). Refer to the example 1 and its results, for Example 3; τ犮5 By arranging the air quantity about 2_丨 from the suction 4 drying composition, the gas velocity 5WSec and the air flow rate are about: into the container (giving the impact by the air), the non-powder type in the container can be The air is generated from the container through the particles discharged a 7 'dry block micronized, and instantaneously out of the machine path 4, the ball is only transferred to the same example 315314 91 1327073, using the installed air respirator (Amherst Process Instrument, USA) (measurement condition 'respiration rate: 60 L/min; respiratory volume: 1 L; acceleration: 19) particle size distribution meter (aerosizei (aerosizei·): Amherest Process Instrument, Inc.)) The particle size distribution of the micronized particles, and the aerodynamic mean particle diameter (" m soil SD) was calculated therefrom. On the other hand, the freeze-dried composition of Comparative Example 2 was completely undispersed by the impact of air having an air velocity of about 35 m/sec and an air flow rate of about 40 ml/sec, and thus the aerodynamic average particle diameter could not be measured. . The geometrical rhyms of the particles present in each suspension in an undissolved state are each cold; the decay indices of the East dried compositions (Examples 3 to 5 and Comparative Example 2), and the particles ejected from the device The aerodynamic mean particle size (//m soil SD) is shown in Table 3.

315314 92 1327073 &lt;Table 3&gt; Cold-bundled dryness * I composition---------------------------------- 〇-RNA+ leucine 4) Superfect + pEGF 3.74 P-C2+ leucine MMAD) 0.225 1.578±1,403 0.189 1.646±1.420 5)Superfect + pEGF 3.74 P-C2 +Lactose 0.080 2.848 Soil 1.837 Comparative Example 2) Superfect+01ig 〇11.12 -RNA+ dextran 40 0-003 Can not be measured completely without dispersing ''The number of shackles is 〇.08〇 to 〇225 (that is, the decay index is more than 0.080% non-motorized ~ not like the frozen free-drying block) In the same manner as in the first embodiment, 'even if the sample before the cold drying is in a non-dissolved state, and it is easy to coagulate and hit the 'Τ ^, it can also be 7 pieces by air (4) 11 μm. The impact generated by the air of the granules collapses m 4 about - 5 micrometers or less suitable for fine lungs ~ the average particle diameter of aerodynamics is relative to this, showing a decaying granular dry powder preparation. - 借 ... 冲 冲 冲 冲 成为 成为 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥 干燥The m gas impact specified in the above can be adjusted to supply energy. (4) Cold-rolling drying of the micronized dry powder administered by the lung:: 'π ie' is applied to the dry powder inhalation system for transpulmonary administration of the present invention. It can be effectively administered through the lungs. In addition, it can be replaced by the use of the cancer inhibitor gene Ρ53 (for lung cancer) and the cystic fibrosis membrane-regulated protein (:R) gene (for cystic fibrosis). The greedy body (pEGFP_C2) used in the present embodiment can introduce a therapeutically effective gene or an antisense molecule into the body by pulmonary administration. Further, 〇Ug〇_RNA is RNAi (RNA dry (4)) The double-strand RNA of the canned heart can be introduced into the short double-stranded rna corresponding to the target gene, which can specifically inhibit the function of the target gene, and can also be applied to the treatment of lung cancer. Therefore, the dry powder inhalation system for transpulmonary administration of the present invention is considered to be a gene It can be used effectively in the treatment. • Example 6 Superactive (manufactured by Qiagen) 3 60 /^ and 〇丨4〇_111^ (made by Otsuka Pharmaceutical Co., Ltd.) 5# layer for the introduction of the active dendrimer for gene introduction , in the presence of MEM MEM I 12〇〇# kgacobrl company), the suspension is suspended, and the composite is opened. The geometric mean particle size of the far complex is measured by a laser refracting and scattering particle size distribution device (SALD_3〇) 〇〇J, Shimadzu Manufacturing Co., Ltd.. Next, each of the suspensions containing these complexes was added to each of the previously prepared L-proline acid solution (2.5 mg/ml). 〇//1 container (caliber diameter must be 18 mm) (10), prepared to freeze-dried 315314 94 1327073 sample. After that, use shed-like freeze dryer (LY〇VAC G Ding _4, LEYBOLD company The system was subjected to freeze-drying, and the obtained non-powder freeze-dried composition (freeze-dried cake) was subjected to calculation of a decay index. Next, a container containing the obtained non-powder-like freeze-dried composition (freeze-dried cake) was installed. The hole diameter designed to be the air jet flow path 3 is 0 1.2 Mm, a spray-type dry powder inhalation device having a hole diameter of 0 丨 8 mm in the discharge flow path 4 (having a bellows body that can supply an air amount of about 2 〇ml, refer to the first embodiment and the first embodiment). With respect to the freeze-dried composition of Example 6, it was confirmed that the amount of air was about 2 〇ml from the inhalation device into the container (given by air having an air velocity of about 35 m/SeC and an air flow rate of about 4 〇ml/sec). In the impact), the non-powder-shaped freeze-dried cake in the trough can be atomized and instantaneously ejected from the container through the particle discharge flow path 4. In the same manner as in Example ,, a particle size distribution meter (gas gel analysis) using an air breathing apparatus (manufactured by Amherst Prence Instrument Co., Ltd.) (measurement conditions, respiration rate: 60 L/min; respiratory volume: 1 L; acceleration: 19) was used. (aer〇sizer): manufactured by Amherest Process InStrument, USA)), which is used to measure the particle size distribution of the micronized particles, and calculate the aerodynamic mean particle size (V m ± SD) from the 〇 will be in a non-dissolved state. The geometric mean diameter of the granules present in each suspension, and the decay index of each lyophilized composition, and the aerodynamic mean particle size of the particles sprayed from the apparatus are shown in Table 4. 95 315314 1327073 <Table 4> Cold composition ~~ Department--- Average grain index index aerodynamic flat ____μ } Average particle size (μηι土 SD, 6) Sniper fect+Olig 13 9 ' ~--- MAD)_\RNA +proline acid 0.275 1.589 ± 1.553 As shown in Table 4, a non-powder freeze-dried composition (freeze-dried cake) with a known number of 0.275 is shown, and the same applies to Example 1 Even if the sample before cold drying is in the non-dissolving makeup b state (in which it is in suspension) and the average particle size of the easy-to-governance integrated geometry is 1 14, the air velocity can also be about 35 m. /sec and the air flow rate decays due to the impact of the air of 4〇ml/sec in the summer, forming an aerodynamic umbrella with an average particle size of 5 μm or less suitable for the pulmonary dry powder preparation . The above examples 2 to 6 of 4 gs gs - .. &lt;,, ·. In the same manner as in the first embodiment, even if the sample before the freeze-drying is in a non-lost state (in which it is in a suspended state), it can be provided by the specific air impact specified in the present invention. It can be prepared into a cold-bloomed dry composition suitable for pulmonary-administered micronized dry powder, that is, even if the added component is insoluble or poorly soluble to the solvent, in the lung of the present invention, the dry (four) end is absorbed. It is also applicable to humans and can be effectively administered via the lungs. Examples 7 to 8 respectively modulate insulin (recombinant human insulin crystal, specific activity: %·4 u/mg, manufactured by Biobras, Belgium) (in Example 7 It is 〇2 mg, in Example 8, it is 水溶液mg) an aqueous solution obtained by dissolving in an aqueous solution of hydrochloric acid, and a solution obtained by dissolving various carriers shown in Table 5 in purified water, if 315314 96 丄W/U73 ^, 5 By adding the ratio mixing, it is possible to obtain the suspension 各个 in each suspension state: the geometric mean particle diameter of the particles contained in the heart floating liquid is measured by a laser 掣 ^ ^ 粒度 粒度 粒度 ( ( ( ( ( ( , , , , , , , , , , The suspension Filled in a container (bottle diameter 0 1 8 mm), and dried in a non-powdered freeze-dried composition (freeze-dried by a dry-type dryer (LY〇VAC GT_4 'LEYB0LD)) : Λ Λ Λ 。 。 。 。 。 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来 接下来16 hole diameter is 01.99mm self-inhalation type dry powder inhalation device (refer to the implementation of the figure). Use it to talk about the bucket, the song brother 3 system) (for the cold Kang dryer, CQpley company about 295ml / &block; The air velocity is about 95m/SeC and the air flow is called the impact generated by the air. The geometrical ratio of the particles in the non-glutinous state in each suspension is calculated. The decay index and grain are not shown in Table 5. c cattle (/〇315314 97 1327073 &lt;Table 5&gt; Composition 'Average particle size index ratio (〇/〇) -___ (μηι)

7) Insulin 0.2mg + white f acid 0.52~~0.292 9TI 0'lmg + arginine 0.042 mg · (PH6.5) 57.9 8) Insulin lmg + phenylalanine 0.63 0.238 〇.6mg + arginine 0.11mg (pH6.4 )

As shown in Table 5, a non-powdered freeze-dried composition (freeze-dried cake) having a decay index of at least (j ug) was used, even though the sample before freeze-drying contained an active ingredient (insulin) in a non-dissolved state, but by the above air impact It is easy to micronize in the container, and can be made into a dry powder preparation suitable for pulmonary administration. Implementing your 丨9 $ 1 1 separately modulating insulin (recombinant human insulin crystal, made by Bi〇bras, Belgium, specific activity: 26 4 u / mg) 1 mg of the solution obtained by dissolving in hydrochloric acid aqueous solution and phenyl phenylalaninate · 5 mg of the solution obtained by dissolving in purified water 'mix them'. If the pH is adjusted by sodium hydroxide, it can be used in 丨Each of the suspensions of the floating sorrows was measured by a laser refracting and scattering particle size distribution measuring apparatus (SALD·30〇〇J, manufactured by Shimadzu Corporation). The suspension was filled in a container (both diameter: 0 18 mm), and lyophilized by a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYBOLD Co., Ltd.) at 315314 98 1327073. The lyophilized composition (freeze-dried ghost) is used to calculate the decay index. Next, the gluten (the diameter of the cylinder must be 18 mm) filled with the non-powder lyophilized composition is installed in the hole designed as the air jet flow path. Spray dry powder inhalation device with 0 丨 · 2 mm and an outflow flow path with a hole diameter of 0 1.8 mm (with a bellows capable of supplying air to the heart) = use it with a two-stage dust detector ( British c〇piey company) (for the impact of the air speed of about 35*:40 on the cold block), calculate the effective particles::: (). will be present in the non-dissolved state in each suspension The geometric mean particle diameter of the particles in each, cold; the decay index and effective particle ratio of the eastern dry composition are shown in Table 6. &lt;Table 6&gt; Freeze-dried composition + phenyl phenylpropionate. 5 mg (pH 6. 0) . i〇) Insulin 1mg + phenylpropionine 0.5mg (ΡΗ6·4) ' η) Insulin 1mg + Phenylpropanoid 6 〇.5mg (pH6_6) . Index b (%) 〇 _39 69.3 75.1 72.0 0.39 0.36 As shown in Table 6, the fading-dry composition (cold bundle drying block) is shown, even Active ingredient (insulin) ^. 0 Island Hampshire surgery Bie sample comprises a non-state solution of the bath. Bu easily micronized vessel, adjustable made fitness / ,. agent in the envelope. Preparation of dry powder bundles administered by the lungs and Examples 12 to 13 315314 99 1327073 Belgium Preparation of insulin (recombinant human insulin crystals)

Biobras specific activity: 26.4 U / mg) l.lmg of the aqueous solution obtained by dissolving the aqueous solution of hydrochloric acid and the solution of the various carriers shown in Table 7 dissolved in purified water 'mixing them and adjusting the pH with sodium hydroxide, can be obtained Suspensions in each suspension state. The geometrical average particle diameter of the particles contained in the suspension was measured by a laser refracting and scattering type particle size distribution measuring apparatus (sald_3〇〇OJ, manufactured by Shimadzu Corporation). Next, the suspension was filled in a container (bottle diameter 0 i 8 mm), and lyophilized by a shed-type freeze dryer (LYOVAC GT-4, manufactured by LEYBOLD Co., Ltd.). The decay index was calculated for the obtained non-powder freeze-dried composition (freeze-dried block). Next, a container filled with a non-powder-like freeze-dried composition (bottle diameter: 018 mm) was attached to a hole having a diameter of 0 1.99 mm designed to be an air introduction flow path 17 and a suction hole 16 was required to be a claw of 99. Self-inhalation type dry powder inhalation device (see Example 3 and 3 =). Use it and use a two-stage dust tester (C〇pley, UK) (for cold/east dry blocks with air velocity of about 9 5 m / sec and air flow of 7 295 ml / sec) ), the effective particle ratio (0) is calculated as the geometric flat particle diameter of the particles present in each suspension in an insoluble state, and the decay index and effective particle ratio (%) of each freeze-dried composition are shown in Table 7. in. 315314 100 1327073 <Table 7 &gt; Freeze-dried composition 1 can be learned &quot;Platinyl bismuth citrate. 5mg (pH6.4) 68.7 1 3) Insulin 0_ lmg + leucine 醯〇 67 nucleoside nucleoside 1.5 Mg(pH6.5) 0.051 58.9 Non-powdered freeze-dried composition (freeze-dried cake) with a non-decay index of at least i5 i, as shown in Table 7, even before freeze-drying The active ingredient (insulin), but which is easily micronized in the container by the above-mentioned air impact, can be adjusted to a dry powder preparation suitable for pulmonary administration. ' Implementing you | 1 4 V, respectively, to modulate insulin (recombinant human islet cheek sputum horse crystallization, made by Belgian B1〇bras, specific activity: 26 4 /mg) 〇.l mg bath in aqueous solution of hydrochloric acid and guanamine The solution obtained by dissolving the acid s s 5 in purified water, mixing them and adjusting n positive pH to 6.5 with sodium hydroxide, can obtain a suspension in suspension. The geometric mean particle diameter of the particles of the suspension G 3 was measured by a laser refracting and scattering type particle size distribution measuring apparatus (SALD-3000J's manufactured by Shimadzu Corporation). Next, the suspension was filled in a trough state (bottle diameter 0 18 mm), and the cold skin was sacrificed by the shed skin 'in, shot, cold/east dryer (LYOVAC GT 4, manufactured by LEYBOLD) Dry up. The leaf heterogeneous decay index was obtained for the non-powdered lyophilized composition (freeze-dried mer). Next, a container filled with a non-powder-like frozen 仏βν/fruit dried composition (cylinder must be 18 mm) is installed in an air 邋^ introduction flow path 17 having a pore diameter of 0 315314 101 1327073 1.99 mm and attracting flow The self-inhalation type dry powder inhalation device (see the third embodiment and the third embodiment) having a hole diameter of 0 1.99 mm. Using the non-powdered freeze-dried composition (freeze-dried block) in the container to impart an impact on the air at a speed of about 1 m/sec and an air flow of about 17 ml/sec, the resulting particles are directly from the device. Sprayed in the installation of lung & gas suction device (manufactured by Amherst Process Instrument, USA) (measurement conditions, respiration rate: ! L / min; respiratory volume: 〇 1L) aer〇sizer (Amherst Process, USA) In the instrument company, the particle size distribution of the particles was measured. Then, the aerodynamic mean particle diameter (μ soil SD) of the fine particles was calculated from the results. The decay index of each freeze-dried composition and the aerodynamic average particle diameter of the particles sprayed from the apparatus are shown in Table 8. &lt;Table 8&gt; Freeze-dried composition geometry, average particle size (μΐΏ) exponential particle size (_±SD, bis-amino acid 0.5 mg U75 ±1·384 as shown in Table 8, showing decay freeze-dried composition (freezing The dry block) 'even the active ingredient (insulin) in the non-dissolved state of the sample before freeze-drying, but is easily micronized by the above-mentioned air flushing in the container, and can be adjusted into a preparation suitable for pulmonary administration. 315314 102 1327073 Reference Examples 1 to 5 Insulin (recombinant human insulin crystal, specific activity: 26.4 U/mg, manufactured by Belgian Biobras Co., Ltd.) (l mg, 2 mg) or insulin and various carriers shown in Table 9 were respectively dissolved in distilled water containing hydrochloric acid. 2 ml was prepared and filled in a container (bottle diameter 0) 8 mm), and cooled by a shed-type freeze dryer (LYOVAC GT-4 'LEYBOLD company); The non-powdered freeze-dried composition (freeze-dried cake) was calculated for the fading &amp; index. Next, a container filled with a non-powder-like freeze-dried composition (bottle diameter 0 18 mm) was installed in the air-introduced flow. Road 1 7 has a hole diameter of 0 1.99 mm and sucks A self-inhalation type dry powder inhalation device having a pore diameter of 0 to .99 mm (refer to the third and third embodiments of the embodiment), and using the same type of dust measuring device (manufactured by Copley, UK) (for The cold east drying block is given an impact of air with an air velocity of about 95 m/sec and an air flow of about 295 ml/sec, and the effective particle ratio (%) is calculated. The decay index and effective particle ratio of each freeze-dried block ( %) is shown in Table 9. . . . &lt;Table 9&gt; -X-_ Index Insulin Insulin lmg 0.1 59 75.0 Reference 2) Insulin img + leucine 1.4 mg 0.145 80.7 f&quot; 3) Insulin 1 mg + proline 1 〇mg 0.1 10 79:4 参4)Insulin 2mg 0.177 42.4 Island 2mg+ lysine 1.4mg 0.137 65.1 As shown in Table 9, 'shows a decay index of at least 〇. 11 〇 non-powdered cold 4 dry composition (freezing The dry block) is easily micronized in the container by the above-mentioned air impact 315314 103 丄J厶/VJ/:), and can be made into a dry powder preparation suitable for pulmonary administration. Kui Keo will separately insulin (recombinant system, "_L, &lt;, · people ^ 姨 素 素 结晶, Belgium Bi〇bras

Yu (LYOVAC GT-4, manufactured by LEYBOLD) is freeze-dried. For the non-powder freeze-dried composition (freeze-dried block) of =, the decay number was calculated. Next, the barn (tube diameter 0 18 mm) of the non-powdered cold-bed drying composition obtained by charging is installed in a hole diameter of 4 1.2 mm designed as the air jet flow path 3 and the flow path of the outflow flow path 4 is A nozzle-type dry powder inhalation device of 0 丨 8 mm (having a bellows capable of supplying about 20 ml of air. Refer to the first embodiment and the first embodiment). Using the non-powdered cold-dried composition (freeze-dried block) in the container, an air impact of about 35 m/sec and an air flow of about 40 ml/sec is applied to spray the generated particles directly from the device. Installation of artificial lung air breathing apparatus (made by Amh: erst Process Instrument, USA; measurement conditions, respiration rate: 60 L/min; respiratory volume · 1 L). Particle size distribution analyzer (aerosizer: Amlierest Process, USA) Instrumentation, r ψ Niven: Pharmaceutical Technology, 72-78 (1993)), and determining the particle size distribution of the particles. Then, the aerodynamic mean particle diameter (# m ± SD) of the fine particles was calculated from the results. A container filled with a non-powdered lyophilized composition (both diameter 0! 8 104 315314 1327073 is attached to a hole designed to be an air guiding passage 17 with a hole diameter of ^99 and a suction flow path of 0 丨 99 mm.叨λ±± mm into the device (refer to the third and third embodiments). Use the second::: device (manufactured by Copley, UK) (for cold (four) block:: work speed of about 95m/SeC and air The flow rate is about 295 mi/sec (吝, the impact of the birth), and the effective particle ratio (%) is calculated. One milk·, two will be the decay index of each freeze-dried block, and the aerodynamic average of the particles sprayed from the device. The diameter U m ± SD) and the effective particle ratio (eight) are shown in Table 10. , :Table 10&gt;

The average effective particle size of air 5 (μ®士SD, ratio (%) MMAD, _ 17759±7^425~~~ 7ΤΤ 1.954±1.454 74:1 2.007 士. 1.438 72 1 1.872±1.477 62.0 2.239±1.435 61.2 L124 0.250 0.124 Reference 6) Insulin + Isoleucine 7) Insulin + leucine ^ 8) Insulin + guanidinium ζ ζ 4 9) Insulin + Phenylalanine 0.204 jlJJ)) Tengdaosu + D- Manna: alcohol 0.160 ------------------------ v ▲• Know as shown in Table 10, showing a non-powdered freeze-dried composition with a decay index of at least 0124 (freeze-dried block), an air impact generated by an air velocity of about 35 m/sec and an air flow of about 40 ml/sec, or an air velocity of about 95 m/sec and an air flow of about 295 ml/sec, in a container Easy to be micronized. Further, the average particle size of the microparticulated particles is 5 micrometers or less by an air impact of about 95 rn/sec at an air velocity of about 295 cc/sec in an air flow, and the dry powder preparation suitable for pulmonary administration can be adjusted. 315314 105 The lyophilized composition of the lyophilized composition can be micronized into the lungs by the transpulmonary administration of the sputum-injection system of the present invention, and the lyophilized composition can be delivered to the lungs. If the lung is administered according to the present invention, the system is 'used (administered) to be in a non-powder state; this 1 ==,: while it is micronized, it can be inhaled and administered for 1: Special operations are carried out by micronization. According to the present invention, there is no such thing as a systemic (preparation system), a loss (in the case of inactivation) and a filling operation, and a drug caused by granular preservation. Do not live and seek) and mix in the manufacturing process with the expectation - quantitative. i can be stable in the case of 杂 杂 而 而 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 活性 制 制 制 制 制 制 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负 负In the case of the invention, the transpulmonary administration uses a dry powder inhalation system to obtain a =1 rate of at least 1. More than or equal to, in addition, according to the present invention, the system 20 is sucked into the system with a dry powder. /. Above, 25% or more, 3〇 is more than the sheep and k冋 to v and more than 35%. And in the β ^ ... of most of the US Patent Publication No. 6153224, the right part attached to the lower part of the lung is 10% of the effective ingredient of the dry powder inhalation device. In addition, it is described in the publication No. 2001-151 673 of the Japanese Unexamined Patent Publication No. 2001-151673, which is incorporated in the sputum, and the sputum of the lungs (the lung arrival rate) is About 丨〇% of the waste discharged from Formulation T. The powder inhalation system is a very useful administration system from the viewpoint of the ratio of the ratio of the dry active particles to the lungs which can be used in the present invention, which is higher than the previous powder preparation for inhalation.

Right · A 7 / dried fruit composition and spray-type dry powder according to the present invention 315314 106 1327073 into the device, only by air to send air from the air jet flow path into the container and the air impact cold By cooling the composition, the composition of the cold east can be micronized. Based on this, it is possible to atomize by using a simple structure of the inhalation device and a simple operation at the time of use. Further, since the inhalation device has a structure which is easy to manufacture, it can be produced at a low cost, and as a result, it can be expanded in a large amount. Further, according to the dry type powder inhalation device of the spray type, the suction amount of the vaporized spray (powder preparation) can be adjusted by adjusting the compression speed of the air pressure feed means such as the air type to conform to the breathing ability of the user. It is also easy to work by inserting the needle portion into the mouth of the container. Furthermore, if the dry powder is inhaled according to the inhalation type of the inhalation type, the air impact can be generated by the user's suction pressure, and the cold can be dried to form (4): (micronized) and can be inhaled by the user. The cold-blooming composition is micronized and administered to the lungs, whereby it is expected to obtain a drug-free drug with no loss and safety. Further, since there is no need for special operation other than atomization (micronization), the operation volume h is the same as that of the ejection type, and by assembling the needles into the roots, the operation of inserting the back of the mouth of the container becomes easy. According to the dry powder inhaling device of the present invention, the needle having the suction flow path and the second milk v inflow path is inserted into the container, and the air pressure in the container can be used. Inhaled from the suction port, the friend introduces a flow path into the container by the air of π to impart an air impact to the freeze-dried composition, and can suck out the powder = μ 7 / product from the container. In the case of the inhalation device of the present invention described in the fourth embodiment, the following effects can be exhibited. l Stay &amp; 315314 107 1327073 In the case of imparting an effective air impact on the freeze-dried composition and attracting the micronized powdery freeze-dried composition from the container, it is necessary to introduce the suction flow path and air The wearing area of the flow path is increased by *, and the diameter of the needle is: the diameter must be increased. However, in order to check the entrance of the needle with a large diameter, the container must be held securely, close to the tip of the needle so as not to deviate from the axis of the needle, and the inlet plug is pressed with the tip of the needle. In the dry powder inhalation device of the present invention, the container holding portion can be held by the holding portion for holding the holding portion of the container, the holding portion, and the holding portion operating portion of the mechanism portion and the operation body for operating the mechanism portion. And = the guide moves on the axis of the needle and close to the tip of the needle, and by operating the operating body: the needle can be inserted into the mouth of the container with a relatively small force. As such, the dry powder inhalation device according to the present invention can accommodate the needle of the container into the container. Further, in the case where the outer casing is formed in a tubular shape, the front portion of the outer casing is formed as the suction opening portion, and the container is formed in the outer casing, and the needle is placed in the cymbal type with the needle tip facing the upper storage chamber. In the outer casing, an inlet port for communicating with the air guiding passage of the needle portion and for introducing the outside air is provided in a wall portion of the outer casing, and the holding portion is in the storage chamber by the holding portion operating portion The pencil-shaped dry powder inhalation device can be formed to advance and retreat in the axial direction of the outer casing, which is easy to use and convenient to carry. It is placed at , and is redundant. If the above-mentioned holding portion is retreated, the above-mentioned Rong Chou Xi Shan x is formed. . The housing body of the inlet and outlet and the holding portion formed by the lid of the above-mentioned inlet and outlet of the housing body of the hinge body 108 are provided with a lid that covers the lid to close the holder, and pulls up the above When the cover is opened, the mechanism is retracted by the above-mentioned mechanism, and the above-mentioned mechanism is used as the above-mentioned mechanism, and the mechanism of the holding portion operation portion can be simplified, which is advantageous in terms of manufacturing cost. x, since it can cover the entrance and exit of the container when the tip of the container is pinned, it becomes easy to use. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross-sectional view showing a dry powder suction (nozzle type 1) of the present invention described in an embodiment. In the figure, the arrows indicate the flow (the same applies to Figures 2 and 3 below). Fig. 4 is a cross-sectional view showing the drying apparatus (self-inhalation type 1) of the present invention described in the second embodiment. Fig. 3 is a cross-sectional view showing the device (self-inhalation type 2) described in the third embodiment. ^ If the end is taken in 2, the self-image of the present invention is a perspective view of the dry powder of the present invention as described in Example 4 (self-inhalation type 3). Fig. 6 is a cross-sectional view of the above dry powder inhaling device (self-inhalation type 3). Fig. 6(a) is the above-mentioned dry powder inhaling device (from a partial sectional view; I enter i 3). Is the cross-sectional view of the action of the dry powder inhalation device (self-type 3) on the side of the needle portion of the dry powder inhalation device. K Inhalation 315314 109 1327073 The πth diagram is a perspective view of a dry powder inhalation device (self-inhalation type 4) according to another embodiment of the present invention. Fig. 1 is a perspective view showing a dry powder inhaling device (self-inhalation type 5) according to another embodiment of the present invention. Fig. 1 is a perspective view showing a dry powder inhaling device (self-inhalation type 5) according to another embodiment of the present invention.

1 Container 1 a Port 2 Freeze-dried composition 3 Air jet flow path 4 Discharge flow. Road 5 Needle 6 Intake port 7 Suction member 8 Cylindrical safety cover 9 Air pressure transmission means 10 Wind box body 11 Suction valve 12 Suction inlet 13 Discharge valve 14 Discharge port 15 Connection port 16a Suction flow path 16 Front port 17a Air introduction flow path 17 Front port 18 Suction port 19 Suction member 20 Containment chamber 21 Housing 21A Hinge 22 Holding portion 23 Guide portion 24 Hold Part operation unit 26 Case body 27 Cover 28 Window 29 Guide inlet 30 Backstop 31 Suction port 110 315314 1327073 32 Mouthpiece 32a Mouthpiece cover 33 Partition portion 34 Peripheral wall portion 35 Extraction body 36 Control lever 37 Mechanism portion 39 Linking body 40 Hinge-chain 41 Hinge 42 Second introduction path 42a Leading groove 42b of partition wall portion 33 Leading groove 43 of peripheral wall portion 34 Clearance 44 One end of second introduction path 42 45 The other end of second introduction path 42 46 Vent hole 47 Wall 48 Operation Body 49 operating body 111 315314

Claims (1)

1327073 Announcement, picking up the scope of patent application No. 92135122? The lyophilized composition for the administration of the lungs is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following (1) to (iii). Characteristics: (0 has a non-powder block form; (11) a decay index of 〇〇5 or more; and φ (111) by withstanding an air velocity of at least lm/sec and an air flow of at least 17 ml/sec Air impact, which can be a particle having an average particle diameter (aerodynamic enthalpy) of less than 1 〇 micron or an effective particle ratio of 丨〇% or more. 2. The freeze-dried composition of claim 1 of the patent scope, A polymer drug as an active ingredient is contained. 3. A method for producing a dry powder preparation for pulmonary administration, which is contained in a container of the following freeze-dried composition, which can be used to impart the following air impact. a device for freeze-drying the composition in the container, introducing air having the two-gas impact capability, whereby the freeze-dried composition forms particles having an average particle diameter of 10 μm or less or an effective particle ratio of 1% or more; The The freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state, and has the following characteristics (i) to (iii): (0 has a non-powdered bulk form, (ii) The decay index is 〇.5 or more, and (iii) by subjecting to an air impact having an air velocity of at least lm/sec and an air flow of at least 17 ml/sec, the average particle size can be corrected at 112 315314 ΐ32Ί〇Ίό Patent application No. 92,135,122 (January 27, 1999) Micron or below or effective granule 4, the third bisth of the patent application is in the range of 1 〇 / ° or more. The method, wherein, 兮 2 = lung investment A high-molecular-weight drug for dry powder preparations....Donggan no-form composition contains as an active ingredient. 5. If the scope of the patent application is the first, and the lung is administered with a dry powder preparation, the phrase is used in the inhalation device. As a device, the dry-dried composition of the dry powder 7 described in a, ^a) or (B) is micronized: (Α) is placed in a container by a dry powder for use in a lung; 7 lyophilized hydrazine composition is micronized and The device for the subject and the particles to be used has: a needle portion having an air jet flow path having a needle portion for discharging the flow path, and an air pressure for conveying air in the air jet flow path for sending the needle portion and a suction port that communicates with the discharge flow path of the needle portion; and configured to: insert the needle portion into a port plug for sealing the container to communicate the air injection flow path and the discharge flow path with the inside of the container, and use the air Sending means that air is ejected into the upper container through the air jet flow path, and the cold-drying composition is atomized by the impact of the jet air and the obtained fine particles are discharged from the suction port through the discharge flow path; or (8) A device for pulverizing and drying a cold-rolled dry composition in a container in a non-powder state by using a dry powder inhaling device, and allowing the subject to inhale the obtained microparticles, comprising: a needle having a suction flow path Department, and the right place name broadcast ^ 800 workers into the flow path of the needle part to 315314 revised version 113 1327073 Patent No. 92135122 (January 27, 1999) and with the above suction a suction port through which the flow path communicates; and a state in which the needle is inserted into the port plug for sealing the container, and the air in the container is sucked from the suction port by the suction pressure of the user while the air is passed through The air introduction flow path flows into the container which has become a negative pressure. The freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are discharged from the suction port through the suction flow path. 6. A dry powder inhalation system for transpulmonary administration, comprising: (1) a container having a freeze-dried composition, the freeze-dried composition is a composition comprising a non-dissolved additive component through a cooling bed Dry to be prepared as 'and having the following characteristics (1) to (iii): (1) having a non-powdered bulk morphology, (ii) having a decay index of 0.05 or more, and (iii) by withstanding an air velocity of at least lm/sec And an air impact of an air flow of at least 17 ml/SeC may be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; (2) having cold air capable of imparting the above air impact to the container Means for drying the composition and means for discharging the micronized powdery freeze-dried composition. 7. The dry powder inhalation system for transpulmonary administration according to claim 6 of the patent application, wherein the container is used in combination with the above-mentioned device during inhalation. 8. The dry-powder inhalation system for transpulmonary administration according to claim 6 of the patent application 'where' is the high-temperature 315314 revision 114 1327073 molecular drug as an active ingredient. Patent Application No. 92135122 (January 27, 1999) 9· rm circumference of the lungs for dry administration of a dry powder inhalation system, containing 'the following (A) or (B) as a device: (4) (4) A device for pulverizing a freeze-dried composition of "non-powder--Yu Rong" and allowing the user to inhale the obtained particles, which has: ', a needle having a jet flow path a needle portion having a discharge flow path, an air dust supply means for discharging the gas to the needle portion, and a suction port communicating with the discharge flow path of the needle portion; and configured to: Inserting a port plug for sealing the container to connect the air jet and the door to the above-mentioned capacity H (4), and using the air pressure feeding means to spray air into the container through the air jet flow path, by the jet air The lyophilized composition is micronized, and the obtained fine particles are discharged from the suction port through the discharge passage; or the dry powder inhalation device for pulmonary administration is contained in the container in a non-powder state. Freeze-dried composition The apparatus for microparticles and inhaling the microparticles obtained by the subject, comprising: a needle portion having a suction flow path; a needle portion having an air introduction flow path; and a suction port communicating with the suction flow path; and configured to: In the state in which the needle portion is inserted into the mouth plug for sealing the container, the inhalation dust of the subject is sucked into the container from the suction port. 115 315314 Rev. 13207073 Patent Application No. 92135122 (January 99) 27th) The air 'at the same time, the air is introduced into the container which has become a negative pressure through the air guiding flow path, and the freeze-dried composition is atomized by the inflowing air impact, and the obtained fine particles are sucked from the suction flow path. The mouth is discharged. 〇. A cold-dried dry k-form is used in the manufacture of a dry, terminal preparation for inhaled transpulmonary administration, wherein the freeze-dried composition has the following characteristics: (I) The composition of the added component of the solution state is freeze-dried and made § week, (II) has a non-powder block form, (ill) has a decay index of 0.05 or more, and (1V) is subjected to an air velocity of at least lm/sec. And an air impact of at least a flow rate of 17 ml/sec, which may be a particle having an average particle diameter of 10 μm or less or an effective particle ratio of 10% or more; and % of the freeze-dried composition is micronized at the time of use. It has the above average particle diameter or the above effective particle ratio. 1 1. The use of the freeze-dried composition of the first aspect of the Shenqing patent scope in the manufacture of a dry powder preparation for transpulmonary administration, wherein the freeze-dried composition comprises a polymer drug as an active ingredient. 12 Jfn by -* main 'A, please freeze-dry composition of the first aspect of the patent, in the manufacture of transpulmonary and in the use of a dry powder preparation, wherein the freeze-dried composition is collected in a container, and The micronized powder is composed of a means for imparting the above-mentioned air impingement to the freeze-dried composition in the container, and a micronized powdery freeze-dried composition can be discharged from the container. 116 315314 Revised version ιυ/ό No. 92135122 Patent application (January 27, 1999) The device of the means of modulation is modulated. Kind. (3) Use of a component liquid of an additive component in a non-dissociated state, which is used for producing a cold-dried composition for preparing a dry powder preparation for pulmonary administration, the freeze-dried composition having the following characteristics: a bulk morphology of the powder, (ii) a decay index of 0.05 or more, and (in) an average particle size of 10 by subjecting to an impact of air having an air velocity of at least im/sec and an air flow of at least Hml/sec. Microparticles having a ratio of micron or less or an effective particle ratio of 10% or more; and micronized to the above average particle diameter or the above-mentioned effective particle ratio at the time of use. H, as the additive component containing the non-dissolved state in the scope of the patent application The use of the liquid, wherein the freeze-dried composition comprises a polymer drug as an active ingredient. 15. The use of a component liquid comprising an additive component in an insoluble state as claimed in claim 13 wherein the freezing The dry composition is contained in the volume Is, and the micronized powder is provided with means for imparting the above-mentioned air impact to the cold-drying composition in the container and It can be prepared by a means for discharging the micronized powdery freeze-dried composition from the container. 315314 Rev. 117