TW200418520A - Dry powder inhale system for pulmonary administration - Google Patents

Abstract

This invention provides a dry powder inhale system for pulmonary administration combined of: (1) a container for receiving freeze-drying composition for pulmonary administration, which is formulated by freeze-drying the liquid containing non-soluble state, and the following (i) to (iii) properties, (i) being in non-powder cake state, (ii) distinguish index is over 0.05, (iii) forming micro particles having average particle radius (particle radius of air mechanics) is over 10 μm or effective particles ratio is over10% by receiving air punch having air speed at least 1 m/sec and air flow at least 17 ml/sec; (2) a device having means for producing above punch to the freeze-drying composition in above container means for discharging the micro particles powder of the freeze-drying composition.

Description

200418520, Description of the invention [Technical field to which the invention belongs] The present invention relates to a novel age, Zijipi powder inhalation system suitable for pulmonary administration. In more detail, the present invention relates to the use of Q freeze-dried compositions contained in A ^, Ren, and Fenwei, which can be made by micronization and adjustable, and the garments can be made through the lung. Clam form, and in this form can be directly inhaled for administration and / or powder inhalation system. -Dry for lung administration

Yes, the hair% π… ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-,-dry-powder-inhaled-powder Specifically ... These techniques are, for example, used in the preparation of micropowder powder suitable for transpulmonary administration in the lungs, and "cold and dry composition for making fantasy", the transpulmonary administration_ 乾 朴 2 粉 i 生 古The Department of Earth also knows the preparation of stalk preparations: using the above-mentioned cold-drying composition for inhalation or pulmonary administration

'And the use of human dried compositions for the manufacture of dry powder formulations for pulmonary administration. "σ Q" means that regardless of the shape, as long as it has a fine shape, what is called "fine particle (fine powder), needle, plate, or fibrous shape" in the present specification is included. [Prior Art] ' … 'When it is known to be administered via the lungs, # the average particle size contained in the medicine is made below 10 micrometers, preferably below 5 micrometers, and it is. = !: "It reaches the lungs with good efficiency. Therefore, the current situation is 疋 · 刖 口 through the lungs to wash the mouth Taguchi β λ w ^ ν. ^ Μ 为了, in order to prepare the pharmaceutical raw material = diameter, material dry method and fairy grinding method into i ^, 仃 processing Process, then fill it into the inhalation device to provide. 315314 6 200418520 Specifically, there have been three known dry powder inhalants: (1) a preparation prepared by filling a powdery composition consisting only of drug particles in an appropriate container; (2) lightly mixing drug particles A preparation prepared by granulating into a larger particle size and filling the resulting powdery composition in an appropriate container; and (3) drug particles and excipient particles (lactose, etc.) larger than the particle size of the drug particles ) A preparation prepared by uniformly mixing and filling a powdery composition composed of the obtained mixed particles into an appropriate container (for example, refer to Japanese Patent Laid-Open No. ^ _171760). It is described in these documents that if these dry powder inhalants are administered into the respiratory tract, the following actions are shown: ("The drug particles in the composition will reach and settle down in the trachea and bronchus, etc. (2) the granulated drug dissociates into particles when flying in the airway, and the generated drug particles will reach and settle in the lower respiratory tract such as the trachea and bronchus; (3) the excipient is settled in the mouth, throat or throat, and Only the drug particles reach and settle in the lower respiratory tract such as the trachea and bronchi. As mentioned above, the previous dry powder inhalants for pulmonary administration are prepared in advance by inhaling the ingredients into desired particles, or the particles are processed by any method Then, it is filled in an inhalation device and then administered through the lungs. Generally, in order to micronize low-molecular-weight drugs, a spray-drying method (Example 1 1.1 71760 2001-1 5 1673, etc.) can be used. The jet mill used therein Method is a method in which a low-molecular-weight drug is impregnated with an air flow of 1000 L / = ln or more and an air impact generated by an air speed above the speed of sound, and the drug is micronized, but The method of micronizing a drug with a low air impact is not known. On the other hand, as for peptides, proteins, and other high-molecular-weight drugs, there is an example of 315314 7 200418520. For example, spraying and dissolving a pharmaceutical stock solution containing additives into an average particle Pinch the particles below 5 microns, and fill the inhalation method with a 12-step device (spray I to fill inhalation. For example, w095 / 3 1479 together with additives A #, p,), use peptide and protein particles And inject it into the inhaled material using a jet mill method; for example, WO91 / 16〇38, etc.). Method ^ East Dry-Jet Grinding Lung ": Dry: Two == Spray dry or jet mill method previously used inhaler, especially for sub-drugs, may not be # # a #, peptide and High scores such as protein may not be ideal. For example, W095 / 31479 觫 由 饼 々 # j 3 of it, as already described in Bluff & already contained in the spray-drying step, if about 25% is lost by 藉 洪 土 -r W τ dry edge: by Yugan method 'It is foreseeable that the egg activity and the reduction of the fun activity in the manufacturing step are reduced. And 'for the ancient "stomach of the low-molecular-weight tritium phase ^ ^, asked the knife fun, is also the same as _ knife in the city, can not know the low-altitude method. The milk is washed into micronization and then Regardless of the spray-drying method or the cold-blowing method, it will be 48 + W ▲ Mugan 4-He-shot grinding method, which will adjust the powder of the dressing from the spray-drying device or spray, and the bamboo door is filled in the rong cry # The recycling sub-segment is also filled with a small portion of charge L :: Γ Therefore, with this operation, it is inevitable that 3 will result from the recovery and filling loss & too μ 4 ^ + The modulation yield of the war will decrease and follow The cost of 彳, and the inclusions ^ ^. Ν, Yi d Temple 4. And, generally, §, the powder is precisely in a small amount. Therefore, it is difficult to fill the powder with a small amount of t: minute. As for the spraying method and the jet grinding method, it is of course necessary to establish the spray-drying method of the high-precision knife θ filled in a small portion ν Φ Guzheng Zhengxia powder filling method. In fact, for example No. 5,826,633 of the National Patent Gazette, a system for filling fine powder with Dingzhi powder , Device and formula 315314 8 200418520 method are all described in detail. [Summary of the invention] The purpose of the present invention is to solve the above problems, ρ φχ-β,-, ... Various kinds of questions-new ones that can be used for trans-pulmonary dysfunction; ::: The purpose of the present invention is to provide a new master preparation system and an administration system, in which the valley is harvested in a container. In this container, the particles are micronized into a suitable formula; the particle size of the lungs is administered and directly inhaled. In order to achieve this purpose, the person who has been in the night will go deeper and deeper and discover that it will be used as a right pair, eight # ^ ^ ^ _ ",, > The pharmacologically active substance into the knife is filled in the container and :, the non-powdered cold green dry composition prepared by the Γ-dong drying method is composed of lower air impact, and can be directly stored in the Those in the container are micronized. Based on this insight, the present inventors further researched repeatedly and found that by drying the composition in a non-powdered state in a container; drying the composition, preparing blood = the impact of air given to the composition, the specific speed and flow rate The method of introducing air into the container and the combination of the hand and the slave device of the micronized powder composition from the container are used in combination, and the user can simply freeze-dry the non-powder during use (especially when inhaled). The preparation is prepared into a particulate state suitable for pulmonary administration, and therefore, pulmonary administration can be achieved by directly inhaling the microparticles. Furthermore, the inventors have discovered that the pharmacologically active substance-containing liquid filled in the container in a liquid state is not limited to the added ingredients (especially the pharmacologically active substance that is an effective ingredient) that are clearly dissolved in the solvent or mixed clearly, Even if these added ingredients exist in an undissolved solvent or in an undissolved state, they can be adjusted into a cold-dried dry composition suitable for pulmonary administration of particles by specific air impact. Therefore, the present inventor is certain that if the 315314 9 200418520 is used to administer the dry inhalation system through the dry bucket for pulmonary administration, the problems related to the previous dry powder inhaler for pulmonary administration can be completely solved. That is, according to the pulmonary administration system according to the present invention, since the helmet is micronized by other devices and then divided into small portions and filled in a container, it is not a problem and can be applied to pulmonary administration. In addition, if the dream according to the present invention: cattle: dry powder inhalation system 'because unlike the spray drying method; :: protein and peptides must be exposed to high temperature: ★ will not be caused by high temperature exposure The problem of reduced pharmacological activity. For pharmacologically active substances such as peptides and proteins of high-priced drugs,-'can reduce the manufacturing cost of the preparation, that is, the present invention is also useful from an economic point of view. … The first hand fills the life field private right right—the dry-powder powder inhalation system of the present invention for injecting into the lungs, can reach the lung's magic, and can efficiently deliver drugs to the lungs . The dry powder for pulmonary administration of the present invention contains an insoluble system of active ingredients, which is characterized by freeze-drying and preparing cold-roll dry-welding of Baishi solution-like heart composition liquid into a non-bird-like block form; The wood and the product are used as preparations for transpulmonary administration. The thus prepared block-shaped cold Dong 7 牦 / wood composition was applied to the dry inhalation device of the present invention, which was formed by a dry inhalation device, and the inhalation system of the present invention was used to inhale with the dry powder of Ezhao Xianli The agent used ..., η ## μ b The blasting method or the dry method is used to break the particles into granules of the desired size in advance, which is suitable for the use of the powdered preparations in the preparation of the inhalation device. Effective particle ratio. Therefore, this:-is positioned as a high-performance transpulmonary administration system. "The terminal inhalation system can be developed by the present invention based on an inquiry based on this knowledge, and includes the following forms. 315314 10 200418520 (item 1) An application for humans for pulmonary administration < ~ lyophilization The composition is prepared by adding the ingredients in a non-dissolved state, 'right μ, human soil wind knife, and freeze-drying the prepared liquid, and has the following characteristics ⑴ to (iii) · · (I) has a non-powder morphology; (ii) the decay index is greater than or equal to 0.05; and ㈣ by: being impacted by air having an air velocity of at least lm / sec and an air flow of at least _ Microparticles with an average particle size of less than 0 micron or an effective particle ratio of 10% or more. (Item 2) The composition of the cold fish age Dongganzhi as described in Item 1 contains a polymer drug as an active ingredient. Item 3) A method for preparing the end-of-the-table preparations by using the lungs for lavatory, including the following cold and dry ingredients, and using the following air in the state of the product: Shock imparts coldness in the container; equipment for dry welding ▽ yttrium smelting, introduction To prepare for the air impact ability, you will benefit from the above-mentioned freeze-dried composition to form particles with an average particle size of less than micrometers or an effective particle ratio of more than one; it should be cooled to dry the composition. It is prepared by cooling the composition liquid containing the added components in a non-dissolved state and drying it, and has the following characteristics: (1) it has a non-powder morphology, and (ii) the decay index is greater than 0 · 05, (111) Essence: Air impact with an air velocity of at least 1 oil and an empty milk flow of at least 17 ml / seC can become particles having an average particle size of 10 microns or less and an effective particle ratio of 10% or more. (4th member) The manufacturer of the dry powder preparation for pulmonary administration as described in item 3, 315314 11 200418520, the drug Γ in the 50% cold; the dry composition contains a polymer L as an effective ingredient, page 5: Middle) For example, the manufacturer of the dry powder preparation for pulmonary administration in item 3 is set as follows: Set: = Dry powder described in Γ Qing ... The lyophilized lyophilized mash composition is micronized. (Α) Pulmonary administration Use dry capacity; Α #, will be collected in a non-powder state :: Xun = dry composition into particles and inhaled by the subject > equipment for U tablets paid, characterized by: The needle part of the road has a needle part for discharging the flow path. In the upper stage, the air for conveying air in the H & M jet flow path is sent by hand. The discharge flow path of the needle part is connected and configured as: and the inlet, 2 = :: : The mouth plug for sealing the above container is used to inject air to the exhaust flow path and communicate with the inside of the above container, and the above air lu sends a hand # to pass air through the upper 4 ^, and the above container is formed by the injection M m, and The obtained cold; U particles of the dried composition particles 丨 U particles are discharged from the suction port through the above discharge flow path 丨 or ⑻ The dry powder inhalation device for pulmonary administration is composed of a cold beam drying device not contained in a container. The obtained device for particles is characterized by having the following features: The suction port connected to the suction channel; & the needle portion and the structure are as follows: 315314 12 200418520 2 The state where the needle portion is pierced to seal the mouth plug of the container, and the suction pressure of the container is taken from the suction mouth Inhaled the air in the container, and on the same day, TΓ caused the air to flow through the upper flow path, and "the inflow from the above-mentioned working milk introduction flow path has become a negative pressure." The fine particles are discharged from the suction port through the suction flow path. (Item 6)-A dry powder inhalation system for pulmonary administration, which uses the following ⑴ and (2) in combination: ⑴ Contains a container with a freeze-dried composition. The composition liquid of the non-solvent additive ingredients is prepared by cold-rolling drying, and has the following characteristics: ⑴ to Gii) (1) It has a non-powder-like morphology, and (ii) the sadness index is 〇 · 〇5 or more, and (out) by bearing at least! m / sec air speed and at least! The air impact of the air flow of 7ιηΐ / _ can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%; the above-mentioned random impact can be imparted to the cold-rolled dry composition in the container. Hand & and means for discharging the powdered cold-roll-dried composition. (Item 7) The dry powder inhalation system for pulmonary administration according to item 6, [the above-mentioned container is used in combination with the above-mentioned device during inhalation. (Item 8) The dry powder inhalation system for pulmonary administration according to item 6, wherein the cold-dried dry composition contains a polymer drug as an active ingredient. (Item 9) If the dry powder inhalation system for pulmonary administration in item 6 of item 315314 13, the following (A) or (B) is used as the device: (A) =! And inhalation with dry powder The device is a device for storing A clean # β 7 East dry composition in a non-powder state in a grain container and making the user inhale the particles provided by the user '. The device is provided with: 2 ^ the needle portion of the air jet flow path A needle part having a discharge flow path, an air pressure hand for conveying air in the air jet flow path of the second 2 :: P, and an suction port communicating with the discharge flow path of the needle part, and is constituted as: The needle part is inserted into the six-pass mouth flow path and the discharge flow path. Two, the mouth plug is used to spray the air: //, Shu Guyi is connected internally, and the above-mentioned air pressure is used-and the second roll is sprayed on the above through the air spray flow path. The impact of crying air causes the particles from the cold-dried composition to pass through the above-mentioned exhaust flow path to be sucked in through the above-mentioned exhaust flow path; or (B) = Γ: powder inhalation device, which collects & Apparatus and device for micronizing dry composition and allowing subject to suck particles ·: It ::: Needle section of the road, having a needle section for the air introduction flow path and a suction port communicating with the ^ drainage path; and the structure is: the needle part is inserted into a state for sealing the mouth of the container, and is Day: Two rolling mills inhale the air in the container from the above suction port, the same as f: the inflow from the air introduction flow path has become a negative capacity-the inner 'fine' is cooled by the impact of the inflowing air; Micro 315314 14 200418520 / Granulated, and the obtained particles are discharged from the suction port through the above suction flow path. (Item 10) A method for administration via the lungs, including ^ ^ ^ lyophilizing the hydrazone composition, and the resulting system is prepared by cold and drying the additive solution containing the undissolved state, and has the following Characteristics: (1) has a non-powdered morphology, (ii) has a decay index of 0.05 or more, and (iii) by withstanding at least lm / sec milking degree and at least 17ml / sec: Air impact can become particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%; at the time of the object, the air impact is imparted to the cold; the dry composition, shape, average Granules: 0 micrometers or less, or an effective particle ratio of 10%, and then administered by inhaling the user to the micronized powder. 1. The method for administration via lung according to item ¥ 1G, wherein the Lengkanggan is contained in a container, and the micronized powder system is prepared underneath: the above-mentioned air impact can be imparted to the container ::: Means for drying the composition and means for discharging the micronized powdered freeze-dried composition from the container. (12th item) The method for pulmonary administration according to item 10, wherein the freeze-dried t composition comprises a polymer drug as an active ingredient. (::, member) The method for pulmonary administration according to item 11, wherein the dry powder inhalation device described in (A) or (B) below is used as the device: (A) Dry powder for pulmonary administration The inhalation device is a device that will contain the powder in a non-powder state. 4 'Donggan No composition is atomized and the user inhales the particles obtained by 15 315314 418520. It is equipped with: a needle with an air jet flow path A needle part having a discharge flow path, on the upper part of the air jet flow path of the needle part, an air pressure hand slave for conveying air, and an suction port communicating with the discharge flow path of the needle part; and is configured as: 'the above The needle is inserted into the supply and discharge flow path. M:: ί to inject air ... Connected internally, and the air pressure X is used to pass the air through the nozzle of the air flow path. The impact of the above-mentioned crying air causes the cold and dry composition to pass through: " and the served particles are discharged from the suction port through the above-mentioned discharge flow path; or '(Β): == Dry powder inhalation device' system The freeze-dried composition contained in a non-powdered state is The device for changing the particulates inhaled by the subject is provided with: a needle portion having an M flow path, and an air inlet through which the air flow path communicates with the suction flow path; and / or, and is configured as: 2 for sealing In the state of the mouth plug of the container, the air in the container is sucked through the suction port of the lice, and the air flows into the negative pressure capacity through the above-mentioned air introduction flow path: inside ': the air impact will The cold / rolled dry composition is discharged from the suction port through the suction flow path through the micro / served particles. (Brother 14 item); a freeze-dried composition is used for inhaled pulmonary administration, where 'the cold' east-dried composition is prepared by freeze-drying a composition liquid containing the addition of 315314 16 200418520 ingredients in an undissolved state It has the following characteristics ... It has a non-powdered morphology, (ii) a decay index of 0.05 or more, and (m) by withstanding an air velocity of at least lm / sec and at least pmi / sec The air impact of the air flow can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of 10% or more; and the freeze-dried composition is powdered to become fine particles with the above average particle size or effective particle ratio To use ,. (15th item) The freeze-dried composition of item 14 is administered via the lung: wherein the cold-knock-dried composition is contained in a container, and the micronized powder is provided with a device capable of flushing the above air. Means of Lengkang drying the composition and means capable of discharging the micronized powder-like form of Lengkang dry composition from Gushan Yangu μ, Ding only and J Yougu from Liuliu . (_ Item 1 =) The freeze-dried composition according to item 丨 4 is used for pulmonary administration, in which the Yan Hai cold-rolled and dried composition contains a high molecular weight drug as an active ingredient. (Item 17) — &, human, soil 〇, seed dry composition in the manufacture of inhaled pulmonary administration Che Yi powder made Zhai 丨 ^^ # _ moxibustion 'The freeze-dried composition has The following characteristics:: The composition liquid of the additive components that are not in the cleavage state is prepared, ⑴) has a non-powder morphology, (iii) the decay index is greater than or equal to 0.05, and The fragrance is ancient and / or has air impact with an air velocity of at least lm / sec and an air flow of at least 17mi / sec 315314 200418520, which can become particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%; and 2. On the day of use, the freeze-dried composition can be micronized to have the average particle diameter or the effective particle ratio. (: 2: 8) If the freeze-dried composition of item 17 is used in the production of dried button powder preparations for fish for lung administration, the compound ^, the freeze-dried composition contains a polymer drug as an active ingredient. (Use item V9) The use of the Lengkang dry composition as described in item 17 in the manufacture of pulmonary powder-dried dry powder preparations, its' ^ ^ ^ 0 /, MQ lyophilized residue composition is collected in Hezu , And the micronized > a Μ < Zhi Mo is made with the means which can impart the impact of the above-mentioned empty milk to the freezing in the container.... Device for means of composition (item 20) A use of a composition liquid containing non-dissolved energy and an additive component of the heart is used for the manufacture of frozen powder preparations for the preparation of P ψ only for use in pulmonary administration The cold and dry composition has the following characteristics: (1) it has a non-powdered morphology, (π) a decay index of 0 05 or more, and (ii) has at least lm / sec salute degree and at least 17ml / sec

The air impact of the air flow can become A j into particles with a thousand-average particle size of less than 10 microns or an effective particle ratio of more than 10%; Effective capsule ratio. (Item 21) As in item 20, it contains the group of non-dissolving and dissolving added ingredients. 315314 18 200418520 The use of liquid, in the cold, the cold; the dry composition contains the polymer drug as an effective ingredient. (Item 22) The use of a composition liquid containing non-dissolved added ingredients as described in item 2G, wherein the freeze-dried composition is contained in a container, = the micronized powder system can be used for the above The means for imparting air freeze to the freeze-dried composition in the combined state and the means for discharging the micronized powdery freeze-dried composition from the container are prepared. [Embodiment] The best (1) freeze-dried composition The cold and dry composition of the present invention is a non-powder dry composition prepared by filling the container with the composition m state containing the insoluble state and the added ingredients and directly filling it in the container. It is better to pack: = owed or several times the effective amount (Effective amount including a single dose is the East dry composition. The freeze-dried composition of the present invention, by selecting and preparing the above group == The decay index of the non-powder composition obtained by the cold and eastern drying treatment (the type and use of the active ingredient and the carrier used in combination with the active ingredient), which is more than 0.05, can be used by The air introduced into the container (impact = blow, mouth ejection pressure), instantly or quickly micronized into suitable for pulmonary administration: where the composition, 'the so-called decay index in the present invention, The inherent 315314 19 200418520 value of the freeze-dried composition measured by the following method: < Decay Index > Filling 0.2 to 0.5 ml of the composition solution with a liquid evil filling in a tube or a tube diameter of 023 mm ... The components that make up the dry composition of cold Cambodia are "the ingredients", which are cold and dry in the east. Then, in the final freeze-dried composition, the volume is 1 ml. The volume is dropped into n-hexane i 〇ml, stir it at 30 rpm for about 10 seconds. m Put the mixed solution into the light path> 1 mm long, the width of the light path [0 mm uv, then name, * and quickly use a spectrophotometer:… 0 nm turbidity. Divide the obtained turbidity by the composition The total amount of the components of the frozen r composition (dry weight. 1 mile). The value obtained is defined as the decay. The lower limit of the decay of the cold-roll drying composition of the present invention is the above-mentioned 0 · 0 5 ， Its rational phase depends on the bed LV Λ 012Λ, ν The heart is in order. Do n’t ... · &Quot;, ϋ · 12 Feng Jia, and 13 is the best. In addition, regarding the upper limit of the cold-kang dry composition of the present invention, f is preferably U, and its ideal order is preferably 0.9, 0.?: Π 0.5 is the best. The cold of the present invention; Donggan: The upper limit is the expectation, and it is expected to have a decay within the range composed of the lower limit of the upper limit of the two selected arbitrarily. It is from 0.05 to 5'0.08 ~; to 0 ·: '0 · 10 to ° · 8, to. .7, to. .6 and. ·〗to. : · 1 Freeze-dried composition U · 5 of the present invention. The block shape of the powder can be removed. 'Fine is prepared by lyophilization / freeze-drying to form a block of non-knowledge.' In the present invention, a non-powder composition means that the active ingredient contains Xizhi Λ, — dried fruit 40% Drying of the composition liquid of the knife by freeze-drying 315314 20 Solid 'commonly referred to as freeze-drying, cracks in the block 2 =: East ⑽ ⑽ or its subsequent breakage to become powdery. To ... become several A large piece, as well as a part y, does not damage the neodymium of the present invention, than the non-powder-free frozen 5% targeted by Ming; wood composition, that is, a cold-drying composition that is not a powder-like block. The Γ composition has a composition of Γ, which is prepared by adding the above-mentioned composition liquid containing non-dissolved state I added ingredients to ^ 0 μ, '? Freeze-dried, and is characterized by == decay index and non-powder. Block-like morphology, and based on the inherent properties of the cold dry composition represented by two = number, can be formed into an average particle size by the air velocity of lm & sec and air impact at least full ec =. Particles below 10 microns or effective particle ratio above 10%. Impact = cold Dry the composition, and withstand the above-mentioned air = ', if you can form an average particle size of 10 microns or less (preferably 5 microns to impart air impact to the freeze-dried composition, if the air with more than summer There is no particular restriction on the impact of air at a speed and an air flow rate of 17 ml / sec or more. Specifically, f, the above air impact is, for example, 1 m / see or more, preferably S 2 m / sec or more, and more preferably 5 = SeC or higher, preferably an impact generated by an air speed of 10 m / sec or more. Among them, the upper limit of the air speed is not particularly limited, but is usually 300, preferably 250 m / sec or more. More preferably, it is 200 m / sec or more, and 仏 is more than 1 50 m / sec. In addition, as long as the effective air particle rate is 10% or more (preferably 20% or more) from the above range, it is more soil. 25 /. Above 'best 30% or more, special training above) 315314 21 200418520 There is no particular restriction on the range of the lower and upper limits of f. Specifically, it is 1 to 300 m / sec, i to 25m / sec, 2 to 25m / sec, 5 to 25m / sec 5 to 200 m / sec, 10 to 200, 10 to 150 m / sec. Second, the above-mentioned air impact, for example, usually by 7 ml / sec or more, 40 ml / sec or more 'Although the upper limit of the impact H air flow caused by an air flow of more than 25 mi / sec is not particularly limited, for example, it may be 900 L / min, in order of 15 L / sec, 10 L / sec 5 L / s ", Li ~ c is better 'and 3L / Sec is the best. Specifically, the air flow rate is not particularly limited as long as it falls within a range formed by the lower limit and the upper limit selected by any of the above 2 f. The consumption range is, for example, 17 ml / sec to 15 L / sec, 20 ml / sec to 10, 20 ml / sec to 5 L / sec, 2ml / _ to 4 L ~ c, and 20 to 3 L. / Sec, 25 ml / sec to 3 L / sec. The effective ingredients used in the present invention are, in principle, as long as they can be used as ingredients of any dry powder inhalant for administration: (pharmacologically active substances: hereinafter also referred to as drugs), there is no special Limit: Son! For example, it can be a low-molecular drug and a high-molecular drug. Another second year: The substance contains so-called "enzymes, hormones, and antibodies such as proteins (including peptides and peptides) and DlSiAe ρχτλ々々 丨 △ physiologically active components. RNA nucleic acid search (including genes and side entry)" as drugs The target disease and local therapy are two kinds. Patients, as the case may be systemic therapy alcohol as low molecular drug cortisone), dehydrocorticoids such as cortisol (hydro- (prednisolone), triamcinolone 315314 22 200418520 (tiiamcinolone) dexamethasone) Betamethasone, beclomethasone, fluticasone, mometasone, budesonide, salbutamol, salbutamol Salmeterol, procaterol, buprenorphine hydrochlodde, apomorphin ° e, taxol, and tobramycin Antibiotics. As polymer drugs (proteins and nucleic acids and other physiologically active components), such as interferon (α, 10,000, 7), interleukin (such as interleukin_bu 2, 3 4 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, etc.), anti-interleukin] α antibodies, interleukin "receptors, interleukin receptor antagonists, inter Interleukin-4 receptor, anti-interleukin-2 antibody, anti-interleukin- & receptor antibody, interleukin-4 antagonist, Interleukin-6 antagonist, anti-interleukin-8 antibody, chemokine 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-10 antibody, interleukin_ι〇 'receptor, anti-interleukin-1 4 Antibody, interleukin-4 receptor, anti-interleukin-1 antibody, interleukin-15 receptor, interleukin-18 receptor, anti-interleukin-18 antibody ^ Erythropoietin (EPO) , Erythropoietin derivatives, granulocyte community stimulating factor (G-CSF), granulocyte macrophage · community stimulating factor (CSF), macrophage · community stimulating factor (M-CSF), calcitonin, selin , Insulin derivatives (LisPro, NVORapid, HOE901, NN-3〇4, etc.), insulinotropic hormones, insulin-like growth factor 'glucagon, somatostatin or its analogs, vascular Vaspressin (vasopressi ^ 315314 23 200418520 or its analogue, amylin, human: body, hormone release hormone, 激素 stimulating hormone, growth stimulus, cause, and field " Adrenal hormones, vascular endothelial cell growth factor, platelet proliferation factor, keratinocyte growth factor, epithelial cell growth factor, fibrin, neurotrophic factor from the brain, hairy body god management: mouth "tumor necrosis factor (TNF), TNF Receptor, TNF inhibitor, daughter ⑽, factor ⑽F), hepatocyte growth factor (HGF), nerve growth factor blood stem cell growth factor, platelet proliferation factor, natriuretic peptide, blood coagulation factor, blood hepatocyte growth factor (S_CSF ), FLT3 ligands, anti-platelet aggregation inhibitory monoclonal antibodies, tissues, plasminogen • activating factor or derivatives thereof, super disproportionation oxidase, trans = Le, immunosuppressants (such as cyclosporine, Taco Rolims ... ⑽: compounds, etc.), cancer suppressor gene p53, cystic fibrosis membrane penetrating regulatory α white ⑽ TR) gene, RNA interferon (RNAi), bridging nucleic acid (BNA), blood "trypsin 'Thrombopoietin (TPO), metastasin, DNAase, sex hormones, oxytocin, thyroid-stimulating hormone-releasing hormone TRH), bactericidal Lu, too ^ to increase in protein (BPI), and influenza vaccines, AIDS-like disease no wheel 1 vaccine field, hysteria and other disease vaccines and tuberculosis vaccines such as Mtb72f preparations. These active ingredients may be used singly or in combination of two or more kinds. The aforementioned various peptides also include natural peptides, genetically recombinant peptides, and chemically synthesized peptides. These active ingredients can be used in a free state or in a salt state. 24 315314 200418520 It can also be used as an arbitrary body. If it is an active ingredient (for example, include it. Off: keep the drug and synthesize a low-molecular drug), it can also be used for nucleic acid package, inclusion, ion binding, etc. Holder = Existing morphology (adsorption, internal lipid membrane constructs, microcapsules, cyclodextrin, dendritic microspheres, nanocapsules, and nanospheres, etc. x, where the liposomes include a monolayer membrane Liposomes and multi-layered, multi-layered, sun-shelled beetle liposomes, o / w or w / o / w emulsions, spherical colloidal particles, thin band colloidal particles, and layered structures, etc. "Molecular molecules" are generally molecules whose molecular chains form a three-dimensionally expanded shape from the center to the outside according to a certain rule. The dendrimers have a spherical structure and have drugs inside them. It also has the function as a nanocapsule. In order to maintain the drug in the inside of the dendrimer, the following methods are known: 1} Using the interaction between the inside of the dendrimer and the drug (hydrophobic interaction and electrostatic interaction) Role, etc.), or in the tree A dense cell structure is formed on the sub-surface, and medicines are physically collected (Document · Keno Kono: Drug Delivery System, 17-6, 462-470 (2002)). The Superfect used in the examples has a certain shape. Formation of active dendrimers (Tang, M.X., Reedema η, CT, and Szoka, Jr. FC: In vitro gene delivery by degraded polyami do amine dendrimers. Bioconjugate Chem. 7,703 (1996)). These molecules branch from the center and are formed by having a positively charged amine group at the terminal and interacting with a phosphate group (negatively charged) of a nucleic acid. In addition, in order to easily introduce DNA and RNA into cells, SuperFect has the 25 315314 200418520 The nature of DNA and RNA condensing into a dense form. • As a preferred holder, examples include: liposomes, dendrimers, retrovirus vectors, adenovirus vectors, adenovirus-associated viruses, Lentivirus (lentiVlrus), herpes simplex virus vector, HVJ (Sendai virus liposomes (such as HVJ coat vector kits, etc.). ', The retainer of the shell structure and dendrimers, etc. Since a foreign gene can be introduced into a cell, it is more widely used than before. In the present invention, a gene-derived liposome and a gene-derived dendrimer can be used in the same way. These are also commercially available. The particle diameter of the retainer (geometric average particle diameter: measured by dynamic light scattering method or laser refraction and scattering method), if it is less than 10 microns, there is no special. It is preferably 5 μm or less. For example, for liposomes and emulsions, the particle size (average particle size of the geometric stem) is 50 to tens of millimeters, and the particle size of the spherical colloid is $ to 50 nm ° # ~ Also, the measurement of the average particle diameter of the geometry Method, in general, the particle size distribution of particles in the field of tens of nanometers can use dynamic light scattering and particle size distribution of particles above tens of microns, and can be measured by laser refraction method. The particle size distribution of particles in the hundreds of nanometers and several micrometers can be measured by any method. Regarding the retention form of the active ingredient in these retainers, although there is no special case in which the membrane of the body is, for example, a plasma membrane structure, for example, in the lipid membrane structure, the surface, the interior, the lipid layer, or the surface of the lipid layer Arbitrary attachment / significant form. The method of forming the holding form is, for example, a method of adding a water system to a mixed and dried substance of a lipid membrane structure 315314 26 200418520 and an active ingredient (gene, etc.), and then emulsifying or suspending with an emulsifier such as a homogenizer ... After the structure and other retainers are dissolved in the organic solvent, the remaining dry matter is stored, and the second dry substance is added, and then the human I is added, and the dry matter obtained by the medium is emulsified in the aqueous solution of the k gene. A method of adding an aqueous solvent containing = :: Γ :, etc. to a retainer such as a lipid membrane structure of the medium, and the existing method: the lipid membrane structure of the body is dried after the medium is dried. Aqueous systems for adding effective ingredients (genes, etc.) to dry matter, Dingjiexigu, and soil C. There is a bulletin. A certain method (in the case of the size (particle size) of Lingzhao JP 2001-2592, use the same pore size The method of extruding and filtering under a membrane type, or a method of using a pressurized type (a tea photo, for example, Japanese Patent Application Laid-Open No. 6_238j42). The characteristics of the present invention are cold; the characteristics of the dried composition-will include non-dissolving evil The composition liquid of the added ingredients is cooled; The non-dissolved state means that the added components cannot be dissolved or mixed in a clear state in the solvent constituting the composition liquid. The non-dissolved solids are contained in the solvent and can be used at any time. The state detected by the means exists. Specifically, for example, in the solvent, it has 〇〇… or more, preferably 0.05 # m or more, f estimate 〇! Door 1 0 · 1 # 111 or more, and even more preferably 0.2 // m or more. , The best 0.5 · m / m or more, know the wind, τ, recognize, < the average particle size of Cheng Hexue (measured by dynamic light scattering method or laser refraction and political radiation method) Conditions that can be detected. If the purpose of the present invention can be achieved, the geometric mean particle diameter of these solids (attentional optical government or laser refraction and scattering> to determine) Although the i limit is not particularly limited, it is usually 纟 20 ..., preferably 15 "or less, and more preferably 1027 315314 200418520 μm. More specifically, the so-called "non-dissolved state" in the present invention includes in the solvent, the geometric average particle diameter (measured by dynamic light scattering method or laser refraction and scattering method) is between 0.01 and 20 " m, 0.05 To 15 / zm, (U to 15 to m, 0.2 to 15 "mu to 16" m'oou 1〇 "melon, 〇1 to 1〇 " m, 0.2 to 10, or 0.5 to 10 // The solid within the range of m: the state where the substance exists in a state that can be detected by any means. The specific form of the non-resolving complaint is, for example, that the added ingredients are constantly dissolved in the solvent to become more than saturated, and that the added is insoluble. In the state of the solvent, that is, the state in which the active ingredient in which the solvent is insoluble or hardly soluble is suspended or turbid in the Erling medium. It is also a method of specifically evaluating the insoluble state. Method ', but you can use the particle size distribution method to determine the particle size distribution of E. indica insoluble matter. The latter method, specifically :: the wrong solution is the target non-dissolved state of the composition solution is diluted with steam = table salt solution After the concentration suitable for particle size measurement, put it into the chamber: Measure the particle size of the sample and place it in the obtained diluent = the so-called "additional ingredients are in a non-poetic state" means that the following carrier itself is in a non-dissolved state in the solvent. The above-mentioned liposomes and microcapsule holders can be kept in the solvent, such as Xidianba / Zhan, Zhandextrin, and dendrimers, etc. Although the knife is in a dissolved state in the maintenance state: In February, the body such as the plastid is in an undissolved state. The ingredients are limited to effective ingredients, = 4 The added insoluble state of the retainer or other arbitrary components (the lower composition liquid ^ / has special restrictions. 315314 28 200418520 The solvent that constitutes the composition liquid at the same time as the known and added ingredients is restricted separately. The ren T is, for example, water, physiological salt solution, and other liquids, culture media, or temples. In addition, the solvent may include organic Solvent, but the final adjustment of clothing (freeze-dried composition for bismuth lung administration) does not produce PP to the human body. The organic solvent is, for example, methanol, ethanol, isopropanol, acetone, and ethylene glycol. ^ ^ Mingzhi freeze-dried composition, as long as The above-mentioned decay of the final preparation: ^ ^ is enough, it will be the above-mentioned active ingredient or the active ingredient alone, and the oral, or the addition of an appropriate carrier α added to the active ingredient. 'If the type and amount of the carrier used are such that the composition liquid containing non-dissolved state with: = knife can be prepared by freeze drying, the final freeze-dried composition satisfies the following ⑴ to (iii) Characteristics: (0 has a non-powdered morphology, (ii) the decay index is greater than 0.05, and ⑽ is subject to an air velocity of at least lm / sec and at least 17 ohms. The air impact of the working oxygen electrode 1 can be Those particles having an average particle diameter of 10 micrometers or less or an effective particle ratio of i0% or more and achieving the effects of the present invention are not particularly limited, and a carrier or a desired amount previously used for freeze-drying can be arbitrarily used. As the carrier, specifically, for example, hydrophobic amines such as valine, leucine, isoleucine, and phenylpropane, or their salts or amidines: glycine I, candied Hydrophilic amino acids, such as amino acids, alanine, arginine, amidine, or these salts or amidoamines; derivatives of amino acids; dipeptides having two or more of the above amino acids that are the same or different , Tripeptides, or their salts or amidines. 315314 29 200418520 They can be counted as 1 county. M, or a combination of two or more. Among them, it is used as amino acid or Katsuyuki Taito to go to J, and is listed as a salt of metal such as sodium and potassium and a metal of metal such as soil; it is formed with inorganic acids such as phosphoric acid and hydrochloric acid and organic acids such as sulfonic acid. The strength of the mouthfeel $,, ', as the amine listener, for example, L · _ white amine it amine hydrochloride. In addition, as a carrier, amino acids other than α-amino acids can be added. Examples of such hydrazines include cold-alanine, r-aminobutyric acid, homoserine, and taurine. . … • Furthermore, as other carriers, for example, monosaccharides such as glucose; disaccharides such as sucrose, maltose, lactose, and trehalose; sugar alcohols such as mannitol; saccharides such as cyclodextrin; dextran 40 and polysaccharides Polysaccharides such as triglucose; polyols such as polyethylene glycol; and sodium fatty acids such as sodium caprate. These carriers may be added singly or in combination of two or more kinds. Among them, the carrier that allows the effective ingredients to reach the lungs efficiently is specifically a hydrophobic amino acid such as isoleucine, valine, leucine, and phenylalanine, or their salts Or ammonium; hydrophobic dipeptides such as leukoamido-valine_acid, leukoamido-phenylalanine, and phenylpropylamine_isoleucine; and leukoamido_leucine Hydrophobic tripeptides such as amino_leucine, leukoamido_ leukoamido-valine, and the like. These may be added singly or in combination of two or more. In the case of interferon_r, from the standpoint of micronization and formulation stability, it is preferable to exclude the above-mentioned hydrophobic amino acid or its salt or amidine, hydrophobic monopeptide, and hydrophobic dipeptide. You can use basic amino acids or their salts or amidines, dipeptides, and triads in combination. Among them, those who test amino acids are, for example, arginine, lysine, histidine and their trips. Soil 卞 人 I Soil 315314 30 200418520 is a combination of benzyl alanine and arginine hydrochloride, a combination of phenylalanine, white and arginine hydrochloride. The content ratio of the active ingredient (drug) contained in the freeze-dried composition. Heat: Don't limit it. For example, the content is 20 mg or less, preferably 10 mg or less, and it is more preferably 2 mg or less, particularly preferably 1 mg or less. If the addition ratio of the above-mentioned carrier is to make the final cold-kang dry composition, the above characteristics of ⑴ to ㈣ are not particularly limited. Although there is no ^ section ratio, one criterion is when the cold-knitted composition is determined as When the content is 100% by weight, the ratio is preferably 0.1 to less than 1, preferably 10 to 100%, and less than 100% by weight, less than 100% by weight, and more preferably 0% by weight.勹 仫 仫 仫 20 to less than 100 'and the present invention as the object to describe the characteristics of ⑴ to 不会 and will not damage ==, and the product as long as it can meet the effectiveness of the composition liquid before drying' 'day The effect 'In order to stabilize the cold ling and prevent the active ingredient after drying and drying, this active ingredient is absorbed in various additives. For example, white and inorganic salts can be added to the above ingredients, and human serum albumin can include human serum albumin. If it is generally applicable to pharmaceuticals, as for surfactants, surfactants, cations, and active agents, regardless of the anionic boundary Can be widely used. For example, it is preferably a non-facial interfacial surfactant (such as Tween-type boundary 〃, ethylene-consuming sorbitan fatty acid ester-based interface active zibu ㈣), and non-ionic such as mountain sorbitol trioleate, etc. The method containing the active ingredients and any of the ingredients is not particularly limited. ——: The composition solution is freeze-dried to produce a freeze-dried preparation 315314 31 200418520 (: make the freeze-dried composition dry). . Although there are no restrictions, depending on the situation, the cooling bed can be quickly freeze-dried. The conditions can be urgent. The dry composition of the present invention can be formed into particles suitable for pulmonary administration by applying a blow. Therefore, Taiqiqiong " freeze-dried composition is suitable for preparation via pulmonary administration 1: for preparation before pulmonary administration of powder preparations on the second: cold health dry composition for preparation preparation). … Again: the cold health dry composition of the present invention includes the specific states disclosed below &, " Lung U Cold / East Dry Composition 'is a composition liquid that contains non-dissolved additives It is prepared by freeze-drying and has the following characteristics (1) to (iii): (i) it has a non-powdered morphology; (ii) its decay index is above 0.05; and (iii) borrows By being subjected to air impact with a working gas velocity of at least 1 / sec and an air flow rate of at least 17ml / sec, it can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%. 1 0 2 · As in item 1 ο 1 item, the composition is freeze-dried, and the decay index is 0.05 to 1.5. 1 03 · As described in Item 1 〇 ^ ~~ Fruit dry composition, in which the hunting force is subjected to the impact of air having a place of at least 2 m / sec, the speed of milk and the air flow of at least 17 ml / sec. It can become fine particles with flat average 4 haiku ten uniform grains below 10 microns or effective particle ratio above 10%. 315314 32 200418520 104 · Scenario 101 item / 々'Donggan without composition, in which, by withstanding the milk speed of the present chart and air of at least n mi / sec in the range of 1 to 300 m / sec The impact of the flow of air can form particles of Λ wind horse ten average grain branches below 10 microns or effective particle ratio of more than 10%. 1 0 5. As described in Item 10, there is no composition in Portugal and Jindonggan, in which, by withstanding * air freezing life of at least 1 m / sec, ^ working milk speed and air of at least 20 ml / sec The impact of flowing air can become fine particles with a weight average particle size of 10 microns or less or an effective particle ratio of 10% or more. 1 0 6 · As in Item 10, the composition of the Portuguese, human warfare, and human health composition, in which, by bearing a speed of at least 1 m / sec < working milk speed and at least 17 ml / sec Air pore punching with an air flow rate of up to 15 L / sec ^ can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%. 1 0 7 · As the appearance 1 〇 1 note Christine 丄 / shell. The already-laid freeze-dried composition can be made into particles with a thousand-average particle size below 5 microns or an effective particle ratio of 20% or more by withstanding the impact of air. It is a low-molecular-weight drug that contains 108. As described in the description of morphology, only < and freeze-dried composition of war. It contains high molecular weight drugs such as protein and nucleic acid, which are made as the effective ingredients of the 109 · item 1 〇 丨 record, the freeze-dried composition of Beyouji. It is a nucleic acid having a cold rolling dry composition as described in item 110 and item 109 as an active ingredient, which is maintained in a bulk state. It is a low-molecular-weight drug that contains Lengkang Dry Na, which is described in the above item, as an active ingredient, and a carrier. The carrier is at least one selected from amino acids, dipeptides, tripeptides, and sugars Group of people. 315314 33 200418520 112. The freeze-dried composition according to item 10, which contains high-molecular-weight drugs such as proteins and nucleic acids as active ingredients and a carrier, and the carrier is at least one species selected from amino acids. The group consisting of dipeptide, tripeptide and carbohydrate 0 113. The freeze-dried composition according to item m, which contains a low-molecular-weight drug as an active ingredient and a carrier, the carrier being at least one selected from hydrophobic A group consisting of amino acid, hydrophobic dipeptide and hydrophobic tripeptide. 114. The cold-dried dry composition according to item 112, which contains high-molecular-weight drugs such as proteins and nucleic acids as active ingredients and a carrier, and the carrier is at least one selected from hydrophobic amino acids, hydrophobic A group of sexual dipeptides and hydrophobic tripeptides. 115. The freeze-dried composition according to item 101, which is a water-soluble composition. 116. Cold as described in item 1G1; the dried composition contains the active ingredient in the last dose. 117. The composition for cold-drying as described in item 101 is prepared by freeze-drying a composition liquid containing an additive component in a non-dissolved state, and has the following characteristics (i) to (iii): (i) has Non-powdered morphology; (ii) a decay index of 0.05 to 1.5; and (iii) by being able to withstand air speeds in the range of 1 to 300 m / sec and airspace of 17 ml / sec to 15 L / sec The impact of the two lice in the & geogrinding can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%. 118. The cold-kang dry composition as described in item 117, 1 * 315314 34 200418520 The gas velocity is 1 to 250 m / sec. • The freeze-dried composition according to item 11 in item 17, wherein the gas flow rate is 20 ml / se (^ 101). Wang (2) Manufacturing method of dry powder for pulmonary administration * Preparation, Humans, humans, and humans are concerned with the production of a dry particle having a particle size suitable for " lung branches by pulverizing a cold-killed dry composition contained in a non-powder state in the inside of the container into the container. Method for powder preparation (dry powder for pulmonary administration). This method can be implemented by containing a non-powdered state in a container: freeze-drying the composition by applying a specific air impact. /,-And σ Manufacture of dry powder preparation for pulmonary administration described in this description = to 'the planting solution containing non-dissolved added ingredients as detailed in the above paragraph is cold-dried and prepared to have a G.G5 or higher decay index Invented non-powdered, cold; East dried the composition, and then imparted an air impact with an air flow of at least i 'two speeds and 17 mi / sec to the evening, so that the non-powdered cold; The dry composition is prepared to have an average particle size of 0 μm or less (preferably 5 μm or less) ) Or a dry powder preparation in the form of particles with an effective particle ratio of 10% or more (preferably 20% or more, more preferably 2S% or more, and more preferably 300 /. 乂 上 '特 佳 35. or more). In addition, the average particle diameter of the microparticles in the present invention means an average particle diameter generally used in the inhaler-related industry, and specifically, it is not a geometric particle diameter, but refers to the average particle diameter of aerodynamics. Diameter (MMad). The average particle size of aerodynamics can be obtained by conventional methods. Specifically: The average particle size of aerodynamics, for example, with an artificial lung air respirator: 315314 35 200418520

Particle size distribution meter (Amberst Process Instrument, Inc., USA), two-stage dust meter (G.W. Hallworth and D.G.

Westmoreland: J. Pharm. Pharmacol., 39, 966-972 (1972), U.S. Patent Publication No. 6 1 5 3 2 2 4), multi-stage hard dust tester, Dali stone mill impact test, Anderson multi-stage impactor, etc. In addition, B. Olsson et al. Reported that the ratio of particles with an average aerodynamic diameter below 5 // m increased, and the transport to the lungs increased (B · 〇lss〇n et a] [: Respirat〇ry Di, tons

Dell Veiy V, 273_281 (1996). A method for estimating the amount that can be delivered to the lungs in this way is, for example, effective particle size measured by a dry particle size distribution meter, a two-stage dust tester, a multiple & hard dust tester, a marble mill impactor or an Anderson multi-stage impactor Ratio and fines. The manufacturing method of the invention is preferably by containing the insoluble Si :: forming solution in a container, freeze-drying a ~ freeze-dried composition in this state, and then introducing air by Inside the container containing the composition, obliquely

Rinse and apply in the "Ling dry composition given the above-mentioned air flushing engine. Fang Xibu master Tki can use ... Month due to drying treatment and powder preparation treatment = use:-cereal device so it will not be lost due to small portions. The problem of pollution and contamination. Hall ° Because the above-mentioned air impact is given to humans, although it is particularly restricted, it is recommended that the hand-drying composition of the freeze-dried composition ...% is also limited, but it is preferably used. (Powder inhalation device.) The drying method described in () for the pulmonary administration of the present invention is to use the method of using the pulmonary discs (a feature of the manufacturing method known as knife clothing), and the patient receiving 4 tinctures At the time of self-use (inhalation 4 is used to prepare the grains in a container and the yttrium-yttrium composition is prepared into a powder preparation having a particle size suitable for lung administration by 315314 36 200418520. In addition, the invention is dried for lung administration Contains the following disclosure # 的 specific state # :, the manufacturing method of the clothes ^ 001 · made by using dry powder for pulmonary administration, the production method includes the right lee, ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The preparation is prepared, and it is, and the prepared liquid is prepared by cold rolling and drying in a container: The freeze-dried composition is contained in a non-powdered morphology, (ii) the decay index is from 0.05 to 1.5, and (m) by withstanding at least im / sec ★ ... promiscuous degree and at least 17ml The air impact of air flow per second can become a rabbit, and it becomes a particle with a thousand-average particle size of 10 microns or an effective particle ratio of more than 0%. By using the above composition, The object can be applied to the above-mentioned air impact device, and the air having the impact of the lice on the other side is introduced, so that the freeze-dried composition can be granulated to an average particle size of less than 10 meters or effective particles. The ratio is above 10%. Health 202. The method for preparing a dry powder preparation for pulmonary administration as described in item 201, wherein the cold-dried dry composition contained in the container contains an active ingredient in an insufficient amount. 2 0 3 · As in the case of item 201, a method for manufacturing a dry powder preparation for the administration of Pulmonaria pulcherrima by pulmonary administration, wherein the prepared material # J 衣 风 闲 U 粒 的Thousand average particle size is less than 5 microns or the effective particle ratio is more than 20%. System, 2G4. As described in item 201, the method for drying powder preparations for pulmonary administration by the method "Medium '4 cold; the decay index of the east dry composition is in the range of ⑴ to 315314 37 200418520 1 · 5. 205. Such a state According to the manufacturing method described in item 2G1, t, the low-molecular-weight drug of the cold-rolled and dried composition package preparation. U is the active ingredient 2 0 6. As described in the sad article 2 01, it is made by the lungs. Dosage for administration + Yashiba ten 丨 Manufacturing method, wherein the cold Ling i λ yttrium ytterbium powder preparation is a protein and a nucleic acid polymer drug. 207, the active ingredient 207, such as aspect 201 According to the manufacturing method described in the above item, Li Zhonghong, Li Hongyi uses dry powder-free formulations of Lihong "Dry Delta Hai freeze-dried composition is a nucleic acid maintained in a retainer state. The active ingredient is 208. The manufacturing method described in item 2G5, wherein the cold; dry welding, and low-molecular-weight drugs of the powder preparation and the carrier, the carrier is at least: seed effect: fraction of peptide , Tripeptides and carbohydrates. " " Amino acid, a 209. The manufacturing method described in item 2G6, in the bean, ^, 入 # and ^ using the dry stack powder preparation of the, lyophilized composition containing

Proteins, nucleic acids and other high-molecular drugs and carriers, W are selected from amino acids, dipeptides, m… ... 4 is a group consisting of at least one peptide and carbohydrates. 2 1 0 · Like appearance 2 0 8 Jp lei—a »Preparation of formula, Ben ι φ * ... 2nd dry powder preparation for pulmonary administration ° / Freeze-dried composition contains low-molecular-weight drugs as active ingredients and Agent, the # 丨 酸 Detail μ "less one selected from the group consisting of a hydrophobic amine group, an aqueous monopeptide and a hydrophobic tripeptide. 211. The method for producing a lung according to item 209, the towel m ^^ The powder formulation contains "315314 38 200418520 as an active ingredient, high molecular drugs such as proteins and nucleic acids, and a carrier, the carrier is small: selected from hydrophobic amino acids, hydrophobic dipeptides and hydrophobic Tri-peptide composition: Fresh 212. Manufacturing method of dry powder for pulmonary administration via pulmonary administration as described in item 201, wherein the cold; east-dried composition is a water-soluble compound, as described in item 213. The method for producing dry powder for pulmonary administration is a method of micronizing the composition in a container having a capacity of 0 to 50 Å to 50 Å so 1 π d. 7 H @ 2 1 4 · The manufacturing method of the dry powder preparation for the administration of red lungs of war, as described in Item 2 01 of the aspect, wherein a product having a minimum of 2 m / The air of sec is quick-drying, and the hole diameter and the air of at least 17ml / air flow are the means of impact. <I place it in the slave, and the air with the impact is introduced into the refrigerated diode fruit yttrium. 2 1 5 · As the appearance of the item 2 0 $ 1 々 叫 called ^ ^… contained in the manufacturing method of dry powder for pulmonary administration, the method of * zhong 'can be used by the container The cold inside = the composition imparts the impact of air with an air velocity of 1 to 3_ ~ and an air flow rate of at least 17 = sec ”于 & 忒, the air with the air impact is introduced into the containment freeze-dried ridge忒 二 ▽ Fruit yttrium 'composition into the container 216 · As the state 201 item seal + γ μ lung injection ㈣㈣ powder preparation "method, in which the hunting. The use of the composition in the container can be provided with At least im / s dryness ~ work delay and at least 20 11ι1 / ςρρ ,, impact of the gas shock generating gas introducing air storage, home clothes ..., the sub-blank will have received this lice coating composition of the freeze-dried composition of the container is performed. 2 1 7 · As in aspect 2 01, respectfully, a method for producing Beijizai's dry powder preparation for pulmonary administration 315314 39 200418520, wherein a freeze-dried composition in a container can be used by using the method Means for generating impact with air having an air velocity of at least lm / sec and an air flow rate of 17ml / sec to WL / sec, and guiding the air provided with the air impact to a cold storage container; 0 2 18. The method for producing a dry powder preparation for pulmonary administration as described in item 201, wherein the dry powder inhalation of item 301 or 302 as described in (3) Dry powder inhalation device described later is used. The device was used as a device to atomize the cold-dried composition. … Preparation: If the method described in item 218 of the dry powder preparation for pulmonary administration is described in the following, ‘the dry powder inhalation device of item 309 described below is used as the dry powder inhalation device, and the dry composition is micronized.时 ~ / 东 乾 ι / ο. As described in «218, dry powder coating for pulmonary administration using the method described below, using the dry powder inhalation method described in Chapter (3) below-the 3G1 dry powder inhalation device will be used for The manufacturing method of the granulated dry powder preparation is 1 yttrium europium, and the amount of air spray per product is 5 i 100 ml. 4 I placed in the container 21 The method of pulmonary administration w as described in item 218 of the manufacturing method is to use the dry powder inhalation device of the dry powder inhalation method of item 302 in the (3) section described below to draw cold, The production method of the dried powder preparation that has been planted in the above §, and the granulation flow rate of the product M is 5 to 300 L / min. Mouth air 222 + Dry powder preparation for pulmonary administration as described in item 201 315314 40 200418520 Clothing manufacturing method 'Contains the composition solution of the non-dissolved additive ingredients by cold beam drying and preparation The following ⑴ to (cold dryness of π〇: the product is contained in a container: ⑴ has a non-powder morphology, gas velocity and 17 ml / sec ⑴) has a decay index of 0.05 to 1.5, and (iii ) By withstanding the air impact with air flow from 1 to 300 m / sec to 15 L / sec, J hand can become particles with an average particle size of 10 microns or less or an effective particle ratio of 10% or more; by using It is known that the freeze-dried material 丄 n 丄 t γ + in the container can be applied to the air impact device, and the air having the air impact is introduced; thereby, the freeze-dried composition has an average particle size. Particles below 10 microns or effective particle ratio above 10%. Report 223. The method for producing a dry powder preparation for pulmonary administration as described in item 222, wherein the freeze-dried composition of the towel and the container is contained in the container in an amount of i dose of the active ingredient. 224. The method for producing a dry powder preparation for pulmonary administration according to item 222, wherein the air velocity is 1 to 25 °. 225. The method for producing a dry powder preparation for pulmonary administration according to item 222, wherein the air flow rate is 20 ml / sec. (3) Dry powder inhalation device The dry powder inhalation device suitable for the production of the dry powder preparation for pulmonary administration of the present invention is not only a freeze-dried preparation (freeze-dried composition) that can be stored in a container in a non-powder state. Material) in the container are 315314 200418520 granulated, and the micronized dry powder preparation is also a device for users to inhale. The device is equipped with (1) non-powdered, non-powdered freeze-dried components that can impart the impact of air that can be atomized, and can cool the micronized powder.涞 The dry composition is administered to the user mu 施 f by inhalation to cool; the micronized composition of the dong ㈣ composition is administered to both. In addition, the slave of J in the above (1) can also be referred to as "the method of introducing the air with the impact of the industrial gas into the container containing the cold and dry composition". In addition, the above-mentioned method of tadpoles can also be referred to as "means for discharging a micronized agent in a container from a container". In the present invention, if there is such a slave, it is possible to use any one of the fortune-tellers or future developers. ^ And ⑴ means, specifically, means by introducing into the container the air which can impinge the above-mentioned air impact on the lyophilized composition contained in the container. The method of (1) may be a method of imparting an air impact having an air velocity of at least 1 m / see and an air flow rate of at least 17 ml / sec to the cold-dried dry I composition in the container. The dry powder preparation prepared into a form suitable for pulmonary administration can be inhaled and administered to a user such as a patient by or through this method. X. It is possible to design a method such as a working room and a flow path :, the composition can be further micronized or dispersed. . The dry powder inhalation device includes a spray type dry medium powder inhalation device disclosed in (a) below, and a self-inhalation type dry powder inhalation device disclosed in (b). Active powder inhaler (ai) dry powder inhalation device, which is a device for inhalation in a non-powdered state in 315314 42 200418520, and has a freeze-dried composition in a container. The needle part of the air nozzle jet flow path, the needle ejection / melon needle part, conveying j &lt; air lice pressure feeding means for industrial aluminum in the air jet flow path of the above ten ports, and And the suction port is connected with the road; and the structure is: the needle portion is inserted into the mouth plug for sealing the container and the air jet flow is communicated with the inside of the container; The air jet flow path is sprayed onto the container β, and the cold and dry composition particles are discharged from the suction population through the discharge flow path by the impact of the spitting working gas. (a-2) The dry powder inhalation device described in (α_υ), wherein the above-mentioned means of air I is a manual type, which has a suction inlet provided with a suction valve and a wind box provided with a spout outlet of a valve; and It is configured to close the suction valve ~ By compressing the air box and opening the discharge valve, the air in the air box can be pressure-fed to the inside through the air jet flow path of the needle part connected to the discharge port. When the discharge valve is closed and the suction valve is opened, the air box is expanded by the elastic restoring force, and air is introduced into the air box. (A 3) As described in (a_i) or (a-2) above The dry powder inhalation device according to the description, wherein the air jet flow path and the discharge flow path are formed in one needle part. 0 (b) Self-inhalation type device (passive p0wder inhaler) (b-1) Dry powder inhalation The device is a device for micronizing the freeze-dried composition contained in a non-powdered state and for inhalation. The device has 43 315314 200418520. The needle part of the road and the suction port communicating with the suction flow path; And the structure is: in the state where the needle portion is provided for the oral inspection of the sealed container, the user's suction pressure sucks the air in the container from the suction port; when the air flows in through the air introduction flow path, it becomes negative , F The above-mentioned cold and dry group is changed by the impact of the flowing air. The particles paid are discharged from the suction port through the above-mentioned suction flow path. (2) ± (b 1) D dry powder inhaled Once inhaled by the user, the Shangcheng, human &amp; system is constituted by the above-mentioned freeze-dried composition of the liver, and β-human particles (b-3) are described in (b-1) or (b_2) from the inhalation port. The dry powder absorbs the suction flow path and the above-mentioned empty U 邕 &amp; device, which forms the upper volunteer lice into the flow path in a hand that introduces air into the container, ten 4. Under normal pressure, air can be introduced from the outside ^ &amp;, L (1) means) 'means just waiting for compressed air. Also, Si Bu Budao 2? None: There are no special restrictions on the use of jet mills, such as the above-mentioned spray-type dry powder. The 1-knife inhalation device squirts out the external air, and can use artificial π eight-strength hand and q dry powder to inhale. The main condition of the device is the self-inhalation type of the month, which is caused by the negative pressure in the container of each +.

Inside the device. In addition, the working air of A two degrees ° naturally attracts the guide. Λ A Yu Nu is sprayed by others and the air-injection of the external air into the device artificially can be done automatically by using any machine. The method can be manual or not. 315314 44 200418520 ΘWhite The dry end suction device used in the present invention, whether it is a spray type or a self-inhalation type, can be used for m, ^ 6 1k The hunting is introduced into the valley state by the above-mentioned air introduction (inflow) means. Inside and outside the empty pain Jia & Crying Meat "The impact of the ceremony will be stored in a non-powdered state. The lyophilized preparation inside will be micronized. For:-Guan Fang, the container used in it, as long as it can For freeze-drying, m Λ ㈣ will have no limit. For example, as far as the material is concerned, such as: Polyethylene, Polypropylene, Polystyrene, etc. Polyolefins are the main two, as well as glass and aluminum. . Also, let's suppress the shape of β King's plastic shape: angular column and ... columns can be cylindrical, cup corner column (diagonal pyramid), square column (square pyramid), six-octagonal column (octagonal pyramid), etc. Polygonal column (polygonal cone). In order to obtain this effect efficiently, the capacity of the container containing the frozen m product can be said as "Donggancan group ^ 丨 is better" to ^ ^ 丨 is. Ml 'to use in the language of 0.2. ”, The tube of the container (the internal power master uses 0 2 It is better to 100mm, and more preferably 2 to 50mm. To 75mm is more, the θ of the freeze-dried product contained in the container includes the unit administration amount (1 旦, the product of the product! 'Preferably, it is the amount of the active ingredient in the fish fork and fork) or several times (specifically, 2 to 3 A, the amount of the active ingredient in the branch. More preferably, A to 3 times). The amount administered is 3 times as much as the amount of the U-throw. Also, the freezing age protection is the same as that of the washing and drying composition, which has a specific amount of 8%. The amount varies, but if it is below, it is preferably 20, but it is not particularly limited, but it is usually 30 mg or less. It is less than or equal to 0, more preferably less than or equal to 10, and particularly preferably ^. The air impact generated by the external air, 315314 45 200418520 is caused by at least one or several times the air flow of human beings and its generated :::::!, Into the container within the limit of the durability of the container, As a matter of fact, as long as the air flow is outside the capacity and the air speed exceeds the above, the air flow is not affected by the air flow It is usually 5 to 300 L / min, j human inhalation once. In addition, in the jet type banknote 4, 士 D ,, 'Tian Tong Zhi is 10 to 200 L / 1 time of air shot Jin helmet &lt; r κ 〖Monthly condition, you can use the hole I rent in the range of 5 to J 〇ml. For the person who uses it, 敕 ^ Father's heart ^ is 1 Θ to 50 m 1 The season is again filled and filled into the container The surface causes an air scab that is equivalent to at least 1 m / sec of Tian Xi at least 1 lm / 々 of freeze-dried composition. A better air impact is at least 2 m / s. The air generated is rushed towards the WseC where it was hiding. The air impact caused by air velocity is better at least 5 m / see it ^ P ^ „I 1 η The air impact produced by the industrial continuity should be more than the air pain caused by air at least 10 m / sec. Air impact. among them

Regarding the upper limit of air impact, I, ..., and other specific limits, for example, an impact generated by an air velocity of 300 m / sec. About Xi # About the upper limit of 5 Hai, the air impact generated by the hole speed of 250 m / sec is preferred, the air impact generated by the air speed of 200 is more preferred, and the air impact generated by the air speed of 150 m / sec is particularly preferred. Air impact. The air impact is not particularly limited if it is an air generator having an air velocity within a range consisting of a lower limit and an upper limit selected from any of the above, such as 1 to 300 m / sec, 1 to 250 m / sec, 2 to 250 m / sec, 5 to 250 m / sec, 5 to 200 m / sec, 10 to 200 m / sec, and air impact in the range of 10 to 150 m / sec. X 'wherein the speed of the air imparted to the freeze-dried composition can be determined as described below. That is, in the spray-type drying 46 shown in the first embodiment below 46 315314 200418520 powder suction device, the air stored in the wind box 10 is forcedly introduced into the container from the air jet flow path 3 and filled in the container. A mechanism that freezes and dries the composition (block-shaped freeze-dried composition: also referred to as "freeze-dried block" hereinafter) to impinge air, and the generated particles are discharged from the discharge channel 4. At this time, the air flow rate flowing through the air jet flow path 3 is calculated by dividing the amount of air stored in the air box 10 by the time for which the air is sent to the container. Then, by dividing the air flow rate by the cross-sectional area of the flow path that introduces air into the container, such as the air jet flow path 3, it is possible to calculate the air velocity that imparts an impact to the freeze-dried composition (freeze-dried block). Air velocity (cm / sec) = air flow rate (ml = cm3 / sec) + cross-sectional area of the air introduction flow path (cm2) Specifically, for example, when the diameter of the air jet flow path 3 is designed to be 1.2 mm, the discharge flow In the case of a spray-type dry powder inhalation device with a hole diameter of 0 1 · 8 mm and an air volume of about 20 ml stored in the air box 10, the air volume of about 20 ml stored in the air box 10 is less than When the freeze-dried composition was forcibly introduced into the container from the air jet flow path 3 for about 0.5 seconds, the air flow rate was about 40 ml / sec. If this value is divided by the cross-sectional area of the air introduction flow path (air jet flow path) (0.06x 0.06x 3.14 = 0.0113 cm2), it will become 3540 cm / sec, that is, the air velocity is about 35 m / sec. . Further, in the self-suction dry powder inhalation device shown in the following embodiment examples 2, 3, and 4, since the air flowing from the air introduction channel 17 is used to impinge on the freeze-dried block, the generated particles are attracted from The mechanism that the flow path 16 is discharged, therefore, the air flow rate through the flow path is regulated by the diameter of the air introduction flow path 17 and the suction flow path 16. Therefore, the air velocity of the freeze-dried composition contained in the container 47 315314 200418520 can be measured by measuring the air flow rate flowing through the air introduction channel 17 and dividing it by the nozzle of the air introduction channel 17 The cross-sectional area is calculated. Air velocity (cm / sec) = air flow rate (ml = cm3 / sec) + cross-sectional area (cm2) of the air introduction channel 17 Specifically, the inhalation device including the container is installed at the European Pharmacopoeia, The third section Supplement _ 2001, pi 13-115) of the cross section of the device a (device A) (two-stage dust measuring instrument · made by Copley, UK) uses a flow meter (KOFLOc DPM-3 ) Measure the air flow through the air introduction channel I ?. For example, 'In a self-inhalation type dry powder inhalation device designed with an air introduction flow path 17 having a hole diameter of 0 1.99 mm and a suction flow path having a diameter of 0 丨 99 mm, a flow meter (KOFLOC DPM- 3) In the case where the measured air flow through the air introduction flow path 17 is n 7 L / min (that is, 295 ml / sec), the air velocity can be divided by the cross-sectional area of the air introduction flow path. (0 · 0955 × 〇 · 9955 × 3.14 = 〇.〇311cm2) to obtain (9486 cm / sec, that is, 95 m / sec) 〇 Also, regarding the air 'L 带 to the freeze-dried composition filled in the container For example, at least 丨 7. The air flow rate is preferably at least μ ml / sec 'more preferably at least 25 ml / s.' In the above description, there is no particular limitation on the upper limit of the air flow rate, for example, 900 L / min. The upper limit is preferably 15 or more. It is more preferably 10 L / sec, still more preferably 5 L / sec, still more preferably 4 L / sec, and particularly preferably 3 L / sec. Specifically, the air flow rate is only required to be arbitrarily selected from the above. Within the range of the lower limit and the upper limit, there will be no special limit 315314 48 200418520. The range is, for example, 17 m / sec to 15 L / sec, 20 ml / sec to 10 L / sec, 20 ml / sec to 5 T / s.τ / Sec '20 ml / sec to 4 L / sec, 20 ml / sec to 3 L / SeC, 25 ml / command to 3 L / sec. Also, the powder inhalation device used in the present invention can be provided with a vacuum Milk is in a state close to the bottom of the container, and the freeze-dried composition of ^ ° 卩 4 freeze-dried composition is used to spit air from the outlet of the flow path (preferably with a fine hole 峪. ^ ^ Y, the soil outlet), such as In the implementation examples, the details are provided with a ^ '&V; rolling V channel or air jet flow needle: two: means to increase the impact pressure of air introduced from the outside. Also, this will change, with The size of the device, with its preferred range;: Γ particularly limited, a diameter ",, compared to the 〇.3 Shu soil υ · :) to 5 mm, more preferably within 8 square day. 〇.8 to 5, especially good range of 1 to 4mm. By introducing air into the crying meat, bite, cry, and let people cry ^ Can be stored in a non-powder state. Among them, the degree of micronization is a particle size suitable for pulmonary administration, i.e., 5 or less. The specific particle size of fi is as follows: the dry powder inhalation device used in the present invention has a specific appearance of 7 ^: the following 300. The dry powder for pulmonary administration is sucked into a bucket. 'The particles are inhaled from a cold-hole examiner contained in a container in a non-powder state by air impact. The result is 30% of the total amount, as indicated in item 3 of the article, and it is placed in a dry powder-free inhalation container. It will be contained in a non-powdered state. The obtained particles were used by the subject to absorb the dried composition, and the article was provided with: 315314 49 200418520, a needle portion having an air jet flow path, and an air jet flow path having the above-mentioned needle portion of the discharge flow path. The air pressure feed for the empty milk and the suction port communicating with the discharge path of the needle part; and the structure is: the needle part is inserted into the mouth for sealing the container so that the empty path and the discharge flow path communicate with the inside of the container , #Pressurized by the above air: ^ Official air is sprayed into the container through the air jet flow path ^ He shot ^ the impact of the gas to make the above cold; Donggan difficult particles become micronized, and the shaped particles are discharged through the above The flow path is discharged from the suction port. 302. The dry powder for inhalation through pulmonary administration as described in the sample item f2, which is to granulate the cold-coated dry composition M stored in a container in a non-powder state, and obtain the obtained particles for inhalation by the subject. A device comprising: a needle portion having a suction flow path, a needle portion having an air introduction flow path, and an suction port communicating with the suction flow path; In this state, the subject ’s inspiratory pressure sucks the air in the container from the suction port, and at the same time, the air flows through the upper air-conducting flow path. It has become a common problem. The above-mentioned air impacts the air The composition is made into particles by cooling and drying, and the obtained particles are discharged from the suction port through the suction flow path. 303. The dry powder for inhalation through pulmonary administration as described by the member 301 is inhaled into the container by spraying air into the container once to make the above cold; Donggan-free composition is micronized and inhaled from the above Mouth drains. 304. The dry powder inhalation device for pulmonary administration as described in item 301 315314 50 200418520, which is constituted by spraying air to the above-mentioned container / dong. The ratio is above 10%, and it is discharged from the above-mentioned suction port. "Effective" 305. As described in aspect 3 () 1, the pulmonary injection is to inhale the above-mentioned air f $ and L red powder into the needle loading part. In the form. The exit path is formed by a 306 · transplantation via lung as described in item 3 (2), which is constituted by the subject A's dry uncle's inhaled contents which are micronized and discharged from the above-mentioned inhalation port. . The 9 freeze-dried composition 307. As shown in item 302, it is constituted by the subject's \: and the inhalation of the dry powder into an average particle size: V ::: under: surgery The dry group is above 10%, and is discharged from the above-mentioned inhalation port of Bu, +, or effective particle ratio. 308 · As described in item 302, it is a form in which the above-mentioned suction powder "" is sucked into the needle loading portion. 34 The air introduction flow path is formed at -root 309 · As in item 308, The "Dry Powder Inhalation Device for Lung Delivery" is a dry powder inhalation device equipped with the following components: Holder for holding a container, 1-shot non-powder for micronization ^ "Close each port to receive air for flushing A plug seal; and a cold beam dried composition in the form of a block, which imposes air impact on the above-mentioned freeze-dried composition of 沭 Α &amp; in the container, and attracts the air-borne composition from the above-mentioned valley state. Means; ', ~ # and micronized powder cold to dry 315314 51 200418520 It has: &amp; 具 # for attracting the above cold from the container; east drying composition ... flow path and for introducing external air into the container An air introduction flow path, a suction port portion communicating with the suction flow path of the needle portion, and a guide portion that guides the holding portion to the axial direction of the needle portion. Description ^ tip ^ The container is advanced toward the needle point of the needle and the mouth of the container is inspected by the needle point: machine two or retracted from the needle point to pull the mouth of the container away from the above. 卩 'and the operating body that operates the mechanism And the mechanism is configured to operate the above-mentioned operation body with a force smaller than the force required for the needle to be inserted into the mouthpiece of the container, with the &amp; * required force as above if # p + 13 卩 and U The casing of the suction σ part, the guide part, and the holding part operation part; and!, ... the needle. 卩 pierce into the mouth to make the suction flow path 1Γ of the needle part into the flow path to the container The internally connected, and at the same time, the freeze-dried p composition is positioned at the front end of the air introduction flow path. The test subject is sucked into the container from the suction port, and the sub-gas is used to pass the empty milk through the air introduction flow path. It can flow into the container to impinge the air on the freeze-dried composition in the container. Valley 3 1 0. As in aspect 3 009, the structure is as follows: the dry powder is sucked into the casing with dry powder. It is cylindrical, with two ends formed at the inner part of the outer shell. Before the shell is formed by the above-mentioned holding portion for receiving the container 315314 52 200418520 to, the needle portion is directed to the above-mentioned storage room with the needle tip facing the storage room, and is arranged in the same manner as the above-mentioned needle portion in a gas form. The inlet port is connected to the entrance and is externally provided on the wall portion of the casing; and through the holding portion operating portion, the holding # of the casing is used to advance and retreat in the axial direction of the storage room. ：:::::: 1 ° Dry powder for pulmonary administration according to item 1 ... of the device =: outside :: ;; description: The above-mentioned entrance and exit Γ is formed at the position where the holding part is retracted, and it is connected to the above-mentioned casing with a twist key. Ontology

The H holding part running part is formed by being covered with the cover of the entrance and exiting. When the cover is closed, the holding part is directed toward: ^ When the door is closed to open the entrance and exit, and the upper part is pulled back to retract And do the above: Hold the needle from the needle part as the body. Shangzi doubles as the operation of the above-mentioned mechanism. (4) Dry powder inhalation system for pulmonary administration. The dry powder inhalation composition for lung administration of the present invention is provided with a specific enrichment. , ... A system composed of means of inhalation devices, 1 in the province of lyophilized composition, and the old one ^ and cold knitting in the container ;; 2 :: Cheng, which is caused by the impact of air ... η Τ pulverized in a non-powder state. Dingyou &lt; ~ 'Dried fruit composition has micro-half W ... can form particles with an average particle size of 10 pulse machine lambs on 10 / 乂. According to Zhao Zhileihe, and the system, the user will use (inhale) the non-powder 315314 53 200418520 to provide the cool and dry composition of the dosage form, that is, from the average particle size within 5 weeks of clothing. Applicable to the lungs, the composition of the particles above the coffee is less than 2 ^ or effective particle ratio. &amp; of dry preparations and can be administered on their own (the service is, II to get the material to be efficiently administered with dry powder to suck people "etc. is very important. Composition, inhalation device and container •, solution = The cold-rolled dry composition is preferably a freeze-dried composition prepared by cold-drying a composition liquid containing non- = evil added ingredients and having the following characteristics: 〃 ( 〇 has a non-powder morphology; (η) a decay index of 0.05 or more; and (m) by being subjected to air impact having a degree of at least lm / sec of ^ ^ ^ and at least 17 ml / sec, It can be fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%. Regarding the composition of the freeze-dried composition and its preparation method, it can be used in detail in Chapter (1) above. 4: Dry composition 'is in a container that has been subjected to cold-blood drying treatment and is in the valley state of Fenhui. It is contained in a container # ^ ^ ^ ~ freeze-dried composition amount two doses (one dose) ) Or several times (specifically 2 to 3-person) and the amount of active ingredients in summer. Better for you, 丄~ G 3 The amount of effective ingredients in the early administration amount (into 1 shot). The contents of the active ingredients contained in the visually-drying composition contained in the container are clear and dry. It varies according to the mouth, and it is not particularly limited if it is appropriately selected from the inhalable amount. 315314 54 200418520 is usually 30 mg or less, preferably 20 mg or less, more preferably 10 mg or less. 5 mg or less. On the other hand, as a dry powder inhalation device, it is preferable to use a dry powder device having the following characteristics: (1) air impact imparting means (or rolling introduction means) and (2) particles Evacuation means (or inhalation and administration means), the air is introduced (inflowed) into the container containing the non-powder freeze-dried composition by means of the upward return (1) air impact application means, and the working gas introduced (inflowed) is used Redemption (jetting pressure) 'This freeze-dried composition is made into micronized particles, and the above-mentioned (2) particle ejection means is used to pulverize and dry the micronized composition and discharged from the container. Administration by inhalation: user 0 -Example 'is, for example, the dry powder detailed in Chapter (3) above, that is, the dry powder inhalation system suitable for pulmonary administration of the present invention, and at least when used, it is used in combination with y,',. ^ ^. The combination of the above-mentioned present invention; the combination of the East dry composition and the above-mentioned dry powder L. The direct system. That is, the dry powder for lung administration for Taiyanming plus + eight-time system is at least used for inhalation to prepare the harvest valley. The above-mentioned cold lingling of the present invention 丨 product 8 ~ v / dried fruit "composition container with powder inhalation device. Rework I B ^ If in accordance with the present invention ^ / hunting by using the above dry powder inhalation: gas ¥ into In the container containing the cold-rolled and dried composition of the present invention, the air velocity and the air velocity of at least 17 ml / s and the air temperature of at least 17 ml / s and the uniformity of at least 1 soil i / ml / sec in the β portion of the β Said &amp; strike, you can 碉 忐 亘 I π # 二 乳 ▲ Place the air to the moon garment to have a particle size that can be mistakenly inhaled and administered by the lung or effective 315314 55 200418520 Effective by inhalation by the lung Particle ratio dry &lt; 钆 轫 powder formulation. Regarding the particle size that can be administered by inhalation through the lung, for example, ^ ^, ^ ^ If the average particle size (specifically, the average particle size of industrial pneumatics, MMAD) is n ^ r; _ 10 μm or less preferably 5 u is below. In addition, regarding the ratio of effective granules that can be effectively used for borrowing ν μ by eight lungs, such as 10% or more, preferably 20% $ ^ 25% or more, 30% or more, especially Better than 35%. According to this system, the prepared stem can be administered (by inhalation) to the user via the lungs. This means that the dry powder inhalation system used by Yi Shi can be described as suitable for borrowing two: the [pulmonary technology and # 古 制 π ^ ,, straw, and the manufacturing system of dry tertiary preparations administered through the lung, and at the same time The powder / powder formulation is administered to the user's delivery system via the lung. " In addition, the dry powder inhalation system for pulmonary administration according to the present invention includes the following specific forms that are not disclosed below. · 40 1 · A type of dry T-knife for pulmonary administration is less than the system. The following (1) and ( 2) Combined use: _ (1) A container containing a freeze-dried composition, the person; # Ρ t, —, Cheng ~, East drying composition will contain the non-dissolved state of the added ingredients, and The liquid is prepared by freeze-drying and has the following characteristics (i) to (iii): (I) it has a non-powdered morphology; (II) its decay index is above 0.05; and (ii) it has The air velocity of at least lm / sec and the air flow of at least 4 air impact, can become particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%; The cold rolling and drying group inside 315314 56 200418520 means for forming and discharging means. Micronized powder freeze-dried composition 402. The pulmonary administration system as described in item 401, wherein the container containing the freeze-dried composition and the amount of the active ingredient of the freeze-dried composition are contained in a dry powder. The inhalation system contains one dose of 403 for each injection. · As described in item 401, it is used in combination when inhaled. · As in item 401, it is cold; Within the fence. Device. The dry powder inhalation for pulmonary administration is in the form of the container and the device described above. The decay index of the dry powder inhalation system for pulmonary administration is in the range of 0.05 to 15. 0 &lt; Dry powder inhalation system for pulmonary administration, wherein the air impact described in the outline is produced by air having a milk flow rate of at least 2 m / s and at least 17 ml / sec. Ecological sample 4 0 1 j sound but ^ _ partial. As described in the state sample, dry powder for pulmonary administration. The air impact recorded in "Where" is generated by air at an air velocity of 3 m / sec and an air flow of at least 17 ml / sec. A dry powder inhalation system for pulmonary administration, wherein the air impact described in the urn is generated by air having at least an air velocity and an air flow rate of at least chest sec. 408. The dry powder inhalation system for pulmonary administration as described in Aspect 40, in which the air impulse described in the above is by air having an air velocity of at least one and an air flow rate of 5 L / sec. 』Support 0 315314 57 200418520 4 09 · As the appearance 4〇1 工 杏 々 # β t The brother, the left lung branch and the inhalation system with dry powder, where 'the cold-determined dry composition has the ability to withstand air impact' can be It has the characteristics of fine particles with an average particle size of 5 micrometers or less, or an effective particle ratio of 20% or more. 4 1 0 · Like aspect 4 〇 1 Jg ~ Yan ί &gt; t, 5 has been contained! Dry powder inhalation system for pulmonary administration, first, and first, wherein the freeze-dried composition of the drug. The low molecular weight of the active ingredients of Yifeng 4 11 • Such as the situation of 401 industrial blinds system, in which the cold Kanggan II and dry powder inhalation system and nucleic acid and other polymer drugs. One is the protein of the active ingredient 412. The system of item 401, wherein the cold-beam dry roasting is performed by electricity: a pile of powder is sucked into the nucleic acid which is in the state of the body. ',,, and the knife remain 4U, as described in item 40, wherein the frozen branch shares a dry powder inhalation system, and the dried fruit contains no drug, a drug, and a carrier, and the carrier is μ The low molecular weight d I of the active ingredient is a group consisting of rtr peptides and carbohydrates selected from month #I. , Amino acid, dipeptide, tri 4U. As described in item 411, wherein the freeze-dried, inhaled polymer powder such as system and nucleic acid with dry powder is used to effectively form the protein amine group of the knife. The acid, bimorph, and bimorph knives are contained in 4 carriers, and the carrier is at least one member selected from the group consisting of peptide-peptides and carbohydrates. 4 1 5 · As for aspect 4 1 3, the system, wherein the freeze-dried ... / Dry powder inhalation drug and carrier for administration, "::: contains low-molecular-weight carrier as an active ingredient at least-selected from the group consisting of hydrophobic amino acids, 315314 58 200418520 aqueous dipeptides and hydrophobic three Groups of peptides. 4 1 6 · Like aspect 4 1 4 顼 汴 contend ^ ^ .. ^., ° Load it! Lung administration with dry powder suction A &amp; system, where the cold rolling dry The composition includes: macromolecules, macromolecules, nucleic acids, and other high-molecular drugs and carriers; the protein of the knife is hydrophobic amino acid, and at least hydrophobic-a group selected from the group consisting of rainbow-like triseptides. 缘 # + Dry powder inhalation system for intrapulmonary administration, in which the frigid dry composition is a water-soluble composition. 糸 4 1 8 · Such as the aspect 4〇1 顼 9 哉 缘 #,,... Has been contained, the dry powder suction system for sitting lung administration. Among them, the device uses the following 0 and 屮. 末 and 糸 μ pulmonary administration The dry powder inhalation device is a device for inhalation of cold chilled and dry powder in a container for inhalation, which is inhaled into the field to be atomized and the obtained particles are broken by the examiner for inhalation. The device includes: an air jet flow path; Needles, and the air 呛 鼾 a々 + of the needles, needles that have a way to discharge ~, air delivery means for the disk m ^ air, and the suction population that communicates with the discharge flow path of the needles And, it is constituted as follows: The above-mentioned needle part is pierced into the poor shaking path and the exhaust flow path, and the upper and lower valleys are tied ... to tie the air jet flow section so that "wanyou: μ 内 # 通通" by The above-mentioned air pressure feeding hand only has 1 milk of the milk sprayed by Shangcheng to spray the air; == is sprayed into the container, and is discharged from the suction port through the above-mentioned discharge flow path. 〖Π） Pulmonary powder inhalation device for pulmonary administration &amp; Yu &amp; Crying by 々, known to be contained in a non-powdered state ^ ~ The freeze-dried composition is micronized and the resulting particles are used by the subject for inhalation The device includes: 315314 59 200418520 ', a needle part having a suction path, an air inlet which communicates with the suction flow path; a needle part of the path, and is configured to be inserted into the needle part for sealing the above The suction pressure of the mouth of the container is sucked into the two through the suction port, and the air is passed through the above medium. The internal working gas flows into the negative milk flow path with the internal milk introduction flow path, and the cold rolled dry matter is finely impacted by the inflowing air. The obtained particles are broken into particles through the above-mentioned ... The suction port is discharged. 4 1 9 · 如 势 样 4 1 8 # The member has a pulmonary administration system, in which the device is a dry powder inhalation system for pulmonary administration, which is a dry powder inhalation device with the following components: The holding portion for holding a container, wherein the container contains a non-powdered block to be subjected to pulverization = air impulse is sealed with a spigot, and a yttrium-rhenium composition is provided to the above-mentioned container. Lengling in the above container attracts dreams by μ ^ impact and from the composition means; μ and the micronized powder cold leng drying has: The suction path has for the above-mentioned container 11 to attract the above-mentioned cold-drying composition ^ Introduction channel and suction port for introducing external air into the container into the suction port communicating with the suction flow path of the needle portion, guiding the holding portion to the guide portion in the axial direction of the needle portion, and holding portion operation portion When the container is held in the holding portion 315314 60 200418520, the container is tilted toward the needle portion, and the needle is inserted into the mouth of the container by the needle point, and The needle tip retreats The mouth bolt is pulled away from the mechanism part for the above-mentioned needle tip, and it is shaken; 4 Rongcang is used as the operating body of the mechanism part, and the mechanism part is configured to be usable smaller than the mouth of the needle part into the container Operate the operating body with force, and a housing that supports the needle portion and is provided with a fan and mouth portion, the guide portion and the holding portion operation portion; and the mouth pin 佶 彺 M is inserted into the needle portion, and the above The suction flow path and air introduction flow path of the needle part communicate with the inside of the container. Lu and. ^ Y ^ ^ rj 时 When the above freeze-dried composition is positioned at the front end of the air introduction flow path ^ ^ 悲, the air is drawn from the suction port by using the suction pressure of the subject Suck the air in the valley and let the air flow into the valley through the air introduction channel, which can impinge the air on the freeze-dried composition in the container. 420. As described in item 401, the trans-pulmonary tray &quot; another inhalation system with dry button powder, and die, wherein the following ⑴ and (2) are used in combination: ⑴ :: a container for cold relay composition 'The cold The dry composition is prepared by cold-drying the composition liquid of the additive components in a non-dissolved state, and has the following characteristics (i) to (iii): (1) it has a non-powder morphology; ( η) the decay index is in the range of 0.05 to 15; and ㈣: from the impact of air with an air velocity of 1 to 300 m / sec and an air flow of 15 l / sec at an i7mi / sec, "" becomes an average The particle size is less than 10 microns or the effective particle ratio is more than 10% and '315314 61 200418520 (2) Equipped with the means for imparting the above-mentioned linear impact to the container and means for discharging the powdered cold powder; Ϊ = means of material Device. 7 / Coming to dry 干燥 · As described in item 420 through the lung system, which contains the cold 庾 section r ζ, worship &amp; end of heart inhalation sigh 3 ~ bed dry button composition, cry, The effective amount of the administered ingredient A $ # p is a container containing 1 Lafeng knife ~ freeze-dried composition. 422. The lung-draining fine drying system described in item 42G, wherein the air velocity is i to 25 m / sec. Learning: 23. The dry powder for pulmonary administration as described in the aspect described above, wherein the air flow rate is 20ml / se ^ Caru. (5) Method for pulmonary administration ^ The present invention relates to a method for pulmonary administration, which includes cooling in a non-powder state; when the composition is dried, it is prepared into a state that can be administered by lungs = And inhaled the dry powder preparation in the form of particles. The transpulmonary method can be performed by using the transpulmonary administration &gt;% inhalation system of the present invention detailed in Chapter (4). The system is preferably composed of Γ containing non-dissolved added ingredients detailed in the containment chapter. The composition liquid is prepared by freeze-drying ^ ^ The container of the freeze-dried composition of the present invention, and the dry powder inhalation system for pulmonary administration composed of the dry powder inhalation device detailed in Chapter (3) The method of administration includes the specific state 501 disclosed below. A method of pulmonary administration, including the use of a freeze-dried composition, 315314 62 200418520 The cold-bead-dried composition is a composition liquid containing non-dissolved added ingredients frozen It is prepared by drying and has the following characteristics ... (i) It has a non-powdered morphology; (ii) The decay index is greater than or equal to 0.05; and it has been subjected to an air velocity of at least lm / sec and at least η. — The air impact of air flow can become particles with an average particle size of less than ι 0 μm or an effective particle ratio of more than 10%; in use, the above-mentioned air impact is imparted to Cold; dry the composition to form particles with an average particle size of 纟 10 microns or less, or an effective particle ratio of ⑽ or more. Then, the user inhales the micronized powder and throws it in. 0502. As recorded in Item 501 The method for administration via the lungs, wherein: 1. The freeze-dried composition contains the active ingredient in a single administration amount. A 503. The method of pulmonary administration as described in item 501, wherein the cold-kang dry composition is contained in the container 1 and the micronized powder system =-prepare the cold for Gu Jie; The composition can be prepared by means of a means for imparting the above-mentioned air impacting hand I and a means for calmly discharging the micronized powdery cold-bed drying composition. Mouth mouth, 504. The pulmonary administration method as described in item 501, wherein the freeze-dried composition has a decay index in the range of 0.05 to 1.5. ^ ^ 5〇5. The method of pulmonary administration as described in Item 503, wherein in (iH): the air impact of the load is by an air velocity of at least 2 m / sec and 17 ml / sec. A flow of air is generated. 506. The method of pulmonary administration as described in item 503, wherein the air impact system described in (iii) 63 315314 200418520 has an error rate of 1 to 300 m / sec.

And at least 17 ml / sec of air vapour. 507. The method of pulmonary administration with a negative load on aspect 503, wherein the air impact salt described in (iii) has an air velocity of at least 1 m / sec and at least 20 ml / sec. Zhi ^? * Two air volumes are generated. 5 0 8 · Like appearance 5 03 Hall ^

Bei Yingzai's method of pulmonary administration, wherein the air impact system described in (iii) M wins ^ Wrong from having an air speed of at least 1 m / sec and a sound of 17ml / sec to 15L / Sec +… bis Air flow is generated by air. 509. The method for administration via lung according to aspect 503, wherein the composition of Lengkang dry dementia comprises a low-molecular-weight drug with Aowen as an active ingredient. 5 10 · Such as aspect 503, a method for administering lung cancer via a negative load, wherein the freeze-dried composition includes proteins and nucleic acids such as active ingredients of horses.

5 11 · Such as state 503> The composition of Dongganduolen contains nucleic acid. The method for pulmonary administration according to item 5, wherein the cold active ingredient is maintained in the state of the retainer 5 12. Item 509, the freeze-dried composition contains as a carrier the at least one member selected from the group. The documented method of pulmonary administration, wherein the low-molecular-weight drug and carrier of the cold active ingredient, amino acid, dipeptide, tripeptide, and carbohydrates are composed of 513. Such as 5101 Jg a soil, ..., 6 The method for administering via the lung, wherein the freeze-dried composition comprises ^ ^ Feng Xiaocheng's proteins and nucleic acid polymers and carriers, and the Panyu Λ carrier is at least one selected from amines. A group of amino acids, dipeptides, tripeptides and sugars. , 315314 64 200418520 5 1 4 · As in aspect 5] The method of pulmonary administration described in item 7 ts _, in which, the human freeze-dried composition contains "7 9 θ i, which is a low-molecular-weight drug that is effective to 7 knives As well as the carrier, the Shihai carrier is a group consisting of at least one day +, self-amplified water-based amino acid, hydrophobic dipeptide, and hydrophobic dipeptide. ^ 5. 如 忧 、 样 513 According to the method of pulmonary administration given by the workers, the cold m 4, ~, polymer strips such as proteins and nucleic acids and carriers that are effectively formed, and the carrier # he-pi… ... are up to ^ species A group consisting of a hydrophobic amino acid, a limbic dipeptide, and a hydrophobic tripeptide. The pulmonary administration method described in item # 503, wherein the freeze-dried composition is a water-soluble composition. Zhizhuo H The method of pulmonary administration described in item 5G3 is a method of administering microparticles into microparticles with an average particle size of 5 1/2, π + +, or less, or an effective particle ratio of 20% or more. 5 1 8. As sad as 5 〇3 Indian Gong Xi Mo 7 Gu _ 4rL 彳 shellfish. The method of pulmonary administration has been included, in which the device uses (3) dry powder Inhalation wear, dry powder inhalation device in the form of item 301 or 3 002 in the middle and early stages of the set of clothes. = 9 · The method of pulmonary administration as described in item 518 of item m, in which the device 4 is used (3 ) The dry powder inhalation device described in the form described in the chapter of the dry powder inhalation device ... 520 · The method of pulmonary administration as described in item 503, wherein the cold-bed drying composition will contain insoluble 1 f form The composition solution of the heart's ice plus ingredients is prepared by freeze-drying, and has the following characteristics: It has a non-powder morphology; (10 The index of decay is in the range of 0.05 to 15; and 315314 65 200418520 (iii ) By withstanding 1 to 300 m / sec working hole angle and 17 ml / sec to 15 L / sec air flow Effective particles: dry particles of 1 υ / ❹ or more; micronized powder, using the above-mentioned cold / easy-dried composition in a container, which can impart the impact of air lice on each elbow to the container. Prepared by a device that discharges the powdered freeze-dried composition 52L The method of pulmonary administration according to item 52G, wherein the air velocity is 1 to 250 m / sec. 522. The state of pulmonary administration according to item 520, wherein the air flow rate is 20 ml / sec to 10 L / sec. (6) Use of freeze-dried composition for inhaled pulmonary administration. Further, the present invention relates to use of freeze-dried composition in a non-powder state for inhaled pulmonary administration. The body contains: 601 · Freeze-dried composition is administered by inhalation through the lungs, where ', this cold health dry composition is prepared by freeze-drying a composition liquid containing non-dissolved added components by freeze-drying And has the following characteristics: (I) has a non-powdered morphology; (II) has a decay index of more than 0.05; and (iii) = withstands an air velocity of at least im / sec and at least 17 ml / sec. The air impact of the air / melon can be made into particles with an average particle size of less than 10 microns or a ratio of active particles of more than 10%; Q freeze-dried composition is powdered to have the above average particle size or have 315314 66 200418520 effect Particle ratio of fine particles to use. 602. If item 601 is described in terms of Gong Xi, Human, Soil ± m ^, and lyophilized composition, the active ingredient is administered via the lungs. The finished product contains Γ above the amount of administration, and is used as described in item 601. The east-dried composition is administered through the lungs. 7 The freeze-dried composition is contained in a container, and the powder is micronized.用 物 可 hydrazine 钿, +, # have the freeze-dried composition in the glutinous state ^ Yu slave and the means of lyophilizing the micronized powder a without composition from the container The device is prepared by 604. 603 items such as respect, human, soil, and Tirgans on the ground. 々 The freeze-dried composition is administered by the lung 1 5 ^-pr βπ ... The mourning index is within the range of 0.05 to 丄〕 & 粑. 605. Such as the 603 item, the order of congratulations, people, soil + m #, 々 lyophilized composition is used in lung administration, where The inundation # 9 / V Donggan-free composition is formed by withstanding an air velocity of at least 2 m / sec and at least ^ strikes, and the air flow of the air flow of $ ml / sec is average. Particles with a particle size of 10 micrometers or more.… Or as described in item 6Q3 of the effective particle ratio above ⑽; the use of East dry composition for pulmonary administration, its The freeze-dried + original, and the finished product is made of air Ding # bearing an air velocity of 1 to 300 m / sec and an air flow of at least # τ «, ^ / Sec, which can form an average particle size in Those with a particle size of less than or equal to 10% or more and an effective particle ratio of more than 10%. 6007. The person described in item 603, Chaqiu &lt; ~ / fruit dried composition on the pulmonary administration The use of the 'Ling Ling Ling' also "composition is formed by withstanding air impact with an air velocity of at least 315314 67 200418520 and an air flow of at least 2Gml / see to form an average particle size | 10 microns or less or effective particle ratio Particles above 10%. 8 · As a dagger, sample 603 workers carry the cold-rolled dry composition, which is administered by the lungs. The freeze-dried composition is used to withstand an air speed of at least 1: sec and 17 nU / sec. / ... The air flow of the air strikes to form particles with an average particle size of less than 1G microns or an effective particle ratio of more than 10%. 609 · As in 603 items, the use of freeze-dried composition of Gong Xi, Ren, and Zhan Zhi on the transpulmonary platter. Among them, the cold and dry composition is subjected to air impact. ^ Particles with a particle size of 5 microns and τ or an effective particle ratio of 2. 6:.: The use of the cold-drying group described in the item 'is used to dry the composition. Low molecular drugs. ^ As an active ingredient, 6 11 · As described in item 603; Use of human pot, # 中 ， 此 冷; ㈣㈣ 物 =, and the product is administered to the high molecular weight drugs such as white matter and nucleic acid through the lung . The effect of the egg of the knife is 6 uses 1: sample 'self-loaded cold; the use of eastern dry composition in the lung investment, /,' heart and dry composition 'contains and maintains the nucleic acid in the state of the body . -Effectively become 613. The molecular drug and carrier as described in item 61. The carrier is at least 1 selected from the group consisting of: base acid :: low 315314 68 200418520 tripeptide and carbohydrate. 614. If used as described in item 611, the towel, the composition of which is administered through the lungs times // 来 刼 组合 物 #molecular substances and nucleic acid polymers, and the egg of the active ingredient is selected from amines Base, -peptide, 1: carrier, the carrier is a group consisting of at least one peptide dipeptide and saccharides. 6 1 5 · A Jie 7 Donggan Wen as described in item 6 1 3 The composition is used for pulmonary administration, in which the freeze-dried composition yv ^ Μ λ, c. ^ ^ 3 is used as a low-knife fun and carrier for the active ingredient. A group consisting of self-hydrophobic amine scriptures, water-soluble monopeptides, and hydrophobic tripeptides. 616 · Leng Jie Shao Tian Tian Shi Shi according to item 614, 7 Donggan No composition is administered via the lung The use of 'where' the cold; Dong drying θ Λ 'AL ·. Λ, ^ ^ wood composition contains protein shellfish and nucleic acids as active ingredients of high-molecular-weight drugs, and the carrier is at least one kind of k &amp; water A group consisting of amino acid, hydrophobic-limb peptide, and hydrophobic tripeptide 0 The composition is administered to the lung through the lung. The composition is administered to the lung through the dry powder inhalation device. The product is administered in the lung through a dry powder inhalation device. The product is administered in the lung including a non-dissolved state. 6. 17. The use of the freeze-drying group according to item 603, wherein the freeze-dried composition is Water soluble 61 8 · The use of freeze-drying group as described in item 603, in which the device uses the dry powder of item 301 or 302 described in Chapter (3) above, and 619 · as the item 618 The use of the freeze-drying group 'wherein' the device is the use of the dry powder inhalation device 620 in the state described in Chapter (3) of the dry state, and the use of the freeze-drying group in the state 603 'wherein the unit The freeze-dried composition is prepared by freeze-drying the composition liquid containing the added ingredients 315314 69 200418520 and having the following characteristics: ⑴ It has a non-powder morphology; (ii) The decay index is in the range of 0.05 to 1.5 ; And (in) By withstanding air impact with an air velocity of! To 300 m / sec and an air flow rate of i7mi / sec to 15 L / sec, the average particle diameter can be less than 10 microns or the effective particle ratio is 1 〇% of particles; The 'granulated powder' is prepared by using a device having a means for imparting the above-mentioned air impact to the freeze-dried composition in a container and a means for discharging the micronized powdery cold-roll-dried composition from the container. ⑶. Cold as described in item ;; Dong drying composition used in pulmonary administration ', where the air flow rate is 1 to 25 m / sec. 622. Freeze-dried composition described in item 620 in The use of pulmonary toilets, where 'the air flow is 20 ml / seU muscle / ㈣. "

(7) Use of freeze-dried composition In the preparation of a freeze-dried composition made of dry powder for inhaled pulmonary administration, it is used. In addition, the present invention relates to the production of dry powder preparations for inhaled transpulmonary administration in a non-powder state, which contains the specific aspects disclosed below: ... The use of powder coating d. The freeze-dried composition has the following characteristics: (i) The composition liquid containing insoluble energy &gt;, 夭 Λ heart bucket addition knife is prepared by cold-drying dry welding Cheng, wood 315314 70 200418520 (π) has a non-powdered morphology, (^) decay index is above 0.05, and

Gv) Hunting is capable of withstanding air impact of 1 m / sec and air impact of at least i7, and can become particles with an average particle size below M Μ or an effective particle ratio of "0% or more; and : At this time, the cold-roll dried composition is micronized to have the average particle size or the effective particle ratio. 7 0 2 · Such as the situation 〇 1 item India Du Xi, Ren, Jijie. The use of the cold-beam-dried composition which has already been loaded ', wherein the freeze-dried composition is one containing γ times & + &gt; +, π 3, 1 slave and 1 active ingredient. / (J3 · If the state 701 items are du Xi, people, hit the LO from the toilet, 载 p, lyophilized button composition used in the manufacture of dry powder preparation for pulmonary use,% arrogance% Ύ It is a freeze-dried composition, and the number of days for delivery is in the range of 0.05 to 1.5. 704. As the state 701, remember the evening of the night, enter the saliva, use #, and lyophilize the composition In the manufacture of transpulmonary techniques and the use of dry powder formulations, i can withstand freeze-drying compositions with a minimum of 2 /, 50 hrs ... once the air speed of 2m / sec and at least 17m sec bis "Air impact in L 'can form particles with an average particle-effect particle ratio of 10% or more. Below the heart or there may be 705. As described in Item 701, measures such as the private wood, wood also The use of dry powder formulations for the manufacture of transpulmonary branches is performed by the following methods: lyophilized composition, and lyophilized composition :: to an air velocity of 30 ° m / SeC and at least 17-c feet The air impact of the lice flow can form flat 706 · As described in item 701; 7 Donggan-free composition is used in the manufacture of your lungs and bismuth dry powder preparations, which 、、 工 / 、 4 Freeze-dried composition system 315314 71 200418520 By withstanding air impact with an air flow of at least lm / sec, it can form two = at least 2 to ^, take ten average particle size below 10 microns. Those with a right-effect particle ratio of more than 10%. Secondly, it is more extensive. As described in item 701, the cold-rolled dry composition described in item _ Lung Cai and the use of dry powder preparation Lung Meng You Cheng-M Order, the Cold; East dry composition system 1 ... at least 1m / sec air velocity and-to

Particles with a particle size below 10% or more. U 708. The use of dry powder preparations for human administration as described in item 701 :: Dry composition without the impact of air in the manufacture of lung hunting, can form an average particle size in the ratio of 2G% The above particles. …, The following two items have two types of dry powder for administration: cold already loaded; east dry composition is included in the manufacture of lungs as effective ingredients = two, = f + 'this cold; east dry composition is ~ another double Ingredients of low molecular drugs. The cold-rolling drying group described in the 7th item of administration 7 contains the dual-purpose, among which, the cold-drying composition includes the active ingredients such as proteins and nucleic acids and other macromolecules. Put the cold as described in item 7G1; the dryness of the composition, the use of the composition in the preparation of transpulmonary preparations', among which the cold-rolled and dried composition contains the nucleic acid that is maintained in the state of the holder. Dry for administration = :::: Dry composition is used in the manufacture of low-molecular-weight drugs and cut-offs that are active ingredients through the lungs. The carrier is at least — 315314 72 200418520 kinds of amidines, dipeptides, tripeptides, and sugars. Group of people. The cold-bed dried composition described in item 710 of the casting plate is used to manufacture the jaw-dried dry composition package for the lungs: active ingredients such as proteins and nucleic acids, and high molecular drugs. Group of people. Species, self-amino groups ... Peptide, tripeptide and carbohydrate groups 7 blood injection: 7 =: cold as described in item 12; Dong drying composition is used in the manufacture of preparations, where 'The Egan composition package is The effective low-molecular-weight drug that can be used as a knife is at least one self-hydrophobic amino acid. The group consisting of sex monopeptides and hydrophobic tripeptides 7 1 5. As in the case of 7 彳 q administration is made from dry powder, δ's & freeze-dried composition is used in the manufacture of transpulmonary as effective use of Γ'1 ' Wherein, the cold; the dried and dried composition includes the protein and the core agent of the knife, and the carrier is i Xiao Cong 夂 Lu Si Tong Mu Zi Le Wu and Feng Ji Feng, at least one selected from the group consisting of hydrophobic tripeptides By. &quot; ^ Methyl-peptide and 71 6 · As described in item 701, xi, ren, and james do π, ° ~ freeze-dried composition made from dried powder for the preparation of Lung Zi B / Zhi Zhi preparations For use, 1 water-soluble composition. The dry composition of Yuanling Ling is 717. As described in item 701, the cold injection and dry welding of the dried stem ingredients are used in the manufacture of lung preparations and final preparations. ; Τ /, Υ 'for menstrual administration, the average particle size of dry powder d particles is 5 neutrinos ratio is more than 20%. , His Majesty, or Effective Particles of Microparticles 71 8 · As stated in Item 701, Human, Occupation, and Use of Freeze-Dried Compositions for the Preparation of Dry Powder Preparations for Lung 315314 73 200418520 for Administration, Contained in 衮% M ~ The composition of freeze-dried button is smashed into the grain, in the valley state, and in the micronized A; Qin # r 4 1 Finally, it is provided with means to impact the micronized powder of the container, and It is made by means of a device for putting the dry-can composition out of the container. Ding Yiyi The cold-rolled and dried composition described in item 718 is used in the manufacture of transpulmonary powder: suction. Among them, the device adopts (3) drying. Inhalation device: as described in § 3 of the form already included.丨 or 3.2 The dry powder is put in / use the cold recorded in item 719; the east dry composition is used in the manufacture of lungs ^ ^ A ^ ^ Haiyizhi adopts (3) dry powder: and described in chapter t of the clothing into The dry powder of the form item 309 is sucked into the dress 721. The cold health dry composition described in item 7G1 is used in the manufacture and the use of the dry powder preparation, in order to dry the composition: + Use the cold (two 2: Constituting the composition liquid containing the added ingredients in a non-dissolved state through cold lyophilization ^ 1) It has a non-powdered morphology; (111) The decay index is in the range of 0.05 to 1.5; and (ii) borrow By being subjected to air impact with an air speed of ˜300 m / sec and an air flow of 17… to 15 L / sec, it can become particles with an average particle size of 10 microns or less or an effective particle ratio of 丨 0% or more. 722 · The freeze-dried composition described in item 721 is used in the manufacture of transpulmonary lungs 315314 74 ZUU4l ^ 520 The use of dry powder preparations for administration W / S 6 c ° Where the air velocity is] to 250 The composition is used in the manufacture of transpulmonary The air flow rate is 20 m I / sec ^ 723. The use of the dry powder preparation for freeze-drying administration as described in item 721, wherein the * to 10 L / sec. (8) added components non-dissolved composition Use of the final formulation household 彳 + # ^ ± freeze-dried composition of the dry powder-coated tablets for pulmonary administration for 5 weeks. This book is about the use of a kind of tianli σ component non-, # #. …: The dissolving composition solution of the cold-dried dry composition required for powder preparations, "the non-modulating method of the additive ingredients used in the St-drying of the composition, and Erling", using their dry-kang dry-dried powder preparations The method of $ system + don't use method (5 week system of drying clothes J for lung administration) is as described above. Examples are given below as examples. In the following example, the present invention is not limited, but the present invention is not limited. In the following examples, the dry composition (freeze-drying of non-powdered freeze-dried evaluation of freeze-dried resin is micronized / coated index and effective particle ratio. (Calculate the index of the powder preparation to the lungs by the method described below) According to the following calculation of the "agricultural index", in the prepared non-powder_, the freeze-dried composition (freeze-dried block) passed through the container No. ## Quoted 1.0 ml of n-hexane. It was stirred for about 2 seconds at 3000 rpm using automatic 315314 75 200418520 shell inspection / combiner NS-8 (manufactured by Pasolina). The resulting mixed solution was put into the optical path 1 mm in length, With a light path width of 10 mm from UV to (made by Shimadzu glc), the turbidity of the mixed solution was quickly measured with a spectrophotometer (UV 240 'made by Shimadzu Corporation) at a measurement wavelength of 500 nm. The obtained turbidity The value obtained by dividing the total prescription amount (the total amount (weight) of the active ingredient and the carrier) is used as the decay index. &Lt; Calculation of the effective particle ratio &gt; Filled with the prepared non-powder freeze-dried composition Container for dry powder suction Into the device. The powder preparation obtained by using the device and given a specific air impact to be micronized is described in the device A (second stage) described in the European Pharmacy Bureau (Εύορκη Pharmacopoeia, Third Edition Supplement 200 15 pll3-ll5) Type dust measuring instrument ·· made by Copley Co., Ltd. in the United Kingdom). After that, they were collected in the first and second stages of the device, and the second cereal grain was suitable for the measurement of Lengkang by bioassay and HPLC. Method for drying the active ingredients in the composition, quantifying the active ingredients contained in the solvents and media of paragraphs 丨 and 2 [Lucas # 人 的 报告 （pharm Res, 15 (4), 562_569 (1998)) and The report by Iida et al. Can also be expected to be delivered to the lungs in section ^ (the aerodynamic particle size recovered in this section is below 6.4 # m) 'usually reaches the active ingredient recovered in section 2 The ratio is called the effective particle ratio (the amount that can be expected to reach the lung, that is, the ratio of fine particles), and it is used as a criterion for evaluating the applicability of inhalants for pulmonary administration. In the following examples and comparative examples, , Quantify the effective results contained in paragraphs 丨 and 2 respectively Weight divided by the weight of the active ingredient in the second paragraph 315314 76 200418520 divided by the total weight of the active ingredient being sprayed (the effective knife included in paragraphs 2 and 2 ', heavy summer: the following (Referred to as "the first stage + the second stage"), and the obtained value is taken as the effective particle ratio (%). In addition, in principle, a two-stage dust detector (manufactured by Copley, UK) is used in the European Pharmacy Agency. In some cases, the flow rate of the suction bow of the air is 60 L / min (that is, the condition), so the following examples and comparative examples follow this. i β 幵 八, "side" dry powder inhalation device (jet type!) One embodiment of the spray type dry powder inhalation device used this month is described with reference to the first figure. "The rice knife powder inhalation device 'is a non-powder sheet or a freeze-dried composition 2 dosed in several doses, which is contained in the bottom of the container, and is micronized and delivered to the lungs. Type device ', which is provided with a needle part 5 provided with an air jet flow = ⑽out flow path 4, and has a suction member 7 which is installed on the base of the needle part 5, H ^ ^ ^ w surrounds 4 needles 邛5 It also has a container 丨 the same shape female full cover 8 and the air pressure feeding means 9. The air pressure feeding year J5: q, seven soils are provided on the wind box body 10 and are equipped with a no-hand movement type and have The cylindrical wind box 10, the discharge of her 3 = the suction inlet 12 with the suction chamber &quot; and the discharge outlet 14 with the discharge jet flow path 3 are provided at the spout 15 formed by the air jet 3 of the needle 5 communicating with each other 'And with the air nozzle jet flow path', when the suction valve U is closed, the warrior closes it in the wind box 10 ... The mountain-shaped heart is discharged into the container 1 by applying a compression force to the roller flow path 3 On the other hand, if the compressive force is released, the elastic restoring force bellows and the ejection valve 13 of the π-phase limb 10 extending over the mountain I will be closed by the other body 10 and the suction valve丨 Open, 315314 77 The agricultural air is introduced into the air box 10. When using the remote dry powder inhalation device, 1 into the cylindrical safety cover 8 so that the needle and eye are shown, the container and the air nozzle jet path 3 and In this state, if the outlet h of the outlet channel h is connected, if the inside of the air box of the air plant plastic conveying means 9 is communicated, the air will pass through the outlet;: spray, ^^ = the front end is cold and dry. The assembly thread 3 passes from the needle 5 to the factory, and the dry composition 2 becomes particles. Needle: The air rush path 4 is sucked from the suction member 7 and discharged from the needle 7 5 by the suction member 7 Suck. The user (patient) can be delivered from the particles, or ... inhale the particles and the material of the mouth plug of the device of the cold-drying composition 2 is combined. For the gelatin or plastic used in the present invention, it is usually as follows: = Chemical: If you choose any material, plastic. The mouth plug of the container of the city and the compound is used in the spray type of Ming λ # and the clothes set, and the air spray volume is set to about 20, such as' the capacity of the container is ς, 1 5 ml, air spray The diameter (diameter) of the flow path 3 is about ^^ 1 &quot; 111 and the diameter (diameter) of the discharge path 4 is about 1.8 mm. Brenzi is not limited to this. The holes ^ of the air jet flow path 3 and the discharge flow path 4 are changed by the preferred range such as the square and the size of the valley, so there are no special restrictions. It is appropriately selected within a range of 3 to 10 llm, preferably 0.3 to 7 mm, more preferably 0.5 to. In addition, the air pressure feeding means 9 can adjust the compression speed of the air box 10 to inhale and discharge the amount of particles required for administration, and the air nozzle can be adjusted to make the freeze-dried composition 2 Mostly micronized. 315314 78 200418520 Implementation of the compound 1 dry powder inhalation device (self-inhalation type self-inhalation type dry powder n used in the present invention, one of the clothes is cautious &amp; form (the υ is illustrated in Fig. 2). The ziyi / wood powder is exposed to dreams, and has a suction flow path 16 and an air introduction flow, a needle part 5 ^, a cylindrical safety tube 8, and a continuous recitation 16 &lt; and an entrance 18 for the suction flow path. The suction member 19, the suction member! 9 are connected to the needle portion 5. When the dry powder suction device is used on the base end side of the lead-in path 16, as shown in Fig. 2, the container 丄

The cylindrical safety cap 8 is inserted, and the needle portion 5 is inserted into the container valley J to 1a, and the suction flow path 16 and the air introduction flow path 17 are communicated with the inside of the container 丨. At this time, the patient's inspiratory pressure is used to draw air from the suction port 18 through the suction flow 2 and the volume 1§1, and at the same time, the external air is introduced into the container M with negative pressure from the air introduction channel 17. At this time, # is caused by the air that acts on the cold; Donggan: the composition 2 is impacted by the air, and the cold; Donggan composition 2 is micronized, and the prepared particles are sent from the suction port 18 to the lung organ of the patient through the suction flow path 16. In addition, the dry powder inhalation device is set such that a large part of the freeze-dried composition 2 can be micronized by the patient's inhalation and discharged from the inhalation port i 8. Also, although the patient's! The air flow rate for each inhalation is 5 minutes to 10's to 200 L / minutes, and more preferably to 10 to 100L's minutes. However, the self-inhalation type dry powder inhalation device of the present invention can be used in accordance with Design the patient's breathing capacity appropriately. The inhalation device shown in FIG. 2 is set according to a patient's breathing capacity so that the volume of the container is about ιιml ml, and the diameter (diameter) of the air introduction flow path 17 and the suction flow path 16 is about 15 mm. With this setting, the patient &lt;! Inhalation, cold; east dry composition 315314 79 200418520: 2 can be completely particulated with approximately heat remaining and discharged from the inhalation port 18.丄 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 second) uses the 3m% day-to-day-figure-brother month. The dry powder inhalation device shown in Fig. 3 is the same as that when the spray-type dry powder inhalation device shown in Fig. 1 is removed from the connection port 15 and the compressed air box with air pressure of 10; The discharge flow path 4 of the spray-type dry powder inhalation device shown in the figure is equivalent to the suction flow path 16 ′ The air spray flow path 3 is equivalent to the air introduction flow path 17, and the suction member 7 having a suction port 6 Of the suction member 19. When using the dry powder inhalation device of the self-inhalation type, the same method as that of the dry powder inhalation device shown in FIG. 2 is used. The suction port 18 of the patient is sucked into the container 1 through the suction flow path 16 The air, the same air, and the external air are introduced into the flow path i 7 and flow into the container worker which becomes a negative pressure. The air is generated by the air inflow with the air inflow, and the cold card is dried to form 2 particles. After that, the obtained particles are delivered from the inhalation population 18 to the lungs of the patient X ′, and the air flow rate of the inhalation of the patient as described above is 5 to 300 L / min. However, the% m π shown in FIG. 3 &lt; The patient's breathing capacity is set to a container capacity of about 5 mi, the pore diameter (diameter) of the air introduction channel 17 is about 丨 2, and the pore diameter (diameter) of the suction channel 丨 6 is about 1.8 mm. As a result, it is set that the majority of the cold-roll-dried composition 2 is micronized by the patient's i inhalation and discharged from the inhalation port 18. If such a self-inhalation type dry powder inhalation device is constituted, the self-inhalation type inhalation device can be changed to a jet by attaching the air pressure feeding means 9 such as the air box 10 to the connection port 15 in a detachable manner. type. By 315314 80 200418520, the same dry powder inhalation device can be used in accordance with the needs of the user to choose one of the inhalation type and spray type. The above-mentioned dry powder inhalation device of the present invention can be any one of self-inhalation type or spray type, and the freeze-dried composition can be configured to form an average particle size of 0 micrometer or less by selecting and setting the size of air impact ( 5 micron or less particles are preferred and there is almost no residual scattering. 81 200418520 Access 32: Cap 27 of port 25. The lid 27 is connected to the case body with a hinge 21A. A container for confirming is provided on the lid 27! The loading window μ. An introduction port 29 for introducing outside air is provided on the wall portion of the casing 21, and a check valve 30 is installed on the guide 2 ". A mouthpiece 32 is installed on the front portion of the casing 21, and the dry powder inhalation device 31 is used without using the dry powder. Close it with the lid 32a. 'The suction opening, a flange-shaped partition wall portion 3 3, * 5 square Γ is formed at the base end portion of the needle portion 5. Another end: :: W33 and the opening of the second attraction opening: partition wall portion The outer edge of 33 faces ... 31 I extends, and the wrong part is to insert the next part 33 into the outer part, and the needle part 5 can be lodged from 4 to eight and 21 to the W end ten mouths &quot; women's clothing in the housing 21. Borrow Due to the mounting direction, the spring direction and the thread direction of the needle portion 5. The A 1 shaft is installed in the holding portion 22 to take out the extraction body 35 from which the container ι is lifted. The control lever 3 6. The mechanism for pulling up the holding device for the trough 1 is 24. The mechanism for reciprocating the holding part 22 on the axis of the housing 21 is 37, and the connecting part 37 is broken. Operate the joystick. Attach to the holder 22, Π ". The -end of the connecting member 39 is connected to the connector 27 with a hinge 40. The other end of the cover 27 'is connected to the cover with a hinge 41 to operate the switch, so that the above-mentioned operation control lever is maintained. The force portion 22 of the cover 27 is lowered by the cover 27 to advance and retreat along the guide portion 23. point. That is, the action point of the hinge 21A is the length of the hinge 41 shown by the arrow C in FIG. 7, and the length of the borrow point / interaction point is greater than that from the hinge 21A to the "lever principle". The part 5 is inserted into the volume 82 200418520 and the force required by the mouth bolt U of the device 1 is 27). Operate the lid for small force (Operation control, as shown in Fig. 6, &lt;, _ 2nd end of the inhalation device), when introducing air supplementally into the dry powder freeze-dried composition, 々— 在Youming 31 attracts the suction mouth 31 of the powdered mouth 32: "The gas flows into this bite via the second introduction path 42 to bite directly to use the attack without burden: #patients or children with low living conditions can be introduced into the path 42. 〆B and inhalation device. X, you can omit the 2nd and 2nd introduction channel 42 next wall ", the introduction groove 42: the introduction groove is installed in the needle wall 5 of the needle inlet 5 and the peripheral wall of the needle factory is in the peripheral wall 34 and the mouthpiece 32 is embedded in the formation. # 34, and a small gap 43 is formed between the mouthpiece 32 and the outer double 21 by the mouthpiece 32 and the outer M 9 1 the next day 42 by the mouthpiece U and the introduction groove 42a and the immortal. One of the second introduction paths 44 is via the gap 43. Fork of the King of the Fork, the other one of the second introduction path 42 is opened at the suction port 31 of the mouthpiece 32. / / 'as shown in Figure 6' at the suction port 31 is provided with the soil 7 of the vent hole 46. Therefore, even if the freeze-dried composition Ya is given an air impact force by the lack of attractive force, etc. In the case where the _ part of the product 2 is a non-known part, the non-powder part can be powdered when it passes through the vent hole M of the wall 47. As shown in FIG. 6 (a), the air of the needle part 5 is introduced into the flow path. The port 17a before 17 is closer to the cold beam drying composition 2 than the port 16a before the suction flow path 16. This can suppress as much as possible the flow velocity of the air flowing into the container from the port Ha before the flow path 丨 7. It can effectively apply air 315314 83 200418520 shock to freeze-dried composition 2. In addition, the uranium port 16a of the suction flow path 16 of the needle 5 is farther from the cold beam drying than the port 17a before the air introduction flow path 17 The object 2 is sucked in the suction flow path 16 of the needle part 5 'The freeze-dried composition 2 can be powdered as much as possible in the container 1. Therefore, the' dryene powder inhalation device is used as follows. First, As shown in FIG. 7, by pulling up the lid 27 and opening the entrance 25 of the casing 21, the holding portion 22 is moved backward to approach the entrance 25 of the casing 21. Then, the container

1 is installed in the holding portion 22 in a manner such that the spigot 1 a is forward. Next, as shown in Fig. 8, by closing the lid to close the entrance 2 5 of the housing 21, use the connection ,,,, and so on. The body 39 presses the holding portion 22 in the direction of the needle portion 5 and puts the foundation of the needle portion 5 into the mouth bolt of the container 1 丨 a so that the suction flow path of the needle portion 5 and the working gas are introduced into the flow path 1 7 communicates with the inside of the container 1. Next, the air in the valley state 1 is sucked by the suction pressure of the patient from the suction port 31 of the mouthpiece 32 through the suction flow path Η of the needle part 5. At this time, the inside of the container j becomes a negative pressure and the check valve% is opened, and the outside air flows into the container 丨 through the air introduction flow path 17 of the needle portion 5. In this case, air impact is generated in the container 1, and the freeze-dried composition 2 is fine-grained for 6 weeks, and the particles are sent from the suction port 3 1 to the stringer through the suction flow path 16

Inside the lung organs. After use, the cover is pulled up and the holding portion 22 is close to the entrance and exit 25 of the outer sleeve U. Then, the lever 35 is used to pull up the take-out body 35 and remove it from the holding portion 22. On the other hand, even if the suction mouth 3 1 from the mouthpiece 32 is blown into the container 1, the micronized freeze-dried composition 2 is discharged to the outside ^ $ 将 香香 至 逆The check valve 30 is blocked. Also, although the air flow rate of a patient's inhalation is usually 315 314 84

O JZ.U to 300 L / min, but the device can breathe according to the patient's breath ^ 0 to the inhalation shown in Figure 10-1, the air introduction channel 17 is set to a capacity of about 5 channels W The caliber (straight pinch) is about 2.5mm; the diameter is about 2.5mm. The suction stream is sucked in, and the freeze-dried composition is hunted by the heart person once and discharged. Most of the other embodiments of the powder inhalation device (shown from FIG. 11 to FIG. 13) which are powdered and dried from the suction port are shown in the dry arrow shown in FIG. Turn ::: Set (self-inhalation type 4), such as direction. The holding hole (not shown) is provided on the circumference of the casing 21, and the follower member which is fastened is buried by ± 4. The turning mechanism part has a spiral groove and a turning motion that is converted to the card making plate 48 to the needle part 95 by the holding part 22, and the turning angle of the turning 48 can be linearly moved about 18 () ^ axis direction. In addition, the operating body, FIG. 12 and 13 suction type 5), is an inhaling device for sucking dry powder (not shown in the figure 21). The body 49 is rotatably mounted on the housing and is operated by the operating body 49. The mechanism part of the wire and operation part has a feeding screw, and the axis direction moves linearly. The holding part 22 is transformed into a person who can freely take out the back part of the needle part 5. ", 22 is formed to be able to be

The gene I n ^ Ik sex lipid (inVitrogen, public version of LlpfectfectjjrNE 2〇〇 (J clothing) 72 // g and pEGFp_C2 315314 85 200418520 (made by Clontech) ) 24 // g is added to 〇ρτι_ MEM I serum-free medium (manufactured by Invitrogen, an improved medium for Igor's minimum required medium) 1200 // 丨, which is a cell culture medium, and suspended and mixed. A complex is formed in the presence of the complex. The geometric average particle diameter of the complex is measured with a dynamic light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.). Next, each of the suspensions containing the complex is 100 // 1. 10 containers (diameter: 0 18 mm) (sample number: 10) were added and mixed, and each container contained an aqueous solution of L-leucine dissolved in water (5 mg / ml) 400 # in advance. Then, freeze drying was performed using a shed-type freeze dryer (LYOCV GT-4, manufactured by LEYBOLD), and the obtained non-powder freeze-dried composition (freeze-dried block) was used to calculate an abnormal decay index. Next , Containing the obtained non-powder freeze-dried composition (cold Freeze-drying block) The container is installed in a spray-type dry powder inhalation device (with an air supply volume of about 20ml2) designed to have an air jet flow path 3 with a hole diameter of 0 12 mm and a discharge path 4 with a required 18 hole diameter. For the cabinet 10 ', refer to Embodiment Example 1, FIG. 1). Confirm that about 20 ml of air is introduced into the container from the inhalation device (apply air at a speed of about 35 m / sec and an air flow rate of about 40 ml / seCi. The generated punching bird) 'can granulate non-powder freeze-dried blocks in the descent, and instantly eject them from the container through the particle discharge flow path 4. Use an artificial lung-type air respirator (Amherst Pr, USA) 〇cess Instrument Co., Ltd., RW Kawasawa: Suppression of concern ... Technology, 72-78 (1 993)) (Measurement conditions, respiration rate · 60L / min; respiration volume: L acceleration 19) Particle size is Bush (aerosizer): manufactured by Amherest Process Instrument, USA, Rw Niven 315314 86 200418520

Pharmaceuticai Technology, 72-78 (i993)) was collected, and the particle size distribution of the U-granulated particles was measured, and the aerodynamic mean particle size (// m ± SD) was calculated therefrom. The geometric mean particle size of the particles existing in the suspension in an undissolved state, the decay index of each freeze-dried composition, and the aerodynamic mean particle size of the particles sprayed from the clothes are shown in Figure 5). Watchmaker. &lt; Table 1 &gt;Cold; Donggan no composition Geometric flat decay index Uniform particle control (μηι)

LipofectAMINE2 000 + PEGFP-C2 + Leucine 0.827 The average aerodynamic particle size (μηι SD, MMAD) ° · 1 86 1.726 ± 1.491. The non-powder-like cold of dry sheet 1 with a non-decay index of 0 · j% is awarded by the air table, which is caused by the impact of the air velocity of about 35111 / ca and the air flow rate of about μ. Change into an aerodynamic average particle; a granular dry powder formulation suitable for pulmonary administration of less than 5 microns. ^ ^ Compared with the sample before cold dehydration, it is in a non-dissolved state (where ^: grudge). It is precisely impinged by the specific air specified in the present invention, and can be adjusted to be micronized and dried suitable for pulmonary administration. The powder is cold: it shows that even before freeze-drying-too & BB ^ K 忒 枓 is in a non-dissolved state, the rabbit powder is administered through the lung in the dry powder inhalation system. versus. In addition, by using the cancer suppressor gene to kiss the fibrosis membrane penetrating regulatory protein (cftr) &amp; spreading dagger-the plastid legs used (Qing Jiao will be able to get ^ ^ fruit ^ 314 314 87 200418520 or antisense molecules It is introduced into the body by pulmonary administration. Therefore, the dried powder inhalation system of the present invention is considered to be effectively used as gene therapy. A Example 2 is more basic than blanket example 1. LipasefectAM for liposomes for liposome; [NE 2000 (manufactured by Invitrogen) 72 "and 〇Ug〇 冰 ναι〇" (manufactured by Otsuka Pharmaceutical Co., Ltd.) 10Vg, in opti_MEMi serum-free medium (invitMga 丨Co., Ltd., a modified medium with at least Iggler's medium) in the presence of a suspension to form a complex. The geometric mean particle size of the complex is measured with a light scattering photometer (ELS-8000, manufactured by Otsuka Electronics Co., Ltd.) Next, ^ 100 // 1 each of the suspension containing the complex is added and mixed into a container (tube diameter 0 18 mm), wherein each container is prepared by adding ^ amino acid in water L-leucine aqueous solution (5 mg / ml) 4〇〇 # prepared cold A sample for drying (Example 2). For the comparative example, an aqueous solution of dextran 40 (5 mg / ml) 400 was used in place of the above-mentioned leucine acid aqueous solution, and freeze-drying samples (0) were prepared in the same manner. (Comparative Example 丨) Then, each sample was cooled with a shed-type freeze dryer (LYOVAC gT-4, manufactured by leybold); dried in the east, and calculated for the obtained non-powder freeze-dried composition (freeze-dried block). The decay index is obtained. Next, a container containing a non-powder freeze-dried composition (freeze-dried block) is installed in an air jet flow path 3 having a hole diameter of 0 i · 2 _ and a discharge flow path 4 having a hole diameter of 0 1 · 8 in a spray-type dry powder inhalation device (with a wind box 10 capable of supplying about 20 ml of air, refer to Embodiment 1 and the drawing). 315314 88 200418520…: For Example 2, Cool and dry the composition. Confirm that the impact caused by air with an air volume of about 35 m / sec and air flow of about 40 ml / sec is introduced by introducing 20 ml of air from the suction device into the μ device. ), Can be the non-powdered cold in the container The Dong dry block is atomized and ejected from Rongyi via the particle exhaust flow path 4 instantly. As with the implementation, an air respirator (Meme Amherst ~ Ka-Ka Coffee Co., Ltd.) is used. Pieces, breathing rate: hunger / he; breathing volume: condition; plus ^ 19) particle size distribution meter (aerosizer): United States

(Amherest i &gt; manufactured by Kasei Kogyo Co., Ltd.) The particle size distribution of the micronized particles was measured and recovered, and the aerodynamic mean particle size (U m ± SD) was calculated therefrom. On the other hand, the freeze-dried composition of Comparative Example 1 was produced by air at a speed of about 35 rn / sec, and the air flow was about 40ml / sec. It is dispersed, so the aerodynamic average particle diameter cannot be measured. The geometric mean particle diameter of the particles existing in each suspension in a state other than the cleavage state, each cold; the decay index of φ pz L tv dried composition (Example 2, Comparative Example 1), and from this device The aerodynamic mean particle size (# m 土 SD) of the particles injected by Jin &amp; Xia F is shown in Table 2. 89 315314 200418520 &lt; Table 2 &gt; Composition 1 Average particle size (μπι) Average particle size (pm: tSD, Example 2) 1.19 LipofectAMINE2 000 + Olig〇_RNA + Leucine ^ ^ 1) 1.19 LipofectAMINE2 000 + Olig〇-RNA + _glucan 40 __MMAD), ° · 165 "^ η ± 1.4-96- ^ 〇 · 002 The method is shown in Table 2 and shows a non-powder freeze-drying method with a decay index of 0165. The block (Example 2) 'is the same as in Example 1. Even though the sample before the freeze-drying is in a non-dissolved state (in which it is suspended), the air capture rate is about 35 m / sec and the air flow rate is about 40 mi /. The impact caused by the air of sec is bad, and it is formed into a particulate dry powder preparation suitable for pulmonary administration with an aerodynamic average particle size of 5 micrometers or less. In contrast, the display decay index is 0.00. 〇2 non-powdered cold beam dry lump (Comparative Example υ, due to the above impact, completely undispersed and micronized, not suitable for η weeks to be made into a dry powder preparation for pulmonary administration. Examples 3 to 5 Comparative Example 2 Supe, an active dendrimer (positive polymer) for gene introduction rfect (manufactured by Qiagen) 36〇g and oHgRNA (manufactured by Otsuka Pharmaceutical Co., Ltd.) 5 // g (Example 3, Comparative Example 2) or PEGFP-C2 (manufactured by Clontech) which is a plastid DNA 24 / zg (Examples 4 and 5), mixed and suspended in the presence of OPTI-MEM 12G (^ 1) to form a composite. The geometric average particle size of the 315314 90 200418520 composite was determined by dynamic light scattering photometry as ls__〇 ' (Made by Otsuka Electronics Co., Ltd.) or a laser refraction and scattering particle size distribution measuring device (SALD-3000J, manufactured by Shimadzu Corporation). Next, each of the suspensions containing these complexes is 100 / zl, such as the surface of a knife. The bucket was added to a container (tube diameter 0 18 mm) (Examples 3 and 4) with a previously prepared aqueous L-leucine solution (5 mg / ml) 400 &quot; 1 and an aqueous solution (5 mg of dissolved lactose) / ml) in a container (tube diameter _ _) (Example 5) (for each example, 10 containers were used) to prepare a sample for cold and dry work. , Aqueous solution of dextran 40 (5 mg / ml) 400 "1 抑 rank and #" &gt; τ ^ AI instead of the L-leucine aqueous solution of yoke example 3. 10 samples were prepared in the same manner (Comparative Example 2). Thereafter, the samples were cooled with a shed-type freeze dryer (LY0VAc gT_4, manufactured by LEYBOLD); the non-powdered cold-rolled dry obtained by Toray Dry Composition (Lengkang dry block), calculate the decay index. Next, install the container containing the obtained non-powdered cold; east-dried composition (freeze-dried block) in a jet designed to have an air jet flow path 3 with a hole diameter of 012, and an ejection flow path 4 with a hole diameter of 01.8 mm. Type dry powder inhalation device (and: the air box 10 that supplies the amount of air, etc., refer to the embodiment example; and Figure 1). As a result, 'for the words 3, 4 and 5 are cold; the dry composition is dry, and the amount of air is about 20ml from the inhalation device into the container (the air speed is about 35m / sec and the air wing ,, Sixth, from the impact of ^ sighing lice * placed at about 40ml / sec air), the non-palatine and non-heart-shaped freeze-dried blocks in the container can be atomized, and the particles are discharged from the container through the particles. Bamboo + hover out of the machine path 4 jet ejection. The same as Example 1, 315314 91 200418520, a particle size distribution meter (aerosol) using an air respirator (manufactured by Amherst Process Instrument, USA) (measurement conditions, respiration rate: 60L / min; respiration volume: 1L; acceleration · 19) (Aerosizer: manufactured by Amherest Process Instrument Company, USA)) It was collected, the particle size distribution of the micronized particles was measured, and the aerodynamic average particle size (# m 土 SD) was calculated from it. On the other hand, a comparative example The freeze-dried composition of 2 is 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, so the average particle size of aerodynamics cannot be measured. The geometric mean particle diameter of the particles present in each suspension in an undissolved state, the decay index of each freeze-dried composition (Examples 3 to 5 and Comparative Example 0, and the aerodynamic mean of the particles sprayed from the device The particle size (〆⑴ soil SD) is shown in Table 3.

315314 92 200418520 &lt; Table 3 &gt; Freeze-dried composition ji Xuepingping_ n-average particle size control (μπι) average particle size (pmitSD, MMAD) _ Example 3) Superfect 11.12 + 〇ligo- RNA + leucine 4 ) Superfect + pEGF 3.74 P-C2 + Leucine 0.225 0.189 1.578 P 1.403 1.646 P 1.420 5) Superfect + pEGF 3.74 P-C2 + Lactose 0.080 2.848 ± 1.837 Comparative Example 0.003 Does not measure completely without dispersion 2) Superfect + OHg〇11.12- As shown in Table 3, RNA + dextran 40 is a non-heart-shaped freeze-dried block that shows a non-dominated ancient person who declines to 0.225 (G change index is greater than 0.080) as in the example. Forehead ..., / Introduced ° formula is in a non-dissolved state (in which /% &gt; pre-shaped evil) and easily condensed into a few. Women's thousand-average particle size is 11 microns; son, can also be damaged by air The speed of about 3 ^ ^ ^, ee, and the impact of the working milk with an air flow of about 40ml / Sl collapsed into 5 «Feng τ, the average particle size formed as aerodynamics is the best suitable for lung μ relative Here, it is shown that the decay index is "㈡". (Compared to J by the above impact ... Lenticular Lengkang ^ is formulated to be administered via the lungs: 77 and micronized, uncomfortable; dry powder formulation. As a result, even after freeze-drying the j month is in an undissolved state (in its 315314 93 is Suspended state), by providing specific energy in the month, the specific air impact specified in the month can be t ... Week I is suitable for pulmonary administration of the composition, that is, also suitable for Taixin-freeze-drying Sφ? It also uses the dry powder inhalation system to effectively administer through the lungs. Moreover, by making the gene ρ53 (applicable to lung cancer) and cysts (made from rrFTp ^ ⑴), and cell spreading fibrosis membrane through-type regulation A protein gene (suitable for cystic fibrosis) instead of the second (_FP_e2) of this embodiment can be used to introduce a gene or an antisense knife that can achieve cardiac effect from the lung into the body. Also, 〇iig〇_ RNA is one of RNAi (RNA interfering substances). It is a 'double-stroke' RNA suitable for RNAi technology. By introducing a short double-stranded rnA corresponding to the target gene, it can specifically inhibit the function of the signaling RNA of the gene. Can also be applied to the treatment of lung cancer, etc. Therefore, the pulmonary administration of the present invention The dry powder inhalation system is considered to be effective for gene therapy. • Example 6 Superfect (manufactured by Qiagen) 360 vg and lig0-RNA (manufactured by Otsuka Pharmaceutical Co., Ltd.), which are active dendrimers for gene introduction 5 # g, mixed and suspended in the presence of OPTI-MEM I 1200 // l (manufactured by GibcoBRL) to form a complex. The geometric average particle diameter of the composite was measured using a laser refracting and scattering type particle size distribution measuring device (SALD-3000J, manufactured by Shimadzu Corporation). Next, each of the suspensions containing these complexes i 00 #! Were separately added to a container (prepared with an aqueous L-valine acid solution (2.5 mg / ml) 400 &quot; 1 (bar diameter 0 18 mm) ) (10 pieces), prepared as freeze-dried samples for use in 94 315314 200418520. After that, it was cooled with a shed-type freeze dryer (LY0VAC gT_4, manufactured by LEYBOLD); dried in the east, and a decay index was calculated for the obtained non-powder freeze-dried composition (freeze-dried block). . Next, the container containing the obtained non-powdered cold-kang dry composition (cold bundle dry smelting block) is installed in the air jet flow path 3 with a hole diameter of 0 1.2 mm 'the diameter of the discharge * path 4 is required J · 8 mm spray-type dry powder inhalation device (with an air box capable of supplying air of about 20 ml, refer to Embodiment Example 1 and Figure 1). As a result, it was confirmed that the cold beam drying composition of Example 6 was introduced into the container from the suction device with an air volume of about 20 ml (applied to an air chamber with an air speed of about 35 m / sec and an air flow rate of about 40 ml / sec. The generated impact can widen the non-powder-like coldness in the container; the East dry block becomes micronized, and is instantly ejected and ejected through the particle exhaust flow path 4. As in Example i, a female air respirator (Amhem, USA) is used. Ργ〇_8 & The price is as fine as the company's κ measurement conditions, respiration rate: hunger / min; respiration rate m: 19) particle size distribution meter (aerosizer): Meme—coffee ss Instrument Manufactured by the company)) Recovered, measured the micronized knives of the filial piety, and measured the aerodynamic mean particle diameter SD) 〇 The geometric average of the particles that will exist in each suspension in an undissolved state Granules' and the decay index of each freeze-dried composition, and the aerodynamic mean particle size (Wm ± SD) of the particles sprayed from the device are shown in Table 4. , 315314 95 200418520 &lt; Table 4 &gt; μ ~ _-_ Variable exponential aerodynamic level __ ^ m) Average particle size (μπι SD, ^ TsTTpeTfect + OlTg 1 3T9 ~~~~~ — MADJ_ 〇-Ι ^ Α + Valinic acid 0.275 1.589 ± 1.553 As shown in Table 4,-;-# ρ and a non-powder freeze-dried composition (freeze-dried block) having a number of 0.275, the same as in Example 1 of each spiritual garden. The samples before freeze-drying are non-soluble &amp; At / ib% (e.g. in a suspended state), and the average particle diameter of the integrated geometry is ~ M never, can also be determined by air velocity 35m / sec and air flow of about 4 40ml / sec. The impact of air decays, forming aerodynamics. The average particle size is 5 micrometers or less, which is suitable for pulmonary administration. Powder formulation. The above examples 2 to 6 ls — _ &lt; ,,,, etc., but the results are not the same as in Example 1, even if the sample before the freeze-drying is Fei, Dingma Mafei / Valley The solution state (in which it is suspended) can be modulated by the specific air impact specified in the present invention. The composition was dried on a cold bed of micronized dry powder administered by the lung, that is, it showed that even if the added ingredients were added, the squeegee was insoluble or hardly soluble to / cereal media. The age of the lung is as follows. It can also be used in the wood powder inhalation system, and can be effectively administered through the lungs. Examples 7 to 8 respectively modulate Tengdaosu (recombinant human insulin crystals, manufactured by Biobras, Belgium). Activity: 26.4u / mg) (0.2 mg 'in Example 7; mg in Example 8), an aqueous solution obtained by dissolving in an aqueous hydrochloric acid solution, and a solution obtained by dissolving various carriers shown in Table 5 in purified water, If they are mixed with 315314 96 200418520, the ratio of each suspension state can be obtained. The geometric mean particle size of the particles contained in the suspension is measured by a radiation and scattering particle size distribution device (SALD-3000J , Manufactured by Shimadzu Corporation). The next step is to fill the suspension in a container (cylinder diameter 018 mm), and place it in a field-shaped cold 'East dryer (LYOVAC GT_4, manufactured by leybold). Freeze-dried. For non-powder obtained Freeze-dried the composition (freeze: block) to calculate the decay index. Next, a container filled with non-powdered cold Kanggan 2 products (tube diameter 0 18 mm) Ansang is designed to introduce air ^ road = since ΓΓ is 01 · mm, and the pore diameter of the suction flow path 16 is 0. The self-inhalation type dry powder inhalation device (refer to Embodiment Examples 3 and 3). Using it and using a two-stage dust tester (manufactured by Copla, UK) (applying an air velocity of about 95 m / sec and air impact of air denier = 29 5 mi / sec to the freeze-dried block), Calculate the effective particle size ^ (%). The geometric properties of the particles present in each suspension in an undissolved state are shown in Table 5. L, the decay index and the effective particle ratio of each freeze-dried composition are shown in Table 5. °) 315314 97 200418520 average, effective active particles ^ polar warp index ratio (%) / order / East dry composition ^ _Ιμνη) /) Tengdaosu 0.2mg + white amine 〇Τ52 ^ 0 · 1η ^ + fine Amino acid 0.042 mg ° * 292 95.3 (PH6.5) 57.9 8) Tensin 1 mg + phenylalanine 0.63 0-6 mg + arginine 0.1mg (pH6.4) ° * 238 as shown in Table 5 Display, display decay ---- freeze-dried composition (freeze-dried block), even though the active ingredient (Tengdaosu) in the non-dissolved state of A is insoluble, two: the sample before drying contains = easy to micronize 'And can be made into a dry powder suitable for pulmonary administration Example 9 $ 1 1 Modulate insulin separately (recombinant human islets called Jer, ,, and mouth, Belgium

Biobras company, specific activity: 26.4 U / mg) l ma ~ a solution obtained by dissolving in technical hydrochloric acid solution and a solution obtained by dissolving 0.5 mg of phenylalanine in purified water, and mixing them, if by hydrogen Sodium oxide adjusts various pH values to obtain suspensions in various suspension states. The geometric average particle diameter of the particles contained in this suspension was measured using a laser refraction and scattering particle size distribution measuring device 2 (SALD-3000J, manufactured by Shimadzu Corporation). Next, the suspension was filled in a container (tube diameter 0 丨 8 mm), and shed-shaped cold; East dryer (LYOVAC 〇 丁, manufactured by LEYBOLD company) 315314 98 200418520 Xingqi * product. Large 'pieces), non-powdered cold-to-dry composition (cold ling drying, clothing index). Next, fill the non-powdered freeze-dried composition with wailing (^^ ° 从 从18 mm) Installed in a jet designed as an air jet channel I through A, Λ 〇 〇: .mm, and the diameter of the outflow channel is 0 1.8 mm, a powder inhalation device (with a wind capacity of about 20ml) The system uses it and calculates the effective particles by using a two-stage dust tester (UK € 0ρΐπ male two for cold; East dry block gives an air speed of about 35 oil &amp; air flow-the impact of air from Sec). The ratio ^ / I of the particles in the non-dissolved state is present in the geometrical flatness of each particle; the decay index and the effective particle ratio of the dried composition are shown in Table 6. (/ 〇) &lt; Table 6 &gt; Acid 0.5 mg (ρΗ6 · 0) 0.39 0.36 75.1 72.0 1〇) insulin 1 mg + phenylpropane 0.55 amino acid 0.5 mg (ρΗ 6.4) · 11) Tengdaosu 1 mg + phenylpropane 0.61 jL! ^ G .5mg (ρΗ6 · 6) __ As indicated, it shows the dry composition (cold-bed drying block), even if it is cold; The skin's active ingredient (insulin), but with the above-mentioned air flushing, it is easy to be micronized in the device, and can be adjusted to be suitable for pulmonary administration. ::: terminal = Examples 12 to 13 315314 99 200418520 separately modulate insulin (Recombinant human insulin crystals, manufactured by Blobas, Belgium, specific activity · 26.4 U / mg) 0.1 mg of water obtained by dissolving in hydrochloric acid aqueous solution, cereal solution and various carriers shown in Table 7 dissolved in purified water. They are mixed and the pH value is adjusted with sodium hydroxide to obtain the% floating liquid of each of the b-shaped floating evils. The geometric average particle diameter of the particles contained in the suspension is measured by a laser refraction and scattering type particle size distribution measuring device (SALD 3, 00J 'Made by Shimadzu Corporation.' Next, 'The suspension was filled in a container (tube diameter 0 丨 8 mm), using a shed-freeze dryer (LY〇VAC GT_4, leybold company). Production) Tokai dryness was performed on the obtained non-powdered freeze-dried composition (freeze-dried block) with a 50-fold abnormal decay index. Next, the non-powdered cold-to-dried composition container (tube diameter 0 18 mm) was filled. ) Installed in the air guide The pore diameter of the flow path 17 is 4 1.99 mm and the pore diameter of the suction flow path 16 is 0. A suction type dry powder inhalation device (refer to Embodiment Examples 3 and 3) is used. A two-stage dust detector is used ( British public 1) (For the freeze-dried block, the impact caused by air with an air velocity of about 95m / sec = about 2 QS 1 / sizing amount m SeC), the effective particle ratio was calculated. The geometry and magic of the particles existing in each suspension in a non-protonated state: the reduction of the decay and the effective particle ratio of each Lengkang dry composition ^ not shown in Table 7 0 I / 〇) 315314 100 200418520 <Table 7 &gt; Index-ratio ------_ freeze-dried composition effect particles complex (〇 / 〇) ^ 68 ^ 7 '58.9 ～ — 一 _ powdery cold sample contains gas impact, dry powder 0.115 0.051 1 2 ) Insulin 0.1 mg + Leucinyl Amino Acid 0.5 mg (ρ Η 6 · 4) 1 3) Insulin 0.1 mg + Leucamine 0.67 Acid 1.5 mg (pH 6.5) · As shown in i 7 It shows that ^ freeze-dried composition (freeze-dried block), even if it is 1 effective ingredient (insulin) in a non-dissolved state before freeze-drying, as: two ^ D] because the above-mentioned empty in the container is easy to micronize, and adjustable loquat Nanyi Chengtong is a preparation prepared by transpulmonary injection. 1 Example 14 Insulin (recombinant human pancreas a 勹 I, ，, 口, said by the Belgian company, "specific activity: 26,4u / mg), respectively, 0.01 mg of an aqueous solution obtained by dissolving in an aqueous hydrochloric acid solution, and lanine acid. The content of 5 mg dissolved in purified water: night 'mix them and adjust the pH value to 65 with sodium nitroxide, you can get the suspension liquid. The geometric average particle diameter of the particles contained in the suspension was measured by t-ray refraction and scattering particle size distribution measurement (Mα 3_), manufactured by Shimadzu Corporation. Next, this suspension was filled in a container (tube diameter 0 18 mm), and subjected to chilling and drying using a shed-type freeze dryer (lyavac 4 'LEYBOLD). For the obtained non-powder freeze-dried composition (freeze-dried cake), a decay index was calculated. Next, install a non-powdered freeze-dried composition container (tube diameter 0 18 mm) in the hole diameter 0 315314 101 200418520 l_99mm designed for the air introduction channel 17 and 019911 ^ Self-inhalation type dry powder inhalation device (refer to Embodiment 3 and Fig. 3). Use it to give non-powder-like chilled cold-dried dry composition (cold; east dry block) with an air speed of about im / sec and an air flow of about 17 claws ... "The impact of the work will generate the particles Directly sprayed from the device to an artificial lung-type air respirator (made by Amhem Process, USA) (measurement conditions, breathing rate: 丨 L / min; breathing volume: 0il) aerosizer (Amherest Process, USA)

Instrument Co., Ltd.), and measured the particle size distribution of the fine particles. From this result, the aerodynamic average particle size (/ ± SD) of the particles was calculated. Table 8 shows the decay index and the aerodynamic mean particle diameter of the particles sprayed from the device for each of the cold and dry compositions. &lt; Table 8 &gt; The average exponential particle size of decay aerodynamics (pm ± SD, MMAD) ′ 〇 · 221 1.875 soil 1.384 average particle size (μηι)

14) Tengdaosu 〇img + 0.57 Amino acid 0.5 mg As shown in Table 8, a non-powdered cold / east dry composition (cold / donggan cane) showing a decay index of at least 0.21 'cold even though east; The sample before drying contains the active ingredient (insulin) in a non-dissolved state, but by the above-mentioned air impact, it is easy to be micronized in Guwei, and can be adjusted into a dry powder preparation suitable for pulmonary administration. ^ 315314 102 200418520 Reference Examples 1 to 5 Insulin (recombinant human insulin crystal, manufactured by Biobras, Belgium, specific activity: 26.4 U / mg) (l mg, 2 mg) or insulin with Table 9, ^ μ yj \ various carriers respectively Soluble in hydrochloric acid-injected distilled German water and prepared into 0.2 ml 'Fill it in a container (tube diameter 0 18 mm) and cool it in a shed shape; use a dry dryer (LYOVAC GT-4, manufactured by LEYBOLD) Cold; East dry. The luxury index was calculated for the obtained non-powder freeze-dried composition (freeze-dried cake). Next, install the non-powder-free freeze-dried composition Rongjing (tube diameter 0 18 mm) in the air inlet flow path 17 designed to have a pore diameter of 1.99 mm and the suction flow path 16 to have a pore diameter of 0 1.99 mm self-inhalation type dry powder inhalation device (refer to Embodiment 3 and Fig. 3). Using it and using a two-stage dust tester (manufactured by Copley Company, UK) (improving the impact of air with a velocity of about 95 m / sec and an air flow of about 295 ml / sec on the Ling / Donggan $ block), Calculate the effective particle ratio i). The decay index and effective particle ratio (%) of each freeze-dried block are shown in. , &Lt; Table 9 &gt; ——_ Index &amp;

$ Tensin 1mg 0.159 ^ 2) Insulin 1mg + Leucine i.4mg 0.145 1 3) Insulin 1mg + Valinic acid i.〇mg 〇.110 1 4) Insulin 2mg 0.177 Insulin 2mg + Leucine i.4mg 0.137 As shown in Table 9, non-powder freeze-dried compositions (freeze-dried blocks) showing a decay index of at least 0 · 丨 丨 〇 are easily impacted by the air in the container 315314 103 200418520, and can be adjusted to be suitable for Dry powder formulations for pulmonary administration. Reference Example 6 j 1 〇 Insulin (recombinant human insulin crystal, manufactured by Biobras, Belgium, specific activity: 26.4 11/1 ^) 1! ^ And various carriers (1.5 mg) shown in Table 7 were dissolved in distilled distilled water containing hydrochloric acid Medium and modulated to 〇5mi. Fill it in a trough (tube diameter 0 18 mm) ’and use a shed-type freeze dryer ginseng (LYOVAC GT_4’ LEYB0LD Modified / made by the company) to cool; dry in the east. For the obtained non-powder freeze-dried composition (freeze-dried cake), the decay index was calculated. Next, install the filled non-powdered cold dry composition container (tube diameter 0 18 mm) in the air jet flow path 3 with a hole diameter of 0 1.2 mm and the outflow channel 4 with a hole diameter of 0 丨· 8 mm spray-type dry powder inhalation device (with a wind box capable of supplying air of about 20 ml: refer to Embodiment Example 1 and Figure 1). Use the non-powder freeze-dried composition (freeze-dried block) in the container to give an air impact of about _ 35m / Sec and an air flow of about 40ml / sec. 'The generated particles are directly sprayed from the device to the installation of artificial lungs Type air respirator (manufactured by American Amherst Process Instrument Company; measurement condition: breathing rate: 60 L / min; breathing volume: 1L) particle size distribution meter (aerosizer): American Amherest Process Instrument company; rw

Niven: Pharmaceutical Technolgy, 72-78 (i993)) and measured the particle size distribution of the microparticles. From this result, the aerodynamic average particle size (/ m ± SD) of the particles was calculated. A container filled with a non-powder freeze-dried composition (tube diameter: 0 315 314 104 200418520 mm) is installed in a self-inhalation designed so that the air introduction flow path n has a diameter of 1 and the suction flow path has a diameter of 4 1.99 mm Type dry powder feeding device (refer to Embodiment 3 and Figure 3). Use it with a two-stage dust tester (made by Copeley Co., Ltd.) (for freeze-drying; block: the impact of air with an air speed of about 95 m / Sec and an air flow of about 295 ml / sec), The effective particle ratio (%) was calculated. Table 10 shows the decay index of each freeze-dried block, the aerodynamic mean particle diameter (m ± SD) of the particles sprayed from the device, and the effective particle ratio. '&lt; Table 10 &gt; Decay index of freeze-dried composition Aerodynamic mean particle size (pm ± SD, MMAD) Effective particle size ratio (%) See 6) Insulin + isoleucine 0.124 1 · 759 ± 1 · 425 71.1 ~~ cf. 7) insulin + leucine 0.250 1.954 ± 1.544 74.1 cf. 8) insulin + valine 0.124 2.007 +1.438 72.1 cf. 9) insulin + phenylalanine 0.204 1.872 +1.477 62.0 cf. 10) insulin + D- Mannitol 0.160 2.239 ± 1.435 61.2 As shown in Table 10, a non-powdered cold beam dried composition (freeze-dried block) showing a decay index of at least 0 · 丨 24, with an air velocity of about 35rn / sec and an air flow rate of about 40ml The air impact generated by / sec or the air velocity is about 95m / sec and the air flow rate is about 295 nli / sec. The air impact generated by the container is easy to be atomized ~ and the air velocity is about 95m / sec and the air flow rate is about 295 ml / The average particle size of the particles impacted by the air generated by sec is 5 micrometers or less, and it can be adjusted into a dry powder formulation suitable for pulmonary administration. The use of the product is possible 1 105 315314 200418520 If the dry powder inhalation system for transpulmonary administration of the present invention is used, the cold-kang dry composition can be micronized to the size required for delivery to the lungs, and the microparticles can be inhaled and administered at the same time. To the lungs. That is, if the dry powder inhalation system for pulmonary administration according to the present invention is used (administrated) and prepared into a non-powdered cryogenic product, it can be administered by inhalation when it is micronized. By using :: 二, special operations are performed for the micronization of the preparation. Therefore, if the dry powder inhalation system (preparation system) for pulmonary administration is used, the manufacturing process will be lost (the inactivation of the drug and the filling operation will be artificial). It can be mixed with inclusions in Λ, but can be placed in one of the kings. It is particularly useful in preparations that use proteins and peptides and / or sexual substances as active ingredients: 'Youmenbei μ has two The dry powder inhalation system for pulmonary administration has a * discharge particle ratio of at least 10% or more. The inhalation of the dry powder for pulmonary administration is inhaled. According to the knowledge, more than 20% of the present invention, 25% is effective. The particle ratio can be increased to National Patent Gazette No. 6153224 :: two X and: 5%: up. And according to the US majority, attached to the lungs / loaded '10% of the effective ingredients of the previous dry powder inhalation device. ' :, The active ingredient (particles) does not exceed the inhaled powder formulation for general inhalation to :: == 5: 6 7 3: as described in the bulletin, the drug reaches approximately i 〇Q / ^ arrival rate), In order to inhale the system from the powder of the preparation, the following can be: View of effective particle ratio Gucheng has higher greed than inhale powder for inhalation, and it can be said to be extremely useful .... Cold for invention; East dry composition and spray type dry powder suction 315314 106 200418520 into The device 'only through the air exhaustion?-叩 &gt;, soil hand & spray air from the air jet flow path into the valley state and empty new species 亍 I ^, #m read money and cold roll money, The cold composition can be made into particles. Based on this, a simple structure can be used to produce a low-cost structure, which can be produced at a low cost by "〆" and "入 衣衣 由", resulting in a large expansion. The spray type is dried in the ancient r ^ M ^ ^ yttrium identification tertiary inhalation device. By adjusting the speed of the air = air pressure feeding method, the amount of suction can be adjusted to meet the user's congratulations: "j ( The private parts are gathered into one, and the needle is inserted into Rong cry b. The operation of attaching the needle $ 土 谷 益 的 口 口 will be easy. If you inhale the dry powder inhalation type according to your own inhalation type, the air pressure will generate air impact. , Hunting consists of (n ^ / h ^ π -χ drying ~ Ling (Mist: haze), and at the same time as the user inhales, the matter is micronized and administered to the lungs', so that: = the amount of drug administration. Also, because I ++ is known to ... It is easy to operate if it is not made into a chemical product (micronized). Also, as with the spray type, Bu Zhikun knows the roots, and puts it into the mouth of the container, and plugs the filial piety on the back. According to the dry powder inhalation device of the present invention, the needle of the air introduction channel is inserted into the mouth plug of the container, and the suction channel and pressure are buried, and the air in the container can be sucked in through the suction port: 't The air introduction flow path of the suction part of the person flows into the container to smash the composition through the needle, the working milk, and the worker's dry stack, and can attract and / or freeze the above-mentioned frozen products from the container. The coldness of the MM; the east drying group, and particularly the case of the inhalation device described in the fourth embodiment, the following effects can be exhibited. &quot; Ming dry powder 315314 107 200418520 In the case where the cold-kang dry composition is provided with a device to attract the powdered cold-kang dry composition, the diameter must be increased. "The wearing area has increased, so the straight part of the needle does not hold ::: The needle with a large diameter is inserted into the plug, and the container must be kept close to the needle tip in a way that does not deflect the axis of the needle, and press the needle with the needle tip . $ Strongly absorbing the suction device By having a holding part operation part which holds the container ... as the body, the holding part for the container can be moved along the axis of the needle and close to the needle tip. As the operating body, a relatively small force can be used to pierce the needle into the container. In this way, if the dry powder inhalation device according to the present invention is used, the needle is surely inserted into the mouth of the container. Gu Yi X, if the structure is "the casing is formed in a cylindrical shape, Qiu is formed before the casing: the suction opening is formed, and the volume is formed in the casing: the needle portion is arranged with the needle tip facing the storage room" Above; Chengnei 'will communicate with the air-guiding flow path of the needle portion and introduce it = introduction σ is provided on the wall portion of the housing' by the holding portion operating portion, the holding portion is in the storage room, above The forward and backward movement of the material shell in the axial direction "can form a pencil-shaped dry powder inhalation device, which is easy to use and convenient to carry. <<, and 'about the above-mentioned case' is formed by forming the case main body with the above-mentioned container exit position at the position where the holding portion is retracted, and a hinge connected to the hinge of 3153J4 108 200418520 = the above-mentioned entrance and exit of the case body. Holding section: The holding section is provided with the above-mentioned mechanism when the cover is closed to close the entrance and exit: f: and the mechanism section that retracts the temple section when the cover is opened to open the entrance and exit, And the above cover Qiu Xi 4. 仏 A ^ Now 卞 also serves as the above-mentioned mechanism, which can simplify the mechanism section of the operation section of the holding section, and has the following: 'Because the pin at the mouth of the container was pierced by the needle tip It is the same as the entrance and exit of the valley state, so it is easy to make the drawing [simple description] Figure i is a cross-sectional view showing the installation Wei type υ described in Example i. Also, the second arrow table in the figure = flow (The same applies to the second and third figures below.) The second figure of the second milk is a cross-sectional view showing the insertion device (self-inhalation type 1) described in the second embodiment of the embodiment. The entrance device described in Embodiment 3 (from A cross-sectional view of a self-inhalation type 2). Dry know 'The last suction figure 4 is a perspective view showing the insertion device (self-inhalation type 3) described in Embodiment Example 4.' The suction figure 5 is the dry powder inhalation device ( Self-suction surface diagram. (A) of Figure 6 of the soil section is the above-mentioned dry powder inhalation device (4 side view of self-suction d) (b) is the 3) diagram of the dry powder inhalation device. Figures 7 to 7 are cross-sectional views illustrating the operation of the dry powder inhalation device type 3). (Head inhalation J ί 5314 109

The perspective view of the first device (from the device (from Figure 11 is a dry powder inhalation type 4 of another embodiment of the present invention inhalation type 4). Figure 12 is a dry powder inhalation of another embodiment of the present invention Perspective view of inhaled type 5). Figure 1 3 is a perspective view of a dry powder inhalation type 5) of another embodiment of the present invention. 1 2 4 Container 1 a spigot Θ / East dry composition 3 Air jet flow path discharge flow path 5 Needle section 6 Suction port 7 Suction member 8 Cylindrical safety cover 9 Air pressure feeding means 10 Air box 11 Suction valve 12 Intake inlet 13 Outlet valve 14 Outlet port 15 Continuation port 16a Suction flow path 16 front end π 17a Air introduction flow path 1 7 Front port 18 Suction port 19 Suction member 20 Storage chamber 21 Housing 21A Hinge 22 Holder 23 Guide 24 Holding part running part 26 housing body 27 cover 28 window 29 introduction port 30 check valve 31 110 suction port 315314 32a mouthpiece cover 34 peripheral wall portion 36 lever 39 connecting body 41 hinge 42a introduction groove 43 of the partition portion 3 3 gap end 47 Wall 49 Operating body biting mouth Next door Take-out body mechanism part hinge 2nd introduction path Peripheral groove of the second introduction path 34 of the introduction wall 42 One end of the second introduction path 42 Another ventilation hole operating body 111 315314

Claims (1)

Scope of patent application: Can be used for lung and cold beam drying composition, which is prepared by freeze-drying a composition solution containing a non-dissolved 4-addition knife, and has the following ⑴ to (iii) Features: (1) Non-powder morphology; (U) Decay index above 0 05; and ㈣ By withstanding air impact with an air velocity of at least lm / sec and an air flow of at least 17 ml / sec, it can become Particles with an average particle size of less than ⑺ microns or an effective particle ratio of 10% or more. • The "dry" composition as described in the scope of patent application for fi, which contains high-molecular drug as an active ingredient .: A manufacturing method for dry powder preparation for pulmonary administration, which is included in the following: ^ dry composition In the container of the material, 'the device that can flush the following air with the cold-dried composition in the container is used to introduce the air with the force to blow the air, so that the freeze-dried composition is formed :, Fine particles with a particle size of less than 10 microns or an effective particle ratio of more than 10%; wherein the freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in a non-dissolved state, and has the following ( i) to (iii) characteristics: (1) has a non-powdered morphology, (ii) has a decay index of 0.05 or more, and (111) has an air velocity of at least lm / sec and at least by bearing 51 The air impact of 17ml / See air flow can become fine particles with an average particle size of less than 10 microns or an effective particle ratio of more than 10%. 315314 112 200418520 4 · The manufacturing method of item 3 in the scope of patent application, where , Aunt Polymer drugs for human, soil, and dry &amp; powder preparations. The '7 dry' composition contains the active method of Shishen's patent scope item 3 as the active ingredient. The inhalation device is used as a dry powder (Α) recorded by the ί⑷ for administration by the lungs :: The dry composition is micronized: Contained in a pet cry + The Μ㈣Μ composition obtained by inhalation in a non-powder state ^^ The device for the subject 1 to serve granules is provided with a needle part of the mouth jet flow path, a needle part for the discharge flow path, and a sending means: the air pressure for conveying air in the air jet flow path is The inhalation of the above-mentioned needle's discharge flow path is communicated and is constituted as follows: the needle is inserted into the mouth jet flow path for sealing the container, and the discharge valve L, 丄, and work disturbance allow the internal communication of the container, and use the above The second method means that the air is sprayed into the container through the air jet flow path, the cold-dried composition is atomized by the impact of the jet air, and the obtained particles are discharged from the suction port through the exhaust flow path; or , I ... and a device for sucking people with dry powder, and is a device for micronizing the cold-roll drying composition contained in a non-powdered state in a container and making the particles inhaled by the subject. The device includes ... " There is a needle part for the suction path, and a needle part with an air introduction flow path is 315314] 13 200418520 and a suction port communicating with the suction flow path; and it is structured as follows: the needle part is inserted into the mouth plug for sealing the container In the state, the air in the container is sucked from the suction port by the suction pressure of the user, and the air is caused to flow into the container that has become a negative pressure through the air introduction channel, and the freeze-dried composition is caused by the impact of the inflowing air. The particles are made into particles, and the obtained particles are discharged from the suction port through the suction flow path. 6. A dry powder inhalation system for pulmonary administration, which is a combination of the following (丨) and (2): (1) a container containing a freeze-dried composition, the freeze-dried composition will include an undissolved state The composition liquid of the added ingredients is prepared by cold-drying, and has the following characteristics (i) to (iii): (1) It has a non-powdered morphology, and (Π) has a decay index of 0.05 or more, And (1U) can withstand an air impact with an air velocity of at least lm / sec and an air flow of at least 17 ml / sec, and can become particles having an average particle size of less than μm or an effective particle ratio of more than 0%; ( 2) Equipped with a means that can apply the above-mentioned air impact to the freeze-dried, dried, and finished products in the container, as well as a method for discharging the powdered cold-kill dry composition. 7. The dry powder inhalation system for pulmonary administration according to item 6 of the patent application, wherein the above-mentioned container and the above-mentioned device are used in combination during inhalation. 8. If the dry powder inhalation system for pulmonary administration according to item 6 of the patent application is 315314 114 200418520 22, the cold 'East dry composition system contains as high as 9. With the dry powder inhalation system, use the following (A) or (B) as the device: ⑷ = With the dry powder inhalation device, which is to cool the grain in the container in a non-powder state; Packing for drying the composition to make the user inhale the obtained particles 1 Needle part with air jet flow path, with row: Needle part of flow path, for conveying air in the air jet flow path of upper needle ^ The air pressure and the suction port communicating with the discharge flow path of the needle part; and the structure is: the needle part #L is inserted into the mouth plug for sealing the container to spray the air flow path and the discharge flow path to the inside of the container; The air is sprayed into the container through the air jet flow path by the air sending means, and the freeze-dried composition is atomized by the impact of the jet air, and the obtained particles pass through the exhaust flow path. Discharged from the suction port; or A dry powder suction device for lung administration, which is intended for non-powder-shaped recipients; the freeze-dried composition of the cereal is micronized and the device is used to inhale the particles obtained by the horse and the person. It has a needle part with a suction flow path, a needle part with an air introduction flow path, and a suction port communicating with the suction channel and the flow path; and is configured as: 115 315314 200418520 Injecting μ, 1, and * the state of the mouth plug of the container, by the suction pressure of the .k person sucked into the hole in the container from the suction port on the same day, the air has flowed in through the air introduction flow path. In the container with negative pressure, the above-mentioned freeze-dried composition is micronized by the impact of the inflowing air, and the particles that have been treated are discharged from the suction port through the suction flow path. 10. A method for pulmonary administration, including the use of cold and dry composition, the cold-roll drying composition is prepared by freeze-drying a composition liquid containing an additive component in an insoluble state in an early state, which has the following Description of characteristics: (i) having a non-powder morphology, (ii) a decay index of 0.05 or more, and (iii) by being subjected to air impact with an air velocity of at least lm / sec and an air flow of at least 17 ml / sec Can become fine particles with an average particle size of less than 微米 microns or an effective particle ratio of more than 0%, In use, by applying the above-mentioned air impact to the freeze-dried composition, particles having an average particle diameter of less than 10 microns or an effective particle ratio of more than 10% are formed, and then the user is inhaled into the micronized powder. And implementation of investment. 11 · The method for pulmonary administration according to item 10 of the patent application scope, wherein the freeze-dried composition is contained in a container, and the micronized powder is provided with a device capable of imparting the above-mentioned air impact to the container. It is prepared by the means of drying the composition by cold and the device that can discharge the micronized powdery cold from the container; the device by the means of drying the composition. 12. If the method for pulmonary administration of item 10 in the scope of patent application, wherein the A 315314 116 freeze-dried composition is packaged ... As in the scope of application for patent scope, the active ingredient is a molecular drug. ⑻ 中 记 ㈣m. Among them, the use device is: Dry powder-free inhalation device as a container (A) Dry powder for pulmonary administration is stored in a container in a container, and / or is to be inhaled by a non-powdered user: Particle group: The object is atomized and the needle portion of the above-mentioned needle portion has a discharge channel, a delivery means, and an air pressure port for conveying air in the channel; and is configured as a "portion of the discharge channel" The connected inhalation IS needle part is used to seal the mouth of the container to spray air: and the discharge flow path communicates with the inside of the container. Spraying on dry group I :: The above-mentioned cold lingers are dried and 'granulated' by the impact of the sprayed air, and the obtained particles are discharged through the above-mentioned exhaust flow path suction port; or lungs, and a device for inhaling with dry powder , It will be non-powdered ~ Device for harvesting grains and grains in the freeze-dried composition by micronizing and inhaling the particulates obtained by the subject, comprising: a needle portion having a suction flow path, a needle portion having an air introduction flow path, and The suction port which is in communication with the suction channel; and is configured as follows: in the state where the mouth of the needle is inserted into the mouth plug for sealing the container, the subject is sucked into the container from the suction port by the suction pressure of 315314 117 200418520 At the same time, the air is flowed into the valley that has become negative I through the air introduction flow path, and the freeze-dried bright composition is micronized by the impact of the inflowing air, and the obtained particles are sucked in from the suction flow path. Mouth drains. 14. A freeze-dried composition is used for inhaled pulmonary administration, wherein: The freeze-dried composition is prepared by freeze-drying a composition liquid containing an additive component in a non-dissolved state, and has the following characteristics: (I) has a non-powdered morphology, (II) has a decay index of 0.05 or more, and (III) can withstand air impact with an air velocity of at least lm / sec and an air flow of at least 17 ml / sec, which can become Microparticles having an average particle diameter of ⑺ microns or less or an effective particle ratio or more; and powdering the freeze-dried composition into particles having the above-mentioned average particle diameter g or effective particle ratio for use. 15. If the cold-bed drying composition of item 14 of the patent application is used for pulmonary administration, wherein the freeze-dried composition is contained in a container, and the micronized powder is provided with the above-mentioned air The means for impact imparting the freeze-dried composition in the container and the means for discharging the micronized powdery freeze-dried composition from the container are prepared. ~ 16. If the freeze-dried composition according to item 14 of the patent application is used for pulmonary administration, the freeze-dried composition contains a South molecular drug as an active ingredient. 315314 118 17 ': = :: = ^ made :, formula_ ^ properties: /, medium, the freeze-dried composition has the following characteristics == dissolved components of the composition of the added component after being dry (ii) has a non- The lumpy morphology of the powder, (di) decay index is above 0.05, and (iv) by the air impact of air velocity of at least 17 to V im / sec and air impact of at least micron air flow, the average particle size can be 10 In the use / fine particles having a particle ratio of 10% or more; and the average composition is micronized to have the above effective particle ratio of A. 1 8 · If you apply for a patent, dry welding for administration = dry composition in the manufacture of transpulmonary system contains 2 systems, of which the cold pure product U is the polymer drug with active ingredients. 19 '^ Special = cold around item 17; East dry composition is contained in the lungs during manufacture: 2: Use of the preparation' wherein 'the freeze-dried composition above 4 彳 |. ^' And the recorded powder _It is equipped with a device that can be used to: read the blow to impart the coldness of the capacity; to discharge the micro-granulated powdery cold-cooled material in the container of the method of drying the composition. 2 ° ': ΐ =; the use of a composition solution of the added ingredients in a solution state, the use of clothing ", the preparation of dry powder preparation for pulmonary administration for cold; The following characteristics. 3I53J4 119 200418520 ⑴ has a non-powdered morphology, (Η) the decay index is greater than 0.05, and (-) by withstanding an air velocity of at least lm / sec and at least 10 :: two air: The impact of the air at the right flow rate can become fine particles with an average particle size of "under" or an effective particle ratio of 10% or more; and when used, it is micronized into the above average particle size or the effective particle ratio. 4 π from m. As in the patent application scope of item 2G, the composition liquid containing the added components in a non-dissolved state! "Wherein, the cold-roll-dried composition contains a South molecular drug as an active ingredient. 22. Use of a composition liquid containing non-dissolved added ingredients in the scope of application for item 2G, wherein the freeze-dried composition is contained in a container, and the micronized powder is provided with the above-mentioned air. The impact imparts the coldness in the container; the means for drying the composition and the powdery cold that can be discharged from the container; the device for the means for drying the composition. 315314 120