A dry powder inhalation system suitable for transpulmonary administration. The dry powder inhalation system is characterized by using a combination of: (1) a vessel housing a freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form, and has: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) a property of becoming fine particles having a mean particle diameter (mass median aerodynamic diameter) of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and (2) a device comprising a member capable of applying the air impact to the freeze-dried composition in said vessel, and a member for discharging the powder-form freeze-dried composition that has been made into fine particles.

Description of the Invention

It is an object of the present invention to solve the various problems of the above-mentioned conventional powdered inhalations for transpulmonary administration. Specifically, it is an object of the present invention to provide a novel preparation system and administration system that enables a freeze-dried composition that has been housed in vessels to be made into fine particles down to a particle diameter suitable for transpulmonary administration in the vessel, and then be used for transpulmonary administration by inhalation as is.

The present inventors carried out assiduous studies to attain the above object, and as a result discovered that if a pharmacologically active substance as active ingredients is filled as a liquid into vessels and then freeze-dried, then the non-powder-form freeze-dried composition thus prepared can unexpectedly be made into fine particles by a relatively low air impact while still housed in the vessel. Based on this knowledge, the present inventors carried out further studies, and as a result discovered that by using a freeze-dried composition, which has been housed in a non-powder form in a vessel, combined with a device comprising member for introducing air at a prescribed speed and flow rate into the vessel so as to be capable of applying a prescribed air impact to the composition, and member for discharging from the vessel the powdered composition that has been made into fine particles, then the freeze-dried preparation can be prepared into a fine particle powder form suitable for transpulmonary administration easily by a user at the time of use (specifically, at the time of inhalation), and thus, transpulmonary administration can be carried out by administering the fine particle powder as is by inhalation. Moreover, the present inventors discovered that a composition liquid containing pharmacologically active substances to be filled as a liquid into vessels can be prepared as a freeze-dried composition capable of being made into fine particles suitable for transpulmonary administration through a predetermined air impact, and further discovered that this is not limited to the case where the ingredients in particular to be the pharmacologically active substance as an active ingredient are clearly dissolved or mixed in a solvent, and moreover, the ingredients may be not dissolved or only partially dissolved (which state is called as "the non-dissolved form") in the solvent.

It was verified that, according to this transpulmonary administration system, all of the previously mentioned problems of conventional powdered inhalations for transpulmonary administration can be solved.

That is, the above-mentioned transpulmonary administration system of the present invention can be used for transpulmonary administration without the problem of contamination, since it is not necessary to subdivide and fill the powder form freeze-dried composition which was made into fine particles in another device, into vessels.

Moreover, according to the above-mentioned administration system, active ingredients such as proteins or peptides are not exposed to high temperature in the manufacturing process as is the case with the spray drying method and the like, and hence there is no problem of the pharmacological activity dropping due to exposure to high temperature. This member that the administration system of the present invention is an extremely useful system in particular with pharmacologically active substances such as peptides and proteins that are expensive drugs, since the manufacturing cost can be reduced. More specifically, the administration system of the present invention is economically useful. Moreover, according to the dry powder inhalation system of the present invention, an extremely high fine particle fraction (the amount of the drug reaching the lungs: fine particle fraction, respirable fraction) is obtained, and hence the drug can be delivered into the lungs efficiently.

The dry powder inhalation system of the present invention is characterized by using a freeze-dried composition in a non-powder cake-like form prepared by subjecting active ingredients-containing composition liquid in the non-dissolved form to freeze-dry as a preparation for transpulmonary administration. The dry powder inhalation system of the present invention in which the freeze-dried composition in a cake-like form thus prepared is applied to a dry powder inhaler is capable of achieving a significantly higher fine particle fraction compared to the case where a preparation made into fine particle powder having a size suitable for transpulmonary administration using a method employed for powder inhalants heretofore known, such as a jet milling method or a spray drying method, is applied to a dry powder inhaler of the present invention. For such reasons, the dry powder inhalation system of the present invention can be ranked as a high-performance transpulmonary administration system.

The present invention was developed based on this knowledge, and includes the following items. Item 1. A freeze-dried composition for transpulmonary administration prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form which has the following properties (i) to (iii): (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) becoming fine particles having a mean particle diameter (mass median aerodynamic diameter) of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec. Item 2. The freeze-dried composition according to Item 1, wherein a high-molecular-weight drug is contained as an active ingredient. Item 3. A method of manufacturing a dry powdered preparation for transpulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec using a device capable of applying said air impact to the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles having a mean particle diameter (mass median aerodynamic diameter) of 10 microns or less or a fine particle fraction of 10% or more;

the freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form and having the following properties: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of the air impact. Item 4. The method of manufacturing a dry powdered preparation for transpulmonary administration according to Item 3, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient. Item 5. The method of manufacturing a dry powdered preparation for transpulmonary administration according to Item 3 comprising pulverizing a freeze-dried composition into fine particles using a dry powder inhaler described under item (A) or (B) as a device:

(A) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of said needle part, and an inhalation port that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals up said vessel is pierced by said needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of said vessel, and air is jetted into said vessel through said air jet flow path using said air pressure-feeding member, thus pulverizing said freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained from the inhalation port via said discharge flow path, or

(B) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with said suction flow path,

and characterized by being constituted such that, in a state in which a stopper sealing up said vessel has been pierced by said needle parts, through the inhalation pressure of the user, air in said vessel is inhaled from said inhalation port, and at the same time outside air flows into said vessel, at a negative pressure, through said air introduction flow path, and as a result said freeze-dried composition is pulverized into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through said suction flow path. Item 6. A dry powder inhalation system for transpulmonary administration, using a combination of:

(1) a vessel housing a freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form, and has: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) a property of becoming fine particles having a mean particle diameter (mass median aerodynamic diameter) of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and

(2) a device comprising a member capable of applying said air impact to the freeze-dried composition in said vessel, and a member for discharging the powder-form freeze-dried composition that has been made into fine particles. Item 7. The dry powder inhalation system for transpulmonary administration according to Item 6, wherein the vessel and the device are used in combination at the time of inhalation. Item 8. The dry powder inhalation system for transpulmonary administration according to Item 6, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient. Item 9. The dry powder inhalation system for transpulmonary administration according to Item 6, wherein the device is:

A) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of said needle part, and an inhalation port that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals up said vessel is pierced by said needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of said vessel, and air is jetted into said vessel through said air jet flow path using said air pressure-feeding member, thus pulverizing said freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained from the inhalation port via said discharge flow path, or

B) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with said suction flow path,

and characterized by being constituted such that, in a state in which a stopper sealing up said vessel has been pierced by said needle parts, through the inhalation pressure of the user, air in said vessel is inhaled from said inhalation port, and at the same time outside air flows into said vessel, at a negative pressure, through said air introduction flow path, and as a result said freeze-dried composition is pulverized into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through said suction flow path. Item 10. A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more by applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition at the time of use, and

administering the resulting fine particle powder to a user by inhalation;

the freeze-dried composition being prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form and having the following properties: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of the air impact. Item 11. The transpulmonary administration method according to Item 10, wherein the freeze-dried composition is housed in a vessel, and the fine particle powder are prepared using a device comprising a member capable of applying the air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel. Item 12. The transpulmonary administration method according to Item 10, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient. Item 13. The transpulmonary administration method according to Item 11, using a dry powder inhaler described under item (A) or (B) as the device:

(A) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of said needle part, and an inhalation port that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals up said vessel is pierced by said needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of said vessel, and air is jetted into said vessel through said air jet flow path using said air pressure-feeding member, thus pulverizing said freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained from the inhalation port via said discharge flow path, or

(B) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with said suction flow path,

and characterized by being constituted such that, in a state in which a stopper sealing up said vessel has been pierced by said needle parts, through the inhalation pressure of the user, air in said vessel is inhaled from said inhalation port, and at the same time outside air flows into said vessel, at a negative pressure, through said air introduction flow path, and as a result said freeze-dried composition is pulverized into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through said suction flow path. Item 14. Use of a freeze-dried composition for transpulmonary administration by inhalation,

the freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in a non-dissolved form and having the following properties: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, and being used by forming into fine particles having said mean particle diameter or said fine particle fraction. Item 15. The use of a freeze-dried composition for transpulmonary administration according to Item 14, wherein the freeze-dried composition is housed in a vessel, and the fine particles are prepared using a device comprising a member capable of applying the air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel. Item 16. The use of a freeze-dried composition for transpulmonary administration according to Item 14, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient. Item 17. Use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration by inhalation,

the freeze-dried composition having the following properties: (i) being prepared by freeze drying a composition liquid containing ingredients in the non-dissolved form, (ii) a non-powder cake-like form, (iii) a disintegration index of 0.05 or more, and (iv) becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec,

and being used by forming into fine particles having said mean particle diameter or said fine particle fraction at the time of use. Item 18. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration by inhalation according to Item 17, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient. Item 19. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to Item 17, wherein the freeze-dried composition is housed in a vessel, and the fine particles are prepared by using a device comprising a member for applying a prescribed air impact to the freeze-dried composition housed in the vessel and a member for discharging the resulting fine particle powder form freeze-dried composition out of the vessel. Item 20. Use of a composition liquid containing ingredients in the non-dissolved form for manufacture of a freeze-dried composition having the following properties, which is used for manufacture of dry powdered preparation for transpulmonary administration: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, and being used by forming into fine particles having said mean particle diameter or said fine particle fraction at the time of use. Item 21. The use of a composition liquid containing ingredients in the non-dissolved form according to Item 20, wherein the freeze-dried composition contains a high-molecular-weight drug as an active ingredient Item 22. The use of a composition liquid containing ingredients in the non-dissolved form according to Item 20, wherein the freeze-dried composition is housed in a vessel, and the fine particles are prepared by using a device comprising a member for applying a prescribed air impact to the freeze-dried composition housed in the vessel and a member for discharging the resulting fine particle powder form freeze-dried composition out of the vessel.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Freeze-Dried Composition

The freeze-dried composition of the present invention is a composition that is prepared in a non-powder dry form by filling composition liquid containing ingredients in the non-dissolved form into a vessel and then freeze-drying the same as is. The freeze-dried composition is prepared by freeze-drying composition liquid in the non-dissolved form containing preferably a single or a plurality of effective doses of active ingredients, and in particular, preferably a single dose of effective dose of active ingredients.

The freeze-dried composition of the present invention is prepared by selecting a composition (types and amounts of active ingredient and carrier used together with the active ingredient) of the composition liquid such that the disintegration index of the freeze-dried composition prepared is 0.05 or more, and thus the freeze-dried composition can be made into fine particles down to a particle diameter suitable for transpulmonary administration in an instant by receiving an impact of external air (air impact, jet pressure) introduced into (flowing into) the vessel.

Note that the disintegration index in the present invention is a value characteristic of the freeze-dried composition that can be obtained by measuring following the undermentioned method.

<Disintegration Index>

0.2 to 0.5 ml of a mixture containing target components that will constitute the freeze-dried composition is filled into a vessel having a trunk diameter of 18 mm or 23 mm, and freeze-drying is carried out. Next, 1.0 ml of n-hexane is instilled gently down the wall of the vessel onto the non-powder-form freeze-dried composition obtained. Agitation is carried out for about 10 seconds at 3000 rpm, and then the mixture is put into a UV cell of optical path length 1 mm and optical path width 10 mm, and the turbidity is measured immediately at a measurement wavelength of 500 nm using a spectrophotometer. The turbidity obtained is divided by the total amount (weight) of the components constituting the freeze-dried composition, and the value obtained is defined as the disintegration index.

Here, an example of the lower limit of the disintegration index of the freeze-dried composition of the present invention can be given as the above-mentioned 0.05, preferably 0.08, more preferably 0.09, yet more preferably 0.1, still more preferably 0.11, still further preferably 0.12, and in particular 0.13 is preferable.

Moreover, there is no particular limitation on the upper limit of the disintegration index of the freeze-dried composition of the present invention, but an example can be given as 1.5, preferably 1, more preferably 0.9, yet more preferably 0.8, and still more preferably 0.7. In particular, 0.6 is preferable, and 0.5 is more preferable. The freeze-dried composition of the present invention preferably has a disintegration index in a range constituted from a lower limit and an upper limit selected as appropriate from the above, with the proviso that the disintegration index is at least 0.05. Specific examples of the range of the disintegration index are 0.05 to 1.5, 0.08 to 1.5, 0.09 to 1.0, 0.1 to 0.9, 0.10 to 0.8, 0.1 to 0.7, 0.1 to 0.6 and 0.1 to 0.5.

Moreover, it is preferable to prepare the freeze-dried composition of the present invention in a non-powder cake-like form by freeze-drying. In the present Invention, `non-powder-form freeze-dried composition` member a dry solid obtained by freeze-drying a composition liquid containing active ingredients, and is generally called a `freeze-dried cake`. However, even if cracks appear in the cake, the cake breaks into a plurality of large lumps, or part of the cake breaks into a powder during the freeze-drying process or during subsequent handling, this cake is still included as a non-powder-form freeze-dried composition that is the subject of the present invention, more specifically, as a freeze-dried composition having a non-powder cake like form, provided the effects of the present invention are not impaired.

As described above, the freeze-dried composition of the present invention is prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and has a disintegration index of 0.05 or more and a non-powder cake-like form and becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, on the basis of properties peculiar to the freeze-dried composition represented by the disintegration index.

A preferable freeze-dried composition is such that, upon receiving the above air impact, the mean particle diameter becomes 10 microns or less and preferably 5 microns or less or a fine particle fraction of 10% or more, preferably 20% or more, more preferably 25% or more, still more preferably 30% or more, and especially more preferably 35% or more.

As described above, the air impact applied to a freeze-dried composition Is not limited, as long as it is generated by air having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec. Specific examples of an air impact include an impact generated by an air having a speed of 1 m/sec or more, preferably 2 m/sec or more, more preferably 5 m/sec or more and a still more preferably 10 m/sec or more, Here, there is no limitation on the upper limit of the air speed, but it is generally 300 m/sec, preferably 250 m/sec, more preferably 200 m/sec and yet more preferably 150 m/sec. The air speed is not limited as long as it is arbitrary selected from the range extending from a lower limit to an upper limit; however, the ranges of 1 to 300 m/sec, 1 to 250 m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200 m/sec or 10 to 150 m/sec can be given as examples.

Examples of the air impact include those generated by air having an air flow rate of generally 17 ml/sec or more, preferably 20 ml/sec or more and more preferably 25 ml/sec or more. There is no limitation on the upper limit of the air flow rate; however, the air flow rate is generally 900 L/min, preferably 15 L/sec, more preferably 5 L/sec and yet more preferably 4 L/sec. Especially, 3 L/sec is very preferable. More specifically, the air flow rate is not limited as long as it is selected from the range extending from a lower limit to an upper limit; however, examples of such a range include 17 ml/sec to 15 L/sec, 20 ml/sec to 10 L/sec, 20 ml/sec to 5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/sec and 25 ml/sec to 3 L/sec.

In principle, there is no particular limitation on the active ingredients used in the present invention, provided it is a substance having some pharmacological activities (pharmacologically active substance: hereinafter, simply referred to as a drug) that can be used as ingredients for a powdered inhalation for transpulmonary administration; nevertheless, low-molecular-weight drugs and high-molecular-weight drugs can be given as specific examples. Such high-molecular weight drugs include physiologically active substances such as proteins (including peptides or polypeptides), for example, enzymes, hormones, antibodies, etc., nucleic acids (including genes and cDNA), RNA, and the like.

Moreover, regarding the disease targeted by the drug, both whole body treatment and local treatment can be envisaged, depending on the case.

Examples of low-molecular-weight drugs include, for example, hydrocortisone, prednisolone, triamcinolone, dexamethasone, betamethasone, beclometasone, fluticasone, mometasone, budesonide, salbutamol, salmeterol, procaterol, buprenorphine hydrochloride, apomorphine, taxol, and antibiotics such as tobramycin.

Examples of high-molecular-weight drugs (physiologically active substances such as proteins and nucleic acids) include, for example, interferons (.alpha., .beta., .gamma.), interleukins (for example, interleukin-1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, etc.), anti-interleukin-1.alpha. antibody, interleukin-1 receptor, interleukin receptor antagonist, interleukin-4 receptor, anti-interleukin-2 antibody, anti-interleukin-6 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-10 receptor, anti-interleukin-14 antibody, interleukin-14 receptor, anti-interleukin-15 antibody, interleukin-15 receptor, interleukin-18 receptor, anti-interleukin-18 antibody, erithropoietin (EPO), erithropoletin derivatives, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), calcitonin, insulin, insulin derivatives (LisPro, NovoRapid, HOE901, NN-304, etc.), insulintropin, insulin-like growth factor, glucagon, somatostatin and analogs thereof, vasopressin and analogs thereof, amylin, human growth hormone, lutenizing hormone releasing hormone, follicle stimulating hormone, growth hormone releasing factor, parathyroid hormone, endothelial cell growth factor, platelet derived growth factor, keratinocyte growth factor, epidermal growth factor, fibroblast growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, tumor necrosis factor (TNF), TNF receptor, TNF inhibitor, transforming growth factor (TGF), hepatocyte growth factor (HGF), nerve growth factor (NGF), blood stem cell growth factor, platelet growth simulator, naturiuretic peptide, blood coagulation factor, blood hepatocyte growth factor (S-CSF), FLT3 ligand, anti-platelet aggregation inhibiting monoclonal antibody, tissue plasminogen activator and derivatives thereof, superoxide dismutase, antisense drugs, immunosuppression agents (for example, cyclosporin, tacrolimus hydrate, etc.), cancer repressor gene p53, cystic fibrosis transmembrane conductance regulator (CFTR) gene, RNA interferance (RNAi), Bridged Nucleic Acid (BNA), .alpha.-1 antitrypsin, thrombopoietin (TPO), metastatin, deoxyribonuclease (Dnase), prolactin, oxytocin, thyrotopin releasing hormone (TRH), bactericidal permeability increasing (BPI) protein, and vaccine preparations, for example influenza vaccines, AIDS vaccines, rotavirus vaccines, malaria vaccines and tuberculosis vaccines such as Mtb72f.

One of these active ingredients can be used alone, or two or more can be used in combination. Note that the various peptides above encompass natural polypeptides, gene recombinant polypeptides, chemically synthesized polypeptides and so on.

These active ingredients can be used in free form or in salt form, alternatively, they can be used in a form such that they are bound by various types of hosts. Such hosts are not particularly limited insofar as active ingredients (for example, high-molecular-weight drugs such as proteins and nucleic acids, etc., low-molecular weight drugs) can be bound by various forms of adhesion/presence (adsorption, absorption, clathration, ionic interactions, etc.). Specific examples of hosts include lipid-membrane structures, microcapsules, cyclodextrins, dendrimers, microsperes, nanocapsules, nanosperes, etc. Lipid-membrane structures include liposomes such as single membrane liposomes, multilayer lipospmes, etc.; emulsions such as the O/W-type or W/O/W-type etc., spherical micelles, corded micelles, layer structural substance, etc.

In general, dendrimers are molecules with a three-dimensional form such that molecule chains regularly branch outwardly from a core regularly based on a predetermined rule. Dendrimers generally have a spherical structure with voids for encapsulting drugs therein, and thus can serve as nanocapsules. The following methods are known for encapsulting drugs in dendrimers: (1) utilizing interactions between the dendrimer interior and drugs (hydrophobic interactions, electrostatic interactions, etc.) or (2) forming a dense shell structure at the dendrimer surface to physically entrap drugs (Kenji Kawano: Drug Delivery System, 17-6, 462-470(2002)). SuperFect employed in Examples is composed of activated dendrimer molecules of a predetermined form (Tang. M. X, Redemann, C. T. and Szoka, Jr. F. C: In vitro gene delivery by degraded polyamidoamine dendrimers. Bioconjugate Chem. 7, 703(1996)). These molecules have a structure branching from the center, and have positively charged amines at the branch terminals so as to interact with the (negatively charged) phosphoric acid groups of nucleic acids. SuperFect is endowed with the property of compacting DNA or RNA so that DNA or RNA can be readily introduced into cells.

Preferably, hosts include liposomes, dendrimers, retrovirus vectors, adenovirus vectors, adeno-associated virus vectors, lentivirus, herpes simplex virus vector, HVJ (Sendai Virus)-liposome (for example, HVJ Envelope VECTOR KIT) etc.

Hosts such as lipid-membrane structures or dendrimers, etc. have been widely used for introducing foreign genes into cells. Liposomes for gene transfer and dendrimers for gene transfer can also be used in the present invention in the same manner, and are available commercially.

Particle diameter (geometric mean particle diameter: Dynamic light scattering or Laser diffraction/scattering) of the hosts is not particularly limited insofar as it is 10 .mu.m or less, and 5 .mu.m or less is preferred. In general, liposomes or emulsions, have for example, a particle diameter (geometric mean particle diameter: Dynamic light scattering or Laser diffraction/scattering) of 50 nm to a few micrometers, and spherical micelles have a particle diameter of 5 to 50 nm.

For measuring the geometric mean particle diameter, in general, dynamic light scattering is used for distribution of particles with the size range of several tens of nanometers and laser diffraction/scattering is used for ten or more microns. For distribution of particles with the size in the range of hundreds of nanometers to several microns, either method may be used.

The manner of binding active ingredients (for example, nucleic acids such as genes, etc.) into the hosts is not particularly limited. For example, when a lipid membrane structure is used, active ingredients are adhered to/present in the membrane, the membrane surface, the membrane interior, the lipid layer inside or the lipid layer surface of the membrane structure.

Examples of methods for obtaining the bound forms include the method of adding aqueous solvent to a dried mixture of the host such as a lipid membrane structure, etc., and the active ingredients (genes, etc.), and then emulsifying them with an emulsifier such as a homogenizer or the like; the method of dissolving a host such as a membrane structure with an organic solvent, and evaporating the solvent to obtain a dried substance, and further adding aqueous solvent including genes to the dried substance obtained and emulsifying the mixture; the method of adding aqueous solvent including active ingredients (genes, etc.) to hosts such as membrane structure substances dispersed in the aqueous solvent; and a method for adding aqueous solvent including active ingredients (genes, etc.) to a dried substance obtained by dispersing hosts such as a membrane structural substance into aqueous solvent and then drying them (Japanese Unexamined Published Patent No. 2001-02592).

The size (particle diameter) can be controlled by a method for carrying out extrusion (extrusion-filtration) under high pressure with a membrane filter having the uniform pore diameter, or by a method using an Extruder (Japanese Unexamined Patent Publication No. 1994-238142).

The freeze-dried composition of the present invention is prepared by freeze-drying a composition liquid containing ingredients (including the above-mentioned active ingredients) in the non-dissolved form. In this specification, `the non-dissolved form` indicates a state where ingredients are neither clearly dissolved nor mixed in a solvent constituting a composition liquid. Such `non-dissolved form` includes a state where solids in the solvent can be detected by various methods. More specifically, as an example, the case can be mentioned where solids having the geometric mean particle diameter (Dynamic light scattering or Laser diffraction/scattering) of 0.01 .mu.m or more, preferably 0.05 .mu.m or more, more preferably 0.1 .mu.m or more, still more preferably 0.2 .mu.m or more, still further preferably 0.5 .mu.m or more can be detected. According to the object of the present invention, the geometric mean particle diameter (Dynamic light scattering or Laser diffraction/scattering) of these solids are determined so that the upper limit thereof is 20 .mu.m or less, preferably 15 .mu.m or less, more preferably 10 .mu.m or less. More specifically, the `non-dissolved form` of the present invention includes a state where solids having the geometric mean particle diameter (Dynamic light scattering or Laser diffraction/scattering) having 0.01 to 20 .mu.m, 0.05 to 15 .mu.m, 0.1 to 15 .mu.m, 0.2 to 15 .mu.m, 0.5 to 15 .mu.m, 0.05 to 10 .mu.m, 0.1 to 10 .mu.m, or 0.2 to 10 .mu.m are present in the solvent and can be detected by various methods. The `non-dissolved form` includes the following examples: a state where ingredients are not completely dissolved into the solvent, and are supersaturated; and a state where ingredients are not dissolved in the solvent, and more specifically, active ingredients which are not dissolved or are hard to dissolve into the solvent are suspended or mudded in the solvent. The non-dissolved form can be typically evaluated by measuring the turbidity of the sample, but can also be evaluated by methods for measuring the particle size distribution of the non-dissolved substances in the solvent with an apparatus for particle size distribution measurement.

In the specification, ingredients in the non-dissolved form specifies not only the case where the active ingredients or the carrier, which will be described later, themselves are not dissolved in the solvent, but also the case where the active ingredients are dissolved in the solvent and bound by a host such as the above-mentioned liposomes, microcapsules, cyclodextrins, dendrimers, etc., while the host such as liposome, etc., is not dissolved in the solvent. The type of ingredients is not particularly limited insofar as the ingredients are in the dissolved form, and may be active ingredients, hosts which are mixed in the composition liquid with active ingredients or another ingredient (which will be described later).

The solvent constituting the composition liquid with the ingredients are not particularly limited, and can include isotonic solutions such as water, physical saline, etc., culture medium, buffer solutions, etc. Organic solvents may be contained in the solvent provided that the end product (freeze-dried composition for transpulmonary administration) adversely affects human body. Such organic solvents include methanol, ethanol, isopropanol, acetone, ethylene glycol, and the like.

The freeze-dried composition of the present invention may comprise the active ingredient alone or the active ingredient and the host, as long as the end products satisfy the above-mentioned disintegration index, or a suitable carrier may be admixed. In the case of using a carrier in addition to the active ingredient, there are no particular limitations on the type and amount of carrier used, so long as the final freeze-dried composition containing the carrier with active ingredients which is prepared by freeze-drying the composition liquid in the non-dissolved form satisfies the following properties (i) to (iii);

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec and the effects of the present invention (making into a fine particle) are attained. Those carriers commonly used for freeze-drying may be used arbitrarily and at desired amounts.

Specific examples of the carrier include hydrophobic amino acids such as valine, leucine, isoleucine and phenylalanine, and salts and amides thereof; hydrophilic amino acids such as glycine, proline, alanine, arginine and glutamic acid, and salts and amides thereof; derivatives of amino acids; and dipeptides, tripeptides or the like having two or more of the same one or different ones of the above-mentioned amino acids, and salts and amides thereof. One of these can be used alone, or two or more can be used in combination. Here, examples of salts of the amino acid or peptide include salts with an alkali metal such as sodium or potassium or an alkaline earth metal such as calcium, and addition salts with an inorganic acid such as phosphoric acid or hydrochloric acid or an organic acid such as sulfonic acid, while examples of amides include L-leucine amide hydrochloride. Moreover, an amino acid other than an .alpha.-amino acid can be used in as a carrier. Examples of such an amino acid include .beta.-alanine, .gamma.-aminobutyric acid, homoserine and taurine.

Other examples of carriers include monosaccharides such as glucose; disaccharides such as saccharose, maltose, lactose and trehalose; sugar alcohols such as mannitol; oligosaccharides such as cyclodextrin; polysaccharides such as dextran 40 and pullulan; polyhydric alcohols such as polyethylene glycol; and fatty acid sodium salts such as sodium caprate. One of these carriers may be used alone, or two or more may be used in combination.

Of the above carriers, specific examples of carriers that are preferable for delivering the active ingredient efficiently into the lungs include hydrophobic amino acids such as isoleucine, valine, leucine and phenylalanine, and salts and amides thereof; hydrophobic dipeptides such as leucyl-valine, leucyl-phenylalanine and phenylalanyl-isoleucine; and hydrophobic tripeptides such as leucyl-leucyl-leucine and leucyl-leucyl-valine. Again, one of these may be used alone, or two or more may be used in combination.

In the case of interferon .gamma., it is preferable to use basic amino acids, and salts and amides thereof, basic dipeptides and basic tripeptides in combination of hydrophobic amino acids, and salts and amides thereof, hydrophobic dipeptides, and hydrophobic tripeptides in view of making into fine particles and preparation stability. The basic amino acids include arginine, lysine, histidine and salts thereof. The combination of phenylalanine and arginine hydrochloride or the combination of phenylalanine, leucine and arginine hydrochloride is preferable.

There are no particular limitations on the proportion of the active ingredients (drug(s)) mixed into the freeze-dried composition; nevertheless, examples of the content are 20 mg or less, preferably 10 mg or less, more preferably 5 mg or less, yet more preferably 2 mg or less, particularly preferably 1 mg or less.

Moreover, there are no particular limitations on the mixing proportion of the carrier(s), provided the final freeze-dried composition satisfies the above-mentioned properties (i) to (iii); nevertheless, as a guideline, per 100 wt % of the freeze-dried composition, the range is generally from 0.1 to less than 100 wt %, preferably from 1 to less than 100 wt %, more preferably from 10 to less than 100 wt %, particularly preferably from 20 to less than 100 wt %.

Note that, in addition to the above-mentioned components, the freeze-dried composition that is the subject of the present invention may have mixed therein various additives, for example for stabilizing the active ingredient(s) in solution before drying, for stabilizing the active ingredient(s) after drying, or for preventing the active ingredient(s) from sticking to the vessel, provided that the above-mentioned properties (i) to (iii) is satisfied and the effects of the present invention are not impaired. For example, the freeze-dried composition may contain human serum albumin, inorganic salts, surfactants, buffering agents and so on. A wide range of surfactants can be used, regardless of whether they are anionic surfactants, cationic surfactants or nonionic surfactants, provided that they are surfactants that are generally used in medicines. Preferable examples are nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters (for example Tween type surfactants) and sorbitan trioleate.

The method of freeze-drying a composition liquid which contains such active ingredients and other ingredients is not particularly limited, and a freeze-drying method commonly used in preparing a usual freeze-dried preparation (freeze-dried composition), such as an injection which is dissolved at the time of usage can be employed. There is no limitation, and a quick freeze-drying method, if required, may be carried out by appropriately varying freeze-drying conditions.

The freeze-dried composition of the present invention can be pulverized into fine particles suitable for transpulmonary administration by applying an air impact of a predetermined value. Thus, the freeze-dried composition of the present invention can be served as a so-called pre-preparation for a powder preparation for transpulmonary administration, which is suitable for providing a powder preparation for transpulmonary administration (a freeze-dried composition for providing a powder preparation for transpulmonary administration).

The freeze-dried composition for use in the present invention encompasses the specific embodiments defined in the following items:

101. A freeze-dried composition for transpulmonary administration having the following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(ii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec.

102. The freeze-dried composition according to item 101, wherein the disintegration index is 0.05 to 1.5.

103. The freeze-dried composition according to item 101 becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

104. The freeze-dried composition according to item 101 becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

105. The freeze-dried composition according to item 101, becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

106. The freeze-dried composition according to item 101, becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

107. The freeze-dried composition according to item 101, becoming fine particles having a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more upon receiving an air impact.

108. The freeze-dried composition according to item 101, containing a low-molecular-weight drug as an active ingredient.

109. The freeze-dried composition according to item 101, containing a high-molecular-weight drug such as a protein, a peptide or the like as an active ingredient.

110. The freeze-dried composition according to item 109, containing a nucleic acid as an active ingredient with held in a holder.

111. The freeze-dried composition according to item 108, containing a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

112. The freeze-dried composition according to item 109, containing a high-molecular-weight drug such as a protein, a peptide or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

113. The freeze-dried composition according to item 111, containing a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

114. The freeze-dried composition according to item 112, characterized by containing a high-molecular-weight drug such as a protein, a peptide or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

115. The freeze-dried composition according to item 101, being a water-soluble composition.

116. The freeze-dried composition according to item 101, containing a single dose of an active ingredient.

117. The freeze-dried composition according to item 101, being a freeze-dried composition for transpulmonary administration prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and has the following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

118. The freeze-dried composition according to item 117, wherein the air speed is 1 to 250 m/sec.

119. The freeze-dried composition according to item 117, wherein the air flow rate is 20 ml/sec to 10 L/sec.

(2) Method of Manufacturing a Dry Powdered Preparation

Moreover, the present invention relates to a method of manufacturing a dry powdered preparation comprising fine particles with a particle diameter suitable for transpulmonary administration (dry powdered preparation for transpulmonary administration) by inhalation, by making a freeze-dried composition that has been housed in a non-powder form in a vessel into fine particles. The manufacturing method can be implemented in the vessel housing the non-powder form freeze-dried composition by applying a predetermined air impact.

Specifically, the method of manufacturing the dry powder preparation of the present invention can be carried out by applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec to the non-powder form freeze-dried composition of the present invention having a disintegration index of at lest 0.05 which is prepared by freeze-drying the composition liquid containing ingredients in the non-dissolved form as described in detail in the above section (1). Thereby, the non-powder form freeze-dried composition can be made into a dry powdered preparation having a mean particle diameter of 10 microns or less, preferably 5 microns or less or a fine particle fraction of 10% or more, preferably 20% or more, more preferably 25% or more, still more preferably 30% or more, and in particular 35% or more.

As used herein, the mean particle diameter of fine particles indicates a mean particle diameter usually adopted in the industry relating to inhalants. Specifically, the mean particle diameter is not a geometric mean particle diameter, but an aerodynamic mean particle diameter (mass median aerodynamic diameter, MMAD) unless otherwise specified. The aerodynamic mean particle diameter can be measured by a conventional method. For example, the mass median aerodynamic diameter can be measured using a dry particle size distribution meter fitted with an Aerobreather, which is an artificial lung model (manufactured by Amherst Process Instrument, Inc., USA), a twin impinger (G. W. Hallworth and D. G. Westmoreland: J. Pharm. Pharmacol., 39, 966-972 (1987), U.S. Pat. No. 6,153,224), a multi-stage liquid impinger, a Marple-Miller impactor, an Andersen cascade impactor or the like. Moreover, B. Olsson et al. have reported that delivery of the particles into the lungs increases at the proportion of particles having a mass median aerodynamic diameter of 5 .mu.m or less increases (B. Olsson et al.: Respiratory Drug Delivery V. 273-281(1996)). The fine particle fraction, fine particle dose or the like as measured by a twin impinger, a multi-stage liquid impinger, a Marple-Miller impactor, an Andersen cascade impactor or the like acts as a method of estimating the amount that can be delivered into the lungs.

The manufacturing method of the present invention can be implemented by filling into a vessel the composition liquid containing ingredients in the non-dissolved form, generating the non-powder form freeze-dried composition by freeze-drying the composition liquid in the non-dissolved form, and applying the air impact defined in the above to the generated freeze-dried composition by introducing air into the vessel housing the generated composition. In this case, freeze-drying process and a process for making a powder into a preparation can be carried out using the same vessel, which can avoid a loss or contamination resulting from subdividing.

The method of applying the air impact to the freeze-dried composition is not limited; however, a dry powder inhaler which will be described in the section (3) below is preferably used.

The method of manufacturing the dry powdered preparation for transpulmonary administration of the present invention is also characterized in that a patient administering the dry powdered preparation can prepare by him/herself the powdered preparation for transpulmonary administration at the time of use (inhalation) by making the freeze-dried composition housed in a vessel into fine particles having a particle diameter suitable for transpulmonary administration.

The method of manufacturing a dry powdered preparation of the present invention encompasses the specific embodiments defined in the following items:

201. A method of manufacturing a dry powdered preparation for transpulmonary administration, comprising:

introducing air into a vessel to apply to a freeze-dried composition an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec using a device capable of applying said air impact to the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more;

the freeze-dried composition prepared by freeze-drying the composition liquid containing Ingredients in the non-dissolved form and having the following properties: (i) has a non-powder cake-like form, (ii) has a disintegration index of 0.05 or more, and (iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of the air impact.

202. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the freeze-dried composition housed in the vessel containing a single dose of an active ingredient.

203. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the fine particles prepared have a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more.

204. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the disintegration index of the freeze-dried composition is in a range of 0.05 to 1.5.

205. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient.

206. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the freeze-dried composition contains a high-molecular-weight drug such as a protein, a nucleic acid or the like as the active ingredient.

207. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the freeze-dried composition contains a nucleic acid with held in the holder.

208 The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 205, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

209. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 206, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

210. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 208, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

211. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 209, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

212. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, wherein the freeze-dried composition is a water-soluble composition.

213. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, being a method of making the freeze-dried composition into fine particles in a vessel having a volume of 0.2 to 50 ml.

214. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, carried out by using a device having a member capable of applying an air impact having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition in the vessel, and introducing air having the air impact into the vessel housing the freeze-dried composition.

215. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, carried out by using a device having a member capable of applying an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition in the vessel, and introducing air having the air impact into the vessel housing the freeze-dried composition.

216. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, carried out by using a device having a member capable of applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec to the freeze-dried composition in the vessel, and introducing air having the air impact into the vessel housing the freeze-dried composition.

217. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, carried out by using a device having a member capable of applying an air impact having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec to the freeze-dried composition in the vessel, and introducing air having the air impact into the vessel housing the freeze-dried composition.

218. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, characterized by making the freeze-dried composition into fine particles using the dry powder Inhaler of item 301 or 302 shown in the section of (3) Dry powder inhaler as the device.

219. The method of manufacturing a powdered preparation for transpulmonary administration according to Item 218, characterized by making the freeze-dried composition into fine particles using the dry powder inhaler according to item 309 shown in the section of (3) Dry powder inhaler as the device.

220. The method of manufacturing a powdered preparation for transpulmonary administration according to item 218, being a method of manufacturing a dry powdered preparation in which the freeze-dried composition is made into fine particles using the dry powder inhaler according to item 301 shown in the section of (3) Dry powder inhaler, wherein the amount of air jetted into said vessel each time using the dry powder inhaler is 5 to 100 ml.

221. The method of manufacturing a powdered preparation for transpulmonary administration according to item 417, being a method of manufacturing a dry powdered preparation in which the freeze-dried composition is made into fine particles using the dry powder inhaler of item 302 shown in the section of (3) Dry powder inhaler, wherein the flow rate of air inhalation from the inhalation port using the dry powder inhaler is 5 to 300 L/min.

222. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 201, comprising:

introducing air into a vessel to apply to a freeze-dried composition an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec using a device capable of applying said air impact to the freeze-dried composition in the vessel,

thereby making said freeze-dried composition into fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more;

the freeze-dried composition prepared by freeze-drying the composition liquid containing ingredients in the non-dissolved form and having the following properties: (i) has a non-powder cake-like form, (ii) has a disintegration index in a range of 0.05 to 1.5, and (iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of the air impact.

223. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 222, wherein the freeze-dried composition housed in the vessel contains a single dose of an active ingredient.

224. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 222, wherein the air speed is 1 to 250 m/sec.

225. The method of manufacturing a dry powdered preparation for transpulmonary administration according to item 222, wherein the air flow rate is 20 ml/sec to 10 L/sec.

(3) Dry Powder Inhaler

The dry powder inhaler used suitably for manufacturing a dry powdered preparation for transpulmonary administration of the present invention is a device used for breaking down a freeze-dried preparation (freeze-dried composition) that has been housed in a non-powder form in a vessel Into fine particles in the vessel, and further allowing a user to inhale the dry powdered preparation.

By comprising {circle around (1)} a member capable of applying an air impact to the non-powder form freeze-dried composition in a degree such that the freeze-dried composition can be pulverized into fine particles, and {circle around (2)} a member capable of administering to a user by inhalation the powder-form freeze-dried composition that has been made into fine particles, the device can carry out both breaking down of the freeze-dried composition into fine particles and administration of the powdered composition to a user by inhalation. Note that the member {circle around (1)} can also appreciated as a member for introducing air having the above-mentioned air impact into the vessel housing the freeze-dried composition. Moreover, the member {circle around (2)} can also appreciated as a member for discharging out of the vessel the powdered preparation that has been made into fine particles in the vessel. In a dry powder inhalation system of the present invention, as long as the device comprises these members, either a conventional publicly-known device or a device which will be developed in the future can also be used.

Specifically, the member {circle around (1)} can be realized by introducing air capable of applying an air impact as above into the vessel housing the freeze-dried composition. Note that the member {circle around (1)} can be altered into a member capable of applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition in the vessel. By using the member {circle around (2)} or via this member, the dry powdered preparation, which has been prepared into a form suitable for transpulmonary administration, can be administered by inhalation to the user such as patient. Note that, for example a chamber or a flow path such that the composition is made into fine particles or scattered may be further provided in the member {circle around (2)}.

The device in question encompasses jet type dry powder inhalers as in (a) below and self-inhaling type dry powder inhalers as in (b) below.

(a) Jet type dry powder inhaler: Active powder inhaler

(a-1) A dry powder inhaler used in the making into fine particles and inhalation of a freeze-dried composition that has been housed in a non-powder form in a vessel,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of the needle part, and an inhalation port that communicates with the discharge flow path, and

being constituted such that a stopper that seals up the vessel is pierced by the needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of the vessel, and air is jetted into the vessel from the air jet flow path using the air pressure-feeding member, thus breaking down the freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained out from the inhalation port via the discharge flow path.

(a-2) The dry powder inhaler described in (a-1) above, being constituted such that the air pressure-feeding member is manually operated and comprises a bellows body having an intake port equipped with an intake valve and a discharge port equipped with a discharge valve, and by contracting the bellows body and thus opening the discharge valve in a state in which the intake valve is closed, air in the bellows body is pressure-fed into the vessel through the air jet flow path of the needle part which communicates with the discharge port, and by expanding the bellows body through an elastic restoring force in a state in which the discharge valve is closed and the intake valve is open, air is introduced into the bellows body.

(a-3) The dry powder inhaler described in (a-1) or (a-2) above, in which the air jet flow path and the discharge flow path are formed in a single needle part.

(b) Self-inhaling type dry powder inhaler: Passive powder inhaler

(b-1) A dry powder inhaler used for inhaling fine particles obtained by breaking down a freeze-dried composition that has been housed in a non-powder form in a vessel,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with the suction flow path,

and being constituted such that, in a state in which a stopper that seals up the vessel has been pierced by the needle parts, through the inhalation pressure of a user, air in the vessel is inhaled from the inhalation port, and at the same time outside air flows into the vessel, which is now at a negative pressure, through the air introduction flow path, and as a result the freeze-dried composition is broken down into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through the suction flow path.

(b-2) The dry powder inhaler described in (b-1) above, being constituted such that most part of the freeze-dried composition is made into fine particles and discharged from the inhalation port through one inhalation of the user.

(b-3) The dry powder inhaler described in (b-1) or (b-2) above, in which the suction flow path and the air introduction flow path are formed in a single needle part.

The member for introducing air into the vessel (member {circle around (1)} mentioned above) may be a member for introducing air from the outside at normal pressure. It is not necessary to use compressed air from a jet mill or the like. There are no limitations on the member for introducing air from the outside. For example, in the case where the jet type dry powder inhaler (active powder inhaler) described above is used, a member for artificially introducing external air into the vessel by jetting can be employed. In the case where the self-inhaling type dry powder inhaler is used, a member for naturally introducing outside air into the vessel by suction through negative pressure formed in the vessel when the user inhales can be employed. Moreover, in the former case, i.e. in the jet type dry powder inhaler, the method of introducing external air into the vessel by jetting artificially may be manual or may be a method that is carried out automatically using a machine.

The dry powder inhaler of the present invention, regardless of the type of the inhaler, whether it is an active powder inhaler or a passive powder inhaler, is capable of breaking down the freeze-dried composition that has been stored in non-powder form in the vessel into fine particles using an impact (jet pressure) of external air introduced into (flowing into) the vessel by the air introduction member.

For example, a vessel, used for freeze-drying can be used here, with no limitations on the material, shape etc. As the material, a plastic mainly including a polyolefin such as polyethylene, polypropylene or polystyrene, glass, aluminum and the like can be given as examples. Moreover, as the shape, a circular cylinder, a cup shape, and a polygonal prism (polygonal pyramid) such as a triangular prism (triangular pyramid), a square prism (square pyramid), a hexagonal prism (hexagonal pyramid) or an octagonal prism (octagonal pyramid) can be given as examples.

To obtain the effects efficiently, the volume of the vessel housing the freeze-dried composition is in a range of 0.2 to 50 ml, preferably 0.2 to 25 ml and more preferably 1 to 15 ml. Moreover, it is desirable to be used the trunk inside diameter of the vessel be 2 to 100 mm, preferably 2 to 75 mm, more preferably 2 to 50 mm.

Moreover, the amount of the freeze-dried composition housed in the vessel is preferably an amount containing a unit dose (single dose) or a plurality of doses, specifically 2 to 3 doses, of the active ingredient. More preferably, it is an amount containing a unit dose (single dose) of the active ingredient. Moreover, the specific amount of the freeze-dried composition will vary according to the type and content of the active ingredient contained in the freeze-dried composition, and is selected as appropriate from amounts that can be inhaled, with there being no particular limitation; nevertheless, the amount is generally 30 mg or less, preferably 20 mg or less, more preferable 10 mg or less, particularly preferably 5 mg or less.

Moreover, the air impact generated by the outside air introduced into the vessel is stipulated through the air flow rate at which air flows into the vessel through at least one or a plurality of inhalations of a person or the air speed thus generated. There is no particular limitation on introducing external air with an air flow rate or air speed greater than this, except of course that the durability of the vessel is a limitation. Generally the air flow rate for one inhalation of a person is 5 to 300 L/min, more specifically 10 to 200 L/min. Moreover, in the case of an dry powder inhaler, a device can be used such that the amount of air jetted each time is 5 to 100 ml, preferably 10 to 50 ml. Preferably, adjustment can be carried out such that an air impact generated through an air speed of at least 1 m/sec is applied to the surface of the freeze-dried composition filled in the vessel. A more preferable air impact is an impact generated by an air speed of at least 2 m/sec, a yet more preferable one is an impact generated by an air speed of at least 5 m/sec, and a still more preferable one is an impact generated by an air speed of at least 10 m/sec. Here, there is no particular limitation on the upper limit of the air impact, but an impact generated by an air speed of 300 m/sec can be given as an example. The upper limit is preferably an impact generated through an air speed 250 m/sec, more preferably an impact generated through an air speed 200 m/sec, yet more preferably an impact generated through an air speed 150 m/sec.

There is no particular limitation on the air impact as long as it is generated by air having an air speed arbitrarily selected from the range extending from a lower limit to an upper limit. Specific examples are impacts generated through an air speed in a range of 1 to 300 m/sec, 1 to 250 m/sec, 2 to 250 m/sec, 5 to 250 m/sec, 5 to 200 m/sec, 10 to 200 m/sec or 10 to 150 m/sec.

Here, the speed of the air applied to the freeze-dried composition can be measured as follows. That is, with the jet type dry powder inhaler shown later as Embodiment 1, a mechanism is adopted in which air stored in a bellows body 10 is forcibly introduced onto the freeze-dried composition (cake-like freeze-dried composition: hereinafter also referred to as `freeze-dried cake`) that has been filled into the vessel from an air jet flow path 3, thus applying an air impact, and discharging the resulting fine particles from a discharge flow path 4. In this case, the flow rate of the air flowing through the air jet flow path 3 can be calculated by dividing the amount of air stored in the bellows body 10 by the time over which the air is fed into the vessel. Next, by dividing this air flow rate by the cross-sectional area of a path to introduce air into the vessel such as the air jet flow path 3, the air speed at which the impact is applied to the freeze-dried composition (freeze-dried cake) can be calculated. Air speed(cm/sec)=air flow rate (ml=cm.sup.3/sec)+cross-sectional area of air introduction flow path (cm.sup.2)

Specifically, in the case for example of a jet type dry powder inhaler designed such that the bore of the air jet flow path 3 is 1.2 mm, the bore of the discharge flow path is 1.8 mm, and the amount of air stored in the bellows body 10 is about 20 ml, in the case that the amount of air of about 20 ml stored in the bellows body 10 is forcibly introduced onto the freeze-dried composition in the vessel from the air jet flow path 3 in about 0.5 seconds, the air flow rate becomes about 40 ml/sec. Dividing this value by the cross-sectional area of the air introduction flow path (the air jet flow path) (0.06.times.0.06.times.3.14=0.0113 cm.sup.2), gives 3,540 cm/sec. The air speed is thus about 35 m/sec.

Moreover, with the self-inhaling type dry powder inhalers shown later as Embodiments 2, 3 and 4, a mechanism is adopted in which air flowing in from an air introduction flow path 17 applies an impact to the freeze-dried cake, and then the resulting fine particles are discharged from a suction flow path 16; the bores of the air introduction flow path 17 and the suction flow path 16 thus stipulate the flow rate of the air flowing through the paths. The air speed applied to the freeze-dried composition in the vessel can thus be calculated by measuring the flow rate of the air flowing through the air introduction flow path 17 and dividing this by the cross-sectional area of the air introduction flow path 17. Air speed (cm/sec)=air flow rate (ml=cm.sup.3/sec)+cross-sectional area of air introduction flow path 17 (cm.sup.2)

Specifically, the flow rate of the air flowing through the air introduction flow path 17 can be measured by installing the dry powder inhaler including the vessel in the slot part of apparatus A (a twin impinger: manufactured by Copley, UK) as mentioned in the European Pharmacopoeia (Third Edition Supplement 2001, p 113-115), and using a flow meter (KOFLOC DPM-3).

For example, with a self-inhaling type dry powder inhaler designed such that the bore of the air introduction flow path 17 is 1.99 mm and the bore of the suction flow path is 1.99 mm, in the case that the air flow rate flowing through the air introduction flow path 17 measured using the flow meter (KOFLOC DPM-3) was 17.7 L/min, i.e. 295 ml/sec, the air speed can be obtained by dividing this value by the cross-sectional area of the air introduction flow path 17 (0.0995.times.0.0995.times.3.14=0.0311 cm.sup.2) (9,486 cm/sec, i.e. 95 m/sec).

Moreover, at least 17 ml/sec can be given as an example of the flow rate of the air applied to the freeze-dried composition filled in the vessel. The air flow rate is preferably at least 20 ml/sec, more preferably at least 25 ml/sec. Here there is no particular limitation on the upper limit of the air flow rate, but an example of 900 L/min can be given. This upper limit is preferably 15 L/sec, more preferably 10 L/sec, yet more preferably 5 L/sec, still more preferably 4 L/sec, particularly preferably 3 L/sec. Specifically, the flow rate should be in a range constituted from a lower limit and an upper limit selected as appropriate from the above, with there being no particular limitation; nevertheless, 17 ml/sec to 15 L/sec, 20 ml/sec to 10 L/sec, 20 ml/sec to 5 L/sec, 20 ml/sec to 4 L/sec, 20 ml/sec to 3 L/sec, and 25 ml/sec to 3 L/sec, can be given as examples of the range.

Moreover, as a member for raising the impact pressure of the air introduced from the outside, the dry powder inhaler used in the present invention can have a mamber for discharging air from a discharge port, as explained in detail below, preferably with a small bore, of a flow path close to the freeze-dried composition housed at the bottom of the vessel, for example a needle part having an air introduction flow path or an air jet flow path as described later in the embodiments. Regarding the bore of the discharge port of the flow path, the preferable range varies according to the size of the vessel and so on, with there being no particular limitations; nevertheless, the bore can be in a range of 0.3 to 10 mm, preferably 0.5 to 5 mm, more preferably 0.8 to 5 mm, much more preferably 1 to 4 mm.

The freeze-dried composition housed in a non-powder form in the vessel can be made into fine particles by introducing air into the vessel. Here, the extent of making into fine particles should be such that the particle diameter is suitable for transpulmonary administration; a particle diameter of 10 .mu.m or less, preferably 5 .mu.m or less, can be given as an example.

The dry powder inhaler for use in the present invention encompasses the specific embodiments defined in the following items:

300. A dry powder inhaler for transpulmonary administration used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles by an air impact, and administering the resulting fine particles to a user by inhalation.

301. The dry powder inhaler for transpulmonary administration according to item 300, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of said needle part, and an inhalation port that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals up said vessel is pierced by said needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of said vessel, and air is jetted into said vessel through said air jet flow path using said air pressure-feeding member, thus pulverizing said freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained from the inhalation port via said discharge flow path.

302. The dry powder inhaler for transpulmonary administration according to item 300, being a device used for pulverizing a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with said suction flow path,

and characterized by being constituted such that, in a state in which a stopper sealing up said vessel has been pierced by said needle parts, through the inhalation pressure of the user, air in said vessel is inhaled from said inhalation port, and at the same time outside air flows into said vessel, at a negative pressure, through said air introduction flow path, and as a result said freeze-dried composition is pulverized into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through said suction flow path.

303. The dry powder inhaler for transpulmonary administration according to item 301, characterized by being constituted such that said freeze-dried composition is pulverized into fine particles and discharged from said inhalation port through jetting air into said vessel once.

304. The dry powder inhaler for transpulmonary administration according to item 301, characterized by being constituted such that said freeze-dried composition is pulverized into fine particles, such that the mean particle diameter is 10 microns or less or the fine particle fraction is 10% or more, and discharged from said inhalation port through jetting air into said vessel.

305. The dry powder inhaler for transpulmonary administration according to item 301, wherein said air jet flow path and said discharge flow path are formed in a single needle part.

306. The dry powder inhaler for transpulmonary administration according to item 302, characterized by being constituted such that said freeze-dried composition is pulverized into fine particles and discharged from said inhalation port through one inhalation of the user.

307. The dry powder inhaler for transpulmonary administration according to item 302, characterized by being constituted such that said freeze-dried composition is pulverized into fine particles, such that the mean particle diameter is 10 microns or less or the fine particle fraction is 10% or more, and discharged from said inhalation port through inhalation of the user.

308. The dry powder inhaler for transpulmonary administration according to item 302, wherein said suction flow path and said air introduction flow path are formed in a single needle part.

309. The dry powder inhaler for transpulmonary administration according to item 308 comprising:

a holder part for holding a vessel that is sealed up with a stopper and houses a freeze-dried composition in a non-powder cake-like form that will be made into fine particles upon receiving an air impact,

a member for applying an air impact to said freeze-dried composition in said vessel, and sucking said freeze-dried composition in a powder-form that has been made into fine particles by the air impact out from said vessel,

a needle part having a suction flow path for sucking said freeze-dried composition out from said vessel, and an air introduction flow path for introducing outside air into said vessel,

a suction port that communicates with said suction flow path of said needle part,

a guide part for guiding said holder part in the axial direction of said needle part,

a holder operating part that has a mechanism part for, when said vessel is held by said holder part, advancing the vessel towards a needle tip of said needle part to pierce the stopper of the vessel with said needle tip, and retreating the vessel from said needle tip to separate the stopper of the vessel from said needle tip, and an operator that operates the mechanism part, and is constituted such that said operating member can be operated with a force smaller than the force necessary for the mechanism part to pierce the stopper of the vessel with said needle part,

and a housing that supports said needle part and is for providing said suction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has been pierced by said needle part to communicate the suction flow path and the air introduction flow path of said needle part with the inside of said vessel and position the tip of the air introduction flow path at said freeze-dried composition, through the inhalation pressure of a user, air in said vessel is inhaled from said suction port, and air is made to flow into said vessel through the air introduction flow path, thus applying an air impact to the freeze-dried composition in said vessel.

310. The dry powder inhaler for transpulmonary administration according to Item 309, characterized in that said housing is formed in a tubular shape, said suction port is formed at a tip part of the housing, a housing chamber for housing said vessel via said holder is formed in said housing, said needle part is disposed in said housing such that said needle tip points towards said housing chamber, and an introduction port for introducing outside air that communicates with the air introduction flow path of said needle part is provided in a wall of said housing,

and the dry powder inhaler is constituted such that said holder part is advanced and retreated in the axial direction of said housing in said housing chamber using said holder operating part.

311. The dry powder inhaler for transpulmonary administration according to item 310, characterized in that said housing is formed from a housing main body having a removal/insertion port for said vessel formed therein in a position in which said holder part is retreated, and a lid for said removal/insertion port that is connected to said housing main body by a hinge,

and the dry powder inhaler is constituted such that said holder operating part has said mechanism part which advances said holder part towards the needle tip of the needle part when said lid is pushed down to close said removal/insertion port, and retreats said holder part away from said needle tip when said lid is lifted up to open said removal/insertion port, and said lid is used as the operating member of said mechanism part.

(4) Dry Powder Inhalation System for Transpulmonary Administration

The dry powder inhalation system for transpulmonary administration of the present invention is a system that combines a freeze-dried composition having a composition such that, by applying an air impact to the freeze-dried composition which exists in a non-powder form having been freeze-dried in a vessel and not subjected to processing such as pulverization, the freeze-dried composition can be made into fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more in the vessel, and a inhaling device comprising prescribed member. According to this dry powder inhalation system for transpulmonary administration, a user him/herself can prepare the freeze-dried composition which has been provided in a non-powder form into a powdered preparation comprising fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more, which is a preparation suitable for transpulmonary administration, at the time of use (the time of inhalation), and administer (take) the powdered preparation.

To obtain the effects of the dry powder inhalation system for transpulmonary administration effectively, it is important to select the composition of the freeze-dried composition, the inhaling device, the vessel and so on appropriately.

It is preferable to use a freeze-dried composition which is prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and is endowed with the following properties (i) to (iii):

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec.

The detailed description of the composition and preparing method of the freeze-dried composition of the present invention in the above section (1) holds for this section.

The freeze-dried composition is subjected to a freeze-drying process in the vessel and it is to be housed therein. The amount of the freeze-dried composition housed in the vessel is preferably an amount containing a unit dose (single dose) or a plurality of doses, specifically 2 to 3 doses, of the active ingredients. More preferably, it is an amount containing a unit dose (single dose) of the active ingredient. Moreover, the specific amount of the freeze-dried composition to be housed in the vessel will vary according to the type and content of the active ingredient contained in the freeze-dried composition, and is selected as appropriate from amounts that can be inhaled, with there being no particular limitation; nevertheless, the amount is generally 30 mg or less, preferably 20 mg or less, more preferably 10 mg or less, particularly preferably 5 mg or less.

As the dry powder inhaler, it is preferable to adopt a device comprising {circle around (1)} a member for applying an air impact (or a member for introducing air) and {circle around (2)} a member for discharging fine particles (or a member for administering by inhalation), in which, by a member for introducing air (member {circle around (1)}) air is introduced into (inflow) a vessel which houses the non-powder-form freeze-dried composition and the freeze-dried composition is pulverized into fine particles using the impact (jet pressure) of the air that has been introduced into (flowed into) the vessel, and then, using the member {circle around (2)} for discharging fine particles, the dried powder composition made into fine particles by the member {circle around (1)} is discharged from the vessel. Then, the fine particles are directly administered to a user.

An example of such device is the dry powder inhaler of the present invention mentioned in the section (3).

The dry powder inhalation system suitable for transpulmonary administration according to the present invention includes a vessel housing the freeze-dried composition of the present invention and a dry powder inhaler of the present invention used in combination at the time of inhalation. In other words, the dry powder inhalation system of the present invention, at least when used for inhalation, comprises the vessel housing the freeze-dried composition of the present invention and the dry powder inhaler of the present invention.

According to the system of the present invention, by introducing air into the vessel housing the freeze-dried composition of the present invention using the dry powder inhaler for applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition in the vessel. Thus, a dry powdered preparation having a particle size suitable for transpulmonary administration by inhalation or having fine particle fraction usable efficiently for transpulmonary administration by inhalation can be obtained.

Examples of the particle diameter suitable for transpulmonary administration by inhalation include the mean particle diameter, more specifically, an aerodynamic mean particle diameter (mass median aerodynamic diameter, MMAD) is 10 microns or less, preferably 5 microns or less. The effective particle proportion (fine particle fraction) used efficiently for transpulmonary administration by inhalation is at least 10%, preferably at least 20%, more preferably 25%, yet more preferably at least 30%, and in particular preferably at least 35%.

Furthermore, the system allows transpulmonary administration of the obtained dry powdered preparation directly to a user by inhalation. Therefore, the dry powder inhalation system for transpulmonary administration of the present invention is a system for producing a dry powdered preparation suitable for transpulmonary administration and, at the same time, a system for transpulmonarily administering the dry powder preparation to a user.

The dry powder inhalation system for transpulmonary administration of the present invention encompasses the specific embodiments defined in the following items:

401. A dry powder inhalation system for transpulmonary administration, using a combination of:

(1) a vessel housing a freeze-dried composition that is prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and has the following properties: (i) a non-powder cake-like form, (ii) a disintegration index of 0.05 or more, and (iii) a property of becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and

(2) a device comprising a member capable of applying said air impact to the freeze-dried composition in said vessel, and a member for discharging the powder-form freeze-dried composition that has been made into fine particles.

402. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the vessel housing the freeze-dried composition contains active ingredients of a single dose.

403. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the vessel and the device are used in combination at the time of inhalation.

404. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the disintegration index of the freeze-dried composition is in a range of 0.05 to 1.5.

405. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the air impact of (iii) is generated by air having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

406. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the air impact of (iii) is generated by air having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

407. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the air impact of (iii) is generated by air having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

408. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the air impact of (iii) is generated by air having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

409. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the freeze-dried composition has a property of becoming fine particles having a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more upon receipt of an air impact.

410. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient.

411. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient.

412. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the freeze-dried composition contains a nucleic acid as an active ingredient with held in the holder.

413. The dry powder inhalation system for transpulmonary administration according to item 310, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

414. The dry powder inhalation system for transpulmonary administration according to item 411, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

415. The dry powder inhalation system for transpulmonary administration according to item 413, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

416. The dry powder inhalation system for transpulmonary administration according to item 414, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

417. The dry powder inhalation system for transpulmonary administration according to item 401, wherein the freeze-dried composition is a water-soluble composition.

418. The dry powder inhalation system for transpulmonary administration according to item 301, wherein the device is:

i) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having an air jet flow path, a needle part having a discharge flow path, air pressure-feeding member for feeding air into the air jet flow path of said needle part, and an inhalation port that communicates with the discharge flow path of said needle part,

and characterized by being constituted such that a stopper that seals up said vessel is pierced by said needle parts, thus communicating the air jet flow path and the discharge flow path with the inside of said vessel, and air is jetted into said vessel through said air jet flow path using said air pressure-feeding member, thus pulverizing said freeze-dried composition into fine particles by the impact of the jetted air, and discharging the fine particles obtained from the inhalation port via said discharge flow path, or

ii) a dry powder inhaler for transpulmonary administration, being a device used for making a freeze-dried composition that has been housed in non-powder form in a vessel into fine particles, and administering the resulting fine particles to a user by inhalation,

comprising a needle part having a suction flow path, a needle part having an air introduction flow path, and an inhalation port that communicates with said suction flow path,

and characterized by being constituted such that, in a state in which a stopper sealing up said vessel has been pierced by said needle parts, through the inhalation pressure of the user, air in said vessel is inhaled from said inhalation port, and at the same time outside air flows into said vessel, at a negative pressure, through said air introduction flow path, and as a result said freeze-dried composition is pulverized into fine particles by the impact of the air flowing in, and the fine particles obtained are discharged from the inhalation port through said suction flow path.

419. The dry powder inhalation system for transpulmonary administration according to item 418, as the device, using the dry powder inhaler comprising:

a holder part for holding a vessel that is sealed up with a stopper and houses a freeze-dried composition in a non-powder cake-like form that will be made into fine particles upon receiving an air impact,

a member for applying an air impact to said freeze-dried composition in said vessel, and sucking said freeze-dried composition in a powder-form that has been made into fine particles by the air impact out from said vessel,

a needle part having a auction flow path for sucking said freeze-dried composition out from said vessel, and an air introduction flow path for introducing outside air into said vessel,

a suction port that communicates with said suction flow path of said needle part,

a guide part for guiding said holder part in the axial direction of said needle part,

a holder operating part that has a mechanism part for, when said vessel is held by said holder part, advancing the vessel towards a needle tip of said needle part to pierce the stopper of the vessel with said needle tip, and retreating the vessel from said needle tip to separate the stopper of the vessel from said needle tip, and an operator that operates the mechanism part, and is constituted such that said operating member can be operated with a force smaller than the force necessary for the mechanism part to pierce the stopper of the vessel with said needle part,

and a housing that supports said needle part and is for providing said suction port, said guide part and said holder operating part,

and constituted such that, in a state in which said stopper has been pierced by said needle part to communicate the suction flow path and the air introduction flow path of said needle part with the inside of said vessel and position the tip of the air introduction flow path at said freeze-dried composition, through the inhalation pressure of a user, air in said vessel is inhaled from said suction port, and air is made to flow into said vessel through the air introduction flow path, thus applying an air impact to the freeze-dried composition in said vessel.

420. The dry powder inhalation system for transpulmonary administration according to item 401, using a combination of:

(1) a vessel housing a freeze-dried composition that is prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form, and has the following properties: (i) a non-powder cake-like form, (ii) a disintegration index in a range of 0.05 to 1.5, and (iii) a property of becoming fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec; and

(2) a device comprising a member capable of applying said air impact to the freeze-dried composition in said vessel, and a member for discharging the powder-form freeze-dried composition that has been made Into fine particles.

421. The dry powder inhalation system for transpulmonary administration according to item 420, wherein the vessel housing the freeze-dried composition housing a freeze-dried composition containing a single dose of active ingredient.

422. The dry powder inhalation system for transpulmonary administration according to item 420, wherein the air speed is 1 to 250 m/sec.

423. The dry powder inhalation system for transpulmonary administration according to item 420, wherein the air flow rate is 20 ml/sec to 10 L/sec.

(5) Transpulmonary Administration Method

The present invention further provides a transpulmonary administration method comprising making a freeze-dried composition in a non-powder form into fine particles suitable for transpulmonary administration at the time of usage (administration), and administering the resulting preparation in a powder form with fine particles by inhalation. The transpulmonary administration method can be carried out using the dry powder inhalation system for transpulmonary administration of the present invention described in detail in the section (4), and preferably using the dry powder inhalation system for transpulmonary administration comprising the vessel which houses the freeze-dried composition of the present invention described in detail in the section (1), which is prepared by freeze-drying the composition liquid containing ingredients in the non-dissolved form and a dry powder inhaler described in the section (3).

The transpulmonary administration method of the present invention encompasses the specific embodiments defined in the following items:

501. A transpulmonary administration method comprising:

making a freeze-dried composition into fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more by applying an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec to the freeze-dried composition at the time of use, and

administering the resulting fine particle powder to a user by inhalation;

the freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and having the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of the air impact.

502. The transpulmonary administration method according to item 501, wherein the freeze-dried composition contains a single dose of active ingredients.

503. The transpulmonary administration method according to item 501, wherein the freeze-dried composition is housed in a vessel, and the fine particle powder are made using a device comprising a member capable of applying the air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel.

504. The transpulmonary administration method according to item 503, wherein the disintegration index of the freeze-dried composition is in the range of 0.05 to 1.5.

505. The transpulmonary administration method according to item 503, wherein the air impact of (iii) is generated by air having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

506. The transpulmonary administration method according to item 503, wherein the air impact of (iii) is generated by air having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

507. The transpulmonary administration method according to item 503, wherein the air impact of (iii) is generated by air having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

508. The transpulmonary administration method according to item 503, wherein the air impact of (iii) is generated by air having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

509. The transpulmonary administration method according to item 503, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient.

510. The transpulmonary administration method according to item 503, wherein the freeze-dried composition contains a high-molecular-weight drug such as a protein, a nucleic acid or the like as the active ingredient.

511. The transpulmonary administration method according to item 503, wherein the freeze-dried composition contains a nucleic acid as the active ingredient with held in the holder.

512. The transpulmonary administration method according to item 509, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

513. The transpulmonary administration method according to item 510, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

514. The transpulmonary administration method according to item 512, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

515. The transpulmonary administration method according to item 513, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

516. The transpulmonary administration method according to Item 503, wherein the freeze-dried composition is a water-soluble composition.

517. The transpulmonary administration method according to item 503, being a method of making into fine particles and administering such that the fine particles have a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more.

518. The transpulmonary administration method according to item 503, using the dry powder inhaler of item 301 or 302 shown in the section of (1) Dry powder inhaler as the device.

519. The transpulmonary administration method according to item 518, using the dry powder inhaler of item 309 shown in the section of (3) Dry powder inhaler as the device.

520. The transpulmonary administration method according to item 503, wherein the freeze-dried composition has the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index in a range of 0.05 to 1.5, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec,

and the fine particles are made using a dry powder inhaler comprising a member capable of applying said air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel.

521. The transpulmonary administration method according to item 520, wherein the air speed is 1 to 250 m/sec.

522. The transpulmonary administration method according to item 520, wherein the air flow rate is 20 ml/sec to 10 L/sec.

(6) Use of a Freeze-Dried Composition for Transpulmonary Administration by Inhalation

The present invention also provides use of a freeze-dried composition in a non-powder form for the transpulmonary administration by inhalation. The use encompasses the specific embodiments defined in the following items:

601. Use of a freeze-dried composition for transpulmonary administration by inhalation,

the freeze-dried composition prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and having the following properties:

(i) has a non-powder cake-like form,

(ii) has a disintegration index of 0.05 or more, and

(iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, and being used by forming into fine particles having said mean particle diameter or said fine particle fraction.

602. The use of a freeze-dried composition for transpulmonary administration according to item 601, wherein the freeze-dried composition contains the active ingredient of a single dose.

603. The use of a freeze-dried composition for transpulmonary administration according to item 601, wherein the freeze-dried composition is housed in a vessel, and the fine particles are made using a device comprising a member capable of applying the air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel.

604. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the disintegration index of the freeze-dried composition is in the range of 0.05 to 1.5.

605. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

606. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

607. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

608. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

609. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more upon receiving an air impact.

610. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient.

611. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient.

612. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition contains a nucleic acid as the active ingredient with held in the holder.

613. The use of a freeze-dried composition for transpulmonary administration according to item 610, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

614. The use of a freeze-dried composition for transpulmonary administration according to item 611, wherein the freeze-dried composition contains a high-molecular-weight drug such as a protein, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

615. The use of a freeze-dried composition for transpulmonary administration according to item 613, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

616. The use of a freeze-dried composition for transpulmonary administration according to item 614, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

617. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition is a water-soluble composition.

618. The use of a freeze-dried composition for transpulmonary administration according to item 603, using the dry powder inhaler of item 301 or 302 shown in the section of (3) Dry powder inhaler as the device.

619. The use of a freeze-dried composition for transpulmonary administration according to item 618, using the dry powder inhaler of item 109 shown in the section of (3) Dry powder inhaler as the device.

620. The use of a freeze-dried composition for transpulmonary administration according to item 603, wherein the freeze-dried composition which is prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form and has the following properties: (i) has a non-powder cake-like form, (ii) has a disintegration index in a range of 0.05 to 1.5, and (iii) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec, and the fine particles are made using a device comprising a member capable of applying the air impact to the freeze-dried composition in the vessel and a member for discharging the resulting fine particle powder-form freeze-dried composition out of the vessel.

621. The use of a freeze-dried composition in transpulmonary administration according to item 620, wherein the air speed is 1 to 250 m/sec.

622. The use of a freeze-dried composition in transpulmonary administration according to item 620, wherein the air flow rate is 20 mi/sec to 10 L/sec.

(7) Use of a Freeze-dried Composition For Manufacture of a Dry Powdered Preparation for Transpulmonary Administration by Inhalation

Furthermore, the present invention provides use of a freeze-dried composition in a non-powder form for manufacture of a dry powdered preparation for transpulmonary administration by inhalation. The use encompasses the specific embodiments defined in the following items:

701. Use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration by inhalation,

the freeze-dried composition having the following properties: (i) prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form, (ii) has a non-powder cake-like form, (iii) has a disintegration index of 0.05 or more, and (iv) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec, and being used by forming into fine particles having said mean particle diameter or said fine particle fraction at the time of use.

702. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition contains the active ingredient of a single dose.

703. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the disintegration index of the freeze-dried composition is in the range of 0.05 to 1.5.

704. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to Item 701, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 2 m/sec and an air flow rate of at least 17 ml/sec.

705. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate of at least 17 ml/sec.

706. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 20 ml/sec.

707. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receipt of an air impact having an air speed of at least 1 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

708. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition becomes fine particles having a mean particle diameter of 5 microns or less or a fine particle fraction of 20% or more upon receipt of an air impact.

709. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition contains a low-molecular-weight drug as an active ingredient.

710. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as an active ingredient.

711. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition contains a nucleic acid as the active ingredient with held in the holder.

712. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

713. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 710, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of amino acids, dipeptides, tripeptides, and saccharides as a carrier.

714. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 712, wherein the freeze-dried composition contains a low-molecular-weight drug as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

715. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 713, wherein the freeze-dried composition contains a high-molecular-weight drug such as proteins, a nucleic acid or the like as the active ingredient, and at least one selected from the group consisting of hydrophobic amino acids, hydrophobic dipeptides, and hydrophobic tripeptides as the carrier.

716. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition is a water-soluble composition.

717. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the mean particle diameter of the fine particles of the powdered preparation for transpulmonary administration is 5 microns or less or the fine particle fraction of the fine particles is 20% or more.

718. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, wherein the freeze-dried composition is housed in a vessel, and the fine particles are prepared by using a device comprising a member for applying a prescribed air impact to the freeze-dried composition housed in the vessel and a member for discharging the resulting fine particle powder form freeze-dried composition out of the vessel.

719. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration of item 718, using the dry powder inhaler according to item 301 or 302 shown in the section of (3) Dry powder inhaler as the device.

720. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 719, using the dry powder inhaler of item 309 shown in the section of (3) Dry powder inhaler as the device.

721. The use of a freeze-dried composition for manufacture of a dry powdered preparation for transpulmonary administration according to item 701, using the freeze-dried composition having the following properties:

(i) prepared by freeze-drying a composition liquid containing ingredients in the non-dissolved form,

(ii) has a non-powder cake-like form,

(iii) has a disintegration index in a range of 0.05 to 1.5. and

(iv) becomes fine particles having a mean particle diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed in a range of 1 to 300 m/sec and an air flow rate in a range of 17 ml/sec to 15 L/sec.

722. The use of a freeze-dried composition for manufacture of a powdered preparation for transpulmonary administration according to item 721, wherein the air speed is 1 to 250 m/sec.

723. The use of a freeze-dried composition for manufacture of a powdered preparation for transpulmonary administration according to item 721, wherein the air flow rate is 20 ml/sec to 10 L/sec.

(8) Use of a Composition Liquid Containing Ingredients in the Non-Dissolved Form for Manufacture of a Freeze-Dried Powdered Composition for Preparing a Dry Powder Preparation for Transpulmonary Administration

Furthermore, the present invention relates to a use of a composition liquid containing ingredients in the non-dissolved form for manufacture of a freeze-dried powdered composition for preparing a dry powder preparation for transpulmonary administration.

It should be noted that the composition in the non-dissolved form containing ingredients for manufacture of a freeze-dried composition, a preparation method thereof, a preparation method of a freeze-dried composition using the same, a method of using the freeze-dried composition obtained (a preparation method of a freeze-dried preparation for transpulmonary administration) are as described in the above.

 

Claim 1 of 4 Claims

1. A dry powder inhalation system for transpulmonary administration, comprising: (1) a vessel housing a freeze-dried composition in non-powder cake form prepared by freeze-drying a liquid composition containing ingredients in a non-dissolved form, and has: (i) a disintegration index of 0.05 or more, and (ii) a property of becoming fine particles having a mass median aerodynamic diameter of 10 microns or less or a fine particle fraction of 10% or more upon receiving an air impact having an air speed of at least 1 m/sec and an air flow rate of at least 17 ml/sec; and (2) a device comprising a member capable of applying said air impact to the freeze-dried composition in said vessel, and a member for discharging the freeze-dried composition that has been made into fine particles.

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