TH43598B - Dry powder inhalation system for pulmonary dosing - Google Patents

Abstract

DC60 (09/09/45) This invention provides a novel dry powder inhalation system suitable for intrapulmonary drug delivery. The dry powder inhalation system of this invention is characterized by the use of the following components: a tube containing a freeze-dried mixture of the active ingredient in a single-dose dose and having: (1) a non-powdered cake-like form; (2) a disintegration index of 0.015 or greater; and (3) the property of particleization with an average particle diameter of 10 µm or less or a fine particle content of 10% or greater when subjected to an air shock of at least 1 m/s and an airflow rate of at least 17 mL/s; and a device incorporating a pathway capable of applying the air shock to the freeze-dried mixture in the tube and a pathway for the discharge of the freeze-dried powder mixture. This invention provides a novel dry powder inhalation system suitable for intrapulmonary drug delivery. The dry powder inhalation system of this invention is characterized by the use of the following components: a tube containing a freeze-dried mixture of the active ingredient in a single-dose dose and having: (1) a non-powdered cake-like form; (2) a disintegration index of 0.015 or greater; and (3) the property of being finely particleized with an average particle diameter of 10 µm or less or a fine particle content of 10% or greater when subjected to an air shock with an air velocity of at least 1 m/s and an airflow rate of at least 17 mL/s; and a device incorporating a pathway capable of applying the air shock to the freeze-dried mixture in the tube and a pathway for the discharge of the finely particleized freeze-dried powder mixture.

Claims (63)

1. Dry powder inhalation system for intrapulmonary drug delivery which uses the following components: (1) a tube containing a freeze-dried mixture containing a single dose of the main drug and having: (i) a cake-like form, not a powder; (ii) a disintegration index of 0.015 or greater; and (iii) the property of particleization with an average particle diameter of 10 µm or less, or a fine particle content of 10% or greater when subjected to an air shock with an air velocity of at least 1 m/s and an airflow rate of at least 17 mL/s; and (2) a device incorporating a pathway capable of applying the air shock to the freeze-dried mixture in the tube and a pathway for the discharge of the freeze-dried powder mixture which has been particleized. 2. A dry powder inhalation system for intrapulmonary drug delivery under claim 1, in which the tube and device shall be used in conjunction at the time of inhalation. 3. Dry powder inhalation system for intrapulmonary drug delivery under Reputation 1, where the dispersion index of the freeze-dried mixture is 0.02 or greater. 4. A dry powder inhalation system for intrapulmonary drug delivery according to claim 1, which shall generate an air shock of the properties according to (iii) by air with an air velocity of at least 2 m/s and an air flow rate of at least 17 ml/s. 5. A dry powder inhalation system for intrapulmonary drug delivery according to claim 1, which shall generate an air shock of the properties according to (iii) by air with an air velocity of at least 1 m/s and an air flow rate of at least 20 ml/s. 6. A freeze-dried powder inhalation system for intrapulmonary drug delivery under Reputation 1, whereby the freeze-dried mixture shall have the property of becoming fine particles with an average particle diameter of 5 microns or less, or a fine particle content of 20% or more upon air impact. 7. A dry powder inhalation system for intrapulmonary drug delivery under Patent 1, in which the freeze-dried mixture contains a low molecular weight synthetic drug as the main active ingredient. 8. A freeze-dried powder inhalation system for intrapulmonary drug delivery under claim 1, in which the freeze-dried mixture contains a high molecular weight drug as the main active ingredient. 9. Dry powder inhalation system for intrapulmonary drug delivery under claim 1, whereby this device is i) a dry powder inhalation device for intrapulmonary drug delivery for use in breaking down a freeze-dried mixture contained in a non-powder form in a vial into fine particles and causing the user to inhale these fine particles, consisting of a needle element with an air jet trajectory, a needle element with an exhaust trajectory, a pressurized air feed path for feeding air into the air jet trajectory of the said needle element, and an inhalation channel in contact with the exhaust trajectory of the said needle element, which is established in such a way that it pierces the stopper sealing the vial by the said needle element, thus bringing the air jet trajectory and exhaust trajectory into contact with the inside of the vial and injecting air into the vial through the said air jet trajectory using the said pressurized air feed path, thus breaking down the freeze-dried mixture into fine particles by the impact force of the injected air and releasing these fine particles through the said exhaust trajectory; or ii) A dry powder inhalation device for intrapulmonary administration for the purpose of breaking down a freeze-dried mixture contained in a non-powder form in a vial into fine particles and causing the inhalation of these fine particles. It consists of a needle element with an aspiration flow path, a needle element with an air intake flow path, and an inhalation channel in contact with the aspiration flow path, and is constructed such that, in a state where the stopper sealing the vial is pierced by the needle element, through the user's inhalation pressure, air in the vial is inhaled through the inhalation channel, and at the same time, outside air, which is then at a lower than atmospheric pressure, flows into the vial through the air intake flow path, and the effect of the impact force of the incoming air is to break down the freeze-dried mixture into fine particles, and these fine particles are released from the inhalation channel through the aspiration flow path. 10. A freeze-dried powder vaporization system for pulmonary drug administration under claim 1, which shall consist of: (1) a tube containing a freeze-dried mixture of the active ingredient in a single dose and having: (i) a cake-like form, not a powder; (ii) a disintegration index in the range of 0.015 to 1.5; and (iii) the property of particleization with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity in the range of 1 to 300 m/s and an air flow rate in the range of 17 µl/s to 15 liters/s; and (2) a device incorporating a pathway capable of applying the aforementioned air shock to the freeze-dried mixture in the tube and a pathway for the discharge of the freeze-dried mixture in the particleized form. 11. Freeze-dried mixtures for transdermal drug delivery that meet the following (i) to (iii) properties: (i) have a cake-like, non-powdered form; (ii) have a disintegration index of 0.015 or greater; and (iii) become fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or greater when subjected to an air shock with an air velocity of at least 1 m/s and an air flow rate of at least 17 ml/min. 12. Freeze-dried mixtures pursuant to claim 11 where the dispersion index is 0.02 or greater. 13. Freeze-dried mixtures under claim 11 where the dispersion index is 0.015 to 1.5. 14. A freeze-dried mixture under claim 11 that becomes fine particles with an average particle diameter of 10 microns or less, or contains 10% or more fine particles, when subjected to an air shock with an air velocity of at least 2 m/s and an air flow rate of at least 17 ml/s. 15. A freeze-dried mixture under claim 11 that becomes fine particles with an average particle diameter of 10 microns or less, or contains 10% or more fine particles, when subjected to an air shock with an air velocity of at least 1 m/s and an air flow rate of at least 20 ml/s. 16. A freeze-dried mixture under claim 11 that becomes fine particles with an average particle diameter of 5 microns or less, or contains 20% or more fine particles upon this air shock. 17. A freeze-dried mixture pursuant to claim 11 containing a low molecular weight synthetic drug as the main active ingredient. 18. Freeze-dried mixtures pursuant to claim paragraph 11, in which a high molecular weight drug is the main active ingredient. 19. A freeze-dried mixture pursuant to claim 18 containing a high molecular weight drug as the main drug and at least one selected carrier compound consisting of amino acids, diphthongs, tripeptides, and saccharides. 20. A freeze-dried mixture under claim 11, which is a freeze-dried mixture for pulmonary administration, which has the following properties (i) to (iii): (i) a cake-like form, not a powder; (ii) a disintegration index in the range of 0.015 to 1.5; and (iii) a fine particle with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity in the range of 1 to 300 m/s and an airflow rate in the range of 17 mL/s to 15 L/s. 21. A dry powder inhalation device for intrapulmonary drug delivery which is used to break down a freeze-dried mixture, packaged in a non-powder form in a vial, into fine particles by air impact, causing the user to inhale these fine particles. 22. A dry powder inhalation device for intrapulmonary drug delivery under claim 21, which is a device for the atomization of a freeze-dried mixture contained in a non-powder form in a vial into fine particles and causing the user to inhale these fine particles, and which consists of a needle element with an air jet trajectory, a needle element with an outlet trajectory, a pressurized air feed path for supplying air to the air jet trajectory of the said needle element, and an inhalation channel in contact with the outlet trajectory of the said needle element, and which is established in such a way that it pierces the stopper sealing the vial by the said needle element, thus bringing the air jet trajectory and outlet trajectories into contact with the inside of the vial, and spraying air into the vial through the air jet trajectory using the pressurized air feed path, thus atomizing the freeze-dried mixture into fine particles by impact of the sprayed air, and releasing these fine particles from the inhalation channel through the outlet trajectory. 23. A dry inhalation device for intrapulmonary drug delivery under claim 21, which is used for the breakdown of a freeze-dried mixture contained in a non-powder form in a vial into fine particles and causing the user to inhale these fine particles, consists of a needle element with an aspiration flow path, a needle element with an air intake flow path, and an inhalation channel in contact with the aspiration flow path, and is designed in such a way that, in a state where the stopper sealing the vial is pierced by the needle element, through the user's inhalation pressure, air in the vial is inhaled through the inhalation channel, and at the same time, outside air, which is at a pressure lower than atmospheric pressure, flows into the vial through the air intake flow path, and the effect of the impact force of the incoming air is to break down the freeze-dried mixture into fine particles, and these fine particles are released from the inhalation channel through the aspiration flow path. 24. Powder inhalation device for intrapulmonary drug delivery pursuant to claim paragraph 23, where the atomizing and discharge flow paths are formed in a single-piece needle element. 25. Powder inhalation device for intrapulmonary drug delivery pursuant to claim 24, which is a powder inhalation device incorporating a clamping element for holding a sealed tube containing a freeze-dried mixture in a non-powdered cake-like form which is atomized by air impact, and a pathway for the application of the air impact to the freeze-dried mixture in the tube and for the aspiration of the freeze-dried mixture in powder form which has been atomized by the air impact; the tube incorporating a needle element with a suction flow path for drawing the freeze-dried mixture out of the tube and an air intake path for introducing external air into the tube; a suction channel in contact with the suction flow path of the needle element; a guiding element for guiding the clamp element in the axial direction of the needle element; and a control element of the clamp element which contains a mechanism for moving the tube forward toward the tip of the needle element to pierce the seal of the tube. The tip of the needle, when held in place by the clamping component and retracted, separates the tube from the tip of the needle and the control assembly. This allows the mechanism to operate with less force than required to pierce the tube cap. The rigid component and the cover supporting the needle and providing the suction channel, guide component, and control assembly are positioned so that, in the state where the cap is pierced by the needle, the suction and intake trajectories of the needle are in contact with the inside of the tube. The tip of the intake trajectory is positioned at the freeze-dried mixture. Through the inhalation pressure of the test subject, air is inhaled from the suction channel and flows into the tube through the intake trajectory. Thus, the air shock is applied to the freeze-dried mixture in the tube. 26. The method for producing a finished powdered drug for intrapulmonary administration includes: introducing air into a tube to actuate the freeze-dried mixture with an air shock force at an air velocity of at least 1 m/s and an air flow rate of at least 17 ml/s using a device capable of applying such air shock force to the freeze-dried mixture in the tube. This results in the freeze-dried mixture being condensed into fine particles with an average particle diameter of 10 µm or less, or with a fine particle content of 10% or more. The resulting freeze-dried mixture has a single-dose dose of the main drug and possesses the following properties: (i) a cake-like consistency, not a powder; (ii) a disintegration index of 0.015 or more; and (iii) condensation into fine particles with an average particle diameter of 10 µm or less, or with a fine particle content of 10% or more upon administration. This air impact 27. A method for the production of a dry powder drug for intrapulmonary administration under claim 26, in which the prepared particles shall have an average particle diameter of 5 microns or less, or shall contain 20% or more fine particles. 28. Method for the production of a dry powdered drug for pulmonary administration under claim 26, where the disintegration index of the dried membrane mixture is 0.02 or greater. 29. A method for the production of a freeze-dried powdered drug for intrapulmonary administration under Patent 26, in which the freeze-dried mixture contains a low molecular weight synthetic drug as the main active ingredient. 30. Method for the manufacture of a freeze-dried powdered drug for intrapulmonary administration under Patent 26, in which the freeze-dried mixture contains a high molecular weight drug as the main active ingredient. 31. The method of producing a dry powder drug for intrapulmonary administration under claim 26, which is carried out using a device with a trajectory capable of delivering an air shock of at least 2 m/s and an airflow rate of at least 17 ml/s to the freeze-dried mixture in this tube, and the introduction of this air shock into the tube containing the freeze-dried mixture. 32. The method of manufacturing a finished dry powder drug for intrapulmonary administration under claim 26, which is carried out using a device with a trajectory capable of delivering an air shock with an air velocity of at least 1 m/s and an air flow rate of at least 20 ml/s to the freeze-dried mixture in this tube, and the introduction of this air shock into the tube containing the freeze-dried mixture. 33. The method for the manufacture of a dry powder drug for intrapulmonary administration under Protection 26, which is characterized by the freeze-drying of the mixture into fine particles using either a dry powder inhalation device under Protection 22 or 23. 34. The method for producing a finished powder drug for intrapulmonary administration according to claim paragraph 26, which includes: the introduction of air into the tube for use in reacting with the freeze-dried mixture by air shock with an air velocity in the range of 1 to 300 m/s and an air flow rate in the range of 17 ml/s to 15 L/s, using an apparatus capable of applying such air shock to the freeze-dried mixture in the tube, thus causing the freeze-dried mixture to become fine particles with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more; in which case the freeze-dried mixture is of the dose-per-administration quantity. The active ingredient has the following properties: (i) it has a cake-like, non-powdery form; (ii) it has a disintegration index in the range of 0.015 to 1.5; and (iii) it breaks down into fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more when subjected to air impact. 35. Method of intrapulmonary administration of the drug, which includes: the atomization of the freeze-dried mixture into fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, by applying an air shock of at least 1 m/s and an airflow rate of at least 17 ml/s to the freeze-dried mixture at the time of administration; and the administration of this atomized powder to the user by inhalation; the freeze-dried mixture contains a single dose of the active ingredient and has the following properties: (i) a cake-like form, not a powder; (ii) a dispersion index in the range of 0.015 or more; and (iii) atomization into fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, upon application of this air shock. 36. The method of intrapulmonary administration pursuant to claim 35, which shall be provided for the freezing-dried mixture to be placed in a vial and for the production of the resulting powder using a device capable of applying air shock to the freezing-dried mixture in the vial, and for the discharge of the resulting powder from the vial. 37. Method of intrapulmonary administration of the drug under claim 36 where the disintegration index of the freeze-dried mixture is 0.02 or greater. 38. Method of administering drugs through the lungs according to claim 36, which will generate an air shock with the properties according to (iii) which is delivered by air with an air velocity of at least 2 m/s and an air flow rate of at least 17 ml/s. 39. Method of administering drugs through the lungs according to claim 36, which will generate an air shock with the properties according to (iii) which is delivered by air with an air velocity of at least 2 m/s and an air flow rate of at least 20 ml/s. 40. A method of intrapulmonary drug administration pursuant to claim 36, in which the freeze-dried mixture contains a low molecular weight synthetic drug as the main active ingredient. 41. A method of intrapulmonary drug administration under claim 36 whereby the freeze-dried mixture contains a high molecular weight synthetic drug as the main active ingredient. 42. The method of administering medication through the lungs under claim 36, where the dry powder inhalation device of either claim 22 or 23 is used. 43. A method of pulmonary administration pursuant to claim 36 whereby the freeze-dried mixture is formed with the following properties: (i) it is in the form of a cake, not a powder; (ii) it has a dispersion index in the range of 0.015 to 1.5; and (iii) it is formed into fine particles with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity in the range of 1 to 300 m/s and an air flow rate in the range of 17 mL/s to 15 L/s, and the resulting fine powder is formed using a device capable of applying this air shock to the freeze-dried mixture in this tube and a route for the discharge of the resulting freeze-dried fine powder mixture from this tube. 44. Use of freeze-dried mixtures for intrapulmonary inhalation of drugs, where the freeze-dried mixture contains a single dose dose of the main drug and has the following properties; (i) it is in a cake-like form, not powder; (ii) it has a disintegration index in the range of 0.015 or more; and (iii) it is formed into fine particles with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity of at least 1 m/s and an airflow rate of at least 17 mL/s, and is administered by such particle formation with such average particle diameter or such fine particle content. 45. Use of freeze-dried mixtures for intrapulmonary administration pursuant to claim 44, whereby the freeze-dried mixture shall be contained in a vial and the resulting powder shall be produced using a device incorporating a path capable of applying air shock to the freeze-dried mixture in the vial and a path for the discharge of the resulting freeze-dried mixture in powder form from the vial. 46. Use of freeze-dried mixtures for intrapulmonary administration under claim 45 where the disintegration index of the freeze-dried mixture is 0.02 or greater. 47. Use of freeze-dried mixtures for intrapulmonary drug administration under claim 45 where such freeze-dried mixture is formed into fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity of at least 2 m/s and an airflow rate of at least 17 ml/s. 48. Use of freeze-dried mixtures for intrapulmonary drug administration under claim 45 whereby the freeze-dried mixture shall become fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, upon contact with an air shock of at least 1 m/s and an airflow rate of at least 20 ml/s. 49. Use of freeze-dried mixtures for intrapulmonary drug administration pursuant to claim 45 where such freeze-dried mixture is reduced to fine particles with an average particle diameter of 5 microns or less, or a fine particle content of 20% or more when subjected to air shock. 50. Use of freeze-dried mixtures for intrapulmonary administration under Response to Clause 45, where such freeze-dried mixture contains a low-molecular-weight synthetic drug as the main active ingredient. 51. Use of freeze-dried mixtures for intrapulmonary drug administration under Response to Clause 45, where such freeze-dried mixture contains a high molecular weight synthetic drug as the main active ingredient. 52. The use of freeze-dried mixtures for drug delivery through a well under claim 45, using a dry powder inhalation device of either claim 22 or 23 as the device. 53. Use of freeze-dried mixtures for intrapulmonary drug administration pursuant to claim paragraph 45 whereby the freeze-dried mixture has the following properties; (i) it has a cake-like form, not a powder; (ii) it has a dispersion index in the range of 0.015 to 1.5; and (iii) it is formed into fine particles with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to an air shock with an air velocity in the range of 1 to 300 m/s and an air flow rate in the range of 17 mL/s to 15 L/s, and the resulting fine powder is formed by using a device with a path capable of applying this air shock to the freeze-dried mixture in this tube and a path for the discharge of the resulting freeze-dried mixture in fine particle powder form from this tube. 54. Use of freeze-dried mixtures for the manufacture of finished powder pharmaceuticals for inhalation, where the freeze-dried mixture has the following properties: (i) a cake-like form, not a powder; (ii) a disintegration index in the range of 0.015 or greater; and (iii) a particle size of an average particle diameter of 10 µm or less, or a fine particle content of 10% or greater, when subjected to an air shock with an air velocity of at least 1 m/s and an air flow rate of at least 17 ml/s, and is used by a particle size of such average particle diameter or such fine particle content at the time of use. 55. Use of freeze-dried mixtures for the manufacture of finished powdered medications for intrapulmonary administration under claim 54, where the disintegration index of the freeze-dried mixture is 0.02 or greater. 56. Use of freeze-dried mixtures for the manufacture of finished powder medications for intrapulmonary administration under claim 54, whereby the freeze-dried mixture shall become fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, upon impact with an air velocity of at least 2 m/s and an air flow rate of at least 17 ml/s. 57. Use of freeze-dried mixtures for the manufacture of finished powder medications for intrapulmonary administration under claim 54, whereby the freeze-dried mixture shall become fine particles with an average particle diameter of 10 microns or less, or a fine particle content of 10% or more, upon impact with an air velocity of at least 1 m/s and an air flow rate of at least 20 ml/s. 58. Use of freeze-dried mixtures for the manufacture of dry pharmaceutical compounds for intrapulmonary administration under claim 54, whereby the freeze-dried mixture shall become fine particles with an average particle diameter of 5 microns or less, or a fine particle content of 20% or more, upon impact with air. 59. Use of freeze-dried mixtures for the manufacture of dry pharmaceutical preparations for intrapulmonary administration under claim 54, whereby these freeze-dried mixtures contain a low-molecular-weight synthetic drug as the main active ingredient. 60. Use of freeze-dried mixtures for the manufacture of finished powdered medications for intrapulmonary administration under claim 54, where the freeze-dried mixture contains a high molecular weight drug as the main active ingredient. 61. Use of freeze-dried mixtures for the production of finished powder medications for intrapulmonary administration under claim 54, where the freeze-dried mixture is packaged in a vial, atomized, and administered to the recipient; an inhalation test using a device capable of delivering an air shock with an air velocity of at least 1 m/s and an airflow rate of at least 17 ml/s to the freeze-dried mixture in the vial at the time of administration; and a discharge pathway for the atomized powder freeze-dried mixture. 62. The use of freeze-dried mixtures for the manufacture of finished powder medications for intrapulmonary administration under claim 61, using a dry powder inhalation device under either claim 22 or 23 as the device. 63. Use of freeze-dried mixtures for the manufacture of finished powdered pharmaceutical products for pulmonary administration under claim 54, whereby the freeze-dried mixture has the following properties: (i) has a cake-like form, not a powder; (ii) has a disintegration index in the range of 0.015 to 1.5; and (iii) is formed into fine particles with an average particle diameter of 10 µm or less, or a fine particle content of 10% or more, when subjected to air shock with an air velocity in the range of 1 to 300 m/s and an air flow rate in the range of 17 ml/s to 15 L/s.