Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
2000-01-12
2001-10-02
Weiss, John G. (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S203230, C128S200140, C128S203220
Reexamination Certificate
active
06295986
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to devices and methods for aerosolizing formulations. More specifically, this invention relates to methods of generating pores in an aerosolization nozzle comprising a membrane.
BACKGROUND OF THE INVENTION
In various areas of technology it is desirable to make use of a thin sheet of material which has an array of regularly spaced, very small holes therein. For example, such might be used in the manufacture of various electronic components. Thin membranes which have one or more holes in them could also be used in the formation of components used in ink jet printers or fuel injectors. A more direct application of such a porous membrane is as a filter. The pore size and pore density could be adjusted to wide range of filter applications. Alternatively, liquid formulations containing a drug could be moved through such a porous member to create an aerosol for inhalation.
Aerosolization is a desirable means for the delivery of therapeutic or diagnostic agents. Aerosol delivery avoids the problems associated with other delivery methods such as oral administration or injection. Injections are painful, present a risk of infection to the health-care provider from an inadvertent needle-stick, and create hazardous waste from the needle and syringe. Additionally, repeated injections can result in scarring. Oral administration must overcome several obstacles to the delivery of agents, including the acidic environment of the stomach, the ability of the agent to pass through the of the intestinal wall, and first-pass metabolism of the agent by the liver. Aerosol delivery, on the other hand, allows the direct delivery of agents to areas such as the nasal tract, the respiratory tract, or the eye, as well as systemic delivery into the circulation by administration to the respiratory tract and uptake into the circulation.
Currently available methods of generating and delivering aerosols to the nasal and respiratory tract include metered-dose inhalers, dry powder inhalers and nebulizers. Available methods of delivering agents to the eye include ointments and eye drops.
Co-owned U.S. Pat. Nos. 5,544,646; 5,718,222; 5,660,166; 5,823,178; 5,709,202; and 5,906,202 describe devices and methods useful in the generation of aerosols suitable for drug delivery. A drug formulation is forcibly applied to one side of a pore-containing membrane so as to produce an aerosol on the exit side of the membrane. Aerosols containing particles with a more uniform size distribution can be generated using such devices and methods, and can be delivered to particular locations within the respiratory tract.
Improved porous membranes for use in such devices would allow more efficient use of formulations, thereby requiring packaging of less formulation, decreasing costs and increasing portability, as well as increasing patient compliance. There is a need for methods of procuding nozzles for use in aerosolization of diagnostic or therapeutic agents.
SUMMARY OF THE INVENTION
The present invention provides an extrusion nozzle that is particularly well suited to extrusion of a formulation into the entraining airstream and delivery of particles having an improved size distribution to the respiratory tract. The nozzles of the invention maximize the conversion of pressure on the formulation container to kinetic energy of the formulation being extruded, and provide aerosol particles of the desired sizes.
The invention further provides a method of forming nozzles for aerosolization of diagnostic and therapeutic agents that allows unique control of the nozzle size and shape. The method generally comprises treating a membrane so as to form pores to a certain depth in the membrane, and further treating the membrane with a plasma, thereby further forming the pores.
The pores are preferably formed using a UV excimer laser having a wavelength of from about 150 nm to about 360 nm. The plasma is preferably an oxygen and argon plasma generated using radiofrequency energy source in a power range of from about 200 to about 800 watts.
In one embodiment, the nozzles are formed completely through the material prior to plasma treatment. In another embodiment, the nozzles are initially formed so that a thin layer remains covering the exit side of the nozzle. This layer can be removed during plasma treatment, or can be burst outwards upon administration of a formulation at a pressure substantially below that which would rupture the remainder of the membrane.
In one aspect of the invention, a method of producing a nozzle for aerosolizing a formulation is provided wherein from about 200 to about 1,000 holes are formed per square millimeter. In a particular embodiment, holes having an average relaxed exit aperture diameter of from about 0.5 to about 1.5 &mgr;m and spaced from about 30 to about 70 &mgr;m apart from each other are formed.
In one aspect of the invention, a neodymium-yttrium lithium fluoride laser is used as the laser source. In another aspect of the invention, the nozzles are formed so as to have an exit aperture of from about 0.5 to about 25 &mgr;m in diameter.
In another aspect of the invention, an oxygen and argon plasma is used to treat the laser-ablated material.
In another embodiment of the invention, a method for manufacturing a drug delivery device is provided wherein a nozzle array manufactured via laser ablation as described is functionally incorporated into an aerosol delivery device. The aerosol delivery device generally comprises a device for holding a container having at least one opening, wherein the opening leads to an open channel, a nozzle positioned at the end of the open channel, formulation in an amount of 100 milliliters or less in the container, and a mechanism for forcing the formulation through the nozzle.
One aspect of the invention is a nozzle for aerosolizing a formulation for respiratory delivery, said nozzle comprising a membrane having about 10 to about 1,000 pores per square millimeter, said pores having an average relaxed exit aperture diameter of from about 0.5 to about 5 &mgr;m and being spaced at a distance of from about 30 to about 70 &mgr;m apart from each other. The membrane is preferably flexible.
In a further aspect of the invention, a nozzle is provided wherein the area surrounding the exit aperture of the pores is elevated above the (otherwise substantially planar) exit side of the film so as to prevent intrusion of liquid into the exit aperture of the pores.
In another aspect of the invention, a nozzle is provided wherein the exit aperture of the pores has a smaller diameter than the entrance aperture.
In yet another aspect of the invention, a nozzle is provided wherein the pores are incompletely formed so that, upon administration of pressure to the entrance side of the film, the exit aperture is formed by bursting outward the exit side of the pores, thereby forming an elevated area preventing liquid intrusion into the exit aperture.
In a further aspect of the invention, a strip containing multiple nozzles is provided.
Another aspect of the invention is a method for aerosolizing a formulation in a way that maximizes the amount of formulation available for inhalation, comprising extruding the formulation into an airstream through a flexible, porous membrane, where the pores are from about 0.5 to about 1.5 micrometers in exit aperture diameter when unflexed, and are spaced about 30-70 &mgr;m apart.
Still another aspect of the invention is a method for aerosolizing a formulation through a nozzle comprising such pores where the area surrounding the exit aperture is elevated above the substantially planar exit side of the membrane.
Yet another aspect of the invention is a method for aerosolizing a formulation through pores having entrance apertures wider than their exit apertures.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.
REFERENCES:
patent: 4238571 (1980-12-01), Mano et al.
patent: 4459210
Patel Rajesh S.
Srinivasan Sudarsan
Aradigm Corporation
Borden Paula A.
Bozicevic Karl
Patel Mital
Weiss John G.
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