Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1997-10-09
2001-07-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S009400, C424S400000, C424S489000
Reexamination Certificate
active
06264922
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the field of nanoparticles and particularly in an aerosol form.
BACKGROUND OF THE INVENTION
Delivery of therapeutic agent to the respiratory tract is important for both local and systemic treatment of disease. With the conventional techniques, delivery of agents to the lung is extremely inefficient. Attempts to develop respirable aqueous suspensions of poorly soluble compounds have been unsuccessful. Micronized therapeutic agents suspended in aqueous media are too large to be delivered by aerosolized aqueous droplets. With conventional processes, it is estimated that only about 10 to 20% of the agent reaches the lung. Specifically, there is loss to the device used to deliver the agent, loss to the mouth and throat and with exhalation. These losses lead to variability in therapeutic agent levels and poor therapeutic control. In addition, deposition of the agent to the mouth and throat can lead to systemic absorption and undesirable side effects.
The efficiency of respiratory drug delivery is largely determined by the droplet size distribution. Large droplets (greater than 10 micrometer) are primarily deposited on the back of the throat. Greater than 60% of the droplets with sizes between 1 and 10 micrometer pass with the air stream into the upper bronchial region of the lung where most are deposited. With droplets less than about 1 &mgr;m, essentially all of the droplets enter the lungs and pass into the peripheral alveolar region; however, about 70% are exhaled and therefore are lost.
In addition to deposition, the relative rate of absorption and rate of clearance of the therapeutic agent must be considered for determining the amount of therapeutic agent that reaches the site of action. Since 99.99% of the available area is located in the peripheral alveoli, rapid absorption can be realized with delivery of the particles to the periphery. For clearance, there is also differences between the central and peripheral regions of the lung. The peripheral alveolar region does-not have ciliated cells but relies on macrophage engulfment for particle clearance. This much slower process can significantly extend the time during which the particles reside in the lung thereby enhancing the therapeutic or diagnostic effect. In contrast, particles deposited in the upper respiratory tract are rapidly cleared by mucociliary escalator. That is, the particles are trapped in the mucous blanket coating the lung surface and are transported to the throat. Hence, this material is either swallowed or removed by coughing.
While it has long been known that smaller droplets of an aerosol reach deeper into the respiratory system (
Current Concepts in the Pharmaceutical Sciences: Dosage and Bioavailability,
J. Swarbrick Ed., Lea and Febiger, Philadelphia, Pa., 1973, pp. 97-148) these have largely been of theoretical interest. Simply knowing that smaller droplets of aersol can be delivered deeper into the respiratory system does not solve the problem of incorporating sufficient therapeutic agent into the aerosol to be efficient, particularly where the therapeutic agent is only slightly soluble in the liquid for the aerosol.
Nanoparticles, described in U.S. Pat. No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm). However, no mention is made of attempts to nebulize (aerosolize or atomize are equivalent terms for the purpose of this disclosure) these compositions and it is not apparent that nebulizing these composition would provide useful aerosols or that there would be any advantage for doing so.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided an aerosol comprising droplets of an aqueous dispersion of nanoparticles, said nanoparticles comprising insoluble therapeutic or diagnostic agent particles having a surface modifier on the surface thereof.
In another aspect of the invention, there is provided a method for forming an aerosol of a nanoparticle dispersion, said nanoparticles comprising insoluble therapeutic or diagnostic agent particles having a surface modifier on the surface thereof, said method comprising the steps of:
a) providing a suspension of said nanoparticles;
b) nebulizing said suspension so as to form an aerosol.
In yet another aspect of the invention, there is provided a method of treating a mammal comprising the steps of:
a) forming an aerosol of an aqueous dispersion of nanoparticles, said nanoparticles comprising insoluble therapeutic agent particles having a surface modifier on the surface thereof;
b) administering said aerosol to the respiratory system of said mammal.
In yet another embodiment, there is provided a method of diagnosing a mammal, said method comprising
a) forming an aerosol of an aqueous dispersion of nanoparticles, said nanoparticles comprising insoluble diagnostic imaging agent particles having a surface modifier on the surface thereof;
b) administering said aerosol to the respiratory system of said mammal; and
c) imaging said imaging agent in said respiratory system.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the invention are aerosols. Aerosols can be defined for the present purpose as colloidal systems consisting of-very finely divided liquid droplets dispersed in and surounded by a gas. The droplets in the aerosols typically have a size less than about 50 microns in diameter although droplets of a much smaller size are possible.
The aerosols of the present invention are particularly useful in the treatment of respiratory related illnesses such as asthma, emphysema, respiratory distress syndrome, chronic bronchitus, cystic fibrosis and acquired immune deficiency syndrome including AIDS related pneumonia.
The aerosols of the invention are made by nebulizing the nanoparticle containing solution using a variety of known nebulizing techniques. Perhaps the simplest of systems is the “wo-phase” system which consists of a solution or a suspension of active ingredient, in the present case, a nanoparticle containing a therapeutic or diagnostic agent, in a liquid propellent. Both liquid and vapor phases are present in a pressurized container and when a valve on the container is opened, liquid propellent containing the nanoparticle dispersion is released. Depending on the nature of the ingredients and the nature of the valve mechanism, a fine aersol mist or aersol wet spray is produced.
There are a variety of nebulisers that are available to produce the aerosols of the invention including small volume nebulizers. Compressor driven nebulizers incorporate jet technology and use compressed air to generate the aersol. Commercially available devices are available from Healthdyne Technologies Inc; Invacare Inc.; Mountain Medical Equipment Inc.; Pari Respiratory Inc.; Mada Mediacal Inc.; Puritan-Bennet; Schuco Inc.; Omron Healthcare Inc.; DeVilbiss Health Care Inc; and Hospitak Inc.
Ultrasonic nebulizers deliver high medication output and are used by patients-suffering from severe asthma, or other severe respiratory related illnesses.
The particles comprise a therapeutic or diagnostic agent. (therapeutic agents are sometimes referred to as drugs or pharmaceuticals. The diagnostic agent referred to is typically a contrast agent such as an x-ray contrast agent but can also be other diagnostic materials.) The therapeutic or diagnostic agent exists as a discrete, crystalline phase. The crystalline phase differs from a non-crystalline or amorphous phase which results from precipitation techniques, such as described in EPO 275,796.
The invention can be practiced with a wide variety of therapeutic or diagnostic agents. The therapeutic or diagnostic agent preferably is present in an essentially pure form. The therapeutic or diagnostic agent must be poorly soluble and dispersible in at least one liquid medium. By “poorly soluble” it is meant that the therapeutic or diagnostic agent has a solubility in the l
Bosch H. William
DeCastro Lan
Wood Ray W.
Elan Pharma International Ltd.
Foley & Lardner
Page Thurman K.
Tran Susan
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