Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1998-06-26
2001-06-05
Moezie, T. (Department: 1653)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S450000, C424S198100, C514S179000, C514S180000
Reexamination Certificate
active
06241969
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pulmonary drug delivery compositions useful for the inhaled administration of corticosteroid compounds and the method of their administration. The delivery compositions are useful for the treatment of ailments and diseases of the lungs. Similar corticosteroid compositions may be used for nasal delivery.
BACKGROUND OF THE INVENTION
Delivery of therapeutic compounds directly to affected lung tissues has several advantages. The drug reaches the target tissue without first entering the systemic circulation and being subjected to dilution by the blood, binding to blood components, or metabolism by the liver and excretion by the kidneys. A high local concentration of drug can be achieved in the lungs while the systemic concentration is kept below that likely to cause adverse side effects. In addition, the apical side of the lung tissue—the side exposed directly to inspired air—can be treated with compounds that might not readily cross the endothelium or epithelium, which form barriers between the apical surface and the blood plasma. Similar considerations apply to the tissues lining the nasal passages and sinus cavities.
Several means have been developed to deliver compounds directly to the passages of the lung or nose. The most common form, especially for water-insoluble drugs, is a powder suspension that is propelled into the mouth while the patient inhales.
Propulsion is accomplished by use of pressurized gas or by any of a variety of mechanical means of entraining a fine powder into a gas or air stream. Common devices for this purpose include metered dose inhalers (MDIs), turbo inhalers, and dry powder inhalers. Each of these uses a different means of propulsion; however, a common characteristic is that once the therapeutic drug leaves the device it is, or becomes, a fine powder. In an MDI, the drug may be suspended or solubilized in a non-aqueous propellant, which is typically a chlorofluorocarbon or fluorinated hydrocarbon that is a liquid under pressure at room temperature. In turbo inhalers and dry powder inhalers, the drug is present in the form of a micronized powder.
The particle size distribution of the aerosolized drug compositions is very important to the therapeutic efficacy of the drug when delivered by inhalation. Studies of inhaled aerosols indicate that particles or droplets of greater than about 5 micrometers in mean aerodynamic diameter are effectively excluded from entry into the lungs and are captured in the nasal passages or throat and swallowed instead. Thus, the drug compounds delivered by these devices must be formulated in such a way that the mass median aerodynamic diameter (MMAD) is below 5 micrometers. In addition, even smaller particle sizes, on the order of 0.5 to 2.5 micrometers, are needed if the drug is to reach the alveolar sacs deep in the lungs. However, particles with aerodynamic diameter less than about 0.5 micrometers are likely to be exhaled before the drug is totally deposited on the lung surface.
Additional considerations for the use of powder-type drug delivery devices for inhalation include the limited amount of drug that can be contained in one or two puffs from the device and the need for the user to skillfully coordinate hand activation of the device with inhalation. This latter limitation is particularly important for those patients who are disabled, children, or elderly.
Nebulizers offer an alternative method of administering therapeutic agents to the lungs. These devices work by means of an air jet or an ultrasonic pulse that is applied to a solution producing a fine mist. Therapeutic agents dissolved or suspended in the solution can be incorporated into the mist. The patient then breathes the mist in and out over the course of several minutes of treatment, during which 1 to 3 mL of the drug formulation is typically nebulized. Considerations of particle size mentioned above also apply to the droplet size of the mists. However, it is possible to rebreathe a portion of the mist during several minutes of treatment and increase the capture of the fine droplet fraction that can penetrate the lung most deeply. In addition, there is no need for coordination between hand action and breathing, making the nebulizer easier to use for patients. It may be possible, in some cases, to administer drugs not soluble in aqueous solution by nebulizing them in suspension. However, the droplet size of nebulized drug-containing suspensions cannot be smaller than that of the suspended particles. Therefore, the finer droplets produced from these systems would not contain any drug.
Thus, one limitation of nebulized formulations is that they are most suitable for those drug compounds that are sufficiently water soluble such that a therapeutic dose of the drug can be dissolved in from 1 to about 3 mL of aqueous solution. One way around this limitation is to formulate with polar organic solvents or aqueous solutions thereof. However, few organic solvents can be safely inhaled for prolonged periods. Most organic solvents that are currently approved for use in inhalation devices are propellants, such as chlorofluorocarbons (CFCs), which will soon be eliminated from manufacturing for environmental reasons, or the newer hydrofluorocarbons and low boiling hydrocarbons, all of which are expected to evaporate prior to penetrating the lungs. Such solvents can evaporate rapidly during nebulization and leave the drug behind in the device or in large particles that would be likely to be deposited in the mouth or throat rather than be carried to the lungs. Indeed, MDIs were developed to circumvent such problems.
Another way to overcome the solubility problem of the drug is to blend cosolvents such as ethanol, propylene glycol, or polyethylene glycol with water. However, there are limits to acceptable levels of these cosolvents in inhaled products. Typically, the cosolvents make up less than about 35% by weight of the nebulized composition, although it is the total dose of cosolvent as well as its concentration that determines these limits. The limits are set by the propensity of these solvents either to cause local irritation of lung tissue, to form hyperosmotic solutions which would draw fluid into the lungs, and/or to intoxicate the patient. In addition, most potential hydrophobic therapeutic agents are not sufficiently soluble in these cosolvent mixtures.
Thus, there is a need to develop improved systems that can solubilize water-insoluble drugs for nebulization, and to minimize the levels of cosolvent necessary to accomplish this. The ideal system would have a cosolvent concentration below about 15% and in certain cases below about 5%. It would consist of non-toxic ingredients and be stable for long periods of storage at room temperature. When nebulized, it would produce droplets having an MMAD less than about 5 micrometers.
Droplet size considerations are not as critical for sinus or nasal administration, but it is still important to use safe, non-irritating ingredients. An additional consideration for both nasal and inhaled delivery is that some of the formulation will inevitably be tasted and swallowed. Therefore, acceptable taste and odor must be considered important parameters, especially for nebulized formulations where exposure is prolonged and where pediatric subjects form an important fraction of the probable patient population.
Anti-inflammatory corticosteroids, which are essentially water-insoluble drugs that act on inflammatory cells in the respiratory mucosa, are a type of therapeutic compounds in need of improved inhaled delivery. These steroids are useful in treating a variety of inflammatory diseases including asthma.
Asthma is a chronic obstructive disease of the lower airways. The major clinical and pathological features of asthma are (partially) reversible airflow limitations due to bronchial constriction, bronchial hyperreactivity to noxious stimuli such as allergens or cold air, and inflammation of the airways. Anti-inflammatory corticosteroids are useful in treating this last condition. Th
Klyashchitsky Boris
Saidi Zahir
Elan Corporation PLC
Moezie T.
Synnestvedt & Lechner LLP
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