United States Patent:  6,103,270

Assignee:  Inhale Therapeutic Systems (San Carlos, CA)

Filed:  May 7, 1999

The invention provides an agglomerate composition composed of units of aggregated fine particles and methods for its manufacture and use. The agglomerate composition units are composed of fine particles having a mean particle size in the range of 1 .mu.m to 5 .mu.m, and usually includes a medicament powder. The agglomerate units have a mean size in the range from 200 .mu.m to 500 .mu.m and have a friability index in the range from about 10 to 60.

SUMMARY OF THE INVENTION

The invention provides an agglomerate composition composed of aggregated units of fine particles along with methods for its manufacture and use. By the term "aggregated unit", it is meant that a number of fine particles are bound together into a single geometric configuration. A plurality of such units are referred to as aggregated units. The aggregated units are unconnected to each other and collectively form the agglomerate composition. The aggregated units will usually have a mean size in the range from 50 .mu.m to 600 .mu.m, preferably between about 150 .mu.m and 500 .mu.m, and more preferably between 200 .mu.m to 500 .mu.m, and are composed of fine particles having a mean particle size in the range from 1 pm to 5 .mu.m. Forming the fine particles into aggregated units in this manner improves the flowability of the fine particles, thereby allowing for easier processing and handling of the particles. The agglomerate composition is formed in such a way that the aggregated units have a friability index (as described hereinafter) in the range from about 10 to 60. Preferably, the particles comprise a medicament powder useful in pulmonary drug delivery procedures where the medicament powder is inhaled by a patient so that the active drug in the powder can reach the distal regions of the lung. Preferable medicament powders include those having medicaments such as proteins, nucleic acids, carbohydrates, buffer salts, peptides, other biomolecules, small molecule drugs, and the like. By forming the medicament powder into an agglomerate composition, the medicament can more easily be moved and metered prior to inhalation while also having the ability to easily be broken down to the fine particles when needed for delivery to the patient's lungs.

In one aspect of the invention, an agglomerate composition is provided which is composed of fine particles formed into aggregated units, with the fine particles having a mean particle size in the range from 1 .mu.m to 5 .mu.m. The aggregated units have a mean size in the range from 200 .mu.m to 500 .mu.m and are formed by employing a nonaqueous solvent binding liquid. The use of a nonaqueous solvent is desirable in that the carbohydrates and proteins of the medicament powders are typically poorly soluble in such a solvent. Poor solubility is desirable so that the formation of crystalline bridges between particles will be minimized. The minimization of crystalline bridges will allow the aggregated units to be broken down into the fine powder when needed. Many nonaqueous solvents also have a low boiling point, and therefore a high vapor pressure, so that they may be readily removed from the aggregated units. Additionally, most nonaqueous solvents have a low surface tension and therefore form weak bonds between particles, allowing the agglomerated units to be broken down into the fine particles when needed. Further, some nonaqueous solvents will not denature proteins. Preferable nonaqueous solvents include, but are not limited to toluene, xylene, benzene, acetone, hexane, octane, chloroform, methylene chloride, and fluorocarbons.

Use of a fluorocarbon liquid in forming the aggregated units is particularly preferable because the fluorocarbon liquid will not dissolve lipophilic and hydrophilic compounds. Further, the fluorocarbon liquid has a low surface tension which forms a relatively weak bond between the fine particles of the aggregated units so that the aggregated units can easily be broken down to the fine particles when needed. Fluorocarbon liquids further have a high vapor pressure and are therefore easy to remove from the particles during formation of the aggregated units. Fluorocarbon liquids are also biocompatible with many pharmaceutical formulations. Preferable fluorocarbon liquids include but are not limited to perfluorodecalin and perfluorooctyl bromide.

In another aspect of the invention, a receptacle is provided having a sealed internal volume and a penetrable wall portion. Within the sealed internal volume is an amount of an agglomerate composition as previously described. The amount of agglomerate composition is preferably a unit dosage of a medicament. When filled with the agglomerate medicament, the receptacle is useful in an inhalation device using a gas stream to withdraw the agglomerate composition from the receptacle where the aggregate units are broken down to the fine particles for delivery to the patient's lungs.

According to one method of the invention, such a receptacle is provided with a fine powder agglomerate composition where the fine powder is characterized by a mean particle size in the range from 1 .mu.m to 5 .mu.m. The fine powder is formed into aggregated units having a mean size in the range from 50 .mu.m to 600 .mu.m, preferably between about 150 .mu.m and 500 .mu.m, and most preferably between 200 .mu.m to 500 .mu.m. The agglomerate composition from the receptacle is extracted in a gas stream for delivery to a patient's lungs, with the gas stream having sufficient disruptive force to break down the aggregated units substantially completely, i.e., at least 30%, preferably at least 50%, and most preferably at least 70%, to the fine particles. In one particular aspect, the agglomerate composition is extracted by flowing the gas stream past a tube inserted into the receptacle.

In one aspect, the gas stream is flowed at a sonic velocity to provide sufficient disruptive force. In another aspect, usually at least 55 percent by weight, preferably at least 70 percent by weight, and more preferably at least 90 percent by weight of the agglomerate composition initially present in the receptacle is extracted into the airstream for delivery to the patient's lungs.

The invention provides a method for agglomerating fine particles. According to the method, a powder of fine particles is combined with a binding liquid to produce a wetted mass, such as a granulation or a paste. The wetted mass is then divided into small volumes which are dried to remove the binding liquid and to produce dry powder agglomerate units having a first size distribution. The dry powder agglomerate units are then adjusted to have a second size distribution characterized by a friability index in the range from about 10 to 60.

The fine particles preferably have a mean particle size in the range from 1 .mu.m to 5 .mu.m. When adjusted to the second size distribution, the dry powder agglomerate units preferably have a mean size in the range from 50 .mu.m to 600 .mu.m, preferably between about 150 .mu.m and 500 .mu.m, and most preferably between 200 .mu.m to 500 .mu.m. The aggregated units will be formed such that substantially all, i.e. about 90% or more, fall within a narrow size distribution, i.e. within about .+-.250 .mu.m, more preferably within about .+-.150 .mu.m, and most preferably within about .+-.100 .mu.m.

In an exemplary aspect, the paste or granulation is divided into small volumes by extruding the paste or granulation through a screen having holes in the range from 40 .mu.m to 650 .mu.m, and more preferably in the range from 150 .mu.m to 500 .mu.m. Preferably, the holes are circular in geometry, thereby producing elongate cylindrical portions of extrudate. The extrudate is preferably dried at a temperature in the range from 15^oC. to 40^oC. Preferable environments for drying the extrudate include the use of forced convection with dry air or by placing the extrudate in a vacuum. To adjust the agglomerate units to the second size distribution, the dry powder agglomerate units are preferably sieved. Optionally, the dry powder agglomerate units can further be adjusted to have a spherical geometry, often referred to as spheronization. In one aspect, the agglomerate units are spheronized by rolling the agglomerate units in a container.

In another exemplary aspect, the binding liquid is preferably a nonaqueous solvent, more preferably a fluorocarbon, and the fine particles will preferably comprise a medicament powder. The amount of binding liquid added to the medicament powder is preferably based on the surface area of the powder. Preferably, the fluorocarbon liquid is perfluorodecalin, and the fine particles have a mean particle size in the range from 1 .mu.m to 5 .mu.m. With such a configuration, the amount of fluorocarbon added is preferably in the range from 0.5 gram to 5 gram per gram of fine particles.

Claim 1 of 4 Claims

1. A method for dispersing fine particles in a flowing gas stream, said method comprising:

providing a receptacle containing a fine powder agglomerate composition, wherein the powder has a mean particle size in the range from 1 .mu.m to 5 .mu.m and the agglomerate composition comprises aggregated units having a size in the range from 50 .mu.m to 600 .mu.m; and

extracting the agglomerate composition from the receptacle in a gas stream having sufficient disruptive force to break down the units substantially completely to the fine particles.

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