1. Field of the Invention
The present invention relates to methods for producing nanoparticles of compounds that are useful in pharmaceutical, food and cosmetic applications. Specifically, this invention is concerned with producing nanometer particles by utilizing a technique in which a solution comprising a solvent and a solute is spray dried in an empty chamber to form nanoparticles.
2. Related Art
Particles of compounds having low water-solubility are commonly used in a wide variety of applications, including ceramics, paints, inks, dyes, lubricants, pharmaceuticals, food products, pesticides, insecticides, fungicides, fertilizers, chromatography columns, cosmetics, lotions, ointments, and detergents. Aqueous dispersions of particles are used in many cases to avoid hazards such as flammability and toxicity associated with organic solvents. Such dispersions typically have a broad range of particle size.
In many cases product performance can be improved by controlling the particle size distribution. In general, smaller particles of a compound will dissolve faster than larger particles of the same compound. Control of particle size is, therefore, important in controlling the rate of solubilization.
Obtaining particle sizes in the nanometer range is often useful for enhancing the effectiveness of compounds. This is particularly true for compounds that are practically insoluble or slightly soluble in water. Nanometer particles provide a large specific surface area, leading to increased dissolution rate and bioavailability of pharmaceutical drug substance, digestibility of food ingredients, as well as functional effectiveness of cosmetic ingredients. In particular, reducing the particle size of practically insoluble or poorly-soluble drug substances has been shown to increase the dissolution rate and consequently, their bioavailability.
A limited number of methods are known in the art for producing materials having nanometer particle sizes. U.S. Pat. No. 5,145,684 to Liversidge et al., describes a method for forming nanoparticles of a water-insoluble drug by wet milling in the presence of a surfactant. Wet bead milling, in which the material, suspended in aqueous medium, is milled by using glass, polymer, aluminum, zirconium or other metal beads. The milling process can be performed in a roller mill, vibratory mill or high energy mechanical mill. A dispersion consisting of a liquid dispersion medium and the above-described particles is described as being stable. U.S. Pat. No. 5,510,118 to Bosch et al., describes a method for forming nanoparticles of a drug by high pressure homogenization. In this method, a suspension of the material is forced to pass through a narrow orifice by applying a high pressure. The high shear applied to the suspension reduces the particle size of the suspension.
With respect to wet bead milling, the batch size for roller or vibratory mills is limited by the size of the container on the mill. High energy mechanical milling is a continuous process capable of achieving nanometer particles in a short period of time. However, the beads are subjected to severe collisions with the metal chamber, such that abrasion could result in glass or metal contamination of the milled material.
The high pressure homogenization method described by Bosch et al. is usually used to reduce the size of liquid globules in dispersed systems, i.e., emulsions or liposomes. The success of high pressure homogenization method for solid materials is dependent on the physical property of the materials.
U.S. Pat. No. 4,851,421 to Iwasaki et al., discloses fine powders containing particles with a diameter of 0.5 micron or less that are formed by wet milling a dispersion liquid of a biocidal substance with a rigid media having a particle diameter of 0.5 mm or less. Biocidal substances include germicides, herbicides, insecticides, miticides and tickicides that are water-insoluble. Iwasaki et al. also disclose that the resulting biocidal fine powder can more promptly permeate through the surfaces of plants as well into insect bodies and microbe cells.
European application EP 0411629, describes a process whereby ultrafine particles of a slightly-soluble drug, whose average diameter is less than 2 to 3 μm, are obtained by milling the drug in the presence of a grinding aid selected from a sugar and a sugar alcohol. The weight ratio of said sugar or sugar alcohol is 2.5 to 50 parts by weight to one part of the drug, and the micronized drug has an average diameter of less than 1 μm.
In a spray-drying process, a dispersion of solid particles is finely sprayed into flowing warm air to afford dried powder of the material. The prior art versions of this technology do not reduce the particle size.
Spray drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. In a typical spray drying process, the feed liquid may be a solution, slurry, emulsion, gel or paste, provided it is pumpable and capable of being atomized. A feed solution is sprayed into a current of warm, filtered air. The air supplies the heat for evaporation and conveys the dried product to a collector. The air is exhausted together with the moisture.
Spray-dried powder particles are homogeneous, approximately spherical in shape, nearly uniform in size. Lactose, mannitol, and flour are spray-dried for use in direct-compression tableting formulations.
Spray drying has also been previously employed to microencapsulate active agents for drug delivery. This use of spray drying comprises spraying a mixed solution of active agent and a co-ingredient that is able to form a matrix or shell around the active agent. PCT application W096/09814, describes such a method to form spray-dried microparticles. One described embodiment is directed to microparticles comprising a low molecular weight drug and lactose. In one example, alcohol dehydrogenase (ADH) and lactose were spray dried to form microparticles (ADH 0.1% w/w; lactose 99.9% w/w). The microparticles were 4-5 μm in diameter, smooth and spherical, and contained air.
Despite the existence of known technologies, a need continues to exist in the field for a method of producing nanometer particles of compounds, where the method can conveniently be scaled up to production scale.