HK1069994B - Powder processing with pressurized gaseous fluids - Google Patents

Description

Powder processing using pressurized gaseous fluids

Technical Field

The present invention generally relates to a process for processing solid or semi-solid particles from solution using a pressurized gaseous fluid while retaining (retentions) and dispersing these processed particles in a carrier material. This technique can be advantageously used in pharmaceutical and chemical processing to produce blends (blends) of particles of solid or semi-solid material and carrier material, granulations (granulations) of particles of solid or semi-solid material and carrier material, carrier material partially or fully coated with particles of solid or semi-solid material, or mixtures thereof.

Background

In order to obtain a uniform distribution of pharmaceutical agents (pharmacogenetic agents) in powder-based formulations, pharmaceutical solid dosage forms such as tablets and capsules require the use of pharmaceutical materials in the form of fine powders (drug substances). In addition, it is often necessary to reduce the size of drugs having very low solubility (solubility) and dissolution rates (dissolution rates) to an order of 10 μm or less in order to obtain satisfactory bioavailability (bioavailabilty). In some cases, it is desirable to have a particle size of less than 1 μm for drugs that are poorly water soluble.

Conventional techniques for processing drug particles from solution have a number of disadvantages. Recrystallization, freeze drying and spray drying all require evaporation of the solvent. Drying techniques leave residual amounts of solvent, which in turn can thermally degrade the drug using heat. Reducing the particle size also leads to thermal degradation by mechanical grinding. All of these techniques can produce particle size changes.

The use of supercritical fluids (SCF) such as CO has been disclosed₂An improved process for the generation of micron and submicron sized particles with narrow particle size distribution (see, for example, U.S. patent 5,833,891 and h.s.tan and s.borsadia, Expert Opinion on Therapeutic Patents, 2001, 11 th, page 861-872). These methods include Supercritical Fluid Extraction (SFE), Rapid Expansion of Supercritical Solutions (RESS), Gas Anti-solvent recrystallization (Gas), and Supercritical fluid Anti-solvent (SAS).

Supercritical fluids (SCF) are substances (for CO) at and above the critical temperature and pressure₂31 ℃ at 1070 psi). Such as CO₂Basically, SCF of (a) is a highly diffusive and dense fluid that compresses at mild temperatures. Relatively speaking, it is non-toxic, inexpensive and chemically inert. SFE is commonly used for selective extraction of various compounds. After extraction, the SCF mixture was expanded into a collection vessel (collection vessel) at low pressure. Since the low pressure gas has a low solvency power, the compound precipitates and is collected in a container. The effluent low pressure gas is vented or recycled to the process. There is a great deal of information on SCF properties in the technical literature (McHugh, M.and Krukonics, V., Supercritical Fluid Extraction, Principles and Practice, second edition, Butterworth-Heinemann, Boston.1993).

The core of various particle formation techniques using SCF is the dissolution or solubilization (solvabilize) of a particular solvent or substance. Although SFE has been used to produce pharmaceutical powders (Larson, k.a. et al, Biotechnology Progress, vol 2, 2 nd, 6 months 1986, p 73-82), it is commonly used to selectively extract SCF-soluble substances from raw materials. In this process, the size of the extracted material after decompression is generally not of interest for this process. The nature of SFE is that it can extract any form of desired substances and impurities: liquid, solid or semi-solid.

The concept of precipitation of SCF-soluble substances by rapid pressure reduction has been disclosed for over a century (J.B. Hannay and J.Hogarth, "On the solubility of solids in gases", Proceedings of the Roy. Soc. London, 29 th, p.324-. The RESS process (us patent 4,582,731) which takes advantage of this property of SCF to crystallize the desired solid material, particle size and other possible physical and bulk (bulk) properties are the main points of concern.

In a RESS process similar to SFE, the solute is placed in a high pressure vessel. The SCF is then pumped into the vessel to dissolve the substance and form a solution of the substance in the SCF. The fluid mixture is then expanded through a nozzle into a vessel at a substantially lower sub-critical pressure where the fluid becomes a low density gas. Because the low pressure gas has a low dissolving capacity, the compounds precipitate and are collected in a container. The large pressure differential across the nozzle causes expansion to occur at an ultrasonic rate and a rapid increase in supersaturation. Rapid expansion can be expressed as a rapid change in density and fluid dissolution capacity, which translates into a rapid rate of recrystallization of the fine microparticles (microparticles) and nanoparticles (nanoparticles) that result in the formation of the substance. The effluent gas is passed through a micro-filter and then vented or recycled. Another method of rapidly reducing the solvency power of an SCF without any substantial change in pressure involves contacting the SCF solution with an inert gas, such as nitrogen or helium, in which the solute is substantially insoluble. The inert gas may be maintained at a pressure similar to that of the SCF solution. The inert gas rapidly mixes with the SCF to reduce its solvency, thereby precipitating the solute.

For materials with little solubility in SCF, SCF may be used as an antisolvent. The GAS method was first disclosed at the International conference of the society of chemical Engineers (US patent 5,360,478; US patent 5,389,263), and later on Gallagher, P.M. et al (Chap.22, Supercritical fluid science and Technology, ACS Symposium Series, 406, Washington, DC, K.P.Johnston, J.M.L.Penninger, ed., ACS Publishing, 1989). In the GAS process, SCF-insoluble solutes are processed from a premixed batch (premixed batch) of an organic solution of the solutes using SCF as an antisolvent by adding SCF to the solution. The SCF is added so that its concentration in the solution increases and the solution expands. When the solution is supersaturated, the solute precipitates.

A limitation of the batch GAS process is the lack of ability to process large quantities of material. In the SAS process, an organic solution of solute is continuously added to a continuously flowing SCF antisolvent. The organic solvent is rapidly mixed and dissolved in the SCF to form a homogeneous high pressure fluid mixture. This will precipitate the solute in the high pressure vessel because the solute is substantially insoluble in the SCF and the SCF is miscible with the organic solvent. The SCF-organic solvent mixture is passed through a microfilter and then passed into a low pressure vessel where the SCF is separated from the organic solvent and expanded.

The SAS method is suitable for processing thermally unstable materials because it has a relatively low processing temperature. Unlike other processes, such as conventional spray drying, in other processes the rate of solvent removal from the surface of the droplets is relatively low and depends to a large extent on the processing temperature, but in this process such rates depend primarily on the density and flow rate of the SCF. These two parameters can be easily controlled over a wide range at relatively low temperatures to control the rate of solvent removal over a fairly wide range. Several equivalent methods of the SAS method have been developed. Coenen et al (U.S. Pat. No. 4,828,702) reported a counter-current process in which a liquid solution of a solid solute was sprayed onto a SCF anti-solvent, such as CO₂To recover the powder solid. Fisher and Muller (us patent 5,043,280) reported a process in which a liquid solution of the active substance was sprayed as a fine mist (mist) into a SCF solution of a carrier material to produce sterile microparticles of the active substance embedded in the carrier material. Yeo et al (Biotechnology and Bioengineering, 1993, Vol.41, p.341) and Debenedetti (U.S. Pat. No. 6,063,910) also describe a process in which the solution is passed through a nozzleSpraying into a high pressure vessel comprising SCF to produce a fine powder of solute.

Schmidt (U.S. Pat. No. 5,707,634) reported a process in which non-sterile solutes were recovered from a solution comprising a SCF antisolvent injected into a high pressure vessel. Subramaniam et al (U.S. patent 5,833,891) disclose a process in which ultrasonic nozzles are used to enhance atomization of a liquid solution spray, which helps to produce finely divided micro-and nanoparticles of active materials.

The SAS process is also referred to in the literature as an "Aerosol Solvent Extraction System (ASES)" and variations of SAS have been referred to as "solvent enhanced dispersion by SCF (SEDS)". See, e.g., Expert Opinion on Therapeutic Patents, 2001, 11, 861-872, of Tan and S.Boradaia.

SEDS (us 5,581,453 and 6,063,138) involve the use of coaxial, non-ultrasonic nozzles. High mass transfer rates are achieved with high ratios of supercritical fluid to solvent, and the high velocity of the SCF also aids in solution atomization.

Particles produced using SCFs have also been used to coat substrates. Subramaniam et al (U.S. patent 5,833,891) describe a process in which particles are crystallized from a liquid solution and then passed to a bed of fluidized center particles (core particles) to form a coating. In this process, SCF is used to fluidize the center particle and crystallize the coating material from solution. This process can be used in a similar manner to the classical Wurster coating process. Benoit et al (U.S. patent 6,087,003) describe a batch process in which the active substance is agitated in a high pressure vessel containing SCF and coating material dissolved therein. The temperature of the SCF is then gradually reduced to a temperature at which it separates into a vapor phase and a liquid phase, at which temperature the center particle is in suspension and the coating material is in solution. The continuous removal of the gas phase increases the concentration of the coating material in the liquid phase and reduces the solubility. This will ultimately result in precipitation of the coating material on the active substance. Because the coating material will have limited solubility in a batch of SCF, the process can be repeated using a pre-loaded coating material attached to the shank of the stirring apparatus. Smith (us patent 4,582,731) discloses a process in which RESS-formed particles are directed to and adhere to a solid, e.g., glass, fused silica, and platinum, surface to form a thin coating film.

The above process is designed to produce microparticles or microcapsules of a coating matrix or of a specific substance. The present invention is premised on the fact that very little finely powdered powders (micronized powders) are used in the pharmaceutical industry as final solid formulations, because the collection, handling, flowing and/or compressing of micro-and nanoparticles is very challenging. Thus, micronized powders of a particular drug are rarely used without further processing. If it is desired to prepare a solid pharmaceutical formulation of a drug, it is generally necessary to mix drug microparticles or nanoparticles with particles of a carrier material. Such carriers as lactose have good processability, flowability and compressibility. Granulation is commonly used in the Pharmaceutical industry to produce non-flowing and dust-free granules from fine powders when mixed with a carrier, and thereby improve the uniformity of drug distribution in the product (Handbook of Pharmaceutical Granulation Technology, Marcel Dekker, N.Y., Dilip, M.P. Editor, Vol.81, 1997). Current methods of processing fine powders using SCF do not address these problems. The following are some of the limitations of the currently used methods:

1. the current methods do not address the problem of capturing fine particles after they are formed. They are designed as small, discrete, precipitated microparticles and nanoparticles that are often difficult to capture in processing vessels. Retaining such particles on the filter is difficult and may result in filter clogging and/or reduced production.

2. The current methods do not address the problems associated with the tendency of fine particles to agglomerate (agglomerate). In the SAS process, the particles crystallize rapidly and wet particles may contact each other and fuse or coalesce. Similarly, in RESS, semi-solid or sticky particles cannot be processed satisfactorily because these particles can rapidly agglomerate. Regardless of the physical properties of these materials, when in intimate contact, microparticles and nanoparticles of materials exhibiting high surface free energy will tend to coalesce and fuse to form large particles. When processing drugs, agglomeration increases the effective size of the particles, making drug solubility and bioavailability inefficient. The use of current methods in this regard is limited because the agglomeration of crystalline materials limits their effectiveness for coating fine micron and nanometer sized particles.

3. Current methods designed to coat the center particle with precipitated fine powder in a fluidized bed are difficult to control. Such methods do not solve the problem of retention of fine particles, i.e. fine particles whose coating is very difficult to fluidize. Fluidized beds require special equipment and controls that do not readily allow SCF processing. The purpose of fluidizing the center particles is to suspend these particles so that they are preferably coated and dried before contacting with other center particles, thus minimizing agglomeration. For many powders, the core particles of the coating are obtained by this method, but a number of control processes are generally required. Specialized fluidization devices typically do not allow agitation, but rather provide a carefully controlled pressure differential within the vessel to affect particle fluidization, uniform distribution of the fluidizing gas, control of bed expansion, and collection of particulates. The superficial velocity of the suspending fluid is critical; too high a velocity will result in central particles remaining in the filter; too low a velocity will result in insufficient expansion/fluidization of the bed. Because the precipitation and drying process is rapid in SCF processing, the droplets can be dried before contact with the center particles, and the resulting very fine crystals can easily remain in suspension. Precipitation adhering to the central particle is unlikely to occur simultaneously and some precipitated particles may separate from the central particle bed. Expansion and fluidization of the powder bed also requires long and large process vessels, especially high pressure vessels. When forming particles and coating other particles, some particles are more difficult to fluidize due to the large number of possible particle-to-particle interactions and changes in bed properties such as particle size distribution. Center particles smaller than 10 μm generally form an unstable fluidized bed. The fine particles, if wet, may form agglomerates or act as cracks that may lead to jetting (spitting). These processing challenges at least partially limit the use of fluidized bed processing in pharmaceutical processing. The prior art documents fully describe the problems associated with fluid bed processing of fine particles.

A drawback of RESS, GAS and SAS processing is the difficulty in capturing, collecting and handling fine powders of micro-and nanoparticles. The filters used in these methods are generally not effective in retaining the generated microparticles and nanoparticles. If the filter pores are fine enough to retain the particles, the filter will quickly become clogged with the particles. This can severely restrict flow through the crystallization vessel, requiring frequent interruptions in filtration to clean or replace the filter. In the case of RESS, the flow resistance causes a significant increase in the pressure in the vessel and a decrease in the pressure drop across the nozzle. At a certain point, the pressure drop has completely disappeared, and the process needs to be stopped. In the case of SAS, flow resistance can also result in a continuous increase in pressure within the vessel throughout the process. Even though devices such as cyclones can retain micron particles, they present difficulties in handling. Since the flow characteristics of powders comprising micro-and/or nano-particles are often poor, it is difficult to discharge these powders for use in downstream processes. Thus, prior to the addition of the formulation, further processing by the same methods as mixing with the carrier material and granulating is still required. Poorly flowing powders are difficult to incorporate into the carrier material, so special blending processes or techniques are often required to achieve the desired blend uniformity. Handling of fine powders is also difficult due to their dustiness. Special handling protection is required and very special procedures are required for effective drugs or toxins.

Summary of The Invention

The present invention is primarily directed to methods of precipitating, retaining and dispersing solutes in carrier materials that take advantage of the unique properties of pressurized gaseous (e.g., supercritical) fluids to precipitate solute particles from solution and to effectively retain and disperse the precipitated particles in carriers with good (good) flow and handling properties. The solute may be precipitated from a liquid solvent or a pressurized gaseous fluid solution. As described herein, the method has wide applicability in the pharmaceutical industry.

In general, the methods of the invention involve:

(a) (1) dissolving a solid or semi-solid material in a pressurized gaseous fluid to form a solution comprising a gaseous fluid solvent and a dissolved solid or semi-solid material solute, or

(a) (2) dissolving a solid or semi-solid material in a liquid solvent, thereby forming a solution comprising the liquid solvent and a dissolved solid or semi-solid material solute;

(b) (1) precipitating particles of solid or semi-solid material from the gaseous fluid solution generated in step (a) (1) by introducing the solution into a zone of low pressure or into a zone containing an inert gas, or

(b) (2) introducing the liquid solution produced in step (a) (2): (1) a region containing a gaseous fluid in which the liquid solvent is substantially soluble but the solid or semi-solid material is substantially insoluble, or (2) subsequently introducing the pressurized gaseous fluid to solubilize the liquid solvent into the pressurized gaseous fluid and to precipitate particles of the solid or semi-solid material from the solution;

(c) directing the solution introduced in step (b) (1) or (b) (2) and the resulting precipitated particles to a mixed bed of support material;

(d) retaining and dispersing at least some of the precipitated particles in the carrier material to produce a blend of solid or semi-solid material particles and carrier material, a granulating agent of solid or semi-solid material particles and carrier material, a carrier material partially or fully coated with solid or semi-solid material particles, or a mixture thereof.

The method can be applied to precipitate (or crystallize) various solid and semisolid materials, such as physiologically active materials (e.g., encapsulation materials), moisture barrier materials (e.g., moisture barrier materials), light barrier materials (e.g., light protection materials), gas protection materials (e.g., gas protection materials), diffusion barrier materials (e.g., diffusion barrier materials), and dissolution or dispersion enhancement materials (e.g., dissolution or dispersion enhancement materials), retaining and dispersing the solid and semisolid materials using various carrier materials, such as pharmaceutically acceptable carriers, adjuvants or excipients or physiologically active materials or mixtures thereof. The method is particularly advantageous for precipitating, retaining and dispersing solid or semi-solid materials in carrier materials, micro-and nanoparticles.

The blends, granulators, and partially or fully coated carrier materials or mixtures thereof prepared by the methods of the invention are particularly suitable for pharmaceutical processing into various pharmaceutical formulations and dosage forms, such as tablets and capsules. Generally in formulating most solid dosage forms, carrier materials having good flow characteristics are used. It is therefore an advantage that the carrier material is present in admixture with the drug. Since the drug powder is not separated from the excipient and the drug powder can adhere to the excipient particles during the manufacturing process, even if the drug content is low, uniform blending can be achieved.

Other advantages of the present invention include the following:

1. if the drug loading in the carrier material is not too high, the particle size distribution of the processed powder prior to processing may approach the size of the carrier material itself. Thus, the flow characteristics of the processed powder can be as good as the flow characteristics of the carrier itself, which reduces difficulties in discharging and handling the powder in downstream processing.

2. The carrier is coated with the drug and then coated with the encapsulating material. This process may be repeated to increase the drug loading, preferably without substantial agglomeration of the drug particles. For drugs that are chemically sensitive or sensitive to water or oxygen, the coating may also be a barrier to provide moisture, light or gas. The coating may also be used as a diffusion barrier to control the release of the drug from the matrix or as a dissolution or solubility enhancer.

3. The invention is not limited to powders. The invention can be used, for example, to blend crystalline micro-and nanoparticles with larger sized materials or in fine particles (granules), pills, non-pareils, tablets, capsules or other mixed materials. The method is also useful for forming a granulating agent of solid or semi-solid material particles with a carrier material.

The invention may be used in a variety of ways, including, but not limited to:

1. resulting in a uniform blend of discrete or loosely adhered drug microparticles and nanoparticles and carrier material.

2. Resulting in a uniform blend of discrete or loosely adhered carrier material and drug material.

3. Producing a granulating agent of drug micro-particles and nano-particles and carrier materials. A binder such as polyvinylpyrrolidone (PVP) may be present in a liquid or gaseous fluid solution in admixture with the drug or in admixture with the carrier powder bed.

4. Coating the drug with a coating material. In the case of drugs that are chemically sensitive or sensitive to water or oxygen, the coating may also be a barrier to moisture, light or gas. The coating may also serve as a diffusion barrier to control the release of the drug from the matrix or to enhance the release.

5. The carrier is coated with the drug and then coated with the encapsulating material. This process may be repeated to increase the drug loading, preferably without substantial agglomeration of the drug particles.

Brief Description of Drawings

Figure 1 depicts a simplified flow diagram of two embodiments of modes 1 and 2 of the present invention.

FIG. 2 supercritical CO at 50 ℃ and 1,000psig₂Photo-microscopic image of treated polystyrene-divinylbenzene microbeads (micro-beads).

FIG. 3 shows the use of the present invention for removing CO from supercritical fluids₂A method for recrystallizing a drug in solution by depositing a light microscopic image of the recrystallized drug on polystyrene divinylbenzene microbeads.

FIG. 4 shows a secondary supercritical CO using the present invention₂A method for recrystallizing a drug in solution, comprising depositing a bright field (tungsten) illumination pattern of the recrystallized drug on a set of lactose particles.

FIG. 5 shows the use of the present invention to remove supercritical CO₂A method of recrystallizing a drug in solution, a UV illumination (high pressure mercury lamp) pattern of recrystallized drug deposited on a set of lactose particles.

FIG. 6 shows the dissolution profile of drug-lactose obtained by supercritical CO using the process of the present invention compared to the conventional physical mixing of drug and lactose₂The dissolution profile of the drug-lactose mixture obtained from processing the drug.

Figures 7A to 7C are SEM (scanning electron microscope) micrographs of the excipient lactose prior to processing according to the invention. FIG. 7A is a 40 magnification; FIG. 7B is at 200 magnification; fig. 7C is a 5,000x magnification.

Figures 8A to 8C are SEM micrographs of drug solutes precipitated from solution by processing without the use of a support material and without agitation. FIG. 8A is a 40 magnification; FIG. 8B is at 200 magnification; fig. 8C is a 5,000x magnification.

Fig. 9A to 9C are SEM micrographs of drug/lactose mixtures obtained using the drug precipitated from a sprayed organic solution and incorporated and/or coated onto lactose according to the present invention. In this example, the organic solution was sprayed through a nozzle at a distance of 1 inch above the lactose powder bed. FIG. 9A is at 40 magnification; FIG. 9B is at 500 magnification; fig. 9C is a 5,000x magnification.

Fig. 10A to 10C are SEM micrographs of drug/lactose mixtures obtained using the method of the present invention of precipitating the drug from a non-sprayed organic solution and incorporating and/or coating the drug onto lactose after introduction of pressurized carbon dioxide. FIG. 10A is a 40 magnification; FIG. 10B is at 200 magnification; fig. 10C is a 5,000x magnification.

Figure 11 is a photomicrograph of lactose prior to processing according to the invention.

Figures 12 to 15 are SEM micrographs of drug/binder/lactose mixtures obtained using the process of the present invention for precipitating drug and binder from a sprayed organic solution and incorporating and/or coating the drug and binder onto lactose. In this example, the organic solution was sprayed at a rate of 1.5mL through a nozzle located 1 inch above the lactose powder bed, mixing at a rate of 1000 RPM. FIG. 12 is a 40 magnification; FIG. 13 is a 500 magnification; FIG. 14 is a 2,000 magnification; fig. 15 is a 5,000x magnification.

Fig. 16 is an SEM micrograph of a drug/binder/lactose mixture obtained using the process of the present invention to precipitate the drug and binder from a sprayed organic solution and incorporate them into and/or coat them onto lactose. In this example, the organic solution was sprayed at a rate of 3mL through a nozzle located 1 inch above the lactose powder bed, mixing at a rate of 1000 RPM. Fig. 16 is a 5,000x magnification.

Figures 17 to 19 are SEM micrographs of drug/binder/lactose mixtures obtained using the process of the present invention for precipitating drug and binder from a sprayed organic solution and blending and/or coating them onto lactose. In this example, the organic solution was sprayed at a rate of 5mL through a nozzle located 1 inch above the lactose powder bed, mixing at a rate of 300 RPM. FIG. 17 is a 500 magnification; FIG. 18 is a 5,000 magnification; fig. 19 is a 10,000x magnification.

Fig. 20 is a dissolution profile of tablets prepared using the drug-lactose mixture of the present invention compared to conventionally processed tablets at a standard dose of 40 ℃ and 75% RH at an initial time and after 12 weeks.

Fig. 21 is a graph showing the dissolution profiles of tablets prepared using the drug-lactose blend of the present invention at three different precipitation rates (i.e., three different drug solution spray rates).

Detailed Description

Terms used in the present application should be understood as having ordinary meanings in the art unless otherwise specified. Other more specific definitions of some terms in this application are as follows:

with respect to a defined value, the term "about" means ± 20%, preferably ± 10%, more preferably ± 5%, even more preferably ± 1% of the defined value. When the term "about" is used in reference to a range value, the term "about" is intended to quantify the respective recited endpoint of the range. For example, the phrase "about 0.8 to 1.6 XT_cAnd from about 0.8 to about 1.6 XT_c"equal.

The term "blend" refers to a homogeneous or heterogeneous mixture.

The term "pressurized gaseous fluid" or "supercritical fluid" refers to (1) a fluid or mixture of fluids that is gaseous at atmospheric conditions and has an appropriate critical temperature (i.e.,. ltoreq.200 ℃), or (2) fluids previously found to be capable of functioning as supercritical fluids. Examples of gaseous fluids include carbon dioxide, nitrous oxide, trifluoromethane, ethane, ethylene, propane, sulfur hexafluoride, propylene, butane, isobutane, pentane, and mixtures thereof. If not otherwise specified, the temperature and pressure of the gaseous or supercritical fluid can range from the near critical point to anywhere within the supercritical region, for example, from about 0.8 to 1.6 XT_cAnd 0.8-15 XP_cIn the range of, wherein T_cAnd P_cThe critical temperature of the fluid in K and the critical pressure, respectively.

The term "microparticles" refers to particles having an average particle diameter in the range of about 1 to 500 μm, preferably in the range of about 1 to 10 μm.

The term "nanoparticle" refers to a particle having an average particle diameter in the range of about 0.001 to 1 μm, preferably in the range of about 0.05 to 0.5 μm.

A "mixed bed" of a carrier material refers to a non-fluidized mixture of the carrier material in the absence or presence of precipitated particles of solid or semi-solid material. A mixed bed of carrier material may be formed, for example, by stirring (stic) or blending (agitate) the carrier material in the absence or presence of solid or semi-solid precipitated particles.

By "non-fluidized" of the carrier material is meant that the carrier material in the mixed bed is not in a gas-suspended fluidized state. For example, merely agitating or blending the carrier material may have at least some effect of expanding the bed of carrier material during the process of the invention, but this is not a gas-suspended fluidized state of the carrier material.

The term "precipitation" or "precipitation by verb" refers to the process of forming crystalline or non-crystalline solute particles or mixtures thereof from a solution. Thus, these terms are intended to include within the context of the present invention the concept of crystallizing dissolved solutes out of solution. When a mixture of solutes (e.g. solid or semi-solid materials) is dissolved in a solution, particles of the material "precipitated" in the context of the present invention include not all dissolved solutes being precipitated, and/or the possibility that the solutes are only partially precipitated from the solution. Thus, the precipitation process of the present invention can be used to separate certain solid or semi-solid materials.

"RESS" refers to a process for precipitating solute particles from a gaseous fluid solution of a solute by expanding the solution in a low pressure region or contacting the solution with a gaseous fluid comprising an inert gas at the same pressure or lower.

The term "semi-solid" refers to a solid material having at least some liquid physical properties. Examples of semi-solid materials include: gels, viscous liquids, oils, surfactants, polymers, waxes, and fatty acids.

The term "semi-solid material" refers to one or more substances that are semi-solid under ambient or processing conditions (processing). Thus, the term "semi-solid material" is intended to include the possibility that the semi-solid material is a mixture of different semi-solid materials.

The term "solid material" refers to one or more substances that are solid at ambient or processing conditions. Thus, the term "solid material" is intended to include the possibility that the solid material is a mixture of different solid materials.

The term "processing conditions" refers to specific conditions under which the process of the invention is carried out.

The term "substantially dissolved", for example with respect to the solubility of the liquid solvent in the gaseous fluid, means that the gaseous fluid is capable of completely dissolving the liquid solute, except for residual liquid solvent contaminants that may be present on the carrier material particles, under the selected processing conditions. Quantitatively, preferably at least about 95%, more preferably at least about 99%, of the liquid solvent is dissolved in the gaseous fluid.

The term "substantially insoluble", e.g., with respect to the solubility of a solid or semi-solid material in a gaseous fluid in mode 2, means that the solid or semi-solid material soluble in the gaseous fluid under the selected processing conditions should not exceed about 50%, preferably not exceed about 25%, more preferably not exceed about 5% by weight. Preferably, the solid or semi-solid material is substantially completely insoluble in the gaseous fluid under the selected processing conditions.

The term "mode 1 (mode)" refers to the process of the present invention using the above steps (a) (1) and (b) (1), wherein a solid or semi-solid material is precipitated from a gaseous fluid solution.

The term "mode 2" refers to the method of the invention using steps (a) (2) and (b) (2) above, wherein a solid or semi-solid material is precipitated from a liquid solution.

In a preferred embodiment of the invention, the supercritical or organic solution is introduced directly as a spray (spray) or jet (jet) into a mixed bed of carrier material, for example a drug or carrier material such as lactose, starch or dicalcium phosphate. The orifice that produces the spray or jet is located within or near the bed of carrier particles so that it can come into rapid contact with the carrier material. Mechanical mixing of the carrier materials is preferred, although not required, because mechanical mixing brings the spray into continuous contact with the different material particles, thereby evenly distributing the precipitated solute throughout the mixed powder, and minimizing contact between solute particles. Mechanical mixing also imparts shear forces to the particles, which aids in spreading the spray droplets or spreading the formed particles over the surface of the carrier material.

In another preferred embodiment of the invention, wherein the solute material is precipitated from a liquid solution (hereinafter referred to as "mode 2"), the carrier material is mechanically mixed in the process. Agglomeration of the particles may be reduced by mechanical stirring and blending with the carrier material, which imparts some shear force that acts as de-agglomeration (deagglomeration) and creates a high mass transfer rate of the liquid solvent of the fluid phase to reduce the contact time between wet particles. Applicants have unexpectedly discovered that powders of support materials having good flowability, handling, and compressibility can be used to trap precipitated (e.g., recrystallized) solute materials using SCFs to produce powders having similarly good properties. The ability of the support material to retain recrystallized material can overcome significant difficulties in SCF processing. Because the support materials are close to each other in the mixed bed, precipitation is confirmed to occur near or on the support particles; the probability of the precipitated micro-and nanoparticles adhering to the support material increases and the probability of adhering to other particles of the same kind decreases; the recrystallized particles rapidly interact with the carrier particles and are not carried away by the continuous flow of SCF carrying away such fine particles. This results in high drug recovery. Thus, the support can be used as a medium for adhering the recrystallized particles, a medium for filtering the recrystallized particles from the fluid mixture, and a medium for dispersing the recrystallized particles. High yields can also be obtained since most of the fine micro-and nanoparticles stay in the carrier material, and thus the need for flow-restricting filters is reduced. Another particular advantage of the method of the present invention is that it can be used to process solid or semi-solid solute materials from liquid or supercritical solutions. When solid or semi-solid materials are formed, they disperse rapidly in the carrier material, thereby minimizing agglomeration of homogeneous solute particles. It should be noted that while the shear forces created by mechanical mixing aid in solute dispersion and deagglomeration, agglomeration can also be increased if desired by controlling processing parameters, such as the rate of addition of the binder solution to the pressurized gaseous fluid. Thus, the process can be used to produce adhesion of recrystallized particles to carrier particles, to granulate such particles, or to improve their flow properties.

I. Mode 1

Steps (a) (1) and (b) (1) of the method of the present invention are analogous to RESS technology, in which gaseous fluid (e.g., SCF) soluble material is deposited from a pressurized gaseous fluid by introducing the pressurized gaseous solution into a region of low pressure or a region containing an inert gas. This technique is described, for example, in the following U.S. patents, each of which is incorporated herein by reference in its entirety: us patent 4,582,731 and us patent 4,734,451. The RESS process can be readily adapted and used by those skilled in the art in the process of the present invention according to RESS technology known in the art.

Generally, any of the conventional conditions (i.e., temperature, pressure, settling vessel and nozzle variations, etc.) commonly used in the art in RESS technology can be used in steps (a) (1) and (b) (1) of the process of the present invention. The person skilled in the art can of course adjust these processing conditions within wide limits to obtain the optimum properties required for the process of the invention. Preferred conditions are as follows: the temperature of the pressurized gaseous fluid solution is preferably greater than the T of the gaseous fluid_cMore preferably about 1 to 1.6 XT_cWithin the range; the pressure of the pressurized gaseous fluid solution is preferably higher than P_cMore preferably in the range of about 1 to 15 XP_cWithin the range; the pressure and temperature within the particle collection vessel or region are preferably at or near ambient conditions. The gaseous fluid is preferably carbon dioxide, nitrous oxide, ethane, ethylene or propane, more preferably carbon dioxide. The gaseous fluid may be recycled in the process if desired.

In a preferred embodiment of the invention, a pressurized gaseous fluid solution of solute is expanded onto or into a mixed bed of carrier particles retained within a particle collection vessel at low pressure. The gaseous fluid enters the vessel from within the bed of carrier particles, or slightly above the upper surface of the bed of carrier particles, or from a location below the bed of carrier particles, and exits the vessel through another opening (opening) in the bottom, side, or top of the vessel. The gaseous fluid preferably enters the vessel from slightly above the upper surface of the bed of carrier particles and exits through an opening in the bottom of the vessel. This will help to ensure that the precipitated particles are in intimate contact with the carrier particles before exiting the particle collection container. Preferably, the bed of carrier particles is agitated using one or more rotary mixing devices. A speed range of between 0 and 5,000RPM, preferably between 50 and 3,000RPM, may be used.

Mode 2

Steps (a) (2) and (b) (2) of the method of the invention are analogous to the SAS and GAS techniques in which the gaseous fluid insoluble material is deposited from a solution obtained by introducing into a zone containing a pressurised gaseous fluid a solution of a material in a liquid solvent (e.g. an organic solvent or a mixture of an organic solvent and water) in which the liquid solvent is soluble but the dissolved solute is substantially insoluble, or into a zone into which a pressurised gaseous fluid is subsequently added to precipitate the gaseous fluid insoluble material. These technologies, including GAS, SAS, ASES, and SEDS and variants thereof, are described, for example, in the following U.S. patents, each of which is incorporated herein by reference in its entirety: us patent 5,360,478; us patent 5,389,263; us patent 4,828,702; us patent 5,833,891; us patent 5,874,029; us patent 5,707,634; us patent 6,063,910; U.S. Pat. nos. 5,851,453; us patent 6,063,138; us patent 5,795,594; us patent 5,770,559 and us patent 5,803,966. The SAS methodology can be readily adapted and used by those skilled in the art into the methods of the present invention in accordance with SAS techniques known in the art.

Generally, when embodiment 2 is practiced by introducing the solution into a vessel containing a pressurized gaseous fluid, any of the conventional conditions commonly used in the art in SAS technology (i.e., temperature, pressure, fluid flow rate, settling vessel and nozzle variations, etc.) may be used in steps (a) (2) and (b) (2) of the method of the present invention. When embodiment 2 is practiced by introducing the solution into a vessel followed by adding a pressurized gaseous fluid to the vessel, any of the conventional conditions commonly used in the art in GAS technology (i.e., temperature, pressure, fluid flow rate, settling vessel and nozzle variations, etc.) may be used in steps (a) (2) and (b) (2) of the process of the present invention. The person skilled in the art can of course adjust these processing conditions within wide limits to obtain the optimum properties required for the process of the invention.

Preferred conditions are as follows: the temperature in the precipitation vessel is preferably above the critical temperature of the gaseous fluid, more preferably between about 1 and 1.6 XT_cWithin the range; the pressure in the precipitation vessel is preferably higher than P_cMore preferably in the range of about 1 to 15 XP_cWithin the range; the ratio of the liquid solution flow rate to the gaseous fluid flow rate should preferably be in the range of about 0.001 to 0.1, more preferably in the range of about 0.01 to 0.05. The pressure, temperature, gaseous fluid flow rate and liquid solution flow rate should preferably be such that the fluid mixture in the precipitation vessel is homogeneous. Preferably, the bed of carrier particles is agitated using one or more rotary mixing devices. Preferably between 50 and 3,000 RPM.

The nozzle used to introduce the liquid solution into the precipitation vessel may be, for example, an orifice nozzle (orifice nozzle), a capillary nozzle, an ultrasonic nozzle or a coaxial nozzle, such as those used in the SEDS process described above. The liquid solution may alternatively be introduced through a conventional flow conduit or orifice without spray atomization. In one embodiment, the solution may be added or mixed with the carrier material quickly before the container is closed, pressurized, and the gaseous fluid flows.

Preferably, the pressurised gaseous fluid is pumped into the vessel from above the upper surface of the bed of carrier powder in a quiescent state. Preferably, the liquid solution is introduced into the vessel from a position below or slightly above the upper surface of the bed of carrier powder in the quiescent state. Since the liquid is sprayed directly on or in the powder bed, it is believed that at least part of the particles are formed by dropping SFE (supercritical extraction) solvent from the solution on the carrier particles. In particular, droplets of a liquid solution may contact and adhere to a carrier material, and then precipitate a solid or semi-solid material from a liquid solvent that extracts the liquid into the gaseous fluid. If this does occur, precipitated particles will be formed from droplets of solution adhering to the support material and possibly forming a thin coating of precipitated material on the support material; selection of a good wetting solvent will therefore enhance the adhesion properties and distribution of solutes on the carrier particles. In the case where the liquid solution is first added to the carrier before pressurization with the gaseous fluid, the gaseous fluid may act to dissolve and expand the liquid solution to the extent that the solid or semi-solid material is no longer dissolved in the gaseous fluid-liquid solvent mixture, thereby effecting precipitation.

Depending on the operating conditions of pressure, temperature, fluid flow rate and stirring intensity, the particles precipitated from the droplets may form particles loosely adhering to the carrier particles, coatings of the carrier particles or granulating agents or mixtures thereof. The present invention thus satisfies the need for a carrier particle coating that wets the surface of the carrier particle in order to obtain a strong coating. Varying the position of the openings or orifices that produce the spray can be used to vary the characteristics of the powder produced. The closer the pores are to the powder bed, the wetter the carrier particles, and the greater the potential for coating or granulating the powder mixture. The process of the present invention is ideally suited for rapid granulation of pharmaceutical formulations. Forming the particles and the granulating agent or coating in situ can reduce some of the downstream processing and processing steps and can therefore reduce health risks and production costs.

Retention and dispersion of precipitated particles in a carrier

In steps (c) and (d) of the process of the present invention, the introduced solution and the precipitated particles produced by means of mode 1 (steps (a) (1) and (b) (1)) or mode 2 (steps (a) (2) and (b) (2)) described above are directed onto or into a bed of support material, thereby retaining the precipitated particles in the support material. This is accomplished by introducing the gaseous fluid solution or liquid solvent solution of (a) (1) or (a) (2) into the appropriate zone specified in step (b) (1) or (b) (2) and then onto or into the mixed bed of support material whereby at least some of the particles precipitated from the gaseous fluid or liquid solvent are retained by the support material. Depending on the processing parameters, this may result in a blend of the solid or semi-solid precipitated material with the carrier material, a granulation of the solid or semi-solid precipitated material with the carrier material or a partially or fully coated carrier material or a mixture thereof.

In modes 1 and 2, the precipitation tank can be partially and completely filled with a carrier material. The process conditions (e.g., temperature, pressure and fluid flow rate) within the precipitation tank itself can be within a wide range and can be readily adjusted by one skilled in the art to achieve the optimum performance required for the process of the present invention. When using embodiment 1, preferred processing conditions are as follows: the pressure and temperature within the precipitation vessel or zone are preferably at or near ambient conditions. Preferably, the bed of carrier particles is agitated using one or more rotary mixing devices. Speeds between 0 and 5,000RPM, for example, speeds of 50 to 3,000RPM are preferred. When using embodiment 2, preferred processing conditions are as follows: the temperature in the precipitation vessel or zone is preferably above the critical temperature of the gaseous fluid, more preferably between about 1 and 1.6 XT_cWithin the range; the pressure is preferably above the critical pressure of the gaseous fluid, more preferably between about 1 and 15 XP_cWithin the range. The ratio of the liquid solution flow rate to the gaseous fluid flow rate should preferably be in the range of about 0.001 to 0.1, more preferably in the range of about 0.01 to 0.05. The pressure, temperature, gaseous fluid flow rate and liquid solution flow rate should preferably be such that the fluid mixture in the precipitation vessel is homogeneous.

In a preferred embodiment, the carrier material is maintained in a mixed state (e.g., by continuous stirring, blending, or mixing in any other manner) during the process of precipitating the solid or semi-solid material to disperse it throughout the bed of carrier material. In particular, in this embodiment the support bed is maintained in a mixed state at least in steps (c) and (d) of the process of the invention. The stirring of the particulate material powder is easily accomplished regardless of its particle size distribution and its variation throughout the process. In this preferred embodiment, because the spray is in close proximity to the bed of carrier material, agitation is such that the carrier powder particles are continuously circulated through the spray and the carrier particles are in close proximity, it is preferred that the recrystallized solute particles are rapidly added to the bed of carrier particles before any substantial coalescence between the solute particles occurs, thereby minimising solute-solute interactions leading to coalescence. For example, vigorous stirring in mode 2 can alleviate the need for finely atomized spraying of organic solutions of fine micro-and nanoparticles of materials that produce precipitates. Mechanical agitation can be performed using any of a number of agitation device designs, including a pitched (pitched), curved (curved) or flat (flat) turbine, anchors (anchors), propellers (impellers), propellers (propellers), dispersers (dispersers), homogenizers (homogenizers), and spiral plates (helicones). Preferably, the bed of carrier particles is agitated using one or more rotary mixing devices. Preferably between 50 and 3,000 RPM.

As mentioned above, the distance between the mixed bed of support material and the opening or orifice through which the gaseous fluid solution or liquid solution is introduced into the precipitation chamber will affect the properties and quality of the resulting mixture. Those skilled in the art will be readily able to adjust this distance as well as the pressure, temperature and liquid and fluid flow rates to achieve the desired product as a blend, granulation or coated carrier material or mixture thereof, while preferably preventing substantial agglomeration between the precipitated particles. In a preferred embodiment, the precipitated particles are directed into or onto the mixed bed of support material by introducing a gaseous fluid solution or fluid solution, for example, through an opening located on or near the surface of the bed of mixed support material or an opening located within the bed of mixed support material.

In another preferred embodiment, the precipitated particles are directed into or onto the mixed bed of support material via an opening located at a distance of at least about 0 to 12 inches, preferably at least about 2 inches, from the surface of the bed of mixed support material or an opening located within the bed of mixed support material. As more solid or semi-solid precipitation material, e.g., drug, coating and/or binder material, is added to the carrier bed, the surface of the bed may increase over time.

As mentioned above, by adjusting the processing parameters, the end product of the process of the invention may be a blend of particles of solid or semi-solid material and carrier material, a granulating agent of particles of solid or semi-solid material and carrier material, or a carrier material partially or fully coated with particles of solid or semi-solid material. The blends, granulators, partially or fully coated carrier materials, or mixtures thereof produced by the methods of the invention can be processed into various pharmaceutical formulations and dosage forms, such as tablets and capsules, using conventional techniques. When a blend is present, the product may be a homogeneous or heterogeneous mixture of carrier material, discrete particles of solid or semi-solid material, and carrier material having the solid or semi-solid material loosely adhered thereto.

In the case of coating techniques, the process of the invention can be repeated one or more times on the initially coated support material, using the same or different coating materials. In particular, the coating process of the present invention may be run one or more times on said coated carrier material to further coat the coated carrier material produced in step (d), wherein in each coating process said solid or semi-solid material may be the same or different in the initial or subsequent coating process.

For example, as described above, the carrier material may be first coated with the drug and then coated with the encapsulating material, and the entire process may be repeated to increase the drug loading. In the case of different coatings, the drug may also be coated with a moisture barrier material, a light resistant material, a gas protecting material, a diffusion barrier material or a dissolution or dispersion enhancing material or combinations thereof. Many variations and applications of this technique are possible.

In the case of a granulating agent, a binder such as PVP may be present in a liquid or gaseous fluid solution mixed with the drug or with the carrier powder bed.

In mode 1 or 2 of the present invention, after contact with the powder bed, the gaseous fluid can flow out of the container. Preferably, the gaseous fluid flows through a substantial portion of the powder bed and then exits the vessel through a filter of a size small enough to retain the carrier particles. Thus, the solute-depleted fluid mixture (solute-depleted fluid mixture) preferably exits the precipitation tank via a filter located at the bottom of the carrier bed. This will ensure high particle retention and a more uniform solvent mass transfer rate to the gaseous fluid in mode 2. In this preferred mode, depending on the position of the spray, stirring is optionally used during this process, in particular in mode i of the invention. Stirring may be required if a uniform distribution of the recrystallized material in the support material is desired. The relatively low viscosity and high diffusivity of gaseous fluids and gases and the high particle retention of the carrier material make this preferred approach possible.

In mode 2, after the solute is precipitated from the liquid solution, the liquid solvent-gaseous fluid mixture is preferably flowed from the precipitation tank and expanded in a low pressure range to separate the gaseous fluid from the liquid solvent. The liquid solvent can be recovered in a cold trap (cold trap), the gaseous fluid discharged or recycled to the process.

FIG. 1 depicts a flow diagram of two specific embodiments of modes 1 and 2 of the process of the invention.

Various solid or semi-solid materials, gaseous fluids and carrier materials can be used in the process of the present invention to produce various types of products.

For example, the precipitated solid or semi-solid material may be selected from physiologically active materials such as chemical drugs and agricultural materials such as herbicides and fertilizers. The solid or semi-solid material may also be an industrial chemical, a food product, a fine chemical, a cosmetic chemical, a photographic chemical, a dye, a coating, a polymer, an encapsulating material, a moisture barrier material, a light resistant material, a gas protecting material, a diffusion barrier material or a dissolution or dispersion enhancing material. In a preferred embodiment, the solid or semi-solid material is a physiologically active material. Of course, mixtures of different solid or semi-solid materials are also contemplated and may be processed in accordance with the present invention.

In a preferred embodiment, the physiologically active material is selected from the group consisting of isopropyl atropine bromide (Ipratropium bromide), tiotropium bromide (tiotropium bromide), oxitropium bromide (oxytropium bromide), tirapavir (tipranavir), albuterol (albuterol), albuterol sulfate (albuterol), clenbuterol (clenbuterol), fensterol (fenoterol), beclomethasone dipropionate (beclomethasone dipropionate), insulin (insulin), amino acids, analgesics (analgesics), anti-cancer agents (anti-cancer agents), anti-viral agents (anti-fungal agents), anti-fungal agents (anti-fungal agents), antibiotics (anti-nucleotides), nucleosides (nucleo), amino acids, peptides, proteins, immunosuppressants (immune inhibitors), vaso (vasodilators), anti-thrombotic agents (anti-thrombotic agents), anti-thrombotic agents (vasolytic agents), anti-thrombotic agents (vasolytic agents), and anti-thrombotic agents (e, such as a method for treating a method of the like, Neurotransmitters (neurotransmitters), sedatives (sedatives), hormones, anaesthetics, anti-inflammatory agents (anti-inflammatories), antioxidants (antioxidants), antihistamines (antihistamines), vitamins, minerals and other physiologically active materials known in the art; the encapsulating material may be selected from the group consisting of the above-mentioned physiologically active materials, gels, waxes, polymers and fatty acids; the moisture barrier material, gas barrier material and diffusion barrier material may each be selected from lecithin and polymers, such as polyethylene glycol, PVP and polyvinyl alcohol; the light-resistant material may be selected from polymers and titanium dioxide. The dissolution or dispersion enhancing agent may be selected from surfactants (e.g. TWEEN) or wetting agents (e.g. SLS, SDS), solubilising agents, dispersing agents, carrier surface modifying materials such as adhesion enhancing polymers (PVP, PVA and cellulose) or silica and the like.

The precipitated particles of solid or semi-solid material generated in the method of the invention may comprise microparticles or nanoparticles of solid or semi-solid material or a mixture thereof. The process is particularly suitable for effectively retaining such fine particles in a carrier material.

The gaseous fluid used in the process of the present invention includes, for example, any of the gaseous fluids commonly used in conventional supercritical fluid processes such as SFE, RESS and SAS. Examples of suitable gaseous fluids include carbon dioxide, nitrous oxide, trifluoromethane, ethane, ethylene, propane, sulfur hexafluoride, propylene, butane, isobutane, pentane, and mixtures thereof.

Liquid solvents that may be used in the process of the present invention include, for example, water or any organic liquid solvent that may be used in conventional SAS processes. Examples of organic solvents that may be used include aliphatic alcohols such as ethanol, methanol, propanol, and isopropanol, acetone, methylene chloride, ethyl acetate, dimethyl sulfoxide, polymers, surface wetting enhancers such as surfactants, and mixtures thereof. Water may be present in a mixture of any of the above organic solvents.

The carrier material used in the method of the invention may be selected from any pharmaceutically acceptable carrier, adjuvant or excipient or physiologically active material or mixture thereof. Preferred examples of pharmaceutically acceptable carriers, adjuvants or excipients which may be used include lactose (including hydrated forms thereof), glucose, sucrose, starch, polyethylene glycol, PVP, polyvinyl alcohol, lecithin, microcrystalline cellulose, hydroxypropylmethyl cellulose, calcium carbonate, dicalcium phosphate, calcium triphosphate (calcium triphosphate), magnesium carbonate and sodium chloride. Preferred examples of physiologically active materials which can be used as a carrier material include ipratropium bromide (I.B.), tiotropium bromide, oxitropium bromide, salbutamol sulfate, clenbuterol, fenoterol, beclomethasone dipropionate, insulin, an amino acid, an analgesic, an anticancer agent, an antibacterial agent, an antiviral agent, an antifungal agent, an antibiotic, a nucleoside, an amino acid, a peptide, a protein, an immunosuppressant, a thrombolytic agent, an anticoagulant, a central nervous system stimulant, a decongestant, a diuretic vasodilator, an anti-stress agent, a neurotransmitter, a sedative, a hormone, an anesthetic, an anti-inflammatory agent, an antioxidant, an antihistamine, a vitamin and a mineral. The carrier material may take a variety of forms depending on the product desired, for example, a powder, a granulated powder, a tablet, a capsule or a caplet. When the support material is a powder, it may be in the form of microparticles or nanoparticles of the support material or a mixture thereof.

In a preferred embodiment, the carrier material is a powder of microparticles and/or nanoparticles comprising a pharmaceutically acceptable carrier, adjuvant or excipient, or microparticles and/or nanoparticles of a physiologically active material or a mixture thereof.

Another particular embodiment of mode 1 of the process of the present invention is directed to a process for precipitating, retaining and dispersing particles in a support material comprising:

(a) dissolving a solid or semi-solid physiologically active material in a pressurized gaseous fluid, thereby forming a solution comprising a pressurized gaseous fluid solvent and dissolved physiologically active material;

(b) precipitating microparticles and/or nanoparticles of a physiologically active material from a gaseous fluid solution generated in (a) by introducing the solution into a low pressure zone or into a zone containing an inert gas via a small orifice;

(c) directing the introduced solution and the microparticles and/or nanoparticles produced in step (b) onto or into a mixed bed of a powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable carrier, adjuvant or excipient;

(d) retaining at least some of the microparticles and/or nanoparticles produced in step (b) in a powdered carrier material to produce a blend of physiologically active material and carrier material, a granulating agent of physiologically active material and carrier material, a carrier material partially or fully coated with physiologically active material, or a mixture thereof.

Additional embodiments are directed to the method of mode 1 above, wherein: the pressurized gaseous fluid is carbon dioxide; the zone into which the gaseous fluid solution is introduced is a low pressure zone; the small hole is positioned on the upper surface of the mixed bed when the mixed bed of the carrier material is static or positioned in the mixed bed when the mixed bed is static; the carrier material is lactose; in steps (c) and (d), the mixed bed of support material is maintained in a mixed state, for example by mixing at a speed of about 300 to 1,000 RPM; and/or the product in step (d) is at least some of the powdered carrier material partially or fully coated with the physiologically active material.

Another particular embodiment of mode 2 of the process of the present invention is directed to a process for precipitating, retaining and dispersing particles in a support material comprising:

(a) dissolving a solid or semi-solid physiologically active material in a liquid solvent to form a solution comprising the liquid solvent and the dissolved physiologically active material;

(b) by introducing the liquid solution produced in step (a): (1) a region containing a pressurized gaseous fluid in which the liquid solvent is substantially soluble but the physiologically active material is substantially insoluble, or (2) subsequently introducing the pressurized gaseous fluid to solubilize the liquid solvent into the pressurized gaseous fluid and precipitate the microparticles and/or nanoparticles of the physiologically active material from the liquid solution;

(c) directing the solution and resultant microparticles and/or nanoparticles introduced in step (b) onto or into a mixed bed of a powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable carrier, adjuvant or excipient;

(d) retaining at least some (at least some) of the microparticles and/or nanoparticles produced in step (b) in the powdered carrier material to produce a blend of physiologically active material and carrier material, a granulating agent of physiologically active material and carrier material, a carrier material partially or fully coated with physiologically active material, or a mixture thereof.

Additional embodiments are directed to the method of mode 2 above, wherein: the liquid solvent is a liquid organic solvent, such as a fatty alcohol solvent; the gaseous fluid is carbon dioxide; the liquid solution is sprayed through an orifice into a region containing the pressurized gaseous fluid, wherein the orifice is located above the upper surface of the mixed bed of support material when the mixed bed is at rest, or within the mixed bed when the mixed bed is at rest; maintaining the mixed bed of support material in a mixed state during steps (c) and (d); and/or the product in step (d) is at least some of the powdered carrier material partially or fully coated with the physiologically active material.

Another embodiment is directed to the method of mode 2 above wherein in steps (b) and (c) the droplets of the liquid solution are contacted with a powdered carrier material and precipitation of the physiologically active material results from extraction of the liquid solvent from said droplets into the pressurized gaseous fluid.

Another embodiment is directed to the process of mode 2 above, wherein both the solid or semi-solid physiologically active material and the solid or semi-solid binder material are dissolved in the liquid solution in step (a); the liquid solvent is methanol or ethanol; the carrier material is lactose; and/or maintaining the mixed bed of support material in a mixed state by mixing at a speed of about 20 to 1,000RPM, preferably about 300 to 1,000 RPM.

The following examples illustrate techniques used to illustrate various aspects of the present invention, but it should be understood that these examples are for illustration only and should not be construed to limit the overall scope of the invention in any way.

The purpose of these examples is to illustrate that the invention can be used to deposit solutes from organic solutions or gaseous fluids or mixtures thereof to form a blend of solute materials on a support, wherein the solute is dispersed predominantly on the support, referred to as discrete particles, a coating or a mixture of coatings surrounding the support particles and discrete particles.

Examples

Example 1: from supercritical CO₂Coating of medium recrystallized drug and polymeric beads

5g of drug was mixed with an inert material (diatomaceous earth) and filled into a 1 l container. Then using supercritical CO at 80 ℃ and 310bar₂Extraction and solubilization of the drug. Then, the drug-loaded efflux CO is caused₂The stream was expanded to low pressure via a 75 μm orifice nozzle in a 300mL mixing vessel containing 25g of white powder consisting of polystyrene divinylbenzene beads with particle size ranging from 40 to 80 μm. The powder was then mixed at 1,000RPM using 2 4-blade propellers attached to a drive shaft. A bottom pusher is located near the bottom of the container. The edge (lip) of the nozzle is placed close to the top of the powder bed so that the drug precipitates as micro-and nanoparticles and rapidly mixes with the powder. The mixing vessel temperature and pressure are 40-50 ℃ and up to 1,000psig, respectively. CO of effluent₂Passed through a filter frit of 60 μm and then discharged.

The resulting powder had a pale yellow, uniformly distributed color, indicating that the drug was uniformly distributed throughout the powder. FIG. 2 shows supercritical CO at 50 ℃ and 1,000psig₂Light microscopic image of treated beads. Polaroid software version 1.1 was used to view images on a microscope (Olympus BH2 polarized light microscope and Polaroid DMC 1 e). The beads were found to be spherical and not CO-coated₂And (4) damage. FIG. 3 is a light microscopic image of the treated beads of the present invention. The surface was found to be covered by foreign matter and a coating was found on the surface. The drug was found to adhere to the beads.

Example 2: from supercritical CO₂Coating of medium recrystallized drug and lactose monohydrate

In this example, the beads used in the above examples were replaced with lactose monohydrate, a widely used excipient material in tablet formulations. The processed powder contained about 10% drug, had a light yellow color, and was found to have flow properties similar to unprocessed lactose. Light microscopy (or bright field microscopy) and scanning electron microscopy did not provide evidence that the drug was within the processed powder. Since the drug is bright fluorescent, and lactose is not fluorescent, fluorescence microscopy was used to demonstrate that the drug particles are fully associated with the lactose particles (associate). Samples were prepared from the dry powder processed by sprinkling a small amount of the powder onto a microscope slide and then adding 3 drops of non-fluorescent impregnating oil (immersion oil) and covering with a number of 1.5 glass cover slips. The formulation remains less than one day at room temperature and light is avoided except for detection in a microscope.

The microscope is a Nikon Microphot with a spectral bandpass (band filter) filter that modulates the fluorescence produced in the isocyanate emission. The samples were examined under bright field (tungsten) illumination and UV illumination (high pressure mercury vapor lamp) at 20X, 40X and 60X magnification. The magnification calibration was performed using a Don Santo scale micrometer (1 mm divided into 10 micron intervals). Images were taken with an SVMicro digital camera.

Figure 4 shows a group of lactose particles treated with drug in bright field irradiation. A typical appearance of a group of particles seen in bright field illumination was observed. Fig. 5 shows the same spot irradiated with UV light. Each particle was fluorescent, indicating that each lactose particle was attached to the drug. Thus, this technique can be used to produce a powder that is intimately and uniformly mixed.

Since the depth of focus is shallow, it is possible to obtain an image through the "optic" of the particle with a high numerical aperture objective (high numerical aperture objective). These images show that the fluorescent drug is selectively located on the surface of the lactose particles, almost as a shell or coating. Very little, if any, drug is found within the lactose particles.

Dissolution of the above drug-lactose mixture was then performed using a standard stirred basket (standard stirred basket) method and then compared to a conventional physical powder drug-lactose mixture using the same dissolution method. The two drug-lactose mixtures analyzed had the same drug/lactose ratio. The dissolution profile, see fig. 6, shows that the material processed with supercritical fluid exhibits faster solubility, sometimes as much as twice the amount of drug released per time period.

Example 3: the drug is precipitated from the sprayed organic solution and incorporated into and/or coated onto the lactose particles using a nozzle above the bed

In this example, 25g of lactose (approx. size: 99% less than 63 μm) was filled into a 300mL container immersed in a thermostated (50 ℃ C.) water bath. The vessel was closed, mixing was started at 1000RPM, and CO was then established across the vessel₂And (4) streaming. When the desired 1500psig pressure was reached, 95mL of a 25mg/mL solution of the drug in methanol was sprayed through a 75 μm nozzle at a rate of 1.5mL/min for 1 hour. The nozzle tip (nozzle tip) was placed about 4 inches above the stationary powder bed. The solution rapidly reacts with supercritical CO₂Mixing to make it insoluble in CO₂The drug substance(s) crystallizes rapidly and mixes within the bed. After the addition of the solution, drying was carried out for about 2 hours. Solvent-supercritical CO bleed₂The mixture was passed through a 60 μm filter and then expanded to atmospheric pressure level. The solvent was recovered in a cold trap and the gaseous fluid was vented to the atmosphere. During this period, CO at near atmospheric pressure flows out₂The flow rate was about 45 standard liters/minute.

Example 4: the drug is precipitated from the sprayed organic solution and incorporated into and/or coated onto the lactose particles using a nozzle in or near the bed

This example is a repeat of example 3 except that the nozzle above the stationary powder bed is lowered to about 1 inch. As expected, the bed covered the nozzle during agitation.

In the 2 resulting products of examples 3 and 4, no difference was found. The product produced theoretically comprised 10% drug loading, appeared visually granular, and had acceptable flow, which was not characteristic of the carrier stock prior to processing. No filter clogging was found, indicating that lactose was very effective in capturing solutes. FIGS. 7A to 7C show SEM micrographs of the excipient lactose prior to processing (FIG. 7A at 40 magnification; FIG. 7B at 200 magnification; FIG. 7C at 5,000 magnification). Figures 8A to 8C are SEM micrographs of drug solutes precipitated from solution by processing without lactose and without agitation (figure 8A is 40x magnification; figure 8B is 200x magnification; figure 8C is 5,000x magnification). This is similar to non-processed feedstock. It can be found that the drug crystallizes in the shape of needle-like, elongated needle-like particles. Fig. 9A to 9C show SEM micrographs of the drug-lactose mixture obtained by the method of example 4 (fig. 9A is 40 × magnification; fig. 9B is 500 × magnification; fig. 9C is 5,000 × magnification). A blend of different sized clusters (clusters) or granules is found in the figure. The drug is present as discrete particles, as particles that adhere to lactose particles and/or as particles coated on lactose.

Example 5: precipitation of the drug from a non-sprayed organic solution and incorporation thereof into and/or coating onto lactose particles

In this example, 25g of lactose (approx. size: 99% less than 63 μm) was filled into a 300mL container immersed in a thermostated (50 ℃ C.) water bath. 100mL of a 25mg/mL solution of drug in methanol was added to the carrier in the container. The vessel was closed, agitation was started at 1000RPM, and then CO via the vessel was established₂And (4) flowing. After the desired pressure of 1,500psig was reached, the process was continued for about 2 hours. At near atmospheric pressure, CO₂The flow rate was about 45 standard liters/minute. Solvent-supercritical CO bleed₂The mixture was passed through a 60 μm filter and then expanded to atmospheric pressure level. Recovering solvent in cold trap and discharging gaseous CO₂To the atmosphere. In this example, the gaseous fluid acts to dissolve and swell the organic solution to a level where the drug is no longer dissolved in the gaseous fluid-organic solvent mixture.

Example 6: precipitation of the drug from the non-sprayed organic solution and incorporation into and/or coating onto the lactose particles using a solvent reduction, pressure increase and initial sedimentation (setting) step

This example is similar to example 5, with 25g of lactose (approx. size: 99% less than 63 μm) being filled into a 300mL container immersed in a thermostated (50 ℃) water bath. 50mL of the solution was concentrated in methanol to a degree of 50The mg/mL drug solution was added to the carrier in the container. The vessel was closed, stirring was started at 1000RPM, and then the CO was slowly added₂Added to the vessel until the desired pressure of 1,500psig is reached. The stirrer speed was reduced to 20RPM, crystallization was carried out for 30 minutes, and then the introduction of gaseous fluid into the vessel and the flow of solvent-gaseous fluid mixture out of the vessel were resumed to effect drying of the powder mixture. At near atmospheric pressure, CO₂The flow rate of (a) is about 45 standard liters per minute. The agitator speed was increased again to about 1000RPM and the process was continued for 1 hour and 15 minutes. Solvent-supercritical CO bleed₂The mixture was passed through a 60 μm filter and then expanded to atmospheric pressure level. Recovering solvent in cold trap and discharging CO₂The fluid is to atmosphere. The gaseous fluid is used to dissolve and swell the organic solution to a level where the drug is no longer dissolved in the gaseous fluid-organic solvent mixture.

The resulting product was very fluffy, about half the density of the feedstock. No difference was found between this example and the above example 5. Although the material is not dense, it does not adhere and is fluid. The filter has only little coating material. Fig. 10A to 10C show SEM micrographs of the drug-lactose mixture obtained by the method of example 5 (fig. 10A is 40 × magnification; fig. 10B is 200 × magnification; fig. 10C is 5,000 × magnification). These pictures show that small, long particles of the drug are uniformly distributed throughout the mixture in clusters of different sizes. Lactose particles were found to have a similar size to the drug particles. The specific reason why large lactose particles are not observed is not known.

Example 7: precipitating the drug from a sprayed organic solution comprising a binder and incorporating it into and/or coating onto lactose particles with good flowability

In this example, 25g of lactose (approx. size: 75% less than 100 μm) having very good flowability was filled into a 300mL container immersed in a water bath at constant temperature (50 ℃). The vessel was closed, agitation was started at 1000RPM, and CO was then established via the vessel₂And (4) streaming. The required number of times of 2 is reached,after a pressure of 000psig, 200mL of a 50mg/mL drug in methanol and 25mg/mL binder (PVP) solution were sprayed through a 75 μm nozzle at a rate of 1.5mL/min for about 2 * hours. The nozzle tip was positioned 1 inch above the stationary powder bed. After the addition of the solution, the mixture was dried for 1 * hours. The solution rapidly reacts with supercritical CO₂Mixing to make it insoluble in CO₂The drug substance(s) crystallizes rapidly and mixes within the bed. Solvent-supercritical CO bleed₂The mixture was passed through a 60 μm filter and then expanded to atmospheric pressure level. The liquid solvent is recovered in a cold trap and the gaseous fluid is vented to the atmosphere. During this period, CO at near atmospheric pressure flows out₂The flow rate was about 45 standard liters/minute.

Example 8: the drug is precipitated from a sprayed organic solution comprising a binder and incorporated into and/or coated onto lactose particles with good flowability at a moderate deposition rate

This example is similar to example 7, except that the spray rate is 3 mL/min. 200mL of the solution was added over 1 * hours. The mixture was dried for an additional * hours.

Example 9: the drug is precipitated from a sprayed organic solution comprising a binder and incorporated into and/or coated onto lactose particles with good flowability by high speed deposition

This example is similar to example 7 except that the agitation speed was reduced to 300RPM and the spray rate was 5mL/min throughout the process. The entire 200mL of solution was added over about 45 min. The mixture was dried for an additional 1 * hours.

The products produced in the last 3 examples 7, 8 and 9 described above were free flowing and granular. The dry blend is theoretically 25% drug, 12.5% binder and 62.5% lactose. When the spraying rate is increased, the size of the fine particles becomes visually large, which is a phenomenon generally occurring in a granulation method of mixing powder and binder. Fig. 11 is a photomicrograph of the lactose starting material, it is evident that the product has uniform spheres and sizes that promote good flowability. FIGS. 12-19 are SEM micrographs of granulated products of examples 7-9. FIGS. 12 to 15 are those of example 7. Fig. 12(40x) shows that the lactose is uniformly coated, with little granulation or agglomeration of the lactose occurring. Fig. 13(500x) and 14(2,000x) show the deposit as elongated particles and droplets of binder and drug material, which upon solvent extraction form a fused solid mass. Droplets, sometimes clusters, also include lactose and drug fragments. Fig. 15(5,000x) shows that the precipitated microparticles and/or nanoparticles are porous deposits with various binder material contents. In fig. 16(5,000x) of example 8, (medium, 3mL/min spray rate), more coating and smaller elongated particles were found. In fig. 17 to 19 (fig. 17-500 x; fig. 18-5,000 x; fig. 19-10,000 x) of example 9, the high spray rate produced granules of lactose starting material, drug and binder. These figures indicate that there are few individual drug particles, and that the drug is fused or co-precipitated with a binder to form a solid or semi-solid material deposit on and between carrier matrices (lactose).

These examples are also intended to demonstrate the great control over the physical properties of the end product and indirectly the performance and use of these materials. The materials of examples 7, 8 and 9 were used to prepare pharmaceutical tablets of this drug product. As can be seen from the dissolution profiles shown in fig. 20 and 21, the dissolution performance of these tablets is much superior to that of the tablets prepared by the conventional method. FIG. 20 shows the supercritical CO using the process of the present invention compared to tablets prepared by the conventional process at initial time and 12 weeks under standard storage conditions of 40 ℃ and 75% RH₂The melting curve of the tablets prepared from the resulting drug-lactose mixture was processed. Tablets containing supercritical fluid processing materials exhibit a faster dissolution rate after 12 weeks of initial and storage conditions. After storage, the tablets did not show any change in dissolution profile, indicating that the process improves stability. Fig. 21 shows a comparison of dissolution rates of tablets prepared using drug-lactose mixtures obtained by processing of examples 7, 8 and 9. FIG. 21 shows the similarity of the curves, which indicates that at different drug solution spray ratesGood process control is possible. Since the SEM micrograph shows greater contact between the drug and the binder, which can act as a dissolution enhancer, a slightly higher dissolution rate is expected for a spray rate of 5 ml/min. It is believed that at higher spray rates of 5ml/min, the solution first deposits on the carrier particles and precipitation can occur by Supercritical Fluid Extraction (SFE) of the solvent on the carrier particles. As shown in fig. 19, precipitation by Supercritical Fluid Extraction (SFE) can form a thin coating of precipitated material on the carrier particles. It is believed that at lower spray rates, some of the solution droplets may be dried before contacting and spreading on the carrier particles, thereby imparting a particulate nature to the precipitated particles, as evidenced by fig. 15 and 16.

Claims (26)

1. A method of precipitating and retaining particles in a carrier material, comprising the steps of:

(a) (1) dissolving a solid or semi-solid material in a pressurized gaseous fluid to form a solution comprising a gaseous fluid solvent and a dissolved solid or semi-solid material solute, or

(a) (2) dissolving a solid or semi-solid material in a liquid solvent, thereby forming a solution comprising the liquid solvent and a dissolved solid or semi-solid material solute;

(b) (1) precipitating particles of solid or semi-solid material from the gaseous fluid solution generated in (a) (1) by introducing the solution into a zone of low pressure or into a zone containing an inert gas, or

(b) (2) introducing the liquid solution produced in step (a) (2): (1) a region containing a pressurized gaseous fluid in which the liquid solvent is substantially soluble but the solid or semi-solid material is substantially insoluble, or (2) subsequently introducing the pressurized gaseous fluid to solubilize the liquid solvent into the pressurized gaseous fluid and to precipitate particles of the solid or semi-solid material from the liquid solution;

(c) directing the solution introduced in step (b) (1) or (b) (2) and the resulting precipitated particles onto or into a mixed bed of support material;

(d) retaining and dispersing at least some of the precipitated particles in a carrier material to produce a blend of solid or semi-solid material particles and carrier material, a granulating agent of solid or semi-solid material particles and carrier material, a carrier material partially or fully coated with solid or semi-solid material particles, or a mixture thereof;

wherein, at least in steps (c) and (d), the support material in the mixed bed is maintained in a mixed state.

2. A method according to claim 1, wherein the precipitated particles of solid or semi-solid material comprise microparticles or nanoparticles of solid or semi-solid material or a mixture thereof.

3. The method according to claim 1, wherein the solid or semi-solid material is a physiologically active material, an encapsulating material, a moisture barrier material, a light resistant material, a gas protecting material, a diffusion barrier material or a dissolution or diffusion enhancing material.

4. A method according to claim 3, wherein the solid or semi-solid material is a physiologically active material selected from the group consisting of ipratropium bromide, tiotropium bromide, oxitropium bromide and tipranavir.

5. The process according to claim 1, wherein the gaseous fluid is selected from the group consisting of carbon dioxide, nitrous oxide, trifluoromethane, ethane, ethylene, propane, sulfur hexafluoride, propylene, butane, isobutane, pentane, and mixtures thereof.

6. The process according to claim 1, wherein the liquid solvent is selected from water, fatty alcohols, acetone, dichloromethane, ethyl acetate or mixtures thereof.

7. The process according to claim 1, wherein the carrier material is in the form of a powder, granulated powder, tablet, capsule or caplet.

8. A method according to claim 7, wherein the support material is in the form of a powder comprising microparticles or nanoparticles of the support material or a mixture thereof.

9. The method according to claim 1, wherein the carrier material comprises a pharmaceutically acceptable carrier, adjuvant or excipient, or a physiologically active material, or a mixture thereof.

10. The method according to claim 9, wherein the carrier material is a pharmaceutically acceptable carrier, adjuvant or excipient.

11. The process according to claim 1, wherein in steps (c) and (d), the mixed bed of support material is maintained in a mixed state by agitation at a speed of about 20 to 1,000 RPM.

12. The method according to claim 1, wherein step (d) results in a blend of the solid or semi-solid material and the carrier material.

13. The method according to claim 12, wherein the blend of solid or semi-solid material particles and carrier particles produced in step (d) comprises a homogeneous or heterogeneous mixture of carrier material, discrete particles of solid or semi-solid material and carrier material having solid or semi-solid material loosely adhered thereto.

14. A process according to claim 1, wherein step (d) produces a granulation of the solid or semi-solid material with the carrier material.

15. A method according to claim 1 wherein step (d) results in at least some of the carrier material being partially or fully coated with particles of solid or semi-solid material.

16. The process of claim 15, further comprising further coating the coated carrier material produced in step (d) by running one or more coating processes of claim 15 on said coated carrier material, wherein in each coating process the solid or semi-solid material used in the initial or subsequent coating process may be the same or different.

17. The method according to claim 1, wherein said method comprises the steps (a) (1), (b) (1), (c) and (d) as defined in claim 1.

18. The method of claim 17, wherein in step (b) (1), the gaseous fluid solution is introduced into a low pressure zone.

19. A method according to claim 1, wherein said method comprises steps (a) (2), (b) (2), (c) and (d) as defined in claim 1.

20. The method of claim 19, wherein in step (b) (2), the liquid solution is introduced into a zone containing a pressurized gaseous fluid.

21. The method of claim 19, wherein in step (b) (2), the liquid solution is introduced into a zone into which a pressurized gaseous fluid is subsequently introduced.

22. The method according to claim 1, comprising the steps of:

(a) dissolving a solid or semi-solid physiologically active material in a pressurized gaseous fluid, thereby forming a solution comprising a pressurized gaseous fluid solvent and dissolved physiologically active material;

(b) precipitating microparticles and/or nanoparticles of the physiologically active material from the gaseous fluid solution generated in step (a) by introducing the solution into a region of low pressure via a small orifice;

(c) directing the solution and resultant microparticles and/or nanoparticles introduced in step (b) onto or into a mixed bed of a powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable carrier, adjuvant or excipient;

(d) retaining and dispersing at least some of the microparticles and/or nanoparticles produced in step (b) in a powdered carrier material to produce a blend of particles of the physiologically active material and the carrier material, a granulating agent of the particles of the physiologically active material and the carrier material, a carrier material partially or fully coated with the physiologically active material, or a mixture thereof;

wherein, at least in steps (c) and (d), the support material in the mixed bed is maintained in a mixed state.

23. The method of claim 22, wherein: the pressurized gaseous fluid is pressurized carbon dioxide; the carrier material is lactose; the orifice for introducing the gaseous fluid solution is located within the mixed bed of support material when the mixed bed is stationary; at least in steps (c) and (d), the mixed bed of support material is maintained in a mixed state by mixing at a speed of about 300 to 1,000 RPM.

24. The method according to claim 1, comprising the steps of:

(a) dissolving a solid or semi-solid physiologically active material in a liquid solvent to form a solution comprising the liquid solvent and the dissolved physiologically active material;

(b) by introducing the liquid solution produced in step (a): (1) a region containing a pressurized gaseous fluid in which the liquid solvent is substantially soluble but the physiologically active material is substantially insoluble, or (2) subsequently introducing the pressurized gaseous fluid to solubilize the liquid solvent into the pressurized gaseous fluid and precipitate the microparticles and/or nanoparticles, precipitating the microparticles and/or nanoparticles of the physiologically active material from the solution;

(c) directing the solution and resultant microparticles and/or nanoparticles introduced in step (b) onto or into a mixed bed of a powdered carrier material comprising microparticles and/or nanoparticles of a pharmaceutically acceptable carrier, adjuvant or excipient;

(d) retaining at least some of the microparticles and/or nanoparticles produced in step (b) in a powdered carrier material to produce a blend of particles of the physiologically active material and the carrier material, a granulating agent of the particles of the physiologically active material and the carrier material, a carrier material partially or fully coated with the physiologically active material, or a mixture thereof.

Wherein, at least in steps (c) and (d), the support material in the mixed bed is maintained in a mixed state.

25. The method of claim 24, wherein: the liquid solvent is an aliphatic alcohol; the liquid solution is sprayed through an orifice into a region containing a pressurized gaseous fluid, wherein the orifice is located within the mixed bed of support material when the mixed bed is at rest; at least in steps (c) and (d), the mixed bed of support material is maintained in a mixed state by mixing at a speed of about 300 to 1,000 RPM.

26. The method according to claim 25, wherein the solid or semi-solid physiologically active material and the solid or semi-solid binder material are both dissolved in the liquid solution in step (a); the liquid solvent is methanol or ethanol; the pressurized gaseous fluid is pressurized carbon dioxide; the carrier material is lactose.