Ferro Corporation

Ferro Pfanstiehl Laboratories, Inc.

Pratibhash Chattopadhyay

Boris Y Shekunov

Jeffrey S Seitzinger

Robert W Huff

Adam K Gibson

K Adam Gibson

A method of producing solid composite lipid/drug nanoparticles that includes the steps of: (1) dissolving a lipid and a drug in a suitable organic solvent to form a solution; (2) emulsifying the solution in a liquid to form an emulsion having a discontinuous phase of micelles comprising the organic solvent, the drug and the lipid, and a continuous phase comprising the liquid; and (3) contacting the emulsion with a supercritical fluid under conditions suitable to keep the supercritical fluid in a supercritical state, whereby the supercritical fluid extracts the organic solvent from the micelles, causing them to precipitate as organic-solvent free solid composite lipid/drug nanoparticles suspended or dispersed in the liquid.

Method for producing solid-lipid composite drug particles

The present invention provides methods and apparatus for producing particles via supercritical fluid processing. In one embodiment, the method includes expanding a supercritical fluid plasticized melt across a pressure drop to form solid composite particles that are simultaneously dispersed, foamed and cooled, and milling the solid particles produced to achieve the desired size distribution. In another embodiment, a pressure vessel containing a supercritical fluid plasticized melt is depressurized to form a cooled solid porous mass, which is then milled to obtain solid composite particles.

Method and apparatus for enhanced size reduction of particles

The present invention provides a method for the production of porous particles that involves extracting an organic solvent from a water-in-oil-in-water emulsion. In accordance with the method of the invention, a first aqueous solution including a porosity-promoting agent is emulsified into an organic solution including a therapeutic constituent and, optionally, a matrix material to form a water-in-oil emulsion. The water-in-oil emulsion is then emulsified into a second aqueous solution including a surfactant to form the water-in-oil-in-water emulsion. Extraction of the organic solvent from the water-in-oil-in-water emulsion, such as by supercritical fluid extraction, causes the therapeutic constituent and optional matrix material to precipitate and thus form an aqueous suspension of porous particles. The aqueous suspension can be centrifuged, filtered and lyophilized to obtain dry porous particles suitable for use in the deep lung delivery of drugs and other therapeutic agents.

Method for the production of porous particles

The present invention provides an apparatus and methods of producing particles that include a polymer, a wax and/or lipid and, optionally, a biologically active substance. In accordance with the methods of the invention, a load stock including a polymer, a wax and/or a lipid that is a solid at standard temperature and pressure and, optionally, a biologically active substance is provided. The load stock is contacted with a supercritical fluid to form a melt. The melt is contacted with a polar solvent under suitable conditions to form an emulsion. The emulsion is expanded across a pressure drop to form solid particles that include the load stock. The methods and apparatus facilitate the production of very small particles that have a narrow particle size distribution.

Method and apparatus for supercritical fluid assisted particle production

The present invention provides a method of producing porous structures, particles or matrixes, which may be comprised of one or a plurality of components, an apparatus for carrying out the method and particles formed in accordance with the method. The method is particularly suitable for producing porous composite or pure particles for pharmaceutical applications. In accordance with the method, a composite comprising a material such as a pharmaceutical, a biodegradable polymers and/or a biological agent is formed. The composite must further comprise a material that is soluble in supercritical fluid. Extraction of the supercritical fluid soluble material produces porous structures, which may be in the form of particles or matrixes.

Production of porous materials by supercritical fluid processing

The present invention provides a method of forming particles using supercritical fluid (SCF). In accordance with the method, one or more growth retardant compounds having both SCF-philic and SCF-phobic groups are present when one or more solute materials reach a supersaturation point and begin to form particle nuclei. The growth retardant compounds can reduce the particle growth rate, increase the nucleation rate and also prevent particle agglomeration. Preferred growth retardant compounds include sugar acetates and fluorocarbons.

Nanoparticles from supercritical fluid antisolvent process using particle growth and agglomeration retardants

The present invention provides methods for purifying polymers. In each embodiment of the invention disclosed herein, a supercritical fluid is contacted with an organic solution that includes a polymer to be purified dissolved in an organic solvent. The supercritical fluid extracts the organic solvent from the organic solution. Impurities such as residual monomers and process solvents are removed with the organic solvent and supercritical fluid, thereby purifying the polymer. The methods of the invention are particularly suitable for use in the purification of biodegradable polymers for use in pharmaceutical applications.

Methods for the purification of polymers

Emulsions for use in precipitating water-insoluble drug nanoparticles. The continuous phase of the emulsions include water and an external surfactant. The discontinuous phase of the emulsions include butyl lactate, a co-solvent, an internal surfactant and a water-insoluble drug that is solubilized in the discontinuous phase. The emulsions allow for the precipitation of nanoparticles of water-insoluble drugs that are otherwise difficult or impossible to precipitate using conventional emulsion techniques.

Butyl lactate emulsions for the precipitation of water-insoluble drug nanoparticles

The present invention provides a method of producing particles via a supercritical fluid processing technique, an apparatus for carrying out the method and the particles produced thereby. The method includes: (1) providing: a supercritical fluid; a first solvent that is soluble in the supercritical fluid; a second solvent that is substantially insoluble in the supercritical fluid and is at least partially soluble in or miscible with the first solvent; and a solute that is soluble in the first solvent and is substantially insoluble in the second solvent and the supercritical fluid; (2) contacting the first solvent, the second solvent and the solute together to form a solution; and (3) contacting the solution with the supercritical fluid to extract the first solvent from the solution and precipitate the solute in the form of particles that are suspended in the second solvent.

Method and apparatus for producing particles using supercritical fluid

The present invention provides methods for producing composite particles using supercritical fluid as a plasticizing and extracting agent, composite particles formed in accordance with the methods and an apparatus for carrying out the methods. In accordance with the methods of the invention, a polymer, a wax and/or a lipid that is a solid at standard temperature and pressure is contacted with a supercritical fluid to form a melt, either before or after the polymer, wax and/or lipid has been contacted with a solution comprising a solute dissolved in a solvent. The supercritical fluid plasticizes the polymer, wax and/or lip and extracts the solvent from the solution, resulting in the formation of a two-fraction system including a first melt-rich fraction that includes the plasticized melt and fine particles of precipitated solute that are dispersed in the melt, and a second fraction that includes the supercritical fluid and the solvent. Expansion of the first fraction across a pressure drop results in the formation of composite particles that include the polymer, wax and/or lipid and the solute.

Method and apparatus for producing composite particles using supercritical fluid as plasticizing and extracting agent

The present invention provides a method of producing particles from solution-in-supercritical fluid or compressed gas emulsions. In accordance with the method of the invention, a solution that includes a solute dissolved in a solvent is contacted with supercritical fluid or compressed gas to form a solution-in-supercritical fluid or compressed gas emulsion. The emulsion is sprayed through an orifice to create spray droplets. The supercritical fluid or compressed gas and the solvent are removed from the spray droplets resulting in the formation of particles that include the solute. In one embodiment of the invention, the solvent is removed from the spray droplets by lyophilization. In another embodiment of the invention, the solvent is removed from the spray droplets by evaporation.

Method for preparation of particles from solution-in-supercritical fluid or compressed gas emulsions

The present invention provides a method of forming particles that involves contacting a solution, which includes a solute and/or other material to be precipitated dissolved or dispersed in a solvent, with a first compressed or liquefied gas at an initial temperature to form a mixture. The mixture is then expanded at a first temperature to form droplets. Depending upon the composition of the droplets and the first temperature, the droplets may be in a solid state or a liquid state. The droplets are then contacted with an extracting fluid at a second temperature to extract the solvent from the droplets. The method can be used to produce micro and nanoparticles suitable for various drug delivery systems.

Method of forming particles

A method and an apparatus for continuously producing particles from an emulsion by supercritical fluid extraction. The emulsion includes a solute suspended or dissolved in the supercritical fluid soluble first phase. The supercritical fluid and the emulsion contact each other such that the first phase dissolves from the emulsion into the supercritical fluid and the solute precipitates to form a suspension in a non supercritical fluid soluble second phase of the emulsion. The supercritical fluid carries away the dissolved first phase. The solvent bearing supercritical fluid, together with the solute suspended in the second phase, is removed from an extraction chamber at a rate that is about the same as a rate that the emulsion and the supercritical fluid flow into the extraction chamber. Thus, a constant mass and pressure is maintained in the extraction chamber and the particles are produced continuously.

Method and apparatus for continuous particle production using supercritical fluid

A method and apparatus for producing particles, the apparatus includes a solution source that supplies a solution, and a fluid source that supplies a fluid. The solution includes a solvent and a solute. A mixer receives the solution and the fluid from the sources, and mixes the solution and the fluid together to form a mixture. The mixture is supplied from the mixer to an expansion assembly at first pressure. The expansion assembly sprays and expands the mixture substantially simultaneously to form frozen droplets, and preferably to form a low-density powder of frozen droplets. A freeze-dry apparatus sublimes the solvent from the particles. A high mass-transfer rate and a uniform open-structure of the powder bed enhances the freeze-drying process. Solid particles having a controlled size distribution are obtained. The particles preferably have a hollow or porous morphology suitable for differing drug delivery applications to include aerosol formulations.

Lyophilization method and apparatus for producing particles

A method of producing microparticles and nanoparticles of a solute via the extraction of solvent, having the solute dissolved therein, from an emulsion using a supercritical fluid. The solute to be precipitated is dissolved in the solvent to form a solution, and the solution is dispersed in an immiscible or partially miscible liquid to form an emulsion. The particles are produced via the extraction of the solvent from the emulsion using the supercritical fluid. The process can produce an aqueous suspension of particles that are substantially insoluble in water, and the solvents used in the process to form the emulsion initially can be recovered and recycled.

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North Royalton, OH, United States of America

Pratibhash Chattopadhyay