Abstract: Embodiments of the invention relate to particles of active substances, methods for preparing the particles, formulations containing the particles, and metered dose inhalers containing the particles or formulations. In one embodiment, an inhaler contains an aerosol formulation containing a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 ?m. The particles may be suspended in a nonsolvent hydrofluorocarbon fluid vehicle (e.g., HFA 134a or 227ea) at a concentration within a range from about 0.2% w/v to about 5% w/v. The formulation exhibits a flocculation volume of about 85% or greater about 1 minute after mixing the particulate active substance and the vehicle. The particulate active substance may contain salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, or derivatives thereof. In some examples, the active substance is dihydroergotamine mesylate.

Abstract: The present invention provides a method of producing a co-crystal, the method comprising the steps of providing a first substance and a second substance, wherein the first and second substances are compatible to form a co-crystal, mixing said first and second substances together, and exposing the mixture of said first and second substances to prolonged and sustained conditions of pressure and shear, sufficient to form a co-crystal of said first and second substance. The prolonged and sustained conditions of pressure and shear are preferably applied in an extrusion process. Associated compositions and uses thereof are also provided.

Abstract: Embodiments of the invention provide a composition of a particulate coformulation which includes particles containing an active substance and an additive, wherein each particle contains a relative additive concentration increasing radially outwards from a particle center to a particle surface along a finite gradient. In one example, the particle surface is an additive-rich surface without a distinct physical boundary between the particle center and the particle surface. The relative additive concentration may have a continuous rate of change across the finite gradient. In some examples, an active substance:additive ratio of the particle surface is sufficiently low to form a protective surface layer around the active substance. Generally, the particle surface is free of the active substance.

Abstract: Embodiments of the invention relate to particles of active substances, methods for preparing the particles, formulations containing the particles, and metered dose inhalers containing the particles or formulations. In one embodiment, an inhaler contains an aerosol formulation containing a particulate active substance of non-micronized, solid particles having a mass median aerodynamic diameter of less than 10 ?m. The particles may be suspended in a nonsolvent hydrofluorocarbon fluid vehicle (e.g., HFA 134a or 227ea) at a concentration within a range from about 0.2% w/v to about 5% w/v. The formulation exhibits a flocculation volume of about 85% or greater about 1 minute after mixing the particulate active substance and the vehicle. The particulate active substance may contain salmeterol xinafoate, budesonide, salbutamol sulfate, dihydroergotamine mesylate, risperidone-(9-hydroxy)-palmitate, bromocriptine mesylate, or derivatives thereof. In some examples, the active substance is dihydroergotamine mesylate.

Abstract: The present invention relates to active substances in particulate form, to methods for preparing them, to formulations containing them and to uses of such substances and formulations. A preferred embodiment is directed to particulate suspensions having improved flocculation behavior in a suspension vehicle, such as a hydrofluoroalkane propellant used in metered dose inhalers.

Abstract: A low resistance fuse apparatus and methods of manufacture includes a first intermediate insulation layer, a second intermediate insulation layer, and a free standing fuse element layer independently formed and fabricated from each of the first and second intermediate insulation layers, The fuse element layer includes first and second contact pads and a fusible link extending therebetween. The first and second intermediate insulation layers extend on opposite sides of the free standing fuse element layer and are laminated together with the fuse element layer therebetween.

Abstract: A low resistance fuse apparatus and methods of manufacture includes a first intermediate insulation layer, a second intermediate insulation layer, and a free standing fuse element layer independently formed and fabricated from each of the first and second intermediate insulation layers, The fuse element layer includes first and second contact pads and a fusible link extending therebetween. The first and second intermediate insulation layers extend on opposite sides of the free standing fuse element layer and are laminated together with the fuse element layer therebetween.

Abstract: The invention provides a method for forming particles of a target substance, comprising (a) co-introducing into a particle formation vessel, under controlled temperature and pressure, a supercritical or near-critical anti-solvent fluid; a first target substance in a first vehicle; and a second target substance in a second vehicle; and (b) using the anti-solvent to disperse the target substances in their respective vehicles and to extract the vehicles, substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation vessel. The second vehicle is immiscible with the first, and contact between the first and second vehicles occurs a sufficiently short period of time before their dispersion by the anti-solvent, and with sufficient physical mixing, as to allow only insignificant, if any, phase separation to occur between the two vehicles between their contact with one another and their dispersion.

Abstract: Preparation of particles of an active substance having a layer of an additive at the particle surfaces, by dissolving both the active substance and the additive in a vehicle to form a target solution, and contacting the target solution with an anti-solvent fluid using a SEDS™ particle formation process, to cause the active substance and additive to coprecipitate. The additive is typically a protective additive, in particular a taste and/or odour masking agent. Also provided is a particulate coformulation made by the method, which has a finite gradient in the relative additive concentration, which concentration increases radially outwards from the active-rich core to the additive-rich surface of the particles.

Abstract: The invention provides a method for forming particles of a substance, by co-introducing into a particle formation vessel, in which the temperature and pressure are controlled, of a supercritical fluid; a solution or suspension of the substance in a first vehicle; and a second vehicle which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid, in such a way that dispersion of the solution or suspension and the second vehicle, and extraction of the vehicles, occur substantially simultaneously and substantially immediately on introduction of the fluids into the vessel, by the action of the supercritical fluid.

Abstract: The invention provides a method for forming particles of a target substance, comprising (a) co-introducing into a particle formation vessel, under controlled temperature and pressure, a supercritical or near-critical anti-solvent fluid; a “target solution or suspension” of the target in a first vehicle; and a second vehicle which is soluble in the anti-solvent fluid; and (b) using the anti-solvent to disperse the target solution/suspension and the second vehicle, and to extract the vehicles, substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation vessel, wherein the second vehicle is immiscible with the first, and wherein contact between the target solution/suspension and the second vehicle occurs a sufficiently short period of time before their dispersion by the anti-solvent, and with sufficient physical mixing, as to allow only insignificant, if any, phase separation to occur between the two vehicles between their contact with one another and thei

Abstract: The invention provides a method for forming particles of a target substance, comprising (a) co-introducing into a particle formation vessel, under controlled temperature and pressure, a supercritical or near-critical anti-solvent fluid; a “target solution or suspension” of the target in a first vehicle; and a second vehicle which is soluble in the anti-solvent fluid; and (b) using the anti-solvent to disperse the target solution/suspension and the second vehicle, and to extract the vehicles, substantially simultaneously and substantially immediately on introduction of the fluids into the particle formation vessel, wherein the second vehicle is immiscible with the first, and wherein contact between the target solution/suspension and the second vehicle occurs a sufficiently short period of time before their dispersion by the anti-solvent, and with sufficient physical mixing, as to allow only insignificant, if any, phase separation to occur between the two vehicles between their contact with one another and thei

Abstract: The invention provides a method for forming particles of a target substance (26), involving: (a) preparing a solution or suspension of the substance in a vehicle (21) which is or includes either a near-critical fluid (21) or a first supercritical fluid; (b) introducing the solution or suspension into a particle formation vessel (32); and (c) contacting the solution or suspension, in the particle formation vessel, with a second supercritical fluid, under conditions which allow the second supercritical fluid to cause precipitation of particles of the target substance from the solution or suspension; wherein the second supercritical fluid is miscible or substantially miscible with the vehicle and is a fluid in which the target substance is insoluble or substantially insoluble.

Abstract: The present invention relates to active substances in particulate form, to methods for preparing them and to their uses. The present invention provides particulate powders, such as might be of use for delivery using a dry powder inhaler (DPI) or similar delivery device, having properties which may be beneficial to the DPI delivery process.

Abstract: The present invention relates to active substances in particulate form, to methods for preparing them, to formulations containing them and to uses of such substances and formulations. A preferred embodiment is directed to particulate suspensions having improved flocculation behaviour in a suspension vehicle, such as a hydrofluoroalkane propellant used in metered dose inhalers.

Abstract: The invention provides a method for forming particles of a target substance (26), involving: (a) preparing a solution or suspension of the substance in a vehicle (21) which is or includes either a near-critical fluid (21) or a first supercritical fluid; (b) introducing the solution or suspension into a particle formation vessel (32); and (c) contacting the solution or suspension, in the particle formation vessel, with a second super-critical fluid, under conditions which allow the second supercritical fluid to cause precipitation of particles of the target substance from the solution or suspension; wherein the second supercritical fluid is miscible or substantially miscible with the vehicle and is a fluid in which the target substance is insoluble or substantially insoluble.

Abstract: The invention provides a method and apparatus for forming particles of a substance, comprising (a) introducing into a particle formation chamber, the temperature and pressure in which are controlled, a first supercritical fluid (SCF) and a solution or suspension of the substance in a vehicle, (b) simultaneously introducing an impinging flow of a second supercritical fluid (SCF), at an angle to, and directed at, the direction of flow of the first supercritical fluid, so as to increase the amount of kinetic energy transferred to the solution or suspension; and (c) using either or both of the first and the second supercritical fluids to disperse the solution or suspension, and to extract the vehicle from it, substantially simultaneously and substantially immediately on introduction of the fluids into the particle chamber.

Abstract: The invention provides a method and apparatus for forming particles of a substance, comprising (a) introducing into a particle formation chamber, the temperature and pressure in which are controlled, a first supercritical fluid (SCF) and a solution or suspension of the substance in a vehicle; (b) simultaneously introducing an impinging flow of a second supercritical fluid (SCF), at an angle to, and directed at, the direction of flow of the first supercritical fluid, so as to increase the amount of kinetic energy transferred to the solution or suspension; and (c) using either or both of the first and the second supercritical fluids to disperse the solution or suspension, and to extract the vehicle from it, substantially simultaneously and substantially immediately on introduction of the fluids into the particle chamber.

Abstract: Preparation of particles of an active substance having a layer of an additive at the particle surfaces, by dissolving both the active substance and the additive in a vehicle to form a target solution, and contacting the target solution with an anti-solvent fluid using a SEDS™ particle formation process, to cause the active substance and additive to coprecipitate. The additive is typically a protective additive, in particular a taste and/or odour masking agent. Also provided is a particulate coformulation made by the method, which has a finite gradient in the relative additive concentration, which concentration increases radially outwards from the active-rich core to the additive-rich surface of the particles.

Abstract: The invention provides a method for forming particles of a substance, by co-introducing into a particle formation vessel, in which the temperature and pressure are controlled, of a supercritical fluid; a solution or suspension of the substance in a first vehicle; and a second vehicle which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid in such a way that dispersion of the solution or suspension and the second vehicle, and extraction of the vehicles, occur substantially simultaneously and substantially immediately on introduction of the fluids into the vessel, by the action of the supercritical fluid.