Nektar Therapeutics

Thar Pharmaceuticals, Inc.

Inhale Therapeutic Systems, Inc.

Mazen H Hanna

Peter York

Ning Shan

Miranda L Cheney

David R Weyna

George Townend

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.

Compositions of particulate coformulation

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.

The invention is directed to novel crystalline forms of lamotrigine. These novel crystalline forms of lamotrigine have improved dissolution and in-vivo absorption profile, as compared to pure lamotrigine. These novel crystalline forms of lamotrigine provide a substantial increase in the blood concentration of lamotrigine, as compared to pure lamotrigine when administered to a subject. These novel crystalline forms of lamotrigine also provide a slower, steady build up of lamotrigine blood concentration suitable for sustained release of lamotrigine in-vivo, as compared to pure lamotrigine.

Crystalline forms of lamotrigine

Process for preparing a cocrystal of an active substance and a cocrystal former, the process involving precipitating the active substance and the cocrystal former together from solution or suspension, in the presence of a supercritical or near-critical fluid, in particular using a GAS, SAS, SEDS or SAS-EM process. The invention also provides a cocrystal prepared using such a process, and its use as a seed crystal in a subsequent process for precipitating a cocrystal of an active substance and a cocrystal former.

Method of creating crystalline substances

The invention is directed to novel crystalline forms of meloxicam. These novel crystalline forms of meloxicam have improved bioavailability, an enhanced rate of dissolution and shorter time to Cin blood, as compared to pure meloxicam.

In vivo studies of crystalline forms of meloxicam

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.

Method of particle formation

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&#x2122; 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.

Particle formation methods and their products

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 their dispersion

The invention provides a method for forming particles of a target substance ( ), involving: (a) preparing a solution or suspension of the substance in a vehicle ( ) which is or includes either a near-critical fluid ( ) or a first supercritical fluid; (b) introducing the solution or suspension into a particle formation vessel ( ); 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. Also provided is apparatus for use in carrying out an embodiment of the method, including a particle formation vessel and means for controlling the temperature and pressure inside it; a fluid mixing vessel and means for controlling the temperature and pressure inside it; first fluid inlet means for introducing into the fluid mixing vessel a vehicle and a solution of a target substance in a primary solvent, so as to form in the fluid mixing vessel a solution of the substance and the primary solvent in the vehicle; and second fluid inlet means for introducing the solution thus formed, preferably together with a second supercritical fluid, into the particle formation vessel. The invention also provides a particulate product formed using the method.

Methods and apparatus for particle formation

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.

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Bradford, United Kingdom

Mazen H Hanna