Acusphere, Inc.

Greg Randall

Howard Bernstein

Julie A Straub

Donald E Chickering, Iii

Sarwat Khattak

David H Altreuter

Mark J Keegan

Paul Kopesky

Donald E Chichering, Iii

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Porous drug matrices and methods of manufacture thereof

Paclitaxel is provided in a porous matrix form, which allows the drug to be formulated without Cremophor and administered as a bolus. The paclitaxel matrices preferably are made using a process that includes (i) dissolving paclitaxel in a volatile solvent to form a paclitaxel solution, (ii) combining at least one pore forming agent with the paclitaxel solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of paclitaxel. The pore forming agent can be either a volatile liquid that is immiscible with the paclitaxel solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. In a preferred embodiment, microparticles of the porous paclitaxel matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Porous paclitaxel matrices and methods of manufacture thereof

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

One or more COX-2 inhibitors are provided in a porous matrix form wherein the dissolution rate of the drug is enhanced when the matrix is contacted with an aqueous medium. The porous matrix yields upon contact with an aqueous medium nanoparticles and microparticles of COX-2 inhibitors having a mean diameter between about 0.01 and 5 &mgr;m and a total surface area greater than about 0.5 m /mL. The dry porous matrix preferably is in a dry powder form having a TAP density less than or equal to 1.0 g/mL. The porous COX-2 inhibitor matrices preferably are made using a process that includes (i) dissolving one or more COX-2 inhibitors in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of COX-2 inhibitors. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug.

Porous COX-2 inhibitor matrices and methods of manufacture thereof

Celecoxib is provided in a porous matrix form wherein the dissolution rate of the drug is enhanced when the matrix is contacted with an aqueous medium. The porous matrix yields upon contact with an aqueous medium nanoparticles and microparticles of celecoxib having a mean diameter between about 0.01 and 5 &mgr;m and a total surface area greater than about 0.5 m /mL. The dry porous matrix preferably is in a dry powder form having a TAP density less than or equal to 1.0 g/mL. The porous celecoxib matrices preferably are made using a process that includes (i) dissolving celecoxib in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the dry porous matrix of celecoxib. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug.

Porous celecoxib matrices and methods of manufacture thereof

Improved spray drying apparati, and methods of use thereof, have been developed. The spray drying equipment includes a primary drying chamber and a secondary drying apparatus which includes tubing having a length sufficient to increase the contact time between the drying gas and the droplets/particles to dry the particles to the extent desired, at a drying rate and temperature which would be too low to provide adequate drying without the secondary drying apparatus. The secondary drying apparatus increases the drying efficiency of the spray dryer system without increasing the drying rate, while minimizing loss in yield. Te secondary drying apparatus can include multiple secondary apparati, which are independently controlled for temperature and/or have different dimensions (cross-sectional areas and/or lengths), to allow for optimization of drying conditions. For example, in one embodiment, the temperatures of the secondary appararati are set to gradually increase, or decrease, enabling the particles to be dried at multiple temperatures and drying conditions. In another embodiment, the apparati have different dimensions to alter the velocity at which the particles are dried, to accommodate changes in particle aggregation or other properties affecting product yield. A preferred application for the spray drying process and equipment is in the production of microparticles, between about 1 and 200 &mgr;m in diameter, which can be used to deliver therapeutic and diagnostic agents.

Spray drying apparatus and methods of use

Improved spray drying methods of have been developed. The spray drying method includes use of a primary drying chamber and a secondary drying apparatus which includes tubing having a length sufficient to increase the contact time between the drying gas and the droplets/particles to dry the particles to the extent desired, at a drying rate and temperature which would be too low to provide adequate drying without the secondary drying apparatus. The secondary drying apparatus increases the drying efficiency of the spray dryer system without increasing the drying rate, while minimizing loss in yield. The ratio of the length of tubing to the length of the primary drying chamber is at least 2:1. The tubing diameter is substantially smaller than the diameter of the primary drying chamber, such that the particles move at higher velocity through the tubing to minimize product losses. The ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing most preferably is about 16:1. The tubing preferably is in a compact coil design, which can more easily be transported and which has minimum space requirements, and may optionally include a jacket to control the temperature of the secondary drying process. A preferred application for the spray drying process and equipment is in the production of microparticles, between about 1 and 200 &mgr;m in diameter, which can be used to deliver therapeutic and diagnostic agents.

Spray drying method

Improved spray drying apparati, and methods of use thereof, have been developed. The spray drying equipment includes a primary drying chamber and a secondary drying apparatus which includes tubing having a length sufficient to increase the contact time between the drying gas and the droplets/particles to dry the particles to the extent desired, at a drying rate and temperature which would be too low to provide adequate drying without the secondary drying apparatus. The secondary drying apparatus increases the drying efficiency of the spray dryer system without increasing the drying rate, while minimizing loss in yield The ratio of the length of tubing to the length of the primary drying chamber is at least 2:1. The tubing diameter is substantially smaller than the diameter of the primary drying chamber, such that the particles move at higher velocity through the tubing to minimize product losses. The ratio of the cross-sectional area of the primary drying chamber to the cross-sectional area of the tubing most preferably is about 16:1. The tubing preferably is in a compact coil design, which can more easily be transported and which has minimum space requirements, and may optionally include a jacket to control the temperature of the secondary drying process. A preferred application for the spray drying process and equipment is in the production of polymeric microparticles, between about 1 and 200 &mgr;m in diameter, which can be used to deliver therapeutic and diagnostic agents.

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Somerville, MA, United States of America

Greg Randall