FIELD

The present technology relates generally to extended release drug delivery devices and more particularly, to porous structures for extended release drug delivery devices.

BACKGROUND

Implantable devices are used to deliver therapeutic agents to a variety of tissues for an extended period of time. Some implanted devices do not provide sustained release of the therapeutic agent for the desired extended period or at the desired therapeutic level. Some of the known implanted devices may rely on polymer membranes or polymer matrices to control the rate of drug release, and many of the known membranes and matrices may be incompatible with at least some therapeutic agents such as ionic drugs and large molecular weight protein drugs in at least some instances. At least some of the known semi-permeable polymer membranes may have permeability that is less than ideal for the extended release of large molecular weight proteins such as antibodies or antibody fragments. At least some of the known semi-permeable membranes can have a permeability of large molecules that may vary over time and at least some of the known semi-permeable membranes can be somewhat fragile, such that drug release for extended periods can be less than ideal in at least some instances. At least some of the proposed devices that rely on pores and capillaries may allow microbes such as bacteria to pass through the capillary and/or pore, such that infection may be spread. At least some of the proposed implanted devices do not provide adequate protection from the patient's immune system, such as from macrophages and antibodies, thereby limiting the therapeutic effect in at least some instances.

In light of the above, it would be desirable to provide improved therapeutic devices and methods that overcome at least some of the above deficiencies of the known therapies, for example with improved drug release that can be maintained when implanted over an extended time.

SUMMARY

In an aspect, described is a therapeutic device for extended release drug delivery including a refillable reservoir configured to receive a therapeutic agent and having an outlet for delivery of the therapeutic agent to a patient from the reservoir over an extended period. A porous structure is coupled near the outlet of the reservoir, the porous structure formed of sintered material. A barrier layer is coupled to the reservoir on or adjacent a surface of the porous structure such that the therapeutic agent passes through both the porous structure and the barrier layer upon delivery from the reservoir through the outlet. The porous structure is tuned to deliver the therapeutic agent at a diffusion rate and the barrier layer is adapted to block passage of particles having an average particle size within an average particle size range that is outside an average particle size range blocked by the porous structure.

The average particle size range blocked by the barrier layer can be greater than about 0.01 um or greater than about 1 nm. The porous structure can have a mean pore size that is between about 3 microns to about 50 microns. The barrier layer can have a mean pore size that is between about 0.01 microns to about 0.1 microns. The surface of the porous structure can be one or both of an inner-facing surface of the porous structure and an outer-facing surface of the porous structure, the inner-facing surface facing the reservoir and the outer-facing surface is on an external side of the reservoir. The barrier layer can be coupled within the reservoir and can be spaced a distance proximal to the inner facing surface of the porous structure. The barrier layer can be a filter membrane formed of silver metal, cellulose acetate, ceramic, glass fiber, borosilicate fiber, mixed cellulose ester (MCE), nylon, polyacrylonitrile (PAN), polycarbonate track etch (PCTE), polyethersulfone (PES), polyester track etch (PETE), polypropylene (PP), PTFE, or PVDF. The sintered material of the porous structure can be stainless steel or titanium.

The porous structure can have pores having a first mean pore size and the barrier layer can be a filter membrane having pores of a second mean pore size. The first mean pore size can be equal to or greater than the second mean pore size. A diffusion rate of the therapeutic agent through the porous structure in the presence of the filter membrane can be substantially the same as the diffusion rate of the therapeutic agent through the porous structure in absence of the filter membrane. The second mean pore size can be effective to block passage of the particles having the average particle size within the average particle size range. The average particle size range of the barrier layer can be equal to or smaller than 0.2 microns and greater than an average particle size range of the therapeutic agent. The particles blocked by the barrier layer can include one or more microbes, bacteria, fungal spores, immune cells, or antibodies. The porous structure can have a first porosity and the barrier layer can have a second porosity. The first porosity can be higher than the second porosity. The first porosity can be from about 16% to about 30% and the second porosity can be from about 1% to about 15%. The porous structure can have a thickness from about 70 microns to about 5000 microns and the barrier layer can have a thickness from about 10 nm to about 150 microns. The barrier layer can mitigate a bolus release of the therapeutic agent through the porous structure upon application of a positive pressure within the reservoir.

In an interrelated aspect, provided is a therapeutic device for extended release drug delivery including a refillable reservoir configured to receive a therapeutic agent and having an outlet for delivery of the therapeutic agent to a patient from the reservoir. A porous structure is coupled near the outlet of the reservoir and is formed of sintered material. A barrier layer is coupled to the reservoir on or adjacent a surface of the porous structure such that the therapeutic agent passes through both the porous structure and the barrier layer upon delivery from the reservoir through the outlet. The barrier layer is configured to block passage of contaminants from entering the eye through the porous structure, or is configured to block passage of contaminants from entering the reservoir through the porous structure, or is configured to block passage contaminants from entering the eye and the reservoir through the porous structure. The contaminants can include one or more of microbes, bacteria, fungal spores, immune cells, and antibodies. The barrier layer can mitigate bolus release of the therapeutic agent upon an increase in pressure within the reservoir.

In an interrelated aspect, provided is a therapeutic device for extended release drug delivery including a refillable reservoir configured to receive one or more therapeutic agents and having an outlet for delivery of the therapeutic agent to a patient from the reservoir. A porous structure is coupled to the reservoir near the outlet from the reservoir. The porous structure is formed of sintered material and has a first porosity and a first mean pore size. A barrier layer is coupled to the reservoir on or adjacent a surface of the porous structure such that the therapeutic agent passes through both the porous structure and the barrier layer upon delivery from the reservoir through the outlet. The barrier layer is a filter membrane having a second porosity and a second mean pore size. The first porosity is greater than the second porosity and the first mean pore size is equal to or greater than the second mean pore size.

In an interrelated aspect, provided is a method of manufacturing a therapeutic device for extended release drug delivery. The method includes selecting a first porous structure having specified characteristics including a porosity (P), a surface area (A), a tortuosity (T), and a thickness (L), wherein the specified characteristics affect molecular diffusion rate of molecules through the first porous structure according to a release rate index=PA/TL. The method includes performing a non-destructive test on the first porous structure to obtain a performance result. The non-destructive test is a gas flow rate test, a bubble point test, or a pressure decay test. The method includes measuring a diffusion rate of a molecule through a second porous structure according to passive, concentration-gradient driven molecular diffusion to obtain a measured diffusion rate. The second porous structure has the same specified characteristics as the first porous structure. The method includes correlating the performance result to the measured diffusion rate to form a correlation. The method includes predicting a measured diffusion rate of the molecule through at least a third porous structure having the specified characteristics using the correlation.

The first porous structure and the second porous structure can be the same porous structure or can be different porous structures. The method can further include forming a porous coating on a porous structure having the specified characteristics. Forming a porous coating can include (a) forming a suspension of sinterable particles in a carrier fluid; (b) coating the porous structure with the suspension using an ultrasonic spray nozzle; and (c) sintering the sinterable particles to the porous structure forming a coated porous structure. The sinterable particles can be stainless steel particles having an average particle size of from 50 nanometers to 350 nanometers. The method can further include performing the non-destructive test on the coated porous structure to obtain a coated structure performance result. The method can further include determining whether the coated structure performance result is significantly different from the performance result of the first porous structure. The method can further include measuring a diffusion rate of the molecule through the coated porous structure to obtain a coated structure diffusion rate. The method can further include predicting a measured diffusion rate of the molecule through the coated porous structure based on the coated structure performance result.

In an interrelated aspect, disclosed is a therapeutic device for extended release drug delivery having a refillable reservoir configured to hold one or more therapeutic agents and having an outlet for delivery of the one or more therapeutic agents to a patient from the reservoir. A porous structure is coupled to the reservoir near the outlet. The porous structure is formed of sintered material and has a first porosity and a first mean pore size. A barrier layer is on or adjacent a surface of the porous structure such that the one or more therapeutic agents pass through both the porous structure and the barrier layer upon delivery from the reservoir through the outlet. The barrier layer has a second porosity and a second mean pore size. The first porosity is greater than the second porosity and the first mean pore size is equal to or greater than the second mean pore size. The barrier layer is formed of a coating of stainless steel particles or a coating of titanium particles sintered to the surface of the porous structure.

The surface of the porous structure can be one or both of an inner-facing surface of the porous structure and an outer-facing surface of the porous structure, the inner-facing surface facing the reservoir and the outer-facing surface is on an external side of the reservoir. The first mean pore size of the porous structure can be between about 3 microns to about 50 microns. A diffusion rate of the one or more therapeutic agents through the porous structure having the barrier layer can be substantially the same as a diffusion rate of the one or more therapeutic agents through the porous structure in absence of the barrier layer. The second mean pore size can be effective to block passage of the second size molecule. The second size molecule can be equal to or greater than 0.2 microns. The second mean pore size can be 0.2 microns. The barrier layer can block passage of a second size molecule to inhibit the second size molecule from passing from the reservoir to outside the device. The second size molecule can be one or more microbes or other contaminants described herein. The barrier layer can block passage of a second size molecule to inhibit the second size molecule from passing into the reservoir from outside the device. The second size molecule can include one or more microbes or immune cells or other contaminants. The first porosity can be from about 16% to about 30% and the second porosity can be from about 1% to about 15%. The porous structure can have a thickness from about 70 microns to about 5000 microns and the barrier layer can have a thickness from about 10 nm to about 150 microns. The barrier layer can mitigate a bolus release of the one or more therapeutic agents through the porous structure upon application of a positive pressure within the reservoir.

In an interrelated aspect, disclosed is a method of manufacturing a therapeutic device for extended release drug delivery including selecting a first porous structure having specified characteristics including a titanium particle size, a porosity and a thickness; performing a non-destructive test on the first porous structure to obtain a performance result. The non-destructive test is a gas flow rate test, a bubble point test, or a pressure decay test. The method includes measuring a diffusion rate of a molecule through a second porous structure according to passive, concentration-gradient driven molecular diffusion to obtain a measured diffusion rate. The second porous structure has the same specified characteristics as the first porous structure. The method includes correlating the performance result to the measured diffusion rate to form a correlation; and predicting a measured diffusion rate of the molecule through at least a third porous structure having the specified characteristics using the correlation.

The first porous structure and the second porous structure can be the same porous structure or can be different porous structures. The method can further include forming a porous coating on a porous structure having the specified characteristics comprises depositing a thin film titanium coating on the porous structure using plasma enhanced chemical vapor deposition to obtain a coated porous structure. The method can further include performing the non-destructive test on the coated porous structure to obtain a coated structure performance result. The method can further include determining whether the coated structure performance result is significantly different from the performance result of the first porous structure. The method can further include measuring a diffusion rate of the molecule through the coated porous structure to obtain a coated structure diffusion rate. The method can further include predicting a measured diffusion rate of the molecule through the coated porous structure based on the coated structure performance result.

In some variations, one or more of the following can optionally be included in any feasible combination in the above methods, apparatus, devices, and systems. More details of the devices, systems, and methods are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings.

