Implantable device for long-term delivery of drugs
Inventors
Martin, Francis J. • Kang, Ling-Ling
Assignees
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Publication Number
US-9561352-B2
Publication Date
2017-02-07
Expiration Date
Abstract
A device for sustained delivery of a poorly water soluble drug is described. A drug reservoir within the device, when in operation, contains an aqueous suspension of the drug mixed with a suspension of an excipient that, in one embodiment, generates acidic groups for a sustained period of time to maintain a desired pH in the aqueous suspension that in turn provides a constant concentration of a soluble form of the drug.
Core Innovation
The invention relates to an implantable long-term drug delivery device for poorly water-soluble drugs. The device includes a non-erodible, non-porous housing member defining a reservoir, with a water impermeable outer surface and first and second opposing ends. The reservoir contains an aqueous suspension in which a sparingly water soluble drug is present in a soluble form and an insoluble form.
A solubility-modifying excipient is included in the reservoir and is capable of generating acid groups when the drug formulation is hydrated. This provides a concentration of the drug in the aqueous suspension while the device releases a therapeutic dose. The internal pH is maintained by continuous generation of acidic groups, and the soluble form is able to freely diffuse out of the device.
Release is governed by the coexistence of soluble and insoluble drug forms and by a porous partition positioned in the first end of the housing member. The insoluble form is retained in the reservoir, while the soluble form diffuses through the porous partition, creating a maintained concentration gradient. This enables release of the therapeutic dose over a period of between about 2 and 12 months, with release dependent on pH of the drug formulation and independent of pore size of the porous partition.
The document further supports implementations in which the porous partition can be selected from porous polymer membranes, sintered metallic membranes, or ceramic membranes, including microporous/nanopore membranes. Solubility-modifying excipients are described that generate acidic groups, including degradable/biodegradable polymers such as PLGA. Example drugs explicitly discussed include risperidone and asenapine, with described sustained release behavior and improved plasma levels when the acid-generating excipient is included.
Claims Coverage
The independent claim defines a long-term implantable drug delivery device with four co-operating inventive features. The main coverage concerns pH-dependent, pore-size-independent release driven by diffusion of a soluble drug fraction across a porous partition while insoluble drug is retained, sustained by an acid-generating solubility-modifying excipient.
Non-erodible, non-porous water-impermeable housing reservoir
A drug delivery device comprising a non-erodible, non-porous housing member defining a reservoir, the housing member having a water impermeable outer surface and first and second opposing ends.
Porous partition retaining insoluble drug while permitting soluble diffusion
A porous partition positioned in the first end of the housing member, wherein the contained sparingly water soluble drug has a soluble form and an insoluble form, and the insoluble form of the drug is retained in the reservoir while the soluble form freely diffuses out of the device across the partition.
Acid-group generating solubility-modifying excipient for pH-dependent drug concentration
A drug formulation comprised of a sparingly water soluble drug and a solubility-modifying excipient, wherein the solubility-modifying excipient is capable of generating acid groups to provide a concentration of the drug in an aqueous suspension when the drug formulation is hydrated, thereby providing release of a therapeutic dose.
Long-term therapeutic-dose release over 2–12 months independent of pore size
Release of the therapeutic dose from the device over a period of between about 2-12 months, wherein release is dependent on pH of the drug formulation and independent of pore size of the porous partition.
Overall, the claim set is directed to a device architecture that couples an acid-generating solubility-modifying excipient with retention of an insoluble drug fraction and diffusion of a soluble fraction through a porous partition, yielding long-term therapeutic-dose release over about 2–12 months with pore-size independence.
Stated Advantages
Provides release of a therapeutic dose of the drug from the device over a period of between about 2-12 months.
Release is dependent on pH of the drug formulation and independent of pore size of the porous partition.
Sustained risperidone release and improved plasma levels are described when PLGA acid-generating excipients are included compared to devices lacking such excipients.
Documented Applications
Subcutaneous implantation for long-term drug delivery with sustained release is described.
A risperidone application is described, including in vitro and in vivo sustained release and improved plasma levels when acid-generating excipients are included.
An asenapine application is described, illustrating output-rate boosting associated with PLGA-based acid/salt formation.
Buprenorphine is mentioned as an example drug.
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