Design, development, and evaluation of a scalable micro perforated drug delivery device capable of long-term zero order release
Year: 2009
Type: article
Abstract: Chronic diseases can often be managed by constantly delivering therapeutic \namounts of drug for prolonged periods. A controlled release for extended duration \nwould replace the need for multiple and frequent dosing. Local drug release would \nprovide added benefit as a lower dose of drug at the target site will be needed as \nopposed to higher doses required by whole body administration. This would provide \nmaximum efficacy with minimum side effects. \nNonetheless, a problem with the known implantable drug delivery devices is \nthat the delivery rate cannot be controlled, which leads to drug being released in an \nunpredictable pattern resulting in poor therapeutic management of patients. This \ndissertation is the result of development of an implantable drug delivery system that is \ncapable of long-term zero order local release of drugs. The device can be optimized to deliver any pharmaceutical agent for any time period up to several years maintaining a \ncontrolled and desired rate. \nInitially significant efforts were dedicated to the characterization, \nbiocompatibility, and loading capacity of nanoporous metal surfaces for controlled \nrelease of drugs. The physical characterization of the nanoporous wafers using \nScanning electron microscropy (SEM) and atomic force microscopy techniques (AFM) \nyielded 3.55 x 10⁴ nm³ of pore volume / μm² of wafer surface. In vitro drug release \nstudy using 2 - octyl cyanoacrylate and methyl orange as the polymer-drug matrix was \nconducted and after 7 days, 88.1 ± 5.0 % drug was released. However, the initial goal \nto achieve zero order drug release rates for long periods of time was not achieved. \nThe search for a better delivery system led to the design of a perforated \nmicrotube. The delivery system was designed and appropriate dimensions for the \ndevice size and hole size were estimated. Polyimide microtubes in different sizes (125-1000 μm) were used. Micro holes with dimensions ranging from 20-600 μm were \nfabricated on these tubes using photolithography, laser drilling, or manual drilling procedures. \nSmall molecules such as crystal violet, prednisolone, and ethinyl estradiol were \nsuccessfully loaded inside the tubes in powder or solution using manual filling or \ncapillary filling methods. A drug loading of 0.05 – 5.40 mg was achieved depending \non the tube size and the drug filling method used. \nThe delivery system in different dimensions was characterized by performing \nin vitro release studies in phosphate buffered saline (pH 7.1-7.4) and in vitreous humor from the rabbit’s eye at 37.0 ± 1.0°C for up to four weeks. The number of holes was varied between 1 and 3. The tubes were loaded with crystal violet (CV) and ethinyl \nestradiol (EE). Linear release rates with R²>0.9900 were obtained for all groups with \nCV and EE. Release rates of 7.8±2.5, 16.2±5.5, and 22.5±6.0 ng/day for CV and \n30.1±5.8 ng/day for EE were obtained for small tubes (30 μm hole diameter; 125 μm \ntube diameter). For large tubes (362-542 μm hole diameter; 1000 μm tube diameter), a \nrelease rate of 10.8±4.1, 15.8±4.8 and 22.1±6.7 μg/day was observed in vitro in PBS \nand a release rate of 5.8±1.8 μg/day was observed ex vivo in vitreous humor. \nThe delivery system was also evaluated for its ability to produce a biologically \nsignificant amounts in cells stably transfected with an estrogen receptor/luciferase \nconstruct (T47D-KBluc cells). These cells are engineered to produce a constant \nluminescent signal in proportion to drug exposure. The average luminescence of \n1144.8±153.8 and 1219.9±127.7 RLU/day, (RLU = Relative Luminescence Units), yet again indicating the capability of the device for long-term zero order release. \nThe polyimide device was characterized for biocompatibility. An automated \ngoniometer was used to determine the contact angle for the device, which was found to \nbe 63.7±3.7degreees indicating that it is hydrophilic and favors cell attachment. In \naddition, after 72 h incubation with mammalian cells (RAW 267.4), a high cell \ndistribution was observed on the device’s surface. The polyimide tubes were also \ninvestigated for any signs of inflammation using inflammatory markers, TNF-α and \nIL-1β. No significant levels of either TNF-α or IL-1β were detected in polyimide \ndevice. The results indicated that polyimide tubes were biocompatible and did not produce an inflammatory response.
Author: Ashish Rastogi
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1934176387