Controlled Release from Porous Platforms - Pharmaceutical Technology

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Controlled Release from Porous Platforms
The authors present a method for controlling the release of therapeutics by applying a plasma polymer layer to the surface of porous materials.

Pharmaceutical Technology
Volume 35, Issue 8, pp. 68-71

Experimental protocols

High-purity aluminum foil (99.99 wt %, Alfa Aesar) with a thickness of 100 μm was used to fabricate anodic aluminim oxide (AAO) substrates, according to the published method (15). Aluminum foil was degreased in acetone, sonicated for 30 min, thoroughly rinsed with MilliQ water, and electrochemically anodized using two-step anodization following previously reported procedures (16, 17). The first anodization was performed for 2–4 h under a 60–80 V and an electrolyte temperature of 1 C in 0.3 M oxalic acid. After the resulting aluminum layer was dissolved, the second anodization was performed as described previously. The anodization conditions were maintained to ensure that all porous layers had the same pore diameters (70–90 nm) and pore thickness (20 μm).

The drugs were loaded through consecutive deposition (20 times) followed by drying under vacuum for 2 h. Release testing was carried out in 5 mL of phosphate buffer (PB) at 37 C. For each point in drug-release determination, 0.5 mL of medium was removed, diluted by 2.5 mL PB, and spectrophotometrically analyzed for drug content. Withdrawn medium was immediately replaced with 0.5 mL of fresh PB.

Plasma polymerization was carried out in a custom-built reactor described elsewhere using a commercial 13.56-MHz plasma generator (Advanced Energy, 16, 17). The depositions were carried out in an atmosphere of pure allylamine (AA) at a pressure of 0.22 Torr. An input power setting of 20 W was used in combination with a matching network to minimize reflected power. The deposition of AA under these conditions was carried out for 50, 200, and 300 s. The deposition rate was about 0.5 nm/s–1, determined by ellipsometry on polished silicon wafers. Scanning electron microscopy (SEM) images were obtained on a Philips XL 30 FEGSEM.

Results and discussion

Controlling drug release from porous materials. To overcome the drawbacks of current approaches, a strategy for controlling drug release rate from porous materials was developed. The aim was to enable zero-order release kinetics with minimal burst release and without compromising the amount of loaded drug, which is important in long-term therapies (18). At the heart of this strategy is the deposition of a plasma-polymer layer with controlled thickness on top of the porous substratum loaded with a drug. The hypothesis was that the plasma-polymer layer would reduce the pore diameters at the surface, which, in turn, would define the rate of drug release form the pores. Plasma polymers are formed on a substrate from a gas phase when a selected precursor is electrically excited (19). Using plasma polymers for the present drug-delivery platform design has several advantages. Firstly, solvents are not involved because plasma polymers are deposited in the gas phase. Solvents may lead to loss or contamination of the loaded drug. Secondly, the thickness of the plasma polymer overlayer can be controlled with nanometer precision by the plasma-deposition conditions (in this particular study, by deposition time), which is important to establish precise control over release rate. Finally, in this study, plasma polymer films were deposited from vapor of allylamine, which resulted in films rich in amine functional groups. These types of films promote the adhesion and function of biological cells (20, 21).

Figure 1: Scanning electron microscope images of the anodic aluminim oxide (AAO) bare surface and (a) AAO modified with allylamine plasma polymer using deposition times of (b) 50 s, (c) 200 s, and (d) 300 s. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
The authors chose AAO as a model porous platform because it can be prepared by a self-ordering anodization process using simple preparation procedures (15, 16, 20–21). It consists of an array of perpendicular and highly ordered pores with a diameter of 80 nm and a depth of 20 μm. To demonstrate control of drug release rate through this approach, the authors selected common antibiotics and a protein as model compounds of various molecular weights. These items include levofloxacin (MW 370), vankomycin (MW 1449), and bovine serum albumin (BSA, MW 66400). As a last step, an allylamine plasma-polymer film of predetermined thickness was deposited on top of the porous material loaded with drug. The thickness of the deposited film was controlled by the time of deposition, which was 50, 120, 200, and 300 s.

Figure 2: The influence of plasma polymer coatings on the release profiles of levofloxacin. The legend shows plasma time depositions.
SEM characterization of the porous substrata after plasma-polymer deposition for 0, 50, 200, and 300 s is shown in Figure 1. After plasma deposition, pore diameters decreased from 80–90 nm to < 20 nm. The thickness of plasma-polymer films deposited from the same precursor on plain silicon wafers were measured by ellipsometry as 41 nm, 89 nm, 134 nm, and 200 nm when films were deposited for 50, 120, 200, and 300 s, respectively. However, the thickness measured on plain surfaces can only be used as a guide. Previous reports demonstrated that plasma polymers deposit differently on porous materials (20). Films grow from the rims of the pores and reduce the diameter of the pores at the surface. Importantly, the plasma polymers do not fill the pores, but only deposit at the pore entrance (16).

Figure 3: The influence of plasma-polymer coatings on the release profiles of vankomycin. The legend shows plasma time depositions.
Drug-release kinetics: proof of concept. The drug-release profiles from AAO for samples with and without plasma-polymer film deposited on the surface are presented in Figures 2–4. Increasing the time of deposition (i.e., film thickness) clearly led to slower release for all three model drugs. Release behavior is also a function of drug type. Extended release of levofloxacin (see Figure 2) of three weeks can only be achieved if the plasma deposition time is prolonged to 500 s. In the case of vancomycin (see Figure 3), which has a molecular weight more than three times larger than that of levofloxacin, extended release can be achieved after plasma deposition of only 50 s. A clear correlation between time of deposition and drug release profiles was observed. From uncoated samples, drug is completely released within 45 min. Depositing plasma polymer for 50 s extends the release to about 200 h. Deposition for 200 s further extends the release because only 50% of drug is released after 500 h. Figure 4 shows the release of BSA. As in the case of antibiotics, increasing the time of deposition led to a slower release rate; release could be extended to six weeks when plasma polymer was deposited for 200 s.

Figure 4: The influence of plasma-polymer coatings on the release profiles of bovine serum albumin. The legend shows plasma time depositions.
The release kinetics from plasma-coated platforms can be described in two phases. The initial fast release within the first 45–60 min (see Figures 2–4) can be regarded as a burst, whereas release patterns from 1 h to completed release can be considered controlled release and fit into first- and zero-order models (see Table I, 20–21). The parameters show that zero-order kinetics best account for the experimental data. Furthermore, zero-order release (i.e., constant k 0) follows the same rank order as plasma-polymer deposition time. With increasing deposition time, the zero-order release constant decreases exponentially (see Table I). Zero-order release kinetics are a desirable release pattern because a constant amount of drug is released in each time interval (13). Such release kinetics, typical for reservoir transdermal delivery systems, are rarely reported for porous devices (15).

Table I: Controlled-release parameters for 1–500 h.
The ability to control the release rate of various drugs, including proteins, makes the authors' system a potential platform for the design of various therapeutic implants and drug-delivery devices. The results demonstrate that it is possible to achieve zero-order release kinetics from porous materials through controlled deposition of a plasma-polymer layer. The method for controlled drug release by deposition of a plasma polymer overlayer also could be extended to any type of porous drug carrier because the deposition techniques are independent of the substrate.


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