Using Skin Impedance Analysis to Help Enable Active and Passive Skin Drug Delivery Protocols

Drug delivery is one of the fastest growing areas in the pharmaceutical industry as leading companies develop various alternatives to injections. Alternative modes of administration such as oral administration, topical administration, pulmonary inhalation (inhalation), etc., after the application of nanotechnology, transdermal drug delivery system is a popular research field. Transdermal delivery methods provide non-invasive therapeutic delivery through a patient’s skin using one of two approaches to overcome the skin’s protective barrier: passive absorption and active penetration.

Topical patches are one of the most commonly used passive drug delivery methods. It is applied to the patient’s skin, and the administered dose is achieved by controlling the application time, which can be safely and comfortably achieved. These drugs are absorbed through the skin into the bloodstream. Nicotine patches are a prime example, but other common uses include motion sickness treatment, hormone replacement therapy, and birth control. But passive drug delivery has two major drawbacks: the rate of drug absorption depends on the skin’s impedance, and only a limited number of drugs can diffuse through the skin’s protective barrier at an acceptable rate. As a result, major investments in the industry are directed towards active drug delivery methods. Active transdermal delivery methods include: the use of ultrasonic energy to accelerate drug diffusion, the use of radio frequency energy to create microchannels in the stratum corneum (the outer layer of the epidermis), and iontophoresis.

Using Skin Impedance Analysis to Help Enable Active and Passive Skin Drug Delivery Protocols

Figure 1 Schematic diagram of iontophoresis

Iontophoresis uses electrical charges to actively deliver drugs through the skin to the bloodstream. The device consists of two chambers of charged drug molecules. The positive charge of the anode will repel positively charged chemicals, while the negatively charged cathode will repel negatively charged chemicals. The electromagnetic field created between the two chambers will actively allow the drug to penetrate the skin in a controlled manner.

The impedance of the skin is a key variable for transdermal drug delivery” title=”dermal drug delivery”>dermal drug delivery. This impedance is complex and depends on age, ethnicity, weight, activity level, and many other factors, and is related to frequency related and therefore difficult to model. Dynamically measuring the impedance of the skin can provide an accurate and practical solution for optimal drug delivery.

Using Skin Impedance Analysis to Help Enable Active and Passive Skin Drug Delivery Protocols

Figure 2. Block diagram of a simple impedance analyzer

Impedance spectrum greatly simplifies the accurate analysis of complex impedances such as human skin. This method fully considers the factors that the impedance of resistance, capacitance and inductance varies with frequency. As the frequency increases, the impedance of the resistor remains the same, the impedance of the capacitor decreases, and the impedance of the Inductor increases. By exciting the test impedance with a known AC waveform, the resistive, inductive and capacitive components of the unknown impedance can be determined. Direct digital frequency synthesizers (DDS) have flexible phase frequency and amplitude, sweep capability, and programmability, making them ideal for exciting unknown impedances. With embedded digital processing and enhanced frequency control, the device produces synthetic analog or digital frequency step waveforms. Figure 2 shows a block diagram of a simple impedance analyzer. The AC waveform generated by the low-power, 75MHz DDS AD9834 is filtered, buffered, and amplitude adjusted by the AD8091 high-speed, rail-to-rail op amp. Another AD8091 buffers the response signal and adjusts its amplitude to match the input voltage range of the AD7476A, a 12-bit 1Msps successive approximation (SAR) analog-to-digital converter.

Using Skin Impedance Analysis to Help Enable Active and Passive Skin Drug Delivery Protocols

However, the simple signal chain described above masks some potential challenges. First, the analog-to-digital converter must simultaneously sample the excitation and response waveforms in the frequency range so that phase information can be preserved. Optimizing this process is critical to overall performance. In addition, due to the numerous discrete components involved, varying tolerances, temperature drift, and noise can affect measurement accuracy, especially when dealing with small signals.

These limitations can be overcome with the AD5933, a 12-bit, 1Msps integrated impedance converter and network analyzer chip, which integrates a DDS waveform generator and a SAR-type ADC on a single chip, as shown in Figure 3.

Figure 4 Skin Impedance Analysis Using AD5933″ title=”Skin Impedance Analysis” > Skin Impedance Analysis Circuit Diagram

The output impedance of the AD5933 is several hundred ohms, depending on the output range. This impedance will affect the measurement of skin impedance, so an AD8531 op amp needs to be used to buffer the signal to reduce the impedance in series with the skin, as shown in Figure 4. Note that the receiver side of the AD5933 is biased to VDD/2 on-chip, so to prevent saturation, this equivalent voltage must be applied to the non-inverting side of the external amplifier.

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