Transdermal Transport In Vitro of Domperidone by Compartmental Modeling Approach

Transdermal delivery can be alternatively chosen for domperidone to improve its low oral bioavailability. Development drugs into transdermal formulation need information about the transport mechanism of the drug. The purpose of this study was to develop models of domperidone transdermal transport in vitro based on compartmental modeling for understanding the domperidone transport mechanism. Domperidone solution (0,5 g/L in a citric buffer, pH 5) was filled into the donor compartment. The comparative study also conducted to examine the effect of different pH on domperidone transdermal transport in pH 1 (4g/L in 0,1 M HCl). The shed snake-skin and cellophane membrane were pretreated for 1 hour with chemical enhancers (oleic acid in propylene glycol) and assembled between the donor and the receptor compartment of the vertical diffusion cell. The receptor compartment was filled in with phosphate-buffered saline at a pH of 6.8. The permeation study was performed for 8 hours. 
Samples concentration was assayed by the UV-Spectrophotometry method. The cumulative permeation profiles of domperidone were analyzed using WinSAAM. Three and four-compartmental models were proposed with the one lag compartment. The evaluation of the appropriate number of compartments in the transport model was examined based on the visual goodness of fit (GOF) and the Corrected Akaike’s Information Criterion (AICc) values. Four-compartmental models with one lag compartment were the best model describing percutaneous domperidone transport either in pH donor of 5 or pH 1. The model indicates domperidone transport follows into two parallel routes, including a lag compartment.


INTRODUCTION
Domperidone, a dopamine antagonist, is an antiemetic and prokinetic agent with a recommended single dose of 10 mg and a total daily dose of 40 mg (Boyce et al., 2012). The extensive first-pass metabolism in the intestine and liver result in a low domperidone's oral bioavailability (13-17%). The elimination half-life of domperidone is about 7-9 hours (Helmy and El Bedaiwy, 2014).
An alternative formulation is via a transdermal delivery route. It can avoid the first-pass metabolism in the liver, increasing the bioavailability of drugs. It also has good acceptance for the patient (Sarath et al., 2014).
However, the drug must pass the barrier of the skin (i.e., stratum corneum).

P r e e P R o o f
Chemical enhancers can improve skin drug penetration. The oleic acid (OA), one of the chemical enhancers, temporarily disrupts the stratum corneum lipid increasing the skin's fluidization and diffusivity (Haque and Talukder, 2018). Furthermore, there are reports that OA in propylene glycol (PG) can synergistically increase drug permeation. This combination has been reported to increase the transdermal transport of thymoquinone, propranolol, and alfuzosin (Haq and Michniak-Kohn, 2018;Hendriati and Nugroho, 2009;Pattnaik et al., 2011) There is no report yet about transdermal delivery of domperidone with OA in PG enhancers, as well as the concern on the transdermal domperidone transport mechanism. This investigation is essential to study domperidone characteristics while passing across the skin layer.
Compartment modeling is a mathematical model representation of part of the body to assess pharmacological or physiological kinetic characteristics (Khanday et al., 2017). This modeling approach describes transdermal transport as a drug mass transfer process from the donor compartment to the acceptor compartment via the skin as an intermediate compartment (Nugroho et al., 2004). Compartmental modeling has several advantages. First, the parameter of transport can be analyzed directly from the original flux data. Second, the entire observed data can be analyzed without excluding some data points, such as the diffusion lag time method.
Compartment modeling also describes the flux as a function of time to P r e e P R o o f predict the steady-state flux, even though the condition has not been achieved (Nugroho et al., 2004).
Several studies have been conducted to describe drug transport based on compartmental modeling. Such an approach has been applied in transdermal iontophoresis in vitro (Nugroho et al., 2004) and in vivo (Nugroho et al., 2005); and in passive transdermal transport in vitro (Nugroho et al., 2014). The models can be built in by WinSAAM, free software for the biological system modeling (Stefanovski et al., 2003).
This study aimed to describe the transport mechanism of domperidone combined with OA in PG, based on the compartmental modeling approach. As a comparative study, we also studied the influence of extreme pH (i.e., pH 1) and enhancer concentrations on the permeation and compartment model of domperidone.

Shed snake-skin pretreatment
Both the shed snake-skin and cellophane membranes were cut into circular shapes 1.5 cm in diameter using scissors. They were then hydrated P r e e P R o o f in phosphate-buffer saline (PBS) at a pH of 6.8 for 30 minutes. The cellophane was used as a supporting membrane for shed snake-skin. The shed snake-skin was put above the cellophane membrane when assembled between the donor and the diffusion cell's receptor compartment. Oleic acid in various concentration (1% for pH 5 and 1; 5; 10% for pH 1) in propylene glycol were prepared. A composition of 3 mL of oleic acid in propylene glycol was filled into the diffusion cell's donor compartment. The receptor compartment was filled in with PBS at a pH of 6.8. The skin pretreatment was performed for 1 hour.

Permeation in vitro
After skin pretreatment, the donor compartment was filled in with 3 mL solution of domperidone (0,5 g/L in the citric buffer, pH of 5 and 4g/L in 0,1 M HCl, pH 1) was filled into the donor compartment while the receptor compartment was filled in with PBS at a pH of 6.8. The permeation was done for 8 hours. A total of 2 mL samples were collected from the receptor compartment and immediately replaced with PBS at a pH of 6.8 in the same volume. Samples concentration was determined by UV spectrophotometer at a wavelength of 285 nm.

Data Analysis
The cumulative permeation of domperidone was calculated. Then, the data were analyzed using WinSAAM (Windows-based Simulation

A compartmental model of domperidone transdermal transport
The in vitro permeation profiles of domperidone across the shed snake-skin is presented in Figure 1.  Figure 3 shows model B could fit better than model A. It is also supported by GOF evaluation, presented in Figure 4, indicated that there was less deviation between observed and software prediction data.

Data in
Further evaluation was conducted to ensure the best model. AICc calculation was performed and presented in  Based on this modeling approach, the parameters were obtained and presented in Table 2. The use of 1% OA in PG on pH 5 showed that the lowest domperidone transport. In contrast, the use of 1% OA in PG on pH 1 showed the highest drug transport. Domperidone is a weak base drug which less soluble in water. The solubility also decreased in higher pH. The transport data suggested that the donor concentration of domperidone influence the permeation. Passive diffusion is driven by a concentration gradient (Nugroho et al., 2004). As the concentration gradient across the skin increased, the percutaneous drug transport is also increased. Pranitha and Lakshmi (2018) reported that pH influenced the permeation of drugs.
Sildenafil citrate, another weak base drug, was reported to have a higher flux in acidic pH (1,2) than at the higher pH levels (4-8) due to the solubility level (Pranitha and Lakshmi, 2018).
The concentration of OA in PG also influences the permeation of the domperidone solution in pH 1. The results in Table 2