In Vitro Models of Skin for Topical and Systemic Drug Delivery Applications
The drug delivery is a significant process in medicine development. The development of topical or systemic drugs requires models that present the mechanism of the drug activity. Topical delivery of medicine has a long story of application. The advantages for the topical delivery are as follow: self-administration and simplicity of application, absence of side effects, high surface area for drugs absorption. However, the method has recently been recognized as far less efficient than the systemic drug delivery (oral or injectable) (Kulkarni, 2009). The paper presents advances in understanding the drug delivery using in-vitro models.
Topical Drug Delivery Models
The artificial in-vitro models are used to represent the healthy intact skin, which has the barrier properties close to the human skin. The models are based on the phospholipid mixture models or diffusion cells. There are research activities directed to development the models using chromatographic-based approach. The models that predict the skin absorption are lipid- and non-lipid (silicone membranes) based.
The chromatography-based models used to study the permeability coefficients and drug-biological membrane interaction are more complicated. It is the immobilized artificial membrane, biological system for partitioning, micellar or liposome chromatography, and stationary keratin phase. However, Flaten et al. (2015) emphasized that chromatography-based models are limited in ability to simulate the topical delivery and therefore they do not have the future prospective.
The prospective lipid-based models are membranes designed to study the influence of ceramide species. These models either simulate the skin (the various types of parallel artificial membrane permeability assay (PVPA)), or stratum corneum (SC) barrier of the skin (as phospholipid vesicle-based permeation assay (PAMPA)), SC with synthetic substitutes of lipids, the models for drug diffusion and permeation simulation, based on membranes (Flaten et al., 2015).
Liposomes take the significant place among the substances that are used to improve the topical drug application. Liposomes reduce systematic absorption so that the drug acts locally and minimal side effects are observed (Maghraby, Barry & Williams, 2008). The probable liposome action mechanism is listed in Fig. 1, where A is the free drug mechanism, B refers to the process of liposome components action, C is the adsorption with the SC, D is the vesicle penetration.
Figure 1: Mechanisms of liposomes action (by Maghraby, Barry & Williams, 2008)
Systemic Drug Delivery Models
The systemic drug delivery is a process that includes numerous consequtive physical and chemical phenomena. These are water or drug diffusion, drug or polymer dissolution, polymer swelling and degradation. Therefore, the process of drug delivery includes the models for all these processes. However, some of the processes can be rather quick, and its model is necessary only from the theoretical point of view. Only the long-lasting processes models have the significant practical application. There are diffusion and swelling models, and the models for polymeric carriers degradation (Siepmann , Siegel & Rathbone, 2012).
Diffusion controlled models are based on the Fick's law that unite mass flow with the gradient concentration and diffusivity. They are presented as differential equations with starting and boundary conditions. The swelling-controlled models typically include drug dissolution, diffusion and polymer dissolution. The swelling and other processes are described using the kinectic equations, and sometimes include the diffustion equations. The models for drug release from the polymer include geometry factors, environmental and physiological conditions (Siepmann, Siegel & Rathbone, 2012). The models for systemic drug delivery are developed on paper, and then their parameters are defined experimentally.
The topical models are based on the drug interaction with the constituents of the skin, while the systemic models are related to the physical or chemical processes involved in the drug intake. The topical and systemic drug delivery models are necessary for understanding and prediction of the drug performance.
The Use of Polymers in the Design of Controlled Release Drug Delivery Systems
The drugs are applied in the certain periods. The active agents of the drugs are typically soluble in water, and their concentration reaches maximum within several minutes, and then the drug recovery process starts. In some cases, this is acceptable, as for the contrast medias. However, for the therapeutic effect, the drug concentration in blood or organs has to be stable for some period of time, usually untill the next dose intake. The controlled drug release is a process that allows gradual release of the agent and thus prolong the therapeutic effect of the drug (Li & Jasti, 2006).
The polymers are widely applied in the pharmaceutical industry. These are the biodegradable polymers: nanoparticles, hydrogels, microspheres, etc. Polymers are the chains of the small structural units of the organic compounds. The polymers applied are either synthetic or natural. There are certain requirements to the polymers: they have to be fully removed from the body, and the degrading products should not be toxic and immunogenic (Shaik, Korsapati & Panati, 2012). Proteins (gelatin, elastin, collagen) and polysaccharides (alginate, dextran, hyaluronic acid) are the natural polymers applied on the industrual scale; the sythetic group of the polymers include polyphophazenes, polyanhydrides, polyurethanes, polyesters, etc. (Siepmann , Siegel & Rathbone, 2012).
The numerous types of polymers are applied, and all of them has the advantages and disadvantages. For instance, the natural polymers are hydrophilic, biocompatible, safe, widely available, and have the specific cell and tissue binding activity. Yet, they require purification, the specification of the raw material are not controlled, the degradation process control is limited. The synthetic polymers can be designed with the certain physicochemical features, easily modified to improve the functionality, do not have the immunogenic effects, the release rate can be controlled. However, they are hydrophobic, require synthesis and the specific reagents (Siepmann , Siegel & Rathbone, 2012).
Pagels and Prud'homme (2015) presented the research of the systems for protein and peptide therapeutics delivery. The main aim of the polymers application is the decrease of frequency administration. The biologics, united with nanoparticles or microparticles, are characterized with the extended period of release (up to weeks). It has been found that the hydrophyllic polymers are good for large proteins delivery, and hydrophobics perform well for smaller molecules.
The polymers can also be applied for dual drugs release and transportation. The work of Anirudhan, Parvathy & Nair (2016) presents the composite matrix based on polymeric micelle and hydrogel, which are the polyethylenglycol and polyvinyl alcohol. The polymeric micelles are good vehicles for water insoluble drugs. The drug release behaviour from the micelle and hydrogel was studied on tramadol and cefixime trihydrate; the basic medium is more favourable for the dual drugs release (Anirudhan, Parvathy & Nair, 2016).
Anirudhan, Peethambaran & Nima (2016) developed a system for the controlled drug delivery by chitosan, modified with graft polymerization and coated with magnetic nanoparticles. The anticancer drug was used in the experiment. The formation of the drug carrier has been proved by various experimental methods. The drug release showed that the maximum release is observed after 48 hours; the cytotoxicity tests determined the less toxic types.
The polymers for gradual drug release is a prospective research area in terms of the possible industrial application. The variety of natural and synthetic polymers are already in commerical use, and numerous research initiatives are realised in the field.
References
Anirudhan, TS, Parvathy, J & Nair, AS 2016, ‘A novel composite matrix based on polymeric micelle and hydrogel as a drug carrier for the controlled release of dual drugs’, Carbohydrate Polymers, vol. 136, pp. 1118-1127.
Anirudhan, TS, Peethambaran, LD & Nima, J 2016 ‘Synthesis and characterization of novel drug delivery system using modified chitosan based hydrogel grafted with cyclodextrin’, Chemical Engineering Journal, vol. 284, pp. 1259-1269.
Flaten, GE, Palac, Z, Engesland, A, Filipović-Grčić, J, Vanić, Z & Škalko-Basnet, N 2015, ‘In vitro skin models as a tool in optimization of drug formulation’, European Journal of Pharmaceutical Sciences, vol. 75, pp. 10-24.
Kulkarni, VS 2009. Handbook of non-invasive drug delivery systems science and technology. Norwich, N.Y., William Andrew.
Li, X & Jasti, BR 2006. Design of controlled release drug delivery systems. New York, McGraw-Hill.
Maghraby, GME, Barry, BW &Williams, AC 2008 'Liposomes and skin: From drug delivery to model membranes', European Journal of Pharmaceutical Sciences, vol. 34, pp. 203-222.
Pagels, R & Prud'homme, RK 2015, ‘ Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics’ Journal of Controlled Release, vol. 219, pp. 519-535.
Shaik, MR, Korsapati, M & Panati, D 2012, 'Polymers in controlled drug delivery systems' International Journal of Pharma Sciences, vol. 2, no. 4, pp. 112-116.
Siepmann, J, Siegel, RA, & Rathbone, MJ 2012. Fundamentals and applications of controlled release drug delivery. New York, Springer.
