Review Article Dermal and Transdermal Delivery of Active Substances from Semisolid Bases A. JANKOWSKI, R. DYJA* AND B. SARECKA-HUJAR Department of Pharmaceutical Technology, Medical University of Silesia in Katowice, 41-200 Sosnowiec, Poland Jankowski, et al.: Dermal and Transdermal Delivery from Semisolids The selection of a semisolid base type (hydrophobic, hydrophilic or emulsion) has an essential influence on the skin and transdermal delivery of active substances. The cutaneous and percutaneous absorption may be influenced by interactions occurring between base components and skin on the one hand and interactions between base components and the active ingredient on the other hand. The present article discusses the utility of different types of semisolid bases as carriers of active substances and summarizes results of studies comparing delivery of active substances from different semisolid bases. Key words: Semisolid dosage forms, semisolid base, skin delivery, transdermal delivery Active pharmaceutical substances are usually applied primarily of aggregated keratin filaments encased to the skin in the form of semisolid formulations for in a cornified envelope that are surrounded by an topical treatment of dermatological diseases or for extracellular milieu of lipids organized as multiple improvement of the skin condition. The skin may lamellar bilayers serving as mortar[5]. also be recognized as an alternative port of entry There are different potential pathways for permeation for systemically acting drugs. For the effectiveness through the stratum corneum. These pathways include: of the formulations applied to the skin, the active appendageal, transcellular or intercellular route[1]. The compounds incorporated into the semisolid base must route to be followed by any active substance depends reach the site of action. However, the skin acts as a on its physiochemical characteristic, although more barrier controlling the entry of molecules from the than one route may be used at the same time[1]. The administered medications[1]. appendageal route along hair follicles, sebaceous Transport of active substances through the skin may be follicles and sweat glands is considered to be of minor described as series of consecutive steps, each of which importance because of their relatively small area (less can potentially be rate limiting[2]. First, the drug needs than 0.1% of the total surface)[1]. Substances that are to diffuse from the formulation to the skin surface[2]. preferentially transported via the transcellular route This process is characterized by the release rate. The have also to cross the intercellular spaces[1]. Therefore, release requires dissolution of the active substance and the intercellular route through the extracellular milieu may be rate limiting process for skin delivery[3,4] due of lipids is considered to be the main pathway for to the fact that only small molecules can penetrate into any molecule moving through the stratum corneum. the skin. Lipid extracellular matrix is continuous, yet very [1,5] After being released, the active substance partitions convoluted . This results in long and tortuous into and diffuses through the stratum corneum, the pathway for any molecule moving through the stratum [1,5] principal skin barrier, which represents the thin corneum . The extreme hydrophobicity and the outer layer (10 µm) of the epidermis and is typically [1,2] This is an open access article distributed under the terms of the Creative comprised of about 10-25 corneocyte cell layers . Commons Attribution-NonCommercial-ShareAlike 3.0 License, which The stratum corneum structurally composed of tightly allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under packed alternating hydrophilic and lipophilic layers the identical terms organized as “bricks and mortar”[1-5]. Human stratum Accepted 25 May 2017 corneum consisted of corneocyte “bricks” composed Revised 15 February 2017 Received 11 August 2016 *Address for correspondence E-mail: [email protected] Indian J Pharm Sci 2017;79(4):488-500 July-August 2017 Indian Journal of Pharmaceutical Sciences 488 www.ijpsonline.com composition and highly rigid ordered distribution of interactions between the active substance and the the three key species of intercellular lipids (ceramides, semisolid base[3]. cholesterol and free fatty acids) contribute for the The penetration through the stratum corneum may stratum corneum barrier function[1,5]. Although these be characterized experimentally by a tape-stripping structured lipids prevent entry of most topically method[9,10]. Skin permeation studies may be applied active substances (other than those which are performed in vitro in diffusion cells with the skin as lipid soluble and of low molecular weight), the lacunar a membrane. The rate of the skin permeation process domains, which represent the likely aqueous pore may be expressed as the amount of the active substance pathway and aqueous pores within the extracellular appearing in the acceptor fluid, similarly as in the matrix of the stratum corneum provide the opportunity release studies[11]. for the delivery of active substances that are lipid insoluble. However, these lacunar domains are From the perspective of topical products (cosmetic or discontinuous and only under certain conditions (e.g. dermatologic), it is necessary to achieve an appropriate occlusion, prolonged hydration) may form a continuous active substance concentration in the skin tissue (skin but collapsible network[5]. retention). However, permeation of active substance through the skin from topical products should be After overcoming the stratum corneum, the active limited to prevent the occurrence of side effects related substance permeates into and diffuses through the to the entering into the bloodstream. Skin retention and viable epidermis, which is situated beneath the stratum permeation may not be correlated so these processes corneum[1,2,5]. The cellular structure of the viable must be characterized separately[12]. epidermis is predominantly hydrophilic throughout its various layers and substances can be transported in its A base type of a semisolid dosage form affects intercellular fluids[1]. Especially for polar substances, dermal and transdermal delivery of an active the resistance to permeation is considerably lower substance and thus its therapeutic efficacy. This than in the stratum corneum and the active substance impact is well illustrated using the example of topical permeates easily to the dermis, which consists of glucocorticosteroid formulations. Topical semisolid connective tissue and contains blood vessels, lymph formulations of betamethasone dipropionate at the vessels and nerves[1]. Chemicals reaching the dermis same glucocorticosteroid concentration (0.05%) are readily absorbed into the bloodstream and may act belong to four different classes in terms of potency (I, systemically[1,6]. Finally, the dermis is located on the II, III, V) depending on a base type (Table 1)[13]. As subcutis, which is made of a network of fat cells[6]. is apparent from Table 1, betamethasone dipropionate formulations with the highest potency (class I: super The percutaneous absorption process may be divided potent) are Diprolene Gel 0.05% and Diprolene Ointment into three steps: penetration, which is entry of the 0.05%, while the least potent formulation is Diprosone active substance into a particular layer or organ and Lotion 0.05% (class V - lower mid-strength)[13]. diffusion within that layer or organ; permeation, which is the penetration through one layer to another, which The components of semisolid base can influence is both functionally and structurally different from the active substances as well as properties of a skin first layer; absorption, which is the uptake of the active TABLE 1: CLASSIFICATION OF BETAMETHASONE [1,6] substance into the vascular system . DIPROPIONATE SEMISOLID FORMULATIONS Transport of active substances through the skin ACCORDING TO POTENCY (release from a formulation, skin penetration and skin Product Potency group Diprolene gel 0.05% Super potent-I permeation) is mainly investigated in vivo but may be Diprolene ointment 0.05% Super potent-I also studied in in vitro conditions. The in vitro study Diprolene cream AF 0.05% Potent-II of the release is performed with a diffusion cell as a Diprosone ointment 0.05% Potent-II process of permeation of the active substance from a Maxivate ointment 0.05% Potent-II semisolid formulation through an artificial membrane Diprosone cream 0.05% Upper mid-strength-III to an acceptor fluid (aqueous buffer pH 5-8 or aqueous Maxivate cream 0.05% Upper mid-strength-III ethanol mixture)[7,8]. In vitro drug release studies are Maxivate lotion 0.05% Upper mid-strength-III Diprosone lotion 0.05% Lower mid-strength-V particularly useful in the early stage of the development Classification according to potency by the National Psoriasis of dermatological formulations as they help to identify Foundation[13] 489 Indian Journal of Pharmaceutical Sciences July-August 2017 www.ijpsonline.com barrier function and thereby affect release of active limiting active substance release rates in in vitro studies. substances from the formulation and their delivery to Poorly water soluble ingredients of hydrophobic bases the skin (retention) and through the skin (penetration, cannot penetrate into the acceptor fluid whereby they permeation)[2,13,14]. The composition of the