Date Published: November 29, 2018
Publisher: Tabriz University of Medical Sciences
Author(s): Rabinarayan Parhi, Suryakanta Swain.
Since two decades or so transdermal route established itself as better alternative to traditional oral route. This is possible due to continuous innovations in transdermal drug delivery (TDD), which not only enables researchers from academia and industry to successfully develop and launch many new pharmaceuticals but also allow to include new classes of drugs that can be developed into transdermal formulations. These successes are achieved due to the use of novel techniques based on either physical or chemical approaches. However, both of these techniques suffer due to their own disadvantages. Comparatively, a simple method of supersaturation to enhance drug permeation across skin has created a new wave of interest. Even though the application supersaturated principle in topical and TDD has been used from 1960s, but proper control of drug release and formation of stable supersaturated states has been the core of intense research in the last decade. Out of various methods used to get supersaturated system, evaporation method is considered as most efficient and practically feasible for TDD. Therefore, in this review concept of supersaturation, selection of solvent system and the mechanism of inhibition of crystallization are discussed. Application of evaporation systems in the development of transdermal formulations such as solutions, semisolids and metered dose therapeutic systems (MDTS) and the commercial evaporative systems are also discussed in this review.
Delivery of drug across the skin i.e., transdermal drug delivery (TDD) offer an alternative route to traditional oral and parenteral routes with many distinct advantages such as avoidance of first pass metabolism by liver and gastro-intestinal tract, improves patient compliance by reducing the frequency of drug administration, minimizes the side effect of drug caused due to temporary overdose, steadier drug plasma concentration, non-invasive drug delivery i.e., without any needle-phobia etc.1-3 Common dosage forms applied topically to provide systemic effect are creams, ointments, gels and patches.4 It is obviously difficult to sustain the effect of drugs present in creams and ointments for the considerable period of time after application because of every possibility of their removal from the skin surface as a result of movement, contact and wetting.5
The concept of supersaturated systems originated from the crystallization theory, in which the formation of supersaturated solution is the first step of crystallization. A supersatuarated solution can be defined as the one which contains more amount of dissolved solute than it would normally contain in a saturated solution at a constant temperature. As supersaturated systems are considered as thermodynamically unstable (labile state), in most of the cases, there is spontaneous formation of crystals (Figure 1). Metastable is a state in which solute material remains in the supersaturated solution without crystallization. This state is maintained until any foreign solid particles are added intentionally/accidentally or the system is subjected to external forces (e.g., ultrasound). Thus, the line between labile and metastable states is mentioned as critical degree of saturation.22
The solvent in which a drug is present can increase the drug permeation through the skin by either ways: (i) by increasing the thermodynamic activity of the drug or (ii) altering the barrier property of the SC. Thermodynamic activity of a drug mainly depends on the solvent in which it is solubilized. Therefore, the selection of solvent is very crucial for enhanced permeation of drug across the skin. It has to keep in mind that maximization of thermodynamic activity is essential to achieve higher concentration of drug in the SC. The flux is related to thermodynamic activity as expressed in the following equation:
Any subsaturated or saturated solution can be converted to supersaturated one by evaporating the solvent as the same amount of solute will be present in gradually decreasing amount of solvent. This is more pronounced if any volatile component/solvent is present the solution. This principle is explored to develop transdermal and topical formulations in order to improve thermodynamic activity of active ingredient and thereby enhance its penetration into/across the skin.35 For instance, an active ingredient not present in supersaturated level in any formulation, but when applied on the skin surface volatile solvent evaporates, thereby reducing solubility in the residual amount of solvent. The reduction of solvent amount lead to the formation of supersaturated state of the active ingredient. Certain topical formulations in the market (e.g., lotions) are forming supersaturated states, resulting in the penetration enhancement of active ingredients.
It is mentioned in the earlier section that the instability is one of the major limitations for the supersaturated systems. The instability is due to rapid crystallization of drug when the volatile component is getting evaporated immediately after the application of these formulations. Formation of crystals not only reduces the initial high activity of the drug but also gives an irregular plasma drug concentration. Therefore, stabilization of thermodynamically unstable states is important step in the development of successful supersaturated systems with desired permeation enhancement across the skin. It is well known that the instability of supersaturated system lead to establish the foundation for crystallization i.e. formation of nucleus, which subsequently resulting in crystal growth. In addition, there are many external factors such as type of solvent, temperature variation (based on the heat of solution), impurities, pH and hydrodynamics. Furthermore, the nucleation time and the time needed to form critical sized nuclei, from where the crystal growth can take place, decreases with the increase in degree of saturation (DS). In order to stabilize the system, one or more of these factors are often used to control both the nucleus formation and its growth.29,37
Flux of a permeant across a membrane from a saturated solution is constant and independent of its concentration. Therefore, under normal conditions, the flux of a drug is limited by its saturated solubility. The flux of drugs across a membrane at the steady state is governed by Fick’s first law of diffusion and expressed as:
Supersaturated principle based on evaporation is mainly applied in transdermal/topical drug delivery and the formulations in which this concept is incorporated are topical solutions and semisolids and spray. The latter formulation is now being widely used in transporting drug across skin. In addition there are many commercial products available based on spray technique. A list of drugs, solvent systems, polymers with their references are presented in Table 1.
Acrux Pvt. Ltd. is the first company to commercialize MDTS with lunching number of products in market such as Evamist®, Lenzetto®, Ellavie®, Axiron®, Nestorone®. These products provide fast-drying, invisible sprays or liquids with outmost cosmetic acceptability. Moreover the other advantages of above system are attainment of steady state plasma concentration for four days after a single application and very low skin irritation rate because of non-occlusive delivery.79,80A list of commercial products based on evaporative principles with their brand name, marketing company, active ingredient, formulation type and use are presented in Table 2.
Estradiol spray system was the first MDTS developed by Acrux Pvt. Ltd. to treat menopause symptoms such as severe hot flushes and it was approved by FDA in three brand names such as Evamist, Lenzetto® and Ellavie®. These were licensed to different companies to market it all across the globe. In 2007, Evamist® licensed to KV Pharmaceuticals to market it in US, but latter on it was distributed by Perrigo from 2014 as the former company was acquired by the latter. Gedeon Richter received multiple marketing approvals for estradiol spray and in 2016 it was launched in Europe and Eurasia in the brand name of Lenzetto®. Ellavie® is a unique estradiol skin spray which is used to treat vasomotor symptoms associated with menopause. From 2009 Ellavie® was marketed and distributed in Australia by Aspen Pharmacare and in Switzerland by Vifor pharma.81
Drug delivery through transdermal route seems to be very attractive concept, but not all classes of drugs will be able to permeate the SC barrier in sufficient amount that can illicit the therapeutic action. The physico-chemical properties which are important for a drug to permeate the barrier layer of skin by passive diffusion includes small molecular size (less than 500Da), log partition coefficient preferentially within range of 1 to 3.5, aqueous solubility of greater than 100 µg/mL, low drug dose suitably less than 10mg/day and melting point less than 200°C.21,89 The individual drugs suitable for TDD are those which undergoes first pass metabolism either in liver of GI tract, causing irritation in the stomach, elimination half life less than 3h and showing absorption window in oral route. At present, no such drug molecules are approved by USFDA which possess all above properties. However, it is possible only when the design and development of drug molecules with maximum number of desired properties to suit TDDD will be developed.
Despite of numerous constraints, drug delivery through transdermal route continues to grow and expand because of the development of new technologies such as the use of sonophoresis, electroporation, microneedle, chemical PEs and novel supersaturation concept. This technological advancement in TDD sector led to successful delivery of drugs ranging from potent (low dose) to moderately potent drug. Among all, supersaturation concept is standing tall as it has the flexibility of delivering the dose in solution, semisolid or in the spray form. In addition the drug dose can be precisely and accurately administered with MDTS which avoids the intra- and inter-patient dose variation. In this context, Aptar group taken a step ahead in developing metered dose spray pumps and dispenser for topical and transdermal products which can be combined with MDTS to achieve dial-a-dose of transdermal delivery with highest degree of accuracy and precision.90
The author declares that this article content has no conflict of interest