Liposomes are often utilized as vehicles in pharmaceuticals and cosmetics for a modified drug delivery. They are considered to be spherical vesicles whose membrane comprises amphiphilic lipids that surround an aqueous core. Hydrophilic substances may be encapsulated in the aqueous core and lipophilic substances in the lipid bilayer so this enables the delivery of 2 types of substances once they are applied on the skin [26, 27].

The fundamental parts of liposomes are phospholipids (phosphatidylcholine, phophatidylethanolamine, phophatidylserine, dipalmitoyl phosphatidylcholine, and others), cholesterol, and water. Liposomes may differ considerably in terms of size and structure. One or more concentric bilayers emclose an aqueous core producing small or large unilamellar vesicles (SUV, LUV) or multilamellar vesicles (MLV), respectively [28, 29].

Liposomes are considered to be the first generation of novel drug delivery systems having diameters ranging from 80 nm to 100µm [14]. Due to their high degree of biocompatibility, liposomes have been used as advanced drug delivery systems for enclosing of molecules [28].

It was reported that Clindamycin hydrochloride multilamellar liposomes had been prepared using either lecithin and cholesterol or Hostaphat KW (Hoechst) and cholesterol acne management. In vitro diffusion studies on the Hostaphat liposomes exhibited a sustained release. Liposomal clindamycin lotion was much more effective in reducing the total number of comedones, papules and mainly pustules. Tretinoin, also known as all trans retinoic acid, is a successful antiacne drug used topically for reducing the size and number of comedones. Unfortunately, its poor aqueous solubility, photoliability, high instability in the presence of heat and light and skin irritating nature strongly limits its topical use. Moreover, tretinoin users experience side effects like erythema, peeling, burning at the application site and increased susceptibility to sunlight. In order to overcome these disadvantages and to improve its effectiveness after topical application, the use of liposomal formulations has been recommended [14].

Among liposomal formulations, positively charged liposomes exhibited enhanced tretinoin release and permeation as compared to negatively charged liposomes. Moreover, liposomal formulations improved tretinoin accumulation into newborn pig skin. Among liposomal formulations, the maximum accumulation values for tretinoin were found with negatively charged liposomes as compared to positively charged liposomes. Additionally, TEM analyses of the newborn pig skin-liposome interaction revealed that liposomes do not penetrate in the skin as intact structures and negatively charged liposomes strongly improved the hydration of pig skin. These reports suggested that the composition and charge of liposomes would play an important role in optimizing tretinoin delivery. Apart from the improved delivery, liposomal encapsulation of tretinoin is also expected to improve its photostability [28].

BPO is a successful topical agent in the treatment of acne. The key mechanism of action of BPO in acne is linked to its eradication property of P. acnes in the sebaceous follicle. Liposomal BPO gels exhibited a better stability profile with lower drug leakage as compared to BPO liposomal dispersions. The liposomal BPO gel showed a significant improvement in the therapeutic response (about 2-fold) at all times of evaluation when compared to the plain BPO gel [14, 30].

Combination therapy comprising of antiacne agents differing in mechanism of action is gaining importance in the effective management of acne. Topical retinoids combined with topical or oral antibiotics were reported to decrease acne lesions quicker and to a larger range than antimicrobial therapy alone [31].

Erythromycin and BPO have also been shown to possess synergism and can improve acne treatment. With this aim we have developed the combination gel containing liposome-encapsulated erythromycin and BPO. The in vitro skin permeation study indicated longer residence of erythromycin and BPO liposomes in the guinea pig skin [32].

The use of antiandrogen has received great attention in acne treatment ever since the sebaceous gland was found to be androgen sensitive. Cyproterone acetate (CPA) has been used since the early 1960s and denotes the first specific antiandrogen of clinical interest. It was reported that acne and hirsutism can be effectively managed with orally delivered CPA. However, oral administration of CPA is associated with side effects like lassitude, loss of libido, nausea and breast tenderness. Hence, a topical CPA formulation with the ability to deliver sufficient doses in order to target sebaceous glands with concomitant reduction in systemic CPA concentration would be an ideal approach in such a case. However, earlier trials conducted using topical CPA formulations were unsuccessful due to the lack of a suitable vehicle for transdermal delivery of CPA. Serum concentrations of CPA were ten-folds lesser after topical administration of CPA as compared to orally delivered CPA. Thus, liposomal CPA has opened a new avenue for effective acne treatment with reduced side effects [33].

Salicylic acid is widely used in the management of dry skin conditions and to minimize acne symptoms due to its keratolytic effect like sodium salycilate. However, users experience mild to strong irritation after application of salicylic acid. Since salicylic acid precipitates into a powder on the surface of the skin after solvent evaporation, it does not require neutralization. Hence, liposomal encapsulation can be an attractive approach for salicylic acid delivery. It was also shown that liposomal preparation of salicylic acid not only extended the salicylic acid release across the skin but also improved the retention of salicylic acid in the skin. Tea tree oil, a natural bioactive obtained from Melaleuca alternifolia, has also attained considerable interest in the topical treatment of acne due to its antibacterial properties. The study suggested that the liposomal approach would be a good option for improving the therapeutic efficacy of tea tree oil [14, 34, 35].

Niosomes are bilayer structures obtained from amphiphiles in aqueous media. Different kinds of surfactants are employed for niosomes formulation. Principally, they are analogous to liposomes. Niosome formation necessitates the existence of specific amphiphiles like polyoxyethylene alkyl ethers, sorbitan esters, polysorbate-cholesterol mixtures, crown ether derivatives, perfluoroalkyl surfactants, alkyl glycerol ethers and others, and aqueous solvent [28].

Niosomes represent second-generation vesicular carriers which have evolved as a substitute to liposomes largely because of their higher chemical stability, enhanced encapsulation efficiency, intrinsic skin penetration-enhancing properties and lower cost of production as compared to liposomes. Various nonionic surfactants like polyoxyethylene alkyl ethers and esters, glucosyl dialkyl ethers, poly glycerol alkyl ethers, crown ethers and sorbitan esters can be utilized to prepare niosomes. Charge inducers like dicetyl phosphate are intercalated in bilayers to incorporate electrostatic repulsions among the vesicles for improving the stability of vesicles. However, charge inducers used in the formulation should be biocompatible. The classification of niosomes, their methods of preparation and advantages in the dermal delivery are similar as described under liposomes [36, 37].

Although the utility of niosomes in dermal delivery for the enhanced delivery of topical agents was realized around a decade ago, their potential in the antiacne drugs administration was not very well studied yet. The potential of niosomes has been explored for delivering tretinoin. Manconi et al. have recently reported the utility of niosomes for encapsulating tretinoin in order to improve its photochemical stability. They prepared multilamellar, large unilamellar and small unilamellar niosomes by using sorbitan esters, polyoxyethylene lauryl ether, and a commercial mixture of octyl/decyl polyglucosides in the presence of cholesterol and dicetyl phosphate. Properties of niosomes are influenced by the surfactant composition and interaction [38, 39].

The photostability of tretinoin in either the ‘free’ or ‘noisome-encapsulated’ form was investigated by carrying out UV irradiation and artificial light irradiation. The integration of tretinoin in vesicles directed to a lessening of the photolysis of tretinoin and the photoprevention exhibited by the vesicles. Not all the studied vesicular formulations improved the stability of tretinoin in comparison with the stability of free tretinoin in methanol. Thus, niosomes can become interesting carriers for dermal delivery of antiacne agents and their ability needs to be explored to the fullest [40].

Aspasomes are novel vesicular carriers recently investigated by Gopinath et al., which are formed by using ascorbyl palmitate, cholesterol and dicetyl phosphate. Aspasomes can gain importance in acne therapy as the potential of ascorbic acid derivatives in acne treatment has been realized. They can be fabricated by the typical film hydration method. Aspasomes have been characterized by conventional techniques for bilayer formation and thermal behavior by differential scanning calorimetry (DSC) analysis. Their advantages in dermal delivery of therapeutic agents are similar to that of liposomes. Moreover, their inherent antioxidant potential can be complementary to the topical acne therapy [40].

Microsponges are biologically inactive, non-irritating, non-mutagenic, non-allergic, non-toxic, and non-biodegradable polymeric drug delivery systems, which exhibited great use in dermopharmaceuticals administration. Microsponges are also defined as porous microspheres, which are prepared by using cross-linked polymers like styrene-divinyl benzene by employing suitable polymerization techniques. Like a true sponge, a single Microsponge system comprises numerous interconnecting spaces within a noncollapsible structure with a large porous surface. These systems are produced mainly by suspension polymerization that leads to structures with an internal surface area ranging from 20 to 500 m² /g. Moreover, the generation of Microsponges of varying size (5-300 µm) is possible as the polymerization conditions can be varied over a wide range. A typical 25µm microsponge can have up to 250,000 pores, forming an entire pore volume of around 1 ml/g. Furthermore, release from the microsponge could be modulated by using various triggers or stimuli like pressure, change in temperature, change in pH, change in polarity and change in solubility. Microsponges mainly entrap the drug by sorption mechanisms [41].

The advantages that the microsponge offers in topical delivery are as follows: improved physical stability and better protection from environmental factors, reduction in side effects associated with the topical antiacne agents, sustained release of active agent thus prolonging the drug activity, ease of incorporation into formulations like gel, cream, liquid or powder, improved elegance and esthetic appeal, high drug payload, reduction in systemic absorption of the topical agents, and programmable and flexible delivery system since the release could be modulated by using various stimuli so as to tailor the release of active moiety on command. Microsponge technology has been successfully applied for improving tolerability of antiacne agents like BPO and tretinoin. Furthermore, tretinoin microsponges have reached commercialization and are currently marketed as Retin-A Micro^®. Retin-A Micro consists of microsponges (based on methyl methacrylate/glycol dimethacrylate crosspolymers) of tretinoin incorporated in an aqueous gel. It is available in two strengths, namely 0.1 and 0.04% [14].

They are also expanding for delivery of cosmetic and dermatologic formulations. Most skin care products are emulsions so during production they require the addition of surfactants (“emulsifiers”). Additionally, when the surfactant agents are spread on the skin, they emulsify and get rid of the natural lipids. Thus, the pharmaceutical factory is evolving them as substitutes to conventional preparations [22].

Microemulsions are thermodynamically stable, isotropic, and transparent, low-viscosity colloidal dispersions comprising micro-domains of oil and/or water stabilized by an interfacial film of alternating surfactant and cosurfactant molecules. They contain swollen micellar (oil-in-water, O/W), reverse micellar (water-in-oil, W/O) and bicontinuous structures.

The advent of microemulsion-based gels (which amalgamate the advantages of microemulsions and gels) has helped in improving the patient compliance of microemulsions. Microemulsion-based gels are produced by using a suitable polymer that is capable of modifying the rheological behavior of microemulsions. However, it is essential to ensure that the polymer does not alter the desirable features of microemulsions. Several gelling agents have already been studied for their potential to form microemulsion-based gels [14].

Azelaic acid, a bioactive molecule utilized in managing acne and different skin complications, was first formulated in the form of microemulsions. Gasco et al. successfully achieved incorporation of azelaic acid into the microemulsion based on topically acceptable components like propylene glycol, decanol, dodecanol and polysorbate 20 and microemulsions were viscosized using Carbopol. An investigation of the in vitro diffusion profile of azelaic acid from marketed gel and microemulsion-based gel revealed that the microemulsion-based gels dramatically improved the transport of the azelaic acid across hairless mouse skin. Additionally, the effect of penetration enhancer like DMSO was studied on the permeation of azelaic acid from microemulsion-based gels. The permeation of azelaic acid increased with an increase in the DMSO content [14, 42].

They are compounds made entirely of carbon that look like a hollow sphere. It was reported that when fullerenes come into touch with the skin, they migrate across the skin intercellularly. Hence, a fullerene could be employed to “trap” active substances and then release them into the epidermis upon skin application. Furthermore, fullerenes are considered to be possibly powerful antioxidants [22].

Hydrogels denote a novel drug delivery system comprising different applications. Their potential in peroral drug delivery and tissue engineering has been very well established and their potential in delivery of dermopharmaceuticals has been realized. Moreover, their biocompatibility and structural diversity have extended their utility for an array of applications. They are hydrophilic polymer linkages that exhibit the capacity of water absoprtion ranging from 10-20% up to thousands of times their dry weight in water [43].

Hydrogels produced in the form of sheets can appropriately be utilized in the dermal or transdermal administration of the active constituents. Moreover, by modulating the composition of the polymeric backbone and reaction conditions (in case of cross-linked hydrogels) hydrogels can be tailored to obtain desired physical properties and release profile. Owing to their versatility, hydrogels can be easily employed for localized delivery of antiacne agents especially the ones exhibiting the problem of skin irritation. In fact, the hydrogels exhibiting notable skin adhesion and moisturizer effect would be an ideal tactic for topical acne treatment.

Lee et al. [44] have successfully applied ‘hydrogel technology’ for improving dermal accumulation of an antiacne agent in order to avoid their percutaneous absorption. The investigation has not only revealed the potential of triclosan as an antiacne agent but also provided the platform technology for efficient topical delivery of various other antiacne agents. Lee et al. have designed peeloff-type adhesive hydrogel patches based on 2 matrix polymers, namely sodium polyacrylate and sodium carboxymethyl cellulose. The cross-linking of these negatively charged polymers was achieved by employing Al³⁺ ion generated in situ. They found that in order to obtain hydrogel in the patch form, the cross-linking reaction should be slow and the solidification of the hydrogel should not be completed before casting the fluidic gel as a thin film.

Hydrogel patches containing triclosan in varying concentrations (from 0.01 to 0.5% w/w) were characterized for in vitro antimicrobial activity against P. acnes (ATCC 6919), adhesivity and in vitro skin permeation. The antimicrobial activity of triclosan hydrogel patches was evident when the triclosan content was 0.05% w/w and it improved with the escalation in the amount of triclosan. In vitro permeation studies carried out on triclosan hydrogel patches using hairless mouse skin clearly indicated the significant increase in the amount of triclosan transported into the skin as compared to the amount transported across the skin [45].

Solid lipid nanoparticles (SLN TM, Lipoearls TM) are advanced drug administration systems that are introduced for combining the advantages but avoiding the disadvantages of conventional colloidal drug carrier systems like polymeric nanoparticles, liposomes and microparticles and emulsions. They have been proved to be promising delivery strategy for efficient administration of many active constituents by numerous application pathways. SLNs have revealed a great ability to efficiently deliver various topical agents and even cosmeceuticals and their applications are continuously being unraveled. It was reported the successful fabrication of SLNs for improved dermal delivery of tretinoin using the novel solvent emulsification diffusion method. Interestingly, SLN-based tretinoin gels were greatly able to improve the tolerability of tretinoin as compared to commercialized products when valued by the Draize patch test in rabbits [14, 45].

They have become an exceedingly common kind of topical preparation for a diversity of skin disorders like acne. The vehicle base of the foam could possess a liquid or semi-solid consistency that contains the same physicochemical properties of conventional vehicles like creams, lotions and gels, but it balances desirable characterstics such as moisturizing/fast-drying effects, or higher drug bioavailability. The aerosol base is dispensed through a gas-pressurized can that discharges the foam. The product features are determined by the type of formulation and the dispensing container that are selected to suit the specific therapy needs. In acne, foams may be preferred for application on large hairy surfaces or on the face as cleansers, because they are easier to spread [22].

Table 3 shows the summary of novel drug delivery systems for antiacne agents.