Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery

Abstract

Nano-emulgel is an emerging drug delivery system intended to enhance the therapeutic profile of lipophilic drugs. Lipophilic formulations have a variety of limitations, which includes poor solubility, unpredictable absorption, and low oral bioavailability. Nano-emulgel, an amalgamated preparation of different systems aims to deal with these limitations. The novel system prepared by the incorporation of nano-emulsion into gel improves stability and enables drug delivery for both immediate and controlled release. The focus on nano-emulgel has also increased due to its ability to achieve targeted delivery, ease of application, absence of gastrointestinal degradation or the first pass metabolism, and safety profile. This review focuses on the formulation components of nano-emulgel for topical drug delivery, pharmacokinetics and safety profiles.

Introduction

The recent progress in drug synthesis and high throughput screening have steered drug discovery and development toward lipophilic drug moieties. Currently, 90% of drugs in the discovery pipeline and more than 40% of the drugs present in the market are of lipophilic nature [1]. The lipophilic nature of the drugs leads to problems like poor solubility, unpredictable absorption, and inter and intra-subject variability concerning pharmacokinetics. Various techniques have been employed to increase the solubility of active moieties. These techniques include physical and chemical modification of API along with formulation strategies, which include particle size reduction, complexation, amorphization, and nano-carrier drug delivery systems as represented in Figure 1 [2–4]. Despite of employing various technologies for enhancing the solubility, delivering the drugs via the oral route is not always feasible owing to their low bioavailability associated with poor absorption, first-pass metabolism, chemical and enzymatic degradation [5,6].

In addition, clinical complications and low concentrations of the drug at the site of action hinder drug delivery through the oral route. For example, the oral administration of Disease-modifying anti-rheumatic drugs (DMARDs) used in the treatment of arthritis are associated with various side effects like carcinogenicity, hepatotoxicity, and hematologic toxicity [7,8]. These clinical complications can be mitigated by delivering the drug through the topical route [9]. In topical delivery, skin being a fundamental defense layer, considers the API’s as external components and restricts their entry into the body. The outer most layer of epidermis called stratum corneum is the first and firm layer to overcome for drug penetration into the skin [10]. Various mechanisms have been explored to enhance the drug permeation. One such mechanism involves disruption of skin layer structure, which can be achieved using techniques such as chemical penetration enhancers, ultrasound, iontophoresis, sonophoresis, electroporation and microneedles [11].

In contrary, the use of nanocarriers was observed to be an effective strategy for circumventing the SC barrier without exacerbating skin damage and achieving efficient drug penetration. They facilitate the drug delivery through the skin utilizing intra and inter cellular transport mechanisms, interacting with skin components to mediate transport or to create depots of the drug for sustained or stimuli-induced release. These novel carrier for topical administration includes but not limited to emulsions (nano/micro), micelles, dendrimers, liposomes, solid lipid nanoparticles and nano-structured lipid carriers [12–14]. Among these, nano-emulsions are found to be a potential drug delivery system because of their high drug-loading capacities, solubilizing capacities, ease of manufacturability, stability and controlled release patterns. These nano-emulsions owing to their lipophilic core allow the movement of more lipophilic molecules across the topical membranes compared to the liposomes [15]. In addition, liposomes stability has always been an issue, as they disintegrate during the penetration process.

Likewise, the low drug loading capacity and uncontrolled release hinders the application of solid-lipid nanoparticles in dermal drug delivery. Similarly, micelles exhibit poor stability and encapsulation efficiency. In the same way, the toxicity and poor controlled release behavior of dendrimers limits its topical application [16]. Nano-emulsions are heterogeneous colloidal mixtures of oil and water, with one component as a dispersed phase and the other as a continuous phase. A surfactant known as an emulsifier is adsorbed at the interface between the dispersed and continuous phases, lowering the surface tension and thus stabilizing the system.

These systems possess high thermodynamic stability leading to longer shelf life compared to simple emulsions, micelles or suspensions, etc. Despite having various advantages, nano-emulsions are limited by their low viscosity leading to low retention time and spreadability [17]. These problems can be resolved by modifying the nano-emulsion into a nano-emulgel by using a suitable gelling agent [18]. The nano-emulgel acts as a colloidal system consisting of a mixture of emulsion and gel. The emulsion part protects the drug from enzymatic degradation, and hydrolysis and improves the permeation like other nano-carriers.

Besides enhancing the penetration of the drug through the skin, it is equally important to retain the therapeutic concentrations of the drug for a sufficient period of time. The gel part improves the viscosity and spreadability resulting in improved retention time, and also reduces the surface and interfacial tension, thus improving the thermodynamic stability. Nano-emulgel possesses various advantages having high drug loading capacity, better penetration, diffusion, and low skin irritation compared to other nano-carriers [19,20]. This article aims to provide insight into the selection of formulation ingredients of a nano-emulgel, characteristics and formulation aspects, advantages, pharmacokinetics and pharmacodynamics, and safety of the same. The objective here is to give an overview of the future and rationale behind the nano-emulgel drug delivery system.

Table 4. Pre-clinical Studies on the nano-emulgel dosage form.

Active Ingredient	Composition	In Vivo Model	Route of Administration	Therapeutic Outcome	Reference
Curcumin	Oil: Labrafac PG + transcutol HP Surfactant mixture: Tween 20 + solutol HS 15 Gelling agent: Carbopol 934	BALB/c mice	Topical	Psoriatic mice treated with the curcumin nano-emulgel showed faster and earlier healing than those treated with curcumin plus betamethasone-17-valerate gel	[69]
Thymoquinone	Oil: Black seed oil Surfactant mixture: Kolliphor EL + transcutol HP Gelling agent: Carbopol 940	Wistar rat	Topical	Nano-emulgel administration of thymoquinone improves its therapeutic efficiency in wound healing studies in Wistar rats	[70]
Curcumin and Resveratrol	Oil: Labrafac PG Surfactant mixture: Tween 80 Gelling agent: Carbopol	Wistar rat	Topical	Curcumin and resveratrol nano-emulgel technology revealed drastically increased curcumin and resveratrol deposition in skin layers. The in-vivo investigation revealed that the NEG formulation resulted in improved burn healing, with histological findings comparable to standard control skin. Thymoquinone nano-emulgel delivery method improves thymoquinone therapeutic effectiveness in wound healing studies in Wistar rats.	[71]
Brucine	Oil: Myrrh oil Surfactant mixture: Tween 80 + PEG 400 Gelling agent: Carboxymethylcellulose sodium	BALB/c mice and Wistar rats	Topical	Curcumin and resveratrol nano-emulgel technology revealed drastically increased curcumin and resveratrol deposition in skin layers. The in-vivo investigation revealed that the NEG formulation resulted in improved burn healing, with histological findings comparable to standard control skin. Thymoquinone nano-emulgel delivery method improves thymoquinone therapeutic effectiveness in wound healing studies in Wistar rats.	[72]
Curcumin	Oil: Labrafac PG Surfactant mixture: Tween 80 + PEG 400 Gelling agent: Carbopol 940	Albino rats	Topical	Curcumin nanoemulgel improved the wound-healing efficacy of curcumin compared to the conventional gel formulation.	[69]
Raloxifene hydrochloride	Oil: Peceol Surfactant mixture: Tween 20 + transcutol HP Gelling agent: Chitosan	Wistar rats	Topical	Raloxifene hydrochloride (RH) loaded nanoemulgel formulation for enhanced bioavailability and anti-anti-osteoporotic efficacy of RH. The bioavailability improved by 26-fold compared oral marketed product.	[73]
Eprinomectin	Oil: Castor oil Surfactant mixture: Tween 80 + Labrasol Gelling agent: Carbomer 940-1	Wistar rats	Topical	Naoemulgel formulation showed improved skin permeability of 1.45-fold compared to emulgel and had no skin-irritating property	[74]
Amisulpride	Oil: Maisine CC Surfactant mixture: Labrosol + transcutol HP Gelling agent: Poloxamer 407, Gellan gum	Wistar rats	Intranasal	Improved pharmacokinetic profile. The Cmax of API in brain after administering through insitu nano-emulgel improved by 3.39-fold compared to intravenous administration of nano-emulsion.	[75]
Disulfiram	Oil: Ethyl oleate Surfactant mixture: Tween 80 + transcutol HP Gelling agent: Deacetylated gellan gum	Sprague Dawley rats	Intranasal	Improved survival rate of rats and reduced tumor progression (Glioblastoma). The survival time of in-situ nano-emulgel treated group is 1.6 times higher than control group	[76]

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Donthi, M.R.; Munnangi, S.R.; Krishna, K.V.; Saha, R.N.; Singhvi, G.; Dubey, S.K. Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery. Pharmaceutics 2023, 15, 164.
https://doi.org/10.3390/pharmaceutics15010164