A review on novel methodologies for drug nanoparticle preparation: Microfluidic approach

Highlights

• Challenges in drug delivery and their solution through microfluidics is presented.

• Microfluidics enables nano-size drug with reproducible physicochemical properties.

• Scope for drug encapsulation by ultrasound enhanced microfluidics is highlighted.

Abstract

The intrinsic limitations of conventional dosages have facilitated the emergence of novel drug delivery methodologies. Drug nanonization and encapsulation in polymeric biomaterials offers a new platform to enhance therapeutic efficiency and patient compliance. The two most basic approaches for drug size reduction are top-down, bottom-up, or a combination of these methods. This review analyzes three widely investigated techniques (viz. spray drying, high pressure homogenization, and ultrasonication) along with microfluidics for drug nanonization and encapsulation in past few years. Also, the existing challenges of aforesaid methodologies and their solution through microfluidics are highlighted. Microfluidics has brought unique opportunities towards complete control over process parameters, owing to miniaturization of fluidic environment. Overall, the emergence of microfluidic technology has created exciting possibilities in the field of controlled drug delivery and has paved a way for clinical translation of nanomedicines.

Introduction

Novel drug delivery methodologies have started to emerge over the conventional dosage forms aiming to enhance therapeutic efficiency and patient compliance. The novel drug delivery approaches seek to reduce the cost involved in new drug development, drug side-effects and to improve the affinity to controlled release (Kumar et al., 2012). The novel drug delivery methods include the controlled release, sustained release, and targeted release dosage. To date, more than 80 applications of nanocrystals have been submitted to the US Food and Drug Administration (USFDA). These therapeutics can be delivered through various routes of administration – 63% of the applications are for the oral route of drug administration (Chen et al., 2017). Drug delivery through pulmonary and nasal tract has also gained significance with ongoing research and development. To ease the drug administration, patient compliance and to provide the flexibility of design of dosage; oral route of delivery is preferred the most in comparison to other methods (Mali et al., 2015). About 40% available drugs belong to the Biopharmaceutical Classification System (BCS) class II drugs which have poor aqueous solubility and low bioavailability. Hence, there is a constant need for the development in drug delivery methods which allows maximum therapeutic effectiveness. This can be achieved by drug encapsulation. Encapsulation of drug in the nano-sized polymeric particles can give minimal drug side effect, controlled drug release, and enhanced bioavailability (Langer, 1998).

In recent years, micro/nano materials have attracted the attention of many researchers towards their biomedical applications (Heath et al., 2016; Mitragotri et al., 2015; Tibbitt et al., 2016). Newly developed carriers hold great promise in accomplishing increased bioavailability, controlled drug release, and enhanced viability that can eventually achieve desired therapeutic response. Among these carriers, micro (Leong and Wang, 2015; Skorb and Möhwald, 2014) and nano (Gref et al., 1995; Wang et al., 2012) structures have gained considerable research interest because of their physical (size, structures, porosity, and mechanical strength) and chemical (compositions, reactivity, biocompatibility, and biodegradability) properties, and flexibility in integrating different functions. In particular, the nano drug delivery system provides a defensive impact against the degradation of drug, controlled therapeutic release profile, and the chance of accurately targeting the drug molecules to the specific site (Blanco et al., 2015). These advantages of nano drug delivery system enable the utilization of lower drug dose with minimal side effects as compared to bare drug molecules (Tang et al., 2016).

The two main methods for producing drug nanoparticles are top-down and bottom-up methods. In the top-down approach, large crystalline drug particles are converted to nanosized drug particles using mechanical force. These methods are easy for industrial scale-up with fine particle producing capacity and reproducibility. However, the major disadvantages of top-down approach are high equipment cost, uncontrolled particle growth, requirement of an intensive amount of energy, and a chance of product contamination (Gera et al., 2017). On the other hand, bottom-up approaches reduce drug particle size using the crystallization process. By using this approach usually, amorphous particles are produced thus enhancing solubility and bioavailability of the drug. However, amorphous form tends to re-agglomerate and has stability issues (Soliman et al., 2017). Bottom-up approaches are simple, rapid, energy efficient, and cost-effective (Azad et al., 2014). These techniques are more efficient at the laboratory scale, and smaller particle size with narrow particle size distribution can be achieved using these methods. The single step bottom-up approaches also have some disadvantages such as low yield, batch-to-batch variation, scaling up, and uncontrolled growth of particles. Nowadays, to produce drug nanoparticles with desirable properties, various combination approaches have been widely studied. In general, a combination technique involves a preprocessing step with a subsequent high energy step. Each approach has its advantages and disadvantages with a common aim of producing particles with good physicochemical stability, narrow particle size distribution, controlled particle growth, high purity, reproducible size, and desired morphology (Möschwitzer, 2010).

The emergence of microreactor technology has brought many opportunities for preparing drug nanoparticles with controlled properties. Microfluidics is defined as the science and technology which deals with fluid flow within micron size channels (Whitesides, 2006). In this micron range, the fluid behavior is majorly affected by fluid viscosity rather than inertia, and high surface area to volume ratio provides quick heat and mass transfer (Zhang et al., 2016). Owing to miniaturization of fluidic environment and continuous mode of operation, microreactor technology offers improved controllability, reduced batch-to-batch variation, narrow particle size distribution, reduced reagent consumption, and high reproducibility. In comparison with conventional processes, these intrinsic properties make microreactor technology attractive for producing drug micro/nano particles. Also, microfluidics has unique characteristics of using pico-to-nanoliter of reagent, millisecond mixing time, real-time monitoring/imaging, and direct scale-up. These characteristics offer microreactor technology as a cost-effective and high throughput technology (Ran et al., 2017). In the last few years, studies on the combination of microfluidic with precipitation and emulsification for drug encapsulation have been reported. Bramosanti et al. (2017) encapsulated Ribavirin in PLGA nanoparticles using microfluidic assisted nanoprecipitation technique. Hydrodynamic flow focusing geometry was utilized to prepare sustained release formulation of Ribavirin. The study demonstrated the significance of microfluidics for enhancing drug encapsulation and to tightly control process parameters (Bramosanti et al., 2017). de Solorzano et al. (2016) investigated microchannel emulsification by encapsulating cyclosporine into PLGA nanoparticles.

The current review revisits three methodologies, viz., (spray drying, high pressure homogenization, and ultrasonication) popularly investigated for drug nanonization and encapsulation in past few years. The advantages and limitations of the aforesaid techniques are discussed along with state-of-the-art in these technologies. The existing challenges of these techniques and their solution through microfluidics are highlighted. The advancement made in the field of drug nanonization and encapsulation through microfluidic technology was reported. Furthermore, the future scope of combining droplet microfluidic emulsification and ultrasonication for drug nanonization and encapsulation was discussed.