A practical framework for implementing Quality by

International Journal of Pharmaceutics 548 (2018) 385–399

Contents lists available at ScienceDirect

International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

A practical framework for implementing Quality by Design to the development of topical drug products: Nanosystem-based dosage forms Ana Simõesa,b, Francisco Veigaa,b, Ana Figueirasa,b, Carla Vitorinoa,b,c,

T

⁎

a

Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal LAQV. REQUIMTE, Group of Pharmaceutical Technology, Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal c Centre for Neurosciences and Cell Biology (CNC), University of Coimbra, Rua Larga, Faculty of Medicine, Pólo I, 1st Floor, 3004-504 Coimbra, Portugal b

A R T I C LE I N FO

A B S T R A C T

Keywords: Nanosystems development Quality by Design Process design Quality target product profile Critical quality attributes Risk assessment

Skin has been increasingly recognized as an important drug administration route with topical formulations, offering a targeted approach for the treatment of several dermatological disorders. The effectiveness of this route is hampered by its natural barrier, the stratum corneum (SC), and hence, different strategies have been investigated to improve percutaneous drug transport. The design of nanodelivery systems, aiming at solving skin delivery issues, have been largely explored, due to their potential to revolutionize dermal therapies, improving therapeutic effectiveness and reducing side effects. Apart from nanosystem benefits, the fulfilment of the reproducibility requirements and quality standards still limit their industrial production. The optimization of nanosystem formulation and manufacturing process is complex, usually involving a large number of variables. Therefore, a science- and risk-oriented approach, such as Quality by Design (QbD) will provide a comprehensive and noteworthy knowledge, yielding high quality drug products without extensive regulatory burden. This review aims to set up the basis for QbD development approach, encompassing preliminary and systematic risk assessments, with critical process parameters (CPPs) and critical material attributes (CMAs) identification, of different nanosystems potentially used in dermal therapies.

1. Introduction Despite the wide use of conventional creams, the bioavailability of active substances from topical formulations remains far from the ideal, often not exceeding 1–2% of the applied dose (Hadgraft and Lane, 2016). For the most topical delivery systems, the ability to diffuse/ permeate through the skin depends on drug physicochemical properties, carrier features and skin conditions. Even though the broad scientific investment, the technological development of new drug delivery systems remains largely unexplored in the skin penetration arena. The skin is the largest and the most external organ of the human body, providing an efficient protective barrier between the body and external environment against the penetration of exogenous agents and also plays a major role as sensory organ. Although this organ represents an ideal site for administration of therapeutic compounds, aiming to exert either local and/or systemic effects, its structure is a complex hurdle to most molecules penetration/permeation (Benson, 2012). It is composed of four distinguishable regions: the stratum corneum (SC) (nonviable epidermis), the viable epidermis, dermis, and subcutaneous tissues (hypodermis). Appendages, such as hair follicles associated to sebaceous glands and sweat ⁎

glands are also present in skin structure (Walters and Brain, 2004). The SC, the outermost layer of the epidermis, is the main and primary barrier for diffusion of molecules across the skin. It presents a distinct structure described as a series of elongated and flattened corneocytes (dead keratinized cells without nucleus), interlinked through desmosomes and surrounded by intercellular lipids. The remarkable composition of the SC, intercellular lipids with a structural arrangement in multiple lamellar layers, is critical for skin barrier function. The other layers and appendages have also essential functions and are important target sites for drug delivery. The predominantly route to transport a substance across the SC is via a tortuous pathway defined by the lipids surrounding the corneocytes (intercellular route), although the transcellular route through the corneocytes may be possible under certain circumstances. In some cases, the appendages could be also potential routes of entry into the skin. These three pathways to skin permeation will depend on the physicochemical characteristics of the substance. The permeation is a complex process starting with drug release from the dosage form, followed by diffusion into and through the SC. Then, partitioning to the more aqueous epidermal environment and diffusion to deeper tissues or uptake into the blood vessels takes place. Drug release

Corresponding author at: Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. E-mail address: csvitorino@ff.uc.pt (C. Vitorino).

https://doi.org/10.1016/j.ijpharm.2018.06.052 Received 26 February 2018; Received in revised form 22 June 2018; Accepted 23 June 2018

Available online 25 June 2018 0378-5173/ © 2018 Elsevier B.V. All rights reserved.


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QbD concept has received an increasing attention in innovative pharmaceutical development, due to its benefits on high quality drug products assurance without extensive regulatory oversights (Rathore, 2009). In the International Conference on Harmonisation (ICH) Q8 guideline, QbD is defined as a systematic approach to pharmaceutical development that begins with predefined objectives and emphasized product and process understanding, as well as control, based on sound science and quality risk management. QbD implementation requires the definition of the quality target product profile (QTPP) and critical quality attributes (CQAs) of drug product, the accomplishment of risk assessment (Q9, 2005) to identify CMAs and CPPs, the definition of a design space through design of experiments (DoEs), the establishment of a control strategy and the continuous improvement and innovation throughout the product lifecycle (Pramod et al., 2016; Q8, 2009). A greater understanding of the product design and its manufacturing process is crucial for more flexible regulatory approaches. The degree of regulatory flexibility relies on the level of scientific knowledge provided in the registration application (Q8, 2009). The application of QbD system in the pharmaceutical industries environment has revealed to be a fundamental key, since it increases pharmaceutical development efficiency with a successful product optimization and a robust manufacturing process, improves the communication between regulators and industry providing regulatory relief and flexibility, decreases post-approval changes and allows real-time quality control with subsequent real-time release (Pramod et al., 2016; Q8, 2009). Therefore, the transversal application of the QbD concept on nanosystem pharmaceutical development will provide significant benefits both for pharmaceutical industry and regulatory authorities. Incomplete understanding of process production has encouraged researchers to implement QbD approach for nanosystem optimization, allowing to support and accelerate the development of optimized nanobased formulations (Fig. 2) (Marto et al., 2015). In this review, an effort is made to standardize possible CQAs, CMAs and CPPs for each nanosystem, accordingly. Some of the difficulties in implementing this approach are also addressed. Different explanations are pointed out to justify why nano-engineered quality assurance is more difficult to be controlled and how QbD methodology can be a valuable approach to overcome these limitations. Our purpose is to clarify and provide a helpful practical framework suitable to be applied in a cross-functional way to the pharmaceutical development of topical nano-based drug products.

from the vehicle (dosage form) and uptake into SC is strongly dependent on solubility and diffusivity of the active substance in each environment. The drug diffusion coefficient or rate is dependent on the drug properties and factors related to the environment, such as viscosity and tortuosity (Benson, 2012; Hadgraft and Lane, 2016; Roberts et al., 2017). Besides the skin physiological factors, drug and vehicle properties also affect drug permeation. The range of substances that are suitable for diffusion through the SC is generally limited to those that are highly potent, due to the low permeation rate of the most molecules. Drug substances with a molecular weight less than 500 Da are required, since the permeant size presents an inverse relationship with skin permeation and, subsequently, with the diffusivity within the SC. A balanced lipid and water solubility with an octanol-water partition coefficient (log P) between 1 and 3 is desirable, since drugs that are too hydrophilic are unable to partition from the vehicle into SC, while drugs that are too lipophilic have high affinity to SC, being unable to partition into deep skin layers. Even though ionized species have a lower log P, drug ionized species have a lower permeability coefficient than its respective unionized species. Ultimately, a low meting point (less 200 °C) also promotes drug solubility into SC lipid domain (Benson, 2012; Hadgraft and Lane, 2016). A good understanding of skin structural features is, thus, crucial to design innovative and optimized topical formulations. The vehicle presents an important role in drug delivery mechanism. For instance, cream vehicle supersaturation will improve thermodynamic activity of the formulation, providing a large driving force for drug transport through the skin. Furthermore, SC barrier function can be narrowed using chemical permeation enhancers or promoting SC hydration by occlusive effect (Chang et al., 2013; Hadgraft and Lane, 2016; Roberts et al., 2017; Walters and Brain, 2004). In this context, nanosystems show a great promise as topical delivery carriers to promote the transport of therapeutic and cosmetic substances to and/or through the skin, allowing them to surpass the skin barrier and reach a specific skin target, at appropriate doses, so as to achieve a safe and effective therapeutic effect (Table 1). Nanosystems are defined as vehicles with particle sizes among 10–1000 nm, wherein active(s) substance(s) could be dissolved in, encapsulated in or attached to the surface. The incorporation of these carriers in topical formulations enables an improvement of drug solubility, bioavailability, permeability, targeted delivery, prolonged effect and stability, enhancing dermal drug performance by increasing the therapeutic efficacy and reducing active toxicity/skin irritancy. The properties of the nanosystem influence its SC penetration, as well as its potential diffusion/permeation through appendages or to the deeper skin layers. The vehicle in which the nanosystem is suspended may also affect its characteristics and SC permeability. Furthermore, skin conditions cannot be disregarded, since they may influence the degree and the depth of nanoparticle penetration (Bastogne, 2017; Li et al., 2017; Roberts et al., 2017). Nanodelivery systems, such as lipid and polymer-based nanocarriers, are a suitable strategy to improve percutaneous drug absorption, enhancing active substance extent and rate transport across the skin (Marto et al., 2016; Neubert, 2011). A simplified representation of human skin containing its major structures and cell types and nanosystems penetration behaviour is illustrated in Fig. 1. Although nanosystems are being widely studied as interesting approaches for topical delivery, the control of quality and safety of pharmaceuticals comprising nanocarriers have become a major problem. In practice, it is impossible testing all nanostructures. Innovative development methodologies must be applied to ensure product quality and safety from the first design stages. In addition, several obstacles related to physicochemical characteristics, limited reproducibility, structure destabilization, complex and not cost-effective formulation and production, with incomplete understanding of manufacturing processes, hinder industrial production and clinical application of nanoformulations (Leroux, 2017). To overcome these hurdles, nanosystem formulation and process design need to be optimized using more scientific and systematic approaches (Kraft et al., 2014; Li et al., 2017).

2. Quality by Design approach – nanosystem development strategy 2.1. Definition of nanosystems QTPP and CQAs The first and one of the most important steps when using QbD is to pre-define the QTPP. Nano-based products QTPP comprises quality parameters that ideally should be achieved to ensure final product quality, taking into account product safety and efficacy. The second step of the QbD based development is to identify the CQAs. CQAs are product quality attributes, derived from QTPP, with impact on the final product quality and for this reason they must be studied and controlled (Q8, 2009). Any change in formulation or process variables might be a threat for CQAs, so that such parameters must be ensured during development and production with the purpose of achieving the required quality (Bhise et al., 2017). Table 2 displays an example of a QTPP and how it is crucial to set up CQAs. Based upon prior knowledge, once defined QTPP and CQAs, an initial risk assessment is performed. The outcome of this procedure is to identify potential high risk variables and to prioritize which studies should be conducted. Risk assessment is a science-based process used in quality risk management (ICH Q9) to determine which material attributes and/or process parameters are critical for the nanosystem quality and which of these variables need to be experimentally investigated and 386

387

++

PNPs

++

+++

++

++ ++

++

++

++

++

++

Lipophilic drug loading efficiency

++

++

+++

+++ +++

+++

+++

+++

+++

+++

Topical delivery

+

+

++

++ ++

+++

+++

+++

++

+

Systemic delivery

+++

+++

+++

++ +++

+++ /+

b

a

+++

+++

++

++ +

+++

+++

++

+a/+++b ++

++

+

Stability

++

+

Sustained release

++

++

+

++ +

+++

++

++

++

+

Skin Irritation

Hair follicles

Hair follicles

Hair follicles

Hair follicles Hair follicles

Hair follicles and sebaceous glands *

–

Hair follicles

Hair follicles, sebaceous and sweat glands

Transappendageal pathway

(Benson, 2010; Immordino et al., 2006; Joseph et al., 2018; Riemma Pierre and Miranda Costa, 2011; Touitou et al., 2000) (Benson, 2010; Marianecci et al., 2014; Venuganti and Perumal, 2009) (Ascenso et al., 2014; Cevc and Blume, 2001; Elsayed et al., 2007) (Ascenso et al., 2014; Dubey et al., 2007; Godin and Touitou, 2005; Touitou et al., 2001) (Ascenso et al., 2015; Ascenso et al., 2014; Dubey et al., 2007; Song et al., 2012) (Bai et al., 2016; Rai et al., 2018; Su et al., 2017) (Pardeike et al., 2009; Souto, 2003; Vitorino et al., 2013) (Pardeike et al., 2009; Souto and Barbosa, 2004; Vitorino et al., 2014) (Amaral et al., 2017; Bachhav et al., 2011; Cagel et al., 2017; Makhmalzade and Chavoshy, 2018; Torchilin, 2007) (Boisgard et al., 2017; Desai et al., 2010; Nagavarma et al., 2012; Venuganti and Perumal, 2009; Wu et al., 2009a)

References

Abbreviations: +, less; ++, moderate; +++, good; NEs, Nanoemulsions; SLNs, Solid lipid nanoparticles; NLCs, Nanostructured lipid carriers; PNPs, Polymeric nanoparticles. a Lipophilic drug. b Hydrophilic drug. *The impact of transappendageal transport pathway remains unclear.

+

++

Transethosomes

Micelles

++

Ethosomes

++

++

Transfersomes

NLCs

++

Niosomes

++ ++

++

Conventional liposomes

NEs SLNs

Hydrophilic drug loading efficiency

Nanosystem

Table 1 Comparative description of different nanosystems.

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Fig. 1. Schematic representation of human skin with nanosystem penetration behaviour. Key: NEs, Nanoemulsions; SLNs, Solid lipid nanoparticles; NLCs, Nanostructured lipid carriers; PNPs, Polymeric nanoparticles.

based development is to identify CMAs and CPPs of nanosystems. CMAs and CPPs are parameters whose variability has impact on specific CQAs and therefore, must be monitored and controlled to ensure that process will produce the intended product quality. These critical variables should be within an appropriate range, limit or distribution to ensure the pre-defined quality. The CMAs and CPPs underlying the different nanosystems for topical application are based on data from the relevant literature. Formulation parameters that show criticality in risk assessment should be screened and optimized through a factorial planning (DoEs) (Q8, 2009). DoE is an essential QbD element and represents a structured and organized experimental process that provides information with higher precision about the effect of variable changes on the product and process response, detects cause-effect relationships as well as interactions among these variables (Q8, 2009). In a QbD approach, the optimization process comprises a reduced number of experiments when compared to the classic strategy, where one factor is considered at a time. In a DoE based QbD development, screening designs, response surface designs and mixture designs can be accomplished. A screening design is an experimental planning which enables to simultaneously evaluate a relatively large number of factors in a small number of experiments. During the screening phase, all factors are tested in order to identify the most influencing ones (CMAs and CPPs). Different experimental designs, such as fractional factorial and Placket-Burman designs are usually used for screening purposes (Bastogne, 2017; Dejaegher and Heyden, 2011; Kovács et al., 2017; Marto et al., 2016; van Heugten et al., 2017). After performing screening experiments, significant variables are

controlled within appropriate ranges to ensure desired product quality (Q9, 2005). Risk assessment should be performed early in pharmaceutical development, but it is essential to be repeated at different development stages as further information becomes available and greater knowledge is obtained (Tomba et al., 2013). Despite all different available risk assessment tools (ICH Q9), it is important to select the most suitable one to the assessment purpose. The starting point should be to gather up systematically all the possible variables that could influence or generate a quality failure. Thereby, to identify these variables, an Ishikawa diagram should be developed. This diagram represents a cause-effect correlation among potential material attributes and process parameters with impact on CQAs (Fig. 3) (Garg et al., 2017a; Kovács et al., 2017; Lan and Shirui, 2017; Q9, 2005; Q10, 2008; Sangshetti et al., 2017; Xu et al., 2011). However, the impact degree of the described variables may be different for each quality attribute. The level of individual formulation variables could be represented through a risk estimate matrix (REM). REM is a systematic and proactive method to identify and mitigate the possible failure modes that are most likely to generate product failure. Therefore, this risk analysis tool aims to identify and to prioritize the formulation and process parameters with highest risk to CQAs, and thus which ones must be studied in more detail. Each factor mentioned in Ishikawa diagram should be later ranked in a REM analysis (Fig. 4) (Garg et al., 2017a; Kovács et al., 2017; Pallagi et al., 2015; Raina et al., 2017). 2.2. Identification of the nanosystem CMAs and CPPs Following the initial risk assessment, the fourth step of the QbD

Fig. 2. Chronological distance between nanosystems development and first QbD approach implementation. To our knowledge, the later dates correspond to the first study applying QbD to the development of the respective nanosystems a(Harkins, 1947); b(Bangham et al., 1965); c(Kreuter, 1979); d(Cevc and Blume, 1992); e (Arshady, 1988); f(Pardeike et al., 2009); g(Müller et al., 2007); h(Sandhu et al., 2017); i(Singh et al., 2005); j(Zidan et al., 2017); k (Jain et al., 2015); l(Shah et al., 2007); m(Patil et al., 2015); n(Kudarha et al., 2015). Key: QbD, Quality by Design. 388


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Table 2 Example of a QTPP and respective CQAs for a cream based on nanosystems. The establishment of this QTPP was based on relevant literature, which is not totally in agreement in what concerns the identified CQAs. QTPP

Target

CQAs

Justification

Dosage form Route of administration Dosage strength Physical form

Nanosystems based cream Topical % w/w Oil in water emulsion cream with API encapsulated into a nanosystem White smooth cream USP < 621 > /Eur. Ph. 2.2.29 USP < 621 > /Eur. Ph. 2.2.29 High (up to 40%)

– – – –

To improve drug skin permeation and control release Local administration avoiding systemic side effects – –

– – Yes Yes

– – To ensure drug availability in the right dose for absorption Impact on drug release, skin permeation, and therapeutic effect

Yes

Impact on drug release, permeation, physical stability and therapeutic efficacy Impact on physical stability

Zeta potential In vitro drug release profile

USP < 429 > /Eur. Ph. 2.9.31 ISO 13321 (1996)/ISO 22412 (2008) USP < 429 > /Eur. Ph. 2.9.31 ISO 13321 (1996)/ISO 22412 (2008) ISO 13099-2:2012 Sustained drug release

Yes Yes

Particle aggregation Skin penetration EE Turbiditya,b,d Dispersion viscosity Structure c

ISO 13321 (1996)/ISO 22412 (2008) In vitro Release Testing Guidance (EMA) Min. 95% USP < 855 > /Eur. Ph. 2.2.1 100–500 mPas Amorphous

Yes Yes Yes – Yes Yes

pH Stability

5.5 or compatible with formulation > |30| mV No visible sign of aggregation Appropriate for the dosage form

Yes Yes

Impact on aggregation and physical stability, skin retention To assess drug release speed and diffusion/permeation behaviour Impact on stability Impact on efficacy To ensure nanosystem drug loading – Impact on drug release and stability Impact on nanosystem drug loading, entrapment efficiency and efficacy Impact on drug loading, release, permeation and stability Quality requirement, impact on safety and efficacy

–

To ensure target shelf-life

Appearance Identification Assay API solubility in carrier system (Drug loading) Particle size Size distribution (Span value; PDI)

Container closure system

Yes

Abbreviations: API, Active pharmaceutical ingredient; CQAs, Critical quality attributes; EE, Encapsulation efficiency; Eur. Ph., European Pharmacopeia; PDI Polydispersity index; QTPP, Qaulity target product profile; USP, United States Pharmacopeia. a Liposomes. b Nanoemulsions. c Nanostructured Lipid Carriers. d Micelles.

Fig. 3. Ishikawa diagram showing critical parameters affecting NLC development. Key: DSC, Differential scanning calorimetry; EE, Encapsulation efficiency; HLB, Hydrophilic-lipophilic balance; HPH, High pressure homogenization; IR, Infrared spectroscopy; Log P, Octanol-water partition coefficient; NLC, Nanostructured Lipid Carriers; PDI, Polydispersity index; XRD, X-ray diffraction.

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Fig. 4. Risk estimation matrix presenting initial risk assessment levels of individual formulation and manufacturing parameters: Low: low risk parameter; Medium: medium risk parameter, High: high risk parameter. Key: CQAs, Critical quality attributes; EE, Encapsulation efficiency; HLB, Hydrophilic-lipophilic balance; HPH, High pressure homogenization; PDI, Polydispersity index.

aqueous core, whereas lipophilic drugs are entrapped into the lipid bilayer. Depending on lipid composition, preparation method and encapsulated drug nature, different liposomes may be produced. According to the number of bilayers, liposomes can be classified as unilamellar vesicles (ULVs) or multilamellar vesicles (MLVs), and regarding the size, an ULV, composed by a single phospholipid bilayer, may be subdivided into small unilamellar vesicles (SUVs) and large unilamellar vesicles (LUVs). Conventional liposomes display a great potential as drug delivery systems for local treatment of skin diseases. The interest in these carriers for dermatological therapy relies on their biocompatible, biodegradable and amphiphilic nature, reduced ability to provide a sustained drug release and an occlusive effect to disrupt the cellular packing of SC lipid bilayer and to fuse with SC lipid domains, improving penetrationenhancing properties in SC and epidermis, drug local concentration and therapeutic efficiency (El Maghraby et al., 2008; Riemma Pierre and Miranda Costa, 2011; Venuganti and Perumal, 2009). Therefore, conventional liposomes have been widely investigated as topical delivery system owing to their accumulation in the SC, upper skin layers and in the appendages (hair follicles, sebaceous and sweat glands), with minimal systemic delivery (Benson, 2010). However, the low drug loading, lack in production reproducibility, and physical (aggregation and coalescence) and chemical (oxidation and hydrolysis) instability, have limited liposome commercialization and application (Joseph et al., 2018; Xu et al., 2012). In order to improve the performance of the conventional liposomes,

then further explored in the optimization phase to define their optimal settings. Optimization stage enables to identify optimal conditions of the critical factors and, consequently, the design space. This analysis helps to establish the optimal ranges for CMAs and CPPs in order to avoid failure of product CQAs and, consequently, to ensure product QTPP. The optimal conditions can be determined by different experimental plans. Response surface designs, such as Central Composite Design and Box Behnken are the most usual models (Bastogne, 2017; Bhise et al., 2017; Huang et al., 2009; Marto et al., 2016; Yu et al., 2014). Response surface plot is a graphical representation about the effect of the different factors (or independent variables) on the identified responses (or dependent variables) and allows exploring formulation and process design spaces. Therefore, these plots can be used to predict the optimal CMAs and CPPs ranges within which parameters variation does not compromise product quality (Chang et al., 2013; Hao et al., 2011). 2.2.1. QbD on lipid-based nanosystems 2.2.1.1. Vesicular systems. Among nanopharmaceuticals, liposomes were the first class of nanosytems developed in the 60 s years (Bangham et al., 1965). These drug delivery systems are spherical vesicular structures of amphipathic phospholipids arranged in one or more concentric bilayers enclosing an aqueous core. The lamellar structures arise when phospholipids are brought in contact with an aqueous phase and the phosphate groups are spontaneously oriented to the hydrophilic environment. Hydrophilic drugs are encapsulated in the 390


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Riemma Pierre and Miranda Costa, 2011). Different methods have been reported to produce transfersomes: thin film hydration, reverse-phase evaporation method and ultrasonication dispersion method (Jain et al., 2010; Mahmood et al., 2014; Malakar et al., 2012; Yang et al., 2002). The film hydration method is the most common one. Briefly, in this technique phospholipids, surfactant and drug are dissolved in ethanol which is evaporated under reduced pressure, to form a lipid film. Then, the lipid film is hydrated (e.g. using a saline phosphate buffer solution) by stirring. Sonication methods may be used to reduce vesicle size. Ethosomes are deformable phospholipid vesicles containing a relatively high content of ethanol (20–45%) in their composition (Dayan and Touitou, 2000). These nanostructures have been found to be suitable delivery system for topical application of both lipophilic and hydrophilic drugs. The mechanism by which ethosomes are able to penetrate into skin has been ascribed to the alcohol penetrating properties. Ethanol provides more vesicular flexibility and malleability, destabilizing lipid bilayers, and disrupt SC lipid domain organization, increasing its fluidity. In addition to these penetration-enhancing mechanisms, the direct interaction of intact ethosomes with lipid skin domains will facilitate drug transport through the skin and higher local deposition. In general, ethosomes present smaller size then conventional liposomes, greater EE and improved stability. The negative charge provided by the ethanol, avoid vesicular system aggregation due to electrostatic repulsions (Dubey et al., 2007; Godin and Touitou, 2005, Touitou et al., 2001; Verma and Pathak, 2010). Different methods are available to prepare these carriers. Film hydration method, reverse-phase evaporation technique or lipids dissolution (e.g. phosphatidic acid, phosphatidyl serine or phosphatidylcholine) in ethanol, assembled by a hot or a cold method, are the general approaches to yield ethosomes (Chourasia et al., 2011; Jain et al., 2015, Jain et al., 2007; Maheshwari et al., 2012). In the classical technique, the cold method, phospholipids are dissolved in ethanol (organic phase) under magnetic stirring and immersed in a water bath. The heated aqueous phase (water, buffer solution or normal saline solution) is added to the organic phase, in a fine stream or dropwise, and stirred in a covered vessel during 5–30 min. The entire system is keeping at 30 °C. Depending on physicochemical properties, the active substance could be dissolved in either the aqueous or the organic phase. Vesicle size reduction may be achieved using sonication or extrusion methods (Abdulbaqi et al., 2016; Dubey et al., 2007; Nandure et al., 2013; Touitou et al., 2000; Zhou et al., 2010). Ethosomes production by film hydration is an extension of conventional liposomes preparation method, but in this case, the lipid film is hydrated by a hydro alcoholic solution (Park et al., 2014). Transethosomes are vesicular systems similar to ethosomes but with an additional compound in their formula, an edged activator (surfactant) or permeation enhancer (propylene glycol, oleic acid). These vesicles combine the benefits of classical ethosomes and deformable transfersomes in the same system defined as transethosomes (Song et al., 2012). Therefore, their skin penetration process might be a fusion of both described mechanisms. Furthermore, transethosomes have shown higher skin penetration/permeation ability, due to the presence of the ethanol and surfactant in their composition, which makes them the most flexible UDV (Ascenso et al., 2015). Besides that, ethosomes have a remarkable retention time in hair follicles and sebaceous glands (Yang et al., 2017; Zhang et al., 2014b). Different methods have been reported for transethosomes production. Similar to the liposomal vesicles, the film hydration technique can be employed. Phospholipids, drug and the edge activator and/or permeation enhancer are dissolved in chloroform or a methanol-chloroform mixture. Then, any traces of organic solvents are removed by a rotary vacuum evaporator. The deposited lipid film is subsequently hydrated with an ethanol solution (Abdulbaqi et al., 2016; Cevc and Blume, 2001; Garg et al., 2017b). Analogous to ethosomes, the most widely used technique to prepare transethosomes is the classical cold method. The difference between both vesicles relies on the organic

further surfactant vesicles have been developed. Among them, niosomes have received great attention due to their lower production costs and higher stability (Manca et al., 2014). Niosomes are self-assembled vesicular nanosystems prepared from non-ionic surfactants and amphiphilic molecules with closed bilayer structure. Similar to liposomes, niosomes might be prepared as ULV or MLV and they are suitable carriers for hydrophilic and lipophilic drugs. The permeation enhancer effect is attributed to their flexibility, and direct fusion with SC. In addition, surfactant molecules may also modify SC lipid structure enhancing skin permeability. The surfactant type influences the rate of drug release from the vesicles. Niosomes preferentially accumulate in the superficial skin layer or follicles, which justify their great application in dermatological therapy (Benson, 2010; Marianecci et al., 2014; Venuganti and Perumal, 2009). Different methods have been developed for the production of liposomes and niosomes: film hydration, emulsification, reverse phase evaporation and solvent injection (Wu et al., 2009a). Liposomes and niosomes are mainly formulated through film hydration. In this technique, the vesicle components (e.g., soy lecithin: cholesterol, phosphatidylcholine: cholesterol) are dissolved in a solvent or a mixture of organic solvents such as methanol or chloroform followed by evaporation under reduce pressure or through lyophilisation, to eliminate any solvent traces, with consequent lipid film formation. The resulted film is then dispersed in a hydration medium to produce an aqueous dispersion of MLVs. SUVs may be prepared reducing MLVs lamellarity and size through sonication or membrane extrusion, with a particular pore size to obtain liposomes with the required particle size (Joseph et al., 2018; Singh et al., 2005; Venuganti and Perumal, 2009; Xu et al., 2011, 2012). Niosomes preparation method comprises hydration of a non-ionic surfactant:lipid mixture, followed by size reduction. Chemical composition, production methods, and physicochemical properties, including size, charge, thermodynamic state and vesicle deformation impact the their effectiveness as drug delivery systems (Fadda and Sinico, 2009). Cholesterol, due to the structural rigidity introduced, and charged molecules may be comprised in vesicular systems formulation to prevent vesicle aggregation, improving the dispersion stability (Basiri et al., 2017; Xu et al., 2011). In the beginning of the 90s, a new generation of flexible, elastic and deformable liposomes – the ultradeformable vesicles (UDV), was developed (Cevc and Blume, 1992). Different types of UDV have been designed, which include transfersomes, ethosomes and transethosomes (Manosroi et al., 2009). These vesicles present nontoxic features, a relatively simple production and acceptable stability. UDV present a distinct topical delivery ability, ascribed to their higher deformability, which allows the elastic vesicle to squeeze through minor skin spaces, resulting in enhanced drug transport/diffusion across the different skin layers. Phospholipids, ethanol, surfactants and permeation enhancers have been extensively used to yield these flexible vesicles (Ascenso et al., 2015; Benson, 2010; Zylberberg and Matosevic, 2016). Transfersomes, the first generation of UDV, are mainly composed by amphipathic components, such as phospholipids (e.g. phosphatidylcholine), self-assembled as vesicle in an aqueous environment. Their permeation behaviour is achieved by the addition of a surfactant, which acts as an edge activator, into the lipid bilayer membrane. Span® 80, Tween® 80, sodium cholate or potassium glycyrrhizinate will destabilize the vesicular structure, giving it more flexibility and deformability. Besides the efficient lipophilic drugs delivery ability, the penetrationenhancing effect of these vesicles can be enlarged to hydrophilic drugs transport. In contrast to conventional liposomes and niosomes, transfersomes revealed significant higher entrapment efficiencies (EE). Interestingly, the transfersomes reveal greater efficiency under nonocclusive environments, since their penetration is governed by the different hydration gradient established between the skin surface and the viable epidermis, which generates an osmotic gradient. Conversely to conventional liposomes, they do not penetrate into the appendage structures (Cevc, 2004; El Maghraby et al., 2000; Elsayed et al., 2007; 391


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demonstrated a greater ability to cross SC and the deeper skin layers, reaching system circulation (Ascenso et al., 2014). The development of liposomes, niosomes, transfersomes, ethosomes and transethosomes can be streamlined using QbD principles. An example of their application, including with CMAs and CPPs identification, is described in Table 3.

Table 3 Application of a Quality by Design approach to liposomes, niosomes, transfersomes, ethosomes and transethosomes development. Parameter

Criticality

CQAs

Drug log P Drug concentration

CMA CMA

Particle size, PDI, EE, stability Particle size, PDI, EE, zeta potential, drug release

Phospholipids Composition

CMA

Particle size, EE, zeta potential, stability, penetration Particle size, PDI, EE, stability Particle size, PDI, EE, viscosity, drug release EE, stability, flexibility Particle size, PDI, EE, zeta potential, stability, drug release

Chain length Concentration

CMA CMA

Tm Cholesterola,b,d

CMA CMA

Edge activator/Surfactantb,c,e Type (ionic or non-ionic)

CMA

HLB Chain length Tm Phospholipids: Surfactant ratioc,e Surfactant: Lipid: Cholesterol ratiob % Ethanold,e

CMA – – CMA

Particle size, PDI, EE, zeta potential, stability, drug release, penetration Particle size, EE, stability, flexibility, penetration Particle size, PDI, EE Drug release EE Particle size, stability

CMA

Particle size, PDI, EE, drug release

CMA

Permeation enhancers (oleic acid)e Film hydration processa,b,c,e Hydration medium composition Temperature (similar to lipid Tm) Hydration time Hydration volume % Alcohold,e Storage temperatured Ultrasonication Time Temperature (above lipid Tm) Amplitude Extrusion Membrane type Membrane pore size Temperature Pressure Number of extrusions Cold methodd,e Phases mixture temperature Stirring time Stirring speed Stirring temperature

CMA

Particle size, zeta potential, flexibility, viscosity, stability, drug release, penetration Particle size, zeta potential, flexibility, drug release, penetration

Concentration

CMA

–

Particle size, EE

–

EE

CPP – CMA CPP

Particle size, PDI, EE, stability EE Particle size, stability Particle size, EE, stability

CPP CPP

Particle size, PDI, EE, stability Particle size, EE, stability

CPP

Particle size, EE, stability

CPP CPP CPP CPP CPP

Particle Particle Particle Particle Particle

CPP

Particle size, PDI, stability

CPP CPP CPP

Particle size, PDI, stability Particle size, PDI, stability Particle size, PDI, stability

size, size, size, size, size,

2.2.1.2. Nanoemulsions. Nanoemulsions (NEs) are a thermodynamically colloidal disperse system whose formulation comprises oily and water immiscible phases, stabilized by an interfacial film of emulsifying agents and co-surfactant, which emerged in the 80 s. NEs biphasic structure, either oil-in-water (o/w) or water-in-oil (w/o) dispersion, enables to deliver lipophilic or hydrophilic drugs, respectively, although the hydrophilic substances may also be loaded into multiple NEs systems (Arshady, 1988; Qadir et al., 2016; Rai et al., 2018). NEs exhibit better stability to sedimentation, flocculation and coalescence than conventional emulsions, due to their small particle size, since a narrow range size decreases the range of the attractive forces between the droplets (Tadros et al., 2004). For the product development, the selection of the excipients and the respective concentrations, the order of addition, and the preparation method, including stirring/shearing speed are parameters that require special attention (Mason et al., 2006). Oily ingredients, such as, isopropyl myristate, propylene glycol monoethyl ether, isocetyl isostearate have been widely used to yield emulsion-based nanosystems. In order to develop successful NEs formulations, emulsifying agents must be carefully selected to reduce the interfacial tension among the oily and water phases, so as to obtain kinetic stability against sedimentation, flocculation and coalescence effects, and to avoid the creaming process. Nonionic surfactants are the first option to produce nano-based emulsion, due to their safety and low irritant effect. Co-surfactants, such as propylene glycol, glycerine and ethylene glycol, are also included in this isotropic system to stabilize the emulsifier interfacial film and to assist its fluidity (Bai et al., 2016; Rai et al., 2018; Wu et al., 2009a). NEs formation depends on the system components. Individual screening method using pseudo-ternary phase studies is usually carried out to select the best ratio of oily phase, surfactant and co-surfactant in order to achieve stable NEs (Aiswarya et al., 2015). Oily phase selection is accomplished by determining the relative drug solubility in the oils considered (Azeem et al., 2009). The surfactant is chosen according to the maximal amount of oil that is solubilized (Tenjarla, 1999). Co-surfactant selection is performed according to its stabilization efficiency. By fixing surfactant:co-surfactant ratio and keeping the surfactant unchanged, the best co-surfactant is determined through the great nanoemulsion region presented in ternary phase study. The greater area of NEs formation, the greater co-surfactant stabilizing ability (Shafiq et al., 2007). Emulsion-based nanosystems have called the attention for skin drug delivery due to a synergistic effect of the increased surface area, enhanced solubility and direct chemical enhancement effect of the excipients within the SC. Active substance incorporation, whether in the internal or the external phase will influence its release behaviour. Likewise other nanosystems, small droplet size of NEs provides a large surface area, ensuring a closer contact between the nanosystem and the SC layer. Their solubilization ability, for both hydrophilic and lipophilic substances, increases NEs drug-loading capacity and drug amount applied through the topical formulation. Droplets and surfactant molecules may interact with intercellular lipid structure, resulting in a direct permeation enhancement effect on the SC surface. On the other hand, the oily phase acts as an occlusive agent, promoting skin hydration and reducing SC barrier function, which may promote drugs absorption topically applied. NEs have also been founded in hair follicles (Roberts et al., 2017; Su et al., 2017; Venuganti and Perumal, 2009). NEs can be obtained through high energy or low energy emulsification methods. High energy emulsification techniques are applied when the emulsification process is not spontaneous. These methods

PDI PDI, EE, lamellarity PDI PDI, EE PDI

Abbreviations: CMA, Critical material attribute; CPP, Critical process parameter; CQAs, Critical Quality Attributes, EE, Encapsulation Efficiency; HLB, Hydrophilic-lipophilic balance; Log P, Octanol-water partition coefficient; PDI, Polydispersity index; Tm, Phase transition temperature. Note: the parameter selection must be based on a previous risk assessment analysis. a Conventional Liposomes. b Niosomes. c Transfersomes. d Ethosomes. e Transethosomes.

phase, where additional components (edge activator or permeation enhancers) must be added for the later (Abdulbaqi et al., 2018; Abdulbaqi et al., 2016; Song et al., 2012; Touitou et al., 2000). Due to their higher deformability, transethosomes have 392


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self-nanoemulsification method has been recently performed for NEs preparation and has received a great attention from the scientific community as it enables to formulate NEs at room temperature, lacking organic solvents and heat (Shah et al., 2007). An application of a QbD approach to NEs development, with CMAs and CPPs identification, is presented in Table 4.

Table 4 Application of a Quality by Design approach to NEs development. Parameter

Criticality

CQAs

Drug log P Drug concentration Oily phase composition Oil concentration

CMA CMA CMA CMA

EE, stability Drug release EE, drug penetration, stability Particle size, viscosity, turbidity, drug release

CMA CMA CMA

EE Particle size, stability, viscosity Particle size, PDI, EE

CMA CMA CMA

EE Particle Particle release Particle Particle Particle

Surfactant Type Concentration HLB Co-surfactant Type Concentration Smix ratio Oil: Smix ratio Oil: Surfactant ratio Water content High speed stirring Type Time Speed Temperature Ultrasonication Time Amplitude Temperature PIC Temperature Addition rate Mixing rate Water content

CMA CMA CMA – CPP CPP – CPP

size, PDI, stability, viscosity size, PDI, stability, viscosity, drug size, stability size, viscosity, stability size, stability, viscosity

Particle size Particle size, viscosity Particle size, zeta potential, stability, viscosity Particle size

CPP

Particle size, PDI, zeta potential, viscosity, stability Particle size, PDI, zeta potential, viscosity, stability Particle size, PDI, stability

CPP CPP CPP CPP

Particle Particle Particle Particle

CPP

2.2.1.3. Lipid nanoparticles. Lipid nanoparticles (LN) have been extensively investigated for different pharmaceutical applications, but there is a growing interest in the field of cosmetic and pharmaceutical dermal formulations containing solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) (Müller et al., 2007). SLNs arise in the early of 1990s as an alternative to conventional liposomes, emulsion and polymeric nanoparticles (Pardeike et al., 2009) and in 2005, it was launched a second LN generation, the NLC (Müller et al., 2007). These novel lipid-based nanosystems consist in a solid lipophilic matrix in which the active agent(s) may be incorporated for different delivery applications. Two generations of lipid nanoparticles are distinguishable and the main difference among them is their lipophilic matrix structure. These nanosystems derive from o/w nanoemulsions and remain solid at body temperature (Müller et al., 2011). SLNs and NLCs are outstanding dermal delivery carriers, due to their singular features which include, drug targeting, biocompatible nature, easily scalable, well-established production methods, enhanced skin bioavailability, occlusion effect associated with skin surface hydration and penetration enhancement, incorporation of low water-soluble active substances, improvement of drug stability and ability to ensure a close contact with the SC lipid domains, resulting in a more efficient and deeper drug penetration into the skin layers. Nevertheless, hair follicle penetration is considered an alternative pathway route. Controlled release of the active(s) may be modulated by changing lipid composition (Pardeike et al., 2009; Roberts et al., 2017; Souto and Barbosa, 2004; Souto, 2003; Venuganti and Perumal, 2009; Vitorino et al., 2014, Vitorino et al., 2013). 2.2.1.3.1. Solid lipid nanoparticles. Solids lipid nanoparticles (SLNs) are considered the first generation of LN technology. Solid lipid nanosystems are produced by replacing the liquid lipid (oil) of an o/w emulsion by a solid lipid or a blend of solid lipids (Pardeike et al., 2009). Particles produced from highly purified solid lipids crystallize in a higher energy modification, such us unstable α and metastable β′ polymorphic forms. During the storage, rearrangement of crystal may occur, resulting in the most ordered and stable β polymorphic form and leading to drug expulsion. The highest degree of crystal order reduces matrix imperfections, limiting the space to accommodate drug molecules and consequently SLNs drug loading ability (Mehnert and Mäder, 2012). 2.2.1.3.2. Nanostructured lipid carriers. Nanostructured lipid carriers (NLCs), the second and smarter generation of solid lipidbased nanosystems, are produced using a blend of a solid lipids and liquid lipids (Vitorino et al., 2013). Although NLCs derive from SLNs, they overcome some limitations associated with the first generation of LN, such as the lower drug loading efficiency and the expulsion of the active from the lipid matrix during the storage. The addition of an oily compound introduces less structural order and then more imperfections are created in the solid matrix, preventing the formation of a perfect crystalline structure. Therefore, the liquid lipids, with different sized molecules, lead to an amorphous structure enabling to enhance active ingredient loading and also to avoid or minimize drug expulsion during the storage (Mehnert and Mäder, 2012; Müller et al., 2007). Different methods have been described in the literature to prepare LN: emulsification-solvent evaporation, emulsification-solvent diffusion, solvent displacement method, ultrasonication, double emulsion technique, HPH, membrane contact technique and supercritical fluid (Müller et al., 2011). However, HPH (Gupta et al., 2017; Pardeike et al., 2009) and ultrasonication (Kovács et al., 2017; Mennini et al., 2016; Shah et al., 2015) techniques are widely used to SLNs and NLCs production.

size, size, size. size,

PDI, stability PDI, stability PDI, stability PDI

Abbreviations: CMA, Critical material attribute; CPP, Critical process parameter; CQAs, Critical quality attributes; EE, Encapsulation efficiency; HLB, Hydrophilic-lipophilic balance; Log P, Octanol-water partition coefficient; PDI, Polydispersity index; PIC, phase inversion composition; Smix, Surfactant: cosurfactant. Note: the parameter selection must be based on a previous risk assessment analysis.

comprise high shear stirring, ultrasonic generators and high pressure homogenizers to break emulsion droplets into nanosize range and include high pressure homogenization (HPH), high speed stirring, ultrasonication and microfluidization methods (Lovelyn and Attama, 2011; Rezaee et al., 2014; Sutradhar and Amin, 2013). According to low energy emulsification techniques, the energy of the system is used to produce small emulsion droplets. These methods are based on changes in temperature and composition parameters, resulting in a modification of the hydrophilic lipophilic-balance (HLB) of the system (Solè et al., 2006). The phase inversion temperature (PIT) method is based on a particular property of emulsifiers, relying on their different water and oil solubility/affinity, depending on progressive changes in system temperature. Some emulsifier molecules are hydrophilic at low temperature and hydrophobic at an elevated temperature. In phase inversion composition (PIC) method, the addition of different elements to the isotropic mixture will disturb the surfactant monolayers, leading to a phase inversion at constant temperature (Rai et al., 2018; Yu et al., 2012). Phase transition is raised by stepwise addition of aqueous phase to isotropic mixture of lipids, surfactants, co-surfactants in the oily phase under gentle agitation, resulting in an o/w emulsion (Lovelyn and Attama, 2011). Besides PIT and PIC methods, self-nanoemulsification, aqueous phase titration and solvent displacement methods (nanoprecipitation) are likewise low energy techniques to obtain NEs (Salim et al., 2016; Su et al., 2017). Out of different techniques, high pressure homogenization (HPH) and ultrasonication are frequently developed in laboratory scale (Amani et al., 2008). Nonetheless, the 393


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2.2.2. QbD on polymeric-based nanosystems 2.2.2.1. Micelles. Micelles are spherical structures of amphiphilic blocks of copolymers surrounded a hydrophobic inner core, able to efficiently carry and release lipophilic drugs, while a hydrophilic outer shell stabilizes the structure integrity. In aqueous solutions, copolymers self-assemble into micelles once exceeded the critical micelle concentration (CMC). Reaching CMC, any polymer addition will increase micelles number and thereby their binding ability (Almeida et al., 2018; Amaral et al., 2017; Lodge et al., 2005; Lu and Park, 2013). These nanosystems were introduced in the 40s years (Harkins, 1947) and since the 1990s (Masayuki et al., 1990) they have been highlighted as drug carriers due to their very small size, slower dissociation rate, sustained release, increased drug bioavailability, solubility and stability, and drug delivery ability to the target (Cagel et al., 2017; Figueroa-Ochoa et al., 2016). Polymeric micelle properties depend on the nature and composition of the starting polymer blocks (Kumar et al., 2001). The interactions between the hydrophobic drug and the core moieties depend on the nature and the size of the copolymer hydrophobic segments. Copolymer blocks nature affects the intermolecular interactions between drug and polymer, and their size influences micelles drug loading capacity (Torchilin, 2007). EE also depends on copolymers block HLB, hydrophobic segment length and drug: polymer ratio. Hydrophobic chains also influence micelle stability. Increasing the hydrophobic portion, the CMC decreases while enhance the stability. Low polymer molecular weight (MW) encompasses higher CMC landing to thermodynamic and kinetic micelle instability (Deshmukh et al., 2017; Shuai et al., 2004). The length of the hydrophilic portion have no critical effect on the CMC (Lee et al., 2003). A suitable polymer selection is extremely important to the success development of micelles as drug delivery systems. Studies related with the application of polymeric micelles to enhance topical drug delivery are uncommon. The mechanism by which these structures induce skin permeation enhancement of loaded substances is still unknown (Šmejkalová et al., 2017). Some authors have suggested that micelles induce changes in the SC lipids, thus acting as penetration enhancers (Loan Honeywell-Nguyen et al., 2002). A relevant study demonstrated a possible drug delivery enhancement using micelles, due to the fact that their small size provide an higher contact surface with the skin or by a film formation in its surface (Bachhav et al., 2011). Recent studies mentioned the presence of polymeric micelles in hair follicles (Kahraman et al., 2016; Makhmalzade and Chavoshy, 2018). More investigations related with the potential of these drug delivery systems for topical applications should be carried out. During the last years, synthetic and natural polymers have been investigated as block building of amphiphilic copolymers. Polymers mostly used in micelles production are copolymers blocks, with a hydrophilic and a hydrophobic portion, subdivided in diblock, triblock, graft-block and star-block copolymers (Kang et al., 2005; Torchilin, 2001). The hydrophilic shell may consist in different polymers, such as poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(ethylene imine) (PEI) and poly(ethylene oxide) (PEO). The hydrophobic core is mainly made up by poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), polystyrene (PS), poly(methyl methacrylate) (PMMA) and poly(propylene oxide) (PPO) (Batrakova and Kabanov, 2008; Kedar et al., 2010) Polymeric micelles may be prepared through different methods. The most common techniques are dialysis method, oil-in-water emulsion method, solvent evaporation method, co-solvent evaporation technique, freeze-drying method (Aliabadi and Lavasanifar, 2006; Gaucher et al., 2005) and thin film hydration (He et al., 2016; Valenzuela-Oses et al., 2017; Zhang et al., 2014a). The most general technique is through dialysis (Bae and Kataoka, 2009). The dialysis method is performed through dissolution of the copolymer and the drug in a water miscible organic solvent, such as acetonitrile, acetone or N,N- dimethylformamide. The resulting solution is dialysed against water over a semipermeable membrane. In this

Table 5 Application of a Quality by Design approach to SLNs and NLCs development. Parameter

Criticality

CQAs

Drug log P Drug concentration Drug: lipids ratio Lipids Composition Concentration

CMA CMA CMA

EE, stability Drug release Particle size, PDI, EE

CMA CMA

Solid lipid: liquid lipid ratioa Surfactant Type

CMA

API solubility, particle size, EE API solubility, particle size, PDI drug release, EE API solubility, particle size, PDI drug release, drug penetration, EE

CMA

HLB

CMA

Concentration (% w/w)

CMA

Hot High Pressure Homogenization Stirring time CPP Stirring speed CPP Pressure CPP Number of cycles High speed stirring Stirring time Stirring speed Stirring temperature Ultrasonication Time Temperature Amplitude

CPP

Particle size, PDI, EE, zeta potential, stability Particle size, PDI, EE, zeta potential, stability Particle size, PDI, EE, drug release, aggregation, stability Particle size, PDI, aggregation, stability Particle size, PDI, aggregation, stability Particle size, PDI, drug release, zeta potential Particle size, drug release, PDI, aggregation, stability, zeta potential

CPP CPP CPP

Particle size, PDI, aggregation, stability Particle size, PDI, aggregation, stability Particle size, PDI, aggregation, stability

CPP

Particle size, PDI, EE, aggregation, stability Particle size, PDI, stability Particle size, PDI, stability

CPP CPP

Abbreviations: CMA, Critical material attribute; CPP, Critical process parameter; CQAs, Critical quality attributes; EE, Encapsulation efficiency; HLB, Hydrophilic-lipophilic balance; Log P, Octanol-water partition coefficient; PDI, Polydispersity index Note: the parameter selection must be based on a previous risk assessment analysis. a NLC.

HPH is an easy scale-up method, which avoids the use of organic solvents, and requires a short time of production. LN may be produced by either the hot or cold HPH technique. In the hot HPH, the molten solid lipid (SLN) or lipid mixture (NLC), with dissolved or dispersed drug, is emulsified in an aqueous surfactant solution heated at the same temperature by high speed stirring. The obtained pre-emulsion is then processed through a high pressure homogenizer yielding a hot o/w emulsion. Once cooled, the emulsion droplets crystallize forming LN (Gupta et al., 2017; Müller et al., 2007). The cold homogenization technique is suitable for temperature-sensitive drugs (Bhise et al., 2017). The first step is similar to hot homogenization, but it is followed by rapid cooling of the molten lipid using liquid nitrogen or dry ice. The blend of solid lipid or the liquid and solid lipids mixture are dispersed in a cold surfactant solution and processed through a high pressure homogenizer at room temperature. High encapsulation efficiency has been achieved for lipophilic drugs, while for hydrophilic drugs a relatively low encapsulation is accomplished (Venuganti and Perumal, 2009). According to the ultrasonication technique, the aqueous phase is added to the melted blend of solid lipids or the liquid and solid lipids mixture, but an inversion in phase’s addition might be also verified. Both phases, heated at the same temperature, are thereafter emulsifying during a short period of time using a high speed stirrer. The resulting pre-emulsion is subjected to ultrasonication at constant temperature. Finally, the dispersion is cooled to solidify the lipid matrix and obtain SLNs or NLCs (Bhise et al., 2017; Kovács et al., 2017; Mennini et al., 2016). An application of a QbD approach to SLNs and NLCs, with CMAs and CPPs identification, is displayed in Table 5. 394


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Controlling self-assembling conditions and selecting an adequate polymer enable the adjustment of PNPs properties, including particle size and distribution, surface charge and release rate. PNPs are usually composed by nontoxic, biocompatible and biodegradable polymers. The most frequently natural polymers applied in PNPs are chitosan, alginate, and gelatin (Nagavarma et al., 2012). In addition, the synthetic polymers widely used for topical drug delivery are poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(methyl methacrylate) (PMMA), polyethylene glycol (PEG) and polyacrylamide (PAM) (El-Say and El-Sawy, 2017; Sathyamoorthy et al., 2017). The main advantage of these particles is the possibility to chemically modify the polymer structure, reducing its toxicity and to conduct nanosystems to a specific target (Kumari et al., 2010). Depending on the requirements of PNPs application and drug physicochemical properties, nanocapsules and nanospheres may be properly formulated by different methods. The choice of the most suitable preparation technique also plays an important role to obtain PNPs with the required characteristics (Crucho and Barros, 2017; El-Say and El-Sawy, 2017). Two main strategies may be addressed to yield PNPs: monomer polymerization or dispersed preformed polymers (Rao and Geckeler, 2011). PNPs formulation through monomer polymerization includes methods, such as emulsion, mini-emulsion, microemulsion, interfacial polymerization, and controlled radical polymerization. On the other hand, PNPs preparation from dispersion of preformed polymers comprises emulsification-solvent evaporation method, emulsification-solvent diffusion method, nanoprecipitation, salting-out, supercritical fluid technology, dialysis and layer-by-layer as different production techniques (Crucho and Barros, 2017; Mora-Huertas et al., 2010; Nagavarma et al., 2012). In PNPs formulation, the low production cost is an important advantage, whereas the potential cytotoxicity of residual organic solvent used in the production and the production process scaling are their most relevant limitations (Kumari et al., 2010). In pharmaceutical industry, emulsion-based colloidal delivery systems are extensively used (Crucho and Barros, 2017; El-Say and ElSawy, 2017). Therefore, emulsification-solvent evaporation method (Marto et al., 2016; Yerlikaya et al., 2013) and nanoprecipitation (Deepak et al., 2014; Vuddanda et al., 2015) are the main techniques used to produce PNPs (Crespy et al., 2013; Schubert and Jr, 2011). In solvent evaporation technique, a preformed polymer is dissolved in an organic phase, such as chloroform, dichloromethane or, with a better toxicological profile, ethyl acetate. The resulting organic solution is dispersed in the aqueous phase containing a surfactant, and then emulsified through sonication or high speed homogenization, yielding a nanodroplet dispersion (o/w emulsion). Subsequently, the organic solvent is removed by evaporation under reduced pressure or through continuous stirring at room temperature to form PNPs (Marto et al., 2016; Vauthier and Bouchemal, 2009; Yerlikaya et al., 2013). In nanoprecipitation method, the polymer is dissolved in a watermiscible solvent, such as acetone, and this phase is added into a stirred aqueous solution by dropwise controlled addition. The fast diffusion of polymer solution to the stabilizer solution results in instantaneously nanoparticles production. The nanoformulation thus obtained may be subjected to magnetic stirring at room temperature for the evaporation of organic solvent (Rose et al., 2015; Srinivas et al., 2017). The implementation of the QbD principles to PNPs development is presented in Table 7.

Table 6 Application of a Quality by Design approach to micelles development. Parameter

Criticality

CQAs

Drug log P Drug concentration

CMA CMA

EE, stability Particle size, drug loading, EE, zeta potential

CMA CMA CMA CMA CMA

Zeta potential, stability Stability EE, stability, drug release Particle size, stability Particle size, EE, zeta potential, stability, drug release

CMA

Particle size, PDI, drug loading, EE, zeta potential Particle size, PDI, drug loading, EE zeta potential – Drug loading, EE Drug loading, EE Drug loading, EE

Copolymer Blocks nature HLB CMC MW MW of hydrophobic portion Dialysis Copolymer/drug ratio Solvent volume

CPP

Dialysis temperature Mw cut-off membrane Dialysis time Number of water changes

– CPP CPP CPP

Abbreviations: CMA, Critical material attribute; CMC, Critical micelle concentration; Mw, Molecular weight; CPP, Critical process parameter; CQAs, Critical quality attributes; EE, Encapsulation efficiency; HLB, Hydrophilic-lipophilic balance; Log P, Octanol-water partition coefficient; PDI, Polydispersity index. Note: the parameter selection must be based on a previous risk assessment analysis.

process, the organic solvent moved out of the dialysis membrane is gradually replaced by water at predetermined time points. This process involves a slow of water-soluble organic solvent remotion that triggers copolymer self-assembly and drug encapsulation. Drug-loaded micelles keep retained in the dialysis bag, while unloaded drug remains outside it (Aliabadi, 2006; Gaucher et al., 2005; Okano and Kataoka, 1996; Xian et al., 2008). An example of a QbD approach applied to micelle development is critically illustrated in Table 6. 2.2.2.2. Polymeric nanoparticles. Over the conventional dosage forms, polymeric nanoparticles (PNPs) have received considerable attention as innovative drug delivery system, particularly for pharmaceutical application, since the 90s years, although they have been mentioned for the first time in the 70s. Composed by natural or synthetic polymers, PNPs comprise nanocapsules and nanospheres, in which the hydrophilic or lipophilic active ingredient is entrapped in an aqueous or oily core, or dispersed in the polymeric matrix, respectively. Furthermore, the active ingredient may be adsorbed, complexed, or conjugated onto the nanosphere surface (Kreuter, 1979; Li et al., 2017; Wu et al., 2009a). Generally, PNPs do not penetrate into the intact SC. Their rigid structure and bioadhesive ability, enable to stick a film of PNPs on the skin and release drug content locally (Desai et al., 2010). Thereby, the main application of PNPs is through topical formulations for superficial drug permanence and limited penetration into the skin (Wu, 2012). PNPs high surface area (nanoscale) enables a longer contact between the nanoparticles and the biological target, and their ability to retain the active substance locally at the site of action has highlighted their advantageous use as drug delivery system for innovative topical therapy. The skin penetration of PNPs is restricted to SC, being mainly transported through the follicular pathway. Note that different deposition patterns have been described across hair follicle, depending on the particle size (Boisgard et al., 2017; El-Say and El-Sawy, 2017; Venuganti and Perumal, 2009). Furthermore, PNPs improve drug stability, preventing its degradation by encapsulation, and allow a better control of drug release through adjustments in the polymer properties (Küchler et al., 2009; Wu et al., 2009b).

3. Industrial production of nanoformulations: several challenges As described above, nanosystem size, distribution and functionality are crucial characteristics for their effective therapeutic applications and, for this purpose, such parameters should be reproducible and scalable. A drug release profile reproducibility is also needed to reach batches uniformity and quality performance. Nanosystem formulation and production are fairly complex, remaining a challenge to pharmaceutical technology in terms of size and PDI reproducibility. 395


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effectiveness as drug delivery system and drug penetration. ▪ Edge activator and ethanol concentration will influence vesicle stability, flexibility, drug release and drug penetration. ▪ In film hydration process, hydration medium composition and hydration time are critical process parameters to conventional liposomes, niosomes, transfersomes and transethosomes size and EE. ▪ In cold method, stirring time speed and stirring temperature are critical variables to ethosomes and transethosomes size and stability.

Table 7 Application of a Quality by Design approach to PNPs development. Parameter

Criticality

CQAs

Drug log P Drug concentration Organic phase Polymer concentration

CMA CMA

EE, stability Particle size, EE

CMA

Polymer molecular weight Solvent type Volume Aqueous phase Surfactant type

CMA

Particle size, PDI, zeta potential, viscosity, stability, EE, drug release Viscosity, stability

CMA CMA

Particle size, PDI Particle size

CMA

Particle size, stability Particle size, stability Particle size, Particle size Particle size, Particle size,

Surfactant concentration

CMA

Solvent type – Volume – Drug: polymer ratio CMA Organic: aqueous phase CMA ratio Emulsification – solvent evaporation method Solvent evaporation rate CPP Homogenization Type CPP Rate CPP Time CPP Ultrasonication Time CPP Temperature CPP Amplitude CPP Nanoprecipitation Needle gauge CPP Organic phase injection CPP rate

4.2. Nanoemulsions ▪ Oily phase composition is a critical material attribute with influence on skin drug penetration. ▪ Oil, surfactant and co-surfactant ratio present a wide impact on particle size and stability. ▪ High speed stirring and PIC are production processes with high risks to NEs particle size, viscosity and consequently to their stability.

PDI, zeta potential, EE, PDI, zeta potential, EE,

PDI, EE EE

4.3. Lipid nanoparticles Particle size, PDI

▪ Lipids and surfactant composition and concentration are critical variables that determine drug solubility, particle size and drug release effectiveness of the SLNs and NLCs. ▪ The NLCs ratio of solid lipid and liquid lipid significantly influences particle size, EE, drug release and drug penetration. ▪ HPH is an LNs production process easily up-scalable, where variables, such as stirring time and speed need to be carefully studied and controlled, since they impact the final particle size, PDI and stability of SLNs and NLCs.

Particle size, PDI Particle size Particle size, PDI, zeta potential Particle size, PDI Particle size, PDI, stability Particle size, PDI, stability Particle size Particle size

4.4. Micelles Abbreviations: CMA, Critical material attribute; CPP, Critical process parameter; CQAs, Critical quality attributes; EE, Encapsulation efficiency; Log P, Octanol-water partition coefficient; PDI, Polydispersity index. Note: the parameter selection must be based on a previous risk assessment analysis.

▪ Copolymer Mw, hydrophobic portion lengths, and CMC are critical material attributes, whose variation have dramatic impact on particle size, stability and drug release. ▪ Dialysis is a common method performed to yield polymeric micelles, where MW cut-off membrane represents a high risk to drug loading and EE.

Furthermore, under changeable conditions, nanosystems instability will difficult their storage during a long period of time, leading to lack of their therapeutic efficacy. In this context, the industry has faced some difficulties to translate nano-based projects into a final drug product, since such plans are based on unproven assumptions or hard to scale up. Nanosystems are not able to achieve the binding robustness level when produced at a large scale and, besides that, the reproduction of the results described in the literature may depend on many factors. A thorough selection of materials, formulation and process parameters is mandatory and generally not mentioned. Lipid and polymer nanoparticles have been widely explored in the nanomedicine era. At laboratory scale, these nanosystems can be obtained through different techniques. As such, it is imperative to understand and optimize their formulation and production methods and to identify possible scale-up problems, issues, since often the desired features of nanoparticles are often missed when up-scaled (Leroux, 2017; Paliwal et al., 2014). Several efforts have been made to overcome these hurdles. Although the QbD-based development keeps debatable for nanosystems, in a near future, the application of this systematic will be promising to translate nanosystem-based products from the laboratory to the market.

4.5. Polymeric nanoparticles ▪ Polymer concentration is a critical parameter in PNPs formulation, due to its impact on particle size, zeta potential, EE, stability and drug release. ▪ Surfactant type and concentration plays an important role in PNPs formulation, since both parameters are responsible for PNPs particle size, PDI, zeta potential, EE and stability. ▪ In nanoprecipitation method, the needle gauge and the organic phase injection rate should be wisely selected to produce the smallest particle size. 5. Conclusions In the last 70 years, the emergence of nanotechnology has opened new opportunities in the medicine field, especially in the development of innovative drug delivery systems for dermal application. Nanostructures formulated as novel drug carriers have gained significant importance in the 21st century, due to their ability to successfully deliver both hydrophilic and lipophilic active substances, to improve particular properties regarding to drug solubility, stability, efficacy, permeation and irritancy, and to deliver the active substance directly in the diseased skin. Nevertheless, potential risks associated with those structures are still difficult to be assessed, remaining even unclear. Topical drug delivery systems have been extensively investigated,

4. Executive summary 4.1. Vesicular systems ▪ Phospholipid composition and concentration should be carefully selected, due to their impact on vesicle particle size, the 396


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since the skin is considered an appealing administration route, despite the barrier imposed by SC to active substances penetration. In general, nanosystems enable to increase drug skin permeation by increasing its residence time in the SC as well as in the epidermis or disrupting the integrity of the SC. Therefore, nanosystems arise as interesting technologies to improve skin drug delivery, either for acting on the skin surface or locally in dermal layer. Nanostructures, such as liposomes, niosomes, NEs, SLNs, NLCs, micelles and PNPs, have been widely formulated for different topical applications. These particular nanosystems can be obtained from specific materials, preparation methods and characterization techniques. During the product development, numerous formulation and process parameter adjustments are required and the optimization of these variables assumes crucial importance to achieve the desired quality of the product and its local therapeutic action. The introduction of the QbD based nanosystem development since the early research stages leads to a systematic research approach, comprising a significant number of formulation and process parameters that need to be identified, understood, and controlled to ensure the predefined product QTPP and consequently therapeutic efficacy and safety. Thus, the design planning methodology dictated by the QbD is clearly useful for optimizing the formulation and also for the understanding of nanosystems production process. Employing this structured methodology on nanosystem development will ensure a significant improvement in product design and a greater potential for the final product to reach the market.

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A practical framework for implementing Quality by

A practical framework for implementing Quality by

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