Properties and therapeutic potential of solid lipid nanoparticles and nanostructured lipid carriers as promising colloidal drug delivery systems

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15

Properties and therapeutic potential of solid lipid nanoparticles and nanostructured lipid carriers as promising colloidal drug delivery systems

Samet O¨zdemir1, Burak C¸elik2 and Melike U¨ner3 1

Department of Pharmaceutical Technology, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey 2Department of Pharmaceutical Technology, School of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey 3Department of Pharmaceutical Technology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

15.1 INTRODUCTION Solid lipid nanoparticles (SLN) are colloidal lipid drug delivery systems combining properties required from sophisticated colloidal drug carriers. Solid lipids are used for preparation of SLN instead of liquid lipids in emulsions. Several research groups have introduced SLN as alternative drug delivery systems to their lipid based counterparts such as liposomes, and polymeric nanoparticles in the late 1990s (Gasco and Morel, 1990; Mu¨ller et al., 1995; Schwarz et al., 1994). At the turn of the millennium, nanostructured lipid carriers (NLC), the second generation of SLN, were developed to increase the drug loading capacity of SLN depending on drug solubility in the solid lipid and to prevent drug loss during storage due to crystallization of the solid lipid to its more stable modifications (Mu¨ller et al., 2002). Studies by Speiser on solid lipid microparticles are of importance in the history of SLN. Speiser’s strategy for controlled drug delivery was developing miniaturized delivery systems. His research group optimized polyacrylic beads for oral administration for the first time (Khanna and Speiser, 1969, 1970; Khanna et al., 1970) followed by microcapsules (Merkle and Speiser, 1973). They developed the first nanoparticles for drug delivery purpose and for vaccination in the late 1960s. Speiser was the first scientist to describe solid lipid particulate drug carriers produced by spray congealing technique in the 1980s. He further focused on reducing the particle size of microparticles for producing lipid nanopellets by

Materials for Biomedical Engineering: Nanomaterials-based Drug Delivery. DOI: https://doi.org/10.1016/B978-0-12-816913-1.00015-5 © 2019 Elsevier Inc. All rights reserved.

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high speed stirring or ultrasonic treatment for oral drug delivery (Speiser, 1990). The research group of Cavalli employed a different production process, a microemulsion technique (Cavalli et al., 1996; Morel et al., 1996), while high pressure homogenization (HPH) technique suitable for large-scale production was introduced by Mu¨ller (Mu¨ller et al., 1997). HPH has been used by the nutrition industry for many years (Biasutti et al., 2010; Ha˚kansson et al., 2011). Superiority of HPH technique over the other techniques on SLN and NLC production along with physicochemical characterization, physical and chemical stability of SLN have been extensively studied, and drug incorporation models and drug release patterns of SLN have been precisely described (Cavalli et al., 2002; Gohla and Dingler, 2001; Jourghanian et al., 2016; Mu¨ller et al., 2000). SLN and NLC provide an excellent combination of advantages of polymeric nanoparticles and their lipid structured counterparts such as liposomes and nanoemulsions. Aims of production and advantages of SLN over other colloidal drug delivery systems have been reported by different research groups (Mehnert and Mader, 2001; Pardeike et al., 2009; Schwarz et al., 1994; Song and Liu, 2005; ¨ ner, 2006). U Aims of production of SLN and NLC include: They are suitable systems for insoluble and soluble actives with high payload. Their 50 1000 nm size range makes SLN and NLC suitable drug carriers for i.v. injection. Bioavailability of active agents can be increased by modification of dissolution rate of SLN and NLC. Thus, controlled release of entrapped actives is possible over several weeks. They improve tissue distribution of active agents. Thus, SLN and NLC are sophisticated carrier systems for achieving efficiency at the cellular level. Targeting of incorporated active agents by modification of their physicochemical properties and chemical treatment. They provide chemical protection for entrapped labile active agents. Properties of SLN and NLC required from a colloidal drug delivery system include: SLN and NLC are acceptable by regulatory authorities around the world. Constituents used for SLN and NLC have GRAS status (Generally Recognized As Safe) due to their low toxicity. They are composed of high melting point short- and middle-length chain triglycerides, phospholipids, and waxes used in pharmaceuticals and cosmetics (CFR—Code of Federal Regulations Title 21—FDA). They can be produced using surfactants at much lower concentrations compared to microemulsions. A SLN dispersion containing a lipophilic phase composed of a maximum 30% solid lipid is generally stabilized by the addition of surfactants up to 5% .

15.2 Types of SLN and NLC

They are safe systems even for long time circulation in the body due to their low toxicity. SLN and NLC may have a wide potential application spectrum such as intravenous, per oral, dermal, and topical. They are suitable systems for large-scale production by HPH technique, which has been used in the food industry for many years. HPH method provides convenient, fast, and cost-effective production for SLN and NLC with excellent reproducibility. Use of organic solvents is not required in their production by HPH and a few methods such as membrane contactor technique, ultrasonication, and high-shear homogenization. They are chemically and physically stable systems for up to two years. They are stable against moist heat sterilization such as autoclaving. In the case of production below 0.22 μm particle size, they can be sterilized by membrane filtration. Additionally, they can be safely lyophilized.

15.2 TYPES OF SLN AND NLC SLN are produced to replace liquid lipid in emulsions by a solid lipid or a blend of solid lipids which are solid at both room and body temperatures. Three types of drug incorporation models have been described for SLN (Fig. 15.1) (Mu¨ller et al., 2002): A solid solution model describes an SLN structure in which the drug is molecularly dispersed in the lipid matrix. A core-shell model is classified as drug-enriched shell and drug-enriched core models. A solid lipid core is constructed when the recrystallization temperature of the lipid is reached in the drug-enriched shell model. This model occurs by employing production methods like HPH involving processing a hot lipid melt and containing actives with hydrophilic residues in their molecules. Thereby, the drug concentrates on the outer shell of lipid nanoparticles by reducing the temperature of the dispersion to room temperature. Rapid drug release accompanied with a burst release effect is obtained from this model of SLN. In contrast to the drug-enriched shell model, the lipid surrounds the drug as a membrane following the drug being supersaturated in the lipid melt precipitating prior to lipid recrystallization by decreasing the temperature of the dispersion in the drug-enriched core model of SLN. This model provides a comparatively slower drug release rate than the solid solution model of SLN. Loading capacity of SLN is affected by solubility of drugs in lipid melt, miscibility of drug and lipid melts, and physicochemical properties of solid lipid such as its melting point and polymorphic state.

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FIGURE 15.1 Solid solution, drug-enriched core, and drug-enriched shell models of SLN.

FIGURE 15.2 Drug expulsion from nanoparticles, along with polymorphic transition of solid lipid during storage.

Drugs locate between the chains of fatty acids and lipid layers in the structure of SLN. Recrystallization of solid lipid with polymorphic transition is not completed immediately after production of SLN. However, solid lipid in nanoparticles tends to transform to a more ordered chemical structure in time (Fig. 15.2). Recrystallization process of solid lipid to its more stable polymorphic forms in SLN leads to drug leakage during storage since the drug can not accommodate among clusters coming closer. In the meantime, drug solubility is continuously reduced, causing drug expulsion from lipid nanoparticles, especially when the drug concentration in the formulation is too high. To overcome these limitations,

15.2 Types of SLN and NLC

NLC, which are a special structure kind of SLN, have been formulated by Mu¨ller et al. (2002). Incorporation of inspatial liquid lipid into solid lipid structure of SLN has been proposed as NLC. Herewith, increasing the drug payload and providing better drug accommodation in nanoparticles can be achieved, thus preventing drug expulsion during storage. NLC can also combine controlled drug release characteristics with some advantages over SLN. NLC are produced using blends of solid lipids and liquid lipids, preferably in a ratio of 70:30 up to a ratio of ¨ ner and Mu¨ller, 2012). 99.9:0.1 (Hu et al., 2005; Pardeike et al., 2009; U Three types of NLC have been described by Mu¨ller et al. (2002) (Fig. 15.3): Imperfect type (imperfectly structured solid matrix): Large distances between fatty acid chains in nanoparticle structure form by mixing spatially different lipids such as triglycerides with different chain lengths. Imperfections achieved in the crystal order of lipid matrix provide accommodation of the drug in a molecular form among amorphous clusters. The highest incompatibility attained by mixing solid lipids with small amounts of liquid lipids leads to the highest drug payload. Amorphous type (structureless solid amorphous matrix): Process of crystallization to the β form of solid lipid is prevented by mixing it with special liquid lipids, for example, hydroxyoctacosanylhydroxystearate, isopropylmyristate, or medium-chain triglycerides such as Miglyol 812. Thus, drug expulsion is prevented by amorphous state of lipid matrix during storage when the drug payload is increased in this structureless amorphous matrix.

FIGURE 15.3 Imperfect, amorphous, and multiple types of NLC.

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Multiple type [multiple oil in fat in water (O/F/W) type]: Oily nanocompartments in solid lipid matrix of nanoparticle form by addition of a higher amount of liquid lipid to the lipophilic phase of NLC. Thus, oily nanocompartments provide highly soluble media for lipophilic drugs, preventing drug leakage during storage, because solubility of drugs in a liquid lipid is higher than in a solid lipid (Jenning et al., 2000).

15.3 PRODUCTION METHODS OF SLN AND NLC SLN and NLC are produced using several methods. Hot HPH is the unique method appropriate for large-scale production in this field. Hot and cold HPH methods have been already used in the pharmaceutical and nutrition industries for many years.

15.3.1 HIGH PRESSURE HOMOGENIZATION (HPH) METHOD This method has been described as involving two basic production techniques for lipid nanoparticles—hot and cold HPH techniques (Jores et al., 2004; Runge and ¨ ner, 2006). High pressure homogenizers are used in this method. Muller, 1998; U An oil-in-water (o/w) emulsion or a microparticle suspension in water is allowed to flow through the adjustable valve of high pressure homogenizers with high pressure. Thus, their droplets or particles are subdivided into very small sizes in the nanometer range. A wide production range up to 60,000 L/h is possible for pharmaceuticals, depending on capacity of production-scale homogenizers. Product at a viscosity of # 1000 cP can be obtained with these homogenizers at an adaptable material feeding temperature of up to 100oC. Hot HPH: A hot aqueous surfactant solution is added to a molten drug and lipid melt. The mixture is homogenized using a high speed stirrer or a high shear homogenizer (usually an UltraTurrax) at a temperature at least 10oC higher then the melting point of the solid lipid. An o/w course emulsion is obtained. It is homogenized using a high pressure homogenizer at a pressure ranging from 1000 2000 bar. Three homogenization cycles are usually applied to the emulsion to obtain a hot nanoemulsion. Hot temperature is maintained during production process at least 10oC above the melting point of the solid lipid. Lipid nanoparticle dispersion is obtained by crystallization of solid lipid in nanoparticles followed by a cooling process of the hot nanoemulsion to room temperature or below. Hot HPH is a fast and reproducible technique with high drug payload. Cold HPH: Drug is dissolved or dispersed in molten lipid. Hot drug and lipid melt are solidified in dry ice or liquid nitrogen. After milling this mass, microparticles are obtained in a size range of approximately 50 100 μm. Then, microparticles are dispersed in a cold aqueous surfactant solution and the dispersion is homogenized, usually for three cycles at room temperature

15.3 Production Methods of SLN and NLC

or below (0oC). Cold HPH is a suitable technique for hydrophilic and heat sensitive drugs since the solid state of the matrix minimizes partitioning of the drug to the water phase and the thermal exposure period is relatively short. A solid solution model of SLN is obtained when using this production technique.

15.3.2 PREPARATION USING A MEMBRANE CONTACTOR This technique is relatively novel for the preparation of SLN and NLC. Charcosset et al. (2005), who have used the membrane contactor technique for preparation of liposomes, first employed this technique for SLN and NLC. A crossflow filtration device as a membrane contactor containing ceramic membranes (0.1 0.45 μm mean pore size) with an active ZrO2 layer on an Al2O3 TiO2 support is used in this method. An aqueous phase containing surfactants is stirred continuously using a mechanical stirrer and circulates tangentially to the membrane surface when the lipid phase is placed in a pressurized vessel and heated at a temperature above the melting point of the lipid. Lipid phase is pressed through the membrane pores, allowing the formation of small droplets. Aqueous phase circulating inside the membrane module sweeps droplets away forming at pore outlets. Lipid nanoparticles are formed followed by a cooling process to room temperature.

15.3.3 HIGH SHEAR HOMOGENIZATION AND/OR ULTRASOUND DISPERSION METHODS A molten drug and lipid mixture is dispersed in a hot aqueous surfactant solution under high shear homogenization and nanoparticles form by cooling hot nanoemulsion down to the room temperature (Hosny et al., 2015). Moreover, hot nanoemulsion is ultrasonicated using a probe for reducing its droplet size before cooling. High shear homogenization and ultrasonication methods require familiar tools which are available in most laboratories. However, some inadequacies are reported for this technique, including dispersion quality due to presence of micro¨ ner, 2006; Wissing et al., particles leading to physical instability upon storage (U 2004). Moreover, metal contamination may occur in the case of the ultrasonication process. Lower amounts of nanoparticles are obtained with higher surfactant concentration in this method compared to HPH method.

15.3.4 PREPARATION THROUGH COFLOWING MICROCHANNELS A coflowing microchannel system consisting of inner and outer capillaries is used for producing lipid nanoparticles according to this method (Yun et al., 2009). For this purpose, drug and solid lipid mixture is dissolved in a water miscible solvent. Solution is injected into an inner capillary when an aqueous surfactant solution is injected into an

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outer capillary, simultaneously. Water miscible solvent of solution displaces from lipid phase to aqueous phase, causing local supersaturation followed by solidification of solid lipid, resulting in the formation of lipid nanoparticles. Microchannels are often blocked by nanoparticles due to their small diameter in the case of a continuous production process. Gas-liquid slug flow may be used to overcome blockages through the microchannels. Nevertheless, this is one of the limiting conditions of this method for large-scale production of SLN and NLC.

15.3.5 SUPERCRITICAL FLUID METHOD In this method, a rapid expansion process of supercritical solution is employed for formation of ultrafine particles of heat sensitive materials (Akbari et al., 2014a). This method is a novel technique for production of SLN and NLC although it has been used for different purposes for a number of years (Santo et al., 2013). A supercritical fluid of a gas is generated providing its pressure and temperature exceed the respective critical value. CO2 (99.99%) is usually used for this technique. A mass composed of drug and lipid is extracted using the supercritical fluid to the point of saturation. A sudden depressurization is provided in a nozzle which produces a large decrease in solvent power and temperature of fluid. This process causes precipitation of nanoparticles in a dry form. As pressure is increased, density of gas increases without a significant increase in viscosity. In the meantime, ability of fluid to dissolve compounds also increases. This method can be performed with an easily and safely accessible critical point at 31.5 C temperature and 75.8 bar pressure.

15.3.6 BREAKING OF OIL-IN-WATER (O/W) MICROEMULSION Fine lipid droplets of a prepared microemulsion are broken to obtain nanoparticles in this method (Dorraj and Moghimi, 2015). A molten drug and lipid mixture is dispersed in a hot aqueous phase containing cosurfactant(s) and surfactant under mechanical stirring. A warm o/w microemulsion forms and is then dispersed in a certain amount of cold water at 2 3 C under stirring. Ratio of hot microemulsion to cold water is typically in the range of 1:25 to 1:50. Formation of lipid nanoparticles occurs following recrystallization solid lipid and precipitation. Fatty acids, which have low melting points (usually 50 70 C) are more suitable solid lipids for this technique. Comparatively high water and surfactants/cosurfactants content of nanoparticle dispersion is the most important disadvantage of this method.

15.3.7 PREPARATION VIA WATER-IN-OIL-IN-WATER DOUBLE EMULSION (W/O/W) Drug is solubilized in the internal phase of a w/o/w double emulsion (Yassin et al., 2010). For this purpose, a hot aqueous drug solution containing surfactant

15.4 Characterization and Imaging of SLN and NLC

is emulsified in a lipid melt under high speed stirring. Warm w/o nanoemulsion is dispersed in the external aqueous phase of a w/o/w emulsion containing a surfactant at 2-3 C under mechanical stirring to obtain lipid nanoparticles.

15.3.8 SOLVENT EMULSIFICATION EVAPORATION OR SOLVENT EMULSIFICATION DIFFUSION METHODS Lipid dissolved in an organic solvent is emulsified in an aqueous surfactant solution using a mechanical stirrer in a water bath (Gonc¸alves et al., 2016). An o/w emulsion is obtained and maintained under ambient conditions to allow evaporation of solvent under reduced pressure. Evaporation of solvent allows coacervation and formation of lipid nanoparticles. This technique is not accepted by regulative authorities for large-scale production all over the world due to organic solvent use and the fact that organic solvent residues may cause cytotoxicity.

15.3.9 SOLVENT INJECTION METHOD Lipid solution in a water miscible solvent is heated to the melting point of solid lipid and injected through a needle into a stirred aqueous phase with or without surfactant (Keshri and Pathak, 2013). Dispersion obtained is then filtered through a paper filter to remove excess lipid. This method has same disadvantages of solvent emulsification evaporation of solvent emulsification diffusion methods.

15.4 CHARACTERIZATION AND IMAGING OF SLN AND NLC Long-term stability of dosage forms, which have desired physical and chemical properties following production process, is a crucial subject, indicating that they can be safely used for medical purposes (Mitri et al., 2011). Thus, several characterization and imaging methods are used, considering different parameters for design of well performing formulations. Particle size and particle charge, surface characteristics, crystallographic and structural properties, and morphology of SLN and NLC are investigated, employing sophisticated techniques.

15.4.1 DETERMINATION OF PARTICLE SIZE SLN and NLC have been decribed in the 50 1000 nm size range, with low ¨ ner, 2015). However, in some special cases like sitemicroparticle content (U specific delivery including gene therapy, nanoparticle size is expected to be in the 50 300 nm range. Nanoparticles must reach the target tract crossing several anatomic barriers, accumulate in the specific site, and be internalized by cells to provide drug delivery. Particle charge of nanoparticles is another crucial parameter in site-specific drug delivery. Furthemore, particle size and charge of SLN and

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NLC must stay within the same range during storage. Determination of any change in particle size and particle size distribution, and particle charge in longterm stability experiments provides strict information about agglomeration and physical stability of formulations. Laser diffractometry (LD) is also called low angle laser light scattering (LALLS), which is employed for characterization of particles in the range of 0.01 3500 μm. Particle size and particle size distribution can be determined with samples in their dispersions or dry form. Samples of 4 10 g and 1 2 g are measured directly or diluted within 1 minute by this method. Samples can be recovered if required since LD is a nondestructive and nonintrusive method. In a laser diffractometer, a laser beam, which is transmitted from He-Ne gas lasers (λ 5 0.63 μm), passes through the sample in a laser scattering cell. Laser is scattered with a diffraction angle as soon as it interacts with nanoparticles. Intensity of scattering laser is inversely proportional to particle size and is detected by a suitable detector. Photon correlation spectroscopy (PCS) is also commonly used to measure particles in the nanometer size range. PCS is also called quasi-elastic light scattering (QELS) or dynamic light scattering (DLS). Brownian motions of nanoparticles in aqueous media are utilized for determination of particle size. Samples should be dispersed in a solvent since this technique is not suitable for dry samples. A laser beam coming from a source is sent through dispersion. Signal scatters light which is detected by a photomultiplier, which is positioned at a scattering angle of 90 degrees. Then, the photomultiplier transforms intensity variations into a variation in voltage. A software evaluates the signal with a correlation function as small particles diffuse faster, resulting in a more rapid fluctuation of the intensity of the light scattered compared to larger particles. Polydispersity index (PI), which is the width of particle size distribution of nanoparticles in area of light scattering, is calculated via an intensity autocorrelation function using a cumulant analysis of PCS. Particle size determination of 100 particles is completed within 1 minute. Samples can be recovered if required, since PCS is also a nondestructive and nonintrusive method.

15.4.2 DETERMINATION OF PARTICLE CHARGE Particle charge of nanoparticles is another crucial parameter in site-specific delivery of SLN and NLC (Gabal et al., 2014). Herewith, their particle charge must stay in the same range. A strict change in particle charge observed in long-term stability experiments might indicate agglomeration of nanoparticles (Heurtault et al., 2003). Particle charge is defined as zeta potential (ZP), which is amount of charge on particle surface. ZP of lipid nanoparticles may increase with chemical groups in the content, which may ionize to produce a charged surface. With use of ionic lipids, surfactants, and/or drugs in formulations of SLN and NLC, nanoparticles also give higher ZP values. Sometimes, surface of nanoparticles itself preferentially adsorbs ions and ZP increases. ZP greater than 60 mV has been mentioned for excellent physical stability of nanoparticles, while greater than

15.4 Characterization and Imaging of SLN and NLC

30 mV indicates good electrostatic stabilization as a rule. However, adsorption of nonionic steric stabilizers usually decreases ZP due to a shift in shear plane of particle in the case of a colloidal drug carrier system which contains steric stabilizers. A variation in kinetic energy caused by light and temperature (e.g., autoclaving) and in crystalline structure of nanoparticles may also lead to a change in particle charge. Velocity of particles in an electric field gives strict information on their surface charge. It is determined using a DLS apparatus or a zetasizer. A laser beam is sent to pass through the center of a sample cell and is scattered at an angle of 17 degrees for this measurement. ZP of sample is identified by system configuration through detected scattered light.

15.4.3 DETERMINATION OF PARTICLE MORPHOLOGY Structural details, surface morphology, and particle shape of SLN and NLC can be visualized by electron microscopy. Sample sizes of 0.001 10 μm may be scanned by electron microscopy (Jores et al., 2004). Electrons are sent to sample and interact with constituent atoms via electrostatic forces (Coulomb forces) in this technique. Focused electrons are collected and processed to obtain a twodimensional or three-dimensional projected image of sample structure, when some electrons are scattered. An electron beam passes through sample and twodimensional images are obtained in transmission electron microscopy (TEM) (Fig. 15.4). This technique is used to investigate ultrastructure of a sample and its components, for example, protein molecules of a cell can be seen. In contrast, an electron beam scans surface of a sample in scanning electron microscopy (SEM). This technique is used to obtain three-dimensional images and excellent surface morphology of sample. Atomic force microscopy (AFM) is a three-dimensional topographic technique with a high atomic resolution. Lateral and vertical resolution of AFM may be up to 30 nm and 0.1 nm, respectively. In this technique, surface of a sample is scanned with a probe imaging its surface properties (Fig. 15.5). In scanning confocal electron microscopy (SCEM), a collection optics is arranged symmetrically to an illumination optics to collect electrons passing beam focus. Superior depth is ensured by resolution of imaging.

15.4.4 CRYSTALLOGRAPHIC ANALYSIS Crystallization temperature, crystallization degree, and polymorphic transition to more stable forms of solid lipid in nanoparticles must be considered for defining characteristics of products such as storage stability, entrapment efficiency, models of SLN and NLC, and their drug release profiles (Jenning et al., 2000; Mehnert and Mader, 2001). Crystallization behavior of SLN and NLC is also affected by various factors including their production method, concentration of solid lipid and surfactant(s), rate of liquid lipid to solid lipid, melting point of solid lipid, incorporation of actives, and particle size of nanoparticles. Differential scanning

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FIGURE 15.4 TEM (A) and SEM (B) images of topotecan loaded SLN based on cetyl palmitate. Reproduced from Chen et al. (2016) with the permission of Elsevier B.V.

calorimetry (DSC) and X-ray diffraction are often used for determination of thermodynamic behaviors in SLN and NLC. Although DSC is an informative method on melting and crystallization behavior of crystalline materials like solid lipid SLN and NLC, X-ray experiments provide the most valuable information on polymorphic state of materials. Manner of arrangement of lipid molecules, their multiple melting phenomena, phase behavior, and characterization and identification of structures of lipid and drug molecules can be detected in X-ray diffraction experiments. Length of spacings of lipid lattice can be assessed and effects of liquid lipid constituent on subcell parameters can also be obtained. X-ray diffraction confirms data on polymorphic behaviors of materials obtained from DSC experiments. DSC experiments are used for investigation of melting and crystallization behavior of lipid nanoparticles such as internal polymorphism and crystal ordering of solid lipid and breakdown or fusion of its crystal lattice. Melting and crystallization behavior of solid lipids in nanoparticles are followed by a heating and/ or cooling process. X-ray diffraction is employed by two techniques: wide-angle X-ray scattering (WAXS) and small-angle X-ray scattering (SAXS). Experiments display length of long and short spacings of lipid lattice in nanoparticles. WAXS is used for charac˚ range, while SAXS is used for characterizaterization of packings in the 3 5 A ˚ range. tion of layer thickness in the 20 50 A

15.4 Characterization and Imaging of SLN and NLC

(A)

(B)

5.03 µm

5.03 µm

444.12 nm

854.41 nA/A

0.00 nm

10.00 nA/A

2.52 µm

2.52 µm

0 µm 0 µm

2.52 µm

5.03 µm

(C)

2.52 µm

5.03 µm

(D)

4592.92 nm

4592.92 nm

81.85 nm

2.74 nA

0.00 nm

–0.55 nA

2296.46 nm

0 nm 0 nm

0 µm 0 µm

2296.46 nm

2296.46 nm

4592.92 nm

0 nm

0 nm

2296.46 nm

4592.92 nm

FIGURE 15.5 Height and tridimensional AFM images obtained from calixarene based SLN in xanthan gel, (A and C) topographic mode, (B) force modulation mode, and (D) lateral force mode. Reproduced from Shahgaldian et al. (2003) with the permission of Elsevier B.V.

15.4.5 STRUCTURAL ANALYSIS Drug excipient interaction and chemical compatibility of ingredients in SLN and NLC can be investigated by structural analysis methods. H1-NMR spectroscopy is often used in investigation of statement of liquid lipid and drug distribution in ¨ ner, 2015). Fourier transform infrared nanoparticles (Gonullu et al., 2015; U (FT-IR) spectroscopy and Raman spectroscopy are also employed to understand supramolecular characteristics of lipid nanoparticles. FT-IR spectroscopy detects vibration characteristics of chemical functional groups in a sample. When an infrared light interacts with matter, chemical bonds stretch, contract, and bend. Thus, any interaction and drug excipient compatibility can be determined. Raman spectroscopy is used to obtain fingerprints of molecules observing vibrational, rotational, and other low frequency modes in a sample.

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15.5 ADMINISTRATION ROUTES OF SLN AND NLC 15.5.1 PARENTERAL ADMINISTRATION SLN and NLC have many superiorities for systemic delivery of active agents via parenteral application. They are able to provide high efficiency for actives at a cellular level according to studies focused on treatment of genetic disorders and life-threatening fatal diseases such as cancer. Incorporation of genetic materials such as deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and oligonucleotides into SLN and NLC presents a pathway for gene transfer to cells for treatment of genetic disorders. For this reason, this makes them one of the most attractive drug carrier systems for site-specific targeting primarily. SLN and NLC can be produced on a large scale by HPH, avoiding use of organic solvent for parenteral use. They are injectable intravenously, subcutaneously, intraarticularly, etc., due to their particle size in the nanometer size range and low microparticle content below 5 μm. SLN and NLC can be applied directly to target organ via an interventional catheterization procedure. Cellular uptake was found to be affected by particle size of SLN and NLC. Nanoparticles should be produced in an optimum size range to obtain the highest efficiency at the cellular level, because they should cross epithelial pores, properly accumulate in target tract and/or organ, and then be internalized by cells in that case. A decrease in size of nanoparticles causes easier uptake and leads to a significant increase in rate of cellular uptake. For example, cutoff size of pores in tumor vessels may reach diameters as large as 200 nm 1.2 μm (Yokoyama et al., 1991). In that case, particle sizes higher than 300 nm may be expected to provide sustained drug delivery. A sophisticated colloidal drug carrier system is required to protect stability of drugs or genetic materials in body fluids in injection site, to bind to target cells, to be internalized, and to deliver its contents to required organelles or sites of cells. However, phagocytic uptake by macrophages of the reticuloendothelial system (RES) is a limiting anatomic barrier to overcome for stability of nanoparticles in the systemic circulation and their distribution in the body. Surface characteristics of nanoparticles ascertain whether or not opsonization will occur and which component will be involved (Wright and Illum, 2000). Physicochemical properties of lipids, surfactants, and coating materials determine the surface characteristics of nanoparticles. Electrical charge of lipids and surfactants and chain length/molecular size of surfactant substantially affect systemic half-life and biodistribution of SLN and ¨ ner and Yener, 2007). For example, PEGylation, NLC (Stossel et al., 1972; U which is a coating process of nanoparticles with polyethylene glycol (PEG) at various molecular weight block copolymers, usually suppresses charge of nanoparticles. Thus, zeta potential becomes less negative due to an extension of plane of shear of nanoparticles (Gref et al., 2000; Tro¨ster et al., 1992). Negatively charged nanoparticles usually have a longer half-life compared to positively

15.5 Administration Routes of SLN and NLC

charged nanoparticles. Both strong negative and positive charges usually lead to phagocytic uptake of nanoparticles more rapidly than weak medium negative charge. Opsonization can be prevented by surface modification of nanoparticles by changing charge and/or lipophilicity of their surface. The first attempts at modification of lipid nanoparticles were surface coating with PEG derivatives (Heiati et al., 1998; Yuda et al., 1996) after a study on decreasing immunological properties of bovine serum albumin using PEG (Abuchowski et al., 1977) and following a few studies on superoxide dismutase (Gray and Stull, 1983), arginase (Savoca et al., 1984), and asparaginase (Abuchowski et al., 1984; Wright and Illum, 2000). Surface hydrophobicity of nanoparticles can be favorably decreased by coating them with PEG. That coating also provides steric stabilization of nanoparticles. Thus, suppressing binding of serum proteins (e.g., apoproteins) and other opsonic factors is ensured (Dierling et al., 2006; Garcia-Fuentes et al., 2005; Heurtault et al., 2003). Sterically stabilized SLN is called stealth SLN, but conversely nonstealth SLN (Bocca et al., 1998; Fundaro et al., 2000). Steath nanoparticles are required for drug transport to target site via intravenous injection. In the case of subcutaneous administration, stealth SLN and NLC accumulate in the mononuclear phagocyte system displaying a depot effect and ¨ ner and sustained drug release profile (Kim et al., 2010; Schwarz et al., 1994; U Yener, 2007; Wissing et al., 2004). The lymphatic system is a new target for developing treatment methods due to its undeniable role in disease responses in the immune system, especially for patients with metastatic cancers. It has been shown that using SLN by subcutaneous, oral, intestinal, and pulmonary routes provides improved lymphatic penetration and retention, and reduces systemic toxicity of drugs (Alex et al., 2011; Cai et al., 2011). Table 15.1 summarizes recent studies on parenteral application of SLN and NLC.

15.5.2 ORAL ADMINISTRATION Oral delivery is the most commonly used noninvasive application route for drugs, with good patient compliance around the world. SLN and NLC can be administered orally as dispersions or they can be incorporated into a dosage form such as tablets, pellets, or capsules. Liquid SLN and NLC dispersions are usually required to be subjected to various drying processes including spray drying and lyophilization before incorporation in conventional dosage forms (Mu¨ller et al., 2000). Moreover, stability of formulations in the gastrointestinal tract (GI) must be investigated to predict their suitability for oral administration as low gastric pH and high ionic strength may result in particle aggregation. Uptake of lipid nanoparticles by intestinal mucosa occurs mainly through transcellular or paracellular mechanisms after oral administration (Harms and Mu¨ller-Goymann, 2011). Transcellular transport occurs through M cells in

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Table 15.1 Recent Studies on Parenteral Delivery of SLN and NLC Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Liquid Lipids

Preparation Methods

Antiinflammatory

Baicalein

NLC

Gelucire 62/5

Vitamin E

Ultrasonication

Tsai et al. (2012)

Antimalarial

Artemether Lumefantrine

NLC

Capmul MCM Glyceryl dilaurate

Oleic acid

Breaking o/w of microemulsion

Prabhu et al. (2016a)

Antineoplastic and anticancer

Aclacinomycin A

SLN

Egg phosphatidyl choline Cholesterol

Solvent emulsificationevaporation

Jia et al. (2016)

Aluminum chloride phthalocyanine

SLN

Compritol 888 CG ATO Stearic acid

Breaking o/w of microemulsion

Goto et al. (2017)

Andrographolide

SLN

Cetyl alcohol

Solvent injection

Parveen et al. (2014)

β-Elemene

NLC

Glyceryl monostearate

HPH

Shi et al. (2013)

Camptothecin

SLN

Cetyl palmitate

HPH

Martins et al. (2012, 2013)

Docetaxel

SLN

Trimyristin Trilaurin Tristearin Tripalmitin

Solvent emulsificationevaporation

Naguib et al. (2014)

Oxaliplatin

NLC

Glyceryl monostearate

HPH

Qiu et al. (2012)

Paclitaxel

SLN

Tripalmitin

High shear homogenization

Leiva et al. (2017)

Maisine 35-1 Labrafil M1944

Medium chain triglycerides

References

Paclitaxel Quantum dots

NLC

Glyceryl monostearate

Resveratrol

SLN

Glyceryl behenate

Sorafenib

NLC

Tripalmitin

Temozolamaide

SLN

Sodium behenate

Tyrphostin AG-1478

NLC

Tripalmitin

Wogonin

SLN

Antiparasitic

Oryzalin

Antiparkinson Hypolipidemic

Oleic acid

Solvent emulsificationevaporation

Olerile et al. (2017)

Solvent emulsificationevaporation

Jose et al. (2014)

Solvent emulsificationevaporation

Bondì et al. (2015)

Breaking o/w of microemulsion

Clemente et al. (2018)

Solvent emulsificationevaporation

Bondi et al. (2014)

Stearic acid

Ultrasonication

Baek et al. (2018)

SLN

Tripalmitin

Solvent emulsificationevaporation

Lopes et al. (2012)

Eplerenone

SLN NLC

Glyceryl monostearate

Oleyl erucate

Ultrasonication

Üner and Özdemir (2016)

Simvastatin

NLC

Stearic acid

Miglyol 812

High shear homogenisation

Harisa et al. (2017)

Captex 355 Miglyol 812

Captex 355 Acconon CC-6

468

CHAPTER 15 Properties and therapeutic potential of solid

Peyer’s patches or enterocytes when paracellular transport occurs via passive diffusion of drugs along the intercellular space of the endothelium. Nevertheless, uptake into the lymph by M cells is the major pathway for absorption of lipid nanoparticles by the oral mucosa. In this case, transport to the portal vein in the liver is bypassed and the hepatic first-pass metabolism is reduced (Muchow et al., ¨ ner and Yener, 2007). Drugs with low solubility in 2008; Mu¨ller et al., 2000; U the gastrointestinal tract often result in poor bioavailability, which can be improved by encapsulation into SLN or NLC due to their submicron size. Increased resistance time in the gastrointestinal system due to their bioadhesive behavior and ability to control drug release behaviors of these systems further increase pharmacokinetic profile of encapsulated drugs (Kalepu et al., 2013). Oral administration has been intensively investigated in recent years, as summarized in Table 15.2.

15.5.3 DERMAL AND TRANSDERMAL DELIVERY Dermal and transdermal delivery of active agents is a preferable route due to high patient compliance. Transdermal delivery differentiates from dermal delivery owing to transportation of drug through skin layers. Dermal delivery provides local effects because delivery of actives goes directly to site of action. On the other hand, transdermal delivery provides transportation of the drug to the systemic circulation (Jain et al., 2017). SLN and NLC have been reported as having been applied topically to the skin for pharmaceutical purposes. Liposomes have been used for topical applications for a long time. Stability problems during storage are the most limiting factor. However, SLN and NLC formulations stable for up to 2 years can be produced. They are composed of biocompatible lipids which offer good tolerability with the skin. They are tolerable formulations for inflammated and damaged skin (Wissing and Muller, 2001). Skin structure is positively affected by SLN and NLC. They may increase thickness of the stratum corneum and help its regeneration. They display occlusive effect since they provide an adhesive film due to their small particle size in ¨ ner the nanometer range and they decrease transepidermal water loss (TEWL) (U et al., 2005a,b). Thus, they increase skin permeation of actives and provide their targeting to specific layers of the skin (Dingler et al., 1999; Gonullu et al., 2015; ¨ ner, 2006; U ¨ ner et al., 2014a,b). SLN Jenning et al., 2000; Pardeike et al., 2010; U and NLC also can provide a sun protective effect by reflecting UV radiation. Using SLN formulations for sunscreens provides a synergistic effect for photoprotection (Wissing and Muller, 2001). They also display a pigment effect by covering undesired skin colors (Dingler et al., 1999). Although their use was often reported for cosmetic purposes (Mu¨ller et al., 2002), colloidal carrier systems have been censured for cosmetics and cosmeceuticals by authorities, because they have a high risk of permeation of actives through the skin and subsequently their transfer to the systemic circulation.

Table 15.2 Recent Studies on Oral Delivery of SLN and NLC Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Antianemic for iron deficiency

Ferrous sulfate

SLN

Stearic acid

Antiasthmatic

Montelukast

NLC

Precirol ATO 5

Antibiotic

Amphotericin B

SLN

Clindamycin

Liquid Lipids

Preparation Methods

References

Solvent emulsificationevaporation

Zariwala et al. (2013)

Ultrasonication

Patil-Gadhe and Pokharkar (2014)

Stearic acid

Solvent emulsificationevaporation

Jain et al. (2014b)

SLN

Stearic acid

HPH

Abbaspour et al. (2013)

Isoniazid

SLN

Compritol 888ATO

Breaking of o/w microemulsion

Bhandari and Kaur (2013)

Glibenclamide

SLN

Precirol ATO 5

Solvent emulsificationevaporation

Gonçalves et al. (2016)

Insulin

SLN

Trimyristin

Solvent emulsificationevaporation

Boushra et al. (2016)

Antiepileptic

Carbamazepine

SLN

Steraic acid

Extraction by supercritical fluid

Akbari et al. (2014b)

Antifungal

Clotrimazole

SLN, NCL

Compritol 888ATO

Labrafac CC

High shear homogenization

Ravani et al. (2013)

Miconazole

NLC

Gelucire 43/01

Miglyol 812

Ultrasonication

Mendes et al. (2013)

Carvedilol

NLC

Stearic acid

Oleic acid

Ultrasonication

Mishra et al. (2016)

Lercanidipine

NLC

Labrafil 2130 M

Linseed oil

Solvent emulsificationevaporation

Ranpise et al. (2014)

Antidiabetic

Antihypertensive

Capryol 90

(Continued)

Table 15.2 Recent Studies on Oral Delivery of SLN and NLC Continued Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Liquid Lipids

Antiinflammatory

Baicalin

NLC

Glyceryl monostearate

Medium chain triglycerides

Celecoxib

SLN

Tristearin Softisan 100

Curcumin

NLC

Emulmetik 900

Oxaprozin

NLC

Precirol ATO 5

Arteether

SLN

Glyceryl monostearate

Artemetherlumefantrine

NLC

Capmul MCM Glyceryl dilaurate

Artesunate

SLN

Lumefantrine

Antimalarial

Antineoplastic

Preparation Methods

References

Solvent emulsificationevaporation

Luan et al. (2015)

Ultrasonication

Fouad et al. (2015)

Lexol

Breaking of o/w microemulsion

Chanburee and Tiyaboonchai (2017)

Miglyol 812

Ultrasonication

Lopes-de-Araujo et al. (2016)

HPH

Dwivedi et al. (2014)

Breaking of o/w microemulsion

Prabhu et al. (2016b)

Glyceryl monostearate

Breaking of o/w microemulsion

Masiiwa and Gadaga (2018)

SLN

Stearic acid Caprylic acid

HPH Ultrasonication

Garg et al. (2017)

Bicalutamide

SLN, NLC

Precirol ATO 5

Triacetin

HPH

Kumbhar and Pokharkar (2013)

Docetaxel

NLC

Precirol ATO 5

Medium-chain triglycerides

Ultrasonication

Fang et al. (2015)

Mitotane

SLN, NLC

Cetyl palmitate Stearic acid

Medium-chain triacylglycerides

HPH

Severino et al. (2013)

Oridonin

NLC

Octadecylamine

Medium-chain triglycerides

HPH

Zhou et al. (2015)

Tamoxifen

NLC

Glyceryl monostearate

Labrafil WL 2609 BS

Ultrasonication Solvent emulsificationdiffusion

Shete et al. (2014)

Zerumbone

NLC

Hydrogenated palm oil

Olive oil

High shear homogenization

Rahman et al. (2013, 2015)

Oleic acid

Antioxidant

Antipsychotic

Antiviral

Hypolipidemic

Epigallocatechin gallate

SLN, NLC

Precirol ATO 5

Miglyol 812

Ultrasonication

Frias et al. (2016)

Resveratrol

SLN, NLC

Cetyl palmitate

Miglyol 812

High shear homogenization

Neves et al. (2013)

Trans-ferulic acid

NLC

Glyceryl behenate

Ethyl oleate

Breaking of o/w microemulsion

Zhang et al. (2016)

Iloperidone

NLC

Lauric acid Gelucire 44/14

Phosal 53 MCT

Ultrasonication

Mandpe and Pokharkar (2015)

Risperidone

SLN

Compritol 888ATO

HPH

Silva et al. (2012)

Lopinavir

SLN

Stearic acid

High shear homogenization

Negi et al. (2013)

Saquinavir

NLC

Precirol ATO 5

Miglyol 812

HPH

Beloqui et al. (2013)

Atorvastatin

SLN, NLC

Stearic acid

Oleic acid

HPH

Khan et al. (2016b)

NLC

Gelucire 43/01 Glyceryl monostearate Compritol 888 ATO

Capryol PGMC

Ultrasonication

Elmowafy et al. (2017)

Fenofibrate

NLC

Compritol 888

Labrafil M 1944CS

Ultrasonication

Tran et al. (2014)

Fluvastatin

NLC

Compritol 888

Almond oil

Ultrasonication

El-Helw and Fahmy (2015)

Lovastatin

SLN, NLC

Precirol ATO 5

Labrasol

HPH

Zhou and Zhou (2015)

Rosuvastatin

NLC

Glyceryl monostearate

Capmul MCM EP

Ultrasonication

Rizwanullah et al. (2017) (Continued)

Table 15.2 Recent Studies on Oral Delivery of SLN and NLC Continued Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Liquid Lipids

Preparation Methods

References

Immunosuppressant

Sirolimus

NLC

Precirol ATO 5

Oleic acid

HPH

Yu et al. (2016)

Tacrolimus

NLC

Glycerol dibehenate

Glyceryl monocaprylate

Solvent emulsificationevaporation Ultrasonication HPH

Khan et al. (2016c,d)

Raloxifene

NLC

Glyceryl monostearate

Capmul MCM C8

Solvent emulsificationevaporation Ultrasonication

Shah et al. (2016b)

Selective estrogen receptor modulator

15.5 Administration Routes of SLN and NLC

Dermal and transdermal delivery of active agents via SLN and NLC have been extensively investigated. Moreover, local or systemic effects of drugs have been searched for. Results obtained from studies have shown that SLN and NLC have promising effects in treatment both of local and systemic disorders (Table 15.3).

15.5.4 NASAL ADMINISTRATION Nasal administration is an alternative route for increasing bioavailability of active agents, which are unstable in the GI tract and/or have absorption problems due to their large molecule size. Nasal mucosa is highly permeable and intensely vascularized, which together lead to fast drug absorption and a rapid onset of action. Drugs administered through intranasal route avoid enzymatic degradation in the ¨ ner and Yener, 2007). The GI tract and bypass the hepatic first pass effect (U intranasal route is noninvasive for drug delivery to the central nervous system and brain by bypassing the blood brain barrier (BBB). The BBB decreases permeability of molecules with presence of tight junctions between endothelial cells that creates high electrical resistance. Endothelial cells also express efflux proteins such as P-glycoprotein that transport drug molecules out of the brain continuously (Gastaldi et al., 2014; Muntimadugu et al., 2016). Delivery of molecules to the brain occurs through the olfactory and trigeminal neural pathway that leads to the olfactory bulb and brain stem. SLN and NLC can deliver actives effectively into the brain by protecting them from degradation and efflux transport, and their small size ensures transport to the olfactory nerves transcellularly (Gabal et al., 2014). There are numerous different studies on the effect of SLN and NLC formulations for delivery of actives to the systemic circulation or brain through the nasal route, as summarized in Table 15.4.

15.5.5 BUCCAL ADMINISTRATION Buccal application of drugs has several advantages over conventional oral administration. Drugs absorbed through the buccal mucosa bypass the gastrointestinal tract and hepatic first pass effect, leading to higher bioavailability. The buccal cavity is easily accessible for patients, a dosage form is easily applied, and drug absorption can be terminated in the case of an emergency. The buccal mucosa is suitable for both local and systemic delivery; the formulation can be designed for rapid delivery as well as controlled delivery of drugs as necessary (Smart, 2005; Madhav et al., 2009). Colloidal drug delivery systems can also be applied via this ¨ ner and Mu¨ller, 2012). In the case of SLN and NLC, surface of nanopartiroute (U cles can be modified by different polymers to ensure mucoadhesion to musin glycoproteins on epithelial tissues lining the oral cavity. They can also be dried and incorporated inside different formulations such as mucoadhesive gels, tablets, or films (Hazzah et al., 2015; Holpuch et al., 2010). A few studies on buccal delivery of active agents in the last 5 years are listed in Table 15.4.

473

Table 15.3 Recent Studies on Dermal Applications of SLN and NLC Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Preparation Methods

References

Antiacne

Adapalene

SLN

Tristearin

Ultrasonication

Jain et al. (2014a)

Isotretionin

SLN

Compritol 888 ATO

Breaking of o/w microemulsion

Raza et al. (2013)

Neem oil

SLN

Cholesterol

Prepration via w/o/ w double emulsion

Vijayan et al. (2013)

Retinyl palmitate

SLN

Compritol 888 ATO

Ultrasonication

Clares et al. (2014)

Roxithromycin

SLN

Compritol 888 ATO

Ultrasonication

Wosicka-Frackowiak et al. (2015)

Spironolactone

SLN

Stearic acid

Solvent emulsification-evaporation

Kelidari et al. (2015)

Spironolactone

NLC

Stearic acid

Ultrasonication

Kelidari et al. (2016)

Tretionin

SLN

Myristyl myristate

High shear homogenization HPH

Ridolfi et al. (2012)

NLC

Stearic acid

Oleic acid

Breaking of o/w microemulsion Ultrasonication

Ghate et al. (2016)

Coenzyme Q10

NLC

Cetyl palmitate

Miglyol 812

HPH

Schwarz et al. (2013)

Diphencyprone

NLC

Precirol ATO5

Squalene

Ultrasonication

Aljuffali et al. (2014)

Finatsteride

NLC

Precirol ATO5

Miglyol 812

Ultrasonication

Gomes et al. (2014)

Flufenamic acid

SLN, NLC

Precirol ATO5

Miglyol 812

Ultrasonication

Schwarz et al. (2012)

Lutein

SLN, NLC

Cetyl palmitate Glyceryl tripalmitate Carnauba wax

Miglyol 812

HPH

Mitri et al. (2011)

Minoxidil

NLC

Cetyl palmitate

Oleic acid

Ultrasonication

Gomes et al. (2014)

Antialopecia

Liquid Lipids

Oleic acid

Anticouperosis

Vitamin A1 and Vitamin K1

SLN

Carnauba wax, Apifil

Antieczematous

Clobetasol propionate

NLC

Compritol 888 ATO

Antifungal

Econazole

NLC

Precirol ATO5

Fluconazole

SLN

Compritol 888 ATO

Miconazole

NLC

Glyceryl mono stearate

HPH

Pyo et al. (2016)

Oleic acid

HPH

Nagaich and Gulati (2016)

Oleic acid

Solvent injection

Keshri and Pathak (2013)

Ultrasonication

El-Housiny et al. (2018)

High shear homogenization, Ultrasonication

Singh et al. (2016)

Olive oil

Table 15.4 Recent Studies on Nasal, Rectal, and Vaginal Delivery of SLN and NLC Application Route

Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Nasal

Antibiotic

Streptomycin

SLN

Compritol 888ATO

Antidepressant

Duloxetine

NLC

Glyceryl monostearate

Venlafaxine

NLC

Antiemetics

Ondansetron

Antiepileptic Anti-Alzheimers

Antineoplastic and anticancer

Antiparkinson

Antipsychotic

Liquid Lipids

Preparation Methods

References

Breaking of o/w microemulsion

Kumar et al. (2014)

Capryol PGMC

Ultrasonication

Alam et al. (2014a)

Compritol 888ATO

Capmul MCM

High shear homogenization

Shah et al. (2016a)

NLC

Glyceryl monostearate

Capryol 90

HPH

Devkar et al. (2014)

Lamotrigine

NLC

Glyceryl monostearate

Oleic acid

Solvent emulsification evaporation

Alam et al. (2014b)

Rivastigmine

SLN

Compritol 888ATO

Ultrasonication

Shah et al. (2015)

Tarenflurbil

SLN

Glyceryl monostearate

Solvent emulsification evaporation

Muntimadugu et al. (2016)

Curcumin

NLC

Precirol ATO 5

Capmul MCM

HPH

Madane and Mahajan (2016)

Quercetin

NLC

Glyceryl monostearate

Capmul GMO

HPH

Patil and Mahajan (2017)

Temozolomide

NLC

Gelucire 44/14

Vitamin E

HPH

Khan et al. (2016a)

Glial cellderived neurotrophic factor

NLC

Precirol ATO 5

Miglyol

Breaking of o/w microemulsion

Hernando et al. (2018)

Ropinirole

NLC

Compritol 888ATO

Labrafac Lipophile WL1349

High shear homogenization

Gabal et al. (2014)

Haloperidol

SLN

Glyceryl monostearate

Solvent emulsificationdiffusion

Yasir and Sara (2014)

Buccal

Rectal

Vaginal

Antifungal

Miconazole

NLC

Gelucire 43/01

Antiinflammatory

Curcumin

SLN

Antiviral

Didanosine

Corticosteroid

Capryol PGMC Miglyol 812

Ultrasonication

Mendes et al. (2013)

Gelucire 50/13

High shear homogenization

Hazzah et al. (2015, 2016)

SLN

Glyceryl tripalmitate

Ultrasonication

Jones et al. (2014)

Triamcinolone acetonide

NLC

Spermaceti

Ultrasonication

Kraisit and Sarisuta (2018)

Antiemetic

Metoclopramide

SLN

Compritol 888ATO

High shear homogenization

Mohamed et al. (2013)

Antiinflammatory

Flurbiprofen

SLN

Tricaprin

High shear homogenization

Din et al. (2015)

Antibacterial

Tilmicosin

SLN, NLC

Hydrogenated castor oil Compritol 888 ATO

Sesame oil

Ultrasonication

Al-Qushawi et al. (2016)

Antifungal

Clotrimazole

NLC

Tristearin

Miglyol 812

Ultrasonication

Ravani et al. (2013)

Antineoplastic and genes

Paclitaxel, siRNA

SLN

Gelucire 50/13

Solvent emulsificationevaporation

Büyükköroğlu et al. (2016)

Antiviral

Ketoconazole Clotrimazole

SLN

PEG-40 stearate acrylate

Breaking of o/w microemulsion

Cassano et al. (2016)

Podophyllotoxin

NLC

Glyceryl monostearate

Solvent emulsification evaporation

Gao et al. (2018)

Soybean oil

Octyl/ decyl acid triglyceride

478

CHAPTER 15 Properties and therapeutic potential of solid

15.5.6 RECTAL ADMINISTRATION Rectal application is one of the oldest pharmaceutical administration routes. Active agents can be delivered through the rectal route for local or systemic delivery. The lower rectum is drained by lower and middle hemorrhoidal veins and bypasses the liver, hence the first-pass metabolism of actives is avoided. This advantage allows drugs to reach the systemic circulation without undergoing metabolism in the liver. Rectal surface area is about 200 400 cm2, which is larger than the nasal or buccal surface and smaller than the GI tract. Rectal dosage forms are also a good alternative to the oral route for children and elderly or ¨ ner and Yener, 2007). The incorpounconscious patients (Jannin et al., 2014; U ration of SLN and NLC is required into a solid or semisolid dosage form for application to the rectum. Studies on SLN and NLC delivery through the rectal route are limited, with very few reported investigations (Table 15.4).

15.5.7 VAGINAL ADMINISTRATION The vaginal tract has a large surface area with a high permeability for active agents due to its rich vascularity. High permeability of vaginal epithelium causes increase in drug absorption via this route. Drugs are not subjected to the hepatic first pass effect and enzyme activity is limited compared to the GI tract. Endurance of dosage forms in the vagina can be achieved more easily than in the rectum. Thus, a proper local or systemic effect can be provided with vaginal administration. Vaginal drug delivery is usually used for local antisepsis and antifungal, antimicrobial, and contraceptive purposes, with a high patient compliance (Bu¨yu¨kko¨roğlu et al., 2016; Hani et al., 2010). A few studies for SLN and NLC applications via the vaginal route are summarized in Table 15.4.

15.5.8 OPHTHALMIC APPLICATION Ocular delivery of drugs is a challenging process. Barriers of the eye, such as corneal and conjunctival epithelial barriers, blinking, tear secretion, and ocular drainage mechanism limit delivery of therapeutics (Bucolo et al., 2012). Because of these mechanisms only 3% 5% of administered dose can reach the ocular tissues. To accomplish effective ophthalmic drug delivery, nano sized dosage forms (nanoparticles, liposomes, dendrimers) have been developed (Sanchez-Lopez et al., 2017a,b). Drug characteristics, such as lipophilicity, partition coefficient, molecular weight, ionization degree, etc., and properties of dosage forms such as surface charge, average size, osmotic pressure, etc., affect their corneal absorption. Lipophilic drugs could easily penetrate through ocular barriers. If molecular weight of active agents is greater than 500 Da corneal penetration is low. Due to electrostatical interactions, positive surface charge increases corneal retention (Sanchez-Lopez et al., 2017a).

15.5 Administration Routes of SLN and NLC

An ideal ophthalmic drug delivery system should provide the drug in ocular tissues at therapeutic levels. Colloidal nanoparticulate systems, such as SLN and NLC, offer advantages for ophthalmic drug delivery (Urtti, 2006). Extended or controlled drug delivery from nanoparticulate systems on corneal areas results in higher bioavailability. Thus, patient compliance also increases by reducing frequency of application. Retention time of the drug on the corneal area is prolonged by SLN and NLC, thus corneal permeation increases. Indeed, ophthalmic delivery of drugs has a crucial role for treatment of eye disorders. SLN and NLC for ocular inflammation, eye infections, glaucoma, cataracts, age macular degeneration, and eye gene therapy have been evaluated in the literature (Table 15.5). Lipid and surfactant contents are critical parameters for production of SLN and NLC. Suggested lipids for ophthalmic drug delivery are triglycerides (trilaurin, capric/caprylic triglycerides), diglycerides (dipalmitin, disteraine), monoglycerides (glyceril monostearate, glyceril palmitostearate), fatty acids (decanoic acid, linoleic acid), and cationic lipids [dioleoyl trimethyl ammonium propane (DOTAP), cetyltrimethylamonium (CTAB)] (Sanchez-Lopez et al., 2017b). On the other hand, surfactants should be selected carefully. Irritation issue must be considered for ophthalmic delivery, so nonionic surfactants could be the best option due to their reduced irritation potential (Leonardi et al., 2014).

15.5.9 PULMONARY ADMINISTRATION Researchers have focused on nanocarrier mediated pulmonary drug delivery for treatment of pulmonary disorders since those systems combine advantages of controlled drug delivery and the pulmonary route. SLN and NLC present benefits for pulmonary drug delivery. For pulmonary applications, they have to meet biocompatibility, sterility, isotonicity, and pH requirements of physiological media. Aerodynamic properties of nanoparticles are also an important factor to achieve effective drug delivery to target site of the respiratory tract. Particle sizes of SLN and NLC in the nanometer range offer aerodynamically desirable properties (Weber et al., 2014). Pulmonary delivery of actives is achieved by inhalation devices. Currently, dry powder inhalers (DPIs), metered dose inhalers (MDIs), and nebulizers are available in the pharmaceutical market. Each device has advantages and drawbacks. DPIs use the patient’s insipiratory air, but effective inhalation is needed (Haughney et al., 2010; Mehta, 2016). MDIs provide exact and reproducible doses, however actuation inhalation coordination can be a problem (Haidl et al., 2016; Roche and Dekhuijzen, 2016). Nebulizers are still the most effective devices for pulmonary applications. An earlier form of nebulizers is air jet nebulizers, which use negative pressure to mix the with drug air stream. Ultrasonic nebulizers produce waves to convert drug solution to aerosols. Vibrating mesh nebulizers have hollow plates at the top of the liquid reservoir to extrude the drug

479

Table 15.5 Recent Studies on Ophthalmic Applications of SLN and NLC Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Antibiotic

Gatifloxacin

SLN

Levofloxacin

Liquid Lipids

Preperation Methods

References

Stearic acid Compritol 888 ATO

Breaking o/w microemulsion

Abul Kalam et al. (2013a,b)

SLN

Stearic acid

Solvent emulsification evoporation

Baig et al. (2016)

Tobramycin

SLN

Stearic acid

Breaking o/w microemulsion

Chetoni et al. (2016)

Itraconazole

SLN

Stearic acid Palmitic acid

Ultrasonication

Mohanty et al. (2015)

Ketoconazole

SLN

Compritol 888 ATO

HPH

Kakkar et al. (2015)

Voriconazole

SLN

Witepsol W35 Stearic acid Compritol 888 ATO

HPH

Furedi et al. (2017)

Antiglaucoma

Brimonidine

SLN, NLC

Glycerol monostearate

Castor oil

High shear homogenization

El-Salamouni et al. (2015)

Antiinflammatory

All-trans retinoic acid

NLC

Wax palm

Oleic acid

High shear homogenization

Zhou et al. (2016)

Diclofenac Sodium

SLN

Compritol 888 ATO Precirol ATO5

Breaking o/w microemulsion

Abrishami et al. (2016)

Flurbiprofen

NLC

Compritol 888 ATO

Miglyol 812

HPH

Gonzalez-Mira et al. (2012)

Ibuprofen

NLC

Precirol ATO5

Miglyol 812

Ultrasonication

Almeida et al. (2016)

Indomethacin

SLN

Compritol 888 ATO

HPH

Hippalgaonkar et al. (2013)

Nepafenac

NLC

Glyceryl monostearate

Ultrasonication

Yu et al. (2017)

Antifungal

Miglyol 812 N

Antiviral

Acyclovir

SLN, NLC

Compritol 888 ATO Stearic acid Cithrol GMS

Beta 1 receptor blocker

Betaxolol HCl

SLN

Glycerol monostearate Phosphatidylcholine

Propranolol HCL

NLC

Compritol 888 ATO

Carbonic acid anhydrase inhibitor

Methazolamide

SLN

Glyceryl monostearate

Corticosteroid

Triamcinolone

NLC

Precirol ATO5

Isoflavanoid

Genistein

NLC

Breaking o/w microemulsion

Seyfoddin and Al-Kassas (2013)

Solvent emulsion evaporation

Hou et al. (2016)

HPH

Zadeh et al. (2018)

Solvent emulsion evaporation

Wang et al. (2014)

Squalene

HPH

Araujo et al. (2012)

Compritol 888 ATO Gelucire 44/14

Miglyol 812

Melt-emulsification

Zhang et al. (2013)

NLC

Compritol 888 ATO Gelucire 44/14

Miglyol 812 N

Ultrasonication

Liu et al. (2016b)

Solvent emulsion evaporation

Leonardi et al. (2015)

Breaking of microemulsion

Liu et al. (2016a)

Preparation via w/o/w emulsion

Fangueiro et al. (2014)

Ultrasonication

Liu et al. (2012)

Neurohormone

Melatonin

SLN

Softisan 100

Polyphenol

Curcumin

NLC

Glyceryl monostearate

Epigallocathecin gallate (EGCG)

SLN

Lipoid S75 Lipoid S100 Cetyltrimethylamonium

Mangiferin

NLC

Glyceryl monostearate, Gelucire 44/14

Xanthonoid

Capryol 90

Oleic acid

Miglyol 812 N

Miglyol 812

Table 15.6 Recent Studies on Pulmonary Applications of SLN and NLC Therapeutic Groups

Active Agents

Formulations

Solid Lipids

Preparation Methods

References

Antiasthmatic

Budesonide

SLN

Hydrogenated palm oil

Ultrasonication

Esmaeili et al. (2016)

Antibiotic

Amikacin

SLN

Cholesterol Stearic acid

Solvent emulsification evaporationUltrasonication

Varshosaz et al. (2013)

Levofloxacin

SLN, NLC

Myristyl myristate

Miglyol 812

Solvent emulsification evaporation Ultrasonication

Baig et al. (2016)

Levofloxacin DNase

SLN, NLC

Myristyl myristate

Crodamol

Ultrasonication

Islan et al. (2018)

Sodium colistemethate

SLN, NLC

Precirol ATO5

Miglyol 812

Solvent emulsification evaporation Ultrasonication

Pastor et al. (2014)

Tobramycin

NLC

Compritol 888 ATO Precirol ATO5

Miglyol 812

High shear homogenization

Moreno-Sastre et al. (2016)

Antifungal

Itraconazole

NLC

Precirol ATO5

Oleic acid

HPH

Pardeike et al. (2016)

Antiinflammatory (COX-2 inhibitors)

Celecoxib

NLC

Compritol 888 ATO

Miglyol 812

HPH

Patlolla et al. (2010)

Antineoplastic and anticancer

Doxurubicin

NLC

Precirol ATO5

Squalene

Ultrasonication

Taratula et al. (2013)

Paclitaxel

SLN

Precirol ATO5

High shear homogenization

Videira et al. (2012)

Yuxingcao essential oil

SLN

Compritol 888 ATO

High shear homogenization

Zhao et al. (2016)

Rosuvastatin

NLC

Lauric acid

Ultrasonication

Patil-Gadhe and Pokharkar (2016)

Hypolipidemic

Liquid Lipids

Capryol 90

Isoflavanoid

Naringrnin

SLN

Glyceryl monostearate

Leukotriene receptor antagonist

Montelukast

NLC

Precirol ATO5

Phenolic acid

Ferulic acid

NLC

Cetyl palmitate

Pulmonary arterial hypotensive

Sildenafil

SLN

Phospholipon 90 G Softisan HS154

Solvent emulsification evaporation

Ji et al. (2016)

Capryol 90

Ultrasonication

Patil-Gadhe et al. (2014)

Oleic acid

HPH

Hassanzadeh et al. (2017)

Preparation through co-flowing microchannels

Paranjpe et al. (2014)

484

CHAPTER 15 Properties and therapeutic potential of solid

solution into aerosol (Dolovich and Dhand, 2011; Martin and Finlay, 2015). DPIs, MDIs, and nebulizers are inhalers for pulmonary delivery of SLN and NLC. Pulmonary drug delivery via lipid nanoparticles has promising effects on systemic and local disorders. In the literature, pulmonary applications of SLN and NLC have been studied on asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and tuberculosis. Nanoparticles were observed to distribute homogeneously in the respiratory tract (Pastor et al., 2014) or accumulate in it. Moreover, systemic effects of some proteinic structures loaded into lipid nanoparticles have been investigated. Table 15.6 summarizes studies on pulmonary applications of SLN and NLC in recent years.

15.6 CONCLUSIONS SLN and NLC are sophisticated colloidal drug carrier systems which combine desirable properties expected from their counterparts. They have drawn distinctly increased attention from various research groups and pharmaceutical companies since they are economical, patient-friendly, and suitable systems for large-scale production to be used in a variety of application routes, as mentioned in this chapter. In the last decade, new formulations of SLN and NLC are investigated for targeting active agents by modifying their chemical properties and coating them with various substances in order to provide an efficient therapy of deadly illnesses. Newly introduced approaches indicate their benefits. As a result, SLN and NLC are the almost promising drug carrier systems in the field of nanopharmaceutics.

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