Lipid-Based Nanocarriers for Drug Delivery and Diagnosis

By Muhammad Raza Shah, Muhammad Imran and Shafi Ullah

Lipid-Based Nanocarriers for Drug Delivery and Diagnosis explores the present state of widely used lipid-based nanoparticulate delivery systems, such as solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), nanoliposomes, micelles, nanoemulsions, nanosuspensions and lipid nanotubes. The various types of lipids that can be exploited for drug delivery and their chemical composition and physicochemical characteristics are reviewed in detail, along with their characterization aspects and effects of their dimensions on drug delivery systems behavior in-vitro and in-vivo. The book covers the effective utilization of these lipids based systems for controlled and targeted delivery of potential drugs/genes for enhanced clinical efficacy.

• Provides the present state of widely used lipid-based nanoparticulate delivery systems
• Explores how lipid-based nanocarriers improve drug delivery safety
• Describes the nanoformulation design and the preparation methods of lipid-based nanocarriers

• Language: English
• Publisher: Elsevier Science
• Release date: Jun 7, 2017
• ISBN: 9780323527309

Muhammad Raza Shah

Muhammad Raza Shah is a full professor at the International Center for Chemical and Biological Sciences, HEJ Research Institute of Chemistry, University of Karachi, Pakistan. He is also the Head of the Center for Bioequivalence Studies and Clinical Research. He is a recipient of several awards, including the Tamgha-i-Imtiaz Award from the President of Pakistan, the Salam Prize, the Professor Atta ur Rahman Gold Medal, and the Dr M Raziuddin Siddiqi Prize, by the Pakistan Academy of Sciences, for scientists under 40 years of age, in the field of chemistry. Professor Shah has authored six books and edited four books, in addition to contributing over 350 peer-reviewed journal papers. One of his authored books was declared as best book of 2017 by the Government of Pakistan’s Higher Education Commission.

Book preview

Pakistan.

Preface

Atta-ur-Rahman, UNESCO Science Laureate

The book entitled Lipid-Based Nanocarriers for Drug Delivery and Diagnosis covers a wide range of topics in drug delivery systems. It is well known that out of every 10,000 or more compounds screened, only one can eventually reach to the consumer market. Major reasons for this high failure rate are drug toxicity, biological degradation, low bioavailability, and intrinsic side effects. Nanotechnology is exponentially expanding in the area of medicines, therapeutics, diagnostics, and drug delivery. A nanocarrier-based delivery system is used to deliver medicinal compounds in the body and improves their safety and efficacy by controlling the rate and targeted release of the medicinal product. Among the carriers explored for the controlled delivery and targeting of drugs, lipid-based nanocarriers have generated increasing interest due to a number of technological advantages that include high biocompatibility and higher drug loading capacity.

The book provides coverage of many important aspects of drug delivery systems, including, lipid-based nanoparticulate delivery systems such as solid lipid nanoparticles, nanostructured lipid carriers, nanoliposomes, micelles, nanoemulsions, nanosuspensions, and lipid nanotubes. The various types of lipids that can be exploited for drug delivery and their chemical composition and physicochemical characteristics are reviewed in detail. The characterization aspects and effects of their dimensions on drug delivery systems behavior in in vitro and in vivo is also discussed. The book also covers the effective use of lipid-based systems for controlled and targeted delivery of potential drugs/genes for enhanced clinical efficacy. The role of lipid nanocarriers in nanomedicines, diagnostics, and therapy is elaborated.

The book should be useful for research institutes, research departments in industry, libraries, universities, and consultants. It will provide a wealth of information for undergraduate and graduate students in the fields of organic chemistry, medicinal chemistry, and pharmacology.

The book should prove useful as an advanced text or reference book for a course on nanocarrier-based drug delivery system. It is written with great effort and care, and it should turn out to be an important reference book, a desktop information resource, and useful supplementary reading for teaching professionals and students.

Chapter 1

Solid lipid nanoparticles

Abstract

Solid lipid particles (SLNs) are the stabilized drug delivery systems having solid lipids and surfactants as their building blocks. They are intended for increasing the solubility and ultimately the bioavailability of power water soluble drugs. Different methods have been reported for their production, utilizing different conditions and equipments. The drug loaded SLNs are characterized for their morphology, particles size, size distribution, zeta potential, functionality, and other important parameters. All these parameters with specific dimensions are extensively exploited for the desired applications of SLNs. SLNs have found their applications for site-specific drug targeting, increased oral bioavailability, and controlled release of the drugs from dosage forms.

Keywords

SLNs; composition; production; characterization; applications

1.1 Introduction

Carrier-based drug delivery systems have attracted increased scientific interest for enhancing the efficacy of current drugs and particularly those with lower aqueous solubility. Among them, great interest has been developed to investigate carriers in the nanosize range to manufacture nanomedicines (Bang et al., 2009; Liu and Park, 2009; Xia et al., 2009). Nanocarriers are known to improve bioavailability, minimize degradation rate, control the release rate, reduce adverse effects, and enhance accumulation of the encapsulated drugs in the diseased target site (Torchilin, 2007). Controlled and sustained release of the active drugs from dosage forms is known to improve patient compliance toward the proposed treatment hence improving clinical outcomes (Shi et al., 2010).

Research in the area of nanoparticles started in the early 1960s with the introduction of parenteral emulsions, which helped in the administration of many low water soluble or lipophilic therapeutic agents. These parenteral emulsions were preferred as the method offered the advantages to be carried out on industrial scale (Kathe et al., 2014). However, some serious issues were associated with these emulsions like separation of the drug from the lipid phase into the aqueous phase was an unavoidable drawback. Similarly the storage or shelf life physical stability of emulsion systems was very inferior. Agglomeration followed by phase separation was evident in nearly all studies. The most striking problems associated with these emulsions were the achieving of a desired sustained release profile. Only extremely lipophilic drugs showed the desired release pattern (Washington, 1996; Prankerd and Stella, 1990).

To solve the problems associated with parenteral emulsions and other drug delivery systems, polymeric nanoparticles were subsequently introduced and developed. Polymer-based nanoparticles are advantageous in terms of their biocompatibility and biodegradability. Chemically modified and naturally occurring polymers are used to impart various functional characteristics to the nanoparticles. Though polymer-based nanoparticles are quite advantageous, still they have certain drawbacks like toxicity, long residence time, residual organic solvents, and industrial scale-up of the process. Liposomes were developed as alternative to overcome the above-cited drawbacks. They were quite biocompatible and biodegradable and had the advantage to deliver many potent drugs that otherwise have serious side effects. Moreover, hydrophilic drugs were successfully entrapped in the aqueous compartments of the liposomal vesicles. This drug delivery system was found to have some inherent shortcomings of low physical stability, nonspecificity, drug expulsion, and clearance by macrophages (Samad et al., 2007; Couvreur et al., 1995).

In the early 1990s, researchers focused their attention toward the development of nanoparticles based on lipid matrices that would be solid at room temperature. This system was intended for drug dosage form based on inert lipids having a solid matrix and that would be quite enough in limiting the drug mobility and providing increased stability. This gifted drug delivery system acquired the advantages of polymeric nanoparticles and micronized emulsions and is known as solid lipid particles (SLNs) (Soppimath et al., 2001; Smith, 1986). By definition, they are colloidal particles in submicron (50–1000 nm) level, consist of biocompatible and biodegradable solid lipids (lipids that are solid at room temperature), stabilized with surfactants, polymers, or their mixtures, and capable to host both lipophilic and hydrophilic drugs. SLNs have emerged as promising drug delivery system bearing the treats, functionalities, and advantages of different carrier systems (Harde et al., 2011; Gasco, 1993). Due their simplicity, versatility, and being promising drug carriers, SLNs have greatly attracted the attention of scientific community involved in formulation. Owing to their definition, they are small size colloidal particles, and are considered to be important from many aspects. As the smaller the particle size, the more likely they are to remain stable, the more potential for targeted responses, and the more capacity to encapsulate increased amounts of drugs (Müller et al., 2002; Wissing et al., 2004). They are a new generation of lipid-based emulsions in submicron-sized where the liquid lipid (oil) has been replaced with a solid lipid. They possess unique properties like small size, high drug loading capacity, large surface area, and the interaction of phases at the interfaces. They have been attractive for their potential to improve the therapeutic efficacy of pharmaceuticals, nutraceuticals, and other materials (Cavalli et al., 1993). Being similar to polymeric nanoparticles, their solid matrix provides great protection to the loaded active ingredients against chemical degradation under harsh biological environment. It also helps the modulation of the drug release profiles. Furthermore, they can be synthesized at mega industrial scale through high-pressure homogenization. All these constructive attributes make SLNs excellent carriers for drug delivery (Harde et al., 2011).

SLNs research has gained wide global importance recently as large number of drugs are formulated using this technique. SLNs are commonly used (1) for parenteral delivery of drugs (Yang et al., 1999), (2) to enhance the oral bioavailability of lipophilic drugs that are not manageable with other delivery systems (Abuasal et al., 2012; Hu et al., 2004), (3) for ocular drug delivery in order to improve their corneal penetration and residence time in the eye (Seyfoddin et al., 2010), (4) for topical drug delivery to treat different skin diseases (Schäfer-Korting et al., 2007), and (5) for pulmonary and rectal drug delivery (Liu et al., 2008; Sznitowska et al., 2001). Targeting delivery of drugs to specific diseased sites has also been reported by different researchers (Chattopadhyay et al., 2008).

1.2 Advantages

SLNs are having the unique potential to be modulated for controlled drug release and drug targeting to specific sites. They can effectively increase drug stability inside the formulation and better shelf life of the final dosage form can be achieved due to stable constituting building blocks. SLNs can incorporate maximum drug into the carrier matrix. Both lipophilic and hydrophilic drugs can be easily incorporated in their structures. The carriers used in SLNs are stable under physiological conditions and well tolerated by the living biological system, so they are devoid of toxicities and allergic reactions. The scientist normally avoids the use of toxic organic solvents during production of SLNs and hence there is no problem in their sterilization and production.

1.3 Structural Composition of Solid Lipid Nanoparticles

Structurally, SLNs are composed of solid lipid(s), surfactant(s), cosurfactant (if needed), and active pharmaceutical ingredients (drugs). All the lipids used in the production of SLNs are of physiological nature having broad structural diversity. The lipids used in the production are broadly categorized into fatty alcohols, fatty acids, fatty esters, partial glycerides or triglycerides. Few research groups have also reported waxes to be used in the production of these nanoparticles (Jenning and Gohla, 2000). SLNs are surface-tailored with surfactants, thus resulting in the enhanced stability of the colloidal system. They are sometimes used in combination with a cosurfactant, if necessary. All the structural components of SLNs are discussed one by one in detail.

1.3.1 Lipids

Being the major constituents of SLNs, solid lipids are considered to be responsible for the stability, release, the entrapment and drug loading. Ideally, they are the lipids which dissolved the drugs in them. Few of the lipids that are frequently employed in SLNs production are fatty acids, steroids, waxes, triglycerides, acylglycerols and their combinations as shown in Table 1.1. Most of the lipids, except that of cetyl palmitate, have been approved as generally-recognized-as-safe. They all are compatible and physiologically well tolerated (Mehnert and Mäder, 2001).

Table 1.1

Solid Lipids Used in Preparation of Solid Lipid Nanoparticles

Prior to their use in the production of SLNs, selection of suitable lipids is an important parameter so to predict the essential characteristics of the nanoparticles. Though no solid guidelines are available, empirical values, such as the solubility of drug in the lipid have been suggested as suitable criteria for selection of a suitable lipid (Bummer, 2004). The solubility of drugs in lipid matrices is critical because it greatly influences the drug entrapment efficiency and loading potential, consequently decides the effectiveness of the lipid nanoparticles as drug delivery system (Kasongo et al., 2011). Using UV-Visible spectroscopy or other chromatographic techniques, the drug solubility can be easily investigated. The drug partitioning between the lipid/oil and aqueous phases can also be assumed following mathematical approaches. These predictions are based on interactions of drug–lipid and drug–water. SLNs can be prepared with increased drug loading capacity if the drug is highly soluble in lipid or having high partition coefficient. As a drug has different solubility in different lipids, its apparent partition coefficients differ for different lipids. This consequently leads to different loading potential in different lipid matrices for the same drug. Though these methods are helpful in selecting a lipid for formulations, their complications are still hindering the prediction of highly compatible and suitable lipids with desirable properties (Shah et al., 2015b).

The type and structure of the lipid used greatly affect SLNs characteristics like size of the particles, stability, drug encapsulation efficiency, and release profile. Generally, it has been noted that average particle size of SLNs dispersion increases when higher melting lipids are used. The main technical point behind this phenomenon is higher viscosity of dispersed phase. Some parameters are specific for every lipid like lipid crystallization, shape of lipid crystals, and lipid hydrophilicity. Most of the lipids are mixtures of different compounds; as a result their composition can be different when obtained from different suppliers. There can also be batch to batch variations. These variations affect the quality of SLNs to a great extent; and can retard crystallization processes, changing the zeta potential and much more like these. When lipid contents in SLNs formulations are increased over 5%–10%, this mostly leads to larger particles and broader particle size distribution (Mehnert and Mäder, 2001; Müller et al., 2002; Chakraborty et al., 2009). As a general practice, lipids with increased lipophilicity results in the increased amount of the hydrophobic drugs to be entrapped in SLNs. Likewise, lipids having free –NH2 and –OH groups on them bind the drugs through amide and ester linkages or by complex ion formation. This caused the drug to be covalently retained in the system and is slowly released when the ester/amide get hydrolyzed (Chakraborty et al., 2009).

Polymorphism in lipids is also a vital factor that greatly affects the properties of lipid-based nanoparticle system. For solid lipids, the occurrence of multiple crystalline forms is considered particularly important as it provides structural defects in which drug molecules can be entrapped. However a perfect crystalline lattice is thermodynamically more stable as compared to others. This can be better understood from the example of triglycerides. The β-forms of triglycerides are thermodynamically more stable than the α-forms and β′-forms (Chapman, 1962). Thermodynamically less stable or metastable forms finally get transformed into more stable form. This transition from one form to another poses a major challenge in development of SLNs as drug molecules are entrapped in the crystal defects of the solid lipids. With the passage of time, their disappearance significantly affects the drug loading capacity of the solid lipids. This ultimately leads to two unwanted effects, the drug expulsion during storage and abrupt drug release after administration of SLNs. The tendency of solid lipids to form perfect crystalline lattice structures or the rate at which metastable-to-stable transitions takes place is another crucial factor that influences the selection of an appropriate lipid. No perfect guidelines are so far available for the selection of lipids based on these properties (Shah et al., 2015b).

The viscosity and contact angle of the lipid (or lipid drug mixture) with water is another parameter that plays a crucial role. Solid lipids with high viscosity are very difficult to be used for SLNs production as they require higher sonication energy. High energy intake ultimately leads to degradation of some drugs like DNA or peptide (Özbek and Ülgen, 2000). Similarly, contact angle of the lipid with water greatly affects the formation of small droplets and hence stable nanoparticles. It is reported that lipids with high contact angle results in larger particles that are not optimum (Martins et al., 2011). SLNs prepared with lipids of less ordered crystal lattices show successful drug inclusion compared to those achieved with highly ordered crystal packing lipids. But their long-term storage stability was found different (Manjunath et al., 2005). Cationic lipids are widely used for lipid-based gene delivery. The presence of positive charge on the surface of SLNs prepared with cationic lipids results in enhanced transfection efficiencies. Two-tailed or branched cationic lipids turned out to be advantageous over single-tailed cationic lipids due to their less cytotoxic effects (Shah et al., 2015b).

1.3.2 Surfactants

Surfactants, surface-active agents, are the other important building blocks of the SLNs systems. Surfactants are amphiphilic compounds that possess a hydrophilic polar moiety and a lipophilic nonpolar moiety. These together constitute the typical head and the tail of surfactants. When used in low concentrations, surfactants adsorb onto the surface or interface of a system. They reduce the surface or interfacial free energy, thus ultimately leads to reduction in surface or interfacial tension between two phases (Shah et al., 2015a).

The general concept is that the SLNs system is a solidified nanoemulsion of lipids in aqueous phase. Now when surfactants are introduced in the SLNs system, they reduce the surface tension between water and lipid phases and thus stabilize the increasing surface area during sonication. Thus process of stabilization requires the sufficient quantity of surfactant. The main things to be considered when using surfactants in preparation of SLNs are their safety, compatibility with other excipients, capability of producing desired size with minimum quantity consumed, and also providing sufficient stability to the SLNs, by covering their surfaces. Mostly used surfactants for stabilization of SLNs are Poloxamer 188, Poloxamer 407, Polysorbate 80, Polysorbate 40, Sorbitone monopalmitate, Sodium dodecyl sulfate, Polyvinyl alcohol, Soya lecithin, and Egg phosphatidylcholine or mixtures of them. Up to some specific limits, the increase in the surfactants concentrations causes reduction in the size of particle size of the surfactant. There are some considerations for surfactants to influence the SLNs formulations. The chemical structure of the surfactants is one of these considerations. SLNs stabilized with highly hydrophilic nonionic surfactants result in more stable SLNs, which are commonly used for intravenous administration. Likewise, charged surfactants are used in SLNs as they provide charge to the nanoparticles and thus prevent their aggregation during storage. In vivo fate of the surfactant is another important parameter to be considered during its selection. It is obvious poloxamer series that prevents the SLNs uptake by reticuloendothelial system (RES) and thus cause them to circulate in the blood for a long time and allows passive targeting. Similarly, SLNs coated with polysorbate 80 can improve the drug delivery to brain (Jaspart et al., 2005; Kovacevic et al., 2011; Kathe et al., 2014; Manjunath et al., 2005).

1.3.3 Other Ingredients Used

A large number of other ingredients are also used for preparation of SLNs for the desired applications. They are intended for stability of the formulations, functionalization of the SLNs surface for targeted delivery of the drugs to specific sites or receptors, and modulating the drug release from formulation in a desired manner. These ingredients include surface modifiers and counter-ions. SLNs intended for the encapsulation of cationic and hydrophilic drugs are added ions like organic anions and anionic polymers (Cavalli et al., 2002, 2003). In case of human cancer cells, folic acid receptors are normally over expressed on their surfaces. Thus these receptors have been identified as a tumor marker, especially in ovarian carcinomas. To effectively target the human cancerous cells, folic acid has been used for SLNs surface modification (Stella et al., 2000). In the same way, folate is also widely used for surface modification of SLNs to specifically target the folate receptors expressed in cancer cells (Stevens et al., 2004). Thiamine ligand contains a distearyl phosphatidyl ethanolamine (DSPE) group and a PEG spacer. When SLNs are coated with thiamine ligand, it associate with blood–brain barrier (BBB) thiamine transporters and accumulates there. This results in increased brain uptake of SLNs (Lockman et al., 2003). For localization of SLNs in a specific region of the body, they are impregnated with magnetite and are then localized in that specific region by applying an external magnetic field. Magnetite containing SLNs are stable in quite large range of temperature (378–478°C) (Igartua et al., 2002). Similarly, when SLNs surfaces are modified with hydrophilic polymers, this reduces their uptake by the RES. The long circulating or stealth carrier-based SLNs continue to stay in the blood for a longer time and thus increase the mean retention time of the drugs in the systemic circulation (Fundarò et al., 2000). These stealth or long circulating SLNs are extensively studied for delivering and targeting of anticancer drugs as they are efficiently and selectively taken up by tumor cells (Madan et al., 2013; Pignatello et al., 2013).

1.4 Incorporation of Drugs in Solid Lipid Nanoparticles

Depending upon the methods of preparation, three different models of drug incorporation into SLNs have been proposed and reported. The apparent structure obtained for SLNs is always a function of the constituents of the formulation, i.e., lipids, active drug molecules, surfactant, and of the conditions employed during the methods of production, i.e., hot and cold homogenization. These are including homogeneous matrix model or solid solution model, drug-enriched shell model, and drug-enriched core model. These models are discussed in detail.

1.4.1 Homogeneous Matrix Model

Homogeneous matrix model is also known as solid solution model. Using this model, molecularly dispersed drug in a homogeneous matrix or drug present in amorphous clusters is achieved when cold homogenization method is used and when very hydrophobic drugs are incorporated in SLNs without surfactants or drug-solubilizing molecules following the hot homogenization method. In the cold homogenization method, the drug is dissolved in molecularly dispersed form in the bulk lipid. The employment of mechanical breaking through high-pressure homogenization results in nanoparticles having the homogeneous matrix structure. Similarly is the case when the oil droplet produced by hot homogenization is cooled crystallizes and no phase partition between lipid and drug observed during this cooling process. This model is considered to be valid for incorporation of the drugs like prednisolone that shows prolonged release profile from 1 day to several weeks (Müller et al., 2002; Zur Mühlen and Mehnert, 1998).

1.4.2 Drug-Enriched Shell Model

The drug-enriched shell model is depicted in Fig. 1.1A. In this model, the lipid core is core enclosed by a drug-enriched outer shell. This proposed structure is obtained as a result of phase partition when hot liquid droplets cool quickly to generate lipid nanoparticles. The structural morphology of the drug-enriched shell can be explained by a lipid precipitation mechanism. Lipid precipitation takes place during production and by repartitioning of the drug that occurs during the cooling stage. Following the hot homogenization method, each droplet contains melted lipids and drug used. Rapid cooling of lipid accelerates its precipitation at the core with the drug accumulating in increased concentration in the outer liquid lipid. Thus when the cooling is completed, it results in the precipitation of a drug-enriched shell. This model is considered appropriate for the incorporation of drugs in SLNs that exhibit abrupt release profile. This rapid release pattern of drugs is specially required for SLNs formulated for dermatological purposes where increased penetration of the drugs is needed, in addition to the occlusive effects of the SLNs (Muchow et al., 2008).

Figure 1.1 Representative models for drug incorporation in solid lipid nanoparticles. (A) Drug-enriched shell model, (B) drug-enriched core model, and (C) homogeneous matrix model.

When clotrimazole was formulated in topical SLNs dosage from, the controlled release of the drug from SLNs formulation was achieved due to its drug-enriched shell structure (Souto et al., 2004). The drug solubility in the surfactant–water mixture at elevated temperature is also a main factor that causes the precipitation of the drugs in the shell. During the process of hot homogenization, drug is released from the lipid core because of its enhanced solubility in the surfactant solution. But as the dispersion temperature drops down, the drug solubility in the surfactant solution decrease. This all result in the enrichment of the shell with drug, in cases where lipid core solidification has already started (Muchow et al., 2008).

1.4.3 Drug-Enriched Core Model

Drug-enriched core model for SLNs is achieved when the adopted process of recrystallization is the opposite of that stated for the drug-enriched shell model. Schematically drug-enriched core model is represented in Fig. 1.1B. When drug gets crystallized before the lipid crystallization, then the morphological structure obtained is termed as drug-enriched core model. The mechanism of this model is not very complex. First of all the drug is solubilized in the melted lipid up to its saturation. When the melted lipid containing drug is cooled, this results in the supersaturation of the drug in the lipid. This in turn leads to recrystallization of drugs prior to recrystallization of lipid. When the lipid melt is further cooled, it causes the recrystallization of the lipid that surrounds the precrystallized drug-enriched core in the form of a membrane. This structural model governed by Fick’s law of diffusion and is ideal for drugs that require prolonged release over a period of time (Müller et al., 2002).

1.5 Preparation Techniques of Solid Lipid Nanoparticles

SLNs are prepared from solid lipids and surfactants with water as solvent using different methods. A broad variety of preparation techniques for SLNs are successfully developed. The selection of method for SLNs preparation depends upon various factors like

• Physicochemical properties of the drug to be incorporated

• Stability of the drug to be incorporated

• Desired particle characteristics of the lipid nanoparticle dispersion

• Stability of the lipid nanoparticle dispersion

• Availability of the production equipment.

1.5.1 High-Pressure Homogenization

High-pressure homogenization is considered to be one of the most reliable technique for the production of lipid-based nanoparticles (Schwarz et al., 1994a). Earlier, high-pressure homogenizers were employed for the preparation of nanoemulsions for parenteral nutrition. The process is easy and can be carried out at industrial level. In this technique, a liquid is forced through a narrow gap of few micrometers by high-pressure homogenizers at high pressure (100–2000 bar). The application of high shear stress and cavitation forces leads to the particles in decreased size. The main crux of the whole high-pressure homogenization process is that the lipid and drug are melted at about 5–10°C above the melting point of the lipid. The lipid concentration is typically kept at 5%–20%. Now the aqueous containing surfactant is added to the lipid phase at the same temperature as that of the lipid. This results in formation of a hot preemulsion due to high-speed stirring. The technique of homogenization is preferred due to its advantages like scalability, avoidance of organic solvent, enhanced stability of the product, and increased loading capacity of the drugs in the SLNs. The use of high temperature and pressure are challenging when drugs of fragile nature and delicate thermal stability are intended to be incorporated in the SLNs (Naseri et al., 2015). When high-pressure homogenization is carried out at elevated temperatures, then it is known as hot high-pressure homogenization. When it is carried out at or below room temperature then it is termed as cold high-pressure homogenization. They are discussed in detail as following:

1.5.1.1 Hot homogenization

In hot homogenization method, active pharmaceutical ingredients or drugs are first dissolved in the lipid melt. Then the dispersion of lipid melt into the hot solution of surfactant results in the formation of a coarse preemulsion. This preemulsion is then heated at a temperature above the melting point of the lipid with stirring (Ahlin et al., 1998). The preemulsion is now passed through a high-pressure homogenizer for 3–5 cycles and applying a pressure of about 500–1500 bar (Schwarz et al., 1994b). This ultimately results in the production of nanoemulsion which is cooled at room temperature or below room temperature. The lipid nanodroplets solidify while cooling and forms an aqueous dispersion of SLNs. The pressure of homogenization and the number of cycles should not exceed than that required for achieving the desired effects. If both are high, then the production cost and chances of metal contamination increase. The control of these parameters is also vital for controlling the size of SLNs. If not controlled well, then the high surface free energy of the particles causes aggregation resulting in larger size particles. This technique cannot be used for thermally labile drugs because of high temperature used during production process. Another drawback of this technique is that the lipids remain as a supercooled melt for longer period due to smaller particles and emulsifier presence. It has been also reported that the technique is not suitable for water soluble drugs (Patel, 2012).

For lipid nanoparticles, particle size is considered as one of the important parameters as it decides the ultimate fate of the incorporated drugs in the biological system (Wu et al., 2011). Nanoparticle size depends upon the composition of lipids, surfactants, and the dispersion medium and the homogenization parameters. SLNs prepared with high-pressure homogenization techniques are reported with an average diameter ranging from 50 to 400 nm (Doktorovova et al., 2014; Dwivedi et al., 2014; Wang et al., 2012). Using this technique, small size SLNs can be obtained hence increasing the emulsifier-to-lipid ratio, increasing pressure of homogenization, adjusting the homogenization time, increasing the homogenization temperature, or adjusting the melt viscosity (Jenning et al., 2002; Patravale and Ambarkhane, 2003).

1.5.1.2 Cold homogenization

In cold homogenization, the drugs are first dissolved in the lipid at a temperature above the melting point of the lipid. Then the resultant mixture is rapidly cooled using dry ice or liquid nitrogen. The use of rapid cooling helps in the uniform distribution of the drugs in the lipid. The solidified mixture is then milled to about 50–100 μm particles using a mortar mill or ball (Muèller et al., 2000). The resultant lipid microparticles are then suspended in a stabilizer or surfactant solution to obtain a suspension. This suspension is then further passed through a high-pressure homogenization at room temperature or below room temperature to obtain SLNs.

This technique is most suited for incorporating thermosensitive drugs in SLNs. As the solid lipid is milled using this technique, the problems associated with lipid modification are avoided (Mehnert and Mäder, 2001). Due to limited chances of the drugs distribution into the aqueous phase, the method can be used for both hydrophilic drugs and hydrophobic drugs. SLNs prepared using this technique have slightly larger size and wide size distribution as compared to those prepared with hot homogenization technique, using the same lipid at similar homogenization conditions like pressure, temperature, and the number of cycles. The size of SLNs can be decreased by increasing number of homogenization cycles (Friedrich and Müller-Goymann, 2003).

1.5.2 Precipitation from Homogeneous Systems

Another technique for the production of SLNs is their precipitation from homogeneous solutions or colloidal systems. This process does not require the use of high energy input, and thus can be performed with conventional laboratory equipments. Small size particles can be obtained using this technique, but preventing of supersaturation phenomena is usually difficult and this leads to the SLNs in larger size. This can be of the following types:

1.5.2.1 Precipitation from warm microemulsions

Gasco et al. introduced the process of solidification of lipid-based nanoparticles when their precipitation occurs from warm microemulsions. The method was used and reported for the preparation of solid lipid colloidal dispersions. This technique is extensively exploited for preparation of SLNs because of its simplicity. Initially, fatty acids were used as the matrix building blocks, but later on the other types of lipids were also used (Cavalli et al., 2000; Ugazio et al., 2001). The drug is added to molten lipid matrix and the drug lipid matrix mixture is mixed well with hot aqueous phase containing water, emulsifier, and cosurfactant, using mechanical stirrer. This results in the formation of optically transparent and homogeneous colloidal system, which is then diluted with cold water and leads to the precipitation of SLNs (Fig. 1.2). When the dispersion is highly diluted, it results in decreased lipid concentrations and ultimately small size particles in the dispersion are obtained. Furthermore, for formulation of initial microemulsion, increased concentrations of surfactants are used. To obtain concentrated nanoparticles out of dilute solution and effectively remove the cosurfactant, the processes of ultrafiltration, dialysis, and centrifugation are employed after their precipitation. To prevent the particles growth in aqueous phases during their storage, they are subjected to freeze drying. When the composition of the systems is modified by using mixtures of fatty alcohols and nonionic surfactants, then direct cooling of the microemulsion occurs and SLNs are obtained on stirring. To obtain better quality small and uniform size SLNs, the composition of the microemulsion is varied so that large space for accumulation of drugs can be provided (Joseph and Bunjes, 2013).

Figure 1.2 Schematic diagram for precipitation of solid lipid nanoparticles from warm microemulsions method.

1.5.2.2 Precipitation from water-miscible organic solvents

The precipitating of SLNs from water-miscible organic solvents like acetone or ethanol (Fig. 1.3) is gaining wide popularity among the formulation scientists and nanotechnologists. The solution containing lipid matrix material, drug, and/or stabilizers is injected into the aqueous phase containing emulsifier placed on agitator or stirrer. This is usually carried out at room temperature or at elevated temperature of the aqueous or organic phase, or both. The use of hot organic solutions turned out to be advantageous as they increase the solubility. For improving the lipid ingredients dispersion, ultrasonication with heat or without heat or their vortexing is usually performed. The presence of residual organic solvents arises toxicological aspects and leads to the dispersion instability, so their removal is of vital importance. The residual organic solvents are removed by the process of evaporation at elevated temperature at reduced pressure. For obtaining concentrated SLNs, the dispersion is centrifuged.

Figure 1.3 Solid lipid nanoparticles preparation from water-miscible organic solvents method.

In the above-mentioned techniques, the production of SLNs is always batchwise. While using microchannel techniques, the precipitation of lipid nanoparticles from organic solutions is always a continuous process. Microchannel assemblies having coflowing assembly with inner and outer capillaries or cross-shaped channels have been used for the preparation of SLNs reported. The solid lipid is dissolved in water-miscible organic solvents and the emulsifiers are dissolved in aqueous solvent. Both the solutions are simultaneously injected into the different channels of the microsystem by separate syringe pumps. Both the phases are combined at a junction in the channels and organic solvents start to diffuse into the aqueous phase. This caused the supersaturation of the lipids in the aqueous phase and thus SLNs are formed (Joseph and Bunjes, 2013; Chirio et al., 2009; Yun et al., 2009).

1.5.3 Microwave-Assisted Microemulsion Technique

Microwave-assisted microemulsion technique utilizes microwave heating for preparation of SLNs. All the ingredients like solid lipid, drug, and aqueous surfactant/cosurfactant system are introduced into controlled microwave heating system at a temperature higher than that of the melting point of the solid lipid. The continuous controlled microwave-based heating and stirring of the formulation form hot microemulsion. Unlike other conventional microemulsion production techniques, all the ingredients are heated in a one step and one vessel in microwave-based microemulsion technique, thus this method is referred to single pot production of microemulsion. To obtain SLNs, the resultant hot microemulsion is then dispersed in cold water (at 2–4°C). This method is preferred because of the easy control of parameters necessary for the production of lipid-based nanoparticles. When this technique was employed for the production of stearic acid-based lipid nanoparticles, highly stable particles with increased drug loading capacity were obtained in the range of 200–250 nm (Shah et al., 2014).

1.5.4 Solvent Emulsification-Evaporation Method

The solvent emulsification-evaporation technique was first described by Sjöström and Bergenståhl (1992) for the production of SLNs. This technique is based on the dissolution of solid lipid in a water immiscible organic solvent like cyclohexane, chloroform, ethyl acetate, methylene chloride, and the active ingredient is then dissolved or dispersed in the solution. The resultant organic phase containing drug is then emulsified in an aqueous surfactant solution with vigorous mechanical stirring. For removal of organic phases, mechanical stirring or reduced pressure is used. Dispersion of the lipid nanoparticles is generation from the precipitation of the lipid phase in the aqueous surfactant solution. To prevent the aggregation of the particles, the organic solvents are removed at a quicker rate. The technique is used for incorporation of hydrophilic drugs by preparing a w/o/w emulsion and dissolving the drug in the internal water phase (Garcıa-Fuentes et al., 2003). As this technique is free of thermal stresses, it is preferred for the encapsulation of heat-sensitive drugs. The residues of the organic solvents in the final SLNs can lead to the possible toxicities. Furthermore, increased lipid contents lead to lower homogenization efficiency because of dispersed phase high viscosity, and therefore the dispersions are very dilute and have very low lipid particle contents. As the water content is always in large quantity, its removal from the final SLNs formulation is also a problem (Sjöström et al., 1993; Patel,

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