Review Article Solid Lipid Nanoparticles: A Promising Drug Delivery Technology

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1 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 2 July September 2009 Review Article Solid Lipid Nanoparticles: A Promising Drug Delivery Technology S. Pragati 1, *, S. Kuldeep 1, S. Ashok 1, M. Satheesh 2 1 Faculty of Pharmacy, Integral University, Dasauli, Kursi Road Lucknow , U.P., India. 2 Faculty of Pharmacy, Dehradun institute of technology, Bhagwantpur, Dehradun, Uttarakhand, India. ABSTRACT: One of the situations in the treatment of disease is the delivery of efficacious medication of appropriate concentration to the site of action in a controlled and continual manner. Nanoparticle represents an important particulate carrier system, developed accordingly. Nanoparticles are solid colloidal particles ranging in size from 1 to 1000 nm and composed of macromolecular material. Nanoparticles could be polymeric or lipidic (SLNs). Industry estimates suggest that approximately 40% of lipophilic drug candidates fail due to solubility and formulation stability issues, prompting significant research activity in advanced lipophile delivery technologies. Solid lipid nanoparticle technology represents a promising new approach to lipophile drug delivery. Solid lipid nanoparticles (SLNs) are important advancement in this area. The bioacceptable and biodegradable nature of SLNs makes them less toxic as compared to polymeric nanoparticles. Supplemented with small size which prolongs the circulation time in blood, feasible scale up for large scale production and absence of burst effect makes them interesting candidates for study. In this present review this new approach is discussed in terms of their preparation, advantages, characterization and special features. KEYWORDS: Nanotechnology; Colloidal carriers; Solid lipid nanoparticles; Liposomes Introduction A high potential for drug delivery has been attributed to particulate drug carriers, especially small particles such as microparticles and colloidal system in nanometer range. Controlled and targetted delivery is one the most enviable requirements from a carrier, which involves the multidisciplinary site-specific or targetted approach (Bocca C et al., 1998). Targetted delivery to the diseased lesions is one of the most important aspects of drug delivery system. To convey the accurate desired dose of the drug and diagnostic agent to the lesions, suitable carriers are required. Nanoparticles have important potential applications for the administration of therapeutic and diagnostic agents (Karanth H et al., 2008). Nanoparticulate drug delivery system may offer plenty of advantages over conventional dosage forms which include improved, reduced toxicity, enhanced biodistribution and improved patient compliance. Pharmaceutical nanoparticles are subnanosizes structures, which contain drug or bioactive substances within them and are constituted of several tens or hundreds of atoms or molecules and morphologies * For correspondence: Pragati Shakya, Tel.: pragatimpharm@yahoo.co.in (amorphous, crystalline, spherical, needles). The purpose of this review is to take a closer look at solid lipid nanoparticle as a carrier for controlled drug delivery. Nanotechnology Nanotechnology is a breakthrough technology expected to bring revolutionary changes in the field of life sciences, including drug delivery, diagnostics, neutraceuticals and production of biomaterials application in the field of medicines is one of the most fascinating areas that include new career therapies, drug delivery systems and biomaterials for implants or prosthesis. Nanotechnology is the science of matter and material that deal with the particle size in nanometers. These are small colloidal particles that are made of nonbiodegradable & biodegradable polymers and their diameter is around 200nm. Nanotechnology and nanoscience are widely seen as having a great potential to bring benefit to many area of research and application Nano device are some where 100 to times smaller human cells. They are similar in size to large biological molecules such as enzymes and receptors. This offers the unprecedented and paradigm changing oppurtunity to study and interact with normal as well as cancer cells at the molecular and cellular level scales and during the earliest stages of the cancer process. Nanoscale device can readily interact with biomolecules on 509

2 510 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 2 July - September 2009 both the surfaces of cells & inside of cells. Nanogen develops this technology. Nanogens technology utilizes the natural (+ve) or (-ve) charge of most biological molecules (Miglietta A. et al., 2000) Nanoparticles Nanoparticles are solid polymeric, submicronic colloidal system range between 5-300nm consisting of macromolecular substances that vary in size 10nm to 1000nm. The drug of interest is dissolved, entrapped adsorbed, attached or encapsulated into the nanoparticle matrix (Muller RH et al., 2000). Depending upon the method of preparation, nanoparticle, nanosphere or nanocapsule can be obtained with different properties and release characteristics for the encapsulated therapeutic agent. Nanosphere are matrix system in which drug is physically and uniformly dispersed through out, then particles prepared by using different polymers such as polyalkylcyanoacrylate & poly lactides or they can be solid lipid nanosphere prepared using lipids like dipalmitoyl phosphatidyl choline (Marengo E 2000). Nanocapsule are ultrafine vesicular system with a diameter less than 1 mcm in which the drug is confined to a cavity surrounded by a unique polymer membrane and having aqueous or oily core containing drug substances. Nanoparticles holds much interest, because in this range materials can have different and enhanced properties compared with the same materials of a larger size due to the following two major principle factors. The increased surfaces are of quantum effect. These factors can enhance properties such as reactivity, strength, electrical characteristics & in vivo behavior and a much greater surface area per unit mass compared with the larger particles leading to greater reactivity. The advantages of using nano particles for nanoparticles loaded with drugs, because of their small size can penetrate through small capillaries and are taken up by cells and allow the drug release at right rate and dose at specific sites in the body for a certain time to release the accurate delivery, which inhances the therapeutic effect and reduces the toxicity and side effects. The use of biodegradable materials for nanoparticles preparation allows sustained release within the target site over a period of days or even weeks. Types of NPS as carrier for drug & diagnostic agents Polymeric NPS Nanosuspensions and nanocrystals Polymeric micelles Ceramic NPS liposome s fullerenes and dendrimers SLNP (Solid lipid nanoparticles) Magnetic nanoparticles Nanoshells coated with gold Nanomers and carbon nanotubes Solid lipid nanoparticles Solid lipoid nanoparticles are one of the novel potential colloidal carriers (Cavalli R et al., 1999) systems in the range of nm as alternative materials to polymers which is identical to oil in water emulsion for parenteral nutrition, but the liquid lipid of the emulsion has been replaced by a solid lipid (Jenning V et al., 2002). They have many advantages such as good biocompatibility, low toxicity and lipophillic drugs are better delivered by solid lipid nano particles and the system is physically stable (Cavalli R et al., 2002). Solid lipid nanoparticles may be a promising sustained release and drug targeting system for lipophilic CNS antitumor drugs (Müller RH et al., 1997; Karanth et al., 2008) Solid lipid nanoparticle synthesis techniques In the 1980 s, Speiser and coworkers were the first to report making solid lipid particles for drug delivery applications (Eldem T et al., 1991). Speiser created an initial nanoemulsion by using high speed mixing or ultrasonication; the nanoemulsion (Siekmann B. et al., 1996; Cavalli R et al., 1998) was subsequently spray dried to produce the nanopellets. Domb later described a very similar process based on high speed mixing and ultrasonication to yield lipid particles, or lipospheres. (Domb J et al., 1995). Both Speiser s and Domb s techniques yielded polydisperse populations that failed to produce many submicron particles. Numerous research groups subsequently commenced research efforts to improve solid lipid nanoparticle synthesis (Cavalli R et al., 1996). Most researchers have approached solid lipid nanoparticle synthesis as some variation of a two-step process: 1) the creation of a precursor oil-in-water nano emulsion and 2) subsequent solidification of the dispersed lipid phase. As a result, traditional emulsion techniques and processing have received much attention. Emulsion droplet size is known to be a function of the shear forces exerted on the droplet surface, interfacial tension, the dispersed phase viscosity, and the continuous phase viscosity. As a result, emulsification science has proceeded on the basis of reducing interfacial tension and viscosity through formulary development and by increasing the shear forces imparted on the liquid-liquid system. Approaching solid lipid nanoparticle synthesis from an emulsion perspective is fraught with significant challenges. Most emulsions produce polydisperse droplets with many droplets sizes exceeding the desired submicron target. To overcome the polydispersity and larger than desired droplet sizes, researchers often subject the precursor emulsions to large mechanical forces such as high shear homogenization

3 Pragati S. et al. : Solid Lipid Nanoparticles: A promising Drug Delivery Technology 511 (HSH), high pressure homogenization (HPH), and ultrasonication. The high energy input increases operating expenses, mechanical contamination risks, and can inhibit the activity of mechanically and thermally sensitive biological molecules. In an effort to avoid the large mechanical energy inputs, some researchers pursue more chemically elegant approaches, namely microemulsions and solvent evaporation techniques. Given the inherent instability of many emulsion systems, the process for solidifying the dispersed phase creates thermodynamically challenging phase transitions that may contribute to polydispersity and particle instability. Finally, the overall formulation and process parameters depend on the chemical nature of the drug to be delivered. This lack of formulation and process robustness necessitates reformulation and process optimization efforts for each drug to be delivered, negatively impacting the economic vitality of the technology by increasing development costs and speed to market. Despite the challenges of emulsionbased approaches, research efforts beginning in the early 1990 s have made substantial strides in successfully synthesizing solid lipid nanoparticles from emulsions. Improving upon earlier work, the research groups of Ahlin and Domb produced solid lipid nanoparticles by high shear homogenization. Ahlin reported poloxamer (0.5 weight %) stabilized trimyristin nanoparticles with average particle sizes from nm using high shear homogenization at room temperature and 25,000 rpm for 10 minutes (Ahlin et al., 1998). Solidification was achieved by dispersing the emulsion in water (T = 16 C) at 5000 rpm for 5 minutes. Higher stirring rates reduced the polydispersity, but did not significantly reduce particle size. Ahlin et al. was unable to establish optimum emulsification and solidification conditions for the high shear homogenization approach. This reflects the complex and ultra sensitive relationship between formulation chemistry and process parameters. Preparation of solid lipid nanoparticles Solid lipid nanoparticles made from solid lipids or lipid blends, produced by high pressure homogenation of melted lipids disperse in an aqueous as outer phase stabilized by surfactants as Tween 80, sodium dodecyl sulphate, lecithin etc (Hu FQ et al., 2004). High pressure homogenation can produce particle dispersion with a solid content of 20-30%. The drug loaded -lipid melt is dispersed in to surfactant solution to give a preemulsion. This preemulsion is passed through high pressure homogenizer to yield hot oil in water emulsion which cools down. The lipid crystallizes and forms solid lipid nanoparticles. The aqueous solid lipid nanoparticles dispersion can be incorporated in traditional in dosage forms like tablets and pelletes, for producing pellet. The water for extrusion mass is replaced by aqueous solid lipid nano particles dispersion (Sjöström B et al., 1992). The pelletes disintegrate and release the SLN completely non aggregated. Alternatively, they can be produce surfactants free using steric stabilizers (Poloxamer-188) or an or an outer phase of an increased viscosity (Ethyl cellulose solution). Solid lipid nanoparticles can be transformed to a dry product by spray drying or lyophillization (Muller RH et al., 1995). Solid lipid nanoparticles can also be produced in nano aqueous media e.g. PEG 600 production in PEG- 600 gives a dispersion which can be directly filled into soft gelatin capsules Basic production techniques of solid lipid nanoparticle There are two basic production techniques for SLN (Gohla SH et al., 2001; Schwarz C et al., 1994). 1) Hot homogenization 2) Cold homogenization Hot homogenization: Lipid is melted to approximately 5 0 C above its melting point, the drug is dissolved or solubilized in the melted lipid, and the drug containing lipid melt is dispersed in an aqueous surfactant solution of the same temperature. The obtained preemulsion is then passed through a high pressure homogenizer. The product of this process is hot o/w emulsion and the cooling of this emulsion leads to crystallization of the lipid and the formation of solid lipid nanoparticle. Demerits: It cannot be employed to incorporate hydrophilic active ingredients/ drugs because due to dispersing the lipid melt in the aqueous surfactant solution would lead to the partitioning of the drug to the water phase, which means that with hydrophilic drugs more than 90% would be lost to the water phase. Cold homogenization- Drug is incorporated into melted lipid and the lipid melt is cooled upto solidification. Solid material is ground by a mortar mill. Obtained lipid microparticle is dispersed in a cold surfactant solution at room temperature or even at temperature distinctly below room temperature. The solid state of the matrix mimics portioning of the drug to the water phase. It has merit over cold homogenization since even during storage of the aqueous solid lipid dispersion, the entrapment efficiency remains unchanged.

4 512 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 2 July - September 2009 Comparison of hot and cold homogenization processes (Maa F et al., 1996) Melting of the lipid and dissolving/dispersing of the drug in the liquid Hot homogenation technique Cold homogenation technique Dispersing of the drug loaded lipid in a hot aqueous surfactant mixture Solidification of the drug loaded lipid in liquid nitrogen or dry ice Premix using a stirrer to form a coarse pre-emulsion Grinding in a powder mill High pressure homogenation at a temperature above the lipids melting point Dispersing the powder in a aqueous surfactant dispersion medium (pre-mix) Hot o/w - nanoemulsion Solidification of the nanoemulsion by cooling down to room temperature High pressure homogenization at room temperature Solid lipid nanoparticle Types of solid nanoparticles The types of SLNs depend on the chemical nature of the active ingredient and lipid, the solubility of actives in the melted lipid, nature and concentration of surfactants, type of production and the production temperature. Therefore 3 incorporation models have been proposed for study. SLN, Type I or homogenous matrix model- The SLN Type I is derived from a solid solution of lipid and active ingredient. A solid solution can be obtained when SLN are produced by the cold homogenation method. A lipid blend can be produced containing the active in a molecularly dispersed form. After solidification of this blend, it is ground in its solid state to avoid or minimize the enrichment of active molecules in different parts of the lipid nanoparticles. SLN, Type II or drug enriched shell model It is achieved when SLN are produced by the hot technique, and the active ingredient concentration in the melted lipid is low during the cooling process of the hot o/w

5 Pragati S. et al. : Solid Lipid Nanoparticles: A promising Drug Delivery Technology 513 nanoemulsion the lipid will precipitate first, leading to a steadily increasing concentration of active molecules in the remaining melt, an outer shell will solidify containing both active and lipid. The enrichment of the outer area of the particles causes burst release. The percentage of active ingredient localized in the outer shell can be adjusted in a controlled shell model is the incorporation of coenzyme Q 10. SLN, Type III or drug enriched core model- Core model can take place when the active ingredient concentration in the lipid melt is high & relatively close to its saturation solubility. Cooling down of the hot oil droplets will in most cases reduce the solubility of the active in the melt. When the saturation solubility exceeds, active molecules precipitate leading to the formation of a drug enriched core. Analytical methods for characterization In order to develop a drug product of high quality, a precise physicochemical characterization of the SLNs is necessary (Cavalli R et al., 2000). The size of the nanoparticle is the most important feature; however other parameters such as density, molecular weight and crystallinity influence the nanoparticle release and degradation properties. Thus in vivo fate vis-à-vis body distribution and interaction with the body environment are however influenced by surface charge, hydrophilicity and hydrophobicity etc (Eldem T et al., 1991). Various analytical procedures which can be used to characterize SLNs in terms of their particle size, crystallinity and associated surface characteristics (Lim SJ et al., 2002; Dubes A. et al., 2003). The most prevailing method for particle size for determination until now is the photon correlation spectroscopy because of its speed. The mean and the polydispersity index (P.I.) can be calculated with the help of modern computer programmes but the presence of different particle sizes which may be dust, crystallization of ingredients, or secondary particle agglomerates can lead to erroneous results. To avoid these results other suitable methods like electron microscopy vis a vis TEM/SEM (Jores K et al., 2004 and Dubes A et al., 2003). These later methods are however time consuming hence photon correlation spectroscopy is the most useful and most prevalent method of particle size analysis (Westesen K et al., 1993). Crystallinity could be determined with the help of DSC, X-ray diffraction, thermal gravimetric analysis and thermal optical analysis. The crystallinity is important to be determined as the incorporated drug may undergo a polymeric transition. Coexistence of additional colloidal structures (micelles, liposomes, supercooled melts, drug-nanoparticles) can be ascertained with the use of technique like magnetic resonance technique, NMR and ESR (Mehnert W et al., 2001). Due to the different chemical shifts it is possible to attribute the NMR signals to particular molecules or their segments. Simple 1 H spectroscopy permits an easy and rapid detection of supercooled melts (Zimmermann E et al., 1999). ESR requires the addition of paramagnetic spin probes to investigate SLN dispersions. The corresponding ESR spectra give information about the microviscosity and microopolarity. ESR permits the direct, repeatable and noninvasive characterization of the distribution of the spin probe between the aqueous and the lipid phase (Westesen K et al., 1997). Experimental results demonstrate that storage induced crystallization of SLN leads to an explusion of the probe out of the lipid into the aqueous phase. ESR spectroscopy and imaging is expected to give new insights about the fate of SLN in vivo. In vitro and ex vivo methods for the assessment of drug release from SLNs In vitro drug release (Chen DB et al., 2001) o Dialysis tubing o Reverse dialysis o Franz diffusion cell Dialysis tubing- In vitro drug release could be achieved using dialysis tubing. The SLNs dispersions is placed in a prewashed dialysis tubing which can be hermetically sealed (Mullen A 1998). The dialysis sac is then dialyzed against a suitable dissolution medium at room temperature; the samples are withdrawn from the medium at suitable intervals, centrifuged and analyzed for drug content using a suitable method (U.V. spectroscopy, HPLC etc). The maintenance of sink condition is essential. Reverse dialysis- In this technique a number of small dialysis as containing 1 ml of dissolution medium are placed in SLN dispersion. The SLNs are then displaced into the dissolution medium. The direct dilution of the SLNs is possible with this method; however the rapid release cannot be quantified using this method (Muhlen A et al., 1998). Franz diffusion cell- The SLNs dispersions is placed in the donor chamber of a Franz diffusion cell fitted with a cellophane membrane. The dispersion is then dialyzed against a suitable dissolution medium at room temperature; the samples are withdrawn from the dissolution medium at suitable intervals and analyzed for drug content using a suitable method (U.V. spectroscopy, HPLC etc). The maintenance of sink condition is essential. Ex vivo model for determining permeability across the gut-by taking the tissue from animal and rinsing it to remove other contents after washing with ice cold standard ringer solution, cut it into segments, and mount side by side diffusion chambers with an exposed tissue area of 1 cm 2.

6 514 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 2 Issue 2 July - September 2009 SLNs loaded with drug placed on the mucosal side, dispersed in ringer containing the paracellular transporter sodium flourescein conferring for tissue integrity. Electrolyte- and ph-stabilities of aqueous solid lipid nanoparticle (SLN) (Zimmermann E et al., 2001) The influence of artificial gastrointestinal (GI) media on the physical stability of solid lipid nanoparticle (SLN) formulations consisting of different lipids and various surfactants/stabilizers have been investigated in vitro, with respect to ionic strength and ph. Laser diffractometry and zeta potential measurements were the techniques applied. Some SLN formulations already showed aggregation/particle growth in the presence of electrolytes at neutral ph (Ahlin P et al., 1998). Other lipid nanodispersions remained physically stable with respect to the influence of electrolytes, but were ph-sensitive. It was possible to produce SLN that were GIT (gastrointestinal tract) stable by an optimized stabilizer composition. There is no optimal surfactant mixture for stabilization of any lipid, e.g. SLN consisting of the lipid Cutina CP showed GIT stability in combination with the stabilizer sugar ester S1670, whereas the stabilization with the surfactant mixture Tween 80/Span 85 was not effective. Vice versa, the emulsifier Pluronic F68 stabilized the lipid Compritol ATO 888 but not the lipid Imwitor 900 sufficiently to avoid aggregation of the SLN dispersion in artificial GI media. The stabilizing properties depend obviously on the specific interactions of the lipid matrix with the emulsifier, e.g. anchoring of the stabilizer on the lipid surface and density on the surface. Advantages of Solid lipid nanoparticle The solid matrix provides highest flexibility in controlling the release profile. The slower degradation velocity in vivo (e.g. compared to liposomes) allows drug release for prolonged periods. Further by coating with or attaching ligands to SLNs there is a increased scope of drug targetting. High drug payload (Cavalli R et al., 2003). SLN formulation stable for even the years have been developed. This is of paramount importance with respect to the other colloidal carrier system (Freitas et al., 1998). SLNs particularly those in the range of nm are not taken up readily by the cells of the RES (Reticulo endothelial system) and thus bypass liver and spleen filtration. Excellent reproducibility with a cost effective high pressure homogenization method as the preparation procedure (Gohla SH et al., 2001). The feasibility of incorporating both hydrophilic and hydrophobic drugs (Fundro A et al., 2000 and Chen D et al., 2001). The solid matrix can (but need not) protect incorporated active ingredients/ drugs against chemical degradation. The carrier lipids are biodegradable and hence safe (Tabatt KSM et al., 2004) Avoidance of organic solvents (Cavalli et al., 2000) Feasible large scale production and sterilization (Muller RH et al., 2000) Solid Lipid Nanoparticle Stability (Freitas C et al., 1999) Lipid nanoparticle stability must be considered from two perspectives, the particle size distribution and the lipid crystalline state. Particle size is a critical safety factor for parenteral administration and self life, as noted previously. Particle size greatly affects biodistribution and RES clearance mechanisms. Particle size also affects the physical appearance of the product, since the human eye can only detect light scattered by particles that are greater than ~ 1. The degree of polydispersity can impact particle size growth via Ostwald ripening and can impact the overall drug release kinetics. The lipid crystalline state strongly correlates with drug incorporation, drug release, and the particle geometry (Mehnert W et al., 2001) Conclusion Lipid nanoparticle drug delivery technology presents significant opportunities for improving medical therapeutics, but the technology s potential remains unrealized. Several technology challenges remain unsolved: appropriate control of particle size and size distribution, short-term and long-term lipid crystallinity, drug loading profile, drug release kinetics, and greater control of biodistribution once. SLNs delivery can be an innovative way to administer molecules into the target site in a controlled manner by possibly overcoming or alleviating the solubility, permeability and toxicity problems associated with the respective drug molecules. High physical stability of these systems is another advantage. On the other hand the use of solid lipids as matrix material for drug delivery is well known from lipid pellets for oral drug delivery (Runge S et al., 1996). So SLNs is a new era technology which has been taken over by the pharmaceutical industry. The possibility of incorporating both the lipophillic and hydrophilic molecules and the possibility of the several administration make the SLNs delivery system all the more promising. SLNs will open a new channel for an effective delivery of a vast variety of drug molecules including analgesics, antitubercular, anticancerous, antiaging, antianxiety, antibiotics, and antiviral agents to the target site.

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