INTRODUCTION:

Solid lipid nanoparticles introduced in 1991 represent an alternative carrier system to traditional colloidal carriers such as emulsions, liposomes and polymeric micro and nanoparticles.[1] Solid lipid nanoparticles [SLN] consists of spherical solid lipid particles in the nanometer range, which are dispersed in water or in aqueous surfactant solution.

Fig 1: Structure of solid lipid nanoparticle [SLN]

The SLNs are submicron colloidal carriers [50-1000 nm] which are composed of physiological lipid, dispersed in water or in an aqueous surfactant solution. They are made of solid hydrophobic core having a monolayer of phospholipid coating. The solid core contains the drug dissolved or dispersed in the solid high melting fat matrix. They have a potential to carry lipophilic or hydrophilic drugs.[2,3]

ADVANTAGES:

1. Small size and relatively narrow size distribution which provide biological opportunities for site specific drug delivery.

2. Controlled release of active drug over a long period can be achieved.

3. Protection of incorporated drug against chemical degradation.

4. Possible sterilization by autoclaving or gamma irradiation.

5. SLNs can be lyophilized as well as spray dried.

6. No toxic metabolites are produced.

7. Avoidance of organic solvents.

8. Relatively cheaper and stable.

9. Ease of industrial scale production by hot dispersion technique.

10. Incorporation of drug can reduce distinct side effects of drug.[2]

DISADVANTAGES:

1. Poor drug loading capacity.

2. Drug expulsion after polymeric transition during storage.

3. Particle growth.

4. Unpredictable gelation tendency.[4]

METHODS OF PREPARATION:

1. High pressure homogenization

A. Hot homogenization

B. Cold homogenization

2. Ultrasonication/ high speed homogenization

A. Probe ultrasonication

B. Bath ultrasonication

3. Solvent evaporation method

4. Solvent emulsification-diffusion method

5. Supercritical fluid method

6. Microemulsion based method

7. Spray drying method

8. Double emulsion method

9. Precipitation technique

10. Film-ultrasound dispersion

1. High pressure homogenization:

It is a reliable and powerful technique, which is used for the production of SLNs. High pressure homogenizers push a liquid with high pressure [100–2000 bar] through a narrow gap [in the range of a few microns]. The fluid accelerates on a very short distance to very high velocity [over 1000 Km/h]. Very high shear stress and cavitation forces disrupt the particles down to the submicron range.

Two general approaches of HPH are hot homogenization and cold homogenization, work on the same concept of mixing the drug in bulk of lipid melt.[5]

A. Hot homogenization:

A pre-emulsion of the drug loaded lipid melt and the aqueous emulsifier phase [same temperature] is obtained by high-shear mixing device. HPH of the pre-emulsion is carried out at temperatures above the melting point of the lipid. In general, higher temperatures result in lower particle sizes due to the decreased viscosity of the inner phase. However, high temperatures increase the degradation rate of the drug and the carrier.[2]

B. Cold Homogenization:

In this technique the drug containing lipid melt is cooled, the solid lipid ground to lipid microparticles and these lipid microparticles are dispersed in a cold surfactant solution yielding a pre-suspension. Then this pre-suspension is homogenized at or below room temperature, the gravitation force is strong enough to break the lipid microparticles directly to solid lipid nanoparticles.[2]

2. Ultrasonication/ high speed homogenization:

SLNs are also prepared by ultrasonication or high speed homogenization techniques. For smaller particle size combination of both ultrasonication and high speed homogenization is required. There are two types of ultrasonication are Probe ultrasonication and Bath ultrasonication.

3. Solvent evaporation method

The lipophilic material is dissolved in a water-immiscible organic solvent [e.g. cyclohexane] containing drug that is emulsified in an aqueous phase. Upon evaporation of the solvent, nanoparticles dispersion is formed by precipitation of the lipid in the aqueous medium by giving the nanoparticles of 25 nm mean size. The solution was emulsified in an aqueous phase by high pressure homogenization.

4. Solvent emulsification-diffusion method:

Here, the lipid matrix is dissolved in water-immiscible organic solvent followed by emulsification in an aqueous phase. The solvent is evaporated under reduced pressure resulting in nanoparticles dispersion formed by precipitation of the lipid in aqueous medium

5. Supercritical fluid method:

This is a novel technique recently applied for the production of SLNs. A fluid is termed supercritical when its pressure and temperature exceed their respective critical value. The ability of the fluid to dissolve compound increases. Carbon dioxide solution is the good choice as a solvent for this method.

6. Microemulsion based method:

SLNs can be produced by microemulsification of molten lipids, as the internal phase and subsequent dispersion of the microemulsion in aqueous medium under mechanical stirring. Microemulsions are clear, thermodynamically stable, microheterogeneous dispersions usually obtained by mixing oil, water, surfactant and co-surfactant. Rapid crystallization of oil droplet on dispersion in cold aqueous medium produces lipid nanoparticles with solid matrix.

7. Spray drying method:

The lipid is first dissolved in a suitable volatile organic solvent. The drug in the solid form is then dispersed in the solution under high speed homogenization. This dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which solvent evaporates instantaneously to form SLNs.

8. Double emulsion method:

This method is the modification of emulsion solvent evaporation. Organic phase solvent, drug, distilled water are forms the W/O emulsion by sonication or homogenization and stabilized at 4^oC. Adding the aqueous phase with stabilizer to form double emulsion W/O/W. Evaporation of solvent to form SLNs. Wash and lyophilized.

9. Precipitation method:

The glycerides are dissolved in an organic solvent [e.g. chloroform] and the solution will be emulsified in an aqueous phase. After evaporation of the organic solvent the lipid will be precipitated forming nanoparticles.

10. Film-ultrasound dispersion:

The lipid and the drug were put into suitable organic solutions, after rotation and evaporation of the organic solutions, a lipid film is formed, then the aqueous solution which includes the emulsions was added. Using the ultrasound with the probe to diffuser at last, the SLN with the little and uniform particle size is formed.[5,6]

CHARACTERIZATION:

1. Particle size:

The physical stability of SLNs depends on their particle size. Photon correlation spectroscopy [PCS] and laser diffraction [LD] are the most powerful techniques for determination of particle size. PCS [also known as dynamic light scattering] measures the fluctuation of the intensity of the scattered light, which is caused by particle movement. The particle size determination by photon correlation spectroscopy [PCS] detects size range of 3nm to 3μm and by laser diffraction in size range of 100 nm to 180 μm. Also other methods used are as shown below.

· Atomic force microscopy [AFM]

· Electron Microscopy

§ Scanning electron microscopy [SEM]

§ Transmission electron microscopy [TEM]

2. Zeta potential:

Zeta potential measurement can be carried out using zeta potential analyzer or zetameter.

3. Physical properties:

· Crystallinity- X-ray diffraction

· Thermal analysis- Differential thermal analysis [DTA]

· Differntial scanning calorimetry [DSC]

4. Determination of incorporated drug:

The amount of drug encapsulated per unit wt. of nanoparticles is determined after separation of the free drug and solid lipids from the aqueous medium. Determine drug concentration by spectrophotometry. Drug content also determined by extracting with suitable solvent and carrying out analysis of extract.

5. Rheology:

Rheological measurement can be conducted in a Brookefield Viscometer.

6. Storage stability:

The physical stability of the SLNs during prolonged storage can be determined by monitoring changes in particle size, drug content, appearance, viscosity as a function of time.

7. In-vitro drug release studies:

Release profile of drug can be conducted in dialysis tubing. The SLN dispersion is introduced into prewashed dialysis tubing, and dialyzed against dissolution medium at constant temperature with constant stirring. The release drug diffuses through dialysis membrane. Samples from dissolution membrane are taken at discrete times, and assay for drug content.[4-6]

APPLICATIONS:

1. SLN as potential new adjuvant for vaccines: Adjuvants are used in vaccination to enhance the immune response. The safer new subunit vaccines are less effective in immunization and therefore effective adjuvants are required.

2. SLN in cancer chemotherapy: To improve the efficacy of chemotherapeutic drugs, simultaneously reduction in side effects associated with them. Improved stability of drugs, encapsulation of chemotherapeutic agents of diversified physicochemical properties, enhanced drug efficacy, improved pharmacokinetics and less in-vitro toxicity are the important features of SLN which make them a suitable carrier for delivering chemotherapeutic drugs.

3. SLN for delivering peptides and proteins: Solid lipid particulate systems such as solid lipid nanoparticles [SLN], lipid microparticles [LM] and lipospheres have been sought as alternative carriers for therapeutic peptides, proteins and antigens.

4. SLN for targeted brain drug delivery: SLNs can improve the ability of the drug to penetrate through the blood-brain barrier and is a promising drug targeting system for the treatment of central nervous system disorders.

5. SLN for parasitic diseases: Parasitic diseases [like malaria, leishmaniasis, tryanosomiasis] are one of the major problems around the globe. Solid lipid nanoparticles [SLNs] and nanostructured lipid carriers [NLCs] due to their particulate nature and inherent structure exhibit good potential in the treatment of parasitic infections.

6. SLN for ultrasonic drug and gene delivery: Ultrasonic drug delivery from micelles usually employs polyether block copolymers and has been found effective in vivo for treating tumors. Ultrasound releases drug from micelles, most probably via shear stress and shock waves from the collapse of cavitation bubbles. Liquid emulsions and solid nanoparticles are used with ultrasound to deliver genes in vitro and in vivo.

7. SLN for improved delivery of antiretroviral drugs to the brain: Studies have shown that nanocarriers including polymeric nanoparticles, liposomes, solid lipid nanoparticles [SLN] and micelles can increase the local drug concentration gradients, facilitate drug transport into the brain via endocytotic pathways and inhibit the ATP-binding cassette [ABC] transporters expressed at the barrier sites. By delivering ARVs with nanocarriers, significant increase in the drug bioavailability to the brain is expected to be achieved.

8. SLN applied to the treatment of malaria: Nanosized carriers have been receiving special attention with the aim of minimizing the side effects of drug therapy, such as poor bioavailability and the selectivity of drugs. Several nanosized delivery systems have already proved their effectiveness in animal models for the treatment and prophylaxis of malaria.

9. Targeted delivery of SLN for the treatment of lung diseases: By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems.

10. SLN in tuberculosis disease: SLN have been used to encapsulate Anti Tubercular Drugs [ATD] and were proved to be successful in experimental tuberculosis. Antitubercular drugs such as rifampicin, isoniazid, and pyrazinamide SLN systems were able to decrease the dosing frequency and to improve patient compliance.

11. Transfection agent: Cationic SLNs for gene transfer are formulated using the same cationic lipid as for liposomal transfection agents. The differences and similarities in the structure and performance between SLN and liposomes were investigated.

12. SLN in cosmetic and dermatological preparations: An area of big potential for SLN and with a short time-to market are topical products based on the SLN technology, that means pharmaceutical but also cosmetic formulations. SLN are considered as being the next generation of delivery system after liposomes.

13. SLN for lymphatic targeting: The solid lipid nanoparticles [SLN] were developed and evaluated for the lymphatic uptake after intraduodenal administration to rats.

14. SLN for potential agriculture applications: Essential oil extracted from Artemesia arboreseens L when incorporated into SLN, were able to reduce the rapid evaporation compared with emulsions and the systems have been used in agriculture as suitable carrier of safe pesticides.[6,7]

CONCLUSION:

Solid lipid nanoparticles represent a particulate system which can be produced with an established technique. They present an interesting approach to the administration of poorly water soluble drugs. SLN are very complex systems with clear advantages and disadvantages to other colloidal carriers. Further work needs to be done to understand the structure and dynamics of SLN on molecular level in vitro and in vivo studies.

REFERENCES:

1. Vijayan V, Aafreen S, Sakthivel S, Reddy K [2013]. Formulation and characterization of solid lipid nanoparticles loaded Neem oil for topical treatment of acne. Elsevier Journal of Acute Disease, pp- 282-286.

2. Vyas SP, Khar RK [2012]. Targeted and Controlled Drug Delivery, novel carrier systems. CBS Publishers & Distributors, pp- 15-16, 346-348.

3. Donald LW [2005]. Handbook of Pharmaceutical controlled release technology. Marcel Dekker, pp- 377-391.

4. Jain NK [2011]. Advances in controlled and novel drug delivery. CBS Publishers & Distributors, pp- 408-423.

5. Ekambaram P, Abdul A, Sathali H, Priyanka K [2012]. Solid Lipid Nanoparticles: A Review. Scientific Reviews and Chemical Communications. 2[1]: 80-102.

6. Garud A, Singh D, Garud N [2012]. Solid Lipid Nanoparticles [SLN]: Method, Characterization and Applications. International Current Pharmaceutical Journal. 1[11]: 384-393.

7. Patil J, Gurav P, Kulkarni R, Jadhav S, Mandave S, Shete M, Chipade V [2013]. British Biomedical Bulletin. 1[2]: 103-118.

Received on 19.09.2014 Modified on 01.10.2014

Res. J. Pharm. Dosage Form. and Tech. 6(4):Oct.- Dec.2014; Page 282-285