INTRODUCTION:

Drug delivery system governs the stability, release, dissolution rate and the systemic absorption of the drug. For a drug to show optimum pharmacological effect it should be given in a proper dosage form. The dosage form should have the capacity to increase the stability of the unstable drugs, site specific action, reduction of toxicity and it should be economic.

The overall performance of the drug not only depends on its activity but also depends on the dosage form in which it is delivered. In conventional drug delivery system the reasons for therapy failure include insufficient drug concentration, poor drug solubility and high fluctuation of plasma levels due to unpredictable bioavailability after peroral administration.

Hence a high potential for drug delivery has been attributed to particulate drug carriers, especially small particles such as microparticles and colloidal system of nanometer range. Colloidal carriers have attracted increasing attention during recent years. They include nanoemulsions, nanosuspensions, micelles, soluble polymer-drug conjugated polymeric nanoparticles, lipid based carriers such as liposomes and solid-lipid nanoparticles.

The era of nanotechnology has revolutionized the drug delivery system and persuades new research strategies to flourish. Nanoparticulate drug delivery system may offer plenty of advantages over conventional dosage forms which include improved, reduced toxicity, enhanced biodistribution and improved patient compliance. Colloidal particles ranging in size between 10 to 1000nm are known as nanoparticles. They are solid polymeric and sub micronic colloidal system and are manufactured from synthetic or natural polymers and ideally optimized to suit drug delivery and reduced toxicity. Over the years, they have emerged as a variable substitute to liposomes as drug carriers. The successful implementation of nanoparticles for drug delivery depends on their ability to penetrate through several anatomical barriers, sustained release of their contents and their stability in the nanometer size. However, the scarcity of safe polymers with regulatory approval and their high cost have limited the wide spread application of nanoparticles to clinical medicine.

To overcome these limitations of polymeric nanoparticles, lipids have been put forward as an alternative carrier, particularly for lipophilic pharmaceuticals. These lipid nanoparticles are known as solid lipid nanoparticles (SLNs). They are one of the novel potential carrier systems in the range of 100-150nm as alternative materials to polymers which is identical to oil in water emulsion for parenteral nutrition, but the liquid lipid of the emulsion is replaced by a solid lipid.

Fig. 1: Structure of solid lipid nanoparticle (SLN)

Fig. 2: A diagrammatic representation on SLN over emulsions and liposomes

SLNs are considered to be the most effective lipid based colloidal carriers and is one of the most popular approaches to improve the oral bioavailability of the poorly water soluble drugs. They are composed of physiologically tolerated lipid components which are in solid state at room temperature. They have many advantages such as good biocompatibility, low toxicity and lipophilic drugs are better delivered by solid lipid nanoparticles and the system is physically stable^1-5.

ADVANTAGES OF SOLID LIPID NANOPARTICLES:

SLNs combine the advantage of polymeric nanoparticles, fat emulsions and liposomes;

1. Controlled release of the incorporated drug can be achieved for several weeks. Further by coating or by attaching ligands to SLNs, there is an increased scope of drug targeting.

2. The nanoparticles and SLNs particularly those in range between 120-200nm are not taken up by the cells of the RES (Reticulo Endothelial System) and thus bypass liver and spleen filtration.

3. Excellent biocompatibility.

4. No toxic metabolites are produced.

5. Very very high longterm stability or improved stability of pharmaceuticals.

6. High and enhanced drug content.

7. Excellent reproducibility with cost effective pressure homogenization method as the preparation procedure.

8. No special solvent required.

9. High drug pay load.

10. The feasibility of incorporating both hydrophilic and hydrophobic drugs.

11. Much easier to manufacture than bio-polymeric nanoparticles.

12. Easy to scale up and it can be subjected to commercial sterilization procedures.

13. Conventional emulsion manufacturing methods applicable.

14. It can be freeze dried to form powdered formulation.

15. Application versatility.

16. Avoidance of organic solvents.

17. Reduces the number of doses required.

DISADVANTAGES OF SOLID LIPID NANOPARTICLES:

Potential disadvantages of solid lipid nanoparticles are such as;

1. Poor drug loading capacity.

2. Drug explusion after polymeric transition during storage.

3. Relatively high water content of the dispersions.

4. Particle growth.

5. Unpredictable gelation tendency.

6. Unexpected dynamics of polymeric transitions^1,3-7.

UPTAKE OF SOLID LIPID NANOPARTICLES:

The majority of orally administered drugs gain access to the systemic circulation by absorption into the portal blood. However, some extremely lipophilic drugs (log P > 5, solubility in TG > 50 mg/ml) gain access to the systemic circulation via lymphatic route, which avoids hepatic first pass metabolism. Therefore, highly metabolized lipophilic drugs may be potential candidates for solid lipid nanoparticles, a lipid based delivery. Compounds showing increased bioavailability in the presence of lipids (dietary or lipid-based formulation) are absorbed via the intestinal lymph as they are generally transported in association with the long chain TGs lipid core of intestinal lipoproteins formed in the enterocyte after re-esterification of free FAs and MGs short chain TGs are primarily absorbed directly in the portal blood. Hence it is likely that the drug transport via the lymphatic formation.

The lymph fluid is emptied (average 3 L per day) via thoracic duct into the subclavian vein, thus protecting the drug from hepatic first-pass metabolism. The drug being transported in the circulatory system, in the form of either micelles or mixed micelles, may then be available in its free form, since upon dilution with a large volume of lymph/blood, surfactant concentration may reduce below its CMC value and micelle may dissociate into monomers. The drug transported as lipid vesicles may remain intact for extended periods and, thereby, can result in the prolonged release of the encapsulated drug.

MECHANISM OF ORAL ABSORPTION ENHANCEMENT:

Few mechanisms are described in enhancing the oral bioavailability of drug molecules by SLNs:

a) Dissolution/solubilisation:

SLNs entering into the GIT, stimulates the gallbladder contractions and biliary and pancreatic secretions, including bile salts (BS), phospholipids(PL) and cholesterol, due to the lipids present in the formulation. These products, along with the gastric shear movement, form a crude emulsion which promotes the solubilisation of the coadministered lipophilic drug. Further, the surface active agents present in the SLNs may further stimulate the solubilization of the lipophilic compound.

b) Affecting intestinal permeability:

A variety of lipids have been shown to change the physical barrier function of the gut wall and hence, enhance the permeability.

c) Prevent first pass metabolism:

Solid lipid nanoparticles have been reported to enhance oral bio availability of certain highly lipophilic drugs by accessing to systemic circulation via lymphatic route hence preventing their first pass metabolism.

d) Gastric residence time:

Lipids in the GI tract provoke delay in gastric emptying which result in increased residence time of the coadministered lipophilic drug in the small intestine. This enables better dissolution of the drug at the absorptive site, and thereby improves absorption.

MECHANISM OF DRUG RELEASE FROM SLN:

To develop controlled release SLN one needs to understand the drug release mechanism to allow a controlled development of formulations. At the very beginning of SLN development particles were produced using model drugs with different physiochemical properties, e.g. lipophilicity and hydrophilicity. Examples for lipophilic drugs studied were tetracain base29 and etomidate base30, but also very hydrophilic drugs such as the ray contrast agent iotrolan produced by Schering AG in berlin31. For tetracain and etomidate a burst release was observed. Study was done on the extent to which x- the burst release depends on particle size/ surface area. It was found that the burst release diminished with increasing particle size and prolonged release could be obtained when the particles were sufficiently large, i.e. lipid macroparticles. From this it was concluded the drug was enriched in an outer shell of the particles. This lead to the core shell model of SLN with enriched drug in an outer shell. The drug has a relatively short distance of diffusion and will be released in a burst. The formation of the shell is explained by the stepwise crystallization process of the drug-lipid mixture. After the hot homogenization step the produced o/w emulsion is cooled, the lipid precipitates first forming a more or less drug-free lipid core. The remaining liquid drug-lipid mixture will enrich continuously in drug content until the eutectum is reached. Reaching the eutecticum leads to the simultaneous crystallization of lipid and drug, forming an outer shell surrounding the drug- free lipid core.

In addition, it must be considered that surfactant is present. This surfactant will interact with the outer shell and affect its structure. The existence of a shell can be proven by atomic force microscopy (AFM) measurements. With a special technique, noncontact imaging, the hardness of the particle is determined by pressing the cantilever of the AFM instrument into the particle. The force required to press the contilever into the particle is a measure of the viscosity of the particle matrix. It can be shown that there is an outer shell of relatively low viscosity that is composed of lipid, drug and partially incorporated surfactant. That means the model could be specific to be the soft shell-hard core model. The prolonged release can be explained by molecular distribution of the drug in the lipid matrix. The very interesting feature is that the release profile changes with production parameters and also changes by using a different lipid. A slow release without distinct burst was obtained by applying the cold homogenization technique. This was attributed to the presence of a solid solution, i.e., prednisolon was distributed in a molecular dispersed form homogeneously in the solid lipid matrix. This is very likely because cooling the drug-containing lipid will lead to the formation of a solid dispersion.

This dispersion was just milled by high pressure homogenization, which means that no or limited melting occurred; the particles were just broken down and retained their structure of a solid dispersion. Of course, we all are aware of the fact that temperature peaks occur during the homogenization process. In addition, there will be a warming up of the dispersion by approximately 20ºC. However, this does not lead to a melting if the difference between reached temperature and melting point of the lipid is sufficiently high. Based on these results, the existence of a solid dispersion model for SLN was proposed. Drug release is governed by diffusion of the drug in the solid matrix (solid phase diffusion). Producing prednisolon-loaded SLN by the hot homogenization technique led to a burst release followed by a prolonged release. The burst release was intensively investigated by changing the production parameters (temperature) and changing the composition of the SLN formulation (that means preferentially surfactant concentration). It was found that the extent of burst release increased with increasing temperature and increasing surfactant concentration. With increasing temperature and increasing surfactant concentration, the solubility of the drug in the water phase increased. Applying the hot homogenization technique lead to an o/w emulsion. At high temperature the solubility of prednisolone in the outer aqueous phase was higher. Cooling down the emulsion lead to the precipitation of the drug containing lipid core; simultaneously, the solubility of the prednisoline in the water phase led to the drug enrichment in the outer shell of the SLN.

Table no 1: Emulsifiers and lipids used for solid lipid nanoparticles:

LIPIDS	EMULSIFIERS/ COEMULSIFIERS
LIPIDS	NAME	HLB
Triglycerides:
Trimyristin (Dynasan 114)	Lecithin	4-9
Tripalmitin (Dynasan 116)	Poloxamer 188	29
Tristearin (Dynasan 118)	Poloxamer 407	21.5
Mono, di and triglycerides mixtures	Tyloxapol	13
Witeposol bases:
Glyceryl monostearate (Imwitor 900)	Polysorbate 20	16.7
Glyceryl behenate (Compritol 888 ATO)	Polysorbate 60	14.9
Glyceryl palmitostearate (Precirol ATO 5)	Polysorbate 80	15
Waxes:		18
Beeswax	Sodium cholate	14.9
Cetyl palmitate	Sodium glycocholate	13-14
Hard fats:	Taurodeoxycholic acid sodium
Stearic acid	Butanol and Butyric acid	7-9
Palmitic acid	Cetylpyridinium chloride	~15
Behenic acid	Sodium dodecyl sulphate	40
Other lipids:	Sodium oleate	18
Miglyol 812	Polyvinyl alcohol	15-19
Paraffin	Cremophor EL	12-14

The better the prednisoline solubility in the water phase, the higher was the enrichment in the outer shell of the SLN. That means the burst release consequently needed to be increased with increased production temperature and increased surfactant concentration. When replacing the cold homogenization technique with the hot homogenization technique, one moves away from the solid dispersion again to the core shell type of SLN. This presents the possibility for an optimal design of drug release profile. If an initial dose is required, one can adjust the production parameters and/or the formulation composition (surfactant concentration) to obtain exactly the initial burst release required. Applying the hot homogenization technique and simultaneously using low surfactant concentration leads to the minimal burst and a prolonged drug release. Recently it was discovered that there is additionally the hard shell core model of SLN. Within an industrial product development the SLN were loaded with coenzyme Q10. The Q10-loaded SLN were routinely investigated by contact AFM. It was assumed that a solid dispersion of Q10 in lipid would be present. Contact AFM revealed that there was an outer shell of increased rigidity; the core was distinctly less rigid. Q10 was released relatively fast. Obviously the Q10 had accumulated in the outer shell but promoted crystallization of the lipid. Possibly Q10 and the lipid had structural properties such that they fitted together very well to form a solid structure (like brick layers). It could be possible that the molecule Q10 fitted into the imperfections of the lipid, leading to a more solid structure. Due to the location of Q10 in the outer shell the drug release was fast, but the presence of Q10 led to a more solid state of the lipid leading to a firm outer shell.

To summarize, at present there are four different models of internal SLN structure proposed;

1) Soft drug-containing shell core model.

2) Drug core/lipid shell model.

3) Solid dispersion model.

4) Drug-free core/hard drug-containing shell model.

The different models shows that drug incorporation into SLN is complex, but at the same time the variety of models gives highest flexibility to modulate drug release if one is able to control the SLN structure formed during production. Knowledge of how to control this process is the major advantage of the companies having the adequate knowledge of SLN production^1-7.

EMULSIFIERS AND LIPIDS USED FOR SOLID LIPID NANOPARTICLES:

Various emulsifiers and lipids used in the formulation of solid lipid nanoparticles are listed in the table no 1.

PREPARATION OF SOLID LIPID NANOPARTICLES:

The various methods used for the preparation of solid lipid nanoparticles are listed below^4,7-12:

HIGH PRESSURE HOMOGENIZATION:

HPH is suitable method for preparation of SLN, NLC, and LDC and can be performed at elevated temperature (hot HPH technique) or at below room temperature (cold HPH technique). The particle size is decreased by cavitations and turbulences. In high pressure homogenization technique lipids are pushed with high pressure (100-200 bars) through a narrow gap of few micron ranges. So shear stress and cavitation (due to sudden decrease in pressure) are the forces which cause the disruption of particle to submicron range. Normally the lipid contents are in the range of 5-10%. At this concentration it does not cause any problem to homogenizer. High pressure homogenization does not show any scaling up problem. Basically, there are two approaches for SLN production by high pressure homogenization, hot and cold homogenization techniques.

Fig. 4: High Pressure Homogenization

1. HOT HOMOGENIZATION:

For the hot homogenization technique the drug loaded melted lipid is dispersed under stirring by high shear device (e.g. Ultra Turrax) in the aqueous surfactant solution of identical temperature. The pre-emulsion obtained is homogenized by using a piston gap homogenizer (e.g. Macron LAB 40 or Macron LAB 60 or APV-2000) and the produced hot o/w nanoemulsion is cooled down to room temperature. At room temperature the lipid recrystallizes and leads to formation of SLN.

Fig. 5: Solid lipid nanoparticles preparation by hot homogenization process

2. COLD HOMOGENIZATION:

Cold homogenization is carried out with the solid lipid containing drug and therefore called as milling of a suspension. Cold homogenization has been developed to prevent: Temperature induced drug degradation, Partitioning of hydrophilic drug from lipid phase to aqueous phase. Complexity of the crystallization step of the nanoemulsion leading to several Modifications and/or super cooled melts. The first step of preparation is same as hot homogenization which includes dispersion or dissolving or solubilisation of the drug in the melted lipid. Then the drug lipid mixture is rapidly cooled either by means of liquid nitrogen or dry ice. The drug containing

Fig. 6: Solid lipid nanoparticles preparation by cold homogenization process

solid lipid is milled by means of mortar or ball mill to micron size (50-100 micron) and these microparticles are dispersed in chilled emulsifier solution yielding a pre-suspension. Then this pre-suspension is subjected to high pressure homogenization at room or below room temperature, where the cavitation force is strong enough to break the microparticles to SLNs. This process avoids or minimizes the melting of lipid and therefore minimizing loss of hydrophilic drug to aqueous phase. Another method to minimize the loss of hydrophilic drug to aqueous phase is to replace water with other media (e.g. oil or PEG 600) with low solubility for the drug. In comparison to hot homogenization, in cold homogenization particle size and polydispersity index (broader size distribution) are more. The cold homogenization only minimizes the thermal exposure of drug, but it does not do so completely due to melting of the lipid/drug mixture in the first step of preparation.

Advantages

· Low capital cost.

· Demonstrated at lab scale.

Disadvantages

· Energy intensive process.

· Demonstrated at lab scale Biomolecule damage.

· Polydisperse distributions.

· Unproven scalability.

MICROEMULSION BASED SLN PREPARATION:

Microemulsion was an optically transparent mixture at 65-70°c or a slightly bluish solution, which is typically composed of a low melting lipid, an emulsifier(s), co-emulsifier(s) and water. When the hot microemulsion is dispersed in cold water (2-3°c) under constant stirring, precipitation of the lipid phase takes place, forming fine particles smaller than 300nm. A typical volume ratio of the hot microemulsion to cold water is usually in the range of 1:25 to 1:50. The excess water is removed by ultra-filtration in order to increase the particle concentration and remove excess of emulsifier(s) residue. Considering microemulsions, the temperature gradient and pH value fix the product quality in addition to the composition of the microemulsion. High temperature gradients facilitate rapid lipid crystallisation and prevent aggregation.

Fig. 7: Microemulsion method to prepare SLN

Advantages

· Low mechanical energy input.

· Theoritical stability.

Disadvantages

· Extremely sensitive to change.

· Labour intensive formulation work.

· Low nanoparticle concentrations.

SOLVENT EMULSIFICATION-EVAPORATION TECHNIQUE:

In solvent emulsification-evaporation method, the lipophilic material and hydrophobic drug was dissolved in a water immiscible organic solvent (e.g. cyclohexane, dichloromethane, toluene, chloroform) and then that is emulsified in an aqueous phase using high speed homogenizer. To improve the efficiency of fine emulsification, coarse emulsion was passed through the microfluidizer. Thereafter, the organic solvents were evaporated by mechanical stirring at room temperature and reduced pressure (e.g. rotary evaporator) leaving lipid precipitates of SLNs. Here the mean particle size depends on the concentration of lipid in organic phase. Very small particle size could be obtained with low lipid load (5%) related to organic solvent. The great advantage of this technique is the avoidance of any thermal stress, which makes it suitable for the incorporation of highly thermolabile drugs. A clear disadvantage is the use of organic solvent which may interact with drug molecules and limited the solubility of the lipid in the organic solvent.

Advantages

· Scalable.

· Mature technology.

· Continuous process.

· Commercially demonstrated.

Disadvantages

· Extremely energy intensive process.

· Polydisperse distributions.

· Biomolecule damage.

SOLVENT EMULSIFICATION-DIFFUSION TECHNIQUE:

In solvent emulsification-diffusion technique, the solvent used (e.g. benzyl alcohol, butyl lactate, ethyl acetate, isopropyl acetate, methyl acetate) must be partially miscible with water and this technique can be carried out either in aqueous phase or in oil. Initially, both the solvent and water were mutually saturated in order to ensure the initial thermodynamic equilibrium of both liquid. Then, the lipid is dissolved in the water-saturated solvent and subsequently emulsified with solvent-saturated aqueous surfactant solution at elevated temperatures. The SLN precipitate after addition of excess water (typical ratio 1:5 – 1:10) due to diffusion of the organic solvent from the emulsion droplets to the continuous phase.

ULTRASONICATION OR HIGH SPEED HOMOGENIZATION:

SLN were developed by high speed stirring or sonication. The major advantages are that, equipment whatever used here is very common in every lab. The problem of this method is broader particle size distribution ranging into micrometer size. This leads to physical instabilities likes particle growth upon aging. Potential metal contamination due to ultrasonication is also a big problem in this method. So, for making a stable formulation, studies have been performed by various research groups combining high speed stirring and ultrasonication at high temperature. This can be achieved by using less than 1% lipid concentration and high surfactant concentration.

Advantages

· Reduced shear stress.

Disadvantages

· Potential metal contamination.

· Physical instability like particle growth upon storage.

Fig. 8: Systematic representation for emulsification-diffusion method

MELTING DISPERSION METHOD (HOT MELT ENCAPSULATION METHOD):

The melting dispersion method is as follows, in first step, drug and solid lipid were melted in an organic solvent regarded as oil phase and simultaneously water phase also heated to same temperature as oil phase. Then in second step, the oil phase added into a small volume of water phase and the resulting emulsion was stirred at higher rpm for few hours. At last it was cooled down to room temperature to give SLNs. The last step was same as solvent emulsification evaporation method except in melting dispersion method no organic solvent had to be evaporated. Reproducibility was less than that of solvent emulsification-evaporation method but more than ultrasonication method.

DOUBLE EMULSION TECHNIQUE:

For the preparation of hydrophilic loaded SLN, a novel method based on solvent emulsification-evaporation has been used. Here the drug is encapsulated with a stabilizer to prevent drug partitioning to external water phase during solvent evaporation in the external water phase of w/o/w double emulsion. This method is particularly used for achieving high incorporation of hydrophilic molecule.

MEMBRANE CONTACTOR TECHNIQUE:

It is a novel technique to prepare the SLN. In membrane contactor technique the liquid phase was pressed at a temperature above the melting point of the lipid through the membrane pores (Kerasep ceramic membrane with an active ZrO₂ layer on an AlO₂-TiO₂ support) allowing the formation of small droplets. The aqueous phase was stirred continuously and circulated tangentially inside the membrane module, and sweeps away the droplets being formed at the pore outlets. SLNs were formed by the cooling of the preparation at the room temperature. Here both the phases were placed in the thermo stated bath to maintain the required temperature and nitrogen was used to create the pressure for the liquid phase.

SUPERCRITICAL FLUID TECHNOLOGY:

This is a relatively new technique for SLN production and has the advantage of solvent-less processing. There are several variations in this platform technology for powder and nanoparticle preparation. SLN can be prepared by the Rapid Expansion of Supercritical carbon dioxide Solutions (RESS) method. Carbon dioxide (99.99%) was good choice as a solvent for this method.

Advantages

· Avoids the use of solvents.

· Particles are obtained as a dry powder, instead of suspensions.

· Mild pressure and temperature conditions.

· Carbon dioxide solution is the good choice as a solvent for this method.

SPRAY DRYING METHOD:

It’s an alternative procedure to Lyophilization in order to transform an aqueous SLN dispersion into a drug product. It’s a cheaper method than Lyophilization. This method cause particle aggregation due to high temperature, shear forces and partial melting of the particle. Freitas and Mullera recommends the use of lipid with melting point >70 °C for spray drying. The best result was obtained with SLN concentration of 1% in a solution of trehalose in water or 20% trehalose in ethanol-water mixtures (10/90 v/v).

APPLICATIONS OF SOLID LIPID NANOPARTICLES:

Per oral administration:

Per oral administration forms of SLN may include aqueous dispersions or SLN loaded traditional dosage forms, e.g. tablets, pellets or capsules. The microclimate of the stomach favours particle aggregation due to the acidity and high ionic strength. It can be expected, that food will have a large impact on SLN performance, and however, no experimental data have been published on this issue. The question concerning the influence of the stomach and pancreatic lipases on SLN degradation invivo remains open, too. The plasma levels and body distribution were determined after administration of CA–SLN suspension versus a CA solution (CA-SOL). Two plasma peaks were observed after administration of CA–SLN. The first peak was attributed to the presence of free drug; the second peak can be attributed to controlled release or potential gut uptake of SLN. These two peaks were also found in the total CA concentration–time profiles of all measured organs. It was also found that the incorporation into SLN protected CA from hydrolysis. The conclusion from this study was that SLN are a promising sustained release system for CA and other lipophilic drugs after oral administration. Increased bioavailability and prolonged plasma levels have been described after per oral administration of cyclosporine containing lipid nanodispersions to animals. An increased uptake of SLN into the lymph has been described by Bargoni after intraduodenal administration.

Parenteral administration:

SLN have been administered intravenously to animals. Pharmacokinetic studies of doxorubicin incorporated into SLN showed higher blood levels in comparison to a commercial drug solution after i.v. injection in rats. Concerning the body distribution, SLN were found to cause higher drug concentrations in lung, spleen and brain, while the solution led to a distribution more into liver and kidneys. Parenteral application is a very wide field for SLN. Subcutaneous injection of drug loaded SLN can be employed for commercial aspect, e.g., erythropoietin (EPO), interferon-β. Other routes are intraperitonial and also intra-articular. Intraperitoneal application of drug-loaded SLN will prolong the release because of the application area. In addition, incorporation of the drug into SLN might reduce irritancy compared to injecting drug micro particles. Possible applications for intra-articular applications are treatment of arthritis. Arthritis inflammation in joints is caused by hyper activation of the macrophages releasing inflammation mediators. The basic concept is to give corticoids to the macrophages to reduce their hyperactivity. Corticoids are generally poorly soluble in water; incorporation in a lipophilic matrix is therefore possible. Macrophages can internalize the SLN. Release of corticoid will follow, leading to a reduction in hyperactivity and consequently inflammation of the joint. Another broad application area is intra venous injection. Critical excipients like Cremophor EL can lead to anaphylactic reactions; administration of the product can only be performed by applying medical precautions. The adsorption of a blood protein onto particle surfaces is supposed to be responsible for the uptake of SLN by the brain by mediating the adherence to the endothelial cells of the blood–brain barrier.

Transdermal application:

The smallest particle sizes are observed for SLN dispersions with low lipid content (up to 5%). Both the low concentration of the dispersed lipid and the low viscosity are disadvantageous for dermal administration. In most cases, the incorporation of the SLN dispersion in an ointment or gel is necessary in order to achieve a formulation which can be administered to the skin. The incorporation step implies a further reduction of the lipid content. An increase of the solid lipid content of the SLN dispersion results in semisolid, gel like systems, which might be acceptable for direct application on the skin. Unfortunately, in most cases, the increase in lipid content is connected with a large increase of the particle size. Surprisingly it has been found that very high concentrated (30–40%), semisolid cetyl palmitate formulations preserve the colloidal particle size. A dramatic increase of the elastic properties was observed with increasing lipid content. The rheological properties are comparable to typical dermal formulations. The results indicate that it is possible to produce high concentrated lipid dispersions in the submicron size range in a one-step production. Therefore, further formulation steps (e.g. SLN dilution in cream or gel) can be avoided. The cosmetic field offers interesting applications. It has been found in vitro that SLN have UV reflecting properties. The UV reflectance is related to the solid state of the lipid and was not evident in nanoemulsions of comparable composition. These observations open the possibility of the development of SLN-based UV protective systems. The use of physiological components in SLN is a clear advantage over existing UV protective systems (UV blockers or TiO₂) with respect to skin penetration and potential of skin toxicity. SLN have also been found to modulate drug release into the skin and to improve drug delivery to particular skin layers in vitro. The loss of water after application on the skin causes changes of the lipid modification and SLN structure. Electron microscopy indicates that dense films are formed after drying (32ºC) of SLN dispersions in contrast to spherical structures which have been proposed previously. The formation of the dense structure will favour occlusive effects on skin. It is interesting to note that the films made from melts of the lipid bulk do not form close films as dried SLN dispersions do. The surfactant plays a significant role in preventing pore formation.

Topical application:

Regarding the regularity aspect, topical application is relatively unproblematic. The major advantages for topical products are the protective properties of SLN for chemically labile drugs against degradation and the occlusion effect due to film formation on the skin. Especially in the area of cosmetics there are many compounds such as retinol or vitamin C which cannot be incorporated because of the lack of chemical stability. Incorporation of retinol is only possible when applying certain protective measures during production (e.g. noble gasing) and using special packing materials (e.g. aluminium). This increases production costs and it would be better to achieve the protection against degradation by the SLN and use a normal production process and a highly acceptable packing material (e.g. polyethylene elastic tube). It could be shown that incorporation of cosmetic ingredients into SLN can change their penetration profile. By choosing a controlled composition of the cream the release of the active ingredient/drug can be triggered. In addition, the occlusion effect of the SLN film formed onto the skin promotes penetration of the active ingredients. Invitro occlusion tests showed a superior effect of solid lipid nanoparticles vs solid lipid microparticles and demonstrated the increase in occlusion by admixing SLN to traditional creams. Apart from the change in penetration, the occlusion can lead to an increased hydration and the smoothing of wrinkles.

Ophthalmic administration:

Many investigations have been made to use nanoparticles for the prolonged release of drugs to the eye. The basic problem of ophthalmologic formulation is the fast removal from the eye, which implies clearance of the applied drug through the nose. It could be shown for nanoparticles that an increased adhesiveness is available leading to higher drug levels at the desired site of action. However, the basic problem was that the nanoparticles are of limited toxicological acceptance, e.g. polyalkylcyanoacrylate nanoparticles which lead to the release of potentially cancerogenic formaldehyde. Other particles are too slowly biodegradable and therefore are not acceptable to the regulatory authorities. It was shown by Gasco that SLN have a prolonged retention time at the eye. This was confirmed by using radiolabiled formulations and γ-scintigraphy. The lipids of the SLN are easy to metabolize and open a new potential for ophthalmological drug delivery without impairing vision.

Pulmonary administration:

A very interesting application appears to be the pulmonary administration of SLN. SLN powders cannot be administered to the lung because the particle size is too small and they will be exhaled. A very simple approach is the aerosolization of aqueous SLN dispersions. The important point is that the SLN should not aggregate during the aerosolization. The nebulizer employed was a peri-boy. The aerosol droplets were collected by collision of the aerosol with a glass wall of a beaker. This basically demonstrates that SLN are suitable for lung delivery. After localization into the bronchial tube and in the alveoli, the drug can be released in a controlled way from the lipid particles. After special feature of SLN is that they are susceptible to nonspecific hydrolysis. This could be shown by degrading SLN produced from a wax, cetylpalmitate. In vivo the cytylpalmitate, despite being a no physiological wax, was much more quickly degraded than the glyceride mixture of behanic acid^5,7,12-15.

CONCLUSION:

The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could use for drug targeting. Hence solid lipid nanoparticles(SLN) hold great promise for reaching the goal of controlled and site specific drug delivery and hence attracted wide attention of researchers. Clear advantages of SLN include the composition (physiological compounds), the rapid and effective production process including the possibility of large scale production, the avoidance of organic solvents and the possibility to produce carriers with higher encapsulation efficiency. Disadvantages include low drug-loading capacities, the presence of alternative colloidal structures (micelles, liposomes, mixed micelles, drug nanocrystals), the complexity of the physical state of the lipid (transformation between different modifications) and the possibility of super cooled melts which cause stability problems during storage or administration (gelation, particle size increase, drug expulsion). Sample dilution or water removal might significantly change the equilibria between the different colloidal species and the physical state of the lipid. The appropriate characterization of the complex surfactant/lipid dispersions requires several analytical methods in addition to the determination of the particle size. Further work needs to be done to understand the structure and dynamics of SLN on molecular level in vitro and in vivo studies.

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Received on 13.10.2012 Modified on 17.10.2012

Research J. Pharm. and Tech. 5(11): Nov. 2012; Page 1359-1368