INTRODUCTION:

Nanoparticles are solid colloidal particles which are having a size or dimensions ranging from 1-100nm.The word nano is derived from a Greek word ‘nanos’ which means extremely small, so nanoparticles are the particles that are extremely small in size. Solid lipid nanoparticles (SLNs) are the novel nanoparticulate systems consisting is of colloidal carriers having a size 50-100nm. In these systems basically physiological lipids are dispersed in a water or in any other surfactant solutions¹. SLNs are made up of a solid hydrophobic core which is coated with a monolayer of phospholipid. The drug is dissolved or dispersed in a solid hydrophobic core. SLNs are able to carry a lipophilic drug with them. SLN combine advantages as well as eliminate some of the disadvantages of polymeric nanoparticles, fat emulsion, and liposomes.

The advantages of using solid lipid nanoparticles is that by using this controlled release of drug can be achieved, will have high drug loading capacity, able to carry both hydrophilic and hydrophobic drugs, good bioavailability, have low acute or chronic toxicity, can be given by various rotes like oral, parentral, rectal, nasal etc and is stable against coalescence, drug leaking and hydrolysis².

There are different mechanisms by which drug releases from solid lipid nanoparticles. These mechanisms are homogenous matrix model, drug enriched shell with lipid core, drug enriched lipid with shell core. SLNs can be prepared by using different methods like hot homogenization method, cold homogenization method, ultrasonication method, supercritical fluid technology etc. and can be characterized using different ways like TEM, SEM, zeta sizer, DSC (Differential Scanning colorimetry), DTA (Differential thermal analysis), TGA (Thermogravimetric analysis) etc. and by some in-vitro methods like rheology, Nuclear magnetic resonance, dialysis method, reverse dialysis method etc. SLN have different applications in different drug delivery system, in different fields³.

Solid lipid nanoparticles have different advantages like they improve the stability of pharmaceuticals, have excellent bioavailability, increase the residence time of drug in eye etc as shown in Table 1.

Table 1: Comparative properties of SLN, Polymeric Nanoparticles, Liposomes, Liquid emulsions

S. No	Property	SLN	PN	Liposomes	Liquid Emulsions
1	Systemic toxicity	Low	≤ SLN	Low	Low
2	Cytotoxiciy	Low	≤ SLN	Low	Low
3	Residues from organic solvents	*	**	** or *	*
4	Large scale production	**	*	**	**
5	Sterilization by autoclaving	**	*	*	**
6	Sustained release	**	**	>SLN	*
7	Avoidance of RES	Based on size and coating	*	**	**

* = No and ** = Yes

Advantages of SLNs⁴

· Control or sustain release of drug can be obtained by solid lipid nanoparticles

· Stability of pharmaceuticals can be increased by SLN.

· SLN has the ability to carry both hydrophilic as well as hydrophobic drugs.

· Lipid matrix in SLN is made up of phospholipid due to which there will be less or no toxicity.

· It is easy to scale-up and sterilize these SLNs.

· Most of the lipids are biodegradable so SLNs have excellent biocompatibility⁴.

Disadvantages of SLNs⁵

· Drug loading capacity of SLNs are very limited.

· Drug expulsion is possible

· Sometimes high pressure may result into degradation of drug⁵.

Comparative Properties of Sln, Polymeric Nanoparticles (Pn), Liposomes, Liquid Emulsions:

There are certain different parameters or properties on which SLN, polymeric nanoparticles, liposomes and liquid emulsions can be compared. Some of these properties are systemic toxicity, sustained release of the dosage form, residuals of organic solvent, cytotoxicity etc. It is observed that SLNs have relatively less systemic toxicity as well as cytotoxicity. This has been shown in Table 1.

Methods of Preparation of SLN:

Hot homogenization method:

In this, first of all lipid will be melted and then dissolve the drug in that melted lipid. On the other side, heat the surfactant solution and then the prepared melted lipid containing drug solution has to be dispersed into the preheated surfactant solution. Then, with the help of stirrer solution will be mixed to form a coarse emulsion above the melting point of lipid solid. Then, this pre-emulsion will be passed through high pressure homogenizer which will result into the formation of solid lipid nanoparticle⁶.

This method is mainly used for the lipophillic drugs and for the drugs having low solubility. Heat sensitive or thermolabile drugs can also be used in this method as very low temperature is required (5-10 degrees)⁶.

Cold homogenization method:

In this method, lipid will be melted and drug will be dissolved into it. Then solidification of drug loaded lipid will be done with the help of either liquid nitrogen or dry ice. Drug containing solid lipid will then grind using powder mill which will result in size reduction of drug containing solid lipid. Then this drug will be dispersed in aqueous surfactant media using high pressure homogenization at either room temperature or below room temperature. This will result in formation of SLN⁷.

This process minimizes the melting of lipid due to which there will be minimum loss of drug in hydrophilic phase⁷.

Ultra-sonication method:

This technique was initially used for the preparation of SLNs. Ultrasonication based on principle of caviation. In this first of all drug is dissolved in melted lipid. Then the heated aqueous surfactant solution will be added to melted drug lipid solution and then emulsified using sonicator (probe or bath sonicator). In order to prevent recrystallization, temperature should be kept at least 5 degree above the melting point. Then the above solution can be filtered through membrane filtration to remove impurities⁸.

Types of Sonicator:

· Probe Sonicator: In this type of sonicator, small amount of volume can be used for sonication. It basically involves large frequency of ultrasound waves so less time will be required for sonication. In this probe is to be dipped into the solution which may sometimes result in impurities in the formulation.

· Bath Sonication: In this type of sonicator, comparatively large volume is required, It basically involves low frequency of ultrasound waves due to which I comparatively take more time for sonication. Formulation prepared using this method will be free from impurities⁸.

Solvent evaporation method:

In this method, in water immiscible organic solvent lipophilic (like cyclohexane, toluene etc.) material and hydrophobic drug are to be dissolved and then using high pressure homogenization it should be emulsified. Then emulsion should immediately pass through microfluidizer to improve the efficiency of emulsion. Then by stirring at low temperature organic solvent should get evaporated leaving precipitates of lipid SLNs. The size of SLN will depend on the amount of lipid added, if amount will be less then size of SLN will be small⁹.

Main disadvantage of this method is addition or use of organic solvent and biomolecular damage⁹.

Advantages: Continuous process, commercially demonstrated

Micro-emulsion method:

This method is basically depending on the dilution of microemulsion. In this method SLNs are prepared by Prepared by stirring the optical transparent mixture containing low melting fatty acid (stearic acid), emulsifier (polysorbate 60 etc.), co-emulsifier (sodium monoocetylsulphate) and water at a temperature of 65-70 degree centigrade. Then the above hot mixture will be dispersed in cold water (2-3 degree centigrade) with continuous stirring.

In this method there will be low mechanical input but nanoparticles prepared by this method will be in very low concentration¹⁰.

Supercritical fluid technology:

This is a unique technique which recently applied for the assembly of SLNs. A fluid is qualifiedassupercritical when its pressure and temperature exceed their respective critical value. The supercritical fluid has unique thermo-physical properties. A gas may have little orno ability to dissolve a compound under ambient condition can completely dissolve the compound under high pressure in supercritical range. Many gases like, CO₂, ammonia, ethane and CH₂FCF₃ were tried, but CO₂ is that the best option for SCF technique because, it’s generally considered to be as safe, doesn’t causes the oxidation of drug material, inflammable¹¹. This technology comprises several processes for nanoparticles production like rapid expansion of supercritical solution (RESS), particles from gas saturated solution(PGSS), gas/supercritical antisolvent (GAS/SAS), aerosolsolvent extraction solvent (ASES), solution enhanced dispersion by supercritical fluid supercritical fluid extraction of emulsions (SFEE). Mainly SAS and PGSS were used for SLN. Supercritical fluid technology can be done using two methods:

Rapid expansion of supercritical solution (RESS):

This method is for the drugs which are soluble in supercritical fluid. In this drug will be dissolved in super critical fluid. Then solution will be sprayed into the region of low pressure and due to which solvent power of supercritical fluid decreases which result in the precipitation of SLNs³.

Super critical anti-solvent:

This method is basically for the drugs which are insoluble in supercritical fluid. In this first dug will be dissolved in methanol and then into the solution of drug and methanol supercritical fluid will be added. Supercritical fluid should be miscible with methanol which ultimate result into the precipitation of SLNs as fine particles¹.

Advantages:

· As it is solvent less method so there will be formation of dry nanoparticles.

· In this there will be rapid precipitation of SLN.

· Will have very low content of organic solvents.

Double emulsion method:

In this method first drug will be added in the aqueous solutionand then that will be emulsified in lipid that is already melted. Then that primary emulsion will be stabilizing using stabilizer like gelatin. Then that primary emulsion will be stirred and filtered. This technique is mainly used to encapsulate hydrophilic drugs like peptides¹².

Membrane Contactor technique:

This is a new technique for the preparation of SLN. In this technique there will be formation of small droplets when a liquid passes through the temperature that is above than melting point of lipid. Then the aqueous phase will be stirred constantly and circulate inside the membrane module and droplets forms at the pore outlets will be swipe away. Then by cooling the preparation at room temperature SLN will be formed. Then to maintain the required temperature both the phases should be placed in the thermostaticbath and nitrogen will be used to create pressure for the liquid phase. This method is also used for the preparation of polymeric nanoparticles. By using this method one can control the size of SLN¹³.

Solvent injection technique:

In this there will be precipitation of lipid from the dissolved solution of lipid. In this solid lipid will be dissolved in water miscible solvents like ethanol, methanol etc Then that solution should be injected into the aqueous phase in the presence or absence of surfactant. Then the solution will be filtered to remove any impurity or excess of lipid.

Organic solvent used in this technique is pharmacological accepted¹⁴.

Drug Release of SLN:

Three models that describe the inclusion of drug in SLN

Fig. 1: Models of drug release from SLN

Homogenous matrix model:

In homogenous matrix model highly lipophilic drugs will be incorporated into SLN using hot homogenization or cold homogenization technique or by avoiding drug solubilizing in surfactant. In the case of cold homogenization technique drug has to be dissolution in the bulk of limited lipid then mechanical force due to high pressure homogenization will lead to collapse of molecular form to nanoparticles which will ultimately give rise to homogenous matrix model¹⁵.

Drug enriched shell with lipid core:

The drug enriched shell with lipid core model will be obtained with during the production and drug will partitioned to water phase. Lipid precipitates first on cooling and form a drug free lipid core mainlydue to phase separation. In same time, drug will re-partition in left over liquid-lipid phase and concentration of drug in the outer shell will increase. Then a drug enriched with a shell will crystallize out. With increase in solubility of drug in aqueous phase the amount of drug partitioning in aqueous phase will increases. The saturation solubility of drug in water phase will increase with increase in temperature of aqueous medium and increase in surfactant concentration¹⁵.

Drug enriched core with lipid shell:

This method will be obtained by dissolving a drug in either melted lipid or when the lipid achieve its saturation solubility. Upon cooling of nano emulsions super saturation of the drug will be achieved in melted lipid which further leads to drug precipitation. On further cooling there will be a precipitation of lipid surrounding the drug enriched core with lipid shell¹⁵.

Characterization of SLN:

Measurement of particle size and zeta potential:

For measurement of particle size and zeta potential ‘Photon correlation spectroscopy’ (PCS) and ‘Laser diffractometery’ are the two powerful and most commonly used techniques. Due to movement of particle there will be fluctuation in the intensity of scattered light which can be measured using PCS also known as dynamic light scattering. By using PCS small particles ranging from few nanometers to 3 microns can be determined but large particles cannot be measured using this technique Shape of the particles can also be determined using electron microscopy in contrast to PCS and LD¹⁶.

Photon correlation spectroscopy (PCS):

This method is based upon the Brownian motion of particles due to which there will be dynamic scattering of laser light. This method is basically used for the small particles that are ranging from few nanometers to about 3 microns. In this PCS there is one sample cell holder, laser or light source and a detector is present. Detector here in PCS used is photomultiplier tubes¹⁶.

Electron microscopy:

In this electron microscopy there are two techniques or methods Scanning electron microscopy and Transmission electron microscopy are used. In this with the help of these two methods particle shape as well as morphology can be determined. SEM use the electrons transmitted through the surface of particle whereas the TEM uses the electrons transmitted through particles¹⁷.

Atomic force microscopy (AFM):

This Atomic force microscopy is the new method to check the original unchanged shape and surface properties of nanoparticles. With the help of AFM force acting between the surface of the sample and the tip of the probe can be determined¹⁶.

Determination of incorporated drug:

It is very important to determine the drug incorporated into SLN as amount of drug incorporated into SLN will directly influence the release mechanism of SLN. After separation of free drug and solid lipid from aqueous medium number of nanoparticles that are encapsulated per weight of nanoparticles can be determined and for this the separation can be done by ultracentrifugation, gel chromatography or centrifugation filtration. Then the drug can be assayed using standard analytical techniques like HPLC, spectrophotometer, spectroflouometeretc¹.

In-vitro drug Release:

Dialysis tubing: By using this dialysis tubing method in-vitro release of SLN can be determined. In this method, in hermetically sealed pre-washed dialysis tubing solid lipid nanoparticles are to be placed. Then in suitable dissolution medium dialysis sac will be dialyzed at room temperature and at suitable time intervals sample will be withdrawn from the dissolution medium and then the solution will be centrifuged and analyzed by using a suitable analysis method⁸.

Reverse Dialysis: In this method number of small dialysis sacs will be prepared which will have 1mL of dissolution medium and them it will be placed in SLN dispersion. Then the SLNs will be displaced into the medium⁸.

Rheology:

Rheology of the prepared solid lipid nanoparticle formulation can be checked using Brookfield viscometer by using aappropriate number of spindle. The viscosity of the prepared SLN will depend upon the dispersed lipid content. If the lipid content in formulation will increase, the flow will become non-Newtonian¹⁸.

Acoustic methods:

In this acoustic method. The attenuation of sound waves can be measured as a means of determining size through the fitting of physical relevant equation. By acoustic energy, the oscillating electric field that is generated by the movement of charged particles can be determined which will be used to determine the surface charge¹⁸.

Nuclear magnetic resonance (NMR):

Size as well as qualitative nature of nanoparticle can be determined using nuclear magnetic resonance. The selectivity observed through chemical shift complement the sensitivity to molecular mobility which will provide information on the physiochemical status of the components present in the nanoparticles¹⁹.

X-ray diffraction spectroscopy and differential scanning colorimetry (DSC):

By using this, geometry of the nanoparticles can be determined, degree of crystallinity of the nanoparticle can be determined. By suing DCS nature as well as specialty of crystallinity within nanoparticle can be determined through the measurement of melting point temperature¹⁹.

Routes of Administration of SLNS:

Various routes of SLN administration are shown in Table -2

Patents On SLN

There are different patents that are file on SLN. As shown in Table 4.

Table 2: Routes of administration of SLNs

Route	Action	Reference
Parentral	Reduce side-effect and increase bioavailability	20
Oral	Controlled release of drug	18
Rectal	Immediate release of drug mainly for pediatric patients	21
Nasal	Fast absorption and rapid action	22
Respiratory delivery	Improve drug bioavailability; Reduce dosing frequency	23
Occular	Increase interaction with ocular mucosa and increase residence time in eye	24
Topical	Due to non-irritant and non-toxicity, use in injured or damaged skin	25

Applications of SLN

Table 3: Applications of SLNs

S. No.	Application	Formulation	Action	Reference
1.	Anti-tubercular chemotherapy	SLNs of Rimapicin, Isoniazid	Decrease dosing frequency	26
2.	Topical use	Vitamin A loaded SLNs	Sustained release	27
3.	Cosmaceuticals	UV blocker SLNs	Controlled release, better penetration	28
4.	Gene vector carrier	Plasmid DNA vectors	Therapy	29
5.	Breast cancer and lymph node metastases	Milotraxone loaded SLNs	Increase safety and bioavailbility	30
6.	Targeted carrier to solid tumors	Methotrexate, tamoxifenin loaded SLN	Tumor targetting	31

Table 4: Patents file on SLN

S. No	Name	Inventor	Patent No.	Filling Date	Reference
1	Method for preparing solid lipid microspheres that will be having a narrow size distribution	Maria R. Gasco	US 5250236	02-08-1991	33
2	Medication vehicles prepared by SLN	Stefan Lucks, Rainer Muller	EP 0605497	16-09-1992	34
3	Polymerized SLN prepared for oral or mucosal delivery of proteins and peptides	KolliparaKoteswara Rao	US 20080311214A1	05-04-2006	35
4	SLN incorporated UV absorber formulation	Bernd Herzog	US 7147841 B2	13-07-2003	36
5	Use of SLN compromising cholesterol propionate	Maria R. Gasco	US 11921634	31-03-2006	37
6	Using dual asymmetrical centrifuge, production of lipid based nanoparticles	Ulrich Massing	EP1838286 B1	23-12-2005	38
7	Minoxidil aqueous solution encapsulated by SLN	Falson, Karine Padots, Fabrice	EP2413918 A1	29-03-2010	39
8	Lipid nanoparticle capsules	Josep, Raquel, Alfonso Kirsten	EP2549977 A2	24-03-2011	40
9	Solid lipid particles, Method, manufacture and use of particles of bioactive agents	Westesen, Britta Siekmann	US 5785976	12-04-1994	41

CONCLUSION:

SLN are very small in size and are able to cross blood brain barrier. These are able to carry both hydrophilic and hydrophobic drugs. Controlled as well as sustained release of drug can be achieved by using these SLN formulations. SLNs can be prepared by various techniques and are able to give through different routes of administration. SLNs have their applications in various delivery systems as well as in different fields.

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Received on 25.02.2021 Modified on 08.09.2021

Research J. Pharm. and Tech 2022; 15(12):5879-5885.

DOI: 10.52711/0974-360X.2022.00992