INTRODUCTION:

Solid lipid nanoparticles were introduced in 1991 represent an alternative and better carrier system to traditional colloidal carriers such as emulsions, liposomes and polymeric micro nanoparticles. Solid lipid nanoparticle is typically spherical with an average diameter between 10 – 1000 nanometers, the colloidal carrier of drug delivery consist of physiological lipid dispersed in aqueous surfactant solution. Solid lipid nanoparticles are the sub micron colloidal carriers composed of a single lipid core matrix that is solid at body temperature, and is coated with a surfactant acting as emulsifiers.

The term lipid is used here in a broader sense and includes mono, di and triglycerides, fatty acids, steroids and waxes. All classes of emulsifiers have been used to stabilize the lipid dispersion. They consists of macromolecular materials in which the active principle is dissolved, entrapped, and or to which the active principles is adsorbed or attached. The most efficient method for formulation of solid lipid nanoparticles are micro emulsification, homogenization technique, ultrasound method, solvent based method and phase inversion temperature techniques. The solid lipid nanoparticle possesses various promising properties

Fig 1: Structure Solid Lipid Nanoparticles

like large surface area, interaction of phases at interface, small size, high drug loading efficiency to enhance the bioavailability of the drug^1-4.

MERITS OF SLN :

· Control and target drug release

· Increased drug stability

· Avoid reticulo endothelial system

· Improve stability of pharmaceuticals

· Enhanced bioavailability of entrapped bioactive compounds

· No special solvent required

· Excellent biocompatibility

· Easy to scale up and sterilize

DEMERITS OF SLN:

· Drug expulsion

· Co-existences of several colloidal species

· irregular gelation tendency

· unexpected dynamics of polymeric transitions

· elevated water content

· High pressure induce drug degradation

· Lipid crystallization^2-4

PROMISING FACTOR OF SLN:

· High drug payload

· No bio-toxicity of the carrier

· prevention of organic solvents

· Incorporation of lipophilic and hydrophilic drugs

· Increased drug stability

· No problems with large scale production and sterilization

· Increased bioavailability of entrapped bioactive compounds

· Possibility of controlled drug release and drug targeting

DIFFERENT MODELS OF SLN:

They are three models proposed on solid lipid nanoparticles based on the drug incorporation within them are as given below^5-7

1. HOMOGENOUS MATRIX MODEL:

In this model solid lipid nanoparticles are also formed from a solid solution of lipid and active ingredient. A solid solution can be attained although SLN are made by the cold homogenization process. A lipid mixture can be made and consists of the active particle in a molecularly dispersed form. Later solidification of this blend, it is ground in its solid state to reduce the enrichment of active molecules in various parts of the lipid nanoparticles.

2. DRUG ENRICHED SHELL MODEL:

In this model the SLN are made by the hot technique and the active ingredient concentration. Inside the melted lipid, low concentration maintained throughout the duration of the cooling process of the hot o/w nano emulsion. The first lipid will precipitate, mainly to increasing concentration of active molecules inside the closing melt and outer shell will solidify and having both active and lipid. The enhancement of the outer area of the particles causes eruption release. The percentage of active ingredient confined in the outer shell can be fix in a controlled shell model is the embodiment of co enzyme Q10.

3. DRUG ENRICHED CORE MODEL:

Core model can be take once the active ingredient concentration within the lipid melt is high on the point of its saturation solubility. The downward cooling of the hot oil droplets in the most cases decrease the solubility of the active ingredients in melt. Once the saturation solubility exceeds, active molecules precipitate resulting, development of a drug enriched core.

Fig 2: Types of Solid Lipid Nanoparticles

PREPARATION METHODOLOGY OF SOLID LIPID NANOPARTICLES:

Solid lipid nanoparticles are prepared from lipid, emulsifier and water/solvent by using different methods are discussed below^1,8-12.

1. HIGH SHEAR HOMOGENIZATION:

It is a stable and controlling technique, which is used for the formulation of SLN. High pressure homogenizers forced a liquid with high pressure bar 100-2000, although a wide gap in vary of some microns. The fluid stimulates on a very short distance to high velocity over 1000 km/H. very high shear stress forces agitate the particles all the way down to the submicron range. Mostly 5-10% lipid content is used upto 40% lipid content has also been measured. The high shear homogenization consists of the following

A) Hot homogenization

B) Cold homogenization

A) HOT HOMOGENIZATION:

Hot homogenization method is carried out the temperature over the melting point of the lipid which is similar to homogenization of emulsion. Generally lipid content is 5-10% . By this technique up to 40% success reached. A pre emulsion of drug loaded lipid melt the aqueous emulsifier phase is obtained through high shear mixing equipment. High pressure homogenization of the pre emulsion completed above the lipid melting point. The standard of the pre emulsion impacts the standard of the final product to a grest extent and its fascinating to get droplets within in the size range of few micrometers. Lower particle size are received at better processing temperature because of Lower viscosity of the lipid phase. The good product is received because of numerous passes through the high strain homogenizer. High pressure homogenizer gradually increase the temperature of the sample. The homogenization cycles 500-1000 bar acceptable. When the problem are happened in hot homogenizer because due to the excessive temperature, might also lead to degradation of the active compound.

Fig 3: Flow chart of hot homogenization

B) COLD HOMOGENIZATION:

This technique was developed to overcome the problems of the hot homogenization method. The temperature resolve and accelerated degradation of active compound. The first step of preparation in among cold and hot homogenization is equal but they are differing from their next steps preparation . The lipid melt is cooled immediately using ice or liquid nitrogen for distribution of drug in lipid matrix. The drug contained solid lipid is milled by means of ball mill or mortar. Thus particle size measure with in the range was about 50 -100 microns. Compared to the hot and homogenization the larger particle size and a broader size distribution are normal to cold homogenized samples. Cold homogenization decreases the thermal exposure disclosure of the samples. It is an inexpensive method but high energy is required.

Fig 4: Flow chart of Cold homogenization

2) ULTRASONICATION (OR) HIGH SPEED HOMOGENIZATION:

Solid lipid nanoparticles were also developed by high speed stirring or sonication. In this method the broader particle size distribution ranging into micrometer range. The equipment whatever used here is very common in every lab. These method leads to physical instabilities likes particle growth upon aging. The problem of these method is Potential metal contamination due to ultra sonication . In various research groups the studies have been performed so,far making a stable formulation, that high speed stirring and ultra sonication are used combined and performed at high temperature. Lipid concentration is less than 1%. Shear stress can be minimized but metal contamination may occur.

Fig 6: Ultrasonic homogenizer or high speed homogenization

3)SOLVENT EMULISIFICATION – EVAPORATION METHOD:

Organic solvent is used to dissolve lipophilic material and aqueous phase is used to emulsify the organic phase. The water immiscible organic solvents were (cyclohexane, dichloromethane, toluene, chloroform) emulsified in an aqueous phase using high speed homogenizer. In this technique During the evaporation of solvent nanoparticles precipitation of lipid occurs, which results in the formation of dispersion. The size particles was depends on organic phase, mean diameter of the obtained particles was 25nm with cholesterol acetate and drug lecithin, sodium glycol cholate blend as emulsifier compromised by presence of micro particles. The avoid of thermal stress, make it suitable for the absorption of highly thermo labile drugs. Interaction of organic solvent with drug molecules may occur. Biomolecule damage may occur due to high energy produced during the preparation of solvent emulsification.

Fig 7: Solvent emulsification technique

4) SOLVENT EMULSION DIFFUSION METHOD:

In these technique the solvents are used like (benzyl alcohol, butyl lactate, ethyl acetate, isopropyl acetate, methyl acetate) thus it was partially miscible with water can be carried out either in aqueous phase or oil phase. The particle range was about 30-100 nm can be obtained. To increase the stability of the formulation , the formulation lyophilized to obtained freeze-dried powder and some time mannitol was added into as a cryoprotector. This method is easy to handle and effective to produce SLN without organic solvents, but it also has limitation of filtration of formed SLN emulsion. In order to remove impurity materials produced during ultrasonication. Evaluation of heat during this process is avoided.

Fig 8: Flow chart of solvent emulsion diffusion method

5.SUPERCRTICAL FLUID METHOD:

This is an another way of method for preparing SLNs by particles from gas saturated solutions PGSS. The SLN production and has the advantage of solvent less processing. In this method the particles are obtained as a dry powder, instead of suspensions. As a solvent carbon dioxide solution is the good choice for this method. Thus SLN can be prepared by the rapid expansion of supercritical carbon dioxide solution RESS method. it should be in mild pressure.

Fig 9: Method preparing of supercritical fluid

6) MICROEMULSION BASED METHOD:

This method is based on the dilution of micro emulsions. As micro emulsions consists two phase systems composed of an inner and outer phase (Eg, o/w micro emulsions). Micro emulsions are made by stirring an optically transparent mixture at 65-70^oc, which characteristically composed of a low melting fatty acid , emulsifier, co-emulsifier and water. Under stirring process hot micro emulsion (75^oC) is dispersed in cold water at(2-3^oC). Using granulation method the granulation fluid is made using SLN dispersion, in order to change to a solid product(Eg. Tablets and Pellets.) For facilitate fast lipid crystallization and to avoid aggregation, more water required for the low particle content in SLN dispersion. Because of dilution step; attainable lipid contents are considerably lower compared with the HPH based formulations.

Fig 10: Process of micro emulsion based method

7) SPRAY DRYING METHOD:

It is cheaper method than Lyophilization . Lyophilization in order to transform an aqueous NLC dispersion into a drug product through by alternative procedures. But this method can cause particle aggregation due to high temperature, shear forces and partial melting of the particle. The SLN concentration was obtained in spray drying method was about 20% trehalose in ethanol water (10/90 v/v) and 1% solution of trehalose in water .

Fig 11: preparation of spray drying method

8) DOUBLE EMULSION METHOD:

In this method the drug was dissolved in aqueous phase and emulsified in melted lipid. Primary emulsion was stabilized by adding stabilizer like gelatin and poloxamer-407. Then this stabilized primary emulsion was dispersed in aqueous phase contain hydrophilic emulsifier. Thus double emulsion was stirred and isolated by filtration. The drug is encapsulated with a stabilizer to prevent the partitioning of drug in to external water phase, during external water phase the solvent evaporation is done through w/o/w double emulsion.

Fig 12: Process of Double emulsification method METHOD5

9) PRECIPITATION TECHNIQUE:

This method explains that In aqueous phase the solution will be emulsified and Glycerides are dissolved in an organic solvent. So, organic solvent the lipid will be precipitated forming nanoparticles after evaporation.

Fig 13: PROCESS OF PRECIPITATION TECHNIQUE

10) FILM-ULTRASOUND DISPERSION:

Lipid and drug add in to organic solutions, after decompression, rotation and evaporation of the organic solutions, a lipid film is created. Then the aqueous solution which incorporates the emulsions was added, Using the ultrasound with the probe to diffuser eventually, the SLN with the microscopic and uniform particle size is added. Thus lipid + tranquilizer include to natural arrangements.

11) SOLVENT INJECTION TECHNIQUE:

For the preparation of SLN it was a new approach there is an advantages over other production methods like easy handling and fast production process without technically sophisticated equipment, use of pharmacologically acceptable organic solvent. It depends on lipid precipitation from the dissolved lipid in solution. In this method the solid lipid was dissolved in water miscible solvent mixture or water miscible solvent mixture. Then through an injection needle this lipid solvent mixture was injected into stirred aqueous phase with or without surfactant. In order to remove any excess lipid resultant dispersion was filtered with filter paper.

Fig 14: Solvent injection technique

12) MEMBRANE CONTRACTOR TECHNIQUE:

The present study deals with a new techniques for the preparation of SLN using a membrane contactor and this process is used for large scale production. Small droplets are formed by using the temperature higher than the lipid melting point and compressing the lipid phase. The formation of pores can be avoided by passing the aqueous phase into the membrane. Cooling the membrane to the room temperature forms the SLNs. Investigation of effect of different parameters on lipid phase and size of SLN can be done. Also, vitamin E loaded SLN are prepared, and their stability is determined.

Fig 15: Process of membrane contractor technique

Table no 1: Ingredients used in preparation of SLN:

S. no	Ingredients	Concentration
1	lipid	3.33%w/v
2	glycerol	2-4%
3	Phospholipids	0.6-1.5%
4	Poloxamer 188	1.2-5% w/w
5	Compritol	10%
6	Soy phosphatidyl choline	95%
7	Cetyl palmitate	10% w/w
8	Tego care 450 (surfactant)	1.2% w/w
9	PEG 2000	0.25%
10	PEG 4500	0.5%
11	Tween 85	0.5%
12	Ethyl oleate	30%
13	Ethanol/butanol	2%
14	Na alginate	70%
15	Tristearin glyceride	95%
16	PEG 400	5%
17	Isopropyl myristate	3.60%
18	Pluronic F 68	40%
19	Tween 80	50%

Table no 2: Drugs and production method of SLN:

Sno	drugs	Lipid/ surfactant	Production method	Reference
1	Diclofenac sodium	Phospholipon 90G/Tween 80	High pressure homogenizer	19
2	Tobramycin	Stearicacid/epikuron 200	Warm o/w microemulsion method	20
3	Baicalin	Triglyceride and soyaphospholipid SL-100/poloxamer 188	Emulsification/ultrasound method	21
4	Cyclosporin- A	Compritol 888 ATO/ Poloxamer188 and Tween 80	High shear homogenization using high pressure homogenizer	22
5	Indomethacin	Compritol 888 ATO/ Poloxamer188 and Tween 80	Hot homogenization method	23
6	Chloramphenicol	Glyceryl monostearate /poloxamer 188	Melt-emulsion and ultrasonication and low temperature solidification technique	24
7	Diazepam	Compritol 888 ATO/ Poloxamer188 and Tween 80	high-shear homogenization and ultrasound techniques	25
8	Irbesartan	Poloxamer 407/ Glyceryl monostearate	High pressure homogenization, solvent evaporation, solvent emulsification, ultrasonication	26

CHARACTERIZATION OF SOLID LIPID NANOPARTICLES:

The various characterization of SLNs are discussed below^9-13.

1.PARTICLE SIZE AND ZETAPOTENTIAL:

Particle size has an important role in determining the stability of SLN’s . Different methods are used for the determination of particle size of SLN’s. Photon correlation spectroscopy and laser diffraction are the important methods. PCS methods determines the particle size by measuring the scattered light intensity due to the movement of particle, particle size ranging from 3nm to 3 µm are detected by using PCS. Laser and particle size detected by diffraction ranges from 100nm - 180µm. PCS also measures micro particles with with larger particle size. Measurement of zeta potential helps in determining the stability of dispersions during the storage . stability of dispersions can be evaluated by zeta potential analyzer or zeta meter. Dispersion medium is used to dilute SLN dispersions with 50- fold. By dilution with dispersion medium, zeta potential can be evaluated. High value of zeta potential indicates disaggregation of SLN particle.

2. STATIC LIGHT SCATTERING (OR) FRAUNHOFER DIFFRACTION:

The pattern of light scattered from a solution of particles is collected and fit to fundamental electromagnetic equations in which size is the primary variable. It is fast and rugged method, but requires more cleanliness than dynamic light scattering and advance knowledge of the particles’ optical qualities.

D_h= Hydro dynamic diameter

D_t = Translational diffusion coefficient

K_b = Boltzmann’s constant

T = Thermo dynamic temperature

Ŋ = Dynamic viscosity

3. ELECTRON MICROSCOPY:

Observation of nanoparticles directly can be achieved by using two methods like Transmission electron microscopy (TEM) and Scanning electron microscopy (SEM). Limit of detection for small sized nanoparticles is the disadvantage for TEM, where as better morphological structures of nanoparticles can be examined by SEM.

4. ATOMIC FORCE MICROSCOPY:

This technique is also known as scanning force microscopy, which forms the images of surface using a probe that scans the specimen, it is very high resolution type of scanning probe microscopy. The probe can be dragged across the sample in contact mode or allowed to non contact mode, with exact nature of particular force which was corresponding to the sub techniques. AFM is its ability to image non conducting samples without any specific treatment. It allows the feature like imagining of delicate biological and polymeric nano and micro structures. It is an very efficient method to evaluate the soft matter nano carrier.

5.DIFFERENTIAL SCANNING CALORIMETRY:

Degree of Crystallinity can be determined by DSC and XRD. Comparison of the melting enthalpy/g of dispersion and bulk material are carried out for determining the rate of Crystallinity. So DSC and XRD play a major role because they are able to afford structural information on the dispersed particles. It is a crucial tools for SLN characterization and many possibilities to increase information of dispersed particles.

6.DYNAMIC RATE SCATTERING (DLS):

DLS also known as Photon Correlation Spectroscopy (PCS) or Quasi - Elastic Light Scattering (QELS). the variation in the intensity of scattered light on the microsecond time scale. this variation results from interference of light scattered by individual particles due to Brownian motion, and is quantified by an auto correlation function. This method lacks required calibration and sensitivity to sub micrometer particles.

7.ACOUSTIC METHODS:

The Acoustic spectroscopy , measures the attenuation of sound waves by the means of size determination through the fitting of physically appropriate equations. The oscillating electric field generated by the movement of charged particles under the control of acoustic energy can be detected to provide information on surface charge of the dispersed particles.

8.NUCLEAR MAGNETIC RESONANCE:

It is most commonly knows as NMR spectroscopy or magnetic resonance spectroscopy. Spectroscopic technique which are used to observe local magnetic fields around the atomic nuclei. NMR Spectroscopy method to identify the monomolecular organic compounds. And also it is used to determines the size and the qualitative nature of nanoparticles.

MODE OF ADMINISTRATION (SLN):

The different modes of administration was mentioned below ^10,14,15.

1. PARENTERAL ADMINISTRATION:

There are wide range of Parenteral applications for the field of SLN. The usual oral administration of peptide and protein drugs is not possible since they prone to degradation by enzymes in GI track. so, they are usually available in parenteral administration and marketed as such .In general, The Parentral Administration of SLN reduces adverse effects and side effects that are integrated with increased bioavailability of a drug .These systems of SLN have excellent drug targeting capability and can act as best drug carrier systems for drug manufacturing companies .

2. ORAL ADMINISTRATION:

SLNs with controlled release behavior reported that it can avoid the degradation of the encapsulated drug by gastric and intestinal action on encapsulated drug and their possible uptake and transport through the intestinal mucosa. However, the evaluation of the colloidal carriers stability in GI track is essential to know that they are suitable for oral administration.

Hydrophobic coated SLNs are technique that are successful protecting from biodegradable colloidal particles.

3. RECTAL ADMINISTRATION:

Rectal administration used for pediatric patients for easy administration and it had reported rapid pharmacological action and good therapeutic efficacy observed in rectal administration compared to oral administration. PEG coating enhance bioavailability when talking especially regarding rectal administration of drug.

4. NASAL ADMINISTRATION:

Nasal administration can helpful in rapid absorption and fast onset of drug action. Nasal route can avoid enzymatic degradation of liable drug in GI tract and drug can be directly goes in action with tissue and exerts its action. In addition, SLNs with hydrophilic coating bring great benefits as nasal drug carrier especially for vaccines.

5. OCULAR ADMINISTRATION:

SLNs can adhere to mucus and Bio compatibility properties can improve interaction with mucosa and increase corneal adherence time of the drug, that can show required pharmacological action. Whereas, colloidal drug delivery models, can enhance ocular bioavailability. Now a days, several industrial areas used SLNs for incorporating antibiotics in ocular administration.

APPLICATIONS OF SOLID LIPID NANOPARTICLES:

The various applications of Solid Lipid Nanoparticles shown below^11,16-18

1. SLN AS POTENTIAL NEW ADJUVANT FOR VACCINES:

Adjuvants are widely used in vaccination in order to enhance the immune response. Newer subunit vaccines are less effective in immunization. Whereas the newer developments are seen in the oil in water type of emulsions, that degrade rapidly in the body.

2. SOLID LIPID NANOPARTICLES FOR DELIVERING PEPTIDES AND PROTEINS:

Proteins and antigens intended for therapeutic purposes may be incorporated into SLN and administered by parenteral or alternative routes. It avoids proteolytic degradation, and sustained release of the incorporated molecules, thus the Formulation in SLN confirms that improved protein stability. The Important peptides such as insulin, cyclosporine A, somatostatin and calcitonin have been incorporated into solid lipid particles.

3. SOLID LIPID NANOPARTICLES 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 disorder. the surfactant coated poly(alkyl cyanoacrylate) nanoparticles specially designed for brain targeting is given by emphasizing the transfer of this method in SLN matrices. The potential advantage of sln over polymeric nanoparticles based on lower cytotoxicity, higher drug loading capacity, and best production scalability.

4. SLN FOR ULTRASONIC DRUG AND GENE DELIVERY:

Ultrasound is being used in diagnostic medicine and had a connection with nano particles. The in vitro study shown that ultra sound drug delivery as more effective in tumor or cancer. 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. The small packaging allows nanoparticles to extravasculate into tumor tissues. Ultrasonic drug and gene delivery from nanocarriers has tremendous potential because of the wide variety of drugs and genes that could be delivered to targeted tissues.

5. SLN FOR LYMPHATIC TARGETING:

The intra duodenal administration of SLN were done to rats and evaluated for lymphatic uptake , in such a way SLN were develop for proper therapeutic effect.

6. SLN IN CANCER CHEMOTHERPY:

SLN improves the stability of drugs, encapsulation of chemotherapeutic agents, improved drug efficacy and pharmacokinetics and reduced in-vitro toxicity are the significant characteristics of SLN .which make them as suitable carrier.

A. SLN AS TARGETED CARRIER FOR ANTICANCER DRUG TO SOLID TUMOR:

Tumor targeting is achieved by SLN loaded with drugs like Camptothecin and Methotrexate. Tamoxifen is an neoplastic drug which is incorporated in sln to prolong the release of drug after IV administration during breast cancer.

B. SLN IN BREAST CANCER AND LYMPH NODE METASTASES:

SLN local injections like Mitoxantrone are formulated to increase the safety and bioavailability of the drug and decrease the toxicity.

7. SLN IN COSMETIC APLLICATION:

The application of SLN as sunscreens and as active carriers for sunscreens of molecular type has investigated . The quantity of molecular sunscreen can be decreased upto 50% by maintaining protection level comparingly with conventional emulsion. A study shown that,on adding 4% SLN to a normal preparation method of O/W cream shown that 31% of hydration increased on the skin after four weeks. So the SLN particles added in sunscreens creams shows best results than a conventional emulsions. This can provide a good scope in developing skin care products

8. SLN FOR POTENTIAL AGRICULTURE:

Artemesia Arboreseens L is a herb from which essential oils extracted and incorporated into SLN, capable of reducing rapid evaporation when compared to emulsions. so they are useful for best carriers of safe pesticides in agriculture fields.

CONCLUSION:

Solid Lipid Nanoparticles drug delivery presents considerable opportunities for improving medical therapeutics. The suitable characterization of the complex surfactant/ lipid dispersions requires several analytical methods in addition to the determination of the particle size kinetic study are to be done. The preparation of SLN and other lipid nanoparticle is possible and practicable in small scale and large scale too. The additional efforts can be put on the dynamics of LNPs on a molecular phase both in vivo and in vitro. The SLNs have the potential to achieve controlled drug delivery having received primary attention and future holds for its systematic exploitations. The advantage of SLN include the composition, the rapid and effective production process including the possibility of large scale production, the avoidance of organic solvents and possibility to produce carriers with higher encapsulation efficiency impose a primary drug delivery technique. However disadvantages like low drug loading capacities, alternative colloidal structures, liposomes, mixed micelles, micelles and drug nanocrystals, the complexity of the physical state of the lipid causing stability problems during storage or administration. Though SLN proves to be a promising drug delivery system and can explore as a novel drug delivery technology for most of the recent medicines.

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Received on 24.07.2018 Modified on 17.08.2018

Research J. Pharm. and Tech 2018; 11(12): 5691-5700.

DOI: 10.5958/0974-360X.2018.01031.4