INTRODUCTION:

Schizophrenia:

Schizophrenia is a severe, long-term, disabling brain disease and a sense of mental fragmentation.

Common symptoms:

Auditory hallucinations, freakish delusions, bizarre or disorganized speech, thinking and leading to faulty perception.

Neurologic disorders are the largest cause of disability adjusted life years and the second leading cause of death globally representing 16.8% of global deaths (GBD 2015 Neurologic Disorders Collaborator Group, 2017).

The burden of neurologic diseases is rising, with unipolar and depressive disorders predicted to become the second largest cause of morbidity by 2030. The development of CNS drugs is currently hampered by the fact that these drugs have to cross the blood brain barrier (BBB) in therapeutic quantities. In actual fact, 98% of drug molecules do not cross the BBB in therapeutic quantities. An alternative method of delivering molecules to the brain is the nose-to-brain route. This route bypasses the BBB. The nose-to-brain route is gaining in popularity, as demonstrated by both preclinical and human studies.

Nose-to-Brain Mechanism of Delivery:

For the purposes of drug delivery, the nasal cavity is divided in to the respiratory area and the olfactory area, with the latter situated high up in the nares and the former closer to the nostrils.^[2] The nasal epithelium is well vascularized and within the olfactory area, olfactory neurons are exposed enabling the transport of drug compounds directly into the brain via the olfactory neurons. Strategies to evade the blood–brain barrier? Depending on the properties of BBB, there are number of strategies that include pharmacological line, invasive methods and physiological. Pharmacological method includes modification of drug that will help to cross the BBB.^[4,9] But these modifications, affect the biological activity of the drug. While the invasive involves use of techniques as interruption of BBB, use of polymers, use of catheters etc. As these are invasive, may lead to damage to brain tissues, toxic conditions, infection chances. This is not cost effective method.^[5]

The physiological way is considered to be better approach as compared to the two methods, as it takes the advantage of transport receptors that help to cross the BBB barrier. These all three methods, suffer from the disadvantage of limited success rate for treatment of neural diseases. Due to the limitations of these methods, research has advanced for the use of nanotechnology, for effective delivery of the drugs across the BBB. Nanoparticles have played an important role for brain drug delivery. So, in this review, we are focusing on the most promising approach of solid lipid nanoparticles for drug brain targeting and delivery.^[11]

Figure 1: Transport route across blood-brain

Introduction of SLN:

Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to tradition colloidal carriers such as- emulsions, liposomes and polymeric micro- and nanoparticles.^{[Gaillard PJ]} Nanoparticles made from solid lipids are attracting major attention as novel colloidal drug carrier for intravenous applications as they have been proposed as an alternative particulate carrier system. SLN are sub-micron colloidal carriers ranging from 50 to 1000 nm, which are composed of physiological lipid, dispersed in water or in aqueous surfactant solution. SLN offer unique properties such as small size, large surface area, high drug loading and the interaction of phases at the interface and are attractive for their potential to improve performance of pharmaceuticals.^[12,13]

In order to overcome the disadvantages associated with the liquid state of the oil droplets, the liquid lipid was replaced by a solid lipid, which eventually transformed into solid lipid nanoparticles. ^[14]

The reasons for the increasing interest in lipid based system are many – fold and include.

1. Lipids enhance oral bioavailability and reduce plasma profile variability.

2. Better characterization of lipoid excipients.

3. An improved ability to address the key issues of technology transfer and manufacture scale-up.

Advantages of SLN^[^15]:

· Control and/or target drug release.

· Excellent biocompatibility.

· Improve stability of pharmaceuticals4.

· High and enhanced drug content.

· Easy to scale up and sterilize.

· Better control over release kinetics of encapsulated compounds.

· Enhanced bioavailability of entrapped bioactive compounds.

· Chemical protection of labile incorporated compounds.

· Much easier to manufacture than biopolymeric nanoparticles.

· No special solvent required.

· Conventional emulsion manufacturing methods applicable.

· Raw materials essential the same as in emulsions.

· Very high long-term stability.

· Application versatility.

· Can be subjected to commercial sterilization procedures.

Disadvantages of SLN:^[^15,16]

· Particle growth.

· Unpredictable gelation tendency.

· Unexpected dynamics of polymeric transitions.

Aims of solid lipid nanoparticles^[^17]

· Possibility of controlled drug release.

· Increased drug stability.

· High drug pay load.

· No bio-toxicity of the carrier.

· Avoidance of organic solvents.

· Incorporation of lipophilic and hydrophilic drugs.

Materials and Methods:^[^18]

Preparation of solid lipid nanoparticles:^[^20]

Figure 2: SLN preparation method

SLNs are prepared from lipid, emulsifier and water/solvent by using different methods and are discussed below:

Methods of preparation of solid lipid nanoparticles

1. High pressure homogenization

a. Hot homogenization

b. 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

Solvent Emulsification and Evaporation:

In this method Solid Lipid nanoparticles are prepared by precipitation of lipids from emulsions. Lipids are dissolved in organic solvents like cyclohexane and then emulsified in aqueous phase by high pressure homogenization. Nanoparticles dispersion is formed by precipitation of the lipid in aqueous medium and evaporation of solvent from emulsion under reduced pressure (40-60mbar). Nanoparticles of 25 nm size range are formed by this method.

High Pressure Homogenization:

Solid lipid nanoparticles can be produced by most reliable and powerful High Pressure Homogenization technique. In this technique liquid push through narrow gap with high pressure (100-2000bar) using High Pressure Homogenizer. The fluid accelerates with very high velocity (1000km/hr) to a very short distance. Very high shear stress and cavitation forces causes disruption of particles down to submicron range.

Hot Homogenization:

In Hot Homogenization lipid is melted above the temperature of its melting point and pre-emulsion of drug in melted lipid and aqueous phase (hot surfactant mixture) is formed by high shear mixing device. Due to higher temperature viscosity is decreased and small size particles are formed. But High temperature may result into degradation of drug and carrier and increased homogenization pressure may lead to increase in particle size due increased kinetic energy of particles.

Cold Homogenization:

Various problems of hot homogenization like temperature induced drug degradation; drug distribution into aqueous phase during homogenization can be overcome by cold homogenization. In this technique drug containing lipid melt is cooled, the solid lipid ground to lipid micro particles. Then pre-suspension is prepared by dispersing these lipid microparticles into cold surfactant solution and then homogenized at or below room temperature due gravitation force lipid microparticles directly break into solid lipid nanoparticles. Microemulsion Based Method This method involves dilution of microemulsions. Microemulsions are composed of low melting fatty acids (e.g. Stearic acid), an emulsifier (eg. Polysorbate 20), coemulsifiers (e.g. Butanol) and water. This mixture is stirred at 65-70˚C.The hot microemulsion is dispersed in cold water (23˚C) with stirring. Due to high temperature gradients rapid lipid crystallisation occurs and aggregation is prevented. Due to Dilution step lipid contents are lower than HPH based formulations.

Ultrasonic Solvent Emulsification Technique:

This method involves the dissolution of lipid phase into organic solvent such as dichloromethane by heating upto 50˚C. Aqueous phase containing mixture of surfactant and emulsifiers is heated upto same temperature and added to organic phase after partial evaporation of dichloromethane at 50˚C and with constant sirring. This emulsion produced is subjected to sonication for appropriate time and finally cooled in ice bath to get solidify lipid nanoparticles.

Spray Drying Method:

Lipids with melting point > 70˚C are recommended for use in spray drying technique. Due to high temperature, shear forces and partial melting of particles aggregation may occur. By using SLN concentration of 1% in a solution of trehalos in water or 20% Trehalose in ethanol-water mixtures (10/90 v/v) best results can be obtained. Double Emulsion Method Drug and stabilizer are encapsulated to prevent the partitioning of drug into external water phase during solvent evaporation in external water phase of w/o/w double emulsion.

Precipitation Method:

This method involves emulsification of aqueous phase and glycerides dissolved in organic solvent like chloroform. The lipid will precipitated forming nanoparticles after evaporation of organic solvent.

Film – Ultrasound Dispersion:

Lipid and drug are mixed with suitable organic solvent. Thin lipid film is formed after decompression, rotation and evaporation of organic solvent. Then aqueous solution which includes emulsion is added. By using ultrasound with probe to diffuser at last, solid lipid nanoparticles are produced.

Evaluation Parameters:^[21]

1. In Vitro Drug Release:

Dialysis tubing: In vitro drug release is greatly explained by dialysis tubing. In this method SLN dispersion was placed in the previously washed dialysis tubing which can be sealed. The dialysis sac then dialyzed against the specific dissolution medium at room Tem. Then sample is removed from dissolution medium at suitable time period, centrifuged and analyzed for particular amount of drug content by using the suitable analytical method.

2. Reverse dialysis:

In this method different type of small dialysis sac which may contain dissolution medium are placed in the SLN dispersion. Then SLNs are then displaced into the medium.

3. Franz diffusion cell:

In the franz diffusion cell presence of the Donor chamber in which the SLN dispersion is placed with a cellophane membrane. The dispersion is then analyzed against the suitable dissolution medium; then sample is removed from dissolution medium at suitable time period and analyzed the drug content by using suitable method like spectroscopy and HPLC method.

4. Ex Vivo for permeability testing:

The rat jejunum (20-30cm distal from the pyloric sphincter) is excised from the rats after scanning the animal used for the study.

Analytical Characterization of SLN:^{[23, 25]}

1. Particle size and Zeta potential:

For the measurement of the particle size photon correlation spectroscopy (pcs) and laser diffraction (LD) are the most powerful technique for the measurement of particle size. This method covers a size range from a few nanometers to about few nanometers to about 3 micron.

2. Measurement of crystallinity and lipid modification:

Lipid crystallization modification may appear due to the small size of particle and presence of emulsifier. The DSC and X-ray scattering are widely used to determine the presence of lipid.

3. Co-existence of additional structure:

The magnetic resonance technique, nuclear magnetic resonance (NMR) and electron spin resonance (ESR) are mostly used to determine dynamic phenomenon and presence of Nano-compartment in the colloidal lipid dispersion

4. Determination of Incorporated drug:

For determination of drug content the drug and solid lipid particles are separated by ultracentrifugation, centrifugation filtration, or gel permeation chromatography. Then drug content can be determined by using spectrophotometer, HPLC or Liquid Scintillation counting.

DISCUSSION:

SLN comprise an effective drug delivery to brain. The advantages of SLNs like controlled release kinetics, improved bioavailability, avoid gastric degradation; physical stability and no special solvent required make them a choice for drug delivery to the brain. SLNs thus open new channels for delivery of drug to brain like antitubercular, antianxiety, antibiotics, neuroleptics etc. SLN are good formulations as targeted drug delivery system.SLN bears the properties of good patient compliance and economical for delivery of drugs.

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Received on 13.10.2020 Modified on 05.11.2020

Res. J. Pharma. Dosage Forms and Tech.2021; 13(1):57-61.

DOI: 10.5958/0975-4377.2021.00010.0