A Comprehensive Review on Novel Lipid-Based Nano Drug Delivery

Novel drug delivery system opens the doors towards nano/micro formulation strategies to overcome the challenges associated with the poorly soluble and permeable drugs. Lipid based nanoparticles are widely accepted that includes liposomes, niosomes and micelles which are FDA approved. Such lipid based drug delivery allows delivery for natural phytoconstituents, biopharmaceutical classification system (BCS) class II and class IV drugs are effectively delivered to improve its solubility, permeability and bioavailability. The article provides the recent advances and application of lipid based dosage form for improvement of therapeutic efficacy.


Introduction
Novel drug delivery system opens the doors towards Nano/ Micro formulation strategies to overcome the challenges associated with the biopharmaceutical classification system (BCS) class II and class IV drugs. 1 Such medication or drug delivery targets the drug at required site that too in low concentration and improves therapeutic efficiency.Novel drug delivery system includes microparticles, nanoparticles such as lipid based liposomes, niosomes, phytosomes, micelles, hydrogels, quantum dots, nanotubes, dendrimers etc. 2 Nanoparticulate drug delivery system have particle size which ranges between 1 to 100 nm.The drug movement across the barrier will get improved due to development of nanosized particulate system. 3Nanomaterials have wide application in the treatment and diagnostic purpose. 4,5urrently lipid based dosage forms are popular that includes liposomes, niosomes, micelles etc which are FDA approved.Such lipid based drug delivery systems have found to be effective for natural phytoconstituents and inorganic particles like gold. 6The advantages of lipid based novel drug delivery system are associated with the majority of drugs.
[9][10][11] 1. Poor solubility and poor permeability of drug.2. Decrease in size of particle leads to increase in effective surface area which ultimately improves dissolution rate of poorly soluble drugs.3. Nanomaterials are being used in many different biological and medical fields because they reframe optical, electrical, chemical and physical properties.4. Increases mobility of particle that helps to increase bioavailability.5. Nanomaterials have application in targeted and controlled delivery of biopharmaceuticals.6. Due to nanosized structure, it can easily cross mucosal membrane whereas Microsystems has capacity to cross epithelial lining.7. Increased drug therapeutics efficacy and reduced side effects.8. Protection of drug from first pass metabolism and enzymatic degradation.

Solubility and permeability
Solubility is one of the key parameter that directly affects the activity and bioavailability of drug.The variety of factors that has influence on solubility of the drugs are pKa of drug, pH at gastrointestinal tract (GIT), presence of luminal pH. 12,13Physiological and physicochemical factors have influence on drug solubility. 14,15olubility depends on chemical, electrical, structural properties of the solute and interaction between solute solvent.The USP 38, European pharmacopoeia categorized solubility in seven different group. 16iopharmaceutics classification system was developed by Amidon et al in 1995.The BCS classification has application for the development of immediate release oral dosage forms.8][19] Solubility and permeability improvement for BCS class II and BCS class IV drugs respectively has a major obstacle for the formulation scientist (Table 1).There are various approaches are reported till today to enhance the solubility for such drugs.Permeability study also shows the movement of drug into the circulatory system through GIT.
][22] Variation in pH environment in GIT has influence on drug solubility for BCS class II drugs.
BCS classification allows the formulator to correlate the physicochemical properties of drug and its solubility, permeability to make a judgment on bioavailability.It reduces the time, cost of drug delivery and development.It is approved by US Food and Drug Administration (USFDA).The regulatory agencies such as European Medicine Agency (EMEA) and World Health Organization (WHO) for bioavailability/bioequivalence standards for approval of drug product and gives directions for In-Vitro, In-vivo dissolution study. 23,24asic fundamentals of BCS classification are the three dimensionless numbers as dose number, absorption number and dissolution number which calculates the amount of drug. 25ose number (high solubility): when the highest clinical dose is dissolved in 250 mL buffer at all pH values within the range 1-7.5.
Permeability: High permeability means the drug product is stable in GIT and drug absorption is greater than 90% of the given dose.Permeability is defined as passage or movement from site of administration (Gastrointestinal track) to the systemic circulation across the biological membranes is called permeability.Permeability depends upon the absorption of drug and absorption is depend upon various properties of drug, receptors, biological membranes, types of transport etc.

Types of lipid based nano drug delivery system
The major obstacle for the drugs to develop into dosage form is associated with poor aqueous solubility, poor permeability, poor absorption, extensive first pass metabolism, systemic metabolism and efflux proteins (P-glycoprotein). 26It is important for further clinical improvements of drugs.Researchers were tried with variety of techniques to overcome these issues which includes Lipid based drug delivery systems, Polymer based drug delivery system, Nanocarriers, Nanocrystals, liquisolid technology, solid dispersions etc (Figure 1).Amongst these techniques lipid based nanoparticulate formulation was found to be beneficial.

Liposomes
Liposomes are the spherical vesicles made up of amphiphilic phospholipids.Phospholipids has capability to encloses both hydrophilic and hydrophobic drugs and possess property to self assemble. 27

Mechanism of liposome formation
The lipids phase is added into the aqueous phase.It forms bilayers by hydrophobic interaction or hydrophilic interaction between lipid-lipid or lipid-water molecules (Figure 2).These formed lipid layers are set as vesicles by external energy such as sonication, homogenization, heating, freezing etc.

Classification of liposomes
The liposomes will be classified based on material used for the preparation, types of lipid or combination of lipids used, based on method of preparation techniques and depending upon the size of vesicles formed (Figure 3).
A. According to size and shape of liposome: Liposomes were classified according to the size, number of bilayers formed in particle and according to their pattern.They are classified as multilamellar large vesicle which is greater than 0.5 µm size.Multilamellar liposomes are those which are with a number of lipidic bilayers.Oligolamellar liposomes means vesicles are same as that   3).B. Based on composition: According to the source of lipids used in preparation of liposome (Table 4).
C. Based on method for preparation of liposome: Various methods are reported for the preparation of liposome as mechanical dispersion, solvent dispersion, de-emulsification, detergent removal method (Table 5).

Niosomes
Niosomes are the non-ionic surfactants containing liposomes.Surfactants such as fatty alcohol, esters and copolymers are used in the development of niosome formulation.Niosomes formulation contains surfactant. 44,45he main component is surfactant.The surfactants possess both hydrophilic and hydrophobic groups and hence these are widely accepted (Table 6).According to head group properties, surfactants are classified as anionic, cationic, amphoteric and nonionic.Nonionic surfactant is mostly used because they are more stable, less toxic and compatible.

Name of method Instruments used
Mechanical dispersion: Process: Co-dissolving lipids in organic solvent, Organic solvent is removed by film deposition under vacuum.
Ethanol injection (water miscible solvent) Fine needle 39 Ether injection (water immiscible solvent) Fine needle 40 Rapid solvent exchange Narrow needle 41 De-emulsification: Process: breakdown of large emulsion vesicles that have capacity to reform when broken down.

Reverse phase evaporation technique
Evaporator 42 Detergent removal method: Process: micelles are formed with the help of detergents.

A. High pressure homogenization (HPH)
HPH is most widely used and accepted technique used in pharmaceutical industries.In the high pressure homogenizer, liquid phase is need to passed with high pressure through narrow orifice of micron or submicron size.This leads to reduction in particle size.HPH process is of two types as hot homogenization and cold homogenization.For both the types drug is to be dissolved in the lipids and dispersion is made.Afterward according to method temperature is need to be maintained.

I. Hot homogenization method
The hot homogenization method includes temperature which is more than the melting point of the lipid.Lipid is allowed to melt and into molten lipid drug is added.This process makes microemulsion also called as pre-emulsion which is maintained at high temperature and mixed with the aqueous phase with surfactants (Figure 5). 53

II. Cold homogenization method
The heat sensitive drugs undergo degradation at high temperature in hot homogenization method.To improve drug stability cold homogenization method is preferred.The dispersion of drug and lipid is added to liquid nitrogen or dry ice to drop down the temperature of the sample.Afterward sample is allowed to cool at room temperature or lower temperature.The resultant powder product is SLNs (Table 7). 53

B. Solvent evaporation/emulsification method
In solvent evaporation/emulsification method lipophilic material is dissolved in an organic solvent and further emulsified in an aqueous phase.It forms a to give an oil in water type of emulsion. 58The prepared emulsion is stirred on mechanical stirrer to allow organic solvent to evaporate.SLNs are formed due to precipitation of lipid phase in water or aqueous phase.In this method polarity of two phases should be of opposite to form o/w emulsion (Table 8). 59mitations 1.Large amount of emulsifiers are needed to get small size particles.

C. Solvent emulsification diffusion Technique
It consists of preparation of suspension from emulsion by a solvent diffusion technique.This process is also based on water miscibility of solvents (Figure 6).The water miscible solvents such as butyl lactate, benzyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate etc are widely used.Suspensions are prepared from emulsions (with partially water miscible solvents).Process depends upon water miscibility of solvents (Tables 9 and 10).Mechanism: It involves addition of organic phase into aqueous phase that leads to formation of o/w emulsion.Emulsion is diluted with water.During agitation provided by mechanical stirrer, dissolved drug in organic solvent gets solidified instantly due to diffusion of the organic solvent from droplets to continuous phase which forms hollow spheres (Figures 7 and 8).
Advantages 66 1.The technique is easy to scale-up.2. Exposure of drug to high temperature and physical stress will be avoided.3. The technique is suitable for both hydrophilic and hydrophobic drugs.
Disadvantages 67 1.The method requires dilution of dispersions 2. Technique requires purification process to remove residual organic solvent.

Nanostructured lipid carriers (NLC)
0][81] The main formulation ingredients include lipids, emulsifiers and water.The preparation methods are similar to that of the SLN.SLN and NLC are similar in characteristic and techniques of preparation (Table 11).In case of SLN   preparations, solid lipids are used whereas for NLC, liquid lipids or blend of solid lipid with a liquid lipid are used (Figure 9).NLC are of three different types according to their form. 82,83. Imperfect type b.Amorphous type c.Multiple type a. Imperfect type Imperfect type of NLC is prepared by different lipids with different structures and it misleads the crystal structure.This misleading can be improved with by changing saturation and number of carbon atoms in lipid.This leads to an increase in the loading capacity for drug.
b. Amorphous type Amorphous matrix is formed by mixing solid lipids with each other which forms amorphous structure.

c. Multiple type
These are prepared by lipid-solid and solid-water  interaction.Multiple type NLC have the advantage of increased drug loading and prolonged release of drugs due to the presence of oil droplets dispersed in solid matrix.Advantages 1. Increased drug loading capacity as that of SLN. 2. Due to use of liquid mixture, differently structured molecules are formed which makes perfect crystal.3. Perfectness of NLC system is its imperfectness for crystalline structure because they carry lattice space in between particles

Microemulsion method
These are the transparent system containing two immiscible fluids stabilized by interfacial surfactant or combinations surfactant with cosurfactants film. 88Microemulsions possess ultralow interfacial tension between the immiscible phases which gives thermodynamic solubility, spontaneous formation, simplicity of preparation, solubilize all lipophilic, hydrophilic and amphiphilic solutes, improve solubilisation and bioavailability of hydrophobic drugs and increases permeation (Table 12).Microemulsion method is the oil based two phasic system which contains aqueous phase and oil phase (Figure 10).Diluting microemulsion in a cold aqueous solution result in nanoemulsion then SLN/NLC prepared by lipid precipitation.

Advantages
1. Thermodynamically stable, clear or colorless.2. large scale manufacturing is possible.Disadvantages includes requirement of high surfactant concentration.

Hydrogel
Hydrogels are three dimensional structures (formed by chemical or physical cross linking), hydrophilic and polymeric networks (cross linked monomers or chains of co-polymers) with water or biological fluid (Figure 11, Table 13). 93The hydrophilicity of hydrogel is due to the chemical structure of polymer backbone or group such as -OH,-COOH,-CONH,-CONH 2 ,-SO 3 H and its less solubility is due to covalent bond between polymer chains or hydrophobic force, micellar packing, ionic bonding, crystallizing groups and due to presence of various bonds in the network gels. 94,95ydrogels are classified as (a) Physical hydrogels: By the formation of bonds like ionic, hydrogen or hydrophobic bonds.(b) Chemical hydrogels: Crosslinked networks, cross linking of water soluble polymers.(c) Ionic hydrogels: Polyelectrolyte are combined with multivalent ion of the opposite charge.
Dried hydrogel also called as xero gels are more absorptive than that and called super absorbent.

Nanocochleates
Nanocochleates are cream role like structure which is formed by the lipid bi-layers by interaction of liposomes and cations (Table 14).The sheet of phospholipids carries high tension at their edges which causes nanocochleates binding with tissue membrane (Figure 12). 101,102

Conclusion
Novel drug delivery systems had emerged as a promising

Figure 7 .
Figure 7. Mechanism of Sphere particle formation by solvent emulsification diffusion technique

Figure 8 .Figure 9 .
Figure 8. Process of solvent emulsification diffusion method for SLN or NLC

Table 2 . BCS Sub classification Class II Solubility Example Gastric pH solubility Instestinal pH solubility
Class II c (Neutral drugs)No dependent on pH change Fenofibrate etc.

46
Advantages 1. Designed for drugs which has poor absorption to enhance bioavailability.2. Solubility/ Permeability is enhanced as niosomeal drug delivery crosses anatomical barriers of GIT via transcytosis of M cells of Peyer's patches in intestine.3. Niosomes has capacity to release drugs in the gradual and controlled manner.4. Niosomes are easily modified due to presence of hydrophilic and lipophilic head groups.

Table 3 .
Types of liposomes according to size

Table 4 .
Types of liposomes based on lipid composition

Table 5 .
Types of methods of preparation of liposomes

Table 6 .
Examples of niosome prepared by film hydration Technique

Table 7 .
Examples of Solid lipid nanoparticles prepared by High Pressure Homogenization techniques

Table 8 .
Examples of solid lipid nanoparticles containing drug prepared by solvent evaporation method 65mesartan medoxomil Glyceryl Monostearate, Soya Phosphatidylcholine and Tween 80As antihypertensive652.Time and energy consuming method.3.Solvents used if not biocompatible needs further purification is needed.

Table 9 .
Examples of solvent emulsification diffusion technique for SLN preparation

Table 10 .
Indian Patents published for solid lipid nanoparticles by various methods

Table 11 .
Literature examples for development of Nanostructured lipid carrier formulations

Table 13 .
Hydrogel types and mechanism of drug release