A Boon To Poorly Soluble Drugs-Lipid Soluble Systems

Received: 27-Sep-2021;Accepted Date: Oct 11, 2021; Published: 18-Oct-2021

Introduction

Nowadays, most of the recent drugs are hydrophobic in nature and are poorly aqueous soluble and that may cause complications while choosing the correct drug delivery system to attain the best bioavailability of these drugs. Factors like poor water solubility and dissolution rate decrease the absorption rate and bioavailability. No doubt, most of the drugs are administered only orally. The oral bioavailability of these medications mainly depends on many factors associated with aqueous solubility, and permeability through lipid membranes [1-3]. Orally administered medications should possess good solubility, which in turn, has good absorption. If solubility is sensitive within the gastric medium, at this stage solubility (low or high) and permeability through lipid membranes (low or high) issues arise. These medications are being categorized into class II (low solubility or high permeability) or class IV (high solubility or low permeability) as stipulated by BCS (Biopharmaceutical classification system). Various approaches have been developed to enhance solubility that attains the best bioavailability of poorly soluble drugs. Amongst the promising drug delivery approaches are lipid based drug delivery systems (LBDDS) [4,5]. This is confirmed when poorly soluble drugs are co-administered with fat meals. LBDDS has recognized that oral availability improves widely.

LBDDSs are of various types of oily suspensions or simple oil solutions to coarse, moderate, multiple and also dry emulsions. LBDDSs are also more complex self-emulsifying drug delivery systems (SEDDS), Self-micro emulsifying drug delivery systems (SMEDDS) or Self Nano emulsifying drug delivery systems (SNEDDS) [6]. Some of the marketed products developed as SEDDS are Calera^® and Ritonavir (ABOTT), Targretin^® and Bexarotene (NOVARTIS), Convulex^® and Valproic Acid (PHARMACIA), Lipirex ^® and Fenofibrate (SANOFI-AVENTIS) [7-10].

The present review focuses mainly on differentiating, oral applications, mechanisms of various lipid based drug delivery systems in enhancing solubility and bioavailability of poor water soluble drugs. Different methods are present to differentiate LBDDSs like SEDDS, SMEDDS and SNEDDS.

Lipid Based Formulations

This lipid based carrier system has been designed to attain local effects, and to regulate and enhance drug delivery of medications [6]. LBDDS contains a mixture of lipids, surfactants and additionally a hydrophilic co-solvent. The Lipid formulation classification systems were categorized into four (I-IV). The LBDDS structure and characteristics are depicted in Table 1 [11].

Table 1: Classification of LBDDSs and their properties

Advantages and Disadvantages

Type I is safe and good compatible, Type II has an unlikely solvent capacity on dispersion, Type IIIa forms clear emulsion, which makes drug absorption without digestion, Type IIIb forms Transparent emulsion, which makes drug absorption without digestion, and Type IV has good solvent capacity for drugs. It disperses and forms a micellar solution. Type I has a solvent capacity limited to lipophilic drugs only; Type II formed an emulsion and has particle sizes ranging from 0.25 μm to 0.2 μm. Type IIIa has a solvent capacity lost upon dispersion and is less easily digested. Type IIIb has a solvent capacity partially lost upon dispersion and less easily digested, and Type IV is found to have the risk of drug precipitation upon dispersion and may not be digestible [12,13].

Mechanism

LBDDSs are more advantageous in enhancing oral bioavailability. SNEDDS are more advantageous over SEDDS/SMEDDS because SNEDDS is smaller in particle size, and this increases the particle’s surface area with low free energy. SNEDDS enhances the permeation of poorly water-soluble drugs, oral absorption and oral bioavailability due to the presence of surfactants and co- surfactants. But Stability is the main disadvantage of SNEDDS and it can be overcome by converting Liquid SNEDDS into Solid SNEDDS.

LBDDSs are called SEDDSs. SMEDDSs are formed by mixing water soluble components (surfactants/co-solvents) with the oil part that belongs to category III [11]. SNEDDS are a mixture of oils (lipids/fatty acids) formed by surfactants, co-surfactants, co-solvents and an aqueous phase that belongs to category IV. In SNEDDS, the usage of oil may form a turbid emulsion and this may be avoided by not using turbid oil like lipids/fatty acids [14-16].

Factors Affecting LBDDS

Some of the factors that influence the LBDDS are as follows:

• Mean droplet size: Reducing the droplet size, decreases interfacial tension and results in increasing the surface area of the particle size, thereby providing faster drug release from the emulsion in a controlled and reproducible manner.

• API lipophilicity: The drugs that are (log p>5) i.e., highly hydrophobic and avoid first pass metabolism by portioning into chylomicrons and thus are taken up into the lymphatic system.

• Nature of the lipids: Absorption depends on the nature of the lipids. Long chain triglycerides provide better absorption than medium chain triglycerides in SMEDDS.

• Lipid digestion: The Proper lipid vehicle has to be selected to avoid fluctuations in the absorption rate.

Types of Lipid-Based Drug Delivery Systems

There are different types of LBDDSs like simple drugs in lipid solutions or suspensions, emulsions, SEDDS, SMEDDS and SNEDDS. According to the Lipid-based classification system, SEDDSs are classified as Type II and IIIa systems. SEDDSs are formulated with the mixing of drugs, lipid vesicles and non-ionic surfactants without water that is accepted to exist as isotropic transparent solutions. SEDDS having the property of self-emulsifying immediately forms fine oil in water emulsions by gastrointestinal motion produced by gastrointestinal fluids. SEDDSs are formulated in soft and hard gelatin prepared by using polymers like HPMC (Hydroxypropyl Methyl Cellulose) [16-18].

SMEDDSs produce smaller emulsion droplets upon dilution that is transparent or translucent stable dispersion and have a droplet size <100 nm, whereas SEDDS is distinguished by having a size <300 nm. SMEDDS contains relatively high concentrations of surfactants (30% to 60%, m/m) and also hydrophilic co-solvents like propylene glycol, polyethylene glycols, which form micro emulsion upon dilution with aqueous media and hence, termed as micro emulsion [19-22].

The IIIb systems are known to be SNEDDS that are formed as transparent fine emulsions or dispersions of oil in water spontaneously, having a size of 200 nm upon dilution with water by continuous stirring. According to LBCS, formulations like SNEDDS are called as type IV systems, because SNEDDS contains one /more hydrophilic solvents, co-surfactants/ co-solvents, that are termed as oil free formulations because they formcolloidal micellar dispersions upon dilution in the aqueous phase. SNEDDS are thermodynamically unstable formulations and can be stabilized by converting liquid SNEDDS into solid SNEDDS to maintain stability by formulating dispersions using different techniques [23,24]. The differentiation of LBCS into SEDDS/ SNEDDS/SMEDDS characteristics that are termed as water free systems is described in the following Table 2 [16,25-27].

Table 2: Differentiation of LBDDS

Criteria for Selection of Excipients for Lipid-Based Formulations

For developing a LBDDS, the selection of excipients is important to produce an efficacious dosage form. API should blend in suitable oil, surfactant, co-solvents and excipients of the best choice and should possess the following properties [28].

1. Non-toxic, Inert

2. Should provide good self – emulsification.

3. Self-dispensability

4. Digestibility of the suitable excipients

5. Purity and chemical stability of excipients.

Oil phase

While selecting the oil phase for formulating, LBDDS should possess properties like chemical stability, polarity, interfacial tension in the water phase, density, viscosity, and phase behavior [15]. For hydrophobic drugs, it may impact on disintegration and may add lymphatic transport leading to drug precipitation in GIT. The oil phase is made up of glycerides, (mixture of mono, di and triglycerides) consisting of long / medium chain unsaturated fats. Additionally, surfactants like polar oils are also used. The following Table 3 describes the characteristics of the glycerides [29- 31]. According to the review data, it was concluded that MCT was selected for LBDDS due to its better properties like solubilization, self-emulsification capacity and better stability of API than the LCT [32]. Mono and diglycerides have good self-emulsification capacity and better solvency properties due to their amphiphilic nature compared with triglycerides [33].

Table 3: Characteristics of the Glycerides

Surfactants

The Selection of a suitable surfactant like emulsifier is a very important factor that influences the formation of the LBDDS structure factors like pH, ionic strength and temperature variation are also influenced by the emulsifier being used. The stability of emulsions is decided by the usage of a combination of surfactants (emulsifier)/co-surfactants(co-emulsifier) with their respective HLB values. An emulsifying agent is used to maintain the steady state between the internal and external phases of the oil in water emulsion interphase by decreasing the interfacial tension and preventing conglomeration. The differentiation of hydrophilic or lipophilic surfactants is described according to the HLB values and displayed in Table 4 [34].

Table 4: Differentiation of surfactants

The selection of suitable surfactants is a critical step during formulations to maintain the safety of the dosage form. Non-ionic surfactants like Poly-ethoxylated lipid derivatives are mostly preferred and used [35,36]. Poly-ethoxylated lipid derivatives consist of fats, alcohols/glycerides that are linked with repeated polyethylene oxide units by ester linkage (glycerides, unsaturated fats) and by ether linkage (alcohols). Hydrophilic attributes are given to polyethylene groups [19,35]. Natural origin surfactants are more preferred than synthetic surfactants because natural surfactants had more safety over synthetic ones [37]. Non-ionic surfactants had reduced toxic effects over cationic and ionic surfactants and also offer better adjustment of pH and ionic strength. The stability of SMEDDS is attained by using surfactants ranging from 30% to 60% [34,38].

Co-Surfactants/co-solvents

During the formulation of LBDDS, co-solvents are used to improve the limitation of the solubilization of substituted drugs and also enhance the dispensability of hydrophilic surface active agents in the oil phase. Medium chain alcohols having 8 to 12 C atoms produce better results; otherwise, can include ethylene glycol, propylene glycol, and glycerol to produce a satisfactory dosage form [11,34,36]. Selection of co-solvents in the case of hydrophobic drugs is taken into consideration to avoid precipitation of hydrophobic drugs after dilution of co-solvents’ formulation in the aqueous phase. Complexation of LBDDS is enhanced by the usage of co-solvents. LBDDSs are stable in the absence of solvents like alcohols/ volatile solvents [6,32].

Oral bioavailability enhancement techniques for poorly water soluble medications

The LBDDS self-emulsifying systems offer better bioavailability by providing continuous supply of medication and improving drug absorption. The drug is protected from enzymatic or synthetic degradation by incorporating medication into the lipid beads [6,38]. Different techniques are used for enhancing oral bioavailability by increasing solubilization, extension of medication retention in the stomach, modifying bio-chemical barriers and physical barriers during absorption of medications and through stimulating intestinal lymphatic transport [12,16,28,39].

Discussion

During the formulation of LBDDS, type III and IV have the nature of drug precipitation [28,37,38]; if the surfactants/ co-surfactants/co-solvents are not properly selected this may affect the bioavailability of medications. To overcome this problem, while selecting excipients the following parameters have to be taken into consideration, like lipid digestion, mean droplet size of emulsion, Active pharmaceutical drug lipophilicity, and compatibility or attractiveness of lipids [40-43]. By using SEDDS, SMEDDS and SNEDDS, scientists have improved the bioavailability of different poorly soluble drugs. The drug details are mentioned in Tables 5-7 (Figures 1 and 2).

Table 5: List of drugs whose bioavailability is enhanced by SEDDS

Table 6: List of drugs whose bioavailability is enhanced by SMEDDS

Table 7: List of drugs whose bioavailability is enhanced by SMEDDS

Figure 1: Mechanism of LBDDS

Figure 2: Graphical abstract

Conclusion

A Lipid Based Drug Delivery System (LBDDS) has been proved to be a promising approach to enhance the absorption, and oral bioavailability of poorly water soluble drugs by spontaneous emulsification and formation of emulsion, micro emulsion and nano emulsion. In the development of LBDDS, different surfactants, co-surfactants are used which may cause compatibility, and stability issues of LBDDS. These issues can be overcome by converting liquid LBDDS (SEDDS/SMEDDS/SNEDDS) into solid LBDDS.

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