NANOSTRUCTURED LIPID CARRIERS –A PROMISING CARRIER FOR IMPROVING ORAL BIOAVAILABILITY OF DRUGS

NANOSTRUCTURED LIPID CARRIERS –A PROMISING CARRIER FOR IMPROVING ORAL BIOAVAILABILITY OF DRUGS

Dhinsha Murugan

Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai, Tamil Nadu, India.

ABSTRACT: To deliver both conventional as well as novel drugs, the oral route was considered as the most preferable one because it reduces patient’s non-compliance, well accepted by the patients, and can also eliminate the discomfort and pain accompanied by parenteral preparations. Even while oral formulations offer numerous advantages, several drawbacks substantially affect bioavailability. In recent years, lipid-based drug delivery techniques have gained more prominence over other nano-based techniques due to their high biocompatibility and increased bioavailability. Nanostructured lipid carriers (NLCs) are one of the lipid-based carriers developed to overcome some major limitations accompanied by solid lipid nanoparticles (SLNs) by replacing specific quantity of solid lipid with liquid lipid. Nanostructured lipid carrier based researches reveal that they can be the most propitious carrier to enhance oral bioavailability of  lipophilic as well as hydrophilic drugs This review mainly focuses on some common barriers that affect the bioavailability of orally administered drugs and provide brief explanation of NLC types, components and fabrication method used in NLC formulations. The present review emphasizes the dominance of NLCs over solid lipid nanoparticles. This review further explains the mechanism of how NLCs improve the oral bioavailability of drugs.

Keywords: Nanostructured lipid carriers (NLC), oral bioavailability, Lipid-based drug delivery system (LBDDS), Nanoparticle,  Lipophilic drug, solubility

INTRODUCTION: In commercially available drug products, around 60% of drugs are administered through oral route ¹. Around 70% of compounds under investigation are considered poorly soluble, and around 40% of currently marketed drugs are also considered poorly soluble ². The molecular weight and lipophilicity of newly synthesized chemical entities are greatly increased because of combinatorial chemistry and screening of molecules to improve its pharmacological effects by minimizing toxicities. It ultimately results in decreasing the aqueous solubility of drug molecules.

The bioavailability of orally administered drugs mainly depends on the solubility of drugs at their site of absorption. Apart from that, permeability is the second criterion that affects the drugs' bioavailability. In 1995, Amidon et al. introduced Biopharmaceutical Classification System (BCS) based on drug solubility (Based on USP aperture) and permeability (Based on intravenous injection comparison).

In the scientific aspect, the oral bioavailability of drugs categorized in BCS class II is augmented by improving the aqueous solubility. BCS class III drugs are augmented by improving intestinal permeability ⁴. For BCS class IV, solubility and permeability improvement are necessary for its oral bioavailability augmentation ¹. Researchers have endeavored a range of ways to improve oral bioavailability For example Polymeric micelles formation, development of nanoparticles, lipid-based formulations like liposomes, emulsions etc. Researchers improve the bioavailability of lipophilic drugs (lipophilic drugs) and highly soluble carriers by creating a mixture of poorly water-soluble drugs (solid dispersion). Researchers have also studied using chelating agents and ionic polymers to enhance the absorption of drugs ⁵. Nanotechnology-based approaches are gaining more popularity in recent times because surface area of the particles increases when their size decreases, resulting in accelerated disintegration by a small order of magnitude. This may be sufficient in certain circumstances to enhance bioavailability. Here, lipid-based carriers used to deliver drugs have given a glimpse of hope in recent decades due to their beneficial effects on the absorption of drugs ⁶.

Physiological Issues in Oral Delivery: Oral medication’s effectiveness is largely determined by how drugs and drug delivery vehicles are processed by the gastrointestinal tract ⁷. Extreme acidic conditions inside the stomach (pH 1-2.5) are the first biological barriers to any orally delivered medicine. Degradation of most of drugs substantially decreases their effectiveness. The Macrolid antibiotic erythromycin-A is rapidly inactivated in the stomach because of its high acid sensitivity. Gastric enzymes (pepsin) and pancreatic enzymes (amylase, lipase, peptidase etc.), which are found in abundance near the small intestine’s major entry (duodenum) can destroy biopharmaceuticals ⁸.

Drug degradation in the intestine, generally caused by luminal fluids, bacteria or enzymes in gut wall has posed substantial problems in bioavailability ⁹. CYP3A family of enzymes is the most common phase-1 drug-metabolizing species in humans. It is thought to metabolize 50–70% of commonly prescribed medications ¹⁰. Researchers have found that CYP3A in the small intestine is typically 10–50% of those in the liver. Nevertheless, some people have had CYP3A equal to or above those seen in the liver ^{9, 10}. Sedatives such as triazolam and diazepam, antidepressants like imipramine, anti-arrhythmias like amiodarone, quinidine and disopyramide, antihistamines like terfenadine and loratidine, calcium channel antagonists like diltiazem, are metabolized by this enzyme ¹¹. P-gp is found in diverse of tissues, including kidney, liver, BBB cells, lungs, adrenals, pancrease, bladder and spleen as well as the stomach, jejunum and oesophagus which are essential for oral delivery of drugs. P-gp mRNA levels grow longitudinally in the gut, with the lowest level in the stomach and the greatest level in the colon, in direct contrast to the CYP3A observation ¹⁰. Cyclosporine, digoxin, edoxaban, tacrolimus are some examples of drugs that are substracted of the P-gp efflux pump. The activity of the metabolic CYP3A4 enzymes and the P-gp system are linked because they perform together to prevent lipophilic drugs from entering the systemic circulation ¹⁰.

The stomach's alkaline microclimate and the small intestine's acid microclimate alters the drug’s absorption. Intestinal mucus and UWL have a major role in limiting lipophilic drug absorption and maintaining an acidic microenvironment in small intestines ¹³. The aqueous diffusion layer proximal to intestinal membrane, often known as unstirred water layer (UWL), has long been suggested as a significant obstacle to drug absorption through intestine ¹⁴. Drug molecules in intestinal lumen must penetrate the UWL in order to reach brush border membrane. Because lipophilic compounds have low solubility in aqueous fluid, diffusion via this layer has been recognized as rate-limiting and it greatly affects the bioavailability ¹⁵. Fig. 1 depicts some of the physiological barriers encountered during the oral route.

FIG. 1: PHYSIOLOGICAL ISSUES IN ORAL ROUTE

Lipid-Based Delivery of Drugs ¹⁶: Lipid-based drug delivery systems are primarily made up of specific lipid combinations. LBDDS can imitate the natural digesting process of lipid-based food in GI tract. So, this LBDDS has recently acquired much interest in improving oral bioavailability of drugs. They have better drug loading capacity and dissolution. LBDDS have a better future as a drug carrier because of their similar composition of biomembrane and enhanced biomembrane penetration. Different types of LBDDS is given in Table 1.

TABLE 1: CLASSIFICATION OF LBDDS ^{17, 18}

Nanostructured Lipid Carrier: In 1990, M. R. Gasco from Italy and R.H. Muller/ Berlin and J. S. Lucks from Germany worked on lipid nanoparticles at the same time, but they used a different method for the formulation, namely the former used the microemulsion technique and latter using high-pressure homogenization technique. Solid lipid is the unique particulate carrier in this formulation; later, these formulations were considered the best alternative to liposomes, polymeric nanoparticles, and nanoemulsion. This formulation was known as solid lipid nanoparticles (first-generation nanoparticles). Followed by SLN, in 1999 Nanostructured lipid carriers were designed to overcome the shortcomings of Solid lipid nanoparticles. These are second-generation nanoparticles. At that time, researchers believed only lipophilic drugs could be loaded into NLC but not hydrophilic drugs. Muller and Orbrich created lipid-drug-conjugates (LDC) to address these issues in 2001. But several recent studies reveal that, apart from lipophilic drugs, NLCs act as the best carriers for hydrophilic drugs, too ¹⁹. For example, Awadeen et al. developed Zolmitriptan/ chitosan nanostructured lipid carrier particles by the Double emulsion (W/O/W) technique. Zolmitriptan is a hydrophobic drug that comes under BCS class III (High soluble; low permeable); by formulating ZT-NLC, the researchers improved the permeability and thereby augmenting the bioavailability of ZT ²⁰. NLCs are nanoparticulate carrier systems having a particle size range of 10 nm to 1000 nm ²⁴. Solid lipid, liquid lipid, solubilizer/surfactant , and water are the main constituents in NLCs. The objective underlying NLC-based formulation is to create particles in which oil is incorporated into the solid lipid core, resulting in increased drug loading capacity and controlled release ²¹.

Comparison between NLC and SLN: Comparison between various properties of NLC and SLN are given in Table 2.

TABLE 2: NLC AND SLN COMPARISON

Types of NLC ²²:

Type I: Imperfect Crystal: Highly disordered matrix, Having many gaps and spaces. Allow more drug particles to be accommodated in amorphous clusters.

Type II ²¹: Multiple Types: High oil content. When oil is introduced more than its solubility phase separation occurs, resulting in a microscopic nano-compartment in which oil is encased in a solid matrix.

Type III: Amorphous type: Addition of hydroxyl stearate, octacosanyl (or) dibutyl adipate in solid lipid form structureless amorphous phase.

NLC Components ²¹: All components employed in NLC have been GRAS (Generally Recognized as Safe) by regulatory authorities. The components used are generally biodegradable, biocompatible, non-toxic, and easy to get regulatory approval. Commonly used excipients in NLCs are solid lipids, liquid lipid, surfactants. Ideal solid lipid to oil ratio is from 70: 30 to 99.9: 0.1 and 0.5% to 5% of surfactants are used as stabilizers ²³. Lipid components used in NLC formulations are listed in Table 3 and surfactants used in NLC formulations are listed in Table 4.

TABLE 3: EXCIPIENTS USED IN NANOSTRUCTURED LIPID CARRIERS ^{25, 27-38}

TABLE 4: SURFACTANTS/ SOLUBILIZERS USED IN NANOSTRUCTURED LIPID CARRIERS

Techniques Used in the Fabrication of NLC ^{22, 23, 25}: Different techniques used to fabricate nanostructured lipid carrier (NLC) are short-listed in Table 5.

TABLE 5: TECHNIQUES USED IN THE FABRICATION OF NLC ²⁵

Technique with High Energy Level:

High-Pressure Homogenization (HPH): In HPH- technique, liquid is squeezed through a confined area at high pressure(100-2000 bar). The high pressure combined with the small gap size results in extremely high acceleration and pressure drop. The mechanism involved: high shear stress and cavitation forces. The hot HPH technique is carried out at temperatures over the lipid's melting point. High-shear mixers are commonly used to create a pre-emulsion. Usually, up to 3 cycles at a bar pressure of 500 and increased temperature are employed.

Formed pre-emulsion (hot) is cooled and solidified. In Cold HPH-technique hot lipid blend and drug mixture are usually solidified with dry ice or with liquid nitrogen.

Cold surfactant solution is added in grinded and crushed lipid Microparticles, forming a cold pre-suspension. Homogenization is carried out in 5-10 cycles at bar pressure of 1500.

High Shear Homogenization: Rotor-stator homogenizer is used in this technique. High shear rate of 5000-25000 rpm is applied at a temperature higher than the lipid’s melting point. High shear homogenization alone does not reduce the particle size. So in HPH-technique and ultrasonication, this approach is typically employed as a pre-homogenization step.

Ultrasonication: The cavitation in aqueous dispersions induced by intense ultrasound with a wave frequency generally around and above 20 kHz is the fundamental for ultrasonication. By applying ultrasound with the help of sonotrode in pre-emulsion, form NLC.

Technique with Low Energy Level:

Microemulsion Technique: This method utilise high amount of surfactants to form micro-emulsion. Molten lipid blend and hot surfactant solutions are mixed together until microemulsion is formed. Under gentle stirring, the heated micro-emulsion is disseminated in a large amount of cold water (2-3 °C). This harden/solidify liquid droplets.

Membrane Contactor: To produce NLC, the gaseous phase in the membrane contactor technique is replaced with molten lipid mixture. Small droplets are formed when the mixture is squeezed through the membrane.

A heated surfactant solution circulates on the other side of the membrane, switching the droplets. The surfactant molecules encase and stabilize the liquid lipid droplets.

Double Emulsion Technique: To formulate hydrophilic drug loaded NLC, this technique is most suitable. Initially primary emulsion (W/O) is formed, then this primary emulsion is further dispersed in aqueous solution to form secondary emulsion (W/O/W).

Technique with Organic Solvent:

Emulsification-Solvent Evaporation Technique: Lipid mixture/blend is dissolved in water immiscible organic solvent (chloroform) and emulsified with surfactant solution. Evaporation of organic solvent form NLC (particle size rages from 25 to 100 nm).

Emulsification-Solvent Diffusion Technique: Lipid mixture/blend is dissolved in partially water-soluble organic solvent (benzyl alcohol) and emulsified with surfactant solution.

When the emulsion is diluted with water, organic solvent diffuse into the aqueous phase and form NLC (particle size below 100 nm).

Solvent Injection Technique: Lipid mixture/blend is dissolved in water-soluble organic solvent (ethanol) and mixed with surfactant solution. Since the organic solvents used are highly aqueous soluble, emulsion is not formed. Lipid precipitate by rapid migration of organic solvent into the aqueous phase.

Stabilization of NLC Formulation: Physical instability of NLC during storage, such as aggregation or gelling, is a key problem. The nanoparticle features of all NLC formulations should be preserved. To assure the physical stability of the NLC during storage, two ways might be used:

• Lyophilizing the nanoparticle dispersion to remove water
• Introducing a preservative to the dispersion.

Lyophilization: Freeze drying the nanoparticle dispersion does not affect the particle size, but freeze-drying without cryoprotectant aggregate the formulation.

Water molecules from the nano-dispersion are completely removed. Some cryoprotectants which are commonly used: sucrose, lactose, mannitol, trehalose, Avicel^® RC591.

Preservatives: To sustain the physical stability of dispersions, preservatives are used. The selection of suitable preservatives is crucial because some preservatives can also destabilize the NLC formulation. Khosa et al. classified the preservatives based on their effect in NLC formulation as given in Table 6.

TABLE 6: CATEGORIZATION OF PRESERVATIVES BASED ON THEIR EFFECT IN NLC

Mechanism of NLC to Enhance Oral Bioavailability ^{10-12, 14, 26}:

Mixed Micelles ^{7, 9}: After ingesting NLC, it is exposed to different GIT environments. Enzyme lipase hydrolyze lipids in NLC into free fatty acids and monoglycerols. In the intestinal lumen, these digested products combine with bile salt and phospholipids to form mixed micelles. During the digestive process drug loaded in NLC are transferred to mixed micelles, considerably increasing the bioavailability. It was reported that smaller lipid particles create mixed micelles more effectively during lipid digestion than bigger particles, which can accelerate the transfer of drugs to mixed micelles. Thus the formed mixed micelles transport drug through aqueous mucus and/or UWL and make it accessible for enterocyte absorption. In enterocyte, the drug is entrapped in chylomicrons (endogenously formed lipid particles by enterocytes from lipid components fed by mixed micelles). Finally, through the chylomicron-mediated pathway, drugs reach lymphatic circulation. Similarly, it reaches systemic circulation through subclavian veins and bypass liver, thus avoiding first-pass metabolism. Also it promotes trans-enterocyte delivery. Studies report that drugs that are transported via paracellular are not susceptible to intracellular enterocyte enzyme metabolism.

Mucus Adhesion ²⁶: Mucus prevents foreign particles from passing through the GIT because of its hydrophilic nature and negative charge. Nevertheless, researchers have used mucus as a technique to improve plasma concentration and therapeutic effectiveness of pharmaceuticals by creating NLC with the capacity to attach to mucus. Mucus-binding nanoparticles have a longer residence time in the GI system, allowing for passive drug administration and improved bioavailability. To give NLC mucoadhesion properties, two alternative techniques are used. The first technique involves electrostatic interaction between negatively charged mucus and positively charged polymer-coated nanoparticles. Second, the creation of covalent bridges between mucus and thiomers bound on NLC surfaces.

Mucus Penetration: Literature demonstrates that the neutral charge eliminates electrostatic attraction between mucin and NLCs, overcomes mucus barrier characteristics, and aids NLC transit over the mucus membrane to the systemic circulation. Nanoparticles coated with PEG offer hydrophilicity while impeding RES acquisition by limiting opsonin adsorption on their surface, which is one of the primary challenges in delivering medicines to locations other than the liver and spleen. Furthermore, PEGylation results in improved nanoparticle transport via the paracellular pathway.

Increase Permeability ^{24, 26}: Intestinal permeability is highly influenced by the surfactants used in NLC formulation. Surfactants promote intestinal permeability by inhibiting P-gp efflux transport. The Poloxamer opens the epithelial cell junction and promotes paracellular transport by deforming the cell membrane.

Prevent Degradation of Drug: Since, the drug is encapsulated with lipid carriers, it protects compounds against chemical and enzymatic breakdown in the hostile GI environment.

Overall Benefits ^{7-14, 21}: Overall benefits of NLC formulations during oral administration are summarised in Fig. 2.

FIG. 2: OVERALL BENEFITS OF NLC

Formulation Enhanced Oral Delivery: Table 7 depicts some NLC formulations that enhance oral bioavailability.

TABLE 7: ORAL DELIVERY OF NLC FORMULATIONS

CONCLUSIONS: Some drugs have high potency, but because of their low solubility, penetration problems, first-pass metabolism, and other GIT actions, the oral bioavailability of these drugs drastically decreases. In the past few decades, researchers have developed a number of new drug entities whose primary aim was to reduce the toxicity of the drug molecules and increase their potency, but to some extent, they still have not succeeded. The reason is the high lipophilicity of the drug and its larger molecular weight. On the other hand, instead of developing new molecules, some researchers developed carriers to deliver drugs. The nanostructured lipid carrier is the most promising nano-carrier because of its vast range of benefits. At first, researchers believed that it was the best carrier for lipophilic drugs, but later research emphasized that NLC also acts as the best carrier for hydrophilic drugs. Because of its smaller particle size and mimicking of the natural lipid-based digestion in the stomach, greater interest is shown in NLC-based formulations. Also, excipients used in these formulations are GRAS listed as non-toxic and biocompatible compared to other polymeric excipients. Several studies are being conducted on NLC. It is expected that in the near future, NLC will also be evaluated as a gene-targeting carrier.

ACKNOWLEDGEMENT: The author would like to express respectful gratitude for permitting to utilization of the College of Pharmacy, Madras Medical College, Chennai, India to carry out the work.

CONFLICTS OF INTEREST: The author has no conflict of interest with any person or institute.

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    How to cite this article:

    Murugan D: Nanostructured lipid carriers - a promising carrier for improving oral bioavailability of drugs. Int J Pharm Sci & Res 2023; 14(10): 4724-32. doi: 10.13040/IJPSR.0975-8232.14(10). 4724-32.

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