INTRODUCTION:

The oral route is more acceptable route because of its benefits, such as cost-effectiveness, painlessness, and higher patient compliance when compared to alternative modes of administration. Researchers are developing a nanocarrier based dosage forms to achieve oral delivery over GIT's barriers¹.These nanocarrier-based oral delivery techniques provide targeted and sustained drug release. Furthermore, these oral nanocarriers can enhance the pharmacodynamic and pharmacokinetic properties of numerous drugs². Main problem associated with delivery of oral nanocarrier is the harsh environment of the GIT, which readily breaks down these drug delivery systems and brings them to metabolism. Thus, well-designed drug delivery systems can prevent drug degradation in the hostile environment of GIT³. It is possible to design smart delivery systems for drugs by taking into account all of the constraints that limit oral drug administration.

Several drugs have been delivered orally using various lipidic drug delivery methods such as liposomes, nanoemulsions, and micelles.These lipidic drug delivery methods have demonstrated several benefits over traditional ones.

However, these lipidic drug delivery systems break down in the stomach in the presence of bile salts and intestinal enzymes.Furthermore, they exhibit stability issues while storage^4,5. In the early 1990s, Muller et al. produced solid lipid nanoparticles (SLNs) by employing solid lipids, thereby solving the stability issue and other difficulties associated with traditional lipidic drug delivery systems⁶. However, SLNs demonstrated expulsion of drug after storage due to their change in high ordered structure⁷. Modified lipidic nanocarriers, NLCs came into development in early 2000 to overcome problems associated with SLNs⁸.

NANOSTRUCTURED LIPID CARRIERS:

Gasco and Muller were working separately on a more efficient drug deliverythan the current lipidic approach. They manufactured solid lipid nanoparticles utilizing several preparation techniques. Muller designed SLNs using the high pressure homogenization approach, while Gasco used the microemulsion method. Solid lipid nanoparticles have a matrix made of solid lipids⁹. SLNs have greater benefits than nanoparticles.In contrast to nanoparticles, SLNs are produced without the use of organic solvents.Additionally, SLNs are more stable than nanoparticles and stay solid at ambient temperature. Still, some progress is needed in the development of SLNs since they have low drug payload capacity^10-12. The incorporation of liquid lipid into the solid matrix creates defects, resulting in increased drug payload while retaining the physical stability of nanocarriers. These generated nanoparticles with imperfect matrices are called NLCs¹³. NLCs have various benefits over SLNs, including an imperfect matrix which prevent expulsion of drug and assures maximum encapsulation of drug (Figure 1)¹⁴. NLCs are capable of incorporating both hydrophilic and lipophilic drugs. Incorporating liquid lipids in NLCs creates imperfect core matrix, allowing for increased drug lodging and hence high drug entrapment within the NLCs¹⁵.

Figure 1: Structure of SLNs and NLCs.

NLCs MEDIATED ORAL DELIVERY:

Even though oral delivery is the most effective way, there are several obstacles in the GIT that make it difficult to use^16,17. Enterocytes, goblet cells, and M cells in Peyer's patches can help the intestinal epithelium function as a favourable platform for drug absorption. The oral drug delivery is beneficial for disorders that require regular dosing for a longer period¹⁸. To address the obstacles associated with oral administration, lipid-based nanocarriers such as NLCs might be an effective nanocarrier approach that offers many advantages including better oral absorption,increased oral bioavailability, and minimal antagonistic action.In this approach, drugs integrated in a lipid matrix can produce regulated or sustained drug release by prolonging the drug's stomach residency¹⁹.

Challenges in oral drug delivery:

Almost more than 60% of drugs that enter the market are taken orally. Drug absorption in the gastrointestinal system is determined by physiological and anatomical barriers such as chemical and enzymatic barriers, as well as permeability-related barriers such as the intestinal epithelium and mucus layer. Poor hydrophilicity and intrinsic dissolving rate have a significant impact on oral medication delivery. Various ways to deliver drugs have been developed to circumvent these physiological and chemical obstacles and increase the oral bioavailability of various medicines²⁰. One of the challenges in nanocarrier stability is broad pH range in the gastrointestinal system. The duodenum has been shown to have a greater concentration of enzymes due to their abundance in biliary and pancreatic secretions, which include lipases, peptidases, and amylase that can help to digest lipidic nanocarriers²¹. pH and enzymatic degradation are two important biochemical barriers that impact the bioavailability of drugs. Nearly 90–94% of drugs are broken down by the digestive tract enzymes and the stomach acidic pH due to deamination, hydrolysis, or oxidation²². The breakdown of several drugs is also facilitated by digestive enzymes found in high quantities in the small intestine, such as chymotrypsin, carboxypeptidases, trypsins, and elastases^23-25. Thus, oral administration using lipid-based nanocarriers is problematic because nanocarriers must overcome harsh gastrointestinal conditions as well as other physical and chemical obstacles.

Mechanism of NLCs disposition:

NLCs release themselves within the body by selective absorption via payer patches. NLCs go through lipid digestion when they move through the GIT. First, duodenum pancreatic enzymes transform the triglycerides found in NLCs into monoglycerides and free fatty acids. When triglycerides break down, the drug is released and enters the body either passively or actively through enterocytes or the chylomicron-mediated route^26-28. The interaction of bile salts, triglycerides fragments and drug in intestine forms micelles. Further, formed micelles release drug, monoglycerides, and fatty acids. Drug gets entrapped in chylomicrons due to interaction of cholesterol, phospholipids, and lipid components. Next, the drug enclosed in chylomicrons is exocytosed. Drugs encapsulated in chylomicrons enter the body through lacteals, avoiding first-pass metabolism.NLCs have the ability to elude enzymatic destruction during transit through the digestive system by entering paracellularly into portal circulation and avoiding the digesting process(Figure 2)²⁹.

Figure 2: Mechanism of disposition of NLCs.

BARRIERS OVERCOME BY NLCS:

Solubility enhancement:

Formulating water insoluble drugs with limited bioavailability as NLCs allows them to be administered orally successfully³⁰. NLCs change from crystalline to amorphous form, they have an innate ability to dissolve in the GIT.The small size of NLCs contributes to their fast disintegration velocity. Additionally, for drugs exhibiting considerable first-pass metabolism, NLCs use selective lymphatic transport³¹. As a result, NLCs have the potential to improve the solubility of a variety of hydrophobic drugs.

Formation of mixed micelles:

Gut enzymes breakdown lipids, forming surface active monoglycerides and diglycerides on NLCs. These molecules then separate, forming micelles. The drug that has been dissolved in the lipids is solubilized in the micelles during the process of micelle generation. One technique for improving the solubility of drugs that are poorly soluble is solubilization. Mixed micelles are generated when previously created micelles interact with surface active bile salts such as sodium cholate. Subsequently, together with the absorption of lipid-degraded product, drugs is also absorbed simultaneously^32,33.

Efflux transporters:

P-glycoprotein has a molecular weight of 170 kDa and is a member of the ATP-binding cassette family. P-glycoprotein is mostly located on the apical side of the kidney, pancreatic, liver, intestinal, and brain endothelial cells³⁴. Lipids in NLCs can influence P-glycoprotein efflux mechanism and so enhance drug pharmacokinetics to a great amount³⁵. The processes by which these lipids impede P-glycoprotein function might entail modifications to the cell membrane's integrity, disruption of ATP hydrolysis, or allosteric blockage of binding sites³⁶.

Extensive hepatic metabolism:

NLCs have the potential to function as carriers capable of protecting drugs from degradation caused by hepatic metabolism while transporting them through the GIT.In the GIT, NLCs combine with bile salts to produce mixed micelles. Then they are preferentially taken up in lymphatic circulation, therefore bypassing the liver³⁷. Furthermore, mixed micelles enhance luminal solubilisation of lipid digested products while simultaneously producing the concentration gradient essential for absorption. The capacity of NLCs to block medicines from hepatic metabolism improves their bioavailability and decreases dose frequency³⁸.

Enhancement in absorption:

NLCs can attach to epithelium, minimizing the variability between fasting and fed states. Enzymes in the stomach break down lipids in the NLCs and with the bile salts they form mixed micelles in which drug gets entrapped. NLCs are taken up by the intestinal tract in a certain form, after which they are transported via lymphatic system to various organs³⁹. This absorption is mediated by M cells in the gut or by intercellularly or paracellularly⁴⁰. Lymphatic uptake of drug ensures inhibition of hepatic thereby enhancement of bioavailability of drugs⁴¹.

Improvement in bioavailability:

Different mechanisms have been proposed to boost the bioavailability of different drugs using NLCs. NLCs can affect P-gp-mediated efflux mechanisms and hence enhance pharmacokinetics of drugs to a great extent⁴². The hydrophobic drugs are absorbed and dispersed throughout the intestinal enterocytes upon oral administration where they interact with lipoproteins resulting to release of chylomicron-associated drug to lymphatic circulation⁴³. For this reason, the oral bioavailability of drugs that the liver substantially metabolizes is greatly enhanced via lymphatic transport^44,45.

CURRENT AND FUTURE DEVELOPMENTS:

Numerous investigations on formulations of nanostructured lipid carriers have been carried out in recent years. The development of NLC formulations has accelerated due to greater understanding of NLC transport processes via oral mode of administration.As a result of their low toxicity, biodegradability, and biocompatibility, NLCs have the potential to be used as nanocarriers. In the future, this drug delivery might be used to effectively administer a wide range of poorly soluble drugs. Therefore, further preclinical and clinical investigations on these nanocarriers are required to enable drug delivery.

CONFLICT OF INTEREST:

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS:

The authors thank the Management and Principal for their support of our work on NLCs.

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Received on 08.02.2022 Modified on 21.06.2023

Research J. Pharm. and Tech 2024; 17(5):2427-2430.

DOI: 10.52711/0974-360X.2024.00380