Editorial Feature

Challenges in Formulating Oral Lipid Nanoparticle-Based Drugs

Lipid nanoparticles (LNPs) are widely utilized as nanocarriers in oral drug delivery because of the lipid matrix's biocompatibility. However, attaining efficient oral drug delivery via lipid nanoparticles is challenging due to several physicochemical barriers. This article focuses on the challenges of formulating lipid nanoparticles for oral drug delivery.

Lipid nanoparticle siRNA antivirals used against Covid-19 and influenza. 3D illustration showing cross-section of lipid nanoparticle carrying siRNA of the virus (orange) entering a human cell

Image Credit: Kateryna Kon/Shutterstock.com

Lipid Nanoparticles: Overview

Lipid particles have been used in pharmaceutical developments for many years. LNPs are colloidal carriers that are submicron in size and have been developed to encapsulate pharmaceuticals while providing various benefits for drug delivery.

Lipid nanoparticles are constructed of a lipid-matrix having an average particle size of 50-1000 nm that should be solid at room and body temperature.

Lipid nanoparticles (LNPs) have been subjected to substantial research in the past two decades. Nanostructured lipid carriers (NLCs), solid lipid nanoparticles (SLNs), lipid nanocapsules (LNCs) and lipid-drug conjugates (LDCs) are among the major types of lipid nanoparticles.

The Benefits of Oral Drug Delivery Using Lipid Nanoparticles

The exceptional characteristics of the lipid components of lipid nanoparticles—such as their high flexibility, biocompatibility, and low toxicity profile—have contributed to their increased attention in recent decades.

Lipid nanoparticles also have the potential to improve the clinical potential and bioavailability of pharmaceuticals with translational limitations such as limited water stability or solubility and also provide alternates to the parental route.

Dudhipala et al., for instance, found that when rosuvastatin calcium was loaded into solid lipid nanoparticles, the drug's bioavailability increased by more than four times when given to rats via oral drug delivery method.

Lipids, in general, boost the absorption of drugs in the GI (gastrointestinal) tract, and when synthesized as nanoparticles (NPs), these compounds enhance mucosal adhesion owing to their minuscule particle size and increase their GI tract residence time.

Lipid nanoparticles may also safeguard loaded drugs from enzymatic and chemical degradation and slowly release molecules of therapeutic drugs through the lipid matrix into blood, leading to better therapeutic profiles than a free drug.

Thus, compared to other polymeric materials, lipid nanoparticles may lessen oral drug delivery systems' adverse effects and long-term toxicity because of their biodegradable and physiological characteristics.

All formulations can be tailored to the features and needs of the oral drug delivery route.

Most of the oils and fats employed in formulating these lipid nanocarriers are derived from dietary lipids, enhancing oral biodegradability and permeability. However, employing lipid-based nanocarriers for oral drug delivery is challenging.

Lipid nanocarriers like LNPs must withstand the hostile gastrointestinal environment and overcome physical and chemical barriers to retain stability and improve pharmaceutical loading efficiency.

Challenges in Formulating Lipid Nanoparticles for Oral Drug Delivery

The GI tract is a hostile habitat for LNPs (nanocarriers) utilized in oral drug delivery because of the harsh conditions they encounter. First, the pH gradient affects the physicochemical stability of the lipid nanoparticles.

The stomach has more acidic conditions (pH 1-2.5), whereas the colon has a pH of 7-8. Because the majority of nanocarriers contain ionisable moieties on their surface, pH values near the isoelectric point would reduce or even eliminate their surface charge.

This can result in destabilization mechanisms, which can lead to their (LNPs) accumulation in gastrointestinal fluids. Second, gastric enzymes such as pepsin and gelatinase may impair the stability of lipid nanoparticles utilized in oral drug delivery.

The stability assessment of lipid-based nanocarriers is critical during the early stages of development.

Researchers must use mimicked fluids having pH values, enzyme concentrations and electrolytes comparable to those observed in intestinal or gastric fluids when conducting stability testing.

To test the formulated LNPs, models of varying complexity that imitate the human intestinal environment must be constructed to anticipate the biological behavior and therapeutic effectiveness of LNPs-based oral drug delivery system.

In subsequent stages of research, nanocarrier development often includes in vivo testing. In this regard, based on the medical necessity and the specific goal of the study, the animal model, age, and selection of gender can be difficult.

It can also be challenging to achieve a high efficiency of drug loading in lipid nanoparticles, particularly when dealing with hydrophilic drugs. Therefore, the selection of proper lipids and manufacturing processes is critical to ensure that the drug is successfully encapsulated.

Nanodrugs inside of lipid bilayer encapsulation 3d rendering

Image Credit: Love Employee/Shutterstock.com

While LNPs can enhance a drug's bioavailability, only some pharmaceuticals are compatible with LNPs for oral drug delivery.

Formulators have to be selective about which drugs are compatible for distribution by lipid nanoparticles and which ones would be better served by alternative techniques.

Strategies for Oral Delivery via Lipid-Based Nanocarriers

These challenges may be transformed into opportunities if current knowledge about GI barriers and how they interact with lipid nanoparticles is comprehended and utilized to develop techniques to optimize lipid-based oral drug delivery.

The behavior and efficacy of the lipid-based nanocarriers in the GI system can be modified by reasonable lipid component selection and design depending on drug characteristics and medical requirements.

Multiple strategies have been explored to improve the potential of LNP-based oral drug delivery. This involves modifying the interaction of LNPs with mucus, targeting certain populations of cells or uptake pathways (for example, lymphatic transport), and inhibiting intestinal drug efflux.

Modifying the surface of lipid-based nanocarriers with hydrophilic polymers such as PEG is another strategy for increasing their gastrointestinal stability.

On the one hand, the steric stabilization provided by polymer chains could compensate for electrostatic instability. The hydrophilic surface, on the other hand, may give additional stability by increasing hydration forces.

Enzymes and other molecules with surface activity may also be prevented from adhering to the nanocarriers.

Kashanian et al. demonstrated that encapsulating solid lipid nanoparticles with PEG-stearate resulted in greater stability in stomach-simulated fluids than uncoated nanoparticles.

Future Outlook

Lipid-based nanoparticles appear to have several advantages due to their potential to increase solubility, facilitate intestinal absorption, and reduce or eliminate the impact caused by food on the absorption of poorly soluble drugs, boosting oral bioavailability.

However, creating these nanoparticles brings a set of challenges, particularly drug loading efficiency and stability issues.

Lipid nanoparticle formulation is expected to evolve, overcoming these issues and increasing the application of these particles in oral drug delivery, as long as the healthcare sector keeps supporting research and development.

Solid Lipid Nanoparticles: An Overview

References and Further Reading

M. Plaza-Oliver, M. J. Santander-Ortega, and M. V. Lozano, “Current approaches in lipid-based nanocarriers for oral drug delivery,” Drug Deliv. Transl. Res., vol. 11, no. 2, p. 471, Apr. 2021, doi: 10.1007/S13346-021-00908-7.

N. Mendoza-Muñoz, Z. Urbán-Morlán, G. Leyva-Gómez, M. De La Luz Zambrano-Zaragoza, E. Piñón-Segundo, and D. Quintanar-Guerrero, “Solid Lipid Nanoparticles: An Approach to Improve Oral Drug Delivery,” J. Pharm. Pharm. Sci., vol. 24, pp. 509–532, Jul. 2021, doi: 10.18433/JPPS31788.

P. Severino et al., “Current State-of-Art and New Trends on Lipid Nanoparticles (SLN and NLC) for Oral Drug Delivery,” J. Drug Deliv., vol. 2012, pp. 1–10, Nov. 2012, doi: 10.1155/2012/750891.

N. Ü. Okur, P. I. Siafaka, and E. H. Gökçe, “Challenges in Oral Drug Delivery and Applications of Lipid Nanoparticles as Potent Oral Drug Carriers for Managing Cardiovascular Risk Factors,” Curr. Pharm. Biotechnol., vol. 22, no. 7, pp. 892–905, Aug. 2021, doi: 10.2174/1389201021666200804155535.

L. Battaglia and M. Gallarate, “Lipid nanoparticles: state of the art, new preparation methods and challenges in drug delivery,” Expert Opin. Drug Deliv., vol. 9, no. 5, pp. 497–508, May 2012, doi: 10.1517/17425247.2012.673278.

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

Arzoo Puri

Written by

Arzoo Puri

Ms. Arzoo Puri has a Master’s degree in biomedical sciences and believes that science is constantly advancing thereby creating new discoveries each day.  She likes to utilize her skills and experience to contribute to the astounding medical advancements that take place every day. In 2022, she completed her master's dissertation and research training from Nanobios Lab, IIT-Bombay, India, and has finished her position as a scientific writer at Eureka, which she had undertaken while pursuing her masters. Her core interests lie in nanotechnology-based research, biomedical science and cannabis science. Her research goals are mainly directed toward the field of biosensors, point-of-care testing devices, bioimplants, drug delivery, medical diseases, and nanomaterials such as Graphene quantum dots.


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