INTRODUCTION:

Most of the drugs which are recently discovered are hydrophobic, and they show low bioavailability when administered through oral route.¹ Also, the newly discovered drugs are not suitable for oral delivery² because the new chemical entities discovered are having high molecular weight and increasing lipophilicity.^3-6

Recently, advances in pharmaceutical research is focused on new delivery systems utilizing new devices to achieve modification of delivery time, targeting, as well as improve the in vivo solubility and hence bioavailability of poorly soluble drugs. Nanoparticulate drug delivery systems consists of diverse group of formulations, each consisting of varying functional and structural properties that are amenable to modifications achieved by varying the composition of lipid excipients and other additives. Nanoparticulate drug delivery systems has evolved, overtime to nano-scale enhancing the efficacy and therapeutic application of these systems.⁷

The novel carriers should ideally fulfill two prerequisites. Firstly, it should deliver the drug at a rate directed by the needs of the body, over the period of treatment. Secondly, it should channel the active drug to the site of action. Conventional dosage forms including prolonged-release dosage forms are unable to meet none of these. Hence there is a strong need to develop the novel drug delivery systems for the effective pharmacotherapy.⁸ Development of drug delivery novel systems has proven their importance in case of drugs of synthetic origin. Similarly, they can play a crucial role in enhancing bioavailability, stability and effectiveness at large in the field of phyto-formulation research. Nanoparticulate based drug delivery systems such as polymeric nanoparticles and nanocapsules, liposomes, solid lipid nanoparticles, phytosomes and nanoemulsion etc. offer a number of advantages including enhancement of bioavailability though solubility improvement and thus better pharmacological activity, enhancement of stability, improving tissue macrophages distribution, sustained delivery, protection from physical and chemical degradation etc.^9-10

Nanoparticulate drug delivery systems with biodegradable and essentially non-toxic vehicles, can encapsulate both hydrophilic and hydrophobic materials and which offer the potential to enhance the therapeutic index of anti-cancer agents, either by increasing the drug concentration in tumor cells and/or by decreasing the exposure in normal tissues exploiting enhanced permeability and retention effect phenomenon and by utilizing targeting strategies. There are many approaches for enhancing bioavailability of the drugs facing poor permeability.^11-13

Nanotechnology is a combination of manufacturing science which is advanced and engineering where nanometre scaled material is being used. There is an advantage of more surface to volume ratio for a nanosized particles compared to bulk material. Nanoparticles also proved to have wide applications in various fields like agriculture to medicine.

Nano-sized inorganic particles of either simple or complex nature, display unique, physical and chemical properties and represent an increasingly important material in the development of novel nanodevices which can be used in numerous physical, biological, biomedical and pharmaceutical applications.^14-16

Nanoparticulate drug delivery system:

A nano-targeted preparation, also known as a targeted nanodrug delivery system, refers to a drug delivery system that concentrates explicitly a drug on a specific tissue or organ by using a particular drug carrier or drug delivery technique. It has the characteristics of specificity, targeting, long duration of drug action, small side effects, and wide drug loading range. It also provides some benefits over conventional preparations, including increasing the solubility of hydrophobic drugs, enhancing the stability of the drug in vivo, and improving its epithelial permeability. Compared with traditional preparations, the most prominent characteristic of targeted preparations is that drugs can be delivered to the target site to the maximum extent, the bioavailability of drugs can be improved, and the therapeutic effect can be maximized. In the continuous development of nanotechnology, the targeted preparations of nanoparticles, liposomes, polymer micelles, dendrimers and microspheres have become more and more prominent in cancer treatment. It has received extensive attention and research.¹⁷

Necessity for nanoparticle-based drug formulations:

There are various reasons why using nanoparticles for therapeutic and diagnostic agents, as well as advancement of drug delivery, is important and much needed. One of them is that, traditional drugs available now for oral or injectable administration are not always manufactured as the optimal formulation for each product. Products containing proteins or nucleic acids require a more innovative type of carrier system to enhance their efficacy and protect them from unwanted degradation. It is notable that the efficiency of most drug delivery systems is directly related to particle size (excluding intravenous and solution). Due to their small size and large surface area, drug nanoparticles show increase solubility and thus enhanced bioavailability, additional ability to cross the blood brain barrier (BBB), enter the pulmonary system and be absorbed through the tight junctions of endothelial cells of the skin. Specifically, nanoparticles made from natural and synthetic polymers (biodegradable and non-biodegradable) have received more attention because they can be customized for targeted delivery of drugs, improve bioavailability, and provide a controlled release of medication from a single dose; through adaptation the system can prevent endogenous enzymes from degrading the drug. Secondly, the development of new drug delivery systems is providing another advantage for pharmaceutical sales to branch out. Innovative drug delivery is driving the pharmaceutical companies to develop new formulations of existing drugs. While these new formulations will be beneficial to the patients, it will also create a powerful market force, driving the development of even more effective delivery methods. The benefit of pharmaceutical companies taking advantage of this new technology is that nanotechnology gives new life to those drugs those were previously considered unmarketable due to low solubility and bioavailability, and high toxicity and marked side effects.^18-20

Different Nanoparticulate based formulations:

Liposomes:

Liposomes are the first ones to be investigated as drug carriers. Liposomes are of 80 to 300 nm size. They are spherical vesicles contained of phospholipids and steroids. Liposomes are proven to have increased the solubility of drugs and also improve pharmacokinetic properties like therapeutic index of chemotherapeutic agents, rapid metabolism, lower side effects and also increased in vivo and in vitro anticancer activity²¹. For liposomes with size greater than 100 nm, as the size increases clearance rate by mononuclear phagocytic system increased. Liposomes that are multifunctional and containing specific antigens, proteins, biological substances could be used to design drugs that act at specific tissue. For targeted drug delivery therapy, it is most promising type of drug delivery.

Encapsulation process is used to incorporate drug into liposomes. pH, composition of liposome, osmotic gradient, and environmental conditions regulate the release of drug from liposomes. Lipid transfer, fusion, adsorption realize the interaction of liposomes with cells. Anticancer drugs²¹, antibiotics, anti-inflammatory and anti-rheumatic drugs are the drugs with liposomal formulations. Even with long history of investigation liposomes haven’t made a significant impact yet. They are being extensively used in cosmetic products.

Polymeric nanoparticles:

Nanoparticle structures with diameter ranging from 10 to 100 nm are polymeric nanomaterials. Synthetic polymers like poly e-caprolactone, polyacrylamide, or natural polymers like Chitosan, gelatin are used to obtain Polymeric nanoparticles. Polymeric nanoparticles are further classified as biodegradable and nonbiodegradable. In order to lower immunological and intramolecular reactions between surface chemical groups polymeric nanoparticles are usually coated with non-ionic surfactants.^22-24

Food and drug administration of US has approved biodegradable polymeric nanoparticles like PLA and PLGA. They are formulated in a way that they are able to encapsulate several low molecular weight compounds. Polymeric nanoparticles are more useful in regard to biocompatibility and biodegradation profiles, when chronic dosing is needed in formulations. One downside of polymeric nanoparticles is that large scale manufacturing and production is an issue. By using a double emulsion solvent evaporation system using oil and water with vinyl alcohol PLGA nanoparticles are formulated as an emulsifier.^25,26

Solid Lipid Nanoparticles:

Solid lipid nanoparticles are first designed in 1990s and are utilized as an alternative for emulsions and liposomes. In biological systems Solid Lipid nanoparticles are more stable than liposomes because of their rigid core that consists of hydrophobic lipids which are solid at room temperature. By including high level of surfactants these aggregates are further stabilized. Solid lipid nanoparticles are less toxic as they are biodegradable. They can be designed with 3 types of hydrophobic designs, and they have pharmacokinetic parameters which can be controllable. These three designs are a drug enriched shell, a drug enriched core and a homogenous matrix. SLNPs could be used to deliver drugs by inhaling, topically and orally. Particles of SLN are made of solid lipids that are like highly purified triglycerides, complex glyceride mixtures or waxes stabilized by various surfactants.²⁷ Nanostructured lipid carriers and Lipid drug conjugates are modifications of lipid based nanoparticles that have been developed to overcome limitations of conventional SLN. By combining liquid lipids with solid lipids nanostructured lipid carriers are formed and as a result special nanostructured lipids are formed for which payload and prevented drug expulsion have increased. There are 3 types of NLCs, imperfect type, multiple type, and amorphous type NLCs.

Dendrimer nanocarriers:

Dendrimer nanoparticles are unique polymers which has well defined structure and size. Some of the dendrimer nanocarriers are glycogen, amylopectin etc., Dendrimer can do multiple jobs like solubility enhancement, drug targeting. Dendrimers can be used using different routes of drug delivery oral, parenteral, nasal and intra ocular. Dendrimers can also behave like vectors in gene therapy. These 3D tree like branched molecules contain some good characteristics like narrow molecular weight distribution, and 3D structure tuned by dendrimer generation and dendron structure, and flexibility for tailored functional groups with high density on the periphery.

Carbon nanotubes:

Carbon nanotubes are first discovered in 1991. Multi walled nanotubes are prepared by pyrolysis of metallocene’s like ferrocene, cobaltocene, and nickelocene under reducing conditions. Single-walled carbon nanotubes (SWNT) were prepared in a related approach using dilute hydrocarbon–organometallic mixtures. Interestingly, pyrolysis of nickelocene in the presence of benzene at 1100 "C yields primarily MWNT. In contrast, pyrolysis of nickelocene in the presence of acetylene yields primarily SWNT, presumably due to the smaller number of carbon atoms per molecule.²⁸

Silica nanoparticles:

Sol-gel methods are used to prepare silica nanoparticles. Researcherhad demonstrated an efficient co condensation process to monodisperse silica nanoparticles. Apart from this several other methods are described and proved to prepare silica nanoparticles like organic aqueous biphasic system described by Tan group.MCM-41 is a mesoporous silica nanoparticle, which is usually synthesized using sol-gel processes with the presence of surfactant like C12-trimethylammonium bromide versus C16-trimethylammonium bromide, to control pore sizes.²⁹

Characteristics of Nanoparticles and impact on bioavailability enhancement:

Nanoparticulate drug delivery systems (NDDS) have emerged as a promising approach for enhancing the bioavailability of drugs, especially those with poor solubility, stability, and permeability. The bioavailability enhancement strategies of NDDS involve multiple mechanisms, including increased solubility, improved permeability, prolonged circulation, and targeted delivery. Nanoparticulate drug delivery systems (NDDS) play a crucial role in improving drug permeability and absorption, directly contributing to enhanced bioavailability. Many drugs, particularly Biopharmaceutics Classification System (BCS) Class III and IV drugs, face challenges in crossing biological barriers due to low permeability. Here are the key approaches:

Particle size:

Particle size is an important factor in deciding nanoparticle characteristics. They decide toxicity, fate biologically and ability of targeting in nanoparticle systems. Along with that they could also affect drug loading, release rate of drug and stability of nanoparticles. Many research studies have proved that nanoparticles of sub-micron sized have more uses than microparticles.³⁰ Intracellular uptake is more in nanoparticles than microparticles and is available to wide range of targets as they are relatively smaller in size and more mobile. It was found in the research that nanoparticles of 100nm had an uptake which is 2.5 times greater than 1µm microparticles. And the uptake is 6 times greater than 10µm microparticles. In another study it was proved that nanoparticles penetrated through submucosal layers in rate in situ intestinal loop model, while microparticles are local to epithelial lining.³¹ Nanoparticles that are tween 80 coated have crossed the blood brain barrier. Compared to microparticles some cell line submicron nano particles can be consumed efficiently.

Particle size will have effect on drug delivery. Smaller particle size of nanoparticulate formulations increases surface area which results in better dissolution and solubility. Particles with size less than 200nm get easily absorbed by cells via endocytosis and transcytosis. Lipid based nanoparticles improves drug retention at absorption site which also imparts better bioavailability, leading to better therapeutic outcomes.³²

Surface properties of nanoparticles:

Nanoparticles are determined easily by immune system of body when they are administered and are cleared by phagocytes for the circulation. The amounts of proteins adsorbed are determined by size of nanoparticles and their surface hydrophobicity, and in vivo fate of nanoparticles is influenced by this.³³ The process of binding opsonin to nanoparticles surface is called opsonisation and it acts as bridge between phagocytes and nanoparticles.

The surface properties of nanoparticles play a crucial role in determining their interaction with biological systems, which directly affects drug absorption, distribution, metabolism, and excretion (ADME). Different key surface properties have influence on bioavailability which are- surface charge i.e. Zeta potential, hydrophobic nature which is suitable for passive targeting and hydrophilic nature which reduces clearance in immune system useful for prolonged drug circulation, mucoadhesive coating enhances mucosal retention and permeability which is useful for poorly absorbed drugs.

Table 1: Effect of Surface Properties on Bioavailability

Surface Property	Effect on Bioavailability	Example Applications
Cationic Charge	Increases cell interaction and mucosal adhesion	Chitosan-coated nanoparticles for oral and nasal delivery
Anionic Charge	Reduces immune clearance, improves circulation time	PLGA nanoparticles for IV drug delivery
PEGylation	Prolongs circulation, reduces clearance	PEGylated liposomes (Doxil®)
Hydrophobic Surface	Enhances cellular uptake	Polymeric nanoparticles for cancer therapy
Hydrophilic Surface	Improves stability, reduces opsonisation	SLNs and nanoemulsions for oral drugs
Ligand Functionalization	Enables active targeting, site-specific delivery	Folate-conjugated liposomes for tumor targeting

Improved Permeability and Absorption:

Lipid-based Nanoparticles (e.g., Solid Lipid Nanoparticles, Nanostructured Lipid Carriers) consists of Lipophilic nanocarriers help drugs bypass efflux pumps and enhance intestinal permeability. Whereas polymeric nanoparticles tailored to improve mucoadhesion and facilitate transcellular or paracellular transport.

Protection from Degradation:

Nanoparticulate Drug Delivery Systems (NDDS) protect drugs from degradation by shielding them from enzymatic breakdown, acidic environments, and metabolic processes. This protection helps improve drug stability and bioavailability, especially for drugs prone to first-pass metabolism, enzymatic hydrolysis, and oxidative degradation.

Nanoparticulate drug delivery system protects drug degradation by different enzymes such as proteases, esterase by providing encapsulation in biodegradable polymers such as chitosan, PLGA and PEG. Lipid based nanoparticles protects drug from hydrolysis and enzymatic degradation in GI tract. PEG coated nanoparticles prevents immune clearance and prolongs the circulation time. In pH-Responsive Nanoparticles drugs are enclosed in acid-resistant polymeric nanocarriers (e.g., Eudragit, chitosan) remain intact in the stomach and release occurs only in the small intestine (neutral pH), ensuring better absorption, better bioavailability. Along with that liposomal and micellar nanoparticles prevent oxidation-sensitive drugs from degrading due to exposure to oxygen or light and its hydrophobic core protects unstable drugs from aqueous environments.

Overcoming Efflux and First-Pass Metabolism:

Drug efflux transporters are membrane-bound proteins responsible for pumping drugs out of cells, limiting drug absorption, distribution, and retention. While they play a protective role by preventing toxic substances from accumulating in the body, they negatively impact drug bioavailability by reducing intracellular drug concentration. Lipid-based and polymeric nanoparticles can inhibit drug efflux transporters, increasing intracellular drug concentration. Whereas, first-pass metabolism (also called first-pass effect or presystemic metabolism) refers to the metabolic breakdown of a drug before it reaches systemic circulation. This process occurs primarily in the liver and intestinal wall, significantly reducing the bioavailability of orally administered drugs. In those cases, lipid nanoparticles promote lymphatic uptake, bypassing hepatic first-pass metabolism.

Drug Release:

Drug release is an important factor for a successful nanoparticulate drug delivery system. Usually drug release depends on few factors,

Solubility of drug

Desorption of the surface drug

Diffusion of drug through nanoparticle matrix

Combination of erosion/ diffusion process

Drug release pattern is variable which also goes for immediate release of nanoparticulate formulations such as nanocrystals and nanoemulsions having rapid bioavailability. Simultaneously nanoparticulate formulations show diffusion controlled release having prolonged effect with good bioavailability status.

Applications of Nanoparticulate Drug delivery system:

Recently several articles have been published both research and review on nano vehicular intracellular drug delivery systems. This article includes several aspects of nanodrug delivery systems and their use in biological systems at cellular levels. Various nano systems and their applications has been reviewed. Nanoparticles based drug delivery systems and their treatment towards chronic pulmonary disease has been explained in.³⁴ With all these research studies it was proved that nanoparticulate drug delivery systems show a promising approach to achieve desired drug delivery properties by modifying pharmacokinetic properties. To overcome diseases that are cause through genes, it is good to combat the root cause rather than treating the disease, and gene therapy for it is a promising strategy.

Liposomes offer good option for delivering chemotherapeutic agents. In addition to that micelles are also great to make insoluble drugs soluble as they have hydrophobic core. Several different forms of nanoparticles have shown good progress in treating cancer, and one of them was carbon nanotubes. It is carbon in allotropic form with framework in cylindrical framework. They are classified into single walled carbon nanotubes and multiwalled depending on the number of sheets in concentric cylinders. Drug can be loaded easily into carbon nanotubes as they have hollow interiors. Use of nanoparticles in diagnostic testing has been explored widely in the recent years, as the current technology that has been use for this is hindered by inadequacies of fluorescent markers like fluorescence fading after single use, dyes and restricted usage. Nanoparticles provide good use to overcome these problems. Recently theranostic nanoparticles have gained lot of attention for diagnostic reasons. The primary reasons of stokes are vascular diseases like atherosclerosis and hypertension. For the diagnosis and detection nanoparticles have been used for atherosclerotic plaques. Same kind of targeting strategies are used to deliver therapeutic agents to this plaque. Identifying the disease at early stages and intervening it may prevent the worst outcomes that may lead to plaque rupture and thrombosis.

Conclusion and Future prospective:

As the many drugs especially from BCS class-II undoubtedly have the issues with the less bioavailability, due to their poor lipid solubility or improper molecular size or many such reasons, which limits the absorption as well as oral bioavailability. So such formulations are challenging task for formulation scientist to enhance oral bioavailability. Nanoparticulate drug delivery system is considered as the most promising and novel technology to enhance drug bioavailability by using various polymers in the formulation. This review is focused on different formulation aspects of such formulations. Although the nanoparticulate drug delivery system is the most accepted technique for bioavailability enhancement there are few limitations regarding stability, manufacturing methods, and official database regarding the solubility of drugs in lipids. Further research work promptly has to be carried out to correlate between in-vitro and in-vivo studies. The present review summarized that the nanoparticulate drug delivery system definitely improves the absorption and ultimately bioavailability of the drugs and which would be enormously helpful for the advancement of sophisticated technology to obtain safe and efficacious formulations.

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Received on 08.04.2025 Revised on 13.05.2025

Accepted on 12.06.2025 Published on 20.06.2025

Available online from June 30, 2025

International Journal of Technology. 2025; 15(1):17-23.

DOI: 10.52711/2231-3915.2025.00004

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.