1. INTRODUCTION:

Hyperlipidemia is the major cause of atherosclerosis and atherosclerosis-associated conditions such as coronary heart disease and ischemic cerebrovascular disease. It is an increase in the level of lipid concentration in the blood stream which leads to the development of atherosclerotic plaque in the inner lining of the wall of arteries or veins. This lipids include fats, fatty acids, cholesterol, phospholipids and triglycerides. Coronary heart disease(CHD) is caused by narrowing the artery that supplies nutrients and oxygen to the heart and it is the main reason of Atherosclerosis. Atherosclerosis is the degenerative changes of the arterial wall which includes the accumulation of lipids, complex carbohydrates, blood and blood products, and cellular waste products. These deposits or plaques progressively decreases the blood flow through the lumen of the artery and reduces its elasticity.¹

1.1 Treatment of Hyperlipidemia:

1.1.1 HMG CoA Reductase Inhibitors (Statin Drugs):

The HMG-coenzyme A reductase enzyme, which is involved in the rate-limiting phase of cholesterol production in the liver, is competitively inhibited by the statins (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin). Also, the statin drugs increases the HDL level, which protects the cardiovascular system.¹

1.1.2 Fibric acid derivatives (Fibrates):

The fibrates, which include clofibrate, fenofibrate, ciprofibrate, and benzafibrate, a widely used as a lipid-modifying agents, resulted in a considerable reduction in plasma triglycerides and is frequently accompanied by a drop in LDL cholesterol and a rise in HDL cholesterol. Fibrates activate specific transcription factors known as the peroxisome proliferator-activated receptors (PPARs). The primary HDL apolipoproteins, apoA-I and apoA-II, are synthesised when PPAR-a is activated, stimulating fibrate effect on HDL cholesterol. Fibrates also lowers the hepatic apoC-III production and increases the lipoprotein lipase which mediates lipolysis via PPAR. Fibrates stimulates the uptake of cellular fatty acid, converting into acyl-CoA derivatives, and catabolism by the β-oxidation pathways which is combined with reduction in fatty acid and synthesis of triglyceride, results in a decrease in very LDL production.²

Table 1: Classification of Antihyperlipidemic Drugs (Hypolipidemics):

Class of Drugs	Examples
HMG CoA Reductase Inhibitor	Lovastatin, Simvastatin, Pravastatin, Atorvastatin Fluvastatin, Rosuvastatin, Pitavastatin
Fibric Acid Derivatives	Clofibrate, Fenofibrate, Ciprofibrate, Bezafibrate
LDL-Oxidation Inhibitor	Probucol
Bile Acid sequestrants	Cholesteramine, Colestipol
Cholesterol absorption inhibitor	Ezetimibe
Pyridine Derivatives	Nicotinic acid, Nicotinamide

1.1.3 Bile Acid sequestrants:

The high positively charged resins known as bile acid sequestrants (cholesteramine, colestipol) bond to the negatively charged bile acids. The bound bile acids are eliminated in the faeces as a result of these resins large size, which prevents them from being absorbed. As a result, the liver supply of bile acids decreases, which causes hepatocytes to convert more cholesterol to bile acid. Reduced hepatic cholesterol levels promotes liver cholesterol synthesis and favours the growth of LDL receptors. LDL clearance and LDL-C levels are both increased by the activation of hepatic LDL receptors.³

1.1.4 LDL Oxidation Inhibitor:

These agents increases the breakdown of low-density lipoprotein in the metabolic pathway for eliminating cholesterol, LDL oxidation inhibitor (probucol) decreases serum cholesterol. Additionally, this medication may act to prevent cholesterol from being absorbed from food and prevent the first stages of cholesterol formation. It may also prevent the oxidation and tissue deposition of LDL cholesterol, which would prevent atherogenesis.⁴

1.1.5 Pyridine Derivatives:

These agents are water-soluble vitamin B, which inhibits the lipolysis of triglycerides by hormone-sensitive lipase, and reduces transport of free fatty acids to liver and decreases the production of hepatic triglyceride. In liver it suppresses the triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acid.¹.

1.1.6 Cholesterol absorption inhibitor

Ezetimibe is effective Cholesterol absorption inhibitor that blocks the absorption of cholesterol from the intestine. It reduces LDL-C between 10 and 19%. Ezetimibe can safely administer with statin and shows the synergistic action to control the cholesterol levels.⁵

1.2 HMG CoA Reductase Inhibitors as a 1^st Line therapy for Hyperlipidemia:

HMG CoA Reductase Inhibitors or statins are referred as a first line therapy and considered the most effective lipid-lowering agents available, both in lowering LDL-cholesterol levels and in the prevention of cardiovascular events. In addition, statins also show anti-inflammatory effects that are independent from their ability to decrease LDL-cholesterol, which may contribute to the clinically beneficial for cardiovascular diseases.⁶

A recent meta-analysis of 23 lipid-lowering agents’ studies, however, revealed that the majority (89%–98%) of the anti-inflammatory benefits of lipid-lowering medication are related to the degree of LDL reduction⁷, which reflects a limited role for a non–LDL–cholesterol related anti–inflammatory mechanism.

1.3 Mechanism of Action of statins:

Statins are similar in structure to HMG-CoA, a precursor of cholesterol, and act as competitive inhibitors of HMG-CoA reductase. It is the rate limiting enzymatic step in cholesterol synthesis in the liver as depicted in the Fig no 1. The HMG CoA reductase inhibitor blocks the synthesis of isoprenoid intermediates in the mevalonate pathway. The liver responds by increasing the number of LDL receptors, which increases hepatic uptake and catabolism of circulating LDL-cholesterol. Statins reduce LDL-cholesterol by 24% to 60% and decrease triglycerides by 5% to 50%, depending on the agent selected and the baseline lipid profile. HDL-cholesterol levels are usually increased. The effects on HDL are a class effect and are small relative to the effects on LDL-cholesterol and TGs.^[6]. It also increases the clearance of LDL-cholesterol from the blood stream which stabilizes the atherosclerotic plaques in the arterial wall.

Fig 1: Mechanism of Action of Statins

1.4 Simvastatin (SIM) as a Potent HMG CoA Reductase Inhibitor:

The statistics in the US reveals 83% of adults were using statin drugs and 17% of adults were using non statin drugs. In statins, they have found that SIM was the most commonly used cholesterol-lowering medication as depicted in Fig no 2^[8]. SIM is an ideal candidate for novel colloidal drug delivery system because of its hydrophobic nature, because some statin drugs are hydrophilic and they are less stable in matrix or the surface of the nanoparticles.

There are various possible routes of administration (eg. Nasal, implantable, mucoadhesive, transdermal)^{9, 10, 11 12}. Effective and suitable for combination therapy, we can combine the statins with cholesterol absorption inhibitors so that we can control cholesterol level via two ways; inhibition of synthesis of cholesterol in statins and inhibition of cholesterol absorption from intestine¹³. Research studies reported that SIM is tolerable and having lesser side effects as compared to other statin drugs.¹⁴

Fig 2: % of Adults using statin drugs[8]

2. COLLOIDAL DRUG DELIVERY SYSTEM (CDDS)

Colloidal drug delivery systems (CDDS) are nanometer-sized vesicles or particulates which are used to deliver the drug. CDDS delivers the drug specifically to its target site at the right period of time to have a controlled release and achieve the maximum therapeutic effect. This concept of targeting is all about to minimize the risk-to-benefit ratio.^[15] The nanoparticles dispersions consisting of small particles of 10-400nm diameter shows the great promising drug delivery system. Due to the higher surface area, it shows improved pharmacokinetics and bio distribution of therapeutic agent and minimizes the toxicity at the target site.

Fig 3: Classification of CDDS

2.1 Inorganic based system:

2.1.1 Metallic nanoparticles:

Metallic nanoparticles are nanosized metals with size range from 10 to 100nm. It possesses unique specialty compared to other nanoparticles and can be synthesized and modified to allow them to bind ligands, antibodies and drugs¹⁵. It is possessing the characteristics such as surface Plasmon resonance (generation of energetic electrons) and optical properties. Silver (Ag)and gold (Au) nanoparticles are used in the branches of science such as catalysis, photography, medical field as anti-tumor and anti-microbial agents^[16][17][18]. Furthermore, it prevents the growth of both gram +ve and gram -ve bacteria.

Fig 4: Metallic nanoparticle

Applications of metallic nanoparticles in the biomedical fields are enormous, and there is strong prospective for continued growth in this area.These are commonly employed for their antibacterial properties.for example, silver nanoparticles (AgNPs) have been implemented into 93 wound dressings, bone cements and implants.¹⁵Gold nanoparticles have optical and anticancer properties that are relevant to healthcare. For example, Alanazi et al. and the team¹⁶discuss the therapeutic and diagnostic uses of surface plasmon absorption and surface plasmon light scattering and Patra et al. and the colleagues¹⁷ described the fabrication and application of gold nanoparticles for targeted cancer therapy.

Case Studies:

Boron nitride (BN) have been confirmed to cause toxicity, damages or inflammation to several tissues or organs¹⁸. Wenzhen Ana and team successfully synthesized PEG-BN nanoparticles by using 6-arm polyethylene glycol amine-boron nitride sheet and H₂O and administered into the mice and biodistribution was studied using radiolabelling techniques and reported that PEG-BN nanoparticles were mainly distributed in lungs, liver, kidney and spleen. The biochemical and pathological changes developed from PEG-BNs nanoparticles also were observed. After administration of SIM in the PEG-BN model mice, the damages were recovered significantly as compared to single exposure group mice in the serum which indicates a better therapeutic effect of simvastatin on the toxicity of PEG-BNs in vivo in mice.

¹⁹EP Figueiredo and the colleague evaluated antimicrobial activity of silver nanoparticles synthesized by F.oxysporum (AgNP_bio) fungal biomass and AgNO₃ which are coupled with SIM opposed to reference and multidrug-resistant bacterial strains. Study reported that synergistic interactions between simvastatin and AgNP_bio synthetized by F. oxysporum, on antimicrobial activity against staphylococcus aureus that is methicillin-resistant (MRSA).The data suggested that the combination of these compounds is a possible treatment option for fighting resistant bacterial infections.

The use of metallic nanoparticles is already established in the healthcare applications, including wound dressings and treatment. Metallic nanotechnology exhibits remarkable biological properties, such as anti-inflammatory and anti-viral activities, in addition to more renowned antibacterial properties. There are several side effects including particle instability, biologically harmful and difficulty in synthesis. Although in metallic nanotechnology, several concerns about toxicity remain and need to be addressed.

2.2 Lipid based system:

2.2.1 Liposome:

Liposomes are small, spherical vesicles made of natural, non-toxic phospholipids and cholesterol. In liposome, the core is hydrophilic and the layer around the core is hydrophobic.²⁰ The hydrophilic drug will go into the core of the liposome and hydrophobic drug will be adsorb onto the lipid bilayer.²¹

Fig 4: (a) Liposome loaded with hydrophobic drug (b) Liposome loaded with hydrophilic drug

Liposomes increases efficacy, therapeutic index and stability via encapsulation and also reduces the toxicity of encapsulated drug²¹. These systems are non-toxic, flexible, biocompatible, completely biodegradable, and nonimmunogenic for systemic and non-systemic routes of administrations²². Low solubility, a short half-life, and phospholipid oxidation and hydrolysis-like reactions are considered as a demerit of liposomes²³. Studies have shown that encapsulated drugs may leak or fuse.

Case studies:

Alina Porfire and the team successfully prepared lyophilized liposomes with SIM was using 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and N-(Carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoyl-sn-glycero-3- phosphoethanolamine (Na-salt) (MPEG-2000-DSPE) and cholesterol by using thin film hydration method. The size of liposomal vesicles was between 125.4 and 173.6nm and entrapment efficiency between 3.4 to 46.2% which falls under the desired region for liposomes.²¹

²²Rong Qi, PhD and colleague reported that SIM-liposomes were successfully prepared by a thin film dispersion method by using soyabean lecithin and cholesterol. SIM-liposomes significantly improved the oral bioavailability of SIM with the liposomes being more effective than the dendrimer.

²³ Alina Porfire and the team successfully describes the development and validation of near infrared (NIR) spectroscopic method to determine the chemical composition of liposomes. NIR spectroscopy is an important tool of the pharmaceutical field for characterizing raw materials, in-process characterization of products and characterization of dosage forms. Liposome was prepared by thin film hydration method using l-alpha-phosphatidylcholine, cholesterol and SIM to be encapsulated in the liposomes. It was found that NIR-chemometric method providing complete information about the chemical composition of liposomal SIM.

²⁴Alina Porfire and the team successfully prepared long circulating liposomes (LCL) of SIM for carcinoma cancer. SIM has potential benefits for prevention and treatment of several types of malignancies. Liposomes was prepared by 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and N-(carbonyl-methoxypolyethylenglycol-2000)-1,2-distearoylsn-glycero-3-phosphoethanolamine (Na-salt; MPEG-2000- DSPE) and cholesterol using thin film hydration method. SIM can be efficiently encapsulated into LCL liposomes. D-optimal experimental design can be successfully used for determination of predictive models for liposomal properties.

The optimum cholesterol concentration should be determined, in order to get good entrapment efficiency for the drug. Lipid concentration has a substantial impact on how long the liposomal system remains active in circulation. The optimum cholesterol concentration should be determined, in order to get good entrapment efficiency for the drug.

2.2.2 Solid lipid nanoparticles (SLNs):

SLNs are comparatively stable colloidal drug delivery system made up of melted lipid which is dispersed in an aqueous surfactant. The drug is dissolved or dispersed in the solid hydrophobic core material. Due to the biodegradable nature of the lipid material these particles exhibit least toxicity.²⁵SLNs offer a controlled drug release lasting up to many weeks and have a high entrapment efficiency. The drug is also more stable in their lipid matrix.

Fig 5: Solid lipid nanoparticle

It has been proved that SLNs combines the advantages and avoid the disadvantages of other colloidal carriers²⁶. Proposed advantages including Possibility of targeted drug delivery and controlled drug release, high drug payload, improved drug stability, and incorporation of hydrophilic and lipophilic drugs, No biotoxicity potential for the carrier, avoidance of organic solvents, no issues with large-scale manufacturing and sterilisation. There some literatures reported disadvantages including particle growth, unpredictable gelation tendency and sometimes burst release.²⁵

Case studies:

SIM shows low oral bioavailability due to its poor aqueous solubility and extensive metabolism by cytochrome-3A units in intestinal guts and liver. ^[26] Zhiwen Zhanga and the team reported the study in which the oral bioavailability of SIM is enhanced in rats. SLNs were prepared by Emulsification solvent evaporation method using SIM, tween 20 (Polysorbate 20) and oleic acid, solutol HS-15(polyoxyethylene esters of 12-hydroxystearic acid) and lecithin and miglyol 812(Glycerides, mixed decanoyl and Octanoyl) Liquid chromatography-tandem mass spectrometry (LC-MS-MS) was used to determine the plasma levels of the drug and its active metabolite. The experimental results showed that SLNs were spherical nano-sized particles with high entrapment efficiency. The in situ intestinal absorption specified that the absorption of SLNs was greatly increased compared with that of free SIM.

²⁷Syed Zaki Husain Rizvia and the team study was reported to develop SIM-loaded SLNs for enhanced antihyperlipidemic activity in hyperlipidemic animal model. SLNs was prepared by nano-emulsion template method using palmitoyl alcohol, tween 80 and tween 40, span 40 and myrj 52 and poloxamer 407. The prepared SLNs underwent physicochemical evaluation such as particle diameter, surface charge, morphology, entrapment effectiveness, thermal behaviour, and crystallinity. In vitro release profile of SLNs in simulated gastric and intestinal fluids was evaluated by using dialysis bag technique and anti-hyperlipidemic activity was assessed in hyperlipidemic rat model.

²⁸Hazem Ali and colleagues combined the SIM and tocotrienols to exert the synergistic effect to inhibit the growth of highly malignant +SA mammary epithelial cells in culture and incorporated into the SLNs. SLNs was successfully synthesized and characterized by microemulsion technique using SIM, Compritol® 888 ATO (glyceryl behenate, melting point: 71–74 ◦C), which is a mixture of ∼15% mono-, 50% di- and 35% triglycerides of behenic acid), tocotrienol-rich-fraction of palm oil (TRF) and lutrol F68. The antiproliferative effects of nanoparticles on malignant +SA mammary epithelial cells were assessed in vitro to determine their anticancer efficacy. The IC₅₀ of the reference alpha-tocopherol nanoparticles was 17.70µM whereas the IC₅₀ of the SIM/TRF nanoparticles was 0.521µM, which confirmed the potency of the combined treatment and its potential in cancer therapy.

²⁹Hagar B. Abo-zalam and the team studied and optimized the SIM loaded SLNs to enhance the bioavailability, efficacy and alleviate adverse effects. SLNs were prepared by hot-melt ultrasonication method using compritol 888 ATO, gelucire 40/14(mono, di and tri-esters of glycerol along with mono and diesters of polyethylene glycols) and poloxamer 407(polymer with oxirane). The prepared SLNs were optimized by box-Behnken experimental design. Six groups of albino rats were randomly assigned and received treatment for 16 weeks. Muscles, liver tissues, and blood samples were taken for biochemical testing, histological examination, and immunohistochemical analysis. All biochemical, histological, and immunohistochemical studies revealed a significant improvement in SLNs loaded with SIM.

The drug permeability and the particle size in SLNs is largely depends on solid lipid material used in the method of preparation. The zeta potential prevents aggregation of the particles, increase in particle size the amount of drug encapsulated increases and consequently, zeta potential increases.

2.3 Polymer Based System:

2.3.1 Polymeric Nanoparticles:

Polymeric nanoparticles are polymeric based system made up of biodegradable and biocompatible polymers or copolymers.Due to their small particle diameter, biodegradability, water solubility, nontoxicity, prolonged shelf life, and stability during storage, these nanoparticles are attractive.^[30] These nanoparticulate systems specifically deliver the drugs, proteins, and DNA or genes to specific targeted tissues or organs.

Fig 6: Polymeric nanoparticle

There are several advantages such as polymeric nanoparticles increase the stability of volatile drugs, significant improvement in oral and iv administration, delivers higher concentration of drugs to the target site.It is an ideal candidate for cancer treatment, vaccination, contraception, and antibiotic administration. The disadvantages including the productivity is more difficult, reduced ability to adjust the dose and requires skills to manufacture.

Case studies:

³¹Usama Farghaly Aly and colleagues successfully developed and validated hydrogel loaded-polymeric nanoparticles of SIM for topical wound healing purpose in laboratory animals. The SIM-polymeric nanoparticles were prepared by the nanoprecipitation method using tween 80, sodium deoxycholate, methylcellulose, PVP K90, PEG 4000 to improve the drug solubility and skin permeation. The obtained polymeric nanoparticles were evaluated by transmission electron microscopy, particle size analysis, solubility testing, drug content testing, and particle size measurement. Following the loading of the polymeric nanoparticles into the hydrogel, the physical properties, in vitro release, and ex vivo permeability were assessed. The prepared gel was tested on rat wounds before being put through a histological investigation. The drug content in the polymeric nanoparticles was found to be 86.43%. It has a smooth surface, a spherical shape, and a consistent size distribution. 81.54 % of the SIM was released after 24 hours, compared to the ex vivo permeation study, where 69.12 % of the SIM was transmitted through the skin after 24 hours. The development of the normal epithelial layer on day 11 following the establishment of the lesion supported the histopathology results showing the SIM polymeric nanoparticles-loaded hydrogel was effective in wound healing.

³²Alaa S. Tulbah and the team described a promising nanotechnology that may be used to inhale a prospective anti-inflammatory and muco-inhibitory drug, SIM, for the treatment of inflammatory lung disorders. SIM-nanoparticles encapsulated with poly-lactic-co-glycolic acid(PLGA) and other ingredients like pluronic acid F127, dichloromethane were fabricated using the solvent and anti-solvent precipitation method. Prior to reconstitution, it was observed that SIM-loaded nanoparticles were stable for 9 months at 4°C in a freeze-dried condition. After SIM-nanoparticle therapy on inflammation epithelial cell models, the formation of mucus was significantly decreased, and the expression of proinflammatory markers was successfully suppressed.

³³E. Priyanka and the team successfully formulated and evaluated gelatine nanoparticles of SIM. The nanoparticles were prepared by employing a polymer sodium alginate. The tween-80 and span-80 were used as hydrophilic and lipophilic surfactant respectively. The different formulations were prepared at different ratios of polymer and surfactant. The prepared formulations were analysed for encapsulation efficiency, drug content, particle size determination and drug release studies. By comparing the results of all formulations, formulation encoded G2 was found to have 75.04% entrapment efficiency, 92.89% drug content and 64%drug release in 12hrs.

Drug release from polymeric nanoparticles is maintained. These systems are used as drug carriers for lipophilic drugs, to enhance the solubility there by oral bio-availability of Poorly water-soluble drugs.It can also be applied in anticancer therapy, vaccine and gene therapy.³⁴

2.4 Surfactant Based System:

2.4.1 Niosomes:

Niosomes are vesicular medicated drug delivery system in which the solution is enclosed in vesicle which is made up of non-ionic surfactants because of this niosomes are amphiphilic in nature. Niosomes may be administered through different method and overcome the drawbacks of liposomes, such as chemical instability. Niosomes can deliver a variety of drugs, including synthetic, natural, hormones, and other bioactive substances.

Fig 7: Niosomes

Niosomesimprove the performance of drug molecule and enhances the availability of the drug at particular site, improve the solubility and oral bioavailability of poorly soluble drug molecule andenhance the skin permeability of the drug when applied topically. The demerits include Hydrolysis and leakage of entrapped drugs, physically unstable, Time-consuming technique required for formulation, and it is an Expensive technique which requires skills.

Case studies:

³⁴Maryam Naseroleslami and colleagues successfully investigated therapeutic effectiveness of SIM-loaded nano-niosomes on myocardial ischemia/ reperfusioninjury. The ingredients are simvastatin, span 60, PEG, cholesterol and ethanol is used and the film hydration method was used to synthesize nano-niosomes. Transmission electron microscopy and dynamic light scattering technologies was emolyed to evaluate and analyse the physico-chemical evaluations of prepared colloidal niosomes. Male Wistar rats used as the test animals for the myocardial ischemia/reperfusion damage. It was reported that the nano-niosomes containing SIM improved the cardiac function and inhibiting the necroptosis pathway. This approach can be applied as a notable drug delivery system to increase stability, bioavailability, and therapeutic efficacy of SIM, when it used against myocardial ischemia/ reperfusion injury.

³⁵Iman Akbarzadeha and the team successfully reported the preparation and optimization of niosomal formulation of SIM by thin film hydration method using SIM, cholesterol, span (span 20, span 40, span 60, span 80), cholesterol and methanol. The optimized niosomal formulation were characterized in size, polydispersity index (PDI), entrapment efficiency (EE), stability, releasing pattern, and antimicrobial action. To create diverse formulations of SIM loaded niosomes, various surfactant and cholesterol ratios were used. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) studies were analysedagainst Staphylococcus aureus and Escherichia coli to assess the antimicrobial properties of the colloidal nano preparation. The Franz diffusion cell technique was used to analyze the drug release rate from noisome. In this study they have reported that the niosomal formulation of SIM, showed better antibacterial efficacy than free SIM. It has been reported that using of niosomes as a colloidal carriers can improve the antibacterial activity of antimicrobial agents.

³⁶Heba F. Salem and colleagues successfully prepared evaluated SIM noisomal gel formulation to resolve the poor bioavailability of SIM via the transdermal administration. The thin-film hydration process was used to create niosomes loaded with SIM, which were then optimised using a 33-factorial design and Design Expert® software. The ingredients employed in the formulation of niosomes are SIM, span60, tween80, cetyl pyridinium chloride (CPC) and cremophorRH 40. The loaded optimum niosomal preparation was examined for its colour, clarity, and homogeneity. For pharmacokinetic and ex vivo permeation studies, the optimum niosomal gel formulation was chosen, and it was compared to free SIM gel and oral SIM solution. According to a biopharmaceuticalcharacterizations, topical SIM-loaded niosomal gel therapy has greater AUC and Cmax than topical SIM gel or oral SIM solution.

The literatures studies have revealed that niosomal formulation of lipophilic drugs enhances the bioavailability, reduces cytotoxicity, alter pharmacokinetics and maintains the release of the drug. Non-ionic surfactants and cholesterol are mostly used in the formation of niosomes. The type and amount of each component of each component for niosomal formulation are necessary for the physicochemical properties of the final product.

2.4.2 Nanoemulsion:

The nanoemulsion droplet size ranges from 20 to 200 nm. ³⁷. Due to the small droplet size and large surface area, it undergoes direct lymphatic absorption there by avoiding first pass metabolism.³⁸Nanoemulsions are biphasic dispersed system constituting of 2 immiscible liquids: either oil in water (o/w) or water in oil (w/o) nano-droplets maintained by non-toxic amphiphilic surfactant³⁹. Due to their small droplet diameter, it gives a clear or hazy appearance which vary from milky white colour of coarse emulsion. Nanoemulsion are having long-term stability as compared to microemulsion.

Fig 8: Nanoemulsion

Nanoemulsions are known to increase the rate of absorption, helpful in taste masking of drug or excipients, less energy is required to formulate and increases the bioavailability of poorly soluble drugs. Nanoemulsions are having limited solubilizing capacity and the surfactant used must be non-toxic.

Case studies:

³⁹Sandip S. Chavhan and the team successfully developed SIM-nanoemulsion to increase solubility and rate of dissolution to increase bioavailability. Nanoemulsion was prepared by Ultrasonication method using SIM, Capryol 90 (propylene glycol monocaprylate), Phospholipon 90G, Methanol and Poloxamer 188. The nanoemulsion were evaluated for particle size determination, zeta potential, transmission electron microscopy, viscosity, in vitro release and stability studies. In vitro release studies showed increased dissolution rate of nanoemulsion as compared with free drug. Pharmacokinetic studies showed relative bioavailability of SIM nanoemulsion was 369.0% with respect to free drug suspension. Pharmacodynamic studies conducted in hyperlipidemic rats revealed that significant decrease in the total cholesterol and triglyceride levels for nanoemulsion as compared with free drug proving the improvement in bioavailability.

⁴⁰Michele Pereira Moreira and the team successfully prepared and evaluated the SIM-loaded nanoemulsion and reported the physicochemical properties and toxicity. The prepared nanoemulsion was evaluated for 30 days, and after that, the toxicity studies was performed using Vero cell culture and the in vivo model of Caenorhabditis elegans. The most ideal situation for storage was found to be at room temperature. A preliminary test found no evidence of toxicity, according to toxicology tests. SIM is a poorly water-soluble drug, and nanoemulsion has considerable potential for enhancing bioavailability. The in vivo studies of drug loaded nanoemulsion have revealed improvement in relative bioavailability, increases the solubility and thus showed significant enhanced hypolipidemic activity.

3. CONCLUSION:

For approximately 30 years, colloidal drug delivery systems have been researched but have not yet developed into the "magic bullet" that Paul Ehrlich predicted. The nanoparticulate formulations already in the market and are mainly concerned with reducing the side effects of the encapsulated drugs. It is been reported that liposomes and nanoparticles avoid the rapid phagocytosis. It is still possible to access the areas of inflammation, infection, and solid tumours without the use of particular targeted technologies. The surface of a nanoparticulate system can be coated with ligands, such as monoclonal antibodies, sugars, lectins, or growth factors, if site specificity for a particular cell or tissue type is desired. Colloidal drug delivery system are particularly useful for formulating new drugs derived from biotechnology (peptides, proteins, genes and oligonucleotides). Liposomes and SLNs are the new emerging technologies in gene therapy and cancer treatment. Small hydrophobic molecules may be dissolved quickly using this approach without the need of irritating solvents. It also provides more rationale design for the development of formulation and also improve the efficacy of both established drugs and new molecules. Since, SIM is lipophilic in nature and there are various possible routes of administrations. It has major solubility and bioavailability problems. CDDS could be a better choice to enhance the drug release, increases bioavailability and avoid solubility problem of SIM.

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Received on 30.10.2022 Modified on 28.01.2023

Asian J. Res. Pharm. Sci. 2023; 13(2):130-138.

DOI: 10.52711/2231-5659.2023.00024