Advancing Oral Drug Delivery: The Impact of Solid Lipid Nanoparticles on Antiplatelet Therapy

Technical Review Article | Open Access | Published 2nd April 2025

Advancing Oral Drug Delivery: The Impact of Solid Lipid Nanoparticles on Antiplatelet Therapy

Sumeet Dwivedi*, Deepa Lalwani, Pravin Kumar Sharma, G. N. Darwhekar | EJPPS | 301 (2025) https://doi.org/10.37521/ejpps30107 | Click to download

Acropolis Institute of Pharmaceutical Education and Research, Indore, (M.P.) - India

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Abstract

The application of nanoparticle technology in oral medicine has spurred substantial research endeavours to improve the solubility, permeability, and chemical stability of different pharmaceuticals. Improving the bioavailability of poorly absorbed drugs that are significantly degraded in the mouth is a major challenge in this research. The creation of solid lipid nanoparticles (SLNs) is the main topic of this review since it seems like a possible solution to these problems. We go over the stability, characterisation, and synthesis of SLNs, highlighting their potential to improve acute coronary syndrome treatment medication administration. The review also delves into the process by which antiplatelet SLNs work to prevent myocardial infarction, providing information about how they can enhance treatment results.

Keywords: Solid lipid nanoparticles, Myocardial infraction, Drug delivery, Acute coronary syndrome, Bioavailability

Introduction

Risk Factors and Treatment of Acute Coronary Syndrome

Unstable angina, non-ST elevated myocardial infarction (NSTEMI), and ST-elevated myocardial infarction (STEMI) are among the heart ischemia syndromes that make up the category known as acute coronary syndrome (ACS). Clinical criteria, such as electrocardiogram (ECG) data and biochemical indicators of myocardial necrosis, are used to diagnose and classify acute coronary syndrome (ACS). A disruption in the blood supply to the coronary artery causes a myocardial infarction (MI), which is a heart attack that manifests as symptoms like tiredness, nausea, dizziness, dyspnoea, retrosternal chest pain, and diminished awareness. High blood pressure, diabetes, obesity, smoking, high cholesterol, poor eating habits, and binge drinking are risk factors. Electrocardiograms, blood testing, and coronary angiography are used in the treatment of MIs.¹,²,³. Treatment involves the use of nitroglycerine, aspirin, and heparin. When a coronary artery atherosclerotic plaque explodes, it blocks the artery and causes a myocardial infarction, which stops blood supply to the heart muscle. This is how a heart attack happens.⁴,⁵,⁶. The symptoms of an acute myocardial infarction (MI), which include nausea, vomiting, sweating, and fainting, are frequently experienced. Risk factors for obesity include alcohol use, male sex, age, smoking, high blood pressure, diabetes, total cholesterol, high-density lipoprotein levels, inadequate physical activity, genetics, and family history of obesity. In those without obvious coronary artery disease, MI may be caused by coronary spasm or dissection.⁷,⁸

An ischemia cascade may result in myocardial infarction, which causes the cardiac cells surrounding the clogged coronary artery to die, necrotize, and stop growing. The location, size, and extent of an infarct can be influenced by variables such the artery, degree of blockage, collateral blood arteries, oxygen demand, and interventional treatments.⁹,¹⁰,¹¹A comprehensive medical history, differential diagnosis, and ECG modifications are all part of the diagnosis and management of MI. Although elevated troponins are the main biomarker for MI, they are unable to distinguish between ischemia and nonischaemic sources or reveal the underlying mechanism of injury.¹²,¹³

Strategies for Antiplatelet Therapy

Antiplatelet therapy provides individualized cardiovascular disease treatment plans. Although acetylsalicylic acid (ASA) has long been the recommended course of treatment, patients now have more options for treatment thanks to the development of newer, more efficacious, and safer medications such as prasugrel, clopidogrel, ticagrelor, indobufen, dipyridamole, cilostazol, and vorapaxar. The length of time and combination should take the patient's clinical characteristics, medical background, and risk of bleeding into account. The best time varies depending on the process and circumstances. Cardiovascular events in ACS are decreased when dual antiplatelet treatment DAPT is used for less than a year. While longer-duration DAPT may lower cardiovascular events, it also raises the risk of bleeding. The ideal amount of time in atrial fibrillation (AF) and after percutaneous coronary intervention (PCI) is still up for debate. It is advised that coronary atrial bypass graft (CABG) patients take ASA after surgery to lessen thrombotic events and enhance graft patency. While DAPT with ticagrelor or clopidogrel and ASA has also demonstrated benefits, there is an increased risk of bleeding. It's still unclear how long DAPT should last after transcatheter aortic valve implantation (TAVI). When compared to people with peripheral artery disease (PAD) who have no symptoms, antiplatelet monotherapy has a marginally positive effect on symptomatic patients. Vorapaxar might offer secondary prevention with a favourable benefit-risk profile. In PAD, antiplatelet treatment can reduce the risk of revascularization and increase the distance that can be walked pain-free. Patients with intracranial symptomatic stenosis experience a reduction in microembolization signals when taking ASA and clopidogrel together. For patients undergoing CAS, DAPT is advised rather than aspirin alone. Adverse clinical outcomes can be predicted by ASA resistance and clopidogrel non-responsiveness.¹⁴

Aspirin

Patients with a history of myocardial infarction (MI), stroke, or PAD have demonstrated several benefits from ASA in terms of lowering the cardiovascular event rate. In order to produce thromboxane A2, a powerful platelet aggregator, cyclooxygenase (COX) 1 and 2 enzymes are irreversibly inhibited by ASA ¹⁴.

Indobufen

Indobufen, a reversible COX inhibitor, has been shown to decrease the probability of recurrent strokes in patients with coronary stents. A Choice study compared indobufen-based and traditional DAPT methods, finding a significant difference in bleeding events, nonfatal myocardial infarction, stroke, stent thrombosis, and cardiovascular death in a single year.¹⁴

Antithrombotic Agents

By preventing platelet aggregation and release, antiplatelet drugs are essential in the treatment of acute coronary syndrome (ACS). Adenosine diphosphate P2Y12 receptor antagonists, aspirin, and glycoprotein IIb/IIIa inhibitors are used in treatment. Following an ACS event, aspirin should be administered as soon as feasible at a maintenance dose of 81 mg daily. In patients receiving PCI or under medical supervision, a P2Y12 antagonist should be administered in addition to aspirin. When used with triple antiplatelet therapy, glycoprotein IIb/IIIa inhibitors can reduce ischemia problems after PCI but can raise the risk of bleeding. A patient's risk-benefit ratio should be taken into consideration while selecting GP IIb/IIIa inhibitors, according to recent evidence.¹⁵,¹⁶

Clopidogrel

Prior to the approval of new therapeutic drugs, clopidogrel was the usual course of treatment for individuals with ACS. A 2001 trial proved the advantages of taking aspirin along with clopidogrel. Compared to placebo, patients receiving dual antiplatelet treatment (DAPT) experienced a lower primary outcome of cardiovascular death, nonfatal MI, or stroke. DAPT did, however, also raise the incidence of significant bleeding.¹⁷

Prasugrel

In a 2007 trial comparing clopidogrel with prasugrel, it was discovered that prasugrel was 2.2% less likely than clopidogrel to cause cardiovascular mortality, MI, and stroke. But it also made bleeding rates higher. There was no net therapeutic benefit for patients with a history of stroke or transient ischemic attack. Patients referred for PCI who had moderate-to-high risk UA, NSTEMI, or STEMI participated in the trial. It is unknown what function prasugrel serves in patients who are not receiving PCI treatment.¹⁸

Ticagrelor

The pivotal trial comprised patients with ACS who were either clopidogrel or ticagrelor-treated. Individuals did not exhibit ST-segment elevation, although they were scheduled for invasive or medication therapy. Ticagrelor was associated with a 1.9% absolute decline in the non-normalized number of patients (NNT) over a 12-month study that was represented by the composite outcome of vascular death, myocardial infarction (MI, or stroke when compared to clopidogrel (9.8 versus 11.7%; HR, 0.84; 95% CI, 0.77–0.92; P.001). Ticagrelor was also associated with a 1.4% absolute reduction in all-cause mortality (4.5 vs. 5.9%; HR, 0.78; 95% CI, 0.69 – 0.89; NNT, 72 patients). However, there was no appreciable difference in the risk of major bleeding between the ticagrelor group and the other therapy groups. Significant bleeding unrelated to coronary artery bypass graft (CABG) surgery occurred more frequently in the clopidogrel group (4.5 vs. 3.8%; HR, 1.19; 95% CI, 1.02–1.38; P.03) (level of evidence 1).¹⁹

Oral Drug Delivery

Drugs can be delivered conveniently and effectively by mouth, and the effectiveness of these treatments is primarily based on how well they absorb in the mouth. Nonetheless, certain medications include unfavourable traits that impede their ability to cross the gastrointestinal (GI) barriers. Solid lipid nanoparticles (SLNs) are one type of nanocarrier system that can be utilized to improve drug absorption by increasing solubility, stability, and transmembrane transport. Because SLNs have a monolayer surfactant shell surrounding a solid lipid core, bioactive compounds can be added and released precisely as needed. These fats increase transcellular uptake, strengthen mucosal adhesion, and facilitate oral absorption. Subsequent investigations will focus on creating intelligent, multipurpose nanocarriers that guarantee optimal sustained release, improved transcellular absorption, greater oral bioavailability, and increased therapeutic efficacy.²⁰

Figure 1: Graphical abstract of Enhanced Absorption via SLN [20] — **Figure 1:** Graphical abstract of Enhanced Absorption via SLN [20]

Oral SLN organization is possible as watery scattering or, alternatively, after being transformed into a typical measuring shape, such as tablets or pellets, powders in sachets or containers. SLN planning types that are provided through an oral course are elastically distributed. The microclimate within the stomach preferences partial consolidation as a result of both high ionic purity and causticity. It remains inside that food that will have a significant impact on SLN performance.²¹

Table 1: Comparison of Conventional Oral Formulation and Solid Lipid Nanoparticles

Parameters	Conventional	SLN
Formulation and Delivery	Usually made without the use of specialized delivery mechanisms, like ordinary oral tablets or capsules. Its poor solubility or breakdown in the gastrointestinal tract may be limiting factors in its bioavailability	Makes use of solid lipid nanoparticles as a vehicle. The medicine is encapsulated by these nanoparticles, which may improve its solubility, stability, and controlled release. The drug's bioavailability and absorption can both be enhanced by SLNs.
Bioavailability and Absorption	May face issues with solubility and absorption, which can affect the extent and rate at which the drug enters systemic circulation	SLNs can enhance the solubility of drug, leading to improved absorption and potentially faster onset of action. The lipid matrix can protect the drug from degradation and facilitate its passage through cellular membranes.
Stability	Might be more susceptible to degradation due to external factors, potentially affecting its efficacy and shelf life.	The lipid matrix in SLNs helps to protect the drug from environmental factors like light, heat, and oxygen, which can improve the stability of the drug over time.
Controlled Release	Typically releases the drug quickly once ingested, which might require more frequent dosing to maintain therapeutic levels	Can provide a controlled or sustained release of the drug, which might reduce the frequency of dosing and help maintain therapeutic levels over a longer period.
Side Effects and Tolerability	Because of the rapid release and different rates of absorption, side effects may be more severe.	Because of the rapid release and different rates of absorption, side effects may be more severe. To summarize, when compared to traditional oral formulations, SLN technology may provide benefits for improving ticagrelor administration, stability, and efficacy

SOLID LIPID NANOPARTICLES

Solid lipid nanoparticles (SLN) are a new class of drug carriers developed in the 1990s to address issues with conventional emulsions. These nano-sized particles, stabilized by a surfactant, consist of a solid lipid matrix that remains solid at room and body temperatures. Their unique characteristics include a nano-size range of 100-1000 nm and a large surface-volume ratio, allowing for customizable physiochemical properties. SLN has been shown to have low toxicity, effective drug targeting, controlled release, high drug loading, resistance to degradation, adaptability, and occlusive qualities. Its primary use is to enhance the absorption and bioavailability of poorly soluble medications.²²

Acid labile or poorly soluble antibiotics require introduction through a different pathway, such as intravenously. Economic pressures and cost considerations are driving the development of new strategies to increase oral drug effectiveness. Neurological diseases and cancer are growing public health issues, with treatment efficacy low and side effects. SLN offers an alternative for improving oral bioavailability, protecting against pH degradation in the gastrointestinal tract, and enhancing treatment efficacy in high-incidence diseases.²²

Enhancing the Oral Bioavailability of Poorly Soluble Drugs Using SLN

SLNs have emerged as a promising option for drug delivery due to their improved in vitro and vivo stability, reduced side effects, and enhanced delivery to specific tissues or cells. However, two issues remain: achieving compatibility with the physiological environment and preventing interaction with the immune system. The drug route to reach the action site is challenging due to the need to cross various physiological barriers. SLN may protect the active ingredient, increase its stability, and conceal it from the immune system or target it to the desired tissue or cell. Mechanisms to enhance oral bioavailability of drugs in SLN formulations include adhesion capacity, lipids similar to physiological ones, and a distinct route. SLN formulations can also act as a Trojan horse, allowing both lipids and drugs to be easily absorbed via chylomicron formation, especially into the lymphatic system. Studies have demonstrated the importance of SLN uptake into enterocytes through the clathrin and caveolae-mediated endocytosis pathway, allowing drugs to reach systemic circulation.²²

Advantages of SLNs

The reticuloendothelial system's (RES) cells can avoid the spleen and liver filtration process because SLNs are too small for them to absorb²³,²⁴.
Provide integrated medications with excellent stability
Possibility of combining medications that are both lipophilic and hydrophilic
Increase the bioavailability of compounds with low water solubility
Sterilization is simple, and scaling up
Sensitive pharmaceuticals are protected from photochemical, oxidative, and chemical degradation by immobilizing drug molecules within solid lipids, which also lowers the possibility of drug leakage.
Lyophilization can be used to achieve drying
Offer options for pharmacological release that is both targeted and regulated.
Compositional substances that are biocompatible and biodegradable²⁵

Disadvantages of SLNs

Drug loading capacity of SLNs is minimal due to their densely packed lipid matrix networks (perfect crystalline structure) and limited room for drug encapsulation ²⁶,²⁷,²⁸,²⁹.
The interaction between the drug and the lipid melt, the type and condition of the lipid matrix, the drug's miscibility with the lipid matrix, and the drug being dissolved or distributed in the lipid matrix are some of the parameters that determine the loading or encapsulation of medicines in SLNs.
The likelihood of medication discharge after a polymeric transition in storage ³⁰,³¹.
There is a lot of water (70–90%) in the dispersions.

Compositional Profile of SLNs

By reducing the interfacial tension between the hydrophobic surface of the lipid core and the aqueous environment, surfactants are essential for stabilizing the SLN structure. Along with co-surfactant, cryoprotectant, and charge modifiers, lipid and surfactant/stabilizer are the primary elements utilized to create SLNs³²

Table 2: Composition of SLNs³³,³⁴

Component	Examples	Concentration (% w/w)	Role
Lipid	Glyceryl behenate, Stearic acid	5 - 30%	Forms the solid matrix of the nanoparticles
Surfactant	Poloxamer 188, Tween 80	1 - 3%	Stabilizes nanoparticles, Prevents aggregation
Co-surfactant	Lecithin, Bile salts	0.5 - 2%	Enhances stability, improves drug loading
Drug (API)	Ticagrelor, Hydrophobic drugs	0.1 - 5%	Active ingredient for therapeutic action
Aqueous Phase	Water	60 - 90%	Medium for dispersing the nanoparticles

Fabrication Techniques of SLNs

Many techniques, such as high- shear homogenization, ultrasonication or high-speed homogenization, cold homogenization, hot homogenization, solvent emulsification/evaporation methods, microemulsion based methods, supercritical fluid-based methods, double emulsion methods, and spray drying methods, have been used to create SLNs.³²

High Shear Homogenization

This technique starts by forming solid lipid nano dispersions via high shear homogenization. Despite the method's simplicity of handling, the presence of microparticles often compromises the dispersion quality. Particle size and zeta potential have been investigated in connection with a number of process variables, such as emulsification time, cooling condition, and stirring rate. In a study, lipids such as tripalmitin and mono-and tri-glyceride blends (WitepsolW35) were utilized, and steric stabilizers (0.5% w/w) included Pluronic® F-68 and glyceryl behenate, a monoester of glycerine and behenic acid. The SLN was homogenized at 20,000 rpm for eight minutes using WitepsolW35 dispersions, which improved its quality. There was another phase of normal temperature stirring at a speed of 5000 rpm after ten minutes of cooling.

High-Speed Homogenization or Ultrasonication

SLN production process shear stress can be minimized by using high-speed stirring or ultrasonication; however, this approach has drawbacks as well, including metal contamination from the homogenizer's high speed during SLN formation and physical instability from large particles or agglomerates.[32]

Hot Homogenization

By adding the drug-containing lipid melt and aqueous emulsifier, a pre-emulsion is created using a high shear mixing homogenizer operating at 500–1500 bar pressure. As a result, the emulsion globules get smaller. At least five homogenizations are required to obtain the proper globule size. Following homogenization, a colloidal hot oil in water emulsion is produced; as this emulsion cools, the lipid crystallizes into solid lipid nanoparticles in the form of globules.³²

Cold Homogenization

Issues with hot homogenization, such as medication loss and rapid breakdown from high temperatures, are addressed by the cold homogenization technique. However, temperature exposure cannot be totally avoided due to heat generation and medication solubilization. The drug-containing melt is rapidly cooled using dry ice or liquid nitrogen to form a solid solution. The microparticles created from this solid solution are homogenized at room temperature after being ground into particles with diameters ranging from 50 to 100 nm.

Microemulsion Based Method

This technique entails diluting a microemulsion in order to precipitate the lipid. SLNs are produced by stirring a solution of water, an emulsifier, co-emulsifiers, and a low melting fatty acid at 65–70 °C. The combination exhibits optical transparency. To disperse the heated microemulsion, it is then combined with cold water. The ratios of hot microemulsion to cold water volume usually range from 1:25 to 1:50. The dilution process is significantly influenced by the content of the microemulsion. This microemulsion is dispersed in a cold aqueous medium after mild mechanical mixing, which causes the lipid phase to precipitate into SLNs.³²

Supercritical Fluid-Based Approach

Because SLNs are made using gas saturated solution (GSS) particles, this approach has the advantage of solvent-less processing. SLN can be arranged via the rapid expansion of supercritical carbon dioxide solutions. The lipid material dissolves under pressure in the supercritical fluid (SCF) along with the melted lipid, which is aided in its melting by GSS. SCF swiftly escapes as the saturated solution is sprayed via the atomizer or nozzle, leaving the little, dry lipid particles behind as the solution swells. The benefits of this approach are validated by the large range of lipid miscibility in SCF and the absence of organic solvents. ³²

Double Emulsion Method

A double emulsion method, which incorporates a stabilizer or surface-active component, is one of the most often used techniques for producing nanostructures encapsulated with hydrophilic medicines. This process, commonly known as the multiple emulsion method, consists of three key steps: To create nanoparticles, the process consists of three steps: (i) making an inverse or water-in-oil emulsion; (ii) adding the W1/O emulsion to an aqueous polymer or surfactant solution and stirring continuously (also known as homogenization or sonication); and (iii) letting the solvent evaporate or filtering the multiple emulsions. Surface modification can be achieved by adding hydrophilic polymers, like PEG, in step two of the double emulsion process since it produces larger particles.³²

Solvent Emulsification Evaporation Method

One technique for creating nanoparticles is the solvent emulsification evaporation method (SEE). It takes three steps to make a coarse emulsion: first, lipid material is added to a certain volume of organic solvent, well mixed, and then combined with water. Subsequently, a high-pressure homogenizer breaks down globules and uses high pressure to transform them into a nano emulsion. To get rid of organic solvent residue, the nano emulsion is either agitated constantly for a whole night or stored under a hood. High entrapment efficiency nanosized, non-flocculated nanoparticles are produced by this technique. Lipid material precipitates in the water and the process is repeated once the organic solvent evaporates.

Spray Drying Method

An alternate process for turning an aqueous SLN dispersion into a pharmaceutical product is spray drying. Although less common, this approach is less expensive than lyophilization when it comes to SLN formulation. The disadvantages of this approach include partial melting of the particles and particle aggregation brought on by high temperatures and shear forces. Lipids with a melting point higher than 70 °C are needed for this procedure. ³²

Drying Techniques of SLNs

Spray Drying

By spray drying, re dispersible powder can be produced in accordance with the standard guidelines for intravenous injections. Carbohydrate addition and decreased fat content during spray drying promote colloidal particle shielding. Because of the low inlet temperatures, lipid melting can be minimized by utilizing ethanol–water mixes (dispersion medium) instead of pure water. It was recommended that SLN concentrations of 1% in solutions of 30% trehalose in water or 20% trehalose in combinations of ethanol and water (10/90 v/v) could be utilized to achieve the best results.³²

Lyophilization

Over extended periods of storage, lyophilization improves the chemical and physical stability of SLN. Moreover, it maintains the original particle size and inhibits degrading reactions. To prevent crystal development, SLN components must have a sufficient chemical strength and a narrow particle size range. Temperature changes that occur during transportation shouldn't have an impact on the SLN formulation. It has been demonstrated that over several months, there has been no change in the particle sizes in aqueous SLN dispersions. Lyophilization entails the protective effect of surfactants. To prevent a rise in particle size, the lipid content of the SLN dispersion should not be higher than 5%.³²

Characterization Techniques of SLNs

The development of SLNs requires characterization in order to define characteristics such as size, molecular weight, surface charge, and solubility that affect the lymphatic system's capacity to absorb and distribute lipid-based nano-formulations.

Surface charge and particle size

Two popular techniques for determining particle size are photon correlation spectroscopy (PCS) and laser diffraction (LD). PCS measures the intensity of scattered light, while LD measures the diffraction angle of the particle radius. By stabilizing colloidal suspension, zeta potential lessens particle aggregation and interaction.

Crystallinity and lipid modifications

Drug gelling or expulsion may result from solid lipid crystallization, so it is important to carefully consider the kinetic energy and behaviour of crystallization. While Raman and Infrared spectroscopy analyse structural features, X-ray diffraction and differential scanning calorimetry evaluate crystallinity.

Entrapment efficiency and loading capacity

Lipid and aqueous phase separation is crucial for determining drug entrapment per unit weight of lipid nano-carrier. Separation methods include ultrafiltration, centrifugation filtration, and dialysis. Drug loading capacity depends on solubility and polymorphic state of lipid material. High lipid solubility is essential for adequate loading capability. Studies show that only 5-10% drugs can be incorporated, with ubidecarenone a coenzyme Q10 achieving 40% drug loading. ³⁵

Morphological characterization

Transmission electron microscope (TEM) and scanning electron microscope (SEM) methods are used for direct imaging and dimensional analysis of nanoparticles due to their higher resolution power and speed. TEM allows visualization after freeze fracturing and substitution, while SEM focuses on fibrinogen polymerization and is useful in infection studies i.e, Pathogens like bacteria and fungi can interact with fibrin networks, altering clot structures, Biofilm formation (e.g., Staphylococcus aureus) can be observed via SEM, showing how bacteria embed in fibrin clots. SEM can detect clot deformation and abnormal fibrin structures in infections, helping in disease diagnosis and research. [35]

Structure and drug distribution of SLNs

Nuclear magnetic resonance can be utilized to determine the size and qualitative characteristics of nanoparticles. This method's selectivity stems from a chemical shift that provides sensitivity to the molecular mobility of the constituents inside the nanoparticles' physicochemical characteristics. ³⁵

In vitro drug release study

Drug release from SLNs occurs through diffusion, influenced by preparation methods, solubility, drug/lipid interactions, surfactant type, lipid matrix composition, and particle size. In-vitro release profiles reveal drug release mechanisms and kinetic behaviour, with immediate release effects during initial release and controlled release after degradation. ³⁵

Dialysis tubing

The dialysis process involves setting a stable lipid nanoparticle dispersion in pre-washed tubing, dialyzing the sac, and observing drug content. In normal dialysis, samples are taken from the outer compartment, while in reverse dialysis, they are taken from the inner compartment. ³⁵

Drug Loading and Release Aspects of SLNs

Lipid nanocarriers for controlled drug release have gained attention for overcoming issues with poorly soluble and toxic drugs. Three valid drug incorporation models for SLNs are the homogenous matrix model, drug enriched shell-core shell model, and drug enriched core-core shell model. In the homogenous matrix model, the core may contain amorphous clusters or molecularly dispersed phases. In the drug enriched shell model, the drug is available near the shell, forming a drug-enriched core. ³²

Drug Release from SLNs

Because drug release from solid-liquid nanoparticles (SLNs) is dependent on the lipid and its composition, it is important for formulations. For versatile or dual release, the medication may be surface-applied or embedded in the matrix. Temperature, surface-active substances, and medication solubility in water all affect the release process. In order to prevent drug burst release and partitioning in the aqueous phase, production is often carried out at ambient temperature. Drug release is also influenced by particle size and drug entrapment type. For example, thermoresponsive SLNs can be programmed to release drugs in reaction to internal or exterior stimuli.³²

Stability issue and storage conditions of SLNs

Because of their lipid composition, surfactant content, and temperature adjustment, SLNs remain stable for more than three years. During preparation and storage, they undergo crystal alteration, with kinetics being influenced by chain length. Shear force, temperature, and light can all cause gel to develop, whereas destabilization can cause gelation and a drop in zeta potential. Prolonged storage requires the use of drying methods such lyophilization, freeze drying, and spray drying. Drug delivery is accomplished by the electrospray technique.³⁶

Examples of SLNs for antiplatelet therapy

Solid Lipid Nanoparticles (SLNs) are being explored for targeted, controlled, and improved delivery of antiplatelet drugs to enhance their efficacy, reduce side effects, and improve bioavailability. Below are some key examples of how SLNs are being developed to optimize antiplatelet therapy:

SLNs for Aspirin Delivery

Purpose: Enhancing oral bioavailability and reducing gastrointestinal (GI) side effects.
Strategy:
- Encapsulating aspirin in SLNs improves its stability and prolongs drug release.
- SLNs provide a protective barrier, reducing gastric irritation.
- Studies show improved systemic absorption and reduced risk of GI bleeding.
Example: Aspirin-loaded SLNs coated with chitosan for controlled release and better intestinal absorption.

SLNs for Clopidogrel (P2Y12 Receptor Inhibitor)

Purpose: Overcoming bioactivation challenges and increasing therapeutic efficacy.
Strategy:
- SLNs protect clopidogrel from premature degradation.
- Controlled release improves the drug's antiplatelet effect over a longer duration.
- SLNs enhance absorption in the gastrointestinal tract, especially in patients with poor metabolism of clopidogrel (CYP2C19 polymorphism).
Example: PEGylated SLNs for enhanced bioavailability and reduced first-pass metabolism.

SLNs for Ticagrelor (Reversible P2Y12 Inhibitor)

Purpose: Sustained release and improved solubility.
Strategy:
- SLNs improve ticagrelor's water solubility and bioavailability.
- Sustained-release SLNs reduce the frequency of dosing, improving patient compliance.
- Reduces peak plasma fluctuations, lowering the risk of bleeding.
Example: SLN-based oral delivery systems to enhance absorption in the small intestine.

SLNs for Dual Drug Therapy (Aspirin + Clopidogrel)

Purpose: Combined delivery for enhanced synergy and patient compliance.
Strategy:
- Co-encapsulation of aspirin and clopidogrel in SLNs provides synchronized release.
- Reduces the need for multiple daily doses, improving adherence.
- Protects both drugs from premature degradation in acidic environments.
Example: Aspirin-clopidogrel co-loaded SLNs with sustained release properties.

SLNs for Glycoprotein IIb/IIIa Inhibitors (Eptifibatide, Abciximab, Tirofiban)

Purpose: Targeted delivery to prevent systemic bleeding risks.
Strategy:
- SLNs loaded with eptifibatide or abciximab for targeted platelet inhibition.
- Surface modification with targeting ligands (e.g., fibrinogen-mimicking peptides) allows selective binding to activated platelets.
- Reduces systemic side effects by focusing the drug action on clot-forming areas.
Example: Functionalized SLNs with platelet-targeting peptides to localize therapy to thrombi.

SLNs for Fibrinolytic and Antithrombotic Combinations

Purpose: Integrating fibrinolysis with antiplatelet effects for improved outcomes in acute coronary syndrome (ACS) or stroke.
Strategy:
- Co-encapsulation of alteplase (tPA) and antiplatelet drugs in SLNs.
- Sustained drug release minimizes repeated dosing requirements.
- Reduces systemic fibrinolysis risks, focusing therapy on thrombi.
Example: Hybrid SLNs delivering a combination of fibrinolytics and antiplatelet agents for controlled clot dissolution.

SLNs are proving to be a highly promising strategy for improving antiplatelet therapy by:

Enhancing bioavailability and solubility of poorly soluble drugs.
Providing controlled or sustained drug release to minimize frequent dosing.
Reducing gastrointestinal side effects, especially with aspirin.
Enabling targeted delivery to minimize systemic bleeding risks.

Application of Solid Lipid Nanoparticles

Lipid nanoparticles (SLN) find use in a wide range of industries, such as food, cosmetics, gene transfer, pulmonary and oral medication delivery, and gene transfer. Because oral medication distribution is non-invasive and patient compliance is high, its weak water solubility restricts absorption. Drug bioavailability in water is increased via lipid-based delivery systems such as self-nanoemulsifying drug delivery systems (SNEDDS), self-micro emulsifying drug delivery systems (SMEDDS), nano emulsions, SLNs, and NLCs. When SLNs are breathed into the lungs for pulmonary medication administration, they offer deep deposition, strong adhesion, and prolonged retention. LNPs can transport macromolecules and small compounds locally or systemically. LNPs interact with biological membranes in gene transfer applications to improve the uptake of genetic molecules. LNPs are used in cosmetics to preserve delicate ingredients and increase skin hydration. Food makers are also interested in LNPs because they offer new ways to encapsulate bioactive ingredients.³⁷

Advantages of Solid Lipid Nanoparticles (SLNs) in the Treatment of Coronary Heart Disease (CHD)

Solid Lipid Nanoparticles (SLNs) offer several advantages in the treatment and management of coronary heart disease (CHD) by improving drug delivery, enhancing bioavailability, and reducing side effects. Here’s how SLNs contribute to better CHD therapy:

Improved Bioavailability of Antiplatelet and Cardiovascular Drugs: Many drugs used in CHD, such as clopidogrel, ticagrelor, and statins, have poor water solubility, leading to low absorption. SLNs enhance drug solubility and permeability, ensuring higher plasma concentrations and better therapeutic effects. Example: SLNs improve the absorption of clopidogrel, which requires bioactivation, reducing variability in patient response.

Controlled and Sustained Drug Release: SLNs allow slow and controlled drug release, which helps maintain stable plasma drug levels over an extended period. This reduces the frequency of dosing, improving patient compliance. Example: Aspirin-loaded SLNs provide sustained antiplatelet activity while minimizing gastrointestinal side effects.

Targeted Drug Delivery to Atherosclerotic Plaques and Thrombi: SLNs can be modified with targeting ligands (e.g., peptides or antibodies) to direct drugs specifically to atherosclerotic plaques or blood clots. Reduces systemic side effects (e.g., bleeding risks in antiplatelet therapy). Example: SLNs coated with fibrin-targeting ligands can selectively deliver glycoprotein IIb/IIIa inhibitors to active thrombi.

Reduction of Side Effects (Especially for Antiplatelet and Statin Therapy): Aspirin & Clopidogrel: SLNs protect the gastric mucosa, reducing gastrointestinal bleeding risks. Statins: SLNs prevent muscle toxicity by allowing lower doses to achieve the same effect. Beta-blockers: Controlled-release SLNs reduce bradycardia and hypotension risks.

Protection of Drugs from Degradation: SLNs protect labile drugs (e.g., nitric oxide donors, statins, fibrinolytics) from degradation by enzymes, pH, or oxidation. Example: SLNs improve the stability of rosuvastatin against oxidation, enhancing its cholesterol-lowering effect.

Potential for Combination Drug Therapy in CHD: SLNs can co-deliver multiple drugs in a single nanoparticle, improving synergistic effects and patient adherence. Example: Aspirin + Clopidogrel SLNs ensure synchronized drug release, optimizing dual antiplatelet therapy (DAPT). Example: Statin + Ezetimibe SLNs enhance lipid-lowering effects while minimizing side effects.

Potential for Non-Invasive or Alternative Drug Administration Routes: SLNs enhance transdermal, oral, and intravenous drug delivery for CHD treatment. Example: Ticagrelor-loaded SLNs for sublingual delivery could provide rapid onset of action in acute coronary syndrome (ACS).

Reduction in Systemic Bleeding Risks for Antithrombotic Therapy: SLNs help concentrate antiplatelet and anticoagulant drugs at the site of clot formation while reducing systemic exposure. Example: SLNs targeting thrombi-bound fibrin ensure localized delivery of thrombolytics, reducing excessive bleeding risks.

References

1. Thygesen, K., Alpert, J.S., Jaffe, A.S., Simoons, M.L., Chaitman, B.R. and White, H.D., 2012. Third universal definition of myocardial infarction. circulation, 126(16), pp.2020-2035.

2. Anderson, J.L., Adams, C.D., Antman, E.M., Bridges, C.R., Califf, R.M., Casey, D.E., Chavey, W.E., Fesmire, F.M., Hochman, J.S., Levin, T.N. and Lincoff, A.M., 2007. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and .... Journal of the American College of Cardiology, 50(7), pp.e1-e157.

3. O'Gara, P.T., Kushner, F.G., Ascheim, D.D., Casey, D.E., Chung, M.K., De Lemos, J.A., Ettinger, S.M., Fang, J.C., Fesmire, F.M., Franklin, B.A. and Granger, C.B., 2013. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American college of cardiology, 61(4), pp.e78-e140.

4. Authors/Task Force Members, Steg, P.G., James, S.K., Atar, D., Badano, L.P., Lundqvist, C.B., Borger, M.A., Di Mario, C., Dickstein, K., Ducrocq, G. and Fernandez-Aviles, F., 2012. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). European heart journal, 33(20), pp.2569-2619.

5. National Heart, Lung, and Blood Institute, 2016. What are the signs and symptoms of coronary heart disease. Bethesda: National Heart, Lung, and Blood Institute.

6. American Heart Association, 2018. Heart attack or sudden cardiac arrest: How are they different. 2014, pp.7-8.

7. Marcus, G.M., Cohen, J., Varosy, P.D., Vessey, J., Rose, E., Massie, B.M., Chatterjee, K. and Waters, D., 2007. The utility of gestures in patients with chest discomfort. The American journal of medicine, 120(1), pp.83-89.

8. Coventry, L.L., Finn, J. and Bremner, A.P., 2011. Sex differences in symptom presentation in acute myocardial infarction: a systematic review and meta-analysis. Heart & Lung, 40(6), pp.477-491.

9. Janoudi, A., Shamoun, F.E., Kalavakunta, J.K. and Abela, G.S., 2016. Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque. European heart journal, 37(25), pp.1959-1967.

10. Longo, D.L., 2012. Harrisons principles of internal medicine.

11. Buja, L.M., 2005. Myocardial ischemia and reperfusion injury. Cardiovascular pathology, 14(4), pp.170-175.

12. Reichlin, T., Hochholzer, W., Bassetti, S., Steuer, S., Stelzig, C., Hartwiger, S., Biedert, S., Schaub, N., Buerge, C., Potocki, M. and Noveanu, M., 2009. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. New England journal of medicine, 361(9), pp.858-867.

13. Balk, E.M., Ioannidis, J.P., Salem, D., Chew, P.W. and Lau, J., 2001. Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis. Annals of emergency medicine, 37(5), pp.478-494.

14. Virk, H.U.H., Escobar, J., Rodriguez, M., Bates, E.R., Khalid, U., Jneid, H., Birnbaum, Y., Levine, G.N., Smith Jr, S.C. and Krittanawong, C., 2023. Dual antiplatelet therapy: A concise review for clinicians. Life, 13(7), p.1580.

15. 2012 Writing Committee Members, Jneid, H., Anderson, J.L., Wright, R.S., Adams, C.D., Bridges, C.R., Casey Jr, D.E., Ettinger, S.M., Fesmire, F.M., Ganiats, T.G. and Lincoff, A.M., 2012. 2012 accf/aha focused update of the guideline for the management of patients with unstable angina/non–st-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update) a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation, 126(7), pp.875-910.

16. Cheng, J.W., 2013. Updates in antiplatelet agents used in cardiovascular diseases. Journal of cardiovascular pharmacology and therapeutics, 18(6), pp.514-524.

17. Budaj, A., Yusuf, S., Mehta, S.R., Fox, K.A., Tognoni, G., Zhao, F., Chrolavicius, S., Hunt, D., Keltai, M. and Franzosi, M.G., 2002. Benefit of clopidogrel in patients with acute coronary syndromes without ST-segment elevation in various risk groups. Circulation, 106(13), pp.1622-1626.

18. Cada, D.J., Levien, T.L. and Baker, D.E., 2010. Prasugrel. Hospital Pharmacy, 45(1), pp.54-66.

19. Wallentin, L., Becker, R.C., Budaj, A., Cannon, C.P., Emanuelsson, H., Held, C., Horrow, J., Husted, S., James, S., Katus, H. and Mahaffey, K.W., 2009. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 361(11), pp.1045-1057.

20. Salah, E., Abouelfetouh, M.M., Pan, Y., Chen, D. and Xie, S., 2020. Solid lipid nanoparticles for enhanced oral absorption: A review. colloids and surfaces B: biointerfaces, 196, p.111305.

21. Lingayat, V.J., Zarekar, N.S. and Shendge, R.S., 2017. Solid lipid nanoparticles: a review. Nanosci. Nanotechnol. Res, 4(2), pp.67-72.

22. Mendoza-Muñoz, N., Urbán-Morlán, Z., Leyva-Gómez, G., de la Luz Zambrano-Zaragoza, M. and Quintanar-Guerrero, D., 2021. Solid lipid nanoparticles: an approach to improve oral drug delivery. Journal of Pharmacy & Pharmaceutical Sciences, 24, pp.509-532.

23. Reddy, A., Parthiban, S., Vikneswari, A. and Senthilkumar, G., 2014. A modern review on solid lipid nanoparticles as novel controlled drug delivery system. Int. J. Res. Pharm. Nano Sci, 3(4), pp.313-325.

24. Garud, A., Singh, D. and Garud, N., 2012. Solid lipid nanoparticles (SLN): method, characterization and applications. International Current Pharmaceutical Journal, 1(11), pp.384-393.

25. Ekambaram, P. and Sathali, A.A.H., 2012. And K. Priyanka et al (2011) Solid Lipid Nanoparticles: A Review, Sci. Revs. Chem. Commun, 2(1).

26. Sun, J., Bi, C., Chan, H.M., Sun, S., Zhang, Q. and Zheng, Y., 2013. Curcumin-loaded solid lipid nanoparticles have prolonged in vitro antitumour activity, cellular uptake and improved in vivo bioavailability. Colloids and surfaces b: biointerfaces, 111, pp.367-375.

27. Huang, X., Chen, Y.J., Peng, D.Y., Li, Q.L., Wang, X.S., Wang, D.L. and Chen, W.D., 2013. Solid lipid nanoparticles as delivery systems for Gambogenic acid. Colloids and Surfaces B: Biointerfaces, 102, pp.391-397.

28. Jain, V., Gupta, A., Pawar, V.K., Asthana, S., Jaiswal, A.K., Dube, A. and Chourasia, M.K., 2014. Chitosan-assisted immunotherapy for intervention of experimental leishmaniasis via amphotericin B-loaded solid lipid nanoparticles. Applied biochemistry and biotechnology, 174, pp.1309-1330.

29. Rawat, M.K., Jain, A. and Singh, S., 2011. Studies on binary lipid matrix based solid lipid nanoparticles of repaglinide: in vitro and in vivo evaluation. Journal of pharmaceutical sciences, 100(6), pp.2366-2378.

30. Westesen, K., Bunjes, H. and Koch, M.H.J., 1997. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. Journal of controlled release, 48(2-3), pp.223-236.

31. Westesen, K., Siekmann, B. and Koch, M.H., 1993. Investigations on the physical state of lipid nanoparticles by synchrotron radiation X-ray diffraction. International journal of pharmaceutics, 93(1-3), pp.189-199.

32. Mishra, V., Bansal, K.K., Verma, A., Yadav, N., Thakur, S., Sudhakar, K. and Rosenholm, J.M., 2018. Solid lipid nanoparticles: Emerging colloidal nano drug delivery systems. Pharmaceutics, 10(4), p.191.

33. Xu, T. and Wu, X., 2020. Preparative separation of mangiferin glycosides by high speed counter current chromatography and comparison of their antioxidant and antitumor activities. RSC advances, 10(43), pp.25780-25785.

34. Naseri, N., Valizadeh, H. and Zakeri-Milani, P., 2015. Solid lipid nanoparticles and nanostructured lipid carriers: structure, preparation and application. Advanced pharmaceutical bulletin, 5(3), p.305.

35. Pandey, S., Shaikh, F., Gupta, A., Tripathi, P. and Yadav, J.S., 2022. A recent update: solid lipid nanoparticles for effective drug delivery. Advanced Pharmaceutical Bulletin, 12(1), p.17.

36. Duan, Y., Dhar, A., Patel, C., Khimani, M., Neogi, S., Sharma, P., Kumar, N.S. and Vekariya, R.L., 2020. A brief review on solid lipid nanoparticles: Part and parcel of contemporary drug delivery systems. RSC advances, 10(45), pp.26777-26791.

37. Naseri, N., Valizadeh, H. and Zakeri-Milani, P., 2015. Solid lipid nanoparticles and nanostructured lipid carriers: structure, preparation and application. Advanced pharmaceutical bulletin, 5(3), p.305.