Reviewing The Role of Novel Drug Delivery Systems in Challenging Bioavailability of Hyperlipidemic Agents

Hyperlipidemia also known as hypercholesterolemia/hyperlipoproteinemia is a grave condition wherein extremely high levels of lipids are present in the systemic circulation. Hyperlipidemia occurs when the intake of cholesterol and fat is increased or when the body synthesises excessive cholesterol and fat or both.1 It manifests in two forms: primary hyperlipidemia, caused by genetic defects, and secondary hyperlipidemia, affected by lifestyle factors and pre-existing medical conditions such as obesity, alcohol consumption and kidney disease.2 The pathophysiology of hyperlipidemia involves two main metabolic pathways, the exogenous metabolic pathway and endogenous metabolic pathway.3 The former deals with absorption of dietary lipids, transported in the form of chylomicrons which are processed by an enzyme (lipoprotein lipase), releasing fatty acids that are used immediately as a source of energy or to be stored in adipose tissue for later use. The liver then takes up any remnants of the chylomicrons. On the other hand, the endogenous pathway involves the transport of cholesterol esters from the liver to target cells, primarily through very low density lipoproteins . These VLDLs are converted into low density lipoproteins, which deliver cholesterol to peripheral tissues and eventually return to the liver. Any sort of disruptions in both of these pathways; due to genetic or environmental factors; leads to an imbalance in lipid metabolism which then results in the accumulation of lipids in the bloodstream eventually leading to hyperlipidemia. This imbalance also expedites the process of atherosclerosis, wherein fatty deposits build up in arterial walls in the form of sticky substances called plaque. This significantly increases the risk of cardiovascular diseases. Research has shown increased levels of plasma cholesterol and LDLs are the primary culprits behind atherosclerosis, while increased plasma levels of high-density lipoprotein (HDL) act as protective shields against this condition.4 Treatment for hyperlipidemia mainly consists of statins and fibrates as of today.5 Statins are the most widely used of them all and they work by inhibiting HMG-CoA reductase, which is vital for cholesterol synthesis in the liver. Despite their popularity and frequent use, statins and other antihyperlipidemic agents like niacin, fibrates, bile acid sequestrants, and others face many limitations such as poor solubility, low absorption rates (therefore low bioavailability), and the need for frequent dosing to achieve optimum efficacy.6 These disadvantages lead to low patient compliance and suboptimal therapeutic outcomes. To overcome these challenges, ‘novel drug delivery systems’ (NDDS) must be developed in order to enhance drug solubility, absorption, bioavailability, and targeted delivery, thereby improving patient compliance and therapeutic efficacy of the drugs.

TYPES OF HYPERLIPIDEMIAS

There are essentially two forms of hyperlipidemia, primary and secondary. 7

Fig 1.1 Classification of Primary Hyperlipidemia

Familial Lipoprotein Lipase Deficiency (Type I) is caused by a genetic defect and occurs very rarely. In this disorder, the main elevated plasma lipoprotein is chylomicrons. This results from mutations in the gene coding for the enzyme lipoprotein lipase (LPL), leading to an inability to hydrolyze the triglycerides in chylomicrons, thus causing their accumulation in the blood.

Familial Hypercholesterolemia (Type IIa) also results from a genetic defect and is less common. The elevated plasma lipoprotein in this disorder is low-density lipoprotein (LDL). LDL cholesterol levels are high due to impaired clearance from the blood, resulting from mutations in the LDL receptor gene.

Polygenic Hypercholesterolemia (Type IIb) is the most common type of primary hyperlipidemia and results from a combination of multiple genetic factors and lifestyle influences. In this disorder, LDL cholesterol levels are elevated.

Familial Dysbetalipoproteinemia (Type III), caused by a genetic defect and considered quite rare, involves elevated levels of intermediate density lipoprotein. This disorder is associated with mutations in the apolipoprotein E gene. This leads to improper metabolism of intermediate density lipoproteins and residues of chylomicrons, therefore resulting in their accumulation in the blood.

Hypertriglyceridemia (Type IV) is a prevalent form of hyperlipidemia characterized by elevated triglyceride levels resulting from either increased amounts of very low density lipoproteins. It encompasses a complex interplay of environmental as well as genetic factors.

Familial Combined Hyperlipidemia (Type V), resulting from a genetic defect and less common, involves elevated levels of both VLDL and LDL. This disorder is often due to genetic mutations affecting multiple aspects of lipid metabolism.

Secondary hyperlipidemia:

The types of secondary hyperlipidemia include hypercholesterolemia, hypertriglyceridemia, and hypocholesterolemia.

Hypercholesterolemia can be caused by a few drugs such as cyclosporine, sirolimus, mirtazapine, isotretinoin, glucocorticoids, diuretics etc. It can be linked to various conditions, like hypothyroidism, nephrotic syndrome, anorexia nervosa, AIP and obstructive liver disease.

Hypertriglyceridemia can be caused by various pre-existing conditions, including pregnancy, acute hepatitis, diabetes mellitus, obesity and ileal bypass surgery. Other conditions that can lead to hypertriglyceridemia include glycogen storage disease, lupus and multiple myeloma. A few drugs can result in hypertriglyceridemia, such as antifunals, immunosuppressants, antiviral agents, alcohol, isotretinoin etc.

Hypocholesterolemia is a condition linked to poor absorption, malnourishment, chronic liver disease and certain chronic infectious diseases such as TB or AIDS.8

VARIOUS TRADITIONAL ANTIHYPERLIPIDEMIC AGENTS AND THEIR MECHANISMS OF ACTION

HMGCoA reductase inhibitors

Statins are one of the most commonly used antihyperlipidemic drugs due to a significant decrease in the complications and risks associated with hyperlipidemia.They work by inhibiting an enzyme called HMGCoA-Reductase, which converts HMGCoA to mevalonate - further used in cholesterol synthesis. Therefore, the inhibition of HMGCoA enzyme leads to controlled blood cholesterol.9

Fibrates

Fibrates exhibit their action via limiting the substrate available for synthesis of triglycerides in the liver and also induces an enzyme that leads to decreased triglyceride production. They modulate the LDL receptor-ligand interaction and cause the stimulation of a mechanism known as reverse cholesterol transport. This combined action leads to increased LDL clearance which further leads to a decreased level of LDL that can be oxidized.10

Fig 1.2 Mechanism of action of fibrates

Cholesterol absorption inhibitors

Cholesterol Absorption Inhibitor inhibits a transporter involved in the GIT which facilitates the cholesterol absorption, which therefore lowers the amount of cholesterol being absorbed into the body. This initiates a cascade of reactions in the liver finally leading to up-regulation of LDL receptors. This up-regulation leads to an increased LDL uptake into cells and therefore decreases the amount present in the blood.11

Fig 1.3 Mechanism of action of Cholesterol Absorption Inhibitors

Nicotinic acid

Nicotinic acid (as niacin) works by decreasing lipids and lipoproteins that contain apolipoprotein B (apo-B) via the alteration of synthesis of triglycerides in the liver or by altering lipolysis that occurs in the adipose tissues. It also inhibits an enzyme playing a vital role in the final step of triglyceride synthesis, thereby decreasing the amount of triglycerides. This also leads to a decreased availability of VLDL. Niacin increases the levels of HDL in the blood by preventing it’s catabolism via inhibition of the receptor.12

Fig 1.4 Mechanism of action of Nicotinic acid

Bile acid sequestrants

Bile acid sequestrants (Cholestyramine) are resins that interrupt the reassimilation of bile acids from the GIT. The aforementioned example, Cholestyramine resin, is an ion exchange resin. Ion exchange resins can sequester themselves to bile acid by exchanging their negative chloride ions with the bile acids and forming a resin matrix. This promotes the liver to increase the production of bile acids. It does so by metabolizing cholesterol (LDL) present in the cells which effectively decreases the levels of LDL.13

NOVEL DRUG DELIVERY SYSTEMS

The novel drug delivery system represents a significant advancement in the field of pharmacology and drug administration. They are meticulously formulated to amplify the potency of drugs, regulate the release to provide a sustained therapeutic effect, improve the pharmacological utility of drugs, and ensure greater safety by precisely targeting drugs to desired tissues.14 For a drug delivery system to be effective, it must fulfill three critical criteria: successful encapsulation of API, effective drug release, and precise delivery to the targeted body part. The usefulness and success of these systems largely depend on their ability to manipulate the biodistribution and pharmacokinetics parameters (determining absorption, distribution, metabolism and excretion of a drug). Traditional methods of drug formulation in methods such as tablets, pills, ophthalmics and parenteral preparations, have been the convention for decades. These standard forms are straightforward and widely used, but they often come with limitations such as variable bioavailability, frequent dosing requirements, and systemic side effects. For instance, oral administration often faces challenges like gastrointestinal degradation and first- pass metabolism, which can reduce the drug’s efficacy.6 In response to these limitations, an assortment of novel drug delivery approaches have been engineered over recent years. One innovative method involves the chemical modification of drugs to enhance their stability, dissolution, and ultimately their bioavailability. Another approach is the entrapment of drugs in small vesicles, such as liposomes or nanoparticles, which can be injected into the bloodstream.15 These vesicles can protect drugs from degradation and facilitate targeted delivery to specific tissues or organs. Other techniques include entrapping drugs within specialized pumps or polymeric materials implanted in desired bodily compartments. Innovations in this field include biodegradable polymers, microneedles, and transdermal patches, which offer non-invasive alternatives to traditional methods. Microneedles provide a painless and efficient way to deliver drugs through the skin, while transdermal patches can offer sustained drug release over several days. Advances in nanotechnology have paved the way for the development of nanocarriers, such as dendrimers, quantum dots, and carbon nanotubes, which can be functionalized to enhance drug delivery and targeting. The continuous evolution of NDDS reflects a growing understanding of drug pharmacokinetics and the need for more precise and efficient drug delivery mechanisms. These systems not only aim to improve therapeutic outcomes but also to enhance the overall patient experience by reducing the frequency of administration and minimizing side effects.

Self Micro Emulsifying Drug Delivery System

SMEDDS, as the name indicates are a class of self emulsifying formulations that can increase the oral availability of drugs that are poorly absorbed. The self-emulsifying property of these formulations is attributed to their composition, which consists of an oil phase, an aqueous phase, and surfactants. Additionally, the peristaltic movement of the intestine provides agitation, further enhancing the emulsification process. This allows the formulation to spread over the GI tract with ease. As the name suggests, they are less than 50 nm in size.16

Table 1.1 Composition of SMEDDS Fenofibrate¹⁷

This method of formulation can be employed for drugs with poor solubility in their traditional dosage forms, such as Lovastatin and Fenofibrate. Fenofibrate, a BCS Class II drug, exhibits low solubility, making it an ideal candidate for incorporation into SMEDDS formulations to optimize its therapeutic efficacy. Another modification that can be done to SMEDDS is the supersaturation of the drug by either using the drug in a rapidly dissolving form or by increasing the energy of its form to be able to attain a drug concentration far greater than its solubility would allow. This involves the usage of less surfactant, therefore decreasing the side effects it produces. This also increases the thermodynamic activity of the preparation.

Ternary Solid Dispersions

This involves using two types of carriers to make up the matrix carrying dispersed solid drugs. This method is able to increase solubility and bioavailability owing to the dual action of the carriers. One carrier is devoted to the increase of solubility whilst the other controls the release and stabilizes the drug. Drugs with poor aqueous solubility such as Fenofibrate and Ezetimibe can be formulated into ternary solid dispersions.18 Poloxamer 188 and TPGS surfactant can be used to formulate a solid dispersion of Fenofibrate to counteract its high lipophilicity. 19

Table 1.2 Examples of Ternary Solid Dispersion Formulations²⁰²¹²²

Nanosuspension

These are colloidal dispersions of nano sized drug molecules that are suspended in aqueous mediums. The act of size reduction always results in an increase in surface area which increases solubility of any drug. This also increases the super-saturability of the drug by increasing the vapor pressure on the drug molecules. However, the risk of precipitation is high with supersaturated drug formulations, therefore a stabilizer such as surfactants/polymers must be used. 23

Table 1.3 Examples of Nanosuspension Formulations²⁴²⁵²⁶

Ion Exchange Resins

An ion exchange resin formulation is a type of formulation consisting of charged groups that are able to swap ions, or ‘exchange’ them in order to change forms. The drug is introduced into the formulation by reacting with a resin, which is an inert polymer that the body does not absorb. This helps not only create a more sustained release but also protects drugs from being unduly metabolized enzymatically. This technique is quite cost effective and requires relatively less energy. Cholestyramine has been formulated into an ion exchange resin: Cholestyramine resin USP. 27

Table 1.4 Examples of Ion Exchange Resin Formulations 27

Nanosponge Drug Delivery

As the name suggests, this formulation consists of sponge-like materials that possess pores in which various molecules can be entrapped. These cavities can contain lipophilic and hydrophilic molecules alike, increasing the solubility as well as the bioavailability. This can also make unpalatable substances and create more pleasant-tasting formulations which ultimately leads to better patient compliance. This structure can also determine the release rate of molecules and protect the drug from deteriorating.14 However, this method of formulation is not the most cost-effective as the polymers required to make the nano sponge body can be quite expensive. Various antihyperlipidemic agents can be formulated into nanosponges: Atorvastatin, Lovastatin, Fenofibrate, Glibenclamide, Glipizide, etc.

Table 1.5 Examples of Nanosponge Drug Delivery Formulations ²⁸²⁹

Bucco-adhesive Drug Delivery System

BDDS refers to the formulations that are topically administered directly into the systemic circulation via the use of bio-adhesive systems. These can be patches, adhesive gels, ointments and even tablets. They can be administered at the buccal mucosa without much obstruction due to the hydrophilic polymers used to formulate the drug. This has a great advantage of by-passing the first pass metabolism and can protect drugs from unwarranted metabolism in the gastrointestinal tract.30 Lovastatin has been developed in the form of bucco-adhesive tablets. This has increased its bioavailability since first-pass metabolism no longer affects the drug.

Table 1.6 Examples of Bucco-adhesive Drug Delivery System Formulations313233

Gastric Floating Drug Delivery System

Gastric Floating drug delivery systems are formulated in such a manner that they remain in the stomach for an extended time period by ‘floating’ atop the gastric contents. This required buoyancy in the form of low-density materials that prevent it from sinking and reaching the intestine too quickly - therefore increasing the gastric residence. These formulations have an extended-release rate and increase bioavailability.34 It also has other effects on the dosing frequency required since the release rate can be altered. This can also be in the form of floating microspheres and even muco-adhesive tablets. Cholestyramine was formulated as such in the form of a microcapsule, which released carbon dioxide when they came into contact with gastric fluids. This involved coating the drug with cellulose acetate butyrate. A similar formulation of Fenofibrate and Simvastatin was prepared, both of which showed a marked increase in bioavailability and gastric retention.

Table 1.7 Examples of Gastric Floating Drug Delivery System Formulations 3536

Pulsatile Drug Delivery System

Pulsatile Drug Delivery System utilises chrono-pharmacology to time the body’s natural rhythm. It releases drugs in specific amounts at certain times or in ‘pulses’ to match the Circadian rhythm. Cholesterol synthesis peaks in the early morning hours 37, which would be the optimum time to administer drugs such as statins - however, it is an unreasonable time for patients. Therefore, statins are traditionally taken at night with varying results. Therefore, Simvastatin was developed in this formulation and it demonstrated superior therapeutic efficacy at the optimal time. Pulsatile drug delivery systems can be designed with specific time delays that can be synchronized with the body’s natural rhythms. Ketogenesis and lipolysis are circadian affected biochemical processes that can be targeted by PDDS. Bezafibrate can induce PPARα-dependent fibroblast growth factor 21 expression which impacts the biochemical processes aforementioned.

However, Bezafibrate only showed noticeable action at nighttime and not during the day, hence a PDDS formulation is the most suitable method of administration.

Table 1.8 Examples of Pulsatile Floating Drug Delivery System Formulations3940

Transferosomes

These are a form of transdermal drug delivery system which consists of a highly elastic lipid bilayer, allowing the drug to easily squeeze through porous skin to reach systemic circulation. They deform themselves to travel through the intercellular gaps and then reform once they cross the skin. This flexibility is due to the edge activators used in their formulation. This form of drug delivery can increase bioavailability and has been applied to Atorvastatin as well as Emodin. However, this method of formulation is quite expensive and can be susceptible to oxidative degradation.41

Table 1.9 Examples of Transferosome Formulations