Elsevier

Drug Discovery Today

Volume 24, Issue 2, February 2019, Pages 567-574
Drug Discovery Today

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Application of nanotechnology to improve the therapeutic benefits of statins

https://doi.org/10.1016/j.drudis.2018.09.023Get rights and content

Highlights

  • Statins are the mainstay of treatment for atherosclerotic cardiovascular disease.

  • Statins have a limited bioavailability due to poor aqueous solubility, low oral absorption and extensive first-pass metabolism.

  • Nanotechnology is a useful tool to enhance the bioavailability of statins.

  • Nanocarriers enhance aqueous solubility and absorption of statins.

  • Fabricated nanoparticulate delivery systems also offer controlled release of statins.

Hyperlipidemia is defined as an elevated level of lipids and lipoproteins in the blood and is considered to be a significant risk factor for accelerating the process of atherosclerosis and, consequently, cardiovascular disease. The level of cholesterol, especially low-density lipoprotein cholesterol (LDL-C), is commonly elevated in hyperlipidemia and represents the primary therapeutic target. Statins are a group of drugs that function by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are extremely efficacious in reducing elevated LDL-C in the serum and preventing atherosclerotic cardiovascular disease. However, statins have some limitations, such as poor aqueous solubility, low oral absorption, and, consequently, limited bioavailability when administered by the oral route. The field of nanotechnology is now well developed and some of these newer nanotechnology strategies offer systems with enhanced aqueous solubility of the statin, increased absorption, bioavailability, and controlled release of the statin at the site of administration. Here, we discuss nano-sized drug delivery systems to enhance the therapeutic potential of statins.

Introduction

Cardiovascular disease is a major cause of death, worldwide. Hyperlipidemia is one of the most important risk factors in the development and progression of cardiovascular disease and is characterized by elevated plasma lipoproteins, including LDL-C and triglycerides (TGs) [1]. Statins are the most common medication prescribed to lower plasma lipids and decrease the risk of developing cardiovascular disease. Statins primarily target LDL-C and the degree to which statins lower LDL-C generally ranges from ∼10% to ∼40% [2].

However, statins have low oral bioavailability primarily because of their limited aqueous solubility and some have a considerable molecular weight. Additionally, significant numbers of patients develop drug-related adverse effects. Improved bioavailability of statins has potential to reduce the adverse effects and toxicity associated with higher statin plasma concentrations [3], and efficient delivery systems may improve this bioavailability. Here, we summarize novel drug delivery systems and their therapeutic utility for statin delivery.

Section snippets

Properties of statins

Statins inhibit HMG-CoA reductase, thereby lowering elevated LDL-C and reducing the incidence of cardiovascular disease [4]. Statins also moderate the plasma concentrations of other lipids, including TG and high-density-lipoprotein cholesterol (HDL-C) [5].

Interactions between HMG-CoA and HMG-CoA reductase cause conversion of HMG-CoA to L-mevalonate, the rate-limiting step in cholesterol synthesis. Competitive inhibition of HMG-CoA reductase by statins reduces cholesterol synthesis in the

Absorption and bioavailability

Statins have recently been evaluated in the prevention of a variety of diseases, including osteoporosis, Alzheimer’s disease, stroke, cardiac diseases, and diabetes, as well as offering benefit post organ transplantation [18]. Statins have potential neuroprotective and neurorestorative effects on cerebrovascular disease, such as ischemic stroke, and in neurodegenerative diseases such as Parkinson’s disease. The beneficial effect appears to be mediated through a reduction in cholesterol level

Concluding remarks

Nanotechnology provides advantages for the delivery of statins, most importantly in oral bioavailability. At least two mechanisms should be considered to enhance the oral bioavailability of statins: (i) increasing their dissolution in the gastrointestinal tract; and (ii) reducing and/or eliminating first-pass metabolism following oral absorption, which can prevent some statins from attaining desired systemic concentrations.

Given that oral administration of statins is preferable, improving

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