Effects of formulation design on niacin therapeutics: mechanism of action, metabolism, and drug delivery

International Journal of Pharmaceutics 490 (2015) 55–64

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Review

Effects of formulation design on niacin therapeutics: mechanism of action, metabolism, and drug delivery Dustin L. Cooper, Derek E. Murrell, David S. Roane, Sam Harirforoosh * Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN 37614, United States

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 December 2014 Received in revised form 10 May 2015 Accepted 11 May 2015 Available online 15 May 2015

Niacin is a highly effective, lipid regulating drug associated with a number of metabolically induced side effects such as prostaglandin (PG) mediated flushing and hepatic toxicity. In an attempt to reduce the development of these adverse effects, scientists have investigated differing methods of niacin delivery designed to control drug release and alter metabolism. However, despite successful formulation of various orally based capsule and tablet delivery systems, patient adherence to niacin therapy is still compromised by adverse events such as PG-induced flushing. While the primary advantage of orally dosed formulations is ease of use, alternative delivery options such as transdermal delivery or polymeric micro/nanoparticle encapsulation for oral administration have shown promise in niacin reformulation. However, the effectiveness of these alternative delivery options in reducing inimical effects of niacin and maintaining drug efficacy is still largely unknown and requires more in-depth investigation. In this paper, we present an overview of niacin applications, its metabolic pathways, and current drug delivery formulations. Focus is placed on oral immediate, sustained, and extended release niacin delivery as well as combined statin and/or prostaglandin antagonist niacin formulation. We also examine and discuss current findings involving transdermal niacin formulations and polymeric micro/nanoparticle encapsulated niacin delivery. ã2015 Elsevier B.V. All rights reserved.

Chemical compounds studied in this article: Nicotinic Acid (PubChem CID: 938) Simvastatin (PubChem CID: 54454) Laropiprant (PubChem CID: 9867642) Keywords: Nicotinic acid Niacin Triglyceride Lipoprotein Flushing Hepatotoxicity Formulation

Contents 1. 2. 3.

4. 5. 6.

7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lipid modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. G Protein-coupled receptor activation . . . . . . . . . . . . . 3.2. Niacin metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Flushing and hepatotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . Niacin reformulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Controlled release formulations . . . . . . . . . . . . . . . . . . Niacin and statin formulations . . . . . . . . . . . . . . . . . . 6.2. Niacin and prostaglandin antagonist formulation . . . . 6.3. 6.4. Topical niacin formulation . . . . . . . . . . . . . . . . . . . . . . Polymeric microparticle and nanoparticle formulation 6.5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Box 70594, Johnson City, TN 37614-1708, United States. Tel.: +1 423 439 8027. E-mail address: [email protected] (S. Harirforoosh). http://dx.doi.org/10.1016/j.ijpharm.2015.05.024 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.

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1. Introduction Nicotinic acid (niacin) is a water soluble, lipid regulating compound used in medical practice to lower circulating blood triglycerides (TGs) and reduce low density lipoproteins (LDL) (Sanyal et al., 2007). Niacin exerts its effects through alterations in key enzymatic pathways that regulate TG and LDL synthesis; while elevating the levels of high-density lipoproteins (HDL) (Kamanna and Kashyap, 2008). It has been postulated that niacin side effects are induced through interactions with the G protein-coupled receptor (GPR) 109A (Kamanna et al., 2009). When activated, this niacin receptor functions by increasing release of arachidonic acid and prostaglandin synthesis, thereby activating vasodilatory prostaglandin receptors resulting in the niacin-associated flushing. The beneficial effect of niacin on TG and LDL regulation is often offset by the vascularization effect within dermal skin cells (Pike, 2005). As such, the control and avoidance of niacin-induced vascularization and flushing is paramount to regulating patient compliance during treatment as the utility of niacin therapy is severely limited by patient non-adherence brought forth by flushing effects (Rhodes et al., 2013). To offset side effect development, several forms of oral drug delivery have been used, with varying results, to control niacin release (Moon and Kashyap, 2002; Rhodes et al., 2013). The first available form of niacin was termed immediate-release (IR) as the drug was a crystalline powder which dissolved upon administration (Pieper, 2003). Following IR, two forms of controlled release, sustained-release (SR) and extended-release (ER), were developed. Of note, the definition of the terms “ER formulations” and “SR formulations” in this review article are those commonly found in the literature on niacin. They are different from those usually applied in the field of controlled drug delivery/pharmaceutical technology. In this article, ER formulations are defined as systems exhibiting release rates, which are intermediate between those of IR and SR niacin formulations. SR formulations have been used to reduce flushing; however, these formulations present with hepatotoxicity as will be discussed (Piepho, 2000). The combination drug Advicor (ER niacin and lovastatin) has been used with promising results (Bays, 2004; Moon and Kashyap, 2002); however, even with ER formulation, oral delivery of niacin has been problematic in regard to flushing onset and patient adherence (Moon and Kashyap, 2002; Rhodes et al., 2013). This review will focus on the mechanistic functions of niacin in regard to modulation of dyslipidemia and atherosclerosis. Focus will also be given to methods used in drug reformulation to offset niacin-induced flushing and novel attempts used for improving niacin side effects as it relates to alternative drug delivery. 2. Clinical significance Niacin is an important therapeutic option for the treatment of atherosclerosis and dyslipidemia (Linke et al., 2009; Pieper, 2003; Villines et al., 2012). To date, it is the only available agent that has been shown to favorably impact all lipid profile parameters (Clark and Holt, 1997; Knopp, 1998; Pieper, 2003). Niacin has been found to effectively lower LDL cholesterol, reduce TGs, and raise beneficial HDL cholesterol (Ito, 2002; Linke et al., 2009). The drug can also reduce lipoprotein a (Lp(a)) levels, an independent risk factor for the development of atherosclerosis (Berglund and Ramakrishnan, 2004; Carlson et al., 1989; Chennamsetty et al., 2012; Noma et al., 1990). Aside from the previously mentioned effects on serum lipid levels, niacin affects overall lipid particle size by reducing LDL particle size and increasing cardio-protective HDL levels (Ding et al., 2014; Sakai et al., 2001). The overall effects of niacin on lipid parameters have clinical importance, as niacin has been found to significantly reduce

cardiovascular events and slow progression of cardiovascular disease (The Coronary Drug Project Research Group, 1975; Barter, 2011; Brown, 2005). In 1955, it was discovered that niacin given in gram doses could lower plasma levels of cholesterol (Ganji et al., 2003). Furthermore, the discovery that niacin can up-regulate HDL levels to a greater degree than other cholesterol lowering agents has led to its wide spread use for treatment of dyslipidemia (Ganji et al., 2003; Villines et al., 2012). Due to its effectiveness, niacin has been used in numerous clinical studies to document its impact on a variety of coronary diseases (The Coronary Drug Project Research Group, 1975; Canner et al., 1986; Ruparelia et al., 2011). The largest study conducted to date on niacin and coronary artery disease, entitled “The Coronary Drug Project” was performed from 1966 to 1975 (Canner et al., 1986). In the study, a total of 1119 men between the ages of 30 and 64 all with past myocardial infarction were treated with 3 g of niacin daily. Niacin supplementation was found to have effectively lowered total cholesterol by 10% and TGs by 26% following 1 year of treatment. It was also noted that recurrent myocardial infarction was decreased by 27% compared to the placebo control group (Ruparelia et al., 2011). 3. Mechanism of action Niacin has been found to operate through a variety of different pathways. In this section, we will discuss niacin’s method of action occurring through specific enzyme inhibition, and interactions with GPR109A. 3.1. Lipid modulation Niacin’s anti-atherogenic mechanism of action is thought to involve multiple pathways of TG synthesis (Kamanna et al., 2009). Niacin functions to inhibit TG lipolysis, reducing free fatty acid (FFA) formation and subsequent release into systemic circulation. In turn, reduction of FFA leads to decreased levels of liver substrate to initiate hepatic TG synthesis. Niacin has also been shown to directly inhibit hepatic TG synthesis (Ganji et al., 2004; Guyton, 2004). Diacylglycerol acyltransferase-2 (DGAT2) is a key enzyme involved in hepatic lipoprotein synthesis. In vitro analysis, utilizing a transformed human liver (HepG-2) cell line, has demonstrated niacin’s ability to inhibit the DGAT2 enzyme, resulting in reduced hepatic TG synthesis and secretion (Ganji et al., 2004) (Fig. 1). Reduction in DGAT2 activity effectively reduces the supply of TG available for nascent apolipoprotein B (ApoB) particles, which may effectively increase intracellular degradation of ApoB and ultimately reduce ApoB containing particles such as very low density lipoproteins (VLDL) and Lp(a) (Fig. 1) (Guyton, 2004). VLDL formation is dependent upon hepatic TG construction, while intermediate density lipoprotein (IDL) and LDL synthesis are dependent upon the degree of VLDL formation. As a consequence of this sequential lipoprotein development, niacin therapy effectively impairs TG synthesis, leading to reduced levels of circulating VLDL, IDL, and LDL (Table 1) (Ganji et al., 2003; Zambon et al., 2014). 3.2. G Protein-coupled receptor activation The niacin stimulation of anti-atherogenic pathways also involves direct activation of GPR109A (Kamanna and Kashyap, 2008), which has been proposed to have differential effects in various tissue types (Pike, 2005). In adipocytes, GPR109A activation can reduce intercellular cyclic adenosine monophosphate (cAMP) levels which control the activity of hormone sensitive lipase (HSL) (Fig. 2A) (Chow et al., 2008; Pike, 2005). As HSL inhibition occurs, a subsequent reduction in lipolysis and free fatty acid release occurs, resulting in reduced liver substrates

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between nicotinuric acid concentration and lipid modulating effects has been elucidated (Berns, 2008; Miller et al., 1962; Pieper, 2003). The amidation pathway is a high affinity, low capacity metabolic pathway that converts niacin into several oxidative– reductive intermediates that have been associated with increased hepatic biomarkers (Bos and Meinardi, 2000; McCormack and Keating, 2005; Pieper, 2003). During amidation, niacin is converted into nicotinamide (MacKay et al., 2012; Pieper, 2002, 2003). Nicotinamide undergoes further conversion to nicotinamide adenine dinucleotide and eventually results in formation of hepatotoxic pyrimidine intermediates (Fig. 3) (Pieper, 2002). 5. Flushing and hepatotoxicity

Fig 1. Niacin directly inhibits DGAT2 activity. DGAT2 inhibition leads to a reduction in TG synthesis and activation of ApoB degradation effectively inhibiting synthesis of ApoB containing lipoproteins, VLDL, LDL, and Lp(a) (Ganji et al., 2004; Kamanna and Kashyap, 2008).

for de novo lipogenesis and TG synthesis. It has been proposed that similar activation of GPR109A on dermal macrophages leads to increased activation of phospholipase A2 (PLA2). PLA2 liberates phospholipid based fatty acids such as arachidonic acid (Yadav et al., 2012). The liberation of arachidonic acid leads to increased synthesis of known vasodilatory prostaglandins (PGs) such as PGD2 and PGE2 (Fig. 2B); which can cause facial and truncal flushing. 4. Niacin metabolism Although flushing is the predominant side effect responsible for lack of adherence in niacin therapy, several other side effects such as nausea, gastrointestinal discomfort, and hepatotoxicity have been reported (MacKay et al., 2012; Piepho, 2000). Some side effects of niacin can be correlated to differences in formulation which alter metabolic processes (Jacobson, 2010; Pieper, 2002). Niacin undergoes extensive metabolism in the liver through two primary pathways: conjugation or amidation (Fig. 3) (Berns, 2008; Pieper, 2003). The extent of metabolite formation is correlated with the degree to which niacin is available for metabolism. The conjugative system is considered a low affinity, high capacity pathway that metabolizes niacin to nicotinuric acid following glycine conjugation (Berns, 2008; Pieper, 2002; Piepho, 2000). Nicotinuric acid is believed to play a role in prostaglandin release and subsequent dermal vasodilation; however, no association Table 1 Overview of niacin effects on lipoprotein profile parameters. Lipoprotein

Effect

Reference(s)

LDL IDL VLDL HDL Apo(b) Lp(a)

# # # " # #

(Chen et al., 2013; Ganji et al., 2003) (Zambon et al., 2014) (Zambon et al., 2014) (Zambon et al., 2014) (Piepho, 2000) (Carlson, 2004)

Variation in niacin metabolism brings about differentiation in niacin-induced effects such as flushing and hepatotoxicity (Berns, 2008; Pieper, 2003). As such, niacin adverse effects can be attributed to dosage form and alterations in drug release, which can affect niacin metabolism. IR formulations quickly saturate the high affinity, low capacity amidation pathway forcing metabolic pathway alteration toward the conjugative pathway; thus resulting in high amounts of niacin converting to nicotinuric acid (Fig. 3) (Pieper, 2002, 2003). Increases in nicotinuric acid formation leads to vasodilation and the flushing effects commonly seen with niacin IR formulations. An example of the degree of niacin-induced flushing experienced by patients was demonstrated in a 2008 study by Merck (Kamal-Bahl et al., 2009). The study analyzed the effect of niacin on 500 human subjects in regard to the development of niacin-induced flushing. It was shown that of the 500 individuals using niacin, 84.6% of users reported experiencing flushing symptoms, with 27.2% of the patient population discontinuing use. Controlled release formulations provide a net reduction in initial niacin release, allowing the amidation pathway ample time to act upon niacin substrates, thus reducing nicotinuric acid formation and inducing niacin metabolic conversion to hepatotoxic pyrimidine intermediates (Berns, 2008; Gupta and Ito, 2002; Piepho, 2000) (Fig. 3). Due to the favorable amidation direction of controlled release niacin metabolism, formulations demonstrating prolonged niacin release are commonly associated with increased hepatic stress (Yadav et al., 2012). A more detailed examination of controlled release formulations will be discussed in Section 6.1. Evidence of niacin-induced hepatic stress can appear in as little as 1 week after initiation of niacin therapy (Bhardwaj and Chalasani, 2007). Compared to other hypolipidemic agents such as the fibrate drug gemfibrozil, the ER formulated prescription based niacin (Niaspan) has been shown to produce similar increases in the liver enzyme, aspartate aminotransferase, (15–16%) when given at therapeutically equivalent doses (Guyton et al., 2000; McCormack and Keating, 2005). Unsupervised consumption of SR niacin products has been linked to severe cases of hepatotoxicity (Bhardwaj and Chalasani, 2007; Fischer et al., 1991). Reports of advanced liver toxicity and even liver failure, although rare, have also been documented with SR niacin formulations (Bhardwaj and Chalasani, 2007; Ellsworth et al., 2014; Fischer et al., 1991). 6. Niacin reformulation The most common approach to niacin reformulation is the alteration of drug release from oral tablet matrices. Typically, this alteration is achieved through addition of select binders and releasing agents which confer delayed tablet dissolution and degradation, thus controlling the release of the active drug component (Table 2). Dual combination formulations using a statin or prostaglandin antagonist have been developed in an

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D.L. Cooper et al. / International Journal of Pharmaceutics 490 (2015) 55–64

Fig 2. The activation of GPR109A in humans can produce altered responses dependent upon receptor location. (A) The proposed mechanism of GPR109A activation on adipocytes leads to reduction in intracellular cAMP levels and development of anti-lipolytic effects through HSL inhibition and subsequent reduction in substrate available for de novo lipogenesis. (B) The proposed activation of GPR109A in dermal macrophages leads to increased PLA2 activity. PLA2 amplifies mobilization of arachidonic acid which can then undergo conversion to vasodilatory mediators such as PGD2 and PGE2, resulting in common flushing effects associated with niacin therapy (Chow et al., 2008; Pike, 2005). HSL, Hormone sensitive lipase; FFA, free fatty acid; PLA2, phospholipase A2.

attempt to increase drug efficacy and reduce adverse side effects, respectively (Brown, 2005; Chen et al., 2013). Other formulation methods such as transdermal delivery or polymeric micro/ nanoparticle niacin encapsulation have also been investigated (Maravajhala et al., 2009; Tashtoush et al., 2013).

6.1. Controlled release formulations Current niacin formulations have sought to offset the flushing phenomena by developing altered forms of oral niacin delivery. Although effective, rapid amidation pathway saturation results in

Fig 3. Pathways of niacin metabolism adapted from Pieper (2003). NUA, nicotinuric acid; NAM, nicotinamide; NAD, nicotinamide adenine dinucleotide; MNA, Nmethylnicotinamide; 2PY, N-methyl-2-pyridone-5-carboxamide; 4PY, N-methyl-4-pyridone-5-carboxamide.

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Table 2 Partial list of common ingredients used in controlled niacin release formulations. Ingredient

Function

Reference(s)

Hydroxypropyl methylcellulose Povidone Wax Docusate sodium Carbomer Carboxy methylcellulose Magnesium stearate Polyethylene glycol Microcrystalline cellulose

Binding agent Binding agent Lipophilic base Lubricant, emulsifier Binding agent Binding and thickening agent Filler, lubricant Lubricant, plasticizer Binding agent

(Chuong et al., 2010; RxList, 2014a,c,d) (RxList, 2014a,c,d) (Chuong et al., 2010; RxList, 2014a) (Chuong et al., 2010) (Chuong et al., 2010) (RxList, 2014b; Shah et al., 1981) (Bolhuis et al., 1981; RxList, 2014b) (Bolhuis et al., 1981; RxList, 2014c,d) (RxList, 2014b)

IR niacin quickly undergoing altered metabolism via glycine conjugation which leads to increased prostaglandin production and the associated flushing effects (Knopp, 2000; MacKay et al., 2012). To reduce the episodic flushing associated with IR niacin, SR niacin products were developed to control drug release, sustain amidation pathway metabolism, and reduce prostaglandin formation (Pieper, 2002). SR niacin products including the Upsher–Smith product, Slo–Niacin, are constructed by combining niacin with resinous, waxy, or plastic matrices (Chuong et al., 2010; Jacobson, 2010; Piepho, 2000). These products were shown to be capable of reducing vasodilatory side effects; however, the SR formulations were found to induce more severe hepatotoxicity than standard IR formulations due to delayed niacin release which amplified amidation metabolism and increased hepatotoxic niacin intermediate formation (Kamanna et al., 2009; Pieper, 2002). ER niacin was developed in response to patient susceptibility to IR niacin-induced flushing and the noted hepatotoxic effects seen in SR niacin formulations (Guyton and Capuzzi, 1998). In an effort to reduce the flushing response and increase patient compliance during niacin therapy, formulations containing matrices of niacin and various polymers such as hydroxylpropyl methylcellulose and polyvinylpyrrolidone (povidone) were developed (Table 3) (Chuong et al., 2010). Such binding agents can effectively alter dosage form dissolution and control drug release, thus reducing niacin-associated side effects. When compared to IR and SR niacin formulations, the literature suggests that ER niacin formulations can operate as an intermediate release drug delivery system (Piepho, 2000). Formulation absorption and niacin release play an important role in mitigating side effect development (MacKay et al., 2012; Pieper, 2002, 2003). In a model suggested by Pieper, IR niacin formulations have approximate absorption rates of 500 mg/hr, while SR niacin formulations show an approximate absorption rate of 50 mg/hr (Pieper, 2002). ER formulated niacin products modeled

with an intermediate rate of release (100 mg/hr) between that of the IR and SR niacin formulations, which can effectively mitigate both flushing and hepatotoxicity commonly seen in the IR and SR formulations, respectively. It should be noted that ER formulations, while showing promise in the reduction of niacin-induced side effects, have seen varied response within the patient population (Kamal-Bahl et al., 2009; Rhodes et al., 2013). Thus continuing the search for effective and ideal forms of niacin delivery which will further improve patient compliance and maintain beneficial aspects of niacin therapy. To date, the United States Food and Drug Administration (FDA) has approved two brand name oral formulations of niacin (Table 4) along with respective generic versions for the treatment of dyslipidemia (MacKay et al., 2012; Piepho, 2000). While most IR-niacin products have not undergone FDA review for dyslipidemia treatment, Upsher–Smith’s Niacor, has received FDA approval for use as a lipid altering agent. The only brand name controlled release (ER) niacin alone formulation having received FDA approval and being marketed for treatment of dyslipidemia is Niaspan; however, there are a few combinational drugs which include controlled release niacin (Table 4) (Backes et al., 2011; Knopp, 2000; Piepho, 2000). 6.2. Niacin and statin formulations Statin drugs are effective agents in the lowering of LDL cholesterol through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which controls the conversion of HMG-CoA to mevalonate during cholesterol synthesis (Pandian et al., 2008). Statins have been shown to be highly effective in reducing LDL levels (Carlson, 2004). Guidelines set forth by the National Cholesterol Education Adult Treatment Panel III (NCEP) recommend treatment of elevated LDL levels as the primary point of treatment for hypercholesterolemia (Moore et al., 2007). As such, statins are widely considered the drug of choice for

Table 3 Examples of niacin excipient profile by brand. Brand

Company

SloNiacin Upsher–Smith Niaspan Niacor Simcor Enduracin Advicor

Abbott Pharmaceuticals Upsher-Smith Abbott Pharmaceuticals Endurance Products Company Abbott Pharmaceuticals

Release Type

Excipient(s)

Reference(s)

SR

Glycerol behenate, hydrogenated vegetable oil, hydroxypropyl methylcellulose, magnesium stearate, silicon dioxide Hydroxypropyl methylcellulose, povidone, stearic acid, and polyethylene glycol

(Chuong et al., 2010)

Croscarmellose sodium, hydrogenated vegetable oil, magnesium stearate and microcrystalline cellulose Hydroxypropyl methylcellulose, povidone, stearic acid, polyethylene glycol, butylated hydroxyanisole, lactose monohydrate, titanium dioxide, triacetin. Carnauba wax, vegetable stearine, magnesium stearate, silica

(Jacobson, 2010; RxList, 2014b)

ER IR ER SR

ER

Hydroxypropyl methylcellulose, povidone, stearic acid, polyethylene glycol, titanium dioxide, polysorbate 80

(Jacobson, 2010; RxList, 2014c)

(Jacobson, 2010; RxList, 2014d) (Endurance Products Company, 2014; Jacobson, 2010; Keenan et al., 1991) (Jacobson, 2010; RxList, 2014a)

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Table 4 Brand name FDA approved niacin formulations. Brand

Active drug(s)

Company

Niacin dose (mg)

Release type

Reference(s)

Niaspan Niacor Simcor Advicor

Nicotinic Nicotinic Nicotinic Nicotinic

Abbot Pharmaceuticals Upsher–Smith Abbot Pharmaceuticals Abbot Pharmaceuticals

500, 750, 1000 500 500, 750, 1000 500, 750, 1000

ER IR ER ER

(Jacobson, 2010; Knopp, 1998; RxList, 2014c) (Backes et al., 2011; Jacobson, 2010; RxList, 2014b) (Jacobson, 2010; Lyseng-Williamson, 2010; RxList, 2014d) (Bays et al., 2003; Jacobson, 2010; RxList, 2014a)

acid acid acid Simvastatin acid Lovastatin

the treatment of hypercholesterolemia. The NCEP also recognizes reduced levels of HDL as a major risk factor in the development of coronary heart disease (Pandian et al., 2008); however, statins have been shown to only have modest effects on HDL levels (Bitzur et al., 2009). Due to the TG and HDL regulating effects of niacin, fixed combination products of statin plus niacin have been heavily researched (Bays et al., 2003; Lyseng-Williamson, 2010; Pandian et al., 2008; Yim and Chong, 2003). When it was discovered that LDL/HDL ratios were indicators of atherogenic disease formation, the effects of niacin inclusion into statin based therapeutic treatments were studied (Cheung et al., 2001). A retrospective analysis looking at the effects of niacin with the statin drug, simvastatin, analyzed 32 enrolled patients with low HDL levels and elevated LDL and TG levels (Zambon et al., 2014). Patients were given up to 4 g per day of niacin along with 20 mg simvastatin. When compared to baseline levels, marked improvements in TG, HDL, LDL, VLDL, and total cholesterol were noted. Patients receiving combination niacin/statin therapy underwent a 31% reduction in total cholesterol, a 38% reduction in TGs, a 40% reduction in VLDL, with a 43% reduction in LDL levels. Furthermore, compared to baseline levels, patients on combination therapy saw a 29% increase in total HDL levels. Niacin/statin therapy provided benefits to patients regardless of age, gender, or baseline cholesterol levels (Guyton and Capuzzi, 1998; Zambon et al., 2014). The results of this study and other trials have demonstrated the positive benefits of statin plus niacin therapy and led to the development of several FDA approved, dual combination prescription based products such as Simcor and Advicor (Table 4) (Bays et al., 2003; Gupta and Ito, 2002; Moon and Kashyap, 2002; Yim and Chong, 2003). Side effects such as flushing, abnormal liver values, and elevated transaminase levels have been documented with niacin/statin use; however, these effects were found to dissipate following treatment discontinuation (Pandian et al., 2008).

(p < 0.05) (Shah et al., 2010). The results of these studies indicated that laropiprant was well-suited to be combined with niacin for the treatment of hypercholesterolemia (Paolini et al., 2008; Vosper, 2011). As such, a niacin/laropiprant combination tablet sold under the brand name Tredaptive was approved for use in the treatment of dyslipidemia in several European countries. However, the combination of niacin/laropiprant was not approved by the FDA due to concerns over the use of laropiprant and the development of several adverse effects (Vosper, 2011). Recently, the examination of a laropiprant and ER niacin combination in conjunction with statin therapy was carried out as part of the Heart Protection Study 2: treatment of HDL to reduce the incidence of vascular events (HPS2-THRIVE) trial (HPS2THRIVE Collaborative Group, 2014). Analysis of data obtained from HSP2-THRIVE found that the combination of niacin with laropiprant resulted in no significant difference in effectiveness in regard to cardiovascular disease prevention compared to control (Masana et al., 2013). However, the dual combination of laropiprant and niacin did result in significant increases of various adverse effects, some of which were considered life threatening (HPS2-THRIVE Collaborative Group, 2014). The HPS2-THRIVE study also found that patients receiving niacin plus laropiprant showed an increased incidence of diabetic disease onset compared to placebo (5.7% vs. 4.3%, respectively) (p < 0.001). Furthermore, there were also significant increases in gastrointestinal adverse effects such as bleeding and ulceration as well as dyspepsia and diarrhea also occurred in groups receiving niacin with laropiprant compared to placebo (4.8% vs. 3.8%, respectively) (p < 0.001). Development of other serious side effects such as myopathy and excessive bleeding and/or infection were also reported (HPS2-THRIVE Collaborative Group, 2013, 2014). As a result, the findings of the HPS2-THRIVE study led to withdrawal of niacin/laropiprant from available European markets (Khan et al., 2014). 6.4. Topical niacin formulation

6.3. Niacin and prostaglandin antagonist formulation The flushing effect of niacin is thought to occur through PG induction and activation of PG-associated receptors (Kamanna et al., 2009). Thus recent research has focused on the simultaneous delivery of niacin with a known PG antagonist to offset flushing episodes and increase patient compliance (Shah et al., 2010). Laropiprant, a strong antagonist of the PGD2 receptor, has been heavily researched as a possible treatment option for niacin and dual combination niacin/statin therapy in an attempt to reduce niacin associated flushing (Perry, 2009). Several studies have shown that dosing combinations of niacin with laropiprant significantly reduces the adverse flushing effect associated with niacin consumption (Maccubbin et al., 2009; Maccubbin et al., 2012; Paolini et al., 2008); while the use of laropiprant with niacin alone has also shown a significant reduction (18.4%) of LDL levels in patients with hypercholesterolemia and/or dyslipidemia when compared to baseline (p < 0.001) (Perry, 2009). When added to statin therapy, the niacin and laropiprant combination given at doses of 1000 mg and 20 mg, respectively, has demonstrated significantly reduced lipid profile parameters when compared to double dosed statin therapy

In 1979, Novartis developed the first transdermal delivery system for topical application of scopolamine (Prausnitz and Langer, 2008; Price et al., 1981). Since its introduction, transdermal delivery has become a common form of delivery used to improve drug bioavailability and/or reduce adverse side effects (Prausnitz and Langer, 2008). Transdermal drug delivery offers several advantages over oral administration which may function to offset the dose dependent development of niacin-induced flushing. Transdermal delivery reduces dosing frequency, maintains constant drug plasma concentration levels, and avoids first pass liver metabolism (Paudel et al., 2010). The patient acceptability of transdermal drug therapy is considerably high, as evidenced by the growing market of current FDA approved transdermal drugs. The transdermal drug delivery market is projected to reach an estimated 32 billion dollars by 2015. These statistics make development of an effective transdermal delivery method for select drugs highly favorable. When applied topically, transdermal drug diffusion promotes controlled drug release through slow drug penetration and drug entrapment within the stratum corneum and dermis (Prausnitz and Langer, 2008). This aspect of transdermal delivery is highly

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favorable in the prevention of niacin-induced vasodilation as the amount of drug released systemically is controlled and maintained through saturation points and diffusion rates of the skin (Paudel et al., 2010; Prausnitz and Langer, 2008). Successful transdermal drugs exhibit partition coefficients heavily favoring lipid and nonpolar compounds (Prausnitz and Langer, 2008). As such, the transdermal application of hydrophilic drugs such as niacin is difficult to formulate. A key challenge in the development of efficient transdermal drug products is the skin permeation barrier (Paudel et al., 2010). Due to the nature of the skin barrier, only a few drugs can be delivered systemically at pharmacologically relevant concentrations. Physical and chemical drug characteristics such as lipophilicity and molecular size (<500 Da) are often favorable for percutaneous drug delivery, which severely limits the number of drugs available for successful transdermal formulation (Bos and Meinardi, 2000). As such, highly hydrophilic compounds, such as niacin, present a challenge to the development of transdermal delivery systems. Although the skin permeation capabilities of some xenobiotics can be achieved through chemical and mechanical processes (Paudel et al., 2010), the addition of select penetration enhancers such as alcohols, fatty acids, and esters can function to enhance the skin penetration capabilities of transdermal gel solutions. Epidermis perforation using microneedles and heat based thermal ablation have also been shown to effectively increase dermal permeation of some drugs (Prausnitz and Langer, 2008). Transdermal application of drugs as a means of alteration in drug release and systemic exposure has been well documented (Paudel et al., 2010). The successful development of niacin based transdermal delivery products is limited by the reduced skin diffusion associated with highly polar compounds. Therefore, transdermal formulations of the parent form of niacin (water soluble nicotinic acid; 16.7 mg/mL) (AHFS Drug Information, 2015) are severely limited. Transdermal formulation of the highly lipophilic niacin pro-drugs, dodecyl and myristyl nicotinate have been performed in an attempt to increase skin penetration and systemic absorption compared to the parent drug (Tashtoush et al., 2013). It has been shown that topical formulation of these prodrugs resulted in effective intracutaneous drug deposition, which may function to prolong niacin delivery via dermal enzyme hydrolyzation. Furthermore, topical delivery of myristyl nicotinate has shown increased percutaneous penetration and delivery of the pro-drug to photo-damaged skin resulting in increased epidermal differentiation and stratum corneum thickness (Jacobson et al., 2007). However, the effect of topical formulation of niacin prodrugs in regard to in vivo control of niacin-induced side effects and effects on lipoprotein parameters have yet to be elucidated. 6.5. Polymeric microparticle and nanoparticle formulation The use of polymer science in drug reformulation and delivery has increased exponentially over the past few decades because of their high degree of biocompatibility, degradation, and low toxicity (Marin et al., 2013). Drug encapsulation into micro- and nanometer polymer shells has shown the ability to increase drug bioavailability, reduce known adverse effects, and control drug release (Kumari et al., 2010; Soppimath et al., 2001). The aspects of altered drug release commonly associated with polymer formulations make their use in niacin formulations for reduction of niacin-induced adverse effects ideal. In past studies, polymeric delivery systems have shown the ability to control drug release and improve delivery of water soluble compounds such as nerve growth factor (NGF) (Marin et al., 2013; Xu et al., 2003, 2002). A study conducted by Maravajhala et al. looked at the release effects of polymeric microparticle encapsulated niacin (Maravajhala et al.,

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2009). In the study, polymer based microparticles of niacin were formulated using a double emulsion solvent diffusion method. It was found that niacin encapsulation using ethyl cellulose resulted in delayed drug release associated with polymer concentrations. Formulations consisting of high or low polymer to niacin ratios (1:0.2 and 1:1, respectively) demonstrated a higher initial burst release (80–90%) over a 10 hr period. Conversely, niacin formulations consisting of an intermediate polymer to niacin ratio (1:0.75) had reduced initial burst effects. Furthermore, when compared to other formulations, intermediate polymer to niacin formulations demonstrated a reduction in drug release (60%) over a 10 hr period. The reduced rate of release seen with intermediate polymer formulations could act to effectively reduce initial and overall systemic drug exposure and mitigate niacin-induced effects. Another study examined the effects of dendrimeric and polymeric conjugation on targeted niacin delivery to cytoplasmic lipid droplets where the TG synthesizing enzyme, DGAT2, is located (Sharma et al., 2011). Using human HepG2 hepatocytes and murine microglia, it was found that niacin conjugation to dendrimer and polymer carriers successfully delivered niacin to these cytoplasmic lipid droplets. As such, it was shown that the use of polymer and dendrimer conjugation could effectively function to localize niacin within targeted subcellular compartments. However, no effect on drug efficacy was elucidated. Theoretically, targeted localization of niacin to subcellular lipid droplets could act to increase drug efficacy through DGAT2 inhibition, subsequently reducing TG synthesis and improving overall lipoprotein levels. However, further investigations are still needed. Despite these findings, the overall effects of niacin using polymer encapsulation and/or conjugation have not been well studied. Effects of polymeric micro/nanoparticle carriers on niacininduced flushing and hepatotoxicity have not been identified. Also, alterations in PG release and maintenance of drug efficacy have yet to be revealed with these unique drug delivery formulations. For a number of drugs, the medical literature shows copious examples of successful polymer based nanoparticle and microsphere controlled release (De Jong and Borm, 2008; Soppimath et al., 2001). While initial results are promising, the overall effect of using micro- and nanoparticle polymer carrier systems for controlled release of niacin has yet to be elucidated. 7. Conclusion Clinical evidence suggest that niacin has a place within therapeutic approaches to heart disease (Endurance Products Company, 2014; MacKay et al., 2012; McKenney, 2003; Villines et al., 2012). It has been shown to be an effective lipid altering agent that beneficially impacts lipoprotein levels and reduces recurrent cardiovascular events (Ganji et al., 2003). Niacin’s methods of action such as DGAT2 inhibition and GPR109A activation can effectively reduce LDL and TG levels while increasing HDL levels (Ganji et al., 2004; Li et al., 2010). These actions suggest that niacin may play an important role in the treatment of atherogenic diseases (Brown, 2005). Despite the overwhelmingly beneficial aspects of niacin therapy, caveats exist in the form of intolerable adverse effects such as flushing. The flushing incidents associated with niacin create difficulty in achieving a high percentage of patient compliance with regard to niacin pharmacotherapy. As such, academic and industrial professionals have investigated several drug delivery reformulations that could potentially offset niacin-induced flushing effects. Advances in drug delivery and niacin reformulation have led to the development of novel orally delivered niacin formulations that have enhanced patient tolerability (Carlson, 2004); however, the incidence of side effects are still problematic (Table 5) (Maccubbin et al., 2009; Rhodes et al., 2013). Altered forms of niacin delivery

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Table 5 Examples of clinical effects involving various niacin formulations. Formulation

Clinical effect

Reference(s)

Positive

Negative

IR niacin

Improved lipoprotein parameters

SR niacin

Improved lipoprotein parameters, enhanced patient compliance Improved lipoprotein parameters, enhanced patient compliance Improved lipoprotein parameters, elevated HDL levels compared to statin only therapy Reduced flushing

Major flushing, G.I. disturbances, low patient (Bassan, 2012; Pieper, 2002) compliance Mild flushing, moderate to severe hepatotoxicity (Bassan, 2012; Bhardwaj and Chalasani, 2007; Rhodes et al., 2013) (Kamanna et al., 2009; McKenney, Moderate flushing, moderate hepatotoxicity 2004; Rhodes et al., 2013) (Jacobson, 2010; Kamanna et al., 2009; Flushing, hepatotoxicity Zambon et al., 2014) (HPS2-THRIVE Collaborative Group, Increased diabetic disease onset, ulceration, diarrhea, myopathy, excessive bleeding 2014; Maccubbin et al., 2008)

ER niacin Niacin + statin Niacin + prostaglandin antagonist

have begun to elucidate possible means of achieving effective drug delivery with minimization of drug-induced side effects (Maravajhala et al., 2009; Tashtoush et al., 2013). The range of niacin reformulation has been predominantly focused on oral delivery and controlled release as this is the preferred method of drug dosing for most individuals. Therefore, much work has been done in regard to the development of highly effective, orally dosed niacin products that can function to control drug release, improve niacin efficacy, or modulate associated side effects. To date, reformulation procedures involving altered rates of tablet dissolution and prolonged matrix release have been met with varying effects in regard to incidence of niacin flushing (Rhodes et al., 2013). Despite elucidation of known mechanisms of action involved in onset of flushing events (e.g. niacin metabolism and effects on prostaglandin expression), highly effective products that significantly reduce the onset of flushing symptoms in a majority of the population have yet to be discovered. Delivery options such as transdermal drug delivery and encapsulation into polymeric nano/microparticles should be considered in developing effective niacin based products which function to significantly reduce adverse effect occurrence. Current formulation processes involving transdermal application of various lipophilic niacin intermediates holds promise in regard to successful development of niacin based transdermal therapeutics (Tashtoush et al., 2013). Applications of microparticle encapsulation of niacin has been shown to be highly feasible in regard to process development (Maravajhala et al., 2009). The common characteristics (i.e. altered release, biodegradation, and tissue specificity) associated with polymeric particle encapsulation makes their use in orally delivered, controlled release niacin products ideal through the ability to not only modulate niacin release but also target drug release to various locations (Maravajhala et al., 2009; Sharma et al., 2011). Research into alternative means of niacin delivery is still sorely lacking and offers potential for the development of highly effective modes of niacin delivery that may function to maintain lipid efficacy commonly associated with niacin, while reducing or eliminating adverse side effect development such as flushing. These alternative delivery methods are commonly used for other drugs because of their propensity to reduce associated side effects and control drug release (Prausnitz and Langer, 2008; Soppimath et al., 2001). The medical community needs to elucidate the effects these delivery methods would have on niacin efficacy and adverse side effect onset. Given the proven effectiveness of niacin in treating dyslipidemia, the elucidation of alternative means of niacin delivery is highly warranted in an attempt to improve currently available products used for niacin therapy. As such, further investigation into alternative niacin drug delivery formulations (e.g. transdermal, nanoparticle, etc.) is needed in order to take steps in developing the most highly effective niacin product.

Conflict of interest The authors state no conflicts of interest regarding the opinions expressed and have received no payment in preparation of this manuscript.

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