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Journal of Pharmaceutical Investigation

, Volume 48, Issue 1, pp 43–60 | Cite as

Nanomedicines: current status and future perspectives in aspect of drug delivery and pharmacokinetics

  • Young Hee ChoiEmail author
  • Hyo-Kyung Han
Open Access
Review

Abstract

Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Especially, various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the analysis of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.

Keywords

Nanomedicines Pharmacokinetics Delivery Guidelines 

Introduction

To date, various nanomedicines have been developed and commercially applied in clinical and non-clinical areas. Nanomedicines have shown essential characteristics such as efficient transport through fine capillary blood vessels and lymphatic endothelium, longer circulation duration and blood concentration, higher binding capacity to biomolecules (e.g. endogenous compounds including proteins), higher accumulation in target tissues, and reduced inflammatory or immune responses and oxidative stress in tissues. These characteristics differ from those of conventional medicines depending on physiochemical properties (e.g.; particle surface, size and chemical composition) of the nano-formulations (De Jong and Borm 2008; Liu et al. 2011; Onoue et al. 2014). Efforts to develop these characteristics of nanomedicines are likely to make them available for treatment of specific diseases which have not been efficiently controlled using conventional medicines, because nanomedicines allow more specific drug targeting and delivery, greater safety and biocompatibility, faster development of new medicines with wide therapeutic ranges, and/or improvement of in vivo pharmacokinetic properties (Onoue et al. 2014). Many nanomedicines have been used for the purpose of increasing efficacy and reducing adverse reactions (e.g., toxicity) by altering efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic properties of the original drugs (Dawidczyk et al. 2014). In particular, higher oral bioavailability or longer terminal half-life can be expected in case of orally administered nanomedicines, leading to reduction of administration frequency, dose and toxicity (Charlene et al. 2014; Dawidczyk et al. 2014). Regulation of pharmacokinetic characteristics of nanomedicines can results in significant advances in their utilization. Considerations of pharmacokinetic characteristics of nanomedicines and formulability for development purposes, direction and status of their development, and evaluation systems are thought to have important implications for effective development and use of more effective and safe nanomedicines. Therefore, we will present examples of effective go/stop evaluation stages through a review of pharmacokinetic characteristics and delivery of nanomedicines, and the status and processes of nanomedicine evaluation by global regulatory agencies through comparative analysis.

Delivery and pharmacokinetics of nanomedicines

Changes in pharmacokinetic characteristics of nanomedicines are due to changes in pharmacokinetic properties of their active pharmaceutical ingredients (API), which include longer stay in the body and greater distribution to target tissues, possibly increasing their efficacy and alleviating adverse reactions (Onoue et al. 2014). Regulation of efficacy and/or adverse reactions of nanomedicines is affected by alteration of pharmacokinetics such as in vivo absorption, distribution, metabolism and excretion in the body.

Physiochemical properties of nanomedicines depend on their composition and formulation, which ultimately affect their efficacy and toxicity (EMA 2015a; TGA 2016). Control of physiochemical properties (e.g. composition or formulation) of nanomedicines and adjustment of the degree of binding between nanomedicines and biomolecules eventually regulate in vivo distribution of nanomedicines (EMA 2015a, b; TGA 2016). For example, it has been reported that the type and amount of binding proteins are significantly reduced when nanomedicines are prepared using PEGylated particles. Further, binding of polysorbate coated particles to ApoE was reported to increase their migration to the brain (EMA 2015a; TGA 2016).

Based on the above concepts connecting and efficacy/toxicity, Table 1 shows targeted delivery methods that can lead to changes in the pharmacokinetics of nanomedicines in the body. Delivery mechanisms of nanomedicines can be divided into intracellular transport, epileptic transport and other types (Table 1). Intercellular transport is regulated and facilitated by intracellularization, transporter-mediated endocytosis, and permeation enhancement through interactions involving particle size and/or cell surface (Francis et al. 2005; Jain and Jain 2008; Petros and DeSimone 2010; Roger et al. 2010). In general, a smaller particle size of nanomedicines increases intercellular transport, which facilitates cell permeation and affects absorption, distribution, and excretion of nanomedicines. In particular, cell internalization by transporter-mediated endocytosis depends on particle size of nanomedicines. When nanomedicine particles are large, opsonization occurs rapidly and their removal from the blood by endothelial macrophages is accelerated. It has been reported that affinity of cell surface transporters to nanomedicines varies depending on the particle size of nanomedicines, and this could also influence rapid removal of large particles from the blood by macrophages. In addition, nanomedicines containing non-charged polymers, surfactants, or polymer coatings which degrade in in vivo due to their hydrophilicity, interact with cell surface receptors or ligands to increase permeability or promote internalization of nanomedicines (Francis et al. 2005; Jain and Jain 2008; Petros and DeSimone 2010; Roger et al. 2010).

Table 1

Target delivery characteristics related to pharmacokinetic properties of nanomedicines

Targeting methods

Mechanism

Results

Intercellular transport

 Cell internalization

Caveolar-mediated endocytosis (< 60 nm)

Clathrin-mediated endocytosis (< 120 nm)

Difference in intracellular defense mechanism depending on particle size

Difference in affinity with cell surface transporter

the easier the permeation to affect absorption, distribution and excretion by the smaller the particle size

Removal from the blood by macrophages by large particles

Increased permeability by changing the interaction with cell surface receptors or ligands by coating with polymers, surfactants

 Transporter-mediated endocytosis

Interactions between molecules and nanoparticles by cell surface receptors in in vivo system

 Permeation accelerator

Perturbation of intracellular lipids by fatty acids

Intracellular transport

 Bioadhesive polymer

Opening reversible tight junction and increase of membrane permeability

Improvement of cytotoxic transport of intrinsic drugs by binding to specific proteins, antibodies and other in vivo polymers

Anti-cancer drugs: Minimizing cytotoxicity in normal cells by reducing the anticancer effect of the site where the drug does not reach the tight junction and transferring it to the normal cells

Reducing the elimination in lungs during inhalation

 Chelator

Opening reversible tight junction and increase of membrane permeability

Others

 EPR effect

Accumulation in tumor cells

Increased anticancer efficacy through increased permeability to cancerous tissue and prolongation of retention time (ie, accumulation)

 Conjugation with antibody, protein, peptide, polysaccharide

Selective delivery to target tissues

Control of delivery to the target using receptor/ligand or physiologic specific days on the surface of the target cell enhances drug efficacy/reduction of adverse reactions

 Coated with unhygienic hydrophilic material

Improved stability and transport to mucus, prevention of opsonization

Reduction of macrophage-induced or mucosal instability such that drugs stay in the body for a long time to increase drug efficacy/reduce harmful reactions

 Control of particle size to avoid removal by mucilage cilia

Retention extension in lung tissue

Degradation in lung mucosa or alleviation of macrophage action

In addition, nanomedicines improve intracellular transport of active pharmaceutical ingredients through binding involving bioadhesive polymers or chelates (Table 1) (Bur et al. 2009; Des Rieux et al. 2006; Devalapally et al. 2007; Francis et al. 2005; Jain and Jain 2008; Mori et al. 2004; Roger et al. 2010). Increased intracellular trafficking of active pharmaceutical ingredients coupled to specific proteins, antibodies, and others in polymers in vivo occurs due to opening of tight junctions and/or increased membrane permeability. In particular, introduction of such a feature in anti-cancer agents can improve the effect of chemotherapy, including targeting brain tumors which are inaccessible to drugs bound by tight junctions, increasing tumor cell targeting, and reducing normal cell targeting. Cytotoxicity against normal cells can be minimized and anti-cancer efficacy achieved using such a nanomedicine strategy. Reduction of nanomedicine elimination in lungs during inhalation leads to increased due to reduced degradation and removal by lung mucosa or macrophages, resulting in increased drug retention time and movement of drug to the target.

Using the enhanced permeability and retention (EPR) effect, it is possible to increase anti-cancer efficacy through increasing tumor permeation and retention time. The EPR effect also makes it possible to selectively deliver nanomedicines to target tissue via conjugation to an antibody, protein, peptide, or polysaccharide, which can be used to modify delivery of nanomedicines to target tissues using receptor/ligand interactions or other physiologically specific target cell interactions, modulating drug efficacy or adverse reactions. Nanomedicines coated with hydrophilic material have improved stability, and their opsonization or accumulation in mucus is prevented. By inhibiting macrophage-induced or mucosal instability, nanomedicines can be retained in vivo, e.g., in lung tissue for prolonged periods of time through particle size, control and avoiding removal by mucus ciliates, which could lead to degradation or macroscopic effects in lung mucosa (Bur et al. 2009). Therefore, a variety of formulations have been developed to use delivery mechanisms which can control pharmacokinetics and pharmacodynamics of nanomedicines.

Classification and pharmacokinetic properties of nanomedicines

Nanomedicines exhibit a range of in vivo kinetic characteristics depending on their formulations. In this context, disadvantages and advantages of each type of formulation commonly used in nanomedicines (Devalapally et al. 2007) are summarized, and pharmacokinetic properties of various nanomedicines formulations are shown in Tables 2 and 3.

Table 2

Classification of nanomedicines considering pharmacokinetic properties

Formulations

Pharmacokinetic properties

Others

Advantages

Disadvantages

Dendrimers

Polysine

Poly(amidoamine)

PEGylated polylysine

Lactoferrin-conjugated

High permeability

Release control

Drug-selective delivery

Improved solubility

Limit of administration routes

Low immunogenicity

Blood toxicity

Engineered nanoparticles

Nanocrystal

SoluMatrix fine particle

Nanosized amorphous

Improved systemic exposure

Increased retention time in mucus

Various routes of administration

Insufficient persistent emission

Gastric mucosal irritation relief of NSAIDs

Toxicity by higher Cmax

Lipid nanosystems

Emulsion

Liposome

Solid lipid nanoparticle

Lectin-modified solid lipid

Degradation or metabolism of formulated materials

Improved systemic exposure

Drug-selective delivery

Accumulation in tumor cells

Quick removal by RES uptake

Limit of administration routes

Low toxicity and antigenicity

Cytotoxicity due to surfactant

Micelles

 

High permeability

Improved solubility

Improved systemic exposure

Insufficient persistent emission

Low immunogenicity

Cytotoxicity due to surfactant

Polymeric nanoparticles

Ethyl cellulose/casein

PLGA alginate, PLGA

PLA-PEG

Hydrogel

Albumin

Chitosan analog

Stable drug release in in vivo

Increased retention time of drug

Required initial burst protection

Limit of administration routes

Low immunogenicity

Required removal of non-degradable polymer

Table 3

Specific pharmacokinetic characteristics of drugs based on the classification of nanomedicines

Formulations

API

Techniques

Administration routes

PK properties

Dendrimer

Doxorubicin

Polylysine dendrimer

IV

Increase of systemic exposure, accumulation in tumor cells

Flurbiprofen

Poly(amidoamine) dendrimer

IV

Increase of distribution and retentions in inflammatory sites

Methotrexate

PEGylated polylysine dendrimer

IV

Prolongation of systemic exposure

Lactoferrin-conjugated dendrimer

IV

Accumulation in lungs

Piroxicam

Poly(amidoamine) dendrimer

IV

Prolongation of systemic exposure

Engineered NPs

Carbendazim

Nanocrystals

PO

Increase of oral F

Cilostazol

Nanocrystals

PO

Increase of oral F

Curcumin

Nanocrystals

PO

Increase of oral F

Danazol

Nanocrystals

PO

Increase of oral F

Diclofenac

SoluMatrix™ fine particle

PO

Rapid absorption, pain relief

Fenofibrate

Nanocrystals

PO

Increase of oral F

Indomethacin

SoluMatrix fine particle

PO

Rapid absorption

Megestrol acetate

Nanocrystals

PO

Increase of oral F

Nitrendipine

Nanocrystals

PO

Increase of oral F

Nobiletin

Nanosized amorphous particles

PO

Increase of oral F, liver protective effect

Tranilast

Nanocrystals

PO

Increase of oral F, rapid absorption

Inhalable nanocrystalline powders

Lungs

Increase of anti-inflammatory effect in lungs

Paclitaxel

Albumin nanoparticles

IV

Tumor targeting

Lipid

Emulsion

Cinnarizine

Self-emulsifying drug delivery

PO

Increase of oral F

Coenzyme Q10

Solid self-emulsifying delivery

PO

Increase of oral F

Cyclosporin A

Self-emulsifying drug delivery

PO

Increase of oral F

Inhalable dry emulsions

Lungs

Increase of anti-inflammatory effect in lungs

Halofantrine

Self-emulsifying drug delivery

PO

Increase of oral F

Simvastatin

Self-emulsifying drug delivery

PO

Increase of oral F

Liposomes

Amikacin

Liposome (Phospholipid/Chol)

IV

Increase of half-life

Amphotericin B

Liposome (PC/Chol/DSPG)

IV

Increase of systemic exposure, decrease of RES uptake

Cytarabine/daunorubicin

Liposome (DSPC/DSPG/Chol)

IV

CL reduction

Doxorubicin

Liposome, PEGylated liposome

IV

Increase of distribution in tumor cells

O-palmitoyl tilisolol

Liposome (PC/Chol)

IV

Increase of distribution

Paclitaxel

Liposome (PC/PG)

IV

Prolongation of systemic exposure

Prednisolone

Liposome (PC/Chol/10% DSPE-PEG2000)

IV

Prolongation and increase of systemic exposure

Solid lipid NPs

Azidothymidine

Solid lipid NPs

IV

Increase of permeability and retention time in brain

Clozapine

Solid lipid NPs

IV

Increase of systemic exposure, CL reduction

Diclofenac Na

Solid-in-oil NPs

Skin

Increase of percutaneous absorption

Insulin

Lectin-modified solid lipid NPs

PO

Increase of oral F

Lidocaine

Solid lipid nanoparticles

Skin

Regulation of skin permeability

Micelles

Camptothecin

Block copolymeric micelles

IV

Increase of systemic exposure

Doxorubicin

Block copolymeric micelles

IV

Increase of systemic exposure, CL reduction

Paclitaxel

Block copolymeric micelles

IV

Increase of systemic exposure, CL reduction

Pilocarpine

Block copolymeric micelles

Eyes

Increase of efficacy

Tranilast

Self-micellizing solid dispersion

PO

Increase of oral F

Polymeric NPs

Celecoxib

Ethyl cellulose/casein NPs

PO

Increase of oral F

Clotrimazole/econazole

PLGA and alginate NPs

PO

Increase of oral F

Docetaxel

PLA-PEG NPs

IV

Increase of half-life and anti-cancer effect

Doxorubicin

PLGA NPs

IV, IP

Increase of half-life, decrease of distribution in heart

Glucagon

PLGA NPs

Lungs

Increase of half-life, increase of oral F

Glucagon

PLGA NPs

Lungs

Increase of oral F and half-life

Insulin

Hydrogel NPs

PO

Increase of oral F

Rifampicin

PLGA NPs

PO

Increase of oral F

siRNA

Chitosan analog NPs

PO

Increase of systemic exposure, gene silencing

VIP derivative

PLGA NPs

Lungs

Anti-inflammatory effect

Dendrimers

Dendrimers are characterized by the presence of polysine, poly(amidoamine), PEGylated polylysine, or lactoferrin-conjugated formulations, with high membrane permeability, controlled release ability, selective delivery of active pharmaceutical ingredients, and solubility improvement. There have been reports of limitations in route of administration and immunogenicity, and blood toxicity cases have also been reported (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010). Applications of dendrimer technology to active pharmaceutical ingredients are exemplified in several reports (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013). Polylysine dendrimer with doxorubicin, an intravenously administered anti-cancer nanomedicine, results in increased systemic exposure and tumor cell of doxorubicin. Poly(amidoamine) dendrimer with flurbiprofen is an intravenously injectable solution with increased distribution to the site of inflammation and increased in vivo retention time. PEGylated polylysine dendrimer with methotrexate or lactoferrin-conjugated dendrimer with methotrexate are intravenous formulations with prolonged systemic exposure and increased lung accumulation, respectively. Poly(amidoamine) dendrimer with piroxicam with is a formulation with increased systemic exposure.

Engineered nanoparticle

Engineered nanoparticles comprise nanocrystals, solumatrix fine particles, or nanosized amorphous particles, which can improve systemic exposure and decrease retention in the mucosal layer. They can be administered via various routes, but result in insufficient sustained release. Examples of engineered nanoparticle application include reducing gastric mucosal irritation due to NSAID nanomedicines, reducing other kinds of toxicity due to high Cmax compared to the original drug (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010).

Carbendazim, cilostazol, curcumin, danazol, fenofibrate, megestrol acetate, nitrendipine, and tranilast are administered orally by increasing oral bioavailability (F) using nanocrystal formulations. Diclofenac and indomethacin formulations, using SoluMatrix™ fine particle technology, are oral formulations with improved absorption rates and pain relief. Nanosized amorphous particles of Nobilet show reduced hepatotoxicity (i.e., protection of liver function) with oral F. Inhalable nanocrystalline powder of Tranilast is a formulation administered directly to lungs and with improved anti-inflammatory effect. Albumin nanoparticles of paclitaxel improves targeting variability by increasing delivery to cancer cells when intravenously administered (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013).

Lipid nanosystems

Lipid nanosystems including emulsions, liposomes, solid-lipid nanoparticles, and lectin-modified solid lipids can be used to control the degradation and metabolism of the formulation and prolong systemic exposure. In addition, the selective delivery of pharmaceuticals can be improved and the pharmacological effect (e.g. anti-cancer effects in anti-cancer nanomedicines) can be enhanced by the increase of its accumulation in cancer tissues However, their disadvantages include rapid removal due to reticuloendothelial system (RES) uptake, limitation of administration routes, cytotoxicity risk due to low anti-genicity, and surfactant use for formulation (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010).

Emulsions were formulated to increase oral F in both self-emulsifying and drug delivery systems, and several nanomedicines with emulsion formulations have been clinically used including cinnarizine, coenzyme Q10, cyclosporin A, halofantrine, and simvastatin. Inhalable dry emulsion of cyclosporin A is used to induce an anti-inflammatory effect in the lungs (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010).

Differences in liposome constituents in liposome formulations have been documented in several reports (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013). Intravenous injectable solutions of amikacin and O-palmitoyl tilisolol in liposomes (Phospholipid/Chol) have been used for half-life extension, amphotericin B in liposomes (PC/Chol/DSPG) shows decreased systemic exposure and RES uptake, and cytarabine/daunorubicin in liposomes (DSPC/DSPG/Chol) has been used to reduce clearance. Pegylated liposome-treated doxorubicin results in increased distribution of doxotubicin to cancer tissues, and prednisolone in liposomes (PC/PG) or (PC/Chol/10% DSPE-PEG2000) results in prolonged systemic exposure. Solid-lipid nanoparticles of azidothymidine result in increased permeability to the brain, those of clozapine result in increased systemic exposure due to clearance reduction, those of diclofenac developed as a transdermal preparation result in increased transdermal absorption, and those of lidocaine as a transdermal preparation result in longer duration of drug efficacy by regulating skin permeability. A lectin-modified solid-lipid N of insulin shows increased oral F (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013).

Micelles

Micelles have advantages of high membrane permeability, and improved solubility and systemic exposure, but disadvantages of insufficient sustained release and cytotoxicity due to surfactant use (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010). Block copolymeric micelles reduce clearance and increase systemic exposure of active pharmaceutical ingredients in intravenously administered formulations of camptothecin, doxorubicin, and paclitaxel. Block copolymer micelle allow direct administration to the eyeball increasing its efficacy. Self-micellizing solid dispersion of tranilast result in increased oral F (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013).

Polymeric nanoparticles

Polymeric nanoparticles include ethyl cellulose/casein, PLGA (PLGA and alginate), PLA-PEG, hydrogel, albumin and chitosan analogs with characteristics of relatively stable drug release and prolonged duration of action. However, there are a few cases in which initial rupture is inhibited, or administration routes are limited. In particular, it is necessary to consider factors involved in elimination of non-degradable polymers from the body (Devalapally et al. 2007; Kawabata et al. 2011; Liu and Fréchet 1999; Mora-Huertas et al. 2010).

Polymeric nanoparticles with increased F include ethyl cellulose/casein nanoparticles with celecoxib, PLGA and alginate nanoparticle with clotrimazole/econazole or rifampicin, hydrogel nanoparticle with insulin, and an oral formulation of siRNA using chitosan analog nanoparticles. An docetaxel IV formulation using PLA-PEG nanoparticles showed a prolonged anticancer effect due to increased half-life. IV or IP formulations of LGA nanoparticles with doxorubicin have been reported to show reduced toxicity through prolongation of half-life and reduction of cardiac distribution. Half-life extension and F increase are also reported in the case of PLGA nanoparticles with glucagon (Asthana et al. 2005; Barenholz 2012; Chaturvedi et al. 2013; Fanciullino et al. 2013; Feldman et al. 2012; Fetterly and Straubinger 2003; Hanafy et al. 2007; Hrkach et al. 2012; Jia et al. 2003; Jinno et al. 2006; Kaminskas et al. 2011, 2012; Kato et al. 2012; Kawabata et al. 2010; Kurmi et al. 2011; Larsen et al. 2013; Manvelian et al. 2012a, b; Manjunath and Venkateswarlu 2005; Matsumura et al. 2004; Morgen et al. 2012; Onoue et al. 2010a, b, 2011a, b, 2012a, b, 2013a, b; Pandey et al. 2005; Pathak and Nagarsenker 2009; Piao et al. 2008; Pepic´ et al. 2004; Prajapati et al. 2009; Reddy and Murthy 2004; Reddy et al. 2004; Sharma et al. 2004; Strickley 2004; Sylvestre et al. 2011; Teshima et al. 2006; Thomas et al. 2012, 2013; Tomii 2002; Watanabe et al. 2006; Wu and Benet 2005; Xia et al. 2010; Zhang et al. 2006, 2008, 2013).

Pharmacokinetic properties of nanomedicines

Pharmacokinetic characteristics of various nanomedicines with different formulations are determined by particle size, shape (chemical structure), and surface chemical characteristics (FDA 2015). Nanomedicines with particle size less than 10 nm are removed by kidneys whereas those with particle size more than 10 nm are sometimes elongated and removed by the liver and/or the mononuclear-phagocyte system (MPS). The aim of regulating particle size in nanomedicines is to increase their retention in target tissues, and to remove them rapidly when distributed to non-target tissues. A protein corona is formed around nanomedicines by non-specific protein adsorption in body, but this is prevented by materials such as polyethylene glycol (PEG) applied on the nano-particle through surface coating. Such protein adsorption induces protein denaturation, which may lead to protein aggregation or phagocytosis due to activated macrophages. Nanoparticle targeting based on chemical properties of nanoparticles and surface coatings comprises active and passive targeting. Passive targeting is defined as non-specific accumulation in disease tissue (usually cancer tissue). This is especially applicable to solid cancers in which targeting results in increased blood vessel and transporter permeations and retention (enhanced permeability and retention, EPR effect) of nanomedicines, and their increased accumulation in tumor tissues. Specific or active targeting is defined as selective transport of nanomedicines containing protein, antibody, or small molecule only to specific tissues and/or specific cells. This may occur via homing to overexpressed cell-surface receptors.

Pharmacokinetic assessment of nanomedicine by regulatory agencies

As mentioned above, a wide variety of nanomedicine have been developed and approved for use in clinical practice and there are also a number of nanomedicines in clinical trials. As of 2016, 78 nanomedicines were on pharmaceutical markets across the world and 63 nanomedicines were approved as drugs or were in the approval process based on search results from ‘http://www.clinicaltrial.gov’. It would be meaningful to summarize key considerations of the approval authorities and use this knowledge for the development and approval of nanomedicines.

Food and Drug Administration (FDA)

Nanoscale materials as defined by the US FDA include nanomaterials (materials used in the manufacture of nanomedicine, additives, etc.) and final products (nanomedicine). The particle size of such materials is typically 1–100 nm and such nanomedicines tend to result in increased bioavailability, decreased dose, improved drug efficacy, and decreased toxicity. Improvements in physical properties through effective formulation have led to improved solubility, dissolution rate, oral bioavailability, targeting to specific organs or cells, and/or improved dosage/convenience, leading to dose reduction with less adverse reactions due to the constituent active pharmaceutical ingredients or surfactants (FDA 2015).

Status of nanomedicines approved by the FDA

The FDA approved 51 nanomedicines by the year 2016, 40% of which were in clinical trials between 2014 and 2016 (Arnold et al. 2001; Benbrook 2015; Berges and Eligard 2005; Bobo et al. 2016; Desai et al. 2006; Duncan 2014; FDA 2006, 2014, 2015; Foss 2006; Foss et al. 2013; Fuentes et al. 2015; Green et al. 2006; Hann and Prentice 2001; Hu et al. 2012; Ing et al. 2016; James et al. 1994; Johnson et al. 1998; May and Li 2013; Möschwitzer and Müller 2006; Salah et al. 2010; Shegokar and Müller 2010; Taylor and Gercel-Taylor 2008; Ur Rehman et al. 2016; Wang-Gillam et al. 2016) (Table 4). Formulated nanomedicines approved by the FDA can be classified into polymer nanomedicines, micelles, liposomes, antibody-drug conjugates, protein nanoparticles, inorganic nanoparticles, hydrophilic polymers, and nanocrystals. Polymer nanomedicines are the simplest forms of nanomedicines and contain soft materials to increase solubility, biocompatibility, half-life and bioavailability as well as to control release of active pharmaceutical gradients from nanomedicines in body. In particular, Paxone®, Ulasta®, and PLEGRIDY® formulated with the use of poly(ethylene glycol) (PEG) are representative polymer nanomedicines resulting in increased half-life and bioavailability in in vivo. Micelles include Estrasorb®, BIND-014, and CALAA-01 as controlled-release forms of lipophilic drugs. Liposomes have reduced toxicity and increased bioavailability, and include Onivyde®, Doxil®, Visudyne®, and Thermodox®. Antibody-drug conjugates (ADCs) have been used to reduce drug cytotoxicity and improve solubility (PEGylation). ADCs are stable in blood and within targeted cancer cells and are expected to be released into intracellular or paracellular compartments after uptake. The pairing and linkage of antibody and drug are important, and are critical factors for their slow clearance and long half-life (approximately 3 and 4 days). Brentuximab emtasine is an example of an ADC nanomedicine which addresses safety issues by reducing toxicity of monomethyl auristane E. In this case, maleimide linkage and conjugation with thiolated antibody results in the release of only 2% monomethyl auristane E even 10 days after administration. ADCs with non-cleavable linkages such as those with tratuzumab are also available. Nanomedicines using protein nanoparticles include Abraxane®, an albumin-bound paclitaxel, and Ontak®, an engineered fusion protein, which consist of endogenous or engineered protein carriers. Inorganic nanoparticles in nanomedicine are drug formulations commonly used for treatment and/or imaging, in which metallic and metal oxide materials are used. Coating with hydrophilic polymers (dextran or sucrose) such as iron oxide is used for iron supplements including Venofer®, Ferrlecit®, INFed®, Dexferrum®, and Feraheme®, which show slow dissolution patterns after intravenous administration and less toxicity due to free iron in high dosage regimens. Because poor absorption of free iron is one of the reasons for increasing iron dosage resulting in severe toxicity, an iron oxide nanomedicine formulation with iron supplementation is clinically meaningful. Inorganic nanomedicines using gold are based on thermal and surface chemistry of gold, and it have not yet been approved by the FDA. Several clinical investigations using nanomedicines formulated with gold have been conducted. CYP-6091 containing colloidal gold with recombinant human tumor necrosis factor rhTNF is in a phase 2 trial, NBTXR3 and PEP503 are radio enhancers containing hifnium metal oxide for brain tumor treatment and inorganic silica nanoparticles for fluorescence-based cancer imaging, respectively, and are in phase 1 trials. Nanocrystal formulations increase nanoscale dimensions and improve dissolution and solubility and include Rapamune®, Tricor®, Emend®, and Megace ES®.

Table 4

Nanomedicines approved by FDA

Formulations

Product names

Pharmaceutical company

Indications

Characteristics

Approval year

Polymer NP: synthetic polymer particles

 PEGylated adenosine deaminase enzyme

Adagen®/pegademase bovine

Sigma-Tau

Pharmaceuticals

Serious immunodeficiency therapy

Improved circulation (retention) in body and decreased immunogenicity

1990

 PEGylated antibody fragment (Certolizumab)

Cimzia®/certolizumabpegol

UCB

Chron’s disease, rheumatoid arthritis, psoriasis, ankylosing spondylitis

Improved circulation (retention) in body and stability

2008

2009

2013

 Random copolymer of l-glutamate, l-alanine, l-lysine and l-tyrosine

Copaxone®/Glatopa

Teva

Multiple sclerosis

Regulation of CL by large amino-acid polymers

1996

 Leuprolide acetate and polymer [PLGH(poly(dl-lactide-coglycolide)]

Eligard®

Tolmar

Prostate cancer

Regulation of drug delivery by prolongation of circulation (retention) in body

2002

 PEGylated anti-VEGF aptamer (vascular endothelial growth factor) aptamer

Macugen®/Pegaptanib

Bausch&Lomb

Decreased vision

Improved aptamier stability by PEGylation

2004

 Chemically synthesized ESA (erythropoiesis-stimulating agent)

Mircera®/Methoxy PEG glycol-epoetin β

Hoffman-LaRoche

Anemia with chronic renal failure

Improved aptamier stability by PEGylation

2007

 PEGylated GCSF protein

Neulasta®/pegfilgrastim

Amgen

Leukopenia by chemotherapy

Improved protein stability by PEGylation

2002

 PEGylated IFN alpha-2a protein

Pegasys®

Genentech

Hepatitis B and C

Improved protein stability by PEGylation

2002

 PEGylated IFN alpha-2b protein

PegIntron®

Merck

Hepatitis C

Improved protein stability by PEGylation

2001

 Poly(allylamine hydrochloride)

Renagel®

[sevelamer HCl]/Renagel®

[sevelamer carbonate]

Sanofi

Chronic renal failure

Regulation of drug delivery by prolongation of circulation (retention) in body and increased target delivery

2000

 PEGylated HGH receptor antagonist

Somavert®/pegvisomant

Pfizer

Acromegaly

Improved protein stability by PEGylation

2003

 Polymer-protein conjugate PEGylated l-asparaginase

Oncaspar®/pegaspargase

EnzonPharmaceuticals

Acute lymphocytic blood clot

Improved protein stability by PEGylation

1994

 Polymer-protein conjugate (PEGylated porcine-likeuricase)

Krystexxa®/pegloticase

Horizon

Chronic gout

Improved protein stability by PEGylation

2010

 Polymer-protein conjugate (PEGylated IFNbeta-1a)

Plegridy®

Biogen

Multiple sclerosis

Improved protein stability by PEGylation

2014

 Polymer-protein conjugate (PEGylated factor VIII)

ADYNOVATE

Baxalta

Hemophilia

Improved protein stability by PEGylation

2015

Liposome

 Liposomal daunorubicin

DaunoXome®

Galen

Karposi sarcoma

Increased drug delivery to tumor cells and decreased systemic toxicity

1996

 Liposomal cytarabine

DepoCyt©

Sigma-Tau

Lymphoma

Increased drug delivery to tumor cells and decreased systemic toxicity

1996

 Liposomal vincristine

Marqibo®

Onco TCS

Acute lymphocytic blood clot

Increased drug delivery to tumor cells and decreased systemic toxicity

2012

 Liposomal irinotecan

Onivyde®

Merrimack

Pancreatic cancer

Increased drug delivery to tumor cells and decreased systemic toxicity

2015

 Liposomal amphotericin B

AmBisome®

Gilead Sciences

Fungal infection

Reduced renal toxicity

1997

 Liposomal morphine sulphate

DepoDur®

Pacira Pharmaceuticals

Loss of pain due to surgery

Prolonged exposure

2004

 Liposomal verteporfin

Visudyne®

Bauschand Lomb

Decreased vision, Ophthalmic hiscomaplastia

Improved drug delivery to lesion vessels and photosensitivity

2000

 Liposomal doxorubicin

Doxil®/Caelyx™

Janssen

Karposi sarcoma, ovarian cancer, Multiple myeloma

Increased drug delivery to target sites and decreased systemic toxicity

1995

2005

2008

 Liposomal amphotericinB lipid complex

Abelcet®

Sigma-tau

Fungal infection

Reduced toxicity

1995

 Liposome-proteins SP-band SP-C

Curosurf®/Poractantalpha

Chieseifarmaceutici

Lung activator for stress disorder

Increased drug delivery at low dose and decreased toxicity

1999

Micelles

 Micellar estradiol

Estrasorb™

Novavax

Menopause hormone Therapy

Clinically release control

2003

 Protein NP

     

 Albumin-bound paclitaxel NP

Abraxane®/ABI-007

Celgene

Breast cancer, non-small cell lung cancer, pancreatic cancer

Improved solubility and drug delivery to target tissues

2005

2012

2013

 Engineered protein combining L-2 and diphtheria toxin

Ontak®

Eisai Inc

T-Cell lymphoma

T cell-selective targeting

1999

Nanocrystal

 Aprepitant

Emend®

Merck

Vomiting agent

Rapid absorption and increased F

2003

 Fenofibrate

Tricor®

Lupin Atlantis

Hyperlipidemia

Increased F

2004

 Sirolimus

Rapamune®

Wyeth

Pharmaceuticals

Immunosupressant

Increased F and decreased dose

2000

 Megestrol acetate

MegaceES®

Par Pharmaceuticals

Anorexia

Increased F and decreased dose

2001

 Morphine sulfate

Avinza®

Pfizer

Mental stimulant

Increased F and decreased dose

2002

2015

 Dexamethyl-phenidate HCl

Focalin XR®

Novartis

Mental stimulant

Increased F and decreased dose

2005

 Metyhlphenidate HCl

Ritalin LA®

Novartis

Mental stimulant

Increased F and decreased dose

2002

 Tizanidine HCl

Zanaflex®

Acorda

Muscle relaxant

Increased F and decreased dose

2002

 Calcium phosphate

Vitoss®

Stryker

Bone substitute

Imitation of bone structure by cell adhesion and growth

2003

 Hydroxyapatite

Ostim®

Heraseus Kulzer

Bone substitute

Imitation of bone structure by cell adhesion and growth

2004

 Hydroxyapatite

OsSatura®

IsoTis Orthobiologics

Bone substitute

Imitation of bone structure by cell adhesion and growth

2003

 Hydroxyapatite

NanOss®

Rti Surgical

Bone substitute

Imitation of bone structure by cell adhesion and growth

2005

 Hydroxyapatite

EquivaBone®

Zimmer Biomet

Bone substitute

Imitation of bone structure by cell adhesion and growth

2009

 Paliperidone Palmitate

Invega®Sustenna®

Janssen Pharms

Schizoaffective disorder

Control of slow release rate in drugs with low solubility

2009

2014

 Dantrolene sodium

Ryanodex®

Eagle Pharmaceuticals

Malignant benign hypothermia

Rapid absorption at high dose

2014

Inorganic/metallic NPs

 Iron oxide

Nanotherm®

MagForce

Hybrid species

Vertical irritant effect by increased uptake

2010

 Ferumoxytol SPION with poly glucose sorbitol carboxy methylether

Feraheme™/ferumoxytol

AMAG pharmaceuticals

Chronic renal failure with iron deficiency

Extended release and reduced dose

2009

 Iron sucrose

Venofer®

Luitpold

Pharmaceuticals

Chronic renal failure with iron deficiency

Increased dose capacity

2000

 Sodium ferric gluconate

Ferrlecit®

Sanofi Avertis

Chronic renal failure with iron deficiency

Increased dose capacity

1999

 Iron dextran (low MW)

INFeD®

Sanofi Avertis

Chronic renal failure with iron deficiency

Increased dose capacity

1995

 Iron dextran (high MW)

DexIron®/Dexferrum®

Sanofi Avertis

Chronic renal failure with iron deficiency

Increased dose capacity

1997

 SPION coated with dextran

Feridex®/Endorem®

AMAG pharmaceuticals

Imaging materials

Vertical irritant effect

1996

2008

 SPION coated with dextran

GastroMARK™/umirem®

AMAG pharmaceuticals

Imaging materials

Vertical irritant effect

2001

2009

Suggested considerations for the evaluation of nanomedicines by the FDA

Based on guidelines and reports from the FDA, considerations for evaluation of nanomedicines are as follows. Evaluation of nano-formulation properties of nanomedicines comprises evaluating physicochemical properties of the nanomaterials, constituents and proportions of the nanomaterials, and quality and manufacturing of the nanomaterials (Eifler and Thaxton 2011; FDA 2010). First, pharmacokinetics of nanomedicines are assessed in the context of their systemic exposure considering (1) rate and amount of absorption and retention in circulation based on blood concentration over time, (2) relationship between prolongation of half-life and whole body exposure duration, and (3) bioavailability changes (Eifler and Thaxton 2011; FDA 2010, 2015). Second, assessment of nanomedicine distribution to blood and tissue is recommended to be done based on apparent volume of distribution, and distribution or accumulation to positive targeting sites based on time-dependent changes. Third, in the context of metabolism, it is important to evaluate whether decomposition or metabolism of nano-formulations or their active pharmaceutical ingredients occur. Fourth, elimination of raw materials used in nano-formulations, and products from decomposition and/or metabolism of nano-formulations and their active pharmaceutical ingredients are recommended for evaluation. The accumulation of nano-formulations in target tissues and elimination through MPS are also investigated. Finally, toxicity assessment of nanomedicines needs to be conducted.

EMA

In 2011, the EMA defined nanomedicines as drugs composed of nanomaterials 1–100 nm in size, and these are classified into liposomes, nanoparticles, magnetic NPs, gold NPs, quantum dots, dendrimers, polymeric micelles, viral and non-viral vectors, carbon nanotubes, and fullerenes (EFSA 2011; EMA 2015a).

Status of nanomedicines approved by the EMA

The EMA has approved 8 of the 11 commercially available nanomedicine drugs developed as first-generation nanomedicines (such as liposomes or iron-containing formulations), and three of them were withdrawn. Investigations were conducted to establish the scientific basis for efficacy and safety of 12 nanomedicines, and were evaluated via the European Medicines Agency (EMA) approval process. Following this initial process, 48 nano medicines or imaging materials are currently in clinical trials (Phase 1–Phase 3) in the EU. In addition, preclinical trials are underway for a number of nanomedicine products (Draca et al. 2013; Ehmann et al. 2013; Hafner et al. 2014; Lawrence and Rees 2000; Ling et al. 2013; Shegokar and Müller 2010) (Table 5).

Table 5

Nanomedicines approved by EMA

Formulations

API

Product name

Pharmaceutical company

Administration route

Indications

Nanocrystals

Aprepitan

Emend®

Merck Sharp and Dohme BV

Capsule

Vomiting after surgery

Fenofibrate

Tricor®/Lipanthyl®/Lipidil®

Recipharm, FR

Tablet

Hyperlipidemia

Olanzapine

Zypadhera®

Lilly Pharma

Powder/solvent

Schizophrenia

Paliperidone

Xeplion®

Janssen Pharmaceutica NV

Prolonged release suspension for injection (im)

Schizophrenia

Sirolimus

Rapamune®

Pfizer Ireland Pharmaceuticals, IE

Tablet

Kidney transplantation rejection

Nanoemulsions

Cyclosporine

Norvir®

Aesica Queenborough Ltd

Soft capsules

HIV infection, kidney transplantation rejection

Pegaspargase (mPEG-asparaginase)

Oncaspar®

Sigma-tau Arzneimittel GmbH

Solution (iv/im)

Acute lymphocytic leukemia

Sevelamer

Renagel®/Renvela®

Genzyme Ltd

Tablet

Dialysis, hyperphosphatemia

Polymer-protein conjugates

Amphotericin B

AmBisome®

Gilead Sciences

Suspension (iv)

Fungal infection

Certolizumabpegol (PEG-anti-TNFFab)

Cimzia™

UCB Pharma SA

Solution (sc)

Rheumatoid arthritis

Methoxypolyethylene glycol-epoetin beta

Mircera®

Roche Pharma

Solution (iv/sc)

Anemia, chronic renal failure

Pegfilgrastim (PEG-rhGCSF)

Neulasta®

Amgen Technology

Solution (sc)

Leukopenia by chemotherapy

Peginterferonalpha-2a (mPEG-interferon alpha-2a)

Pegasys®

Roche Pharma

Solution (sc)

HBV/HCV infection

Peginterferonalpha-2b (mPEG-interferon alpha-2b)

PegIntron®

Schering-Plough

Solution for injection (sc)

HIV inflammation

Pegvisomant (PEG-HGH antagonist)

Somavert®

Pfizer Manufacturing

Solution for injection (sc)

Peripheral hypertrophy

Liposomes

Cytarabine

DepoCyt®

Almac Pharma

Suspension (intrathecal)

Brain cancer

Daunorubicin

DaunoXome®

Gilead Sciences Ltd

Suspension (iv)

Kaposi sarcoma by HIV

Doxorubicin

Myocet®

GP-Pharm

Suspension (iv)

Breast cancer

Doxorubicin

Caelyx®

Janssen Pharmaceutical

Suspension (iv)

Breast cancer, ovarian cancer, Kaposi sarcoma

Mifamurtide

Mepact®

Takeda

Suspension (iv)

Myosarcoma

Morphine

DepoDur®

Almac Pharma

Suspension(epidural)

Pain

Paclitaxel

Abraxane®

Celgene

Powder for suspension

Breast cancer

Propofol

Diprivan®/Propofol-Lipuro®/Propofol®

Astra Zeneca

Emulsion (iv)

Anesthesia

Verteporfin

Visudyne®

Novartis Pharma GmbH, Nürnberg

Suspension (iv)

Decreased vision, myopia

Nanoparticles

Inactivated hepatitis A virus

Epaxal®

Crucell

Suspension (iv)

Hepatitis A vaccines

90Y-ibritumomab tiuxetan

Zevalin®

Bayer Pharma

Solution (iv)

Lymphoma

Virosomes

Adjuvanted influenza vaccine

Inflexal® V

Crucell

Suspension (iv)

Influenza vaccines

Glatiramer (Glu,Ala,Tyr,Lys copolymer)

Copaxone®

Teva Pharmaceuticals

Solution (sc)

Multiple sclerosis

Polymeric drugs

Sodium ferric gluconate

Ferrlecit®

Aventis Pharma

Solution (iv)

Anemia with iron deficiency

Nanocomplex

Ferric carboxymaltose

Ferinject®

Vifor

Solution (iv)

Iron deficiency

Ferumoxytol

Rienso®

Takeda

Solution (iv)

Anemia with iron deficiency, chronic renal failure

Iron sucrose [iron(III)-hydroxidesucrose complex]

Visudyne®

Novartis

Solution (iv)

Iron deficiency

Iron(III) isomaltoside

Monofer®

Pharmacosmos

Solution (iv)

Iron deficiency

Iron(III)-hydroxide dextran complex

Ferrisat®/Cosmofer®

Pharmacosmos

Solution (iv)

Iron deficiency

Suggesting points for the evaluation of nanomedicines in EMA

EMA presents that pharmacokinetic and pharmacodynamic properties of nanomedicines were determined by chemical composition and physicochemical properties. So, EMA suggest to consider six possibilities to evaluate nanomedicines considering the chemical composition and physicochemical properties (EFSA 2011; TGA 2016) including (1) nano-formulations are unstable at the time of manufacture and are converted into non-nanosized form, (2) the state of conversion into non-nanosized form when the drug substance in the manufacturing site is present as a matrix, (3) conversion to non-nanosized forms due to lack of bio-similarity under in vitro non-stable conditions, (4) conversion from nano-forms to non-nanosized forms during toxicity assessment (5) co-existence of nano forms and non-nano forms at the in vivo administration site, and (6) existence of the nano form in biological samples and tissues after absorption. In view of these various considerations for nanomedicine evaluation, EMA suggested the need to discuss the following aspects for the evaluation of nanomedicines (EFSA 2011; EMA 2015a, b; Ehmann et al. 2013; TGA 2016). Overall, physicochemical properties, stability, and functionality of nanomedicines should be evaluated. To this end, interactions and reactivity with biointerfaces due to coatings or additives in the final nanomedicines, suitability of biomarkers of in vivo functionality of nanomedicines, in vivo distribution and bio-persistence of nanomedicines, long-term safety of decomposition products, and adequacy of dose and dose interval settings have emerged as key factors for the evaluation process. Notably, liposome formulations, iron-based formulations, and nanocrystal formulations which can be considered first-generation nanomedicines and have already been marketed and used, have proved their effectiveness and safety over a long period. Based on this status, evaluation methods for approval of second-generation nanomedicines have been suggested for consideration (Ehmann et al. 2013; EMA 2013a, b, EMA 2015b).

Future perspectives on nanomedicines considering their pharmacokinetic properties

Given the considerations for development and use of nanomedicines, indispensable steps to attain clinical significance include assessment of the nature of formulations, pharmacokinetic properties, and the approval process for nanomedicines. Therefore, based on recent trends in nanomedicine development and guidelines of the FDA and EMA, we propose a simple algorithm to guide the recommended ADME evaluations of nanomedicines (Fig. 1). In the proposed algorithm, stability in the manufacturing process and simulated human conditions determine whether ADME properties of the drugs of interest are assessed or not. Assessment varies based on administration routes and distribution. For example, evaluation varies based on whether orally administered nanomedicines are found in nano forms or non-nano forms in the gastro-intestinal tract. Thus, the proposed algorithm provides critical and practical checkpoints in nanomedicine development and assessment.

Fig. 1

A proposed new algorithm to assess ADME of nanomedicines

Notes

Acknowledgements

This research was supported by a Grant (16173MFDS542) from Ministry of Food and Drug Safety in 2016.

Compliance with ethical standards

Conflict of interest

These authors (Young Hee Choi and Hyo-Kyung Han) declare that they have no conflict of interest.

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corrected publication November 2018

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Authors and Affiliations

  1. 1.College of Pharmacy and Integrated Research Institute for Drug DevelopmentDongguk University-SeoulGoyangRepublic of Korea

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