Journal of Controlled Release 248 (2017) 7195

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Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review article

BCS class IV drugs: Highly notorious candidates for

formulation development
Rohan Ghadi a,, Neha Dand b
a
IPDO, Innovation Plaza, Dr Reddy's Laboratories Ltd., Bachupally, Hyderabad, 500090, India
b
Department of Pharmaceutics, Bharati Vidyapeeth's College of Pharmacy, CBD Belapur, Navi Mumbai, 400064, India

a r t i c l e i n f o a b s t r a c t

Article history: BCS class IV drugs (e.g., amphotericin B, furosemide, acetazolamide, ritonavir, paclitaxel) exhibit many character-
Received 14 October 2016 istics that are problematic for effective oral and per oral delivery. Some of the problems associated include low
Accepted 8 January 2017 aqueous solubility, poor permeability, erratic and poor absorption, inter and intra subject variability and signi-
Available online 11 January 2017
cant positive food effect which leads to low and variable bioavailability. Also, most of the class IV drugs are sub-
strate for P-glycoprotein (low permeability) and substrate for CYP3A4 (extensive pre systemic metabolism)
Keywords:
Bioavailability
which further potentiates the problem of poor therapeutic potential of these drugs. A decade back, extreme ex-
Dissolution rate amples of class IV compounds were an exception rather than the rule, yet today many drug candidates under de-
Enhanced permeation velopment pipeline fall into this category. Formulation and development of an efcacious delivery system for BCS
P-gp efux class IV drugs are herculean tasks for any formulator. The inherent hurdles posed by these drugs hamper their
translation to actual market. The importance of the formulation composition and design to successful drug devel-
opment is especially illustrated by the BCS class IV case. To be clinically effective these drugs require the devel-
opment of a proper delivery system for both oral and per oral delivery. Ideal oral dosage forms should produce
both a reasonably high bioavailability and low inter and intra subject variability in absorption. Also, ideal systems
for BCS class IV should produce a therapeutic concentration of the drug at reasonable dose volumes for intrave-
nous administration. This article highlights the various techniques and upcoming strategies which can be
employed for the development of highly notorious BCS class IV drugs. Some of the techniques employed are
lipid based delivery systems, polymer based nanocarriers, crystal engineering (nanocrystals and co-crystals),
liquisolid technology, self-emulsifying solid dispersions and miscellaneous techniques addressing the P-gp efux
problem. The review also focuses on the roadblocks in the clinical development of the aforementioned strategies
such as problems in scale up, manufacturing under cGMP guidelines, appropriate quality control tests, validation
of various processes and variable therein etc. It also brings to forefront the current lack of regulatory guidelines
which poses difculties during preclinical and clinical testing for submission of NDA and subsequent marketing.
Today, the pharmaceutical industry has as its disposal a series of reliable and scalable formulation strategies for
BCS Class IV drugs. However, due to lack of understanding of the basic physical chemistry behind these strategies
formulation development is still driven by trial and error.
2017 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
2. Lipid based drug delivery systems (LBDDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.1. Mechanism of improved bioavailability of BCS class IV drugs by LBDDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
2.2. Potential applicability of LBDDS for improving bioavailability of BCS class IV drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
2.2.1. Emulsions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
2.2.2. Self-emulsifying drug delivery systems (SEDDS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
2.2.3. Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.2.4. Solid lipid nanoparticles (SLNs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Corresponding author.
E-mail address: rohanghadi13@gmail.com (R. Ghadi).

http://dx.doi.org/10.1016/j.jconrel.2017.01.014
0168-3659/ 2017 Elsevier B.V. All rights reserved.
72 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195

2.2.5. Nanostructured lipid carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

2.2.6. Lipid polymer hybrid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2.2.7. Lipid nanocapsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3. Polymer nanocarrier based approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
3.1. Mechanism of improved bioavailability of BCS class IV drugs by polymer nanocarrier based approach. . . . . . . . . . . . . . . . . . . . 78
3.2. Potential applicability of polymer based nanocarriers for improving the bioavailability of BCS class IV drugs . . . . . . . . . . . . . . . . . 79
3.2.1. Polymeric micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.2.2. Polymeric nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
3.2.3. Dendrimers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4. Pharmaceutical crystal engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1. Nanocrystal technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
4.1.1. Mechanism of improved bioavailability by nanocrystal technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.1.2. Potential applicability of nanocrystal technology to BCS class IV drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
4.2. Co-crystal technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4.2.1. Potential applicability of co-crystal technology to BCS class IV drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5. Liquisolid technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.1. Mechanism of improved bioavailability of BCS class IV drugs by liquisolid technology . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.1.1. Increased drug surface area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.1.2. Increased drug solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
5.1.3. Improved wetting properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
5.2. Potential applicability of liquisolid technology to BCS IV class drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
6. Self-emulsifying solid dispersion formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.1. Examples of surface active excipients used in the fabrication of self-emulsifying solid dispersions. . . . . . . . . . . . . . . . . . . . . . 84
6.1.1. Gelucires. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.1.2. Tocopheryl polyethylene glycol 1000 succinate (TPGS). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.1.3. Pluronics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.2. Mechanism of improved bioavailability of BCS class IV drugs by self-emulsifying solid dispersion formulations. . . . . . . . . . . . . . . . 84
6.3. Potential applicability of self-emulsifying solid dispersion formulations to BCS class IV drugs . . . . . . . . . . . . . . . . . . . . . . . . 85
7. P-glycoprotein (P-gp) inhibition strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
7.1. P-gp inhibition by lipidic and polymeric excipients and formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
7.2. P-gp inhibition by using specic and non-specic P-gp inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
7.3. P-gp circumvention by using novel peptide prodrug approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
8. Current roadblocks in the clinical development of formulation strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
9. Regulatory aspects for the development of BCS class IV delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

1. Introduction
The rate and extent of drug absorption from the gastrointestinal (GI)
tract are very intricate and affected by many factors. These include
physicochemical factors, physiological factors, and factors related to
the dosage form [1,2]. Despite this complexity, the Biopharmaceutics
Classication System (BCS) developed by Amidon et al. [3] revealed
that the essential key parameters controlling oral drug absorption are
the solubility/dissolution of the drug dose in the GI milieu and the per-
meability of the drug through the GI membrane. These important pa-
rameters are characterized in the BCS as one of the most signicant
tools in modern pharmaceutics and biopharmaceutics of oral drug prod-
ucts. The progress made in combinatorial chemistry and innovative
high-throughput screening has led to the production of a vast number
of potential drug candidates. However, at the same time these tech-
niques have introduced more poorly water-soluble drugs in the phar-
maceutical pipeline. It is estimated that N40% of marketed drugs are
poorly water-soluble [4,5]. Lipinski et al. pointed out that leads obtained
through high-throughput screening (HTS) tend to have higher molecu-
lar weights and greater lipophilicity than leads in the pre-HTS era [4].
Dissolution of the drug in the aqueous milieu of the GI is almost always
a prerequisite for oral absorption, and hence, inadequate aqueous solu-
bility often causes limited or poor oral bioavailability. Furthermore the
problems associated with poor stability and membrane permeability
adds on to the dilemma of low bioavailability [4,6]. All these problems
are plaguing the lead molecules or drug candidates in the pipeline of
most major pharmaceutical companies. Low/variable bioavailability of
a drug is one of the major hurdles for formulation scientists, because it
can lead to compromised product performance and the drug is unlikely
to reach its molecular target. Such drugs require a high dose but have
low systemic exposure, result in adverse effects because of the high
dose and may vary in their effect in individual patients [7].
Based on the BCS, drugs are classied into four categories according
to their solubility and permeability properties as follows; high solubili-
tyhigh permeability (class I); low solubilityhigh permeability (class
II); high solubilitylow permeability (class III); and low solubilitylow
permeability (class IV) [3]. The drugs exhibiting low solubility but rea-
sonable membrane permeability such as phenytoin, glibenclamide, car-
bamazepine, ibuprofen etc. are categorised as BCS class II. The rate-
limiting process of absorption for class II drugs is the dissolution step.
Formulation plays a major role in determining the rate and extent of ab-
sorption of such drugs from the gastrointestinal tract. A number of for-
mulation strategies have been developed to improve the delivery of BCS
class II drugs like complexation, micronization, crystal modication etc.
They are based on techniques either to increase the drug dissolution
rate or to achieve sustained solubilization of the drugs. The poorly
water-soluble drugs with poor membrane permeability (Table 1) be-
long to BCS class IV such as amphotericin B (AmB), furosemide (FUR),
acetazolamide, ritonavir (RTV) etc. Usually techniques used for BCS
class II drugs do little to improve the absorption of class IV drugs due
to the limited membrane permeability. As a result, the best solution to
improve the bioavailability of class IV drugs is to go back to the lead op-
timisation phase of drug discovery and modify their structures to obtain
the appropriate physicochemical properties. However, discovering a
novel therapeutic agent, itself is a challenging, time-consuming and
costly process. It takes US $8001200 million and 1015 years to devel-
op a new chemical entity. Also, very few of the millions of compounds
after being tested reach the market. Hence, sending a drug molecule
back to the lead optimisation phase is not a feasible option because of
the constraints associated with time, cost, labour and resources. As a
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195 73

Table 1
List of BCS Class IV drugs according to the WHO model list of essential medicines and reported literature.

Drug Category BCS class References

Drugs with reliable solubility and permeability data Aluminium hydroxide Gastro intestinal agent Class IV [8]
(WHO model list of Essential medicines) Furosemide (FUR) Diuretic Class IVa,b [813]
Indinavir (IDV) Anti-viral Class IVa,c,d [8]
Nelnavir (NFV) Anti-viral Class IVa,c,d [8]
Ritonavir (RTV) Anti-viral Class IVa,c,d [8,14]
Saquinavir (SQV) Anti-viral Class IVa,c,d [8,14,15]
Acetazolamide Diuretic Class IVb [8,16]
Drugs for which complete solubility and/or permeability data are lacking data Azathioprine Immunosuppressive Class IV [8,16]
(WHO model list of Essential medicines) Amphotericin B (AmB) Anti-fungal Class IV [1719]
Drugs with solubility and permeability issues (Reported in literature) Hydrochlorothiazide (HCT) Diuretic Class IV [19,20]
Colistin Anti-microbial Class IV [19]
Chlorthalidone Anti-hypertensive Class IV [19]
Chlorothiazide Diuretic Class IV [19]
Cyclosporine A (CyA) Immunosuppressive Class IVc [14,21]
Paclitaxel (PTX) Anti-cancer Class IVa,d [2225]
Docetaxel (DTX) Anti-cancer Class IVa,d [25]
Famotidine (FAM) Gastro protective agent Class IVb [11,26]
Aprepitant Anti-emetic Class IV [14]
Lopinavir (LPV) Anti-viral Class IVa,c,d [27]
Etravirine Anti-viral Class IVa,d,c [28]
a
First pass effect.
b
Substrate for uptake transporter.
c
Signicant positive food effect.
d
Substrate for CYP3A4.

result, proper formulation is of key importance to establish a successful
product for the administration of BCS class IV drugs. Fig. 1. gives an in-
sight on the various BCS IV drugs and the numerous hurdles posed by
them in the successful oral and peroral delivery. This article highlights
the various strategies which can be employed for improving the bio-
availability and successful delivery of BCS class IV drugs. These strate-
gies include lipid based delivery systems, polymeric nanoparticulate
systems, crystal engineering (nanocrystal technology, co-crystal tech-
nology), liquisolid technology, self-emulsifying solid dispersions and
P-efux inhibition strategies.
2. Lipid based drug delivery systems (LBDDS)
LBDDS have gained increasing interest in pharmaceutical eld be-
cause of their potential to improve the bioavailability of drug molecules
which are difcult to formulate [29]. There is a current resurgence of in-
terest in lipid based dosage forms because of the proven commercial
and pharmaceutical benet for compounds such as CyA, lipid soluble vi-
tamins, and the HIV protease inhibitors. Also, the industry is trending
toward the discovery/development of increasingly hydrophobic (and
potent) new chemical entities. Finally, the resolution of many of the pre-
viously problematic technology transfer, stability and regulatory issues
makes lipid based delivery systems as a good option for clinical transla-
tion of drug products.
Lipids as carriers have the potential of providing endless opportuni-
ties in the area of drug delivery due to their ability to enhance gastroin-
testinal solubilization and absorption by selective lymphatic uptake of
poorly bioavailable drugs [30]. The different properties of lipids such
as physiochemical diversity, biocompatibility etc. have an ability to en-
hance oral bioavailability of poorly water soluble, lipophilic drugs and
also poorly permeable drugs like BCS class IV as shown in Fig. 2. This
could be attributed to some unique properties of lipids such as high sol-
ubilization potential, manufacturing scalability, industrial adaptability,
biocompatibility and distinct route of absorption thereby eliminating
various physiological barriers such as pre-systemic metabolism, gastro-
intestinal degradation, P-gp efux and permeability related issues. The
lipid excipients mainly comprise of monoglycerides, diglycerides, tri-
glycerides, oils constituting various combinations of glycerides, phos-
pholipids, sphingolipids and even high fat meal. Also, many modied
and tailored made oils and lipids have reached the market to aid in
easy formulation development.
2.1. Mechanism of improved bioavailability of BCS class IV drugs by LBDDS
The balance between a drug's solubility in the aqueous environment
of the gastrointestinal lumen and its permeation across the lipophilic
membrane of enterocytes determines its rate and extent of absorption.
After oral administration of lipid-based formulations, gastric lipase initi-
ates the digestion of exogenous dietary triglyceride (TG) and formula-
tion TG. Simultaneously, the mechanical mixing (propulsion, grinding
and retropulsion) of the stomach facilitates formation of a crude emul-
sion (comprised of aqueous gastric uid and lipid digestion products).
Later in the small intestine, TG is broken down to diglyceride, mono-
glyceride and fatty acids by pancreatic lipase together with its cofactor
co- lipase 203, acting primarily at the sn-1 and sn-3 positions of TG to
produce 2-monoglyceride and free fatty acid. Pancreatic phospholipase
A2 digests the formulation-derived or biliary-derived phospholipids
(PL) by hydrolyzing at the sn-2 position of PL to yield
lysophosphatidylcholine and fatty acid. The presence of exogenous
lipids in the small intestine stimulates the secretion of endogenous
biliary lipids from the gall bladder, including bile salt (BS), PL and
cholesterol. Previously formed monoglycerides, fatty acids, and
lysophospholipid (products of lipid digestion) are subsequently incor-
porated in to a series of colloidal structures, including micelles and
unilamellar and multi-lamellar vesicles in the presence of bile salts.
The solubilization and absorptive capacity of the small intestine for
lipid digestion products and drugs (D) is signicantly enhanced due to
these formed lipid metabolites.
The formed micelles will then be absorbed by enterocytes, where it
gets converted to the chylomicrons upon re-esterication via monoacyl
glycerol or phosphatidic acid pathway and subsequent stabilization by
phospholipids. However, the penetration of unstirred water layer and
mucin in gastrointestinal tract is rate limiting factor. The formed chylo-
microns are then subjected to lymphatic transport system via mesenter-
ic lymph and ultimately enter the systemic circulation by lymphatic
drainage at thoracic duct [31]. The other transcellular routes by which
lipid based drug delivery systems get transported across enterocytes in-
clude macropinocytosis, clathrin-mediated, caveolae-mediated, and
clathrin- and caveolae-independent endocytosis (principally lipid rafts
74 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195

Fig. 1. BCS Class IV drugs- the inherent hurdles posed by them in their oral and per oral delivery along with the strategies to overcome them.
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195 75

Fig. 2. Key advantages associated with lipid based drug delivery systems which improve oral and peroral delivery of BCS class IV drugs.

comprising of sphingolipids- and cholesterol-rich microdomains) [32]. to improve drug absorption through mitigation of presystemic drug me-
Fig. 3. depicts various absorption mechanisms by which lipid tabolism associated with gut membrane-bound cytochrome P-450
nanocarriers improve the oral bioavailability of BCS Class IV drugs. enzymes or via inhibition of the P-glycoprotein efux transporter [33
More recently, certain lipids and lipidic excipients have been suggested 36]. Various types of lipid based nanocarriers implemented for

Fig. 3. Absorption mechanisms implemented by lipidic nanocarriers for improving the bioavailability of BCS class IV drugs.
76 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
improving the bioavailability of BCS class IV drugs include
microemulsions, nanoemulsions, lipid nanocapsules, self-emulsifying
systems, lipid nanoparticles, hybrid lipid nanoparticles, liposomes and
surface engineered liposomes to name a few.
2.2. Potential applicability of LBDDS for improving bioavailability of BCS
class IV drugs
Since many decades, lipids have been widely used for improving the
oral bioavailability of various difcult-to-deliver drugs. The usual prob-
lem associated with most of the drugs includes either low aqueous sol-
ubility or poor intestinal permeability, both of which can adequately be
taken care by LBDDS [30]. Lipid-based formulations have emerged as an
effective and versatile technology for many BCS class IV drugs. The prin-
cipal lipidic drug delivery systems and their application to improve the
bioavailability of BCS Class IV drugs are highlighted in this section.
2.2.1. Emulsions
Emulsion based approach has been one of the most ancient methods
for delivery of lipophilic drugs. Presently two versions of emulsions viz.
microemulsions and nanoemulsions have been employed for improving
the oral deliverability of BCS class IV drugs. The unique characteristics
include thermodynamic (microemulsions) or kinetic (nanoemulsions)
stability, supersolvency, small droplet size, high industrial scalability
(as low energy requirements for manufacturing) and use of lipidic ex-
cipients as absorption enhancers. Traditionally, these systems comprise
of appropriate blend of oil, surfactant and co-surfactant dispersed in
aqueous phase tailor made as per the physicochemical properties of
drug substances [37].
The oral administration of a microemulsion formulation containing
dimethyl isosorbide, Tween 80 and D, L--tocopherol and incorporating
PTX in the presence of P-gp inhibitor (KR-30032) to rats allowed PTX
oral bioavailability to be increased from 4.6% to 41%. This effect was
dose-dependent and was saturable above 20 mg/kg of KR-30032 [38].
Yin et al. prepared a microemulsion system of DTX and evaluated for
its solubilization capacity and oral bioavailability improvement [39].
Compared to the commercial product Taxotere, the apical to
basolateral (A B) transport of DTX across the Caco-2 cell monolayer
from the microemulsion system was signicantly improved (0.624 g/
cm2, p b 0.01). Moreover, the oral bioavailability of the system in rats
rose dramatically (34.42%) compared to that of the orally administered
Taxotere (6.63%). This increase in bioavailability was probably due to
the combined effect of the enhancement in solubility, the inhibition of
P-gp efux system and the increase in permeability. These results en-
couraged further development of DTX microemulsions as an oral drug
delivery system. Bhutani et al. investigated the potential of AmB
microemulsion for the treatment of invasive fungal disease [40]. The op-
timized microemulsion exhibited 2-fold higher drug permeation as
compared to plain drug solution. It also showed higher skin deposition,
lower skin irritation and better anti-fungal activity. The in vitro anti-fun-
gal activity in Trichophyton rubrum fungal species showed higher zone
of inhibition. The results indicated that, microemulsion can be used as
a promising alternative for AmB therapy. Also, Jha et al. attempted oral
microemulsion formulation of famotidine for enhancing the bioavail-
ability [41]. The developed microemulsion system improved the perme-
ability (93.43%) by increasing the lipophilicity due to the oil phase and
also by destabilizing the membrane stability due the surfactants.
2.2.2. Self-emulsifying drug delivery systems (SEDDS)
SEDDS are the most advanced approach of emulsion based drug de-
livery systems and relies on the physiological uids for the in situ forma-
tion of micro/nanoemulsion. This formulation strategy comprises of
drug dissolved in oils and stabilized by surfactants and co-surfactants,
which upon exposure to the aqueous environment under gentle agita-
tion leads to spontaneous formation of emulsion. Although the exact
mechanism of self-emulsication is yet to be understood and is unclear
however it has been postulated that it happens when entropy change
for dispersion exceeds the energy required to increase the surface area
of dispersion [42,43].
Recently, co-administration of DTX with curcumin loaded SEDDS led
to about 3.2-fold increase in the oral bioavailability of DTX as compared
to the free drug. The inhibitory effect of curcumin on P-gp and cyto-
chrome P450 was also attributed to this increment in oral bioavailability
of DTX [44]. Sultan et al. [45] investigated the potential of self-micro
emulsifying drug delivery systems (SMEDDS) and niosomes as carriers
for widening the gastrointestinal absorption window of FUR. The drug
was incorporated in SMEDDS and was encapsulated into niosomes.
The intestinal absorption was monitored at two anatomical sites (duo-
denum and jejuno-ileum) by employing in situ rabbit intestinal perfu-
sion technique. Perfusion of drug solution (control) revealed poor
intestinal permeability with percent fraction absorbed (%Fa) from the
duodenum and jejuno-ileum being 1.3 and 0.6% per cm, respectively.
Formulation of furosemide as SMEDDS increased the %Fa from the duo-
denum and jejuno-ileum to reach 1.7 and 1% per cm, respectively.
Niosomal encapsulation increased the %Fa from duodenum and
jejuno-ileum to record 1.9 and 1.2% per cm, respectively. The increase
in the %Fa was also revealed as a reduction in the length required for
95% absorption of the drug which was reduced from 557.2 to
245.8 cm and to 279.8 cm after delivery as niosomes or SMEDDS, re-
spectively, in case of jejuno-ileum. The same trend was recorded with
the duodenum.
Seo et al. prepared DTX loaded self-nano emulsifying drug delivery
systems (SNEDDS) to improve the bioavailability and anti-tumour po-
tential of DTX [46]. DTX-SNEDDS remarkably improved the systemic
circulation of DTX by augmenting the rate and extent of drug absorption
and thereby bioavailability. However, the most important aspect of the
work was that Taxotere-induced toxicity was overcome by DTX-
SNEDDS with a plausible anti-tumour response. Thus, DTX-SNEDDS of-
fered an exciting mode and opened a new arena for DTX delivery to im-
prove its chemotherapeutic potential. Also, Chen et al. prepared a solid
supersaturable self-emulsifying drug delivery system (S-sSEDDS)
using DTX [47]. The in vivo studies indicated that the area under the con-
centrationtime curve (AUC0) of the DTX-S-sSEDDS increased by
nearly 8.77-fold, 1.45-fold more than those of the DTX powder and
the conventional SEDDS. Similarly, Gao et al. explored PTX loaded (S-
sSEDDS) for improving the oral bioavailability of PTX [48]. Pharmacoki-
netic studies conducted in rats showed that the bioavailability of PTX in
PTX-S-sSEDDS was 9.5% compared to 2% in the orally dosed Cremophor-
ethanol, a further increase in bioavailability to 22.6% was noted in the
presence of CyA. SMEDDS composed of -tocopherol, TPGS, propylene
glycol, sodium deoxycholate and Cremophor RH40 was used to im-
prove the oral bioavailability of PTX. Compared with Taxol the oral
bioavailability of PTX included in SMEDDS increased by 28.652.7% at
various doses [49]. Also, Deshmukh et al. enhanced the dissolution
and oral bioavailability of RTV using the Solid Self-Microemulsifying
Drug Delivery System (S-SMEDDS). S-SMEDDS improved the plasma
prole in terms of maximum plasma concentration (Cmax), and area
under curve (AUC024h), which is almost two-folds higher than the
aqueous suspension of RTV [50].
Garg et al. developed solid self-nanoemulsifying oily formula-
tions (S-SNEOFs) for enhancing the systemic bioavailability of LPV
and targeting the same to the sanctuary site, i.e., lymphatic system
for complete HIV inhibition [51]. The performance evaluation
through in situ single pass intestinal perfusion (SPIP) studies as-
cribed the signicant enhancement in absorptivity parameters of
the SNEOFs vis--vis the pure drug. Also, chylomicron ow block
SPIP studies revealed lymphatic uptake of LPV from the SNEOFs.
Overall, in vivo pharmacokinetic studies in rats revealed signicant
improvement in the rate and extent of oral bioavailability of the
SNEOFs compared to the pure drug. These studies further substanti-
ated the intestinal lymphatic transport of LPV for the management of
the sanctuary site HIV. In a nutshell, the SNEOFs offered a complete
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
and holistic solution for the management of the viral loads in the
lymph and blood.
2.2.3. Liposomes
Liposomes are the most sophisticated class of lipid based drug
delivery systems known for improving the deliverability of various dif-
cult-to-deliver drugs. These are vesicular structures prepared from
phospholipids and are capable of accommodating both hydrophilic
and lipophilic drug substances within them [52,53]. These are reported
to have huge potential in improving the bioavailability of various drugs
[13,54].
Rathore et al. attempted mannosylated liposomes bearing AmB for
effective management of visceral leishmaniasis [54]. The in vivo anti-
leishmanial activity performed on Leishmania donovaniinfected golden
hamster, revealed that AmB solution showed reduction in the parasite
load by 42.5 1.8%. The mannose-coupled liposomes showed a maxi-
mum reduction in parasite load (i.e., 78.8 3.9%). The biodistribution
study clearly showed the higher uptake of mannosylated liposomes in
the liver and spleen and hence the active targeting to the reticulo-endo-
thelial system, which, in turn, would provide a direct attack of the drug
to the site where the pathogen resides, rendering the other organs free
and safe from the toxic manifestations of the drug. Wu et al. synthesized
and characterized a liposomal formulation of PTX targeting the folate re-
ceptor (FR), which was designed to overcome vehicle toxicity associat-
ed with the traditional Cremophor EL-based formulation and to provide
the added advantages of prolonged systemic circulation time and selec-
tive targeting of the FR. FR-targeted liposomes containing PTX showed
3.8-fold greater cytotoxicity compared to non-targeted control lipo-
somes in KB cells [55]. Vural et al. developed chitosan coated liposomal
carrier system for delivery of FUR to improve its biopharmaceutical
characteristics [13]. An eight-fold increase in FUR permeability was ob-
tained for coated liposomes when compared to uncoated formulations.
According to the cytotoxicity studies, chitosan coated liposome formu-
lations showed less cytotoxicity than uncoated ones. Chitosan coating
increased the viability of the liposomes. The permeation enhancer effect
observed for the chitosan coated liposomes make them attractive candi-
dates that could be effective to improve bioavailability of Class IV drugs
after oral administration.
2.2.4. Solid lipid nanoparticles (SLNs)
SLNs are the alternative version of emulsions in which the liquid oil
is replaced by solid lipids. Specic advantages include modulation of
drug release, increased drug stability, exclusion of organic solvents
from the manufacturing process, manufacturing scalability and indus-
trial adaptability [56]. In the latest years SLN offered new perspectives
in the formulation of poorly water-soluble drugs.
In this context, Alex et al. [57] successfully encapsulated LPV in glyc-
eryl behenate based solid lipid nanoparticles (Lo-SLN) for its ultimate
use to target intestinal lymphatic vessels in combined
chemotherapythe so-called Highly Active Anti-Retroviral Therapy
(HAART). From the intestinal lymphatic transport study, it became evi-
dent that SLN increased the cumulative percentage dose of LPV secreted
into the lymph, which was 4.91-fold higher when compared with a con-
ventional drug solution in methyl cellulose 0.5% (w/v) as suspending
agent (Lo-MC). The percentage bioavailability was signicantly en-
hanced. The AUC for the Lo-SLN was 2.13-fold higher than that obtained
for the Lo-MC of similar concentration. Negi et al. also developed glycer-
yl behenate based SLNs of LPV to improve its oral bioavailability. Higher
oral bioavailability (3.56-fold) was found for LPV loaded SLNs in com-
parison to bulk LPV due to higher lymphatic drug transport (p b 0.05)
[27].
Aji et al. developed SLNs to increase the availability of LPV in the CNS
[58]. SLNs exhibited a Cmax and Tmax of 632.86 81.61 ng/mL and 25
7.75 min, respectively, with a signicant increase in bioavailability in a
rat model compared with a free-drug suspension. An appreciable in-
crease in cerebrospinal uid concentration was detected with SLNs.
77
Compritol-based solid lipid nanoparticles with a poloxamer coating
can be effectively absorbed through the lymphatic system, prolong the
circulation of drug in blood by acting as a reservoir and can effectively
target the drug to the CNS due to the combined effect of lipophilicity
and surface charge. The high biocompatibility, biodegradability and
nontoxicity of compritol make the compritol-based solid lipid nanopar-
ticles an excellent carrier for enhanced CNS delivery of LPV.
Punna Rao et al. prepared stearic acid-based LPV loaded SLNs using a
hybrid design and compared in vivo performance of optimized formula-
tion with marketed LPV/RTV co-formulation [59]. Optimized SLNs ex-
hibited nanometric size (223 nm) with high entrapment efciency
(83%). In vitro drug release study of SLNs showed biphasic sustained re-
lease behaviour. Signicant increase in oral bioavailability of LPV from
LPV SLNs (5 folds) and LPV/RTV co-formulation (3.7 folds) was ob-
served as compared with free LPV. LPV SLNs showed better tissue distri-
bution of LPV in HIV reservoirs than LPV/RTV co-formulation. In vitro
studies demonstrated that SLNs provided metabolic protection to LPV
and went endocytosis during absorption.
2.2.5. Nanostructured lipid carriers
Nanostructured lipid carriers (NLCs) are the advanced generation of
SLNs overcoming the problems associated with the later such as limited
drug loading capacity, restructuring during storage and subsequently
expulsion of drug during storage. The said advantages could be attribut-
ed to higher solubility of drugs in oils as compared to solid lipids.
Beloqui et al. evaluated the potential of NLCs as a tool to enhance the
oral bioavailability of SQV [15]. SQV transport across Caco-2 monolayers
was enhanced up to 3.5-fold by NLCs compared to SQV suspension. The
size and amount of surfactant in the NLCs inuenced SQV's permeabili-
ty, the transcytosis pathway and the efux of SQV by P-gp. SQV-NLCs
circumvented P-gp efux and used both caveolae- and clathrin-mediat-
ed transcytosis. By modifying critical physicochemical parameters of the
NLC formulation, the P-gp drug efux and also the transcytosis mecha-
nism of the nanoparticles was altered. The ndings were encouraging
and opened a new option for the delivery of class IV drugs and P-gp sub-
strates by the oral route and support further nanotechnology ap-
proaches on this regard. Also, the same group evaluated the
mucopenetrating properties of dextranprotamine (DexProt) coating
on NLCs as per SQV permeability enhancement. In the Caco-2 mono-
layers, DexProtNLCs increased upto 9-fold SQV permeability in com-
parison to uncoated nanoparticles. In the Caco-2/HT29-MTX
monolayers, DexProtNLCs presenting a surface charge close to neu-
trality signicantly increased SQV permeability. Hence, DexProt com-
plex coating can be a promising strategy to ensure successful
nanoparticle mucus-penetration, and thus, an efcient nanoparticle
oral delivery [60].
2.2.6. Lipid polymer hybrid nanoparticles
To address the limitations of polymeric nanoparticles and liposomes,
a new generation delivery vehicle of therapeutics termed lipidpolymer
hybrid nanoparticles (LPNs) has been developed. LPNs are coreshell
nanoparticle structures comprising polymer cores and lipid/lipidPEG
shells, which exhibit complementary characteristics of both polymeric
nanoparticles and liposomes, particularly in terms of their physical sta-
bility and biocompatibility. Signicantly, the LPNs have recently been
demonstrated to exhibit superior in vivo cellular delivery efcacy com-
pared to that obtained from polymeric nanoparticles and liposomes
[61].
Liu et al. developed folic acid conjugated nanoparticles of mixed lipid
monolayer shell and biodegradable polymer core (LPNP) for targeted
delivery of DTX [62]. After 0.5 h and 2 h incubation, the cellular uptake
efciency of the non-targeted LPNPs was measured to be 18.99 0.75%
and 25.39 0.54%, respectively. Instead, after 0.5 h and 2 h incubation,
the cellular uptake efciency of the targeted LPNPs was measured to be
26.24 0.68% and 39.09 0.64%, respectively. The targeting effect of
folic acid conjugation was thus signicant of 38.2% increment for 0.5 h
78 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
incubation and 54.0% increment for 2 h incubation, respectively. Also,
the IC50 after 24 h treatment was 0.0509 mg/mL for Taxotere,
0.00658 mg/mL for the non-targeted LPNPs formulation and
0.00323 mg/mL for the targeted LPNPs formulation. Thus, targeted
LPNPs formulation was 50.91% more effective than the non-targeted
LPNPs formulation and 93.65% more effective than Taxotere.
Joshi et al. developed and evaluated hybrid lipopolymeric system
comprising carboxymethyl chitosan (CMC), covalently tethered to
phosphatidylethanolamine units on the surface of lipid nanovesicles,
for oral delivery of PTX. The bioploymer was intended to act as a blan-
ket, thereby shielding the drug from harsh gastrointestinal conditions,
whereas the lipid nanovesicle ensured high encapsulation efciency of
PTX and its passive targeting to tumour. CMC-conjugated nanovesicles,
upon oral administration in rats, improved the plasma concentration
prole of PTX, with 1.5-fold increase in its bioavailability and 5.5 folds'
increase in elimination half-life in comparison with Taxol. Also, CMC
in addition to providing a gastric resistant coating also imparted stealth
character to the nanovesicles, thereby reducing their reticuloendotheli-
al system (RES)-mediated uptake by liver and spleen and bypassing the
need for PEGylation. In vivo efcacy in subcutaneous model of B16F10
showed signicantly improved tumour growth inhibition and survival
with CMC-tethered nanovesicles as compared with unmodied
nanovesicles, both administered orally. LN-C-PTX exhibited therapeutic
efcacy comparable to Taxol and Abraxane and also showed reduced
toxicity and improved survival.
Jain et al. prepared AmB loaded polymer lipid hybrid nanoparticles
(AmB-PLNs) comprised of lecithin (anionic lipid) and gelatin (Type A,
cationic below its isoelectric point 7.09.0) [63]. The developed formu-
lation exhibited a sustained drug release prole with a release pattern
best tted to Higuchi kinetics. Experiments on Caco-2 cell lines revealed
a 5.89-fold increase in the intestinal permeability of AmB-PLNs whereas
in vivo pharmacokinetic studies exhibited a 4.69-fold increase in the oral
bioavailability upon incorporation of AmB into PLNs as compared to that
of free drug. The developed formulation showed signicantly lesser
heamolytic toxicity as compared to the free drug, Fungizone (micellar
solution of AmB) and Fungisome (liposomal formulation of AmB). Fur-
thermore, blood urea nitrogen (BUN) and plasma creatinine levels, in-
dicative of nephrotoxicity, were also found to be signicantly lesser
for developed PLN formulation as compared to free drug and Fungizone
while comparable to that of Fungisome. The histopathology of the kid-
ney tissues further conrmed the absence of any changes in the mor-
phology of the renal tubules.
Sambaraj et al. [64] formulated and evaluated a novel silica-lipid hy-
brid (SLH) microparticulate system for improved oral delivery of FUR.
Silica-lipid hybrid microparticles included the drug solubilizing effect
of dispersed lipids and stabilizing effect of hydrophilic silica particles
to increase drug solubilization, which lead to enhanced oral bioavail-
ability. In vitro dissolution studies conducted under simulated gastric
medium revealed 2 to 4-fold increase in dissolution efciencies for
SLH microparticles compared to that of pure drug and marketed formu-
lation Lasix. SLH also showed enhanced permeability when compared
to other formulations and marketed drug. The results indicated that that
SLH microparticles were better than pure drug and marketed drug
formulation.
2.2.7. Lipid nanocapsules
Lipid nanocapsules are the novel colloidal nanocarriers having typi-
cal core shell arrangement of the constituents with liquid reservoir
(usually oils) as core coated by protective membrane. The protective
membrane generally comprises of polymer chains present in the surfac-
tant which is aligned as exterior coat during the preparation of lipid
nanocapsules. The lipid nanocapsules are principally known for their
biocompatibility, biodegradability, superior encapsulation of drug mol-
ecules, very high drug payloads, specic absorption mechanism across
the gastrointestinal tract, sustained release, membrane efux
transporter inhibition, targeting potential (active and passive) and
most importantly oral deliverability [65].
Recently, the stability of the PTX loaded lipid nanocapsules was
established in the gastrointestinal tract. The stability of these systems
was attributed to the presence of the surface PEG coating, which specif-
ically protected the aggregation of internal lipid constituents due to
acidic pH in the stomach and against pancreatin activity in intestine.
However, weaker protection was exhibited in the presence of bile
salts and hence pre-prandial administration of lipid nanocapsules for
better stability prole along the gastrointestinal tract could be sought
[66]. With these promising results, the uptake of the lipid nanoparticles
across the in vitro Caco-2 cell monolayer model was evaluated. About
3.5-fold increase in the apparent permeability of PTX upon its loading
in lipid nanocapsules was observed as compared to free drug; vesicle
mediated transcytosis being the proposed mechanism for improved
permeability [32]. These results were in correlation with pharmacoki-
netic studies conducted by another group. PTX-loaded lipid
nanocapsules demonstrated a 3-fold increase in the oral bioavailability
of PTX in comparison with Taxol orally administered. This effect on
the oral PTX bioavailability was directly related to the presence of the
surfactant Solutol HS15, which inhibited the P-gp efux system. Be-
sides, lymphatic transport of PTX and the nanocapsule structure might
also be benecial for the oral permeability of PTX [67].
3. Polymer nanocarrier based approach
Polymer based nanocarriers have shown their potential to in-
crease the oral and peroral delivery of various drugs [6870]. Sub-
stantial efforts have been made to improve the bioavailability vis-
-vis therapeutic efcacy and safety prole. A variety of biopharma-
ceutical parameters have been reviewed to manipulate the in vivo
fate upon administration [71,72]. Briey, particle size, shape and sur-
face properties of the nanoparticles play a crucial role in the uptake
across the gastrointestinal membrane and were found to signicant-
ly affect the absorption prole. The nanocarriers with particle size of
50300 nm, positive zeta potential and hydrophobic surface were
found to have preferential uptake from gastrointestinal tract as com-
pared to their counterparts. However, the retention of these proper-
ties in the gastrointestinal lumen is equally important and efforts
should be made in this direction to maximize the delivery efciency
of the carrier system these properties in the gastrointestinal lumen is
equally important.
3.1. Mechanism of improved bioavailability of BCS class IV drugs by poly-
mer nanocarrier based approach
The principal advantages of polymeric nanocarriers include their
increased solubilization potential, superior encapsulation, altered
absorption pathways, prevention of metabolic degradation within
gastrointestinal tract, chemical versatility of materials eligible for
nanomedicines, exibility in surface functionalization, drug and dis-
ease specic tailor made design capability, targeting potential and
ability to incorporate wide variety of drug substances. Nanocarriers
by the virtue of their ability are able to bypass the different hurdles
that are responsible for poor oral absorption of majority of BCS
class IV drugs. Various identied absorption mechanisms through
which nanocarriers increase the oral bioavailability of drug mole-
cules include increased absorption from enterocytes (due to in-
creased solubilization and dissolution), mucoadhesion (interaction
between the positively charged nanocarrier with negatively charged
mucin), tight junction modulation (capability of nanocarriers to in-
teract with the tight junction proteins), receptor mediated endocy-
tosis and transcytosis (clathrin- and calveolae-dependent and
-independent endocytosis), phagocytosis via specialized microfold
cells (M cells) of the Peyer's patches and other mucosa associated
lymphoid tissues (MALT).
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
3.2. Potential applicability of polymer based nanocarriers for improving the
bioavailability of BCS class IV drugs
3.2.1. Polymeric micelles
Polymeric micelles are the systems containing hydrophobic cores
surrounded by hydrophilic corona that is exposed to aqueous environ-
ment. The hydrophobic cores act as a reservoir for lipophilic drug mole-
cules and corona acts as the steric stabilizer of the overall system
thereby assuring the integrity of the system in aqueous environment
holding the adequate amount of guest drug molecules [73]. Polymeric
micelles have recently gained wide acceptance as the carrier systems
considering their various advantages such as superior stability com-
pared to surfactant micelles, enhanced solubilizing power, longer circu-
lating time due to outer hydrophilic shell, small size and targeting
capability [74].
Shaor et al. designed a formulation of 1, 2-distearoyl-sn-glycero-
3-phosphoethanolamine-N-[methoxy(polyethylene glycol)- 2000]
(PE-PEG) based micelles loaded with antimicrobial agent, AmB, and
surface-modied with angiopep-2. The targeted micelles exhibited
a signicantly enhanced ability to carry AmB into the brain. In addi-
tion, the micellar AmB formulations demonstrated decreased cyto-
toxicity and hemolysis in vitro compared with Fungizone [75]. PTX,
with an aqueous solubility of approximately 0.3 g/mL, was loaded
into 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-
methoxy(PEG)/TPGS (PEG-DSPE/TPGS) micelles. The aqueous solu-
bility of PTX was enhanced by up to 5000 times to achieve an aque-
ous solubility of approximately 5 mg/mL [76]. The most impressive
enhancement in PTX solubility was achieved by the work of Kim et
al., in which it was reported that the aqueous solubility of PTX was
as high as 38.9 mg/mL through encapsulation in micelles. In this
study, nicotinamide derivatives, i.e. N, N-diethylnicotinamide and
N-picolylnicotinamide (DENA) were shown to be powerful
hydrotropes for PTX. Copolymers with a segment containing such
nicotinamide derivatives could be used to produce polymeric
micelles with hydrotropic properties toward PTX. In addition,
micelles composed of PEG-b-poly(vinylbenzyloxy)- N, N-
diethylnicotinamide (PEG-b-PVBODENA) could achieve a remark-
ably high drug loading (37.4% w/w) for micelle-based delivery
systems. The drug loading increased proportionally to the length of
the hydrotropic DENA segment. As a comparison, PEG-b- PLA mi-
celles could only load up to 27.6% (w/w) of PTX under similar condi-
tions [77,78].
3.2.2. Polymeric nanoparticles
Polymeric nanoparticles are nano-colloidal cargos, preferably in the
size range of 101000 nm, made up of wide variety of polymers. They
have been widely studied and evaluated for the oral and per-oral deliv-
ery of many drugs and chemotherapeutic agents. The principal advan-
tage of this system includes their robust structural characteristics
imparting very high stability in the gastrointestinal tract. Furthermore,
the hydrophobicity and hydrophilicity within the polymeric system
can be manipulated to accommodate wide variety of drug molecules
[79]. The properties of biocompatibility and biodegradation further en-
hance their delivery potential. A large number of polymers including the
co-polymers have been employed for the preparation of polymeric
nanoparticles (nanocapsules and matrix based nanoparticles). Table 2
reveals various types of polymeric nanoparticles that have been imple-
mented to improve the oral and per oral delivery of various BCS class IV
drugs.
3.2.3. Dendrimers
Dendrimers are the hyper branched and uniformly distributed mac-
romolecules that possess denite molecular weight, shape, size and spe-
cic chemical and physical properties including hostguest entrapment
properties [97]. The tailor made design makes these sophisticated sys-
tems eligible for incorporation of wide variety of drugs that otherwise
79
pose potential delivery challenges. The drug molecules can be either
physically entrapped or chemically conjugated to the dendritic struc-
tures during or after synthesis of macromolecular systems. Further-
more, encapsulation of drug molecules within the dendritic structures
selectively eliminates solubility and permeability related issues.
Jain et al. developed muramyl dipeptide (MDP) conjugated
multimeric poly(propyleneimine) (PPI) dendrimers for targeted deliv-
ery of AmB to macrophages [98]. Therapeutic activity and toxicity of
dendrimeric formulation of AmB (MdPPIA) were compared with
marketed formulations of AmB. Highly signicant (P b 0.01) reduction
in toxicity was observed in hemolytic toxicity and cytotoxicity studies
in erythrocytes and J774A.1 macrophage cells, respectively. Formulation
MdPPIA showed appreciable macrophage targeting potential in cell up-
take studies. The developed formulation MdPPIA showed higher or
equivalent antiparasitic activity against parasite infected macrophage
cell lines and in vivo infection in Balb/c mice.
Teow et al. investigated the ability of a third-generation (G3)
polyamidoamine (PAMAM) dendrimer-based carrier to enhance the
permeability of PTX and to overcome cellular barriers [99]. G3
dendrimers were surface modied with lauryl chains (L) and conjugat-
ed with PTX via a glutaric anhydride (glu) linker, followed by labeling
with FITC. Biological evaluation of the dendrimer and conjugates was
conducted using the Caco-2 cell line and primary cultured porcine
brain endothelial cells (PBECs). Cytotoxicity studies showed that the
conjugation of L and PTX on G3 dendrimer signicantly (p b 0.05) in-
creased the cytotoxicity against both cell types. Permeability studies of
dendrimerdrug conjugates demonstrated an increase in the apparent
permeability coefcient (Papp) in both apical to basolateral A B and
basolateral to apical B A direction across both cell monolayers com-
pared to unmodied G3 and free drug. L6- G3-glu-PTX conjugate had
approximately 12-fold greater permeability across both cell monolayers
than that of PTX alone.
Devarakonda et al. investigated the efciency of lower generation
PAMAM dendrimers to improve the solubility and release kinetics of
FUR [100]. The increase in the solubility of FUR in the presence of
dendrimers was primarily due to the electrostatic interactions between
the positively charged tertiary amines of the dendrimers and negatively
charged carboxylate anion of FUR, resulting in a favourable solubiliza-
tion effect. The results showed that the PAMAM dendrimers could be
exploited to improve the solubility and dissolution of FUR, however
the enhancement depended on the choice of dendrimer, generation
size, and surface functional group of the dendrimer.
4. Pharmaceutical crystal engineering
Crystal engineering is a new and emerging method of controlled
crystallization that can be described as the exploitation of noncovalent
interactions between molecular or ionic components for the rational de-
sign of solid-state structures. Crystal engineering technologies can be
applied to pharmaceutical substances like BCS class IV drugs to improve
drug solubility and permeability through controlled crystallization pro-
cesses such as by forming co-crystals, nanocrystals, lipid nanocrystals,
metastable polymorphs, high energy amorphous forms and ultrane
particles.
4.1. Nanocrystal technology
Nanocrystals, is currently offering promising potential to address the
low solubility and poor bioavailability problems of many drug candi-
dates [101]. A drug nanocrystal is a nano-sized crystalline particle con-
taining 100% drug with nominal utilization of excipients like surface
stabilizing agents. The pharmaceutical benets of nanocrystals include
improvement in formulation performance, such as enhanced dissolu-
tion velocity and saturation solubility due to increased surface area/vol-
ume-ratio [102]. Nanocrystal formulations exhibit a high drug load;
reproducibility of oral absorption, improved dose-bioavailability and
80 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195

Table 2
Polymeric nanoparticles implemented to improve the oral and per oral delivery of BCS Class IV drugs.

Polymeric system
(Functionalization) Drug Outcome References

PAA-cysteine (GSH) PTX About 7-fold increase in apparent permeability and about 5-fold increase in oral bioavailability as compared to free paclitaxel [80]
Polyanhydrides PTX Relative Bioavailability up to 80% [81]
(Cyclodextrins)
Polyanhydrides (PEG PTX Relative bioavailability up to 70% [82]
2000)
PLA (Vitamin E TPGS) DTX Bioavailability increased by 22-fold [83]
PLA (TPGS) PTX 1.8-Fold increase in the cellular uptake by HT29 cell lines as compared to plain PLGA nanoparticles and 40% reduction in IC50 [84]
values as compared to taxol
PLGA (DMAB-TPGS) DTX About 16-fold decrease in the IC50 value for in vitro cytotoxicity against MCF-7 cell lines as compared to marketed formulation [85]
at 72 h
PLGA (Montmorillonite) PTX Signicant improvement in the entrapment efciency by 57177% for Caco-2 cells and 1155% for HT-29 cells was observed [86]
PLGA (WGA) PTX About 2-fold increase in the cellular uptake by Caco-2 and HT-29 cell lines as compared to plain nanoparticles [87]
PLGA (WGA) PTX Signicantly higher cytotoxicity against A549 and H1299 cell lines [88]
PLGA PTX 7-Fold higher toxicity of formulation in A2780 cell lines and signicant activity in 2780 CE resistant cell lines [89]
PLGA (Mannose) AmB Enhanced uptake, potential anti-leishmanial activity and higher disposition in macrophage-rich organs, suggesting improved [90]
macrophage targeting
Pullulan acetate LPV Relative bioavailability of LPV from nanoparticles was 2 folds higher than the free drug, higher distribution of nanoparticles to [91]
lymphoid organs
PCL LPV Increase in oral bioavailability of LPV by 4-folds [92]
PLGA (TPGS) AmB Lower haemolysis, nephrotoxicity and relative oral bioavailability was found to be 800% as compared to Fungizone. [93]
PLGA AmB Superior in vitro antifungal activity (two times more efcacious than AmBisome) [94]
PLGA CyA Signicantly higher intestinal uptake as compared to Sandimmune Neoral and cyclosporine suspension, relative [95]
bioavailability of nanoparticulate formulation was found to be 119.2%
PLGA (Folic acid) SQV Enhanced cytotoxicity and cellular uptake by the cancerous cells via folate receptor-mediated endocytosis (RME) mechanism [96]

PLGA: Polylactide-co-glycolic acid; PCL: poly--caprolactone; PLA: Polylactic acid; PEG: Polyethylene glycol; WGA: Wheat germ agglutinin; PAA: polyacrylic acid; GSH: glutathione.

versatile administration routes along with proportionate and increased
patient compliance. Also reduction of number of oral units to be taken,
low incidence of side effects due to the excipients and an overall im-
provement of efciency and safety can also be achieved.
4.1.1. Mechanism of improved bioavailability by nanocrystal technology
Nanocrystals and their uptake are not fully understood although
several studies have reported various mechanisms as well as pathways.
Paracellular pathway is a route for potential uptake of nanocrystals.
However, owing to the strict diametric constriction (b 10 ) of the
pores present in between juxtaposed cells, exponentially larger
nanocrystals (~100 nm onwards) nd it difcult to pass through. Fig.
4(A) illustrates paracellular pathway of enterocytes which hinders
transport of nanocrystals. However, some researchers claim the open-
ing of these junctions by the application of some specic chemicals (sur-
factants) such as sodium deoxycholate which might facilitate the entry
of nanocrystals, but there is no adequate experimental evidence on this
[103]. In case of cancer the paracellular uptake at site of action may take
place owing to the well-known enhanced permeability and retention
(EPR) effect (high fenestra frequency) [104]. Some nanocrystals are
taken up directly by cells via multiple endocytotic pathways including
clathrin-mediated, non-clathrin mediated (caveolae), macro-pinocyto-
sis, as well as phagocytosis [105]. Fig. 4(B) demonstrates the above spe-
cialized mechanisms of nanocrystal transport via enterocytes. After
endocytosis nanocrystals possibly become available for lymphatic
transport instead of venous transport. The reasons might be the low
pore size (roughly 3 nm) of the vascular epithelium. Reports on the up-
take of nanocrystals via M-cells are also found in literature. These spe-
cialized cells are believed to transport nanocrystals through an active
transepithelial vesicular transport system from the lumen directly to
lymphoid cells and tissues; though the overall efciency of this process
remains questionable as M cell populates b 1% of the intestinal epithelia
[106].
Following intravenous administration, nanocrystals may remain in-
tact or enter into a molecular dispersion due to high intrinsic solubility,
dissolution rate, and rapid dilution accessing the site of action for ther-
apeutic effect [107]. Alternatively, intact nanocrystals keep moving in
the systemic circulation as colloidal particles. During their ight,
nanocrystals are recognized as foreign bodies and engulfed by the de-
fence (phagocytic) cells such as macrophages. In phagocytic cells
nanocrystals dissolve slowly in phagolysosomes. Consequently, the hy-
drophobic drug might pass through the phagolysosomal membrane and
enter into the cytoplasm, and then diffuse out of the cell down its con-
centration gradient [108]. Fig. 4(C) depicts the fate of nanocrystal after
intravenous administration. Nanocrystals of size b100 nm behave like
molecular solution whereas those N 500 nm are accumulated in the
liver. This characteristic of nanocrystals can be successfully used in
targeting different diseases/disorders [109].
4.1.2. Potential applicability of nanocrystal technology to BCS class IV drugs
Oral administration of AmB as a nanosuspension produced a sub-
stantial improvement in its oral absorption in comparison to orally ad-
ministered conventional commercial formulations such as Fungizone
and AmBisome. Apart from improving oral absorption, nanosus-
pensions offered improved dose proportionality, reduced fed/fasted
state variability and reduced inter-subject variability [111]. The devel-
opment of PTX nanocrystals for oral delivery has recently been often
proposed as a promising approach to overcome the drawbacks of classic
products on the market. For instance, several studies have considered
the possibility of modifying the nanocrystal surface in order to enhance
their properties. To this end, Patel et al. [112] focused their investigation
on developing a PTX nanocrystal formulation in order to overcome the
drug's poor solubility and permeability. In particular, positively charged
nanocrystals were prepared by sonoprecipitation with a high-pressure
homogenization method to investigate a combination of arginine
based cationic surfactant and hydroxypropylmethylcellulose. Both the
dissolution and permeability of PTX were signicantly improved by
nanocrystal formulation, and the in vitro and in vivo results clearly sug-
gested it to be a promising approach in the anticancer eld.
Also to augment passive targeting, ligands selective for receptors
over expressed on cancer cells are appended to nanocrystals. This
opens up the avenue for active receptor based targeting by tailoring
nanocrystals [113]. Liu et al. described the concept of proof by activating
PTX nanocrystals through application of folic acid conjugated stabilizer.
In comparison to non-ligated PTX nanocrystals, ligated nanocrystals
showed enhanced in vitro cytotoxic activity due to preferential uptake
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195 81

Fig. 4. (A) Graphical representation of intracellular tight junction and failure of nanocrystals to pass through paracellular pathway, (1) enterocytes, (2) intracellular tight junction (b10 ),
and (3) failure of nanocrystals to pass through the paracellular pathway, (4) uptake of nanocrystals by enterocytes after treatment with surfactants, and (5) M-cell mediated uptake of
nanocrystals. (B) Diagrammatic representation of clathrin mediated, and non-clathrin (caveolae) mediated endocytosis of nanocrystals after oral administration, (1) nanocrystals on
the enterocyte surface, (2) magnied view of nanocrystals over the cell membrane, (3) clathrin-mediated phagosome and endocytosis of nanocrystals, (4) release of nanocrystals to
the other side of cell via clathrin-mediated transport, (5) nonclathrin (caveolae) mediated endocytosis of nanocrystals, and (6) release of nanocrystals to the other side of cell via non-
clathrin (caveolae) mediated transport. (C) Proposed in vivo fate of nanocrystals after intravenous administration (1) injection of nanocrystals to blood vessels, (2) nanocrystals in the
blood stream in molecular solution and intact nanocrystal form, (3) phagocytic cells, (4) formation of molecular solutions of nanocrystals in blood, (5) phagocytosis of intact
nanocrystals and further solubilization in cytosol of phagocytes, and (6) drug in molecular solution form comes out due to concentration gradients of phagocytes and outer
environment. Adopted and modied from [110].

via over expressed folic acid receptor on KB cells [114]. Puligujja et al.
produced long-acting folic acid-receptor targeted RTV-boosted
atazanavir nanoformulations to improve the antiretroviral therapy
[115]. Folic acid was covalently linked to two types of poloxamers,
that is, poloxamers 407 and 188. Subsequently, the conjugate was
used to nanoencapsulate antiretroviral drug nanocrystals. These coated
nanoparticles targeted the folic acid receptor favouring drug tissue de-
pots and permitting an enhanced accumulation to the reticuloendothe-
lial system with an improved pharmacodynamics activity in mice.
Table 3 depicts the various BCS class IV drugs for which the nanocrystal
technology led to increased bioavailability and therapeutic potential.
Taking into account potential advantages and reduced side ef-
fects, nanocrystals can be considered as suitable candidates for in-
vivo delivery of BCS Class IV drugs. It is a unique approach to solve
bioavailability related issues. Industrially feasible manufacturing
techniques can serve to bring nanocrystals from researcher's bench
to patient's bed at an accelerated rate. Nanocrystals are versatile
pharmaceuticals which can be delivered through almost all routes
of administration such as oral, parenteral, dermal, and ocular. They
are adept to convenient sterilization techniques, a key driver for de-
velopment of parenteral formulations. Incorporation of appropriate
stabilizers followed by drying (freeze/spray) can ensure long term
stability of nanocrystals. Nanocrystals decorated with functionalized
ligands have generated a new ray of hope by being able to target var-
ious organs with higher afnity. Furthermore, nanocrystals might be
an opportunity to produce generic versions of presently available
82 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195

Table 3
Nanocrystals implemented to improve the bioavailability of BCS Class IV drugs.

Drug (route) Therapeutic use Benet Reference

PTX (i.v.) Cancer Signicant anti-tumour efcacy of nanocrystals over Taxol [116]
PTX & Cancer Enhanced antitumour activity due to targeting folate receptors [114]
camptothecin
(oral & i.v.)
DTX (i.v.) Cancer DTX nanocrystals proved a better opportunity to inhibit tumour growth and reduce toxicity in comparison to [117]
marketed formulation.
AmB Organ targeting (Brain) Nanocrystals coated with polysorbate 80 and sodium cholate showed enhanced brain uptake than AmB [118]
solution
Aprepitant Chemotherapy induced The fed-fasted ratio was reduced and the bioavailability was improved in the beagle dogs at a dose of 2 mg/kg [119]
nausea and vomiting
RTV HIV The nanosuspension showed a signicantly increased solubility when compared to coarse drug powder (3.5 [120]
fold), 90% drug dissolved in FeSSIF compared to the commercial product which showed ~50% in the same
medium
RTV HIV Improved inhibition of CYP3A4, enhanced permeability across Caco-2 cells lower cytotoxicity across hepatic, [121]
intestinal, and immune cell types by nanodispersions compared to an aqueous solution of RTV.
LPV HIV The surface-stabilized LPV-NPs (without RTV) demonstrated a 3.11-fold enhancement in bioavailability in [122]
comparison to free LPV with RTV (conventional formulation).

costly drugs. In conclusion, engineered nanocrystal technology has
huge potential to deliver pre-existing or newly developed notorious
class IV drugs in a more acceptable and effective dosage form with
high commercial applicability.
4.2. Co-crystal technology
Recently, pharmaceutical co-crystals have gained interesting atten-
tion to act as drug candidates in solid-state drug development. The mo-
lecular components of co-crystal complexes are the target molecule
(traditionally the drug molecule) and the co-crystal former(s) (also
known as the co-crystallizing agent or co-former). Co-crystals are
formed by intermolecular interactions, or synthons, that form between
the drug and a potential co-crystal former, which in turn leads to the
creation of supramolecular assemblies. A pharmaceutical co-crystal
does not only provide new opportunities to modify the physicochemical
properties, dissolution rate, and drug bioavailability of an API, but also
creates intellectual property for a new patent of an API for extending
their life cycle. Thus, the investigations of pharmaceutical co-crystals
have been rapidly expanded by growing the number of research publi-
cations and patent applications [123].
4.2.1. Potential applicability of co-crystal technology to BCS class IV drugs
Sanphui et al. addressed the poor solubility of the diuretic drug HCT
by preparing co-crystals [20]. The co-crystal of HCT with p-
aminobenzoic acid showed a six-fold increase in solubility compared
with pure HCT, and stability up to 24 h in an aqueous medium. The
co-crystals of HCT with nicotinamide, resorcinol and pyrogallol showed
a 1.5 to 2- fold increase in solubility. Goud et al. reported a co-crystal of
FUR, a low soluble and low permeable antihypertensive drug with caf-
feine using liquid assisted grinding [124]. The co-crystals with improved
physicochemical properties exhibited higher solubility, more stability
and increased dissolution rates than the pure compound. The solubility
and intrinsic dissolution rate for the co-crystal was found to be 6 and 2
times more respectively, than FUR.
5. Liquisolid technology
Liquisolid systems are considered as free-owing and compressible
or compactable powders containing a non-volatile liquid vehicle and
solid drug particles. The solid drug particles can be dissolved or partly
dissolved by the liquid vehicle (co-solvent). This liquid system may be
converted into a dry looking, free-owing and compressible powder
by mixing with suitable excipients termed the carrier and coating mate-
rials. In liquisolid formulations, the excipient with a capability to adsorb
liquid on its surfaces is called the carrier which usually has the highest
contribution in the formulation. The excipient with very high surface
area which usually covers the carrier surfaces containing liquid to im-
prove owability of liquisolid powders is known as coating materials.
The outline of liquisolid preparation is presented in Fig. 5.
5.1. Mechanism of improved bioavailability of BCS class IV drugs by
liquisolid technology
In the literature, several mechanisms of enhanced drug release have
been postulated for liquisolid systems. The three main suggested mech-
anisms include an increased surface area of drug available for release,
increased solubility of the drug and improved wettability of the drug
particles.
5.1.1. Increased drug surface area
Even if the drug within the liquisolid system is completely dissolved
in the liquid vehicle, it is still located in the powder substrate in a solu-
bilized, molecularly dispersed state. Therefore, the surface area of drug
available for release is much greater than that of drug particles within
directly compressed tablets. Accordingly, with increasing drug content
exceeding the solubility limit and thus increasing fraction of undis-
solved drug in the liquid vehicle the release rate decreases. With various
drugs, it could be shown that the release rates are directly proportional
to the fraction of the molecularly dispersed drug (FM) in the liquid for-
mulation [125127]. FM is dened by Spireas et al. as the ratio between
the solubility (Sd) in the liquid vehicle and the actual drug concentra-
tion (Cd) in this vehicle carried by each system [126]. Therefore:
FM Sd=Cd
where FM = 1 if Sd = Cd.
5.1.2. Increased drug solubility
In addition to the rst mechanism of drug release enhancement, it is
expected that Cs, the solubility of the drug, might be increased with
liquisolid systems. In fact, the relatively small amount of liquid vehicle
in a liquisolid compact is not sufcient to increase the overall solubility
of the drug in the aqueous dissolution medium. However, at the solid-
liquid interface between an individual liquisolid primary particle and
the release medium, it is possible that in this microenvironment the
amount of liquid vehicle diffusing out of a single liquisolid particle to-
gether with the drug molecules might be sufcient to increase the solu-
bility of the drug if the liquid vehicle acts as a co-solvent. The overall
increase in the solubility of drugs caused by liquisolid systems was con-
rmed by Yadav et al. [128130].
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
Fig. 5. Liquisolid technology for improving the bioavailability of BCS Class IV drugs, (A) The components of a liquisolid system, (B) method for the formulation and development of
liquisolid system, (C) Potential advantages and outcomes of liquisolid system.
5.1.3. Improved wetting properties
Due to the fact that the liquid vehicle can either act as surface active
agent or has a low surface tension, wetting of the liquisolid primary par-
ticles is improved. Wettability of these systems has been demonstrated
by measurement of contact angles [131] and water rising times [128,
130]. Liquisolid compacts show lower contact angles compared to con-
ventional tablets due to the presence of a surface active agent, for exam-
ple, polysorbate 80 [127,131].
5.2. Potential applicability of liquisolid technology to BCS IV class drugs
The technique of liquisolid compacts has been successfully
employed to improve the in vitro release prole of many poorly water
soluble drugs. Further, this technique has also been tried to improve
the bioavailability of many BCS class IV drugs like FAM [132], FUR
[133,134], CyA [135] and HCT [136]. Fahmy et al. formulated FAM
liquisolid systems to improve its dissolution and also investigated the
in vitro and in vivo performance of the prepared liquisolid tablets
[132]. All the tested liquisolid tablet formulations showed higher drug
dissolution rates than the conventional, directly compressed tables. In
83
addition, the selected optimized formula released 78.36% of its content
during the rst 10 min which is 39% higher than that of the directly
compressed tablets. Further, the bioavailability study indicated that
the prepared optimized liquisolid formula did not differ signicantly
from the marketed FAM tablets concerning Cmax, tmax, and AUC (08) at
P b 0.05. Akinlade et al. enhanced the in vitro dissolution properties of
FUR, by utilising liquisolid technique [133]. Liquisolid tablets containing
Synperonic PE/L 81 as a new liquid vehicle exhibited greater dissolu-
tion due to the physical properties of this liquid vehicle which led to in-
creased wetting properties and solubility of the drug; demonstrating
higher drug release than those of conventionally made tablets by direct
compression.
Khaled et al. evaluated the absorption characteristics of experimen-
tally developed HCT liquisolid tablets using six male beagle dogs [136].
Signicant differences were found between the two formulations i.e.,
liquisolid tablets and commercial tablets with regard to AUCt, AUC,
Cmax, and F parameters. Liquisolid tablets consistently showed higher
values of the aforementioned parameters. The mean values of the abso-
lute bioavailability of HCT from the commercial and the liquisolid tab-
lets were found to be 72.6 and 83.7%, respectively and signicantly
different. This nding reects an increase in the bioavailability of the
84 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
drug by 15% when formulated as liquisolid tablets. The Cmax value
achieved following the administration of the liquisolid tablets was
32% higher than that of the commercial tablets. The mean absorption
time for the liquisolid tablets was 1.58 h, which was 55 min shorter
than the commercial tablets (2.5 h). Although this difference was not
statistically signicant, this reected the rapid absorption of the
liquisolid tablets. The parametric 90% condence intervals of the mean
values of AUCt, AUC, and Cmax were 107.5132.2, 102.8131.7, and
110.7153.7%, respectively. These intervals are, generally, higher than
the expected interval range for bioequivalency (80125%, using log
transformed data). This should be expected as liquisolid tablets showed
greater extent of absorption than the commercial tablets. In conclusion,
HCT liquisolid tablets showed signicantly greater extent of absorption
than the commercial tablets. Zhao et al. tried to enhance the dissolution
rate of CyA, a poorly water-soluble drug by developing a self-micro-
emulsifying (SME) tablet formulation by using the liquisolid compact
technique [135]. Microcrystalline Cellulose (Avicel PH 101 and Avicel
PH 102) and Magnesium Aluminometasilicate (Neusilin S1) were se-
lected as the carrier material and coating material respectively for pre-
paring the liquisolid compact. The obtained powder mixture had good
owability (Hausner's Ratio = 1.243, Carr's Index = 19.565) and good
compactability (Hardness = 5.18 0.33kp, Tensile Strength =
0.47 0.03Mpa). The dissolution results showed that the dissolution
rate of SME tablets was much higher when compared to the conven-
tional tablets prepared by direct compression.
6. Self-emulsifying solid dispersion formulations
These formulations consist of a dispersion of the drug in an inert ex-
cipient matrix, where the drug could exist in either the nely divided
crystalline, solubilized or amorphous states or a mixture thereof. This
can increase the dissolution rate of the drug in, and subsequent absorp-
tion from, the GI tract relative to the stable crystalline drug substance.
The introduction and use of newer thermo-softening, surface-active
and self-emulsifying excipients (Examples in Section 4.1) have
surmounted the various issues that impeded the commercial develop-
ment of solid dispersions. These excipients have the potential to further
increase the absorption of poorly water-soluble drugs relative to previ-
ously used PEG solid dispersions and may also be lled directly into hard
gelatin capsules in the molten state, thus obviating the former require-
ment for milling and blending prior to lling. In addition, more recently
introduced hot-melt extrusion technology has proven to be of value in
resolving some of the remaining manufacturing issues associated with
solid dispersions.
6.1. Examples of surface active excipients used in the fabrication of self-
emulsifying solid dispersions
6.1.1. Gelucires
One excipient that has stimulated interest in self-emulsifying solid
dispersion formulations is Gelucire 44/14 (Gattefoss Corp., St. Priest,
France). This self-emulsifying excipient exists as a waxy semi-solid at
ambient room temperature and is a mixture of glyceryl and PEG 1500
esters of long-chain fatty acids. The sufxes, 44 and 14, in the excipient
trade name refer to its melting point and hydrophiliclipophilic balance
(HLB), respectively. Gelucire 44/14 has also been extensively used in
combination with other surfactants and solubilizing agents to enhance
the performance of solid dispersions [137,138]. It has the ability to
self-emulsify on contact with aqueous media forming a ne dispersion
i.e. micro emulsion. Surfactive power improves the solubility and wetta-
bility of the active pharmaceutical ingredients in vitro and in vivo. The
increased bioavailability of the drugs could also be associated with the
inhibition of the enterocyte efux transporter (P-gp inhibition). It ex-
hibits good thermoplasticity for use as a binder in melt granulation
and melt extrusion techniques, associated with rapid formation of sta-
ble crystalline phase. The safety of use is supported by extensive
toxicological evaluations and precedence of use in approved pharma-
ceutical products.
6.1.2. Tocopheryl polyethylene glycol 1000 succinate (TPGS)
Another lipid-based excipient useful for preparing self-emulsifying
solid dispersion formulations is FDA approved water soluble d--
tocopheryl polyethylene glycol 1000 succinate (TPGS; Vitamin E TPGS,
Eastman Chemical, Tennessee, U.S.A.). This excipient, which is listed in
the United States Pharmacopoeia, is a water-soluble, surface-active,
and self-emulsifying derivative of vitamin E that is capable of solubiliz-
ing many poorly water-soluble drugs. Apart from being a very good
emulsier, it also has P-glycoprotein (P-gp) inhibiting property. It is
being increasingly employed to overcome bioavailability issues associ-
ated with poorly soluble compounds especially in case of anticancer
drugs where it helps to overcome the MDR. Also, because of its relatively
low melting point (~40 C), molten TPGS formulations are suitable for
lling into both soft and hard gelatin capsules; however, hard gelatin
capsules require band-sealing in order to prevent leakage of the
contents.
6.1.3. Pluronics
Another surface active lipid excipient class that has shown signi-
cant promise for application in self-emulsifying solid dispersion formu-
lations is the block copolymer consisting of hydrophilic poly(ethylene
oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO), various
grades of which are commercially available as poloxamers (Pluronics)
[139,140]. They possess both solvent and surfactant properties and suit-
able melting range which are well suited for capsule lling operations.
They are well characterized with respect to quality, chemical compati-
bility, and performance in promoting the absorption of hydrophobic
drugs through solubilization or increased wetting of the drug particles.
They also enhance cell membrane permeability and decrease intestinal
efux through inhibition of the P-gp transporter.
6.2. Mechanism of improved bioavailability of BCS class IV drugs by self-
emulsifying solid dispersion formulations
The lipid based commercially marketed products of CyA, RTV and
SQV are encapsulated liquids. The primary limitation of these lipid-
based dosage forms is the requirement that the drug possess sufcient
solubility in the formulation to allow delivery of a single dose in a stan-
dard oral capsule dosage form. In instances where insufcient solubility
in the formulation precludes the development of a fully solubilized
lipid-based formulation, preparation of a solid dispersion of the drug
in a semi-solid, lipid based formulation could provide a viable path for-
ward. However, the performance of non-self-emulsifying solid disper-
sions (e.g., those prepared using PEGs) is often limited by the
relatively rapid dissolution rate of the water-soluble excipient matrix
as compared to that of the dispersed drug substance. This results in
the formation of a highly concentrated solution of drug which precipi-
tates on the surface of the dissolving excipient plug, forming a poorly
soluble coating that prevents further dissolution of dispersed drug
contained within the excipient matrix. For this reason, solid dispersions
must be pulverized and sifted to increase their surface area in order to
facilitate drug release. This is a difcult task as solid dispersions pre-
pared with such common excipients as PEGs are usually soft and tacky
and may not be readily milled. Moreover, the powders thus produced
often have poor ow and mixing properties and are difcult to ll into
capsules or compress into tablets.
In comparison, solid dispersion formulations prepared from surface-
active lipid or lipid like excipients prevent the formation of a poorly
water-soluble drug surface layer on the excipient plug during dissolu-
tion. While a portion of the released drug may still precipitate in the dis-
solution medium once its dissolved concentration exceeds the
saturation solubility, it would typically be present in a nely divided
state due to the surface active properties of the excipient. The associated
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
high surface area of the nely divided drug substance would facilitate its
rapid dissolution in the GI uid. This is shown schematically in Fig. 6. for
solid dispersions lled into hard gelatin capsules. Another major advan-
tage of solid dispersion formulations prepared from lipid or surface ac-
tive excipients is realized in the relative ease with which they are
manufactured. Solid dispersions prepared from these excipients may
be directly lled into hard gelatin capsules in the molten state, which
subsequently solidify upon cooling to ambient room temperature,
thus eliminating the need for grinding, sifting, and mixing. The melting
temperature of the molten excipient, however, must not exceed ~70 C,
which is the maximum acceptable ll temperature for hard gelatin cap-
sules [141].
6.3. Potential applicability of self-emulsifying solid dispersion formulations
to BCS class IV drugs
Investigators have studied the role of TPGS in enhancing the absorp-
tion of drugs, which are both poorly soluble and poorly permeable
[142]. Sokol et al. [143] reported enhanced absorption of CyA from vita-
min E TPGS formulations administered to pediatric patients, as com-
pared to formulations without vitamin E TPGS. Formulations including
TPGS allowed a 40% to 72% reduction in the CyA dosage required to
maintain therapeutic plasma drug concentrations. Similarly, Chang et
al. [144] reported a signicant increase in CyA bioavailability in healthy
volunteers when administered with TPGS. In both of these instances,
the investigators suggested not only drug solubilization, but also inhibi-
tion of the intestinal P-glycoprotein transporter as a contributing factor
to the enhanced CyA bioavailability.
Sinha et al. developed self-emulsifying solid dispersion of RTV by dif-
ferent methods (solvent evaporation [SE], melt method [MM]) and in-
vestigated them for in vitro and in vivo performance for enhancing
dissolution and bioavailability, respectively [145]. Since the drug pos-
sessed food-related absorption, the effect of biorelevant media (fasted
[FaSSIF] and fed [FeSSIF] state simulated intestinal uid) on dissolution
behaviour was also studied. RTV and Gelucire formed a eutectic mixture
in the ratio of 1:4. In vitro dissolution studies showed that release of RTV
from solid dispersions was more than that of pure drug, which was due
to the nano size of dispersion. When the dissolution was performed in
FaSSIF and FeSSIF media, maximum dissolution was obtained with
FeSSIF media, which conrmed food-related absorption of drugs. The
apparent rate of absorption of RTV from SE (Cmax 20,221.37 ng/mL,
tmax 0.5 h) was higher than that of MM1 (Cmax 2462.2 ng/mL, tmax
1 h) and pure drug (Cmax 1354.8 ng/ml, tmax 0.5 h). The results indicated
that the solid dispersion is a promising approach for the bioavailability
enhancement of RTV and can be used for the solid dosage form develop-
ment for oral use in order to commercialize. Ibrahim et al. [146] pre-
pared solid dispersion of FAM solid using two hydrophilic carriers,
namely Gelucire 50/13 and Pluronic F-127 and the solid dispersions
Fig. 6. Potential advantages of self-emulsifying solid dispersions.
85
were used to prepare pellets. The dissolution study depicted that, the
presence of the drug in solid dispersion enhanced its dissolution in com-
parison with the drug itself. Also, the drug release from the
manufactured pellets was found to be improved in the case of solid dis-
persions (drug: carrier 1:3). A complete drug release occurred after
30 min from pellets containing solid dispersions, while only about 30%
of the loaded FAM was released from pellets containing untreated
drug after 2 h.
7. P-glycoprotein (P-gp) inhibition strategies
The intestinal efux pump, P-glycoprotein (P-gp), located in the api-
cal membranes of intestinal absorptive cells, can reduce the bioavail-
ability of a wide range of drugs which are substrates for this
membrane transporter. The BCS class IV drugs which are substrates of
P-gp efux pumps mainly belong to the class of HIV protease inhibitors
(IDV, SQV, LPV, NFV) and taxanes (PTX, DTX). Various formulation strat-
egies to effectively inhibit P-gp mediated efux of BCS class IV drugs
have been tried and evaluated as shown in Fig. 7. These strategies inde-
pendently and in combination, are: (a) co-administration of another P-
gp substrate/specic inhibitor, (b) incorporation of a nonspecic lipid
and/or polymer excipient in the formulation which blocks the activity
of P-gp efux pump and (c) novel peptide prodrug approach. The rst
approach, although very effective in inhibiting P-gp, utilizes a second ac-
tive compound in the formulation and thus imposes regulatory con-
straints and long development timelines on such combination
products. Excipient inhibitors appear to have minimal nonspecic phar-
macological activity and thus potential side effects of specic active
compound inhibitors can be avoided. Case studies have been presented
where specic active compounds, surfactants, polymers, and formula-
tions incorporating these molecules are shown to signicantly improve
the intestinal absorption of poorly soluble and absorbed BCS class IV
drugs as a result of P-gp inhibition and enhanced drug transport in
vitro. (See Fig. 8.)
7.1. P-gp inhibition by lipidic and polymeric excipients and formulations
There are many reports in the literature on the modulation of the ac-
tivity of P-gp using lipidic and polymeric excipients. The following case
studies are representative of this rapidly growing eld of
biopharmaceutics and its applicability to BCS class IV drugs. Enhance-
ment of PTX solubility and permeability by TPGS in vitro/in situ and ef-
fects on in vivo drug absorption has recently been reported by Varma
et al. [22]. In situ studies using rat ileum tissue in Ussing chambers, the
bi-directional transport of 14CPTX was also monitored in the presence
of increasing concentrations of TPGS. The apical-to-basolateral (A B)
permeability of PTX was found to increase in the presence of TPGS
while the basolateral-to apical (B A) was decreased with maximum
effect at 0.1 mg/mL of TPGS. Increasing TPGS concentrations above
0.1 mg/mL, resulted in a decrease in A B permeability with no change
in the B A permeability, which suggests the involvement of mono-
meric and not micellar TPGS in P-gp inhibition [22]. Wasan et al. [147]
conducted studies to ascertain that the incorporation of (AmB) into a
glyceride-rich excipient Peceol (glyceryl monooleate) signicantly in-
creased gastrointestinal absorption of AmB in white male Sprague-
Dawley rats. Based on preliminary studies, [147] it was proposed that
incorporation of AmB into mixed micelles composed of Peceol would
signicantly enhance gastro-intestinal (GI) tract absorption by decreas-
ing P-gp mediated drug efux. A signicant lower MDR-1 mRNA and P-
gp protein expression within Caco-2 cells was observed following 1-
and 7-day treatment with Peceol 0.1% to 1.0% (v/v) compared to non-
treated controls [148]. Taken together, these ndings suggested that
Peceol increased the gastrointestinal absorption of AmB by decreasing
MDR-1 mRNA and P-gp protein expression, resulting in lower PGP-me-
diated AmB efux [148].
86 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
Fig. 7. Various P-gp based approaches to improve the bioavailability of BCS Class IV drugs. (A) Potential mechanism for the inhibition of P-gp efux pump. (B) Strategies to inhibit/modulate
P-gp efux pump.
Zhang et al. prepared polymeric micelles based on monomethoxy
poly(ethylene glycol)-b-poly (D, L-lactic acid) (mPEG-PLA) to improve
the oral bioavailability of CyA [149]. In vitro release test showed that
the cumulative release percentage, about 85%, of CyA from polymeric
micelles within 24 h was comparable to that from Sandimmune Neoral,
the currently available oral formulation of CyA. A relative oral bioavail-
ability of 137% in rats compared with Sandimmune Neoral was demon-
strated for CyA-loaded polymeric micelles. The other aim of the work
was to study the transport mechanism of mPEG-PLA micelles across
the intestinal barrier. It was found that polymeric micelles signicantly
increased the permeability of CyA across Caco-2 monolayers without
signicantly affecting transepithelial electrical resistance values, and
the apparent permeation coefcient (Papp) of CyA was signicantly
higher in the A B direction compared to that in the B A direction,
suggesting that polymeric micelles underwent an active A B transport
that probably involved endocytosis which was conrmed by confocal
microscope observation. The permeation of CyA through Caco-2
monolayers showed that the Papp was signicantly increased when
CyA was formulated with the copolymer below its critical association
concentration (CAC) and no signicant difference was found above its
CAC, implying that mPEG-PLA monomers affected the intestinal P-gp ef-
ux pumps.
7.2. P-gp inhibition by using specic and non-specic P-gp inhibitors
Lipid excipients and formulations incorporating specic active com-
pounds/inhibitors of P-gp continue to serve as a useful approach to in-
hibit P-gp and improve the oral bioavailability of drugs with P-gp
limited absorption. Reduction in the bioavailability of PTX due to efux
by P-gp has been a major challenge in its successful oral delivery. It was
reported by Woo et al. that in the rat, approximately 54% of the dose of
the orally administered PTX is lost due to efux by P-gp, 38% due to gut
lumen metabolism, and 3.5% by gut wall and liver metabolism [38]. Im-
provement of the oral bioavailability of PTX has been widely reported in
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
Fig. 8. Various strategies to inhibit/modulate P-gp efux pump, (A) Specic and non-specic P-gp inhibitors, (B) P-gp inhibition by using specic, non-specic and other functional
excipients, (C) P-gp circumvention by using novel peptide prodrug approach.
the literature [48,49,150,151]. The most commonly used approach is the
co-administration of a specic P-gp substrate and/or incorporation of a
nonspecic inhibitor in the formulation. Woo et al. using KR-30031, a
verapamil analog with fewer cardiovascular effects than verapamil,
showed that in Caco-2 cells the A B transport of PTX (5 mM) was in-
creased in the presence of KR-30031 (25 mM) and this effect on drug ef-
ux was similar to that of verapamil (25 mM). A microemulsion
formulation containing dimethylisosorbide, Tween 80 and DL--to-
copherol and incorporating 6 mg/mL PTX was administered by oral ga-
vage to anesthetized rats. A dose of 25 mg/kg of PTX was used with and
without 5,10, 20, and 30 mg/kg of KR-30031 or 20 mg/kg of Verapamil.
KR-30031 increased the oral bioavailability of PTX from 4.6% to 41%
(34% P-gp and 7% liver metabolism inhibition) in a dose dependent
manner and this effect was saturable above 20 mg/kg of KR-30031
[38]. Earlier studies in improving the oral absorption of PTX were fo-
cused on the co-administration of CyA or one of its analogs. By combin-
ing the marketed lipid formulations of PTX (Taxol) and CyA
(Sandimmune), the peroral bioavailability of PTX in mice increased
from 9.5% to 67%. Increase was 10-fold when CyA was substituted by
87
its non-immunosuppressive analog PSC833 [151]. In a study, 14CPTX
in a solution containing Cremophor: ethanol (1:1) that was further di-
luted with saline was administered perorally to anesthetized rats with
and without the co-administration of TPGS (50 mg) or Verapamil
(25 mg). Both TPGS and Verapamil increased the Cmax and AUC of PTX
although the effect of TPGS on both parameters was greater. The bio-
availability of PTX increased 6.3-fold and 4.2-fold with TPGS and Verap-
amil, respectively [22]. Chaurasiya et al. investigated the concomitant
use of SMEDDS and a novel third-generation P-gp inhibitor, GF120918
(elacridar), for the effective transport of taxanes (PTX and DTX) [25].
The investigation was done across an in vitro model of the intestinal ep-
ithelium and uptake into tumour cells. In Caco-2 cell permeation study,
PTX-loaded SMEDDS along with GF120918 showed a four-fold increase
in apparent permeability, while DTX-loaded SMEDDS in combination
with GF120918 showed a nine-fold increase in permeability, as com-
pared to plain drug solution. Cell uptake studies on A549 cells were per-
formed with microemulsions formed from both SMEDDS formulations
loaded with rhodamine 123 dye and showed good uptake than plain
dye solution. Confocal laser scanning microscopic images further
88 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
conrmed the higher uptake of both SMEDDS formulations in the pres-
ence of GF120918.
7.3. P-gp circumvention by using novel peptide prodrug approach
Besides efux transporters, such as P-gp, a number of nutrient inux
transporters are also expressed on the cellular membranes. These nutri-
ent transporters are responsible for the inux of various nutrients and
drugs into various epithelial (enterocytes) and endothelial cells (e.g.
blood brain barrier) [152154]. Recently, peptide transporters (PEPT1
and PEPT2) have gained lot of attention among drug delivery scientists.
Intestinal peptide transporter especially PEPT1, has been a key target
protein for prodrug design. Several prodrugs have already been de-
signed such that the modied compounds become substrates of peptide
transporters leading to enhanced absorption of these compounds across
various physiological barriers [155157]. When a substrate binds to a
nutrient transporter it triggers a congurational change in the transport
protein as a result of which it is translocated across the membrane and
released into the cell cytoplasm. During this process the substrate is not
freely available in the inner leaet of the cell membrane and may avoid
recognition by P-gp as a substrate.
Jain et al. have reported that dipeptide conjugates of SQV circumvent
P-gp mediated efux which resulted in enhanced permeability across
MDCK-MDR1 cells [158]. Peptide transporters had been exploited in
this study since these transporters are robust and high capacity trans-
porters. Utilization of this transporter to ferry the dipeptide prodrugs
of SQV across the physiological barriers proved to be a highly effective
strategy. Similarly, Jain et al. have demonstrated that peptide prodrug
modication of SQV to valine-valine-saquinavir (Val-Val-SQV) and gly-
cine-valine-saquinavir (Gly-Val-SQV) can lead to an increased perme-
ability across rat jejunum [159]. Absorption rate constants in rat
jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be
14.1 3.4 103, 65.8 4.3 103, and 25.6 5.7 103 min1,
respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV rel-
ative to SQV can be attributed to their translocation by the peptide
transporter in the jejunum. Such increased permeability could be attrib-
uted partially to the peptide transporter mediated inux of these agents
and partially to circumvention of their P-gp mediated efux. Next, Jain
et al. demonstrated that the prodrugs have signicantly lower interac-
tion with MRP-2 relative to SQV [160]. Transepithelial transport of
Val-Val-SQV and Gly-Val-SQV across MDCKII-MRP2 cells exhibited an
enhanced absorptive ux and reduced secretory ux as compared to
SQV. Intestinal perfusion studies revealed that synthesized prodrugs
had higher intestinal permeabilities relative to SQV. They concluded
that peptide transporter targeted prodrug modication of MRP-2 sub-
strates lead to shielding of these drug molecules from MRP-2 efux
pumps. On the other hand, Agrawal et al. attempted to evade the rst-
pass metabolism and efux of LPV by synthesizing peptide prodrugs
valinevalinelopinavir (V-V-LPV) and glycinevalinelopinavir (G-V-
LPV) [161]. Both V-V-LPV and G-V-LPV displayed better solubility,
metabolism and intestinal permeability proles as compared with the
parent drug LPV. Since these prodrugs were substrates for peptide
transporters, they bypassed efux pumps and were capable of deliver-
ing more intact drug to improve oral bioavailability. Evasion of efux
also lowered the chance of resistance development on chronic LPV ex-
posure. Thus, efcient delivery of LPV resulted in enhanced therapeutic
efcacy which is of high clinical signicance in HAART. Rouquayrol et al.
examined the transepithelial transport of various protease inhibitor
(IDV, SQV, and NFV) conjugates using Caco-2 cell monolayers as
a model of the intestinal barrier [162]. They found that conjugation of
L-valine, L-leucine or L-phenylalanine (through their carboxyl) to the
protease inhibitors constitutes a most appealing alternative, which im-
proves their absorptive diffusion and reduces their recognition by efux
carriers. The 3- to 6-fold absorption enhancement resulting from the
conjugation of the protease inhibitors to the amino acids indicates
that potentially lower doses of protease inhibitors (as their conjugates)
can be administered orally to HIV (+) patients. Thus transporter
targeted prodrug modication of P-gp substrates could lead to shielding
of drug molecules from efux pump. This approach has high clinical sig-
nicance as it can aid in enhancing intestinal absorption and oral bio-
availability of poorly absorbed PIs and other P-gp substrates.
8. Current roadblocks in the clinical development of formulation
strategies
As highlighted in this article, the various formulation strategies for
BCS Class IV drugs can be explored for their successful delivery. The ben-
ecial properties of various strategies can be taken advantage of in
many ways for the design of impactful medicines and dosage forms. Sig-
nicant expansion of this sector is expected in the upcoming years as
more and more drugs in the development pipeline are added to the
portfolio of BCS Class IV drugs. However, development of a successful
BCS Class IV drug delivery has to face signicant challenges on their
way to the clinics as shown in Table 5.
First and foremost, the bottleneck in the translation of sophisticated
formulation strategies is the production of large-scale batches under
Good Manufacturing Practices (GMP) conditions. The various formulation
strategies discussed in the article are often developed, initially, in the lab
and there is a signicant gap between academic and industrial production
settings. Micrograms or milligrams of product are usually produced in ac-
ademic laboratories while grams or kilograms are necessary for pre-clin-
ical screening, clinical trials, and, ultimately, clinical use. As a general
notion scale up of any laboratory process is difcult; but scaling up nano-
particle based delivery systems production is even more challenging
[163165] because subtle variations in the manufacturing procedure
can signicantly alter the product characteristics, which ultimately deter-
mine the therapeutic outcome. In addition, the formulation of drug deliv-
ery systems is usually a multi-step process. At small scale, it is easy to
achieve reproducibility; however, at the larger, industrial scale, successive
operation streams become more complicated to control making batch-to-
batch reproducibility more difcult.
As for any pharmaceutical product, the implementation of a robust
quality control (QC) system is the key to ensure successful manufacturing.
Identication of the product's critical quality attributes will help set up
standards to determine when a batch meets or fails the appropriate re-
quirements and can be released or not. Incorporating a quality by design
approach upfront in product development will contribute to gain thor-
ough product and process knowledge and therefore dene solid QC sys-
tem [166]. Also, the development of tightly controlled and robust
manufacturing should be established as early as possible in the develop-
ment process to facilitate the identication of process parameters that
can be deleterious for the product and to ensure batch-to-batch reproduc-
ibility. This necessitates cooperation between R&D, QC and manufacturing
subdivisions [166]. The process variables can include environmental con-
ditions (temperature, pH, pressure), formulation parameters (character-
istics and origin of raw materials, ratio between the different
components, solvents used) or be related to the formulation operations
(time, speed, ow conditions) and/or the equipment used. The various
formulation strategies discussed in this article usually implements a num-
ber of operations (e.g., emulsication, sonication, centrifugation, extru-
sion, solvent evaporation, purication, lyophilization, and/or
sterilization) that all need to be optimized and controlled in series [22,
47]. The use of process optimization software such as Aspen, ProSim can
help identify the key parameters and optimize the manufacturing design,
even at an early stage of the development. In addition, quality by design
and extensive formulation testing under a variety of conditions can help
construct a comprehensive understanding of relations between
manufacturing conditions and nal product characteristics. The denition
of critical steps and variables will in turn facilitate scaling up the
manufacturing process [167169].
In addition, adequate analytical methods have to be developed and
validated to assess product quality at the intermediate and nal steps.
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
For example, lipid and nanoparticle based delivery systems require a
panel of analytics that are specic to this class of systems and unusual
in classical pharmaceutical development. The literature on their
manufacturing processes and industrial characterization methodologies
is limited [170172]. Nevertheless, some of the specic characterization
methods common to lipid and nanoparticle-based drug delivery systems
include dynamic light scattering (DLS) for size and size distribution mea-
surement, Zetasizer (Malvern) for zeta potential measurement, microsco-
py techniques (AFM, SEM, cryo-TEM) as a complementary size
determination method and/or for morphology. As the volume of
manufacturing grows, there will need to be further discussion among
the eld as to what tools or techniques are most appropriate for each
physico-chemical property, which software or data processing method
is most relevant to handle these data sets, and how these data should
be reported and communicated. In addition, these methods have to be
sensitive enough to detect potential small variations that could impact
the nal product quality and a major challenge will be the implementa-
tion of in-process controls along the manufacturing chain. Also, training
the personnel to the specicities, hurdles and challenges related to the
discussed formulation strategies is an important aspect of the success of
the manufacturing.
Furthermore, for systems that are intended for parenteral adminis-
tration, nding an adequate method of sterilization is a nal crucial
step of the manufacturing, and has to be validated on a case by case
basis, as the formulation can be impacted differently by the sterilization
method, depending on their components, formulation strategy and/or
method of preparation [172,173]. Gamma irradiation or autoclaving
can be damaging for certain formulation strategies and can affect prod-
uct characteristics. Sterile ltration of the nal product can be an alter-
native for systems with a size distribution below 0.22 m. If the size is
greater than the lter cut-off, loss of material might occur. Finally, asep-
tic technique is another possible option to consider, even though it can
be difcult to execute in the case of multi-steps processes [171,173].
Finally, it should be noted that most of the development of nanoparti-
cle-based delivery systems and investigational strategies involving the P-
gp inhibitors is still done in academic labs, start-ups or small and medium
enterprises (SME). The last two represent 75% of the 200 companies de-
veloping nanoparticle-based products. For these small entities, securing
investments is crucial to product development, which is a long and
cost-intensive process. In addition to the technical and manufacturing
challenges, they have to face the traditional reluctance of large pharma-
ceutical companies to nanoproducts and often have to provide stronger
preclinical data sets compared to small molecules on account of the
lower perceived chance of success and the technical complexity that can
discourage investors or large pharmaceutical companies to move for-
ward. The high cost associated with nanoparticle-based product develop-
ment favours the propensity toward specic therapeutic indications, such
as oncology where the market is huge and rare diseases where the regu-
latory barrier to entry is lower [174176].
9. Regulatory aspects for the development of BCS class IV delivery
systems
Several drug delivery systems of BCS Class IV drugs have been ap-
proved by the US Food and Drug Administration (FDA) and European
Medicines Agency (EMA) for a variety of therapeutic indications as
shown in Table 4. Signicant expansion of this sector is expected in up-
coming years however, the developers have to face signicant regulato-
ry challenges on their way to the clinics.
From a regulatory point of view, quality and safety issues associated
with preclinical and clinical studies are the key difculties likely to be
encountered in launching a lipid-based dosage form in the market,
and above all the manifestations of the therapeutic efcacy. The overall
drug stability and absence of immunological reactions to the oils or lipid
excipients have to be demonstrated. Sufcient details explaining the use
of lipid excipients and the types of dosage form, the drug release
89
mechanism, and their manufacture should be provided to persuade
the regulatory authorities of their acceptability [177]. Safety assessment
and the potential inuence of biopharmaceutical factors on the drug or
lipid excipients need to be explored. It may be difcult to predict in vivo
performances of a lipid dosage form based on in vitro results obtained
through conventional dissolution methods in view of the convoluted
GI processing of lipid formulations. More mechanistic studies should
be conducted to facilitate a better understanding of the pharmaceutical
characteristics of lipid formulations and interactions between lipid ex-
cipients, drug, and physiological environment. The lack of predictability
for product quality and performance may be due to the nature of empir-
ical and iterative processes traditionally employed [178].
With the aim of rationalizing the design of lipid formulation and to
better understand the fate of a drug after oral administration in a
lipid-based formulation, a consortium, composed of academics and in-
dustrial scientists, has been created (http://www.lfcsconsortium.org/).
The consortium sponsors and conducts research to develop in vitro
methods to assess the performance of LBDDS during dispersion and di-
gestion, which are critical parameters. The primary objective is to devel-
op guidelines that rationalize and accelerate the development of drug
formulations through the identication of key performance criteria
and the validation and eventual publication of universal standard tests
and operating procedures [179]. In order to establish approved guide-
lines, appropriate dialogue with pharmaceutical regulatory bodies
(FDA, EMEA) is also foreseen.
More consideration needs to be paid to the characteristics of various
lipid formulations available, so that guidelines and experimental
methods can be established that allow identication of candidate for-
mulations at an early stage. Methods need to be sought for tracking
the solubilization state of the drug in vivo, and there is a need for in
vitro methods for predicting the dynamic changes, which are expected
to take place in the gut. Attention to the physical and chemical stability
of drugs within lipid systems and the interactions of lipid systems with
the components of capsule shells will also be required. Whilst these
present challenges there is a great potential in the use of lipid formula-
tions. The priority for future research should be to conduct human bio-
availability studies and to conduct more basic studies on the
mechanisms of action of this fascinating and diverse group of
formulations.
Pharmaceutical co-crystals have not yet been ofcially addressed
from the perspective of generic regulatory approval. In some respects,
co-crystals are intermediate between hydrates/polymorphs (which
are ANDA-eligible) and salts (which, in general, are not). Unlike poly-
morphs, which generally speaking contain only the API within the crys-
tal lattice, co-crystals are composed of an API with a neutral guest
compound (also referred to as a conformer) in the crystal lattice [180].
Similarly, unlike salts, where the components in the crystal lattice are
in an ionized state, a co-crystal's components are in a neutral state
and interact via non-ionic interactions. Like hydrates, co-crystals are
non-ionic supramolecular complexes; but like salts, co-crystals involve
complexation with substances of greater potential toxicity than water
[181]. At present no formal regulatory policy exists governing the clas-
sication of pharmaceutical co-crystals. In response to the need for reg-
ulatory guidance, the Ofce of Pharmaceutical Science Centre for Drug
Evaluation and Research (CDER) at the FDA has issued guidance for
pharmaceutical co-crystals [182]. This guidance provides the current
thinking on the appropriate classication of co-crystal solid-state
forms, the data that should be submitted to support the classication,
and the regulatory implications of such a classication.
Similarly, for nanoparticle-based delivery systems there are current-
ly no specic requirements from the regulatory agencies (FDA and
EMA) for the preclinical and clinical testing, only reection papers pro-
viding guidelines on the pharmaceutical development of a specic type
of nanoparticle-based drug delivery systems have been published [183],
and to date the evaluation process follows a similar path as for small-
molecules drugs. The development of a new drug starts with preclinical
90 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195

Table 4
FDA and EMA approved BCS Class IV drug products and their therapeutic indications.

Authorized
BCS class IV drug Brand Company Formulation strategy markets Indication

Cyclosporine Neoral Novartis SMEDDS US Organ transplantation, rheumatoid arthritis, psoriasis

Sandimmune Novartis SMEDDS US Organ transplantation
Gengraf Abbott SMEDDS US Organ transplantation
Panimun Bioral Panacea Biotec SMEDDS US Organ transplantation
Restatis Allergan Anionic microemulsion US Keratoconjunctivitis sicca (dry eye syndrome)
Ikervis Santen Pharmaceuticals Cationic microemulsion Europe Keratoconjunctivitis sicca (dry eye syndrome)
Aprepitant Emend Merck & Co. Nanocrystals US, Europe Chemotherapy induced nausea and vomiting
(suspension)
Saquinavir Fortavase Hoffmann La Roche, Inc. SMEDDS US HIV infection
Invirase Hoffmann La Roche, Inc. SMEDDS US HIV infection
Ritonavir Norvir Abbott SMEDDS US HIV infection
Ritonavir; Kaletra Abbott SMEDDS US HIV infection
Lopinavir
Amphotericin B AmBisome Astellas Liposome US Fungal infections, leishmaniasis
Abelcet Sigma-tau Lipid complex US Fungal infections
Paclitaxel Taxol HQ Speciality Pharma Micelles US Breast cancer, lung cancer, ovarian cancer
Abraxane Abraxis BioScience Albumin nanoparticles US, Europe Mestatic breast cancer
Docetaxel Taxotere Sano aventis Micelles US, Europe Breast cancer, prostate cancer, non-small cell lung cancer
Docefrez Sun Pharma Micelles US, Europe Breast cancer, prostate cancer, non-small cell lung cancer

*The list provided above is restricted to the formulation strategies discussed in this article and does not take into account the conventional dosage forms of BCS Class IV drugs approved by
FDA and EMA.

testing followed by the submission of an Investigational New Drug
(IND) application in order to initiate the clinical trial, which is organized
in three phases (Phase I, II and III clinical trials). Only for approximately
5% of the initial tested entities (including all INDs, nanoparticle based
and non-nanoparticle based) will the clinical evaluation procedure re-
sult in the submission of a New Drug Application (NDA) and, ultimately,
market authorization. Each new nanoparticle-based drug delivery sys-
tem has to follow the complete evaluation process, even if the active
pharmaceutical ingredient (API) alone has been in clinical use for
many years [176]. The pharmaceutical regulatory environment, the
health care strategies, the demographics and the wide economic envi-
ronment affect the competitive nanomedicine-related drug market ap-
proval. Despite all difculties along the development process, a
considerable number of nanoparticle-based drug delivery systems are
already in the market, approved by the FDA, EMA or foreign equivalent
[184].
The FDA recognizes that nanotechnology is an emerging technol-
ogy that has the potential to be used across the full spectrum of FDA-
regulated products, including drugs, biological products, and medi-
cal devices. Over the past several years, the FDA has taken multiple
steps to help ensure the responsible development of nanotechnology
products. In 2011, the FDA issued a draft guidance for industry enti-
tled Considering Whether an FDA regulated Product Involves the
Application of Nanotechnology to present its current thinking on
nanotechnology and to seek public comment [185,186]. As noted in
that draft guidance, the FDA has not adopted a regulatory denition
of nanotechnology or related terms. The FDA's Centre for Drug Eval-
uation and Research provided an update on its ongoing work related
to the use of nanotechnology in drug products to the Advisory Com-
mittee for Pharmaceutical Science and Clinical Pharmacology in Au-
gust 2012 [187]. As explained in this update, the FDA evaluated its
existing regulatory review processes for drug products and deter-
mined that current procedures are adequate to identify and address
the potential risks associated with the use of nanomaterials in drug
products. Certain areas were identied for improvement, including
the need for increased regulatory science research and the training
of review staff. The FDA also established specic policies and proce-
dures for use by internal reviewers of human drug and animal drug
submissions. As noted in the draft guidance documents, the FDA en-
courages industry to consult early with the agency to address ques-
tions related to the safety, effectiveness, or regulatory status of
nanotechnology products. These early consultations afford an
opportunity to clarify the manufacturer's obligations and discuss
methodologies and data needed to meet those obligations [186].
Not all excipients are inert substances, and some may be toxic at
augmented concentrations. In the Code of Federal Regulations, the
FDA has published a list of substances that are generally recognized as
safe (GRAS). Apart from this, it also maintains a list of inactive ingredi-
ents for excipients entitled inactive ingredient database (IID) that are
approved and can be incorporated in marketed products. This guide
provides the list of maximum amount allowed for excipients, which
can be used for a specic route of administration. Once an inactive in-
gredient has been approved for a product through a particular route of
administration, it can be used in any new drug formulation and does
not require extensive review. The formulator can take the information
from both GRAS and IIG when developing a new formulation. Currently,
the FDA does not have any process or mechanism to evaluate the safety
of excipients individually. Instead, the excipients are reviewed and ap-
proved as components of the drug or biological product in the applica-
tion. Since excipients play an integral part in the formulation and cannot
be reviewed separately from the drug formulation, the regulatory pro-
cess is appropriate from a scientic standpoint [179].
10. Conclusion
The formulation of drugs is carried out with the principle objective of
enhancing their bioavailability. The BCS class IV drugs which exhibit
poor solubility and membrane permeability are challenging for the for-
mulation scientist with regard to bioavailability and exhibiting opti-
mum therapeutic potential. The various formulation development
strategies highlighted in this review like lipid based delivery systems,
polymer based nanocarriers, crystal engineering (nanocrystals and co-
crystals), liquisolid technology, self-emulsifying solid dispersions can
be explored and experimented further to increase their commercial ap-
plicability. For example, the recent advances in LDBBS have led to the
successful commercialization of few BCS class IV [saquinavir
(Fortovase), ritonavir (Norvir)] lipid-based formulations. Similarly,
the advent of novel scalable technologies for the production of
nanocrystals has eased the journey of BCS Class IV drug aprepitant
(Emend) from researcher's bench side to clinic. The progressive eluci-
dation of the remaining strategies and their mechanisms involved in
improving the bioavailability of BCS Class IV drugs is yet to be addressed
in depth to advance the technology. Further research has to be carried
out regarding the design of a proper in vivo model to correlate the
 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
Table 5
The advantages and bottlenecks to commercialization of BCS Class IV drug formulation strategies.
Formulation
strategy Advantages
Lipid based Proven commercial and pharmaceutical benet for compounds
drug delivery such as CyA (Sandimmune) and the HIV protease inhibitors
systems (Kaletra)
Ability to encapsulate high drug content (compared to other car-
rier systems e.g. polymeric nanoparticles)
The feasibility of carrying both lipophilic and hydrophilic drugs
Most of the lipids used are biodegradable, and as such they have
excellent biocompatibility, are non-toxic, non-allergenic and
non-irritating
Formulated by water-based technologies and thus can avoid or-
ganic solvents
Easy to scale-up and sterilize and are less expensive than
polymeric/surfactant based carriers
Easy to validate.
Polymeric Proven commercial and pharmaceutical benets for a few formu-
nanocarriers lation strategies like polymeric micelles (Taxotere, Taxol)
Increased solubilization potential and superior encapsulation
Chemical versatility of materials eligible for nanomedicines
Versatile routes of administration
P-gp inhibition Proven commercial and pharmaceutical benets for formulation
approach strategy dealing with co-administration of P-gp inhibitor
(Kaletra)
Versatile routes of administration
Self-emulsifying Availability of newer thermo-softening surface active and self--
solid emulsifying excipients
dispersions Can be lled directly into hard gelatin capsules in molten state,
obviating the requirement of milling and blending prior to lling
Industrially feasible manufacturing techniques available like hot
melt extrusion
Liquisolid Industrially feasible manufacturing techniques available
technology
Nanocrystals Proven commercial and pharmaceutical benets for aprepitant
(Emend)
Versatile routes of administration
Industrially feasible manufacturing techniques available
Adept to convenient sterilization techniques a key driver for de-
velopment of parenteral formulations
Incorporation of appropriate stabilizers followed by drying
(freeze/spray) can ensure long term stability
Opportunity to produce generic versions of presently available
costly drugs
Co-crystals Creates intellectual property for a new patent of an API for ex-
tending their life cycle
Versatile routes of administration
data obtained in vitro studies to the actual in vivo experience. In conclu-
sion, a number of delivery options have been developed for improving
the physicochemical and pharmacokinetic behaviours of BCS Class IV
drugs in academic and industrial research. A better understanding of
the physicochemical properties of drug substances and the limitations
of each delivery option would lead to efcient formulation development
91
Bottlenecks to commercialization
Insufcient drug solubility in the excipient matrix, which precludes administration
of the entire dose in a single oral capsule
Physical and chemical stability of drugs solubilized in lipid excipients have not yet
been adequately addressed
Lipid excipients themselves may be subject to physical changes or chemical degra-
dation over time
The excipients need to be used in their regulatorily accepted concentrations. If
distinctly higher concentrations need to be used, a limited toxicity study should be
performed to prove the safety of the excipients at that concentration.
Lack of standard nano nomenclature: imprecise denition for nanomedicines
Lack of precise control over nanoparticle manufacturing parameters and control
assays
Currently used compounds/components for synthesis of nanoparticle based deliv-
ery systems often pose problems for large scale good manufacturing (cGMP) pro-
duction
Lack of quality control: issues pertaining to separation of undesired nanostructures
(byproducts, catalysts, starting materials) during manufacturing
Scalability complexities: enhancing the production rate to increase yield
Reproducibility issues: control of particle size distribution and mass
High fabrication costs
Lack of rational pre-clinical characterization strategies via multiple techniques
Biocompatibility, bio distribution and toxicity issues: lack of knowledge regarding
the interaction between nanoparticles and bio surfaces/tissues
Consumer condence: public's general reluctance to embrace innovative medical
technologies without clearer safety or regulatory guidelines
Relative scarcity of venture funds
Ethical issues and societal issues are hyped up by the media
Big pharma's continued reluctance to seriously invest in nanomedicine
Patent review delays, patent thickets, and issuance of invalid patents by the U.S.
Patent and Trademark Ofce
Regulatory uncertainty and confusion due to baby steps undertaken by U.S. Food
and Drug Administration: a lack of clear regulatory/safety guidelines
Highly experimental approach limited to academic lab settings and yet to be ex-
plored
Biocompatibility, toxicity data related to various P-gp inhibitors is limited
Scalability complexities: enhancing the production rate to increase yield
High fabrication cost
Physical and chemical stability of drugs solubilized in lipid excipients have not yet
been adequately addressed
Lipid excipients themselves may be subject to physical changes or chemical degra-
dation over time
Regulatory scenario (NDA application and review process) is still obscure and the
regulatory agencies need to shed some light on it
Maintenance of particle size, size distribution and polymorphism poses a particu-
larly big challenge
Strategic control of crystal morphology and shape is by and large an expertise of
precipitation techniques (bottom up approaches) and is a face of research which is
yet to be explored effectively
The lab scale equipment presents higher surface area to volume ratios while the
production level equipments presents a higher volume to surface ratio. This differ-
ence is one of the considerable factors which slows down the processing during
scale up.
Large scale equipment consumes more time when compared to lab equipment.
These long processing times are likely to lead to adverse conditions such as
adsorption, precipitation, viscosity alterations and may affect the mass and mo-
mentum transfer rates, the shear rate and stress factors
Regulatory scenario (NDA application and review process) is still obscure and the
regulatory agencies need to shed some light on it
for these highly notorious BCS class IV drugs. Also, before commerciali-
zation of the various formulations strategies, it will be essential to per-
form pharmacoeconomic studies to demonstrate both social and
economic added value of these novel products when compared with
established treatments. Also, in case of formulations pertaining to anti-
cancer agents the important indicators such as increment in QALY
92 R. Ghadi, N. Dand / Journal of Controlled Release 248 (2017) 7195
(quality-adjusted life expectancy years) or costs associated to future
consecutive hospitalizations should be considered in the development
of these new sophisticated formulations. From a regulatory perspective
also, the scenario is obscure and the various regulatory agencies need to
throw light on the various guidelines to be adhered, for the successful
commercialization of the novel formulation strategies.
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