Drug Development and Industrial Pharmacy

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Review and analysis of FDA approved drugs using

lipid-based formulations

Ronak Savla, Jeff Browne, Vincent Plassat, Kishor M. Wasan & Ellen K. Wasan

To cite this article: Ronak Savla, Jeff Browne, Vincent Plassat, Kishor M. Wasan & Ellen K.
Wasan (2017) Review and analysis of FDA approved drugs using lipid-based formulations, Drug
Development and Industrial Pharmacy, 43:11, 1743-1758, DOI: 10.1080/03639045.2017.1342654

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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 2017
VOL. 43, NO. 11, 1743–1758
https://doi.org/10.1080/03639045.2017.1342654

REVIEW ARTICLE

Review and analysis of FDA approved drugs using lipid-based formulations

Ronak Savlaa , Jeff Browneb, Vincent Plassatc, Kishor M. Wasand and Ellen K. Wasand
a
Catalent Pharma Solutions, Somerset, NJ, USA; bCatalent Pharma Solutions, St. Petersburg, FL, USA; cCatalent Pharma Solutions, Beinheim,
France; dCollege of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada

ABSTRACT ARTICLE HISTORY

Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement tech- Received 27 March 2017
nologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While Revised 12 May 2017
researchers have used several general rules of thumb to predict which compounds are likely to benefit Accepted 6 June 2017
from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that
KEYWORDS
these rules of thumb focus in different areas and are used independently of each other. The Lipid-based drug delivery
Developability Classification System attempts to link physicochemical characteristics with possible formula- systems; developability
tion strategies. Although it provides a starting point, the formulator still has to empirically develop the for- classification system;
mulation. This article provides a review and quantitative analysis of the molecular properties of these physicochemical properties;
approved drugs formulated as lipid systems and starts to build an approach that provides more directed biopharmaceutics; clinical
guidance on which type of lipid system is likely to be the best for a particular drug molecule. translation

Introduction There are numerous ‘Rules’ and ‘Classification Systems’ avail-

An increasing percentage of drug molecules in pharma develop-
ment pipelines can be classified according to the
Biopharmaceutics Classification System (BCS) as Class II com-
pounds (compounds having good permeability but poor solubil-
ity). Additionally, a considerable percentage of today’s pipeline
molecules are both poorly soluble and poorly permeable (BCS
Class IV). These newer drug molecules are discovered and opti-
mized through relatively novel technologies such as high-through-
put screening, fragment-based drug discovery, or computational
modeling. While, they demonstrate superior potencies and specif-
icities compared to their predecessors, many also possess inherent
challenges in terms of oral delivery [1]. The low solubility and
poor permeability of these compounds translates into suboptimal
patient outcomes due to poor oral bioavailability and variable
pharmacokinetics.
Simple formulation approaches (conventional tablets or pow-
der in capsule) are not enough to address these issues.
Bioavailability enhancement technologies (LBDDS, solid amorph-
ous dispersions, API salt formation, or API particle size reduction)
have been developed to address the issue of low solubility by
improving the dissolution rate and/or the apparent solubility of
these drug molecules. A molecule’s dissolution rate can be
enhanced by increasing the surface area (particle size reduction)
or by stabilizing the amorphous form of the drug in a polymer
(hot melt extrusion and spray drying). Lipid excipients and sur-
factants can be used to present and maintain the drug molecule
in solution form both pre- and post-administration. Of the bio-
availability enhancing technologies, LBDDS are the most well
studied and well established as a formulation approach for
addressing solubility and/or permeability issues [2]. Therefore, we
focus our efforts in this review on LBDDS.
able to formulation scientists for prediction of in vivo perform-
ance. Formulators are working to create in silico tools and using
classification systems coupled with in vitro dissolution tests in
biorelevant media for predicting in vivo outcomes during the
formulation design and screening phases of product develop-
ment. While predicting the self-emulsification behavior of LBDDS
excipient combinations is reasonable, formulators lack the in
silico tools to accurately predict how specific drugs will behave
in specific formulations [3]. The aim of this study was to ana-
lyze the physicochemical characteristics of these drugs and clas-
sify them according to the different systems to see what, if any,
correlations exist between physicochemical properties and classi-
fication systems or between classification systems. Furthermore,
this exercise could validate the belief that simple physicochemi-
cal properties are insufficient for de novo LBDDS formulation
design and highlight key areas for the focus of future studies.
We first examined U.S. Food and Drug Administration (FDA)
approved drugs (based on NDA approvals) that have been for-
mulated using LBDDS. We focused only on approved drugs with
the rationale that they were robust enough to progress through
all phases of drug development and receive FDA approval. Next,
we classified the drugs using the Lipid Formulation Classification
System (LFCS). We calculated physicochemical properties that
may influence the choice of LBDDS used for formulation and
used these properties to group the drugs into the BCS and
Developability Classification System (DCS). Based on the these
calculations and classifications, we sought any correlations that
would provide guidance as to what types of drug molecules are
good fit for LBDDS and what specific type of LBDDS. We con-
clude by proposing therapeutic categories, compound categories,
and other untapped areas that can benefit from the advantages
offered through the use of LBDDS.

CONTACT Ronak Savla ronak.savla@catalent.com Scientific Affairs Manager, Catalent Pharma Solutions, 14 Schoolhouse Road, Somerset, NJ 08873, USA
Supplemental data for this article can be accessed here.
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
1744 R. SAVLA ET AL.
FDA approved orally administered products that use
lipid formulations
The increasingly overall water-insoluble nature of drug candidates
has been accompanied by the increased use of solubilization tech-
nologies for FDA approved drugs. A recent analysis revealed that

6% of all approved new molecular entities from 1975 to 2013 uti-
lized solubilization technologies [2]. The same analysis showed that
LBDDS are the most widely used solubilization technology. An ana-
lysis by Strickley in 2007 estimated that LBDDS oral drug products
account for 2–4% of all commercially available drug products [4].
A review of the literature and drug databases (DailyMed,
DrugBank, and Drugs@FDA) revealed 27 unique drug molecules
that were FDA approved as 36 different oral LBDDS. (Table 1)
[5–7]. A few of the approved drugs have been discontinued.
According to the Federal Register, none have been for safety or
efficacy reasons. The three HIV protease inhibitor formulations
were replaced by newer formulations. Saquanavir (FortovaseV) was
R our review, there were 16 drugs that utilized Type I LBDDS, 3
discontinued because a film-coated tablet dosage form with a
lower pill burden was introduced. Ritonavir/lopinavir (KaletraV)
R TYPE IV (Table 1). Type I lipid formulations contain oils that need
was replaced by a solid dispersion formulation, which does not
require refrigeration, had higher drug loading per dosage unit,
and reduced daily pill burden. Amprenavir (AgeneraseV) was suc-
R their early use), and often the LFCS formulation type first
ceeded by a pro-drug, fosamprenavir.
Analysis of these approved products can offer insights to those
physicochemical characteristics of a drug molecule that make
LBDDS an attractive formulation option. As seen in Table 1 and
Figure 1, there is a wide diversity, in terms of pharmacological
class and chemical structures, of approved drugs that have been
formulated using lipid systems. In short, LBDDS are a versatile plat-
form which can benefit a wide range of drug molecules. One rea-
son for the versatility is the range of excipients used in LBDDS.
The major categories of LBDDS excipients are lipids, water insol-
uble surfactants (HLB <12), water soluble surfactants (HLB >12),
and hydrophilic cosolvents. The choice and relative percentage of
excipients in LBDDS influence drug solubility, LBDDS dispersability,
and formulation properties. This in part explains its historic and
current popularity for formulating poorly soluble and/or perme-
able drugs.
The interest and growth in lipid based systems can be traced
to several findings and developments. Unless they are in solution
following oral administration, poorly soluble drugs have poor
absorption, variable pharmacokinetics, and tend to experience sig-
nificant positive food effect. Lipid formulations partially improve
the solubility of drugs by stimulating the same physiologic events,
although to a lower magnitude, as administration of drugs with a
fatty meal [8].
The soft capsule has become the most common dosage form
for the administration of lipid formulations (Table 1). Soft capsules
are the utilized dosage form for 25 of 36 lipid formulations, 6
products are hard shell capsules, and 5 are oral solutions, The
advantages of soft capsules have been extensively documented
elsewhere [9,10]. The introduction of NeoralV in 1995 is a widely
R
cited example illustrating how a self-emulsifying system (the first
IIIA LFCS product) can address clinical concerns and result in a
product providing a better treatment for patients. There were sev-
eral approved LBDDS on the market prior to 1995 (NDA Approval
Date of Neoral) and many more that followed (Table 1). Early lipid
formulations consisted of pure oils (LFCS Class I and some Class II).
Designing lipid formulations
Unlike other formulation approaches, the absorption process of
LBDDS is complex and dynamic. The formulation design
considerations have clear and direct implications on drug absorp-
tion in vivo. The formulator needs to possess knowledge about
physical chemistry, thermodynamics, and gastrointestinal physi-
ology to ensure that drug precipitation does not occur in the
gastrointestinal tract following dispersion and/or digestion of the
formulation. While most LBDSS are designed to solubilize the drug
in the formulation prior to administration, endogenously, the drug
in the formulation matrix experiences environmental transition
from a solution state in formulation, to an emulsified state due to
dispersion upon initial contact with GI fluid, and finally a mixed
micellar phase after lipid digestion.
LBDDS is an umbrella term for numerous delivery systems [oil
solutions, emulsions, dispersions, micelles, self-emulsifying drug
delivery systems (SEDDS), and self-microemulsifying drug delivery
systems (SMEDDS)] and can be broadly classified into four types
according to the LFCS proposed by Pouton (Table 2) [11,12]. In
drugs formulated as Type II, 5 drugs as Type III, and 2 drugs as
to be digested in order to form mixed micelles. Type I formula-
tions are typically biocompatible and simple (thereby explaining
attempted if the dose of API can be fully solubilized in the fill. The
vitamin D analogs and retinoids are formulated as Type I LBDDS
LFCS Type II lipid formulations consist of mixtures of lipids and
water- insoluble surfactants (HLB <12). They self-emulsify into
crude oil-in-water (o/w) emulsions usually with energy input. LFCS
Type III lipid formulations contain water- soluble surfactants (HLB
>12) and co-solvents. These formulations spontaneously self-emul-
sify upon contact with an aqueous environment. They are com-
monly referred to as self-emulsifying drug delivery systems
(SEDDS) when dispersion droplet size is >200 nm or as self-micro
emulsifying drug delivery systems (SMEDDS) when dispersion
droplet size is <200 nm. Finally, LFCS Type IV lipid formulations do
not contain oil and are based on water-soluble surfactants and co-
solvents. The fine dispersions formed when in contact with an
aqueous environment translates to rapid drug release and absorp-
tion. The solvent capacity of these systems for maintaining a
poorly soluble compound is usually limited which often results in
the precipitation of the compound in the GI tract.
Excipient use in LBDDS
LBDDS include a wide range of excipients. Some considerations
that a formulator must consider include: regulatory acceptance,
safety, solvent capacity, dispersion characteristics (usually in biore-
levent media), digestability, interactions with efflux and metabol-
ism processes (P-gp and CYP), stability, purity and amount/type of
impurities, compatibility with the capsule, and cost. Excipient
safety is a major consideration since the vast majority of FDA
approved drugs using a LBDDS are intended for chronic use.
Lipids
By definition, LBDDS typically contain drug dissolved or suspended
in oils (triglycerides or mixed glycerides). Of the 36 FDA approved
formulations, 8 formulations did not contain oils and were classi-
fied as Classes III or IV according to the LFCS. Early lipid formu-
lated drugs contain almost exclusively oils. Ritonavir (NDA
approval: 1996) was the first LBDDS formulated drug that did not
contain oil (Table 1). The biggest advantage of using oil is that
lipophilic drugs are solubilized and dissolution of the drug within
the GI tract is not required. Once digested, there are higher odds
Table 1. FDA approved drugs utilizing lipid systems.
Biopharmace- Lipid formula-
New drug utics classifica- Developability tion classifica- Oils: triglycerides or Water-insoluble Water-soluble
Molecule/trade application tion system classiciation tion system Drug Dosage form, mixed mono and surfactants surfactants (HLB Hydrophilic
name (NDA) Year (BCS) system (LFCS) category Dose strength diglycerides (HLB <12) >12) cosolvents
Ergocalciferol 1941 3 IIb I Vitamin D Vitamin D Resistant LFHS, 50,000 IU Soybean oil
V R
(Drisdol ) analog Rickets: 12,000 to
500,000 IU units daily.
Hypoparathyroidism:
50,000 to 200,000 IU
units daily concomi-
tantly with calcium lac-
tate 4 g, six times per
day
Calcitriol 1978 2/4 I I Vitamin D 0.25–0.5 lg qd Soft gelatin cap- Fractionated triglycer-
V R
(Rocaltrol ) analog sule, 0.25 and ides of coconut oil
0.5 lg
Valproic acid 1978 1 I I Anti-epileptic 10–15 mg/kg/day Soft gelatin cap- Corn oil
RV
(Depakene ) sule, 250 mg
Isotretinoin 1982 2 IIb I Retinoid 0.5–2 mg/kg in 2 divided Soft gelatin cap- Beeswax, hydrogen-
V R
(Accutane ) doses sule, 10, 20, ated soybean oil
Discontinued 40 mg flakes, hydrogen-
ated vegetable oil,
soybean oil
Cyclosporin A 1983 2 IIb II Calcineurin 2–10 mg/kg/day in two Oral solution, Olive oil polyoxyethylated Ethanol 12.5%
V R
(Sandimmune ) inhibitor divided doses 100 mg/mL oleic
glycerides
Dronabinol 1985 2/4 IIb I Cannabinoid 2.5–20 mg/day Soft gelatin cap- Sesame oil
V R
(Marinol ) sule, 2.5, 5,
10 mg
Clofazimine 1986 2 I Antileprosy 100 mg/day Soft gelatin cap- Beeswax
V R
(Lamprene ) sule, 50 and
100 mg 100 mg
Discontinued
Cyclosporin A 1990 2 IIb II Calcineurin 2–10 mg/kg/day in 2 div- Soft gelatin cap- Corn oil Linoleic Ethanol 12.7%
V R
(Sandimmune ) inhibitor ided doses sule, 25 and macroglycerides
100 mg
Ranitidine 1994 3 H2-receptor 150 mg bid or 300 mg qd Soft gelatin cap- Medium chain Mixed glycerides of
R
V
(Zantac ) antagonist sule, 150 and triglycerides long chain fatty
Discontinued 300 mg acids (Gelucire
33/01)
Cyclosporin A 1995 2 IIb IIIA/IIIB Calcineurin 2–10 mg/kg/day in two Soft gelatin cap- Corn oil mono-di- Polyoxyl 40 Ethanol 11.9%,
VR
(Neoral ) inhibitor divided doses sule, 10, 25, 60, triglycerides hydrogenated glycerol,
100 mg castor oil propylene
glycol
Cyclosporin A 1995 2 IIb IIIA/IIIB Calcineurin 2–10 mg/kg/day in 2 div- Oral solution, Corn oil-mono-di- Polyoxyl 40 Ethanol 11.9%,
VR
(Neoral ) inhibitor ided doses 100 mg/mL triglycerides hydrogenated propylene
castor oil glycol
Tretinoin 1995 IIb I Retinoid 45 mg/m2/day as two Soft gelatin cap- Beeswax, hydrogen-
V R
(Vesanoid ) evenly divided doses sule, 10 mg ated soybean oil
Discontinued flakes, hydrogen-
ated vegetable oil,
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY

soybean oil
R
V
Ritonavir (Norvir ) 1996 4 IIb IIIA Protease 600 mg bid (adults) Soft gelatin cap- Oleic acid Polyoxyl 35 castor Ethanol
inhibitor sule, 100 mg oil
(continued)
1745
Table 1. Continued
1746

Biopharmace- Lipid formula-

New drug utics classifica- Developability tion classifica- Oils: triglycerides or Water-insoluble Water-soluble
Molecule/trade application tion system classiciation tion system Drug Dosage form, mixed mono and surfactants surfactants (HLB Hydrophilic
name (NDA) Year (BCS) system (LFCS) category Dose strength diglycerides (HLB <12) >12) cosolvents
Saquinavir 1997 4 IIb Protease 1200 mg bid without Soft gelatin cap- Medium chain mono-
V R
(Fortovase ) inhibitor ritonavir; 1000 mg bid sule, 200mg and di-glycerides
Discontinued with ritonavir
Progesterone 1998 2 IIb I (susp) Hormone 200 mg qd Soft gelatin cap- Peanut oil
R
R. SAVLA ET AL.

V
(Prometrium ) sule, 100 and
200 mg
Amprenavir 1999 2 IIb IV Protease 1200 mg bid or 1200 mg Soft gelatin cap- Vitamin E TPGS PEG400, propyl-
V R
(Agenerase ) inhibitor qd with ritoanvir sule, 50 mg ene glycol
discontinued
Bexarotene 1999 IIb IV Retinoid 300-750 mg qd Soft gelatin cap- Polysorbate 20 PEG400
V R
(Targretin ) sule, 75 mg

Doxercalciferol 1999 2/4 I I Vitamin D Determined by target Soft gelatin cap- Coconut oil Alcohol
V R
(Hectorol ) analog intact parathyroid hor- sule, 0.5, 1,
mone level (iPTH) 2.5 mcg
Usually 10 mcg three times
weekly at dialysis
Sirolimus 1999 IIa III mTOR kinase 6 mg loading dose fol- Oral solution, Phosphatidylcholine, Polysorbate 80 1.5–2.5% etha-
V R
(Rapamune ) inhibitor lowed by 2 mg qd 1 mg/mL mono- and di-glyc- nol, propyl-
erides, soy fatty ene glycol
acids, ascorbyl
palmitate
Cyclosporin A 2000 2 IIb IV Calcineurin 1:1 dose conversion from LFHS, 25, 50, Polysorbate 80, Propylene gly-
V R
(Gengraf ) inhibitor Sandimmune 100 mg Polyoxyl 35 col, alcohol
2.5 mg/kg/day in two div- castor oil 12.8% v/v
ided dose (RA and
Psoriasis)
Cyclosporin A 2000 2 IIb IV Calcineurin 1:1 dose conversion from Oral solution, Polyoxyl 40 Propylene
V R
(Gengraf ) inhibitor Sandimmune 100mg/ml hydrogenated glycol
2.5 mg/kg/day in two div- castor oil,
ided dose (RA and Polysorbate 80
Psoriasis)
Ritonavir/lopinavir 2000 4 III Protease 400/100 mg (3 Soft gelatin Soft gelatin cap- Oleic acid Polyoxyl 35 castor Propylene
R
V
(Kaletra ) inhibitors capsule) bid sule, 133.3 mg oil glycol
Discontinued 800/200 mg (6 Soft gelatin lopinavir/
capsule) qd 33.3 mg
ritonavir
Dutasteride 2001 2/4 IIa I 5 alpha-reduc- 0.5 mg qd Soft gelatin cap- Mono-di-glycerides of
V R
(Avodart ) tase sule, 0.5 mg caprylic/capric acid
inhibitor
Isotretinoin 2003 (ANDA) 2 IIb Retinoid 0.5–1 mg/kg/day given in LFHS, 20, 30, Hydrogenated vege- Polysorbate 80
V R
(Claravis ) two divided doses 40 mg table oil, soybean
oil, white wax
Omega-3-acid ethyl 2004 I Fish oils for 4 g qd or 2 g bid Soft gelatin cap- Soybean oil
V R
esters (Lovaza ) lipid sule, 1 g
regulation
Tipranavir 2005 4 IIb IIIA Protease 500 mg with 200 mg Soft gelatin cap- Mono-/di-glycerides of Polyoxyl 35 castor Ethanol, propyl-
V R
(Aptivus ) inhibitor ritonavir qd (adults) sule, 250 mg caprylic/capric acids oil ene glycol
14 mg/kg with 6mg/kg
ritonavir (pediatric)
(continued)
Table 1. Continued
Biopharmace- Lipid formula-
New drug utics classifica- Developability tion classifica- Oils: triglycerides or Water-insoluble Water-soluble
Molecule/trade application tion system classiciation tion system Drug Dosage form, mixed mono and surfactants surfactants (HLB Hydrophilic
name (NDA) Year (BCS) system (LFCS) category Dose strength diglycerides (HLB <12) >12) cosolvents
Tipranavir 2005 4 IIb IV Protease 500 mg with 200 mg Oral solution, Vitamin E TPGS PEG 400,
V R
(Aptivus ) inhibitor ritonavir qd (adults) 100 mg/ml propylene
14 mg/kg with 6mg/kg glycol,
ritonavir (pediatric) water
Paricalcitol 2005 4 IIa I Vitamin D 1 or 2 mcg daily Soft gelatin cap- Medium chain trigly- Alcohol
V R
(Zemplar ) analog 2 or 4 mcg three times a sule, 1 and cerides fractionated
week 2 mcg from coconut oil or
palm kernel oil
Lubiprostone 2006 2/4 I I Chloride chan- 24 mcg bid for chronic Soft gelatin cap- Medium chain
V R
(Amitiza ) nel activator idiopathic constipation sule, 8 and triglycerides
and opioid-induced 24 mcg
constipation
8 mcg bid for irritable
bowel syndrome with
constipation
Fenofibrate 2006 2 IIb III Peroxisome 50 to 150 mg daily HSC, 50 and Gelucire 44/14
V R
(Lipofen ) proliferator 150 mg (lauroyl mac-
activated rogol glyceride
receptor a type 1500)
(PPARa)
acvtivator
Topotecan HCl 2007 1 I I Topoisomerase 2.3 mg/m2/day orally once LFHS, 0.25 and Hydrogenated vege- Glyceryl
V R
(Hycamtin ) inhibitor daily for 5 consecutive 1 mg base table oil monostearate
days repeated every 21
days
Loratadine 2008 2 Antihistamine 10 mg qd Soft gelatin cap- Caprylic/capric Polysorbate 80
R
(ClaritinV) sule, 10 mg glycerides
Isotretinoin 2012 2 IIb Retinoid 0.5–1 mg/kg/day given in LFHS, 10, 20, 25, Soybean oil, stearoyl Sorbitan
V R
(Absorica ) two divided doses 30, 35, 40 mg polyoxylglycerides monooleate
Enzalutamide 2012 2 IIb I Androgen 160 mg qd Soft gelatin cap- Caprylocaproyl
R
V
(Xtandi ) receptor sule, 40 mg polyoxyglycerides
inhibitor
R
V
Nintedanib (Ofev ) 2014 2/4 IIb II Tyrosine kinase 150 mg bid with food Soft gelatin cap- MCTs, hard fat Lecithin
inhibitor (Ofev) sule, 50 and
100 mg
Calcifediol 2016 2/4 I II/III Vitamin D 60 mcg qd at bedtime Soft gelatin cap- Mixture of lipophilic emulsifier with a HLB <7 and an absorption enhancer with
(RayaldeeTM) analog sule, 30 mcg HLB of 13–18
Oily vehicle- mineral oil, liquid paraffins, or squalene
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
1747
1748 R. SAVLA ET AL.

Figure 1. Multidimensional (2D) scaling of the chemical structures of the dataset reveals high structural diversity. The axes (V1 and V2) represent chemical space in
two directions.

Table 2. Lipid formulation classification system.

Excipients in formulation
Content of formulation (%w/w)
Oils: triglycerides or Water-insoluble Water-soluble Hydrophilic cosolvents
mixed mono and surfactants surfactants (e.g. PEG, proylene glycol,
Characteristics diglycerides (HLB <12) (HLB >12) transcutol)
Type I Pure oils 100 — — —
Limited or no dispersion
Digestion required
Type II SEDDS 40–80 20–60 — —
Moderate dispersion needed to form an emulsion
Likely to require digestion
Type IIIA SMEDDS 40–80 — 20–40 0–40
Rapid dispersion to form micro- or nano-emulsion
May need digestion
Type IIIB SMEDDS <20 — 20–50 20–50
Rapid dispersion to form micro- or nano-emulsion
Digestion likely not needed
Type IV Oil free — 0–20 30–80 0–50
Rapid dispersion results in micellar solution
No digestion needed

that the drug will stay in solution in vivo due to the micellization
process. Oils can be divided into long chain triglycerides (LCT) and
medium chain triglycerides (MCT) [9]. Formulations containing
these typically require digestion before absorption. Lipid digestion
or lipolysis converts triglycerides into mono- and di-glycerides and
fatty acids. The incorporation of mixed glycerides (mono- and di-
glycerides and free fatty acids) in a formulation can improve the
solvent capacity of lipid formulation in cases of compounds that
have low solubility in triglycerides alone. Another advantage of
using mixed glycerides is that they are similar to lipid digestion
products. Undigested triglycerides have poor miscibility in the
aqueous environment of the gastrointestinal tract, which leads to
variation in gastric emptying and absorption [13]. Corn oil was the
oil component of cyclosporine (SandimmuneV) capsules (Table 1).
R
The improved formulation (NeoralV) substituted corn mono- and
R
di-glycerides for corn oil. The clinical result was less food effect
and improved pharmacokinetic uniformity [14,15].
Surfactants and co-solvents
Surfactants are commonly used in lipid formulations to enhance
drug solubility and self-emulsifying properties of the vehicle itself
to minimize dependence on a patient’s digestion factors.
Generally, nonionic surfactants have lower toxicity compared to

ionic surfactants; therefore, LBDDS usually include nonionic surfac-
tants. The marketed protease inhibitors, with the exception of
saquinavir, contain considerable amounts of surfactants.
Amprenavir capsules and tipranavir oral solution used vitamin E
TPGS, which can behave as both a solubilizer and permeation
enhancer. Ritonavir, ritonavir/lopinavir, and tipranavir capsules use
polyoxyl 35 castor oil as the surfactant. Polyoxyl 35 castor oil is
used to improve solubilization, but also has been shown to modu-
late P-glycoprotein (P-gp) activity on the apical membrane of the
intestine and improve absorption of lipophilic drugs [16]. P-gp on
the intestinal villi is known to limit oral absorption of peptidomi-
metics such as protease inhibitors [17]. Therefore, polyoxyl 35 cas-
tor oil can serve a dual purpose in formulation of drugs that are
substrates for P-gp. As an example, early studies showed that
saquinavir is a P-gp substrate and its oral bioavailability may be
limited by P-gp efflux [18]. However, the formulation does not
contain any excipients that have the potential to inhibit drug
efflux. More recent studies using digoxin as a probe in healthy
subjects have shown that both saquinavir and ritonavir have
inherent potential to inhibit P-gp [19]. In some studies, ritonavir
has also been demonstrated to induce P-gp activity [20], suggest-
ing a complex interaction of the drug and transporter which is still
not completely understood.
Co-solvents such as propylene glycol and ethanol are used to
increase drug solubilization but also serve to enhance the disper-
sion rate of lipid formulations and are often included in SEDDS
and SMEDDS. However, upon dispersion in the GI fluids, they rap-
idly partition into the aqueous phase and reduce the solvent cap-
acity of the formulation often leading to drug precipitation.
Physicochemical properties of lipid-formulated drugs
Choosing an appropriate formulation approach whether it be a
lipid formulation or another type of formulation is typically an
empiric endeavor that consumes significant time and resources
(including API quantity). Because of limited API quantity at early
stages, many scientists forego lipid formulation evaluation at drug
discovery stages and instead utilize more conventional formulation
approaches such as aqueous suspensions and powder in a capsule
[21]. The Lipid Formulation Classification System was developed to
be used in conjunction with in vitro tests to create a system for
the standardization of LBDDS which serves as a database correlat-
ing formulation composition to predicted in vitro–in vivo perform-
ance [11]. During the development of a lipid formulation such as
SEDDS, the formulator must take into account many considera-
tions regarding the formulation strategy including excipients, solu-
bility, stability, and scale-up and production [22]. In general, the
key design criteria for development of LBDDS are drug solubiliza-
tion and prevention of drug precipitation in vivo. Beyond this,
there exists the need for practical guidelines based on a database
of molecules’ physiochemical properties to assist the formulator in
predicting the most promising formulation pathways for a given
drug compound. There are a couple of general rules based on
experience. Pouton and Porter [23] state that drugs with a LogP

2 and high melting points (numerically undefined) are usually
poor candidates for lipid system and better suited for nanomilling
or amorphous formulations. Lipid systems are excellent vehicles
for highly lipophilic drugs (LogP >5). However, there are insuffi-
cient studies, particularly comparative studies, for the large portion
of drugs that fall between these two extremes in LogP (drugs with
LogP between 2 and 5). Similarly, Chen et al. [21] proposed the
following drug profile required for lipid formulations: aqueous
solubility <10 mcg/ml; LogP >5; solubility in oils and lipids
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1749
>25 mg/ml; relative low melting point; and good chemical
stability.
Therefore, based on the need for additional guidelines for for-
mulator’s considering a LBDDS approach, we sought to retrospect-
ively analyze any commonalities or outliers in the set of FDA
approved drugs using a LBDDS to address this need. We con-
structed box-and-whisker plots for the different physicochemical
properties to illustrate the range, quartiles, and median values for
each parameter. Restricting our analysis to this set of data pro-
vides some degree of assurance that these formulations are robust
and have withstood the rigors of in vitro, animal, and human test-
ing. The major drawback to this approach is that the dataset
reviewed is somewhat limited in terms of number of drugs.
Chemical structure similarity of FDA approved drugs in LBDDS
Using an online program developed by the Girke lab, ChemMine
Tools, we performed a multidimensional scaling of the drug mole-
cules as shown in Figure 1 [24]. The chemical structures of the
drugs were entered into ChemMine Tools online platform and the
dissimilarity analysis was performed with a similarity cutoff of 0.7.
This approach clusters compounds by structural similarity. The pro-
gram generates atom pair descriptors that are used to calculate a
similarity matrix based on common and unique atom pairs among
the compound set using the Tanimoto coefficient, which is the
proportion of shared features between two compounds divided
by the sum of common and unique features. The Tanimoto coeffi-
cient can range from 0 to 1 with a higher value means greater
similarity. The distance matrix is calculated using an all-against-all
comparison based on atom pair similarity and translating the simi-
larity scores into distance values. We assessed the chemical struc-
tures in a two dimensional plane. The axes V1 and V2 are the axes
defining two directions in a plane. As seen in Figure 1, the mole-
cules are quite diverse in structure. The axes represent molecular
spaces in two dimensions. The most common drug classes (circled
in Figure 1) are vitamin D analogs, protease inhibitors, and reti-
noids. These classes occupy different regions of the graph. The
five vitamin D analogs are distinct from any other molecule struc-
tures and located on the left side of the graph. The retinoids are
distinct from the other molecules as well and located on the
upper right. The protease inhibitors occupy space on the bottom
right. Tipranvair is the only non-peptidomimetic protease inhibitor
and is evidenced as slightly outside of the cluster of the other pro-
tease inhibitors. The protease inhibitors are proximate to sirolimus
and cyclosporine. The similarity is likely due to the peptidomimetic
nature of protease inhibitors. This mapping illustrates that LBDDS
is applicable to a wide range of molecular structures.
Molecular weight of FDA approved drugs in LBDDS
The molecules in Table 1 exhibit a wide range of molecular
weights from 144 Daltons (Da) for valproic acid to 1202.64 Da for
cyclosporine with the median molecular weight of 416.64 Da
(Figure 2(A)). A large portion of these drugs have ‘high’ molecular
weights; 9 of the 27 drug molecules have molecular weights
above 500 Da. This group of high molecular weight drugs is com-
prised of the protease inhibitors, cyclosporine A, dutasteride, nin-
tedanib, and sirolimus (Supplementary Table S1).
Permeability profiles of FDA approved drugs in LBDDS
There is evidence that the components of LBDDS impact intes-
tinal permeability by changing the passive permeability and/or
1750 R. SAVLA ET AL.
Figure 2. Quantitative assessment of chemical properties. (A) molecular weight, (B) polar surface area, (C) LogP, (D) logarithm of octanol solubility, and (E) correlation
between octanol solubility and LogP.
by inhibiting efflux transport [25–28]. Medium chain fatty acids,
lysophospholipids, surfactants, and cosurfactants increase passive
permeability via tight junction opening or via increased mem-
brane solubilization and increased membrane fluidity [29]. We
sought to evaluate drug molecules in our dataset to see which
ones had the physicochemical characteristics indicative of poor
permeability and if they were formulated with excipients that
have been shown to improve permeability. A study of over 1100
GlaxoSmithKline drug candidates revealed that < 10 rotatable
bonds and a polar surface area (PSA) < 140 Å display better per-
meation rates [30]. Another study showed that in addition to
PSA, LogD at pH ¼7.4 and radius of gyration influence Caco-2
permeation [31]. In our analysis, we looked at the PSA, which is
the summation of the surface area of all polar atoms (oxygen
and nitrogen) and their attached hydrogens. We also calculated
the permeability in human jejunum at pH 6.5 using the ACD The
median PSA of the dataset is 59.45 Å (Figure 2(B)) indicating that
overall these molecules have very good permeability properties.
In general, the protease inhibitors have relatively high PSAs
(>100 Å). These molecules also have high molecular weights
(> 500 Da). Only three drugs (ritonavir, saquinavir, and sirolimus)
in our dataset have a PSA above 140 Å (Supplementary Table
S1). Ritonavir (NorvirV) is a LFCS Type III LBDDS and consists of
R
oleic acid, polyoxyl 35 castor oil, and ethanol. Saquinavir
(FortovaseV) is a LFCS Type I LBDDS and contains only medium
R
chain mono- and di-glycerides. Sirolimus (RapamuneV) was for-
R
mulated as a LFCS Type III LBDDS using phosphatidylcholine,
mono- and di-glycerides, soy fatty acids, ascorbyl palmitate, poly-
sorbate 80, ethanol, and propylene glycol. Polyoxyl 35 castor oil
and polysorbate 80 have been shown to modulate P-glycoprotein
efflux pump and effects on phospholipid membranes [32,33].
Good permeation is a prerequisite for molecules that exert their
pharmacological effect via nuclear receptor binding (retinoids,
vitamin D analogs, and progesterone) or need to cross the
blood-brain barrier (dronabinol or valproic acid). It is no surprise
that these molecules have the lowest PSAs (PSA range: 20.23–60.
69 Å).
Solubility profiles of FDA approved drugs in LBDDS
Poorly water soluble drugs represent a diverse set of compounds
with different physicochemical properties. Most scientists believe
that lipid systems are designed for highly lipophilic drugs (LogP
>2). Broadly speaking, poorly water soluble drugs can be classified
as non-lipophilic hydrophobic (brick dust) or lipophilic hydropho-
bic (grease balls) [34]. ‘Brick dust’ compounds have tight crystal
lattices (and higher melting temperatures), are not soluble in gly-
ceride excipients, and require formulation with surfactants or co-
solvents (LFCS Types IIIB and IV). On the other hand, ‘grease balls’
have good solubility in lipid excipients and can be formulated into
LBDDS (LFCS Types I, II, and IIIA).
Our analysis showed the dataset of approved drugs in Table 1
primarily consisted of lipophilic compounds with a median LogP
of 4.85 and an interquartile range of 3.66–5.97 (Figure 2(C)). This
analysis reveals a significantly higher LogP profile than most
approved drugs based on an analysis by Leeson and Springthrope
looking at LogP and molecular mass trends for pipeline and
approved drugs [35]. In their year-by-year analysis of 592 drugs
launched between 1983 and 2007, the median cLogP for launched
drugs failed to eclipse a cLogP of 4 for any year. With one excep-
tion, the median cLogP for every year fell between cLogP of 2 and
4. There was weak correlation of increasing median cLogP with
each passing year and the slope of the straight fit line was very
small. A commonly held belief is that drugs with a LogP >2 [23],
are good candidates to be formulated as LBDDS. Based on the
analysis by Leeson and Springthrope, nearly half of drug candi-
dates should be formulated as LBDDS. The LogP >2 rule of thumb
is not sufficiently discriminatory and sets the LogP bar too low.
Our analysis showed that the median LogP of 4.85 for lipid formu-
lated drugs. Amprenavir, ranitidine, and topotecan were the only
compounds with a LogP below 2 (Supplementary Table S1) and
are likely outliers. The molecules with the next lowest LogP values
were valproic acid and lubiprostone with values of 2.54 and 2.76,
respectively. This suggests that using a LogP of 2 to filter mole-
cules that benefit from lipid formulation may be setting the level

too low. A better approach to decide whether a drug is a good
candidate to be formulated as a LBDDS is to look at other factors
as done with the DCS.
We set to further analyze the data set’s LogP values. Our goal
was to determine if LogP value is a sufficient parameter to deter-
mine whether a compound has suitable solubility in lipid exci-
pients to be formulated in a lipid system. A compound’s LogP is a
partition coefficient and influenced by two variables: its solubility
in octanol and its solubility in water. We sought to assess the rela-
tive contribution of each variable on the LogP. In other words, are
higher LogP driven by increasing lipid solubility, decreasing water
solubility, or both? Using predicted LogP and predicted water
solubility values, we were able to calculate the octanol solubility
of FDA approved drugs formulated in lipid systems (Figure 2(D)).
The calculated octanol solubility served as a surrogate for suffi-
cient solubility in lipid excipients/lipid formulation solvent cap-
acity. The water content in lipid formulation is absent or
negligible. Therefore, we sought to assess if drug solubility in octa-
nol has value as a predictor whether a lipid formulation is the
best option compared to LogP. While this is true, LogP may be a
better measure of consequences of LBDDS in vivo. This approach
aims to minimize substantial influence of poor water solubility on
LogP prediction. From Figure 2(E), it is seen that the logarithm of
the octanol solubility (Log[Oct]) has a linear relationship with the
predicted LogP. The slope and y-intercept above 1 indicate that
overall, the compounds in the dataset have a lipophilic tendency.
Based on our dataset (Figure 3(A)), there is no preference for
lipid formulation class (LFCS) based on a molecule’s LogP value.
Type I formulations, which are pure oils, have been used for drugs
with a wide range of LogP values. It is surprising that Type I lipid
formulation have been developed for hydrophilic molecules. The
formulation rationale is not apparent.
To support further formulation development studies, formula-
tors try to target drug solubility of 25–50 mg/ml (log scale:
Figure 3. Integration of different classification systems. (A) applicability of lipid
formulation based on compound’s LogP. Markers represent individual LogP and
line represents median LogP (B) relationship between BCS and DCS.
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1751
1.4–1.7) in lipid excipients [21]. Our calculations show that 7 drugs
have octanol solubility below this rule of thumb. Lubiprostone is a
LFCS Type I, ranitidine is LFCS Type IV, and the rest fall into LFCS
Type IV. Because lipid formulations are multicomponent systems
and have complex behavior, it is difficult to create an in-silico pre-
diction for determining if a drug has sufficient solubility in lipid
systems for further formulation development.
Enzalutamide (LogP 3.75, log[Oct] 0.88) has both poor aqueous
and octanol solubility, which combine to demonstrate a rather
high LogP. Ranitidine, topotecan and amprenavir had the lowest
predicted LogP (ALOGPS) at 0.79, 1.84, and 1.85, respectively.
Amprenavir (72–74  C) [36] and ranitidine (69–70  C) have low
melting points. Topotecan has a melting point of 213–218  C
.Based on the above mentioned general rule, topotecan would be
better formulated as an amorphous solid dispersion.
Classification according to BCS and DCS
The BCS was proposed by Amidon and colleagues to correlate in
vitro dissolution and in vivo bioavailability and illustrate that solu-
bility and permeability were important to oral drug absorption
[37]. Drugs fall within one of four classes based on their perme-
ability and solubility. The majority of lipid formulated drugs fall
into either BCS Class 2 (good permeability, poor solubility) or Class
4 (poor solubility and permeability). The four exceptions in our
dataset are ergocalciferol (BCS Class 3), valproic acid (BCS Class 1),
ranitidine (BCS Class 3), and topotecan (BCS Class 1).
While the BCS is a good regulatory system for identifying drugs
that may be candidates for biowaivers based on in vitro dissolution
data, it is not very useful for formulators to determine suitable for-
mulation approaches. Many of the problematic compounds fall
within the BCS Class 2, but there is insufficient knowledge of their
solubility behavior. The Developability Classification System (DCS)
was developed by Butler and Dressman to be used as a formula-
tion tool [38]. The DCS makes a couple of important amendments
to the BCS. The solubility of the highest strength dose unit is
replaced by the highest single dose, the medium for solubility
determination is changed from buffer to fast state simulated intes-
tinal fluid, and the fluid volume is for solubility determination is
increased from 250 to 500 ml to be more representative of in vivo.
The permeability and solubility characteristics (good or poor) for
each of the four classes align between the BCS and DCS. Like Class
1 BCS drugs, DCS Class 1 drugs have good solubility and perme-
ability. Drugs falling into Class 2 DCS have good permeability and
poor solubility. They are subdivided Classes IIa and IIb based on
their solubility limited absorbable dose. The absorption of drugs in
DCS Class IIa is considered to be dissolution rate-limited because
the dissolution rate is too slow for all drug particles to be in solu-
tion at the absorption site. The absorption of Class DCS IIb drugs is
solubility-limited, which means that there is insufficient GI tract
fluid to dissolve the dose. DCS Class III drugs have good solubility
and poor permeability and those in DCS Class IV have poor perme-
ability and solubility.
Classification of compounds in the dataset according to the
DCS resulted in the molecules being placed in the following DCS
Classes: Class I (n ¼ 6), Class IIa (n ¼ 5), IIb (n ¼ 15), III (n ¼ 0), and
IV (n ¼ 1) (Figure 4). The dose/solubility ratio was calculated and
plotted on the x-axis. A higher value indicated poorer solubility in
fasting state simulated intestinal fluid. The calculated effective per-
meability in human jejunum is plotted on the y-axis. As expected,
the majority of drug molecules fall within DCS Class IIb, those
compounds with intrinsic solubility limitations. It is interesting to
note the relatively high percentage of drugs that were classified
1752 R. SAVLA ET AL.
Figure 4. DCS plot of FDA approved drugs formulated using LBDDS with LFCS represented by different markers.
as DCS Class I. Ranitidine was the only drug with poor permeabil-
ity (< 1  104 cm/sec). As seen in Figure 3(B), most BCS Class 2
drugs are DCS IIb with several falling into DCS Class I and IIa. The
majority of drugs in BCS Classes 3 or 4 are typically DCS Class IIb
compounds with a few in DCS Classes IIa and IV.
We sought to evaluate whether DCS class could aid formulators
to choose the most appropriate lipid formulation type (LFCS) for
solubilization of the entire drug dose and prevention drug precipi-
tation in vivo. In the DCS plot (Figure 4), we indicated the LFCS
Class using different shapes for each drug. We had expected that
Type I LBDDS, which consist of pure oils, would be best suited for
the most poorly soluble drugs (those with the highest dose/solu-
bility ratio). However, there were several DCS Classes 1 and 2a
drugs formulated as Type 1 LBDDS. There are numerous factors in
addition to excipient type. Fatty acid chain length of lipid exci-
pients is important as it influences lipid digestion and drug solu-
bilization. Less lipophilic drugs that can be easily solubilized to the
aqueous GI environment can be best formulated with medium
chain glycerides [39]. Highly lipophilic drugs are better formulated
using long chain glycerides in order that these drugs remain in
the undigested oil phase or partition into mixed micelles following
in vivo administration [40]. Furthermore to plotting the drugs on
the DCS plot, we sought to examine if drugs that fall within a cer-
tain region of the DCS plot will be better formulated as a self-
emulsifying system (LFCS IIIA or IIIB). From our analysis (Figure 4),
there is no clear correlation between DCS Class and LFCS formula-
tion type, and in fact the data is in some cases counter-intuitive.
This is the likely due to the limited dataset. As shown is Figure 4,
the majority of molecules falling into DCS class I appear to be for-
mulated as Type I lipid formulations. Type I lipid formulations
were used for the DCS classes I, IIa, and IIb (Figure 4). DCS IIb
compounds, which were the most common, were shown to be
formulated using all types of lipid systems with a preference for
Type I lipid formulations.
FDA approved molecules in LBDDS beyond rule of five
Lipinski’s Rule of Five (Ro5) is a rule of thumb used during drug
development to evaluate drug-likeness of a molecule or determine
if a molecule is likely to be orally active in humans [41]. The Ro5
describes chemical properties important for pharmacokinetics and
does not predict pharmacodynamics. There are four criteria: 5
hydrogen bond donors (HBD);  10 hydrogen bond acceptors
(HBA); molecular weight (MW) < 500 Daltons; and LogP <5. The
Rule is said to be ‘broken’ when 2 criteria are not met. Adhering
to the strict guideline, most commercial oral drugs do not violate
the Ro5. We evaluated the list of FDA approved drugs formulated
as lipid systems to see if any drugs violated the Ro5 and found
5 cases:
Sirolimus (MW 914.17, LogP 7.45, HBA 12)
Saquinavir (MW 670.84, HBD 6)
Tipranavir (MW 602.7, LogP 6.29)
Dutasteride (MW 528.50, LogP 5.45)
Cyclosporine (MW 1202.64, HBA 16)
It is rather widely accepted that target biology and chemical
properties influences the physicochemical properties of ligands.
These targets tend to have lipophilic or large, flat binding pockets.
An analysis of recently patented molecules, Bergstro €m et al. [42]
discovered that molecules are almost exclusively lipophilic for cer-
tain targets. Approximately 50% of the targets had molecules with
an average LogP 4. With a limited dataset of approved drugs
using LBDDS, we were unable to extend our analysis across a tar-
get or drug class. Our analysis revealed that 64% (16 of 25) drug
molecules had a LogP >4. Of the molecules violating the Ro5,
three compounds have high LogP values.
An analysis by Paul Leeson showed that while increasing lipo-
philic character of drugs began after 1990 (predicted LogP of
2.5

from 1950–1990, predicted LogP
3.3 since 1990), there are been
a steady increase in molecular weights since the 1950s (MW
300
in the 1950s to
450 in the 2000s) [43]. In our dataset, molecular
weight >500 is the most common physicochemical property viola-
tion for molecule breaking the Ro5. Our review revealed that 9 of
25 molecules had molecular weights >500. Protease inhibitors are
known for the high molecular weights, but tipranavir is only prote-
ase inhibitor with a LogP that violates the Lipinski parameter. This
may be explained based on chemical structure since tipranavir
does not contain a peptidomimetic hydroxyethylene core and
other protease inhibitors do.
LBDDS to reduce magnitude of food effect
The absorption of poorly water soluble drugs is improved when
administered with food, termed positive food effect [3]. This find-
ing led to the rationalization that formulating these drugs as
LBDDS could improve bioavailability. LBDDS induce, but to a lower
magnitude, the same physiological events seen during meal con-
sumption. Pancreatic and gallbladder secretions initiate lipid diges-
tion and solubilization of digestion products in mixed micelles.
Eventual colloidal particles solubilize lipids and coadministered
drugs. Based on the foundation, LBDDS are an attractive formula-
tion option for poorly water soluble drugs that experience a posi-
tive food effect and we hypothesized that the pharmacokinetics of
drugs formulated as LBDDS should not have significant food
effects. The general relationship between food effect and BCS
Classification states that Class 1 compounds have no food effect,
Class 3 have a negative food effect, and Classes 2 and 4 have a
positive food effect [44,45]. We reviewed the package inserts to
see if there was any mention of food effect or dosing with regard
to meals. Table 3 summarizes the findings. The labels for 21 drug
products included language on administration with food. The
drugs labeled to be taken with or without food show increased,
decreased, or unchanged area under the plasma-time curve (AUC)
or Cmax, but the magnitude of change in the pharmacokinetic
parameter is not clinically relevant. Of the drugs labeled to be
taken with food, eight drugs experience positive food effect and
one (lubiprostone) has negative food effect. Lubiprostone is
labeled to be taken with food to maintain a lower Cmax. This may
be to minimize side effects caused by spikes in serum
concentrations.
We hypothesize based on our review of approved drugs formu-
lated as LBDDS experience food effect to a lesser degree than
drugs with similar solubility properties that are no formulated in
lipid-based systems. In support of our hypothesis, we compared
the physicochemical properties of solubility (LogP), permeability
(effective permeability), and dose for the approved drugs listed in
Table 3 to an analysis of these same parameters (LogP, effective
permeability, and dose) in a comparator test set of 15 oral
approved drugs consisting of protein kinase inhibitors, BRAF inhib-
itors, and MEK inhibitors that are not formulated as lipid-based
systems. The rationale for selecting the above three parameters
(LogP, effective permeability, and dose) is based on previous stud-
ies that suggest these three physiochemical properties can be
used to accurately categorize the food effect (positive, negative, or
neutral) in 80% of a test group of drugs [45]. We wanted to first
ensure that the two sets of approved drug were comparable in
terms of physicochemical properties that influence food effects
(LogP, effective permeability, and dose). To do so, we calculated
the median values and performed the two-tailed Mann-Whitney
U test with a significance level of 0.05 to compare to difference
in median values between the two data sets of approved drugs.
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1753
The three selected parameters of approved drugs that were not
developed as LBDDS, compared to those that were, had the fol-
lowing median values and p values, respectively: LogP 4.02 and
3.85, p values of .13888; effective permeability 6.88  104 cm/s
and 6.92  104 cm/s, p values of .82588; and median dose 250 mg
and 100 mg, p values of .07508. None of the measurements
between the two sets were shown to be statistically different
(p < .05); therefore, the two data sets are comparable. The median
magnitude of food effect on area under the curve for the oral
comparator set was þ35% (range –31 to þ400%) and for the
LBDDS set, the median magnitude was þ16.5% (range –13
to þ100%). However, the difference was not statistically significant
with a p value of .63122. Therefore, it cannot be concluded from
this exercise that LBDDS blunt the food effect.
Future directions in oral LBDDS delivery
From our analysis, it is evident that lipid formulations are versatile
platforms for drugs with a wide range of physicochemical proper-
ties. These drugs tend to be lipophilic and permeable thus con-
firming the widely held belief about ideal candidates to be
formulated as lipid formulations. Lipid formulations are commonly
used for certain classes of drugs such as retinoids, vitamin D ana-
logs, and protease inhibitors. There are several unexplored areas
where lipid formulations may play a role in the future.
Drugs for cardiovascular disease
Currently approved drugs using lipid formulation technology cover
many therapeutic categories, but none are used for cardiovascular
disease treatment. Cardiovascular drugs are one the most com-
mon pharmaceutical categories with more than 100 FDA approved
drugs and represent an enticing area for lipid formulations. Rao
et al. analyzed the pharmacokinetic profiles of cardiovascular
drugs and discovered that over 80% had bioavailability challenges
[46]. The primary reasons for these challenges were extensive first
pass metabolism and poor water solubility. Because of the low
and variable bioavailabilities of some of the best selling drugs, the
authors recommended the use of advanced delivery systems to
optimize the drugs and presented several case studies demon-
strating solubility improvement and enhanced absorption of car-
diovascular drugs when formulated into SEDDS. Several
cardiovascular drugs experience negative food effects (captopril,
moexipril, quinapril, ramipril, losartan, and pravastatin) and may
not be the best candidates for lipid formulations.
Oral delivery of peptides
Lipid formulations are used for several high molecular weight mol-
ecules including peptides and peptidomimetics. Peptides are
becoming increasingly common in clinical practice especially for
the treatment of diabetes. Insulin and glucagon like peptide 1
(GLP-1) analogs are typically administered by subcutaneous injec-
tions. These peptides have high molecular weights, short half-lives
and high clearance. Bioengineering modifications have been used
to improve the pharmacokinetics. However, these improved pepti-
des must still be injected.
The use of colloidal carriers offers protection against enzymatic
degradation in the gastrointestinal tract [47]. Microemulsions are
more likely than polymeric carriers to be developed into an
approved oral drug product, indicated by the number of approvals
using each approach. For example, peptides are hydrophilic drugs
that can be classified as BCS Class III compounds. Permeation and
1754 R. SAVLA ET AL.

Table 3. Food effects and pharmacokinetics of approve drugs.

With With or
Molecule/trade name BCS/DCS food without food Increased Decreased No change
Isotretinoin 2/IIb X Cmax and AUC more than doubled fol-
(AccutaneV)
R
lowing high fat meal
Ritonavir (NorvirV) Absorption þ13% with a meal
R
4/IIb X
Clofazimine 2 X Bioavailability þ62% with food, higher
(LampreneV)
R
peak concentration, faster Tmax
Saquinavir (FortovaseV)
R
4/IIb x 12-h AUC after single dose was
increased from when given with
breakfast
Bexarotene (TargretinV) AUC þ35% and Cmax þ48%
R
?/IIb X
Ritonavir/lopinavir X Moderate fat meal: AUC þ48% and
(KaletraV) Cmax þ23%
R

High fat meal: AUC þ97% and Cmax

þ43%
Lubiprostone 2,4/I X Cmax decreased AUC was unchanged
(AmitizaV)
R
by55% when administered
with high fat meal
Fenofibrate (LipofenV) AUC þ58% and þ25% when adminis-
R
2/IIb X
tered with high fat and low fat
meals
Nintedanib (OfevV)
R
2,4/IIb X AUC increased by 20% and Tmax
delayed
V
R
Tipranavir (Aptivus ) 4/IIb X X No clinically significant
changes
V
R
Cyclosporin A (Neoral ) 2/IIb X Decreased AUC by 13%
and Cmax by 33%
Progesterone 2/IIb X Increased bioavailability with food
(PrometriumV)
R

Amprenavir 2/IIb X Not taken with high fat meal Cmax and AUC
(AgeneraseV)
R
decreased and Tmax
prolonged
Sirolimus (RapamuneV) AUC þ23–35%
R
?/IIa X Effect on CMAX was
inconsistent
V
R
Dutasteride (Avodart ) 2,4/IIa X Cmax decreased by
10–15%
Loratadine (ClaritinV)
R
2 X No clinically significant
changes
Omega-3-acid ethyl X
esters (LovazaV)
R

Paricalcitol (ZemplarV)
R
4/IIa X AUC and Cmax were
unchanged. Tmax
was delayed by 2 h
Topotecan HCl 1/I X AUC similar. Tmax was
(HycamtinV)
R
delayed
Isotretinoin (AbsoricaV) AUC and Cmax þ50% and þ26%,
R
2/IIb X
respectively. Tmax was delayed
V
R
Enzalutamide (Xtandi ) 2/IIb X Similar AUC when fast-
ing or fed

stability in the GI tract are the primary challenges to the oral
absorption of peptides. As a result of their hydrophilic nature, pep-
tides can reside in the aqueous phase of water-in-oil (w/o) micro-
emulsions. The oil phase can minimize exposure to water and
protect against degradation. Surfactants, co-surfactants, and
medium chain diacylglycerols in the formulation may improve
membrane permeability and therefore enhance peptide drug bio-
availability. Furthermore, there is potential to reduce peptide deg-
radation in the acidic stomach and the enzymatically active
regions of the gastrointestinal tract given the protection afforded
by a w/o microemulsion [48–50].
Oral anticancer drugs
Protein kinase inhibitors have led the way in the development of
oral anticancer agents. Compared with traditional chemotherapeu-
tic agents, these newer drugs are targeted, have better side effect
profiles, and are administered orally and chronically. The majority
of these drugs have poor water solubility and significant food
effects. More specifically, the majority of these agents have a posi-
tive food effect and are labeled to be taken on an empty stomach,
2 h before or 1 h after a meal [51,52]. The increase in AUC and
Cmax due to food can result in supratherapeutic and toxic concen-
trations of the anticancer drugs, a number of which carry FDA black
box warnings for potentially life-threatening risks associated with
the drug [53]. One of the most common and serious side effects
would be QTc prolongation, potentially creating dangerous cardiac
arrhythmias. Considering that patients with chronic disease typically
take multiple medications for multiple conditions, they may not be
able to adhere to a strict guideline of taking a medication on an
empty stomach. Lipid formulations are known to mimic, to a certain
extent, the high fat content of a meal and increase solubilization of
the drug molecule [54]. Therefore, lipid formulations of anticancer
agents have the potential to improve the absorption and minimize
the food effect of anticancer agents thereby eliminating safety con-
cerns arising from lack of patient adherence.

Table 4. Oral amphotericin formulations in development.
Formulation Type of DDS
Deoxycholate/phytantriol/poloxamer 407 Nanostructured liquid-crystalline
[60] particles (cubosomes)
Copaiba oil, phosphatidylcholine, surfactants Nanoemulsified carrier system
[77]
Mono- and diglycerides, Vitamin E-TPGS SEDDS
[78,79]
Glyceryl monooleate [70,73] Lipid suspension
Phosphatidylserine, calcium [80] Cochleate
Glyceryl dilaurate, phosphatidylcholine and Solid lipid nanoparticles
polyethylene glycol (15)-hydroxystearate
[62]
a
AUC oral formulation/AUC oral Fungizone, at the same dose.
b
Oral bioavailability of 10 mg/kg compared to IV Fungizone 0.8 mg/kg over 48 h.
Amphotericin B
Amphotericin B is a polyene macrolide antibiotic used in the treat-
ment of serious systemic fungal infections, acting by binding to
fungal cell wall sterols. The drug has amphoteric features as well
as hydrophobic and hydrophilic portions of this relatively large,
small-molecule drug (MW¼ 924). It has pKa’s of 2, 5.5 and 10.0. At
28  C, its water solubility is only 0.75 mg/mL and it is also practic-
ally insoluble in ethanol [55].
To understand the goals and limitations of developing the
highly desirable oral formulation of Amphotericin B, it is important
to understand the history and biophysical behavior of LBDDS
intravenous formulations. The deoxycholate formulation
(FungizoneV injection) was developed in the 1970 s to address the
R
solubility problems; however, its use is limited by infusion-related
reactions and dose-related nephrotoxicity. To reduce renal toxicity
and increase the therapeutic efficacy of Amphotericin B, intraven-
ous lipid formulations of Amphotericin B including Ablecet (1995),
Amphotec (1996), and Ambisome (1997) were approved [56].
Abelcet (Amphotericin B lipid complex injection) is comprised of
5 mg of Amphotericin B per dose with the lipid excipients L-
a-dimyristoylphosphatidylcholine (DMPC, 3.4 mg) and L-a-dimyris-
toylphosphatidylglycerol (DMPG, 1.5 mg) [57]. The complex forms
a stable ribbon-like structure with Amphotericin B with a hetero-
geneous 2–5 lm diameter size range [58,59], which is hypothe-
sized to be responsible for its altered biodistribution and toxicity
profile compared to the desoxycholate formation. An alternative
LBDDS was Amphotec/Amphocil, which is comprised of disc-like
structures containing cholesterol sulfate that are significantly
smaller, at around 120 nm [60]. Ambisome is comprised of unila-
mellar phospholipid liposomes <100 nm in mean diameter, com-
prised of hydrogenated soy phosphatidylcholine and distearoyl
phosphatidylglycerol. The size and composition of the structures is
important because it determines not only stability in circulation
but also organ biodistribution, with a significant portion of the
dose going to organs of the reticuloendothelial system.
While these lipid-formulations have been very successful, the
major limitations of their use are that they must be administered
intravenously and they are very expensive. Hyperkalemia and
other electrolyte disturbances can be a problem with liposomal
Amphotericin B [61]. The oral bioavailability of Amphotericin B
is <5% and for the deoxycholate form is only 2% [62]. Barriers to
oral absorption are considerable due to its lack of both solubility
and lipophilicity. However, LBDDS are ideal for Amphotericin B in
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1755
Relative oral bioavailabilitya
compared to oral FungizoneV
R
Preclinical efficacy
2.85 nd
(rats, 10mg/kg)
10.5 nd
(rats, 10 mg/kg)
nd Visceral leishmaniasis (mice): 10 mg/kg
Fabs 6.25%b bid 5 d: 99% inhibition liver
parasites
2.21 Aspergillus fumagatus (rats)
(rats, 50mg/kg) 50mg/kg 1 dose: 95% reduction in
organ CFUs
nd Aspergillus fumagatus (immunocom-
promised mice) 40 mg/kg/day: 70%
survival on day 14
Fabs 105%
order to achieve not only improved oral absorption but also the
desired biodistribution as discussed above, by accessing the
lymphatic transport pathways utilized by dietary lipids [63–67].
When suspended in PeceolV (glyceryl monooleate), amphotericin B
R
(AmpB)’s bioavailability is significantly improved [68–70]. AmpB in
a Peceol/Gelucire 44/14 (lauroyl macrogol-32 glycerides)-based for-
mulation (iCo -010) has demonstrated efficacy in several animal
models of systemic fungal infections [71] as well as visceral leish-
maniasis [72,73]. Organ distribution of amphotericin B is shifted
away from the kidney, the site of dose-limiting toxicity, with a cor-
responding increased splenic and hepatic uptake when the drug is
administered as LBDDS [67].
An alternative LBDDS is the multi-layered, spiral-shaped cochle-
ate formulation [74]. Precipitates of phosphatidylserine and cal-
cium incorporating amphotericin B were prepared by Sesana et al.
[75] and demonstrated to have in vitro activity against Leishmania
chagasi. However, further development of amphotericin B lipid
cochleates has been limited, perhaps in part due to the low bio-
availability of the cochleate formulation [76]. There are additional
LBDDS in preclinical testing that have promising improvements in
bioavailability as well, indicated in Table 4. It remains to be seen
which oral formulation is eventually developed and accepted. This
will depend not only differential efficacy and toxicity in humans,
but also the ease of manufacturing scale-up and market
competition.
Conclusion
LBDDS are the most studied bioavailability enhancing technology
and have been utilized in dozens of FDA approved drugs. Our pri-
mary focus was to analyze approved drug molecules that bene-
fited from being formulated in LBDDS. We examined the
physicochemical characteristics of these drugs, and we classified
them according to different classification systems (BCS, DCS, and
LFCS) to see if there were any correlations between physicochemi-
cal characteristics and classification systems or between classifica-
tion systems. Our analysis of the properties of FDA approved
drugs showed a diverse set of drug molecules including a range
of molecular weights, solubilities, PSA, and chemical structures. As
expected, the majority of these molecules have poor solubility and
good permeability. We introduced a new physicochemical param-
eter of octanol solubility, as a surrogate for drug solubility in lipid
systems/solvent capacity, and demonstrated its potential value for
guiding lipid formulation. Specifically, logarithm of the octanol
1756 R. SAVLA ET AL.
solubility (Log[Oct]) has a linear relationship with the predicted
LogP not related to simply poor water solubility. A Log[Oct] val-
ue >2.5 may be a more useful predictor of suitability in LBDDS
than LogP alone. Although the analysis revealed some clear
emerging trends with respect to choosing the best lipid formula-
tion type based on DCS class, e.g. DCS class I molecules are typic-
ally formulated as Type I lipid formulations, the dataset would
benefit from expansion in order to make a firm recommendation.
It is hoped that future studies will expand this dataset with an
integrated assessment of the various physicochemical properties
to give the best guidance for new oral drug formulation design.
Disclosure statement
No potential conflict of interest was reported by the authors.
RS, JB, and VP are employees of Catalent Pharma Solutions.
ORCID
Ronak Savla http://orcid.org/0000-0002-0907-4714
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